Contributing Authors

Marcus Altfeld – Boston

Georg Behrens – Melbourne

Mario Ostrowski – Toronto

Andrea Rubbert – Köln

Christiane Schieferstein – Frankfurt

Reinhold E. Schmidt – Hannover

Bruce D. Walker – Boston

Eva Wolf – München

HIV Medicine 2003

www.HIVMedicine.com

Edited by

Christian Hoffmann

and

Bernd Sebastian Kamps

Flying Publisher

Editors

Christian Hoffmann, M.D.

University of Schleswig Holstein

Infectious Diseases Outpatient Clinic Kiel

Chemnitzstr. 33

24116 Kiel, Germany

Fax: + 49 431 1697 1273

www.HIVMedicine.com

www.SARSReference.com

Bernd Sebastian Kamps, M.D.

Flying Publisher

Rue Saulnier

75009 Paris

France

www.FlyingPublisher.com

HIV Medicine is an ever-changing field. The editors and authors of HIV

Medicine 2003 have made every effort to provide information that is accurate

and complete as of the date of publication. However, in view of the rapid

changes occurring in medical science, HIV prevention and policy, as well as the

possibility of human error, this site may contain technical inaccuracies,

typographical or other errors. Readers are advised to check the product

information currently provided by the manufacturer of each drug to be

administered to verify the recommended dose, the method and duration of

administration, and contraindications. It is the responsibility of the treating

physician who relies on experience and knowledge about the patient to

determine dosages and the best treatment for the patient. The information

contained herein is provided "as is" and without warranty of any kind. The

contributors to this site, including Flying Publisher and AmedeoGroup, disclaim

responsibility for any errors or omissions or for results obtained from the use of

information contained herein.

Assistant Editors: Nyasha Bakare, Dianne Lydtin

Design: Attilio Baghino, www.a4w.it

ISBN: 3-924774-37-4

Preface

Hardly any field of medicine has ever undergone a similar

stormy development to that of the therapy of HIV infection.

Little more than 10 years passed, between the discovery of the

pathogen and the first effective treatment! However, there is

also hardly a field that is subjected to so many fast- and short-

lived trends. What today seems to be statute, is tomorrow often

already surpassed. Nevertheless, therapeutical freedom must not

be confused with freedom of choice. This book presents the

medical knowledge that is actual today: from December 2002 to

January 2003.

Because HIV medicine changes so fast, HIV Medicine 2003

will be updated every year. Additional chapters about

opportunistic infections, malignancies and hepatitis are freely

available at our Web site www.HIVMedicine.com.

Under certain conditions, the editors and the authors of this

book might agree to remove the copyright on HIV Medicine for

all languages except English and German. You could therefore

translate the content of HIV Medicine 2003 into any language

and publish it under your own name – without paying a license

fee. For more details, please see

http://hivmedicine.com/textbook/cr.htm.

Christian Hoffmann and Bernd Sebastian Kamps

Hamburg/Kiel and Paris/Cagliari, January 2003

Contributing Authors

Marcus Altfeld, M.D.

Partners AIDS Research Center

Massachusetts General Hospital

Bldg. 149, 13th Street, 5th floor

Charlestown, MA 02129

USA

Tel: 617-724-2461

Fax: 617-726-5411

MAltfeld@partners.org

Georg Behrens, M.D.

Immunolgy Division

Walter And Eliza Hall Institute of Medical Research

PO Royal Melbourne Hospital

Parkville, 3050, Victoria

Australia

Fax: 61-3-9347-0852

behrens@wehi.edu.au

Mario Ostrowski, M.D.

Clinical Sciences Division

University of Toronto

Medical Sciences Building, Rm 6271

1 King's College Circle

Toronto, ON M5S 1A8

Canada

Tel: 416-946-5805

FAX: 416-978-8765

E-mail: m.ostrowski@utoronto.ca

6 Contributing Authors

Andrea Rubbert, M.D.

Medizinische Klinik I

Universitätsklinik Köln

Joseph-Stelzmann Str 9

50924 Köln

Germany

Tel +49 221-478-5623

Fax: +49 221-478-6459

Christiane Schieferstein, M.D.

Medizinische Klinik II

Uniklinikum Frankfurt

Theodor-Stern-Kai 7

60590 Frankfurt am Main

Germany

Tel: +49 69-6301-0

schieferstein@wildmail.com

Reinhold E. Schmidt, M.D., Ph.D.

Abteilung Klinische Immunologie

Zentrum Innere Medizin der

Medizinischen Hochschule Hannover

Carl-Neuberg-Straße 1

30625 Hannover

Germany

Tel: +49 511-532-6656

Fax: +49 511-532-9067

Schmidt.Reinhold.Ernst@MH-Hannover.de

Contributing Authors 7

Bruce D. Walker, M.D., Ph.D.

Partners AIDS Research Center

Massachusetts General Hospital

Bldg. 149, 13th Street, 5th floor

Charlestown, MA 02129

USA

Tel: 001 617-724-8332

Fax: 001 617-726-4691

bwalker@helix.mgh.harvard.edu

Eva Wolf, Dipl. Phys. Univ., M.P.H.

MUC Research GmbH

Karlsplatz 8

80335 München

Germany

Tel: +49 89 - 558 70 30

Fax: +49 89 - 550 39 41

Contents 11

Hoffmann, Kamps, et al.

Contents

Chapter 1: Pathogenesis of HIV-1 Infection 15

Introduction 15

The Structure of HIV-1 17

The HIV Replication Cycle 21

HIV and the Immune System 31

References 41

Chapter 2: Acute HIV-1 Infection 47

Introduction 47

Signs and Symptoms 47

Diagnosis 48

Treatment 50

References 51

Chapter 3: HIV Therapy 2003 53

1. Perspective 53

2. Overview of Antiretroviral Drugs 61

3. Goals and Principles of Therapy 120

4. When to Start HAART 146

5. How to Start with HAART 163

6. When to Change HAART 194

7. How to Change HAART 199

8. Salvage Therapy 204

9. When to Stop HAART 215

10. Monitoring 230

Chapter 4: Management of Side Effects 247

Gastrointestinal Side Effects 248

CNS Disorders 249

Peripheral Polyneuropathy 250

12 Contents

HIV Medicine 2003 – www.HIVMedicine.com

Renal Problems 250

Hepatotoxicity 251

Anemia, Leukopenia 252

Allergies 253

Pancreatitis 256

Avascular Necrosis 257

Osteopenia/Osteoporosis 258

Lipodystrophy, Dyslipidemia 259

Hyperglycemia, Diabetes mellitus 259

Increased Bleeding Episodes in Hemophiliacs 260

References 260

Chapter 5: The Lipodystrophy Syndrome 263

Background 263

Clinical Manifestation 263

HAART, Lipodystrophy Syndrome and

Cardiovascular Risk 267

Pathogenesis 268

Diagnosis 272

Therapy 275

References 280

Chapter 6: HIV Resistance Testing 285

Assays for Resistance Testing 285

Background 287

Interpretation of Genotypic Resistance Profiles 289

Summary 296

References 301

Chapter 7: Drug Profiles 307

Abacavir (ABC) 307

Amprenavir (APV) 309

Contents 13

Hoffmann, Kamps, et al.

Atazanavir (AZV) 312

Combivir

314

Delavirdine (DLV) 314

Didanosine (ddI) 316

Efavirenz (EFV) 318

Emtricitabin (FTC) 320

Indinavir (IDV) 321

Lamivudine (3TC) 324

Lopinavir (LPV) 326

Nelfinavir (NFV) 329

Nevirapine (NVP) 330

Ritonavir (RTV) 334

Saquinavir (SQV) 337

Stavudine (d4T) 339

T-20 (Enfuvirtide) 341

Tenofovir (TDF) 343

Tipranavir 345

Trizivir

346

Zalcitabine (ddC) 348

Zidovudine (AZT) 349

14 Contents

HIV Medicine 2003 – www.HIVMedicine.com

Introduction 15

Hoffmann, Kamps, et al.

Chapter 1:

Pathogenesis of HIV-1 Infection

Andrea Rubbert and Mario Ostrowski

Introduction

Since the initial description of the human immunodeficiency

virus type I (HIV-1) in 1983 (1,2) and HIV-2 in 1986 (3), these

two viruses have been identified for almost 20 years as the pri-

mary cause of the acquired immunodeficiency syndrome

(AIDS). As HIV-1 is the major cause of AIDS in the world to-

day, our discussion will be primarily limited to HIV-1 infection.

Worldwide, the number of HIV-1 infected persons exceeds 40

million, the majority of whom live in the developing countries

of Asia, sub-Saharan Africa and South America.

The introduction of protease inhibitors and non-nucleoside re-

verse transcriptase inhibitors (NNRTI) to antiretroviral treat-

ment regimens in 1995 began the era of highly active antiretro-

viral therapy (HAART), and resulted in dramatic improvements

in the mortality and morbidity of HIV disease, as determined by

a decreased incidence of opportunistic infections, tumors, and

deaths. Despite all the therapeutic advantages achieved during

the last decade, including the development of highly active

antiretroviral therapy ("HAART"), once an individual has be-

come infected, eradication of the virus still remains impossible.

In addition, new problems relating to the short- and long-term

toxicity of drug treatments and the occurrence of resistance

mutations in both circulating and transmitted viruses are

emerging. In most countries in South East Asia and Africa, the

incidence and prevalence of HIV-1 infection continues to in-

crease and surpass that of Europe and North America. However,

due to the high costs of drug regimens and the lack of a

healthcare infrastructure in these developing countries, the

16 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

widespread use of HAART is currently not feasible. The further

course of the HIV-1 pandemic therefore mainly depends on

how and to what degree the developing countries with a high

HIV-1 prevalence are able to take advantage of the medical

progress achieved in Europe and North America, and whether

an effective prophylactic vaccine might become available in the

near future.

An understanding of the immunopathogenesis of HIV-1 infec-

tion is a major prerequisite for rationally improving therapeutic

strategies, developing immunotherapeutics and prophylactic

vaccines. As in other virus infections, the individual course of

HIV-1 infection depends on both host and viral factors.

The course of infection with HIV-1 in HIV-infected humans

may vary dramatically, even though the primary infections

arose from the same source (4). In some individuals with a

long-term nonprogressive HIV-1 infection (i.e. lack of decline

in CD4 counts, or chronic infection for at least seven years

without the development of AIDS), a defective virion was

identified (5). Thus, infection with a defective virus, or one

which has a poor capacity to replicate, may prolong the clinical

course of HIV-1 infection. However, in most individuals HIV-1

infection is characterized by a replication competent virus with

a high turn-over of virions produced daily. Host factors may

also deter-mine whether or not an HIV-1 infected individual

will rapidly develop clinically overt immunodeficiency or

whether this individual may belong to the group of long-term

nonprogressors, who represent about 5% of all infected patients.

The identification and characterization of host factors contrib-

uting to the course of HIV infection, including immunological

defense mechanisms and genetic factors, will be crucial for our

under-standing of the immunopathogenesis of HIV infection

and for the development of immunotherapeutic and prophylac-

tic strategies.

The Structure of HIV-1 17

Hoffmann, Kamps, et al.

The Structure of HIV-1

HIV-1 is a retrovirus and belongs to the family of lentiviruses.

Infections with lentiviruses typically show a chronic course of

disease, a long period of clinical latency, persistent viral repli-

cation and involvement of the central nervous system. Visna

infections in sheep, simian immunodeficiency virus infections

(SIV) in monkeys, or feline immunodeficiency virus infections

(FIV) in cats are typical examples of lentivirus infections.

Using electron microscopy, HIV-1 and HIV-2 resemble each

other strikingly. However, they differ with regard to the mo-

lecular weight of their proteins, as well as having differences in

their accessory genes. HIV-2 is genetically more closely related

to the SIV found in sootey mangabeys (SIVsm) rather than

HIV-1 and it is likely that it was introduced into the human

population by monkeys. Both HIV-1 and HIV-2 replicate in

CD4

T cells and are regarded as pathogenic in infected per-

sons although the actual immune deficiency may be less severe

in HIV-2 infected individuals.

The Morphologic Structure of HIV-1

HIV-1 viral particles have a diameter of 100 nm and are sur-

rounded by a lipoprotein membrane. Each viral particle contains

72 glycoprotein complexes which are integrated into this lipid

membrane and are each composed of trimers of an external gly-

coprotein gp120 and a transmembrane spanning protein gp41.

The bonding between gp120 and gp41 is only loose and there-

fore gp120 may be shed spontaneously within the local envi-

ronment. Glycoprotein gp120 may also be detected in the serum

(6) as well as within the lymphatic tissue of HIV-infected pa-

tients (7). During the process of budding, the virus may also

incorporate, from the membrane of the host cell into its lipo-

protein layer, different host proteins, such as HLA class I and II

proteins, or adhesion proteins, such as ICAM-1 that may facili-

tate adhesion to other target cells. The matrix protein p17 is an-

chored to the inside of the viral lipoprotein membrane. The p24

18 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

core antigen contains two copies of HIV-1 RNA. The HIV-1

RNA is part of a protein-nucleic acid complex, which is com-

posed of the nucleoprotein p7 and the reverse transcriptase p66

(RT). The viral particle contains all the enzymatic equipment

that is necessary for replication: a reverse transcriptase (RT), an

integrase p32 and a protease p11 (overview in: 8) (Fig. 1).

Figure 1: Structure of a HIV virion particle. For detailed explanations see text.

The Organization of the Viral Genome

Most replication competent retroviruses depend on three genes:

gag, pol and env : gag means "group-antigen", pol represents

"polymerase" and env is for "envelope" (overview in: 9)

(Fig. 2). The "classical" structural scheme of a retroviral ge-

nome is: 5'LTR-gag-pol-env-LTR 3'. The LTR ("long terminal

The Structure of HIV-1 19

Hoffmann, Kamps, et al.

repeat") regions represent the two end parts of the viral genome

that are connected to the cellular DNA of the host cell after in-

tegration and do not encode for any viral proteins. The gag and

env genes code for the nucleocapsid and the glycoproteins of

the viral membrane; the pol gene codes for the reverse tran-

scriptase and other enzymes. In addition, HIV-1 contains in its

9kB RNA six genes (vif, vpu, vpr, tat, rev and nef) that con-

tribute to its genetic complexity. Nef, vif, vpr and vpu were clas-

sified as accessory genes in the past, as they are not absolutely

required for replication in vitro. However, the regulation and

function of these accessory genes and their proteins have been

studied and characterized in more detail within the last years.

The accessory genes, nef, tat and rev, are all produced early in

the viral replication cycle.

Figure 2: HIV and its genes. For detailed explanations see text.

Tat and rev are regulatory proteins that accumulate within the

nucleus and bind to defined regions of the viral RNA: TAR

20 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

(transactivation-response elements), found in the LTR; and

RRE (rev response elements), found in the env gene, respec-

tively. The tat protein is a potent transcriptional activator of the

LTR promoter region and is essential for viral replication in

almost all in vitro culture systems. Cyclin T1 is a necessary

cellular cofactor for tat (10). Tat and rev stimulate the tran-

scription of proviral HIV-1-DNA into RNA, promote RNA

elongation, enhance the transportation of HIV-RNA from the

nucleus to the cytoplasm and are essential for translation. Rev is

also a nuclear export factor that is important for switching from

the early expression of regulatory proteins to the structural pro-

teins that are synthesized later.

Nef has been shown to have a number of functions. Nef may

induce downregulation of CD4 (11) and HLA class I and II

molecules (12) from the surface of HIV-1 infected cells, which

may represent an important escape mechanism for the virus to

evade an attack mediated by cytotoxic CD8

T cells and to

avoid recognition by CD4

T cells. Nef may also interfere with

T cell activation by binding to various proteins that are involved

in intracellular signal transduction pathways (overview in:13).

In SIV-infected rhesus macaques, an intact nef gene was essen-

tial for a high rate of virus production and the progression of

disease. HIV-1 with deletions in nef was identified in a cohort

of Australian long-term non-progressors (5). However, more

recent reports indicate that some of these patients are now de-

veloping signs of disease progression together with a decline of

CD4

T cells. Thus, although deletions of the nef gene may

slow viral replication, they cannot always prevent the develop-

ment of AIDS.

Vpr seems to be essential for viral replication in non-dividing

cells such as macrophages. Vpr may stimulate the HIV-LTR in

addition to a variety of cellular and viral promoters. More re-

cently, vpr was shown to be important for the transport of the

viral preintegration complex to the nucleus (overview in: 14)

and may arrest cells in the G2 phase of the cell cycle.

The HIV Replication Cycle 21

Hoffmann, Kamps, et al.

Vpu is important for the virus "budding" process, because mu-

tations in vpu are associated with persistence of the viral parti-

cles at the host cell surface. Vpu is also involved when CD4-

gp160 complexes are degraded within the endoplasmatic re-

ticulum and therefore allows recycling of gp160 for the forma-

tion of new virions (15).

Vif is important for intracellular transport mechanisms of viral

components. Co-localization of vif with vimentin, a protein be-

longing to the cellular cytoskeleton, was demonstrated. Virions

that are deficient in vif may still be transmitted from cell to cell,

but not from a cell free medium. Vif also seems to affect viral

morphogenesis (Overview in: 16).

The HIV Replication Cycle

HIV Entry

CD4 as a primary receptor for HIV

CD4 is a 58 kDa monomeric glycoprotein that can be detected

on the cell surface of about 60% of T-lymphocytes, of T-cell

precursors within the bone marrow and thymus, and on mono-

cytes and macrophages, eosinophils, dendritic cells and micro-

glia cells of the central nervous system. The extracellular do-

main of CD4 on T cells is composed of 370 amino acids; the

hydrophobic transmembrane domain and the cytoplasmic part

of CD4 on T cells consist of 25 and 38 amino acids, respec-

tively. Within the extracellular part of CD4, four regions D1-D4

have been characterized that represent immunoglobulin-like

domains. Residues within the V2 region of CD4 (amino acids

40-55) are important for the binding of gp120 to CD4 and this

region overlaps the part of the CD4 where its natural ligands,

HLA class II molecules, bind.

The identification of the gp120 binding site on the CD4 of

CD4

T cells stimulated attempts to use soluble CD4 (sCD4) to

neutralize the circulating virus in patients, with the goal being

22 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

the inhibition of viral spread. However it became evident that

even though laboratory viral isolates were easily neutralized by

sCD4, a neutralization of primary, patient-derived isolates had

not been achieved.

In contrast, sCD4 was able to induce conformational changes

within the viral envelope that promoted the infection of target

cells (18).

CD4 attaches to the T cell receptor complex (TCR) on CD4

cells and binds to the HLA class II molecules on antigen-

presenting cells. The binding of gp120 to CD4 is not only a cru-

cial step for viral entry, but also interferes with intracellular

signal transduction pathways and promotes apoptosis in CD4

cells (19).

CD4, as a primary and necessary receptor for HIV-1, HIV-2 and

SIV, was already characterized in 1984 (20, 21). However, ex-

periments using non-human cell lines transfected with human

CD4 showed that expression of human CD4 on the cell surface

of a non-human cell line was not sufficient to allow en-try of

HIV. Therefore the existence of additional human co-receptors

necessary for viral entry was postulated. On the other hand,

some laboratory HIV-1 isolates as well as some HIV-2 and SIV

isolates are able to infect human cells independently from CD4.

Interestingly, monoclonal antibodies against CD4 induced con-

formational (CD4I) epitopes to bind to the gp120 of CD4-

independent viruses. This observation suggests that the gp120

of CD4-independent viruses already exposes the regions that

are necessary for co-receptor recognition and binding and there-

fore binding to CD4 is not a prerequisite of entry for these vi-

ruses. CD4-independent viruses are easy to neutralize using the

serum of HIV-infected patients, suggesting that the immune

response selects against CD4-independent viruses (22).

Chemokine receptors as co-receptors for HIV entry

A milestone for the characterization of the early events leading

to HIV-1 entry was an observation by Cocchi and his co-

workers in 1995. CD8

T cells from HIV-infected patients are

The HIV Replication Cycle 23

Hoffmann, Kamps, et al.

able to suppress viral replication in co-cultures with HIV-

infected autologous or allogenic CD4

T cells and this is inde-

pendent from their cytotoxic activity (23). Cocchi identified the

chemokines MIP-1α, MIP-1ß and Rantes in supernatants from

CD8

T cells derived from HIV-infected patients, and was able

to show that these chemokines were able to suppress replication

in a dose-dependent manner of some, but not all viral isolates

tested (24). MIP-1α, MIP-1ß and Rantes are ligands for the

chemokine receptor CCR5, and a few months later several

groups were able to show that CCR5 is a necessary co-receptor

for monocytotropic (M-tropic) HIV-1 isolates (25, 26, 27). A

few weeks earlier, the chemokine receptor CXCR4 (fusin) was

described as being the co-receptor used by T-cell tropic (T-

tropic) HIV-isolates (28). Monocytotropic (M-tropic) HIV-1

isolates are classically those viruses that are most easily propa-

gated in macrophage cultures, are unable to infect T-cell lines

(i.e., immortalized T cells), but are able to easily infect primary

T cells from peripheral blood samples. Conversely, T-cell tropic

HIV-1 isolates have classically been identified as being those

that are easily propagated in T-cell lines, and grow poorly in

macrophages, but are also able to easily infect primary T cells

from peripheral blood samples. Thus, it should be noted that

both M-tropic and T-tropic HIV-1 variants can easily infect

primary human non-immortalized T cells in-vitro. Chemokines

("Chemotactic cytokines") and their receptors have been previ-

ously characterized with regard to their role in promoting the

migration ("chemotaxis") of leukocytes and their proinflamma-

tory activity.

Chemokines are proteins of 68-120 amino acids which depend

on the structure of their common cysteine motif, and which may

be subdivided into C-X-C (α-chemokines), C-C (ß-chemokines)

and C-chemokines. Chemokines typically show a high degree

of structural homology to each other and may share the recep-

tors they bind to. Chemokine receptors belong to the group of

receptors with seven transmembranic regions ("7-

24 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

transmembrane receptors"), which are intracellularly linked to

G-proteins.

SDF-1 ("stromal cell-derived factor 1") was identified as the

natural ligand of CXCR4 and is able to inhibit the entry of T-

tropic HIV-1 isolates into activated CD4

T cells. Rantes

("regulated upon activation T cell expressed and secreted"),

MIP-1α ("macrophage inhibitory protein") and MIP-1ß repre-

sent the natural ligands of CCR5 and are able to inhibit the en-

try of M-tropic HIV-1 isolates into T cells. A schematic model

is depicted in Figure 3: T-tropic HIV-1 isolates mainly infect

activated peripheral blood CD4

T cells and cell lines and use

CXCR4 for entry into the CD4

-positive target cell. M-tropic

isolates are able to infect CD4

T cells, monocytes and macro-

phages and depend on the use of CCR5 and CD4 for viral entry.

The interaction of gp120 and the cellular receptors is now un-

derstood in more detail. Gp120 primarily binds to certain epi-

topes of CD4. Binding to CD4 induces conformational changes

in gp120 that promote a more efficient interaction of the V3

loop of gp120 with its respective co-receptor. Membrane fusion

is dependent on gp120-co-receptor binding. Gp41, as the trans-

membrane part of the envelope glycoprotein gp160, is crucial

for the fusion of the viral and the host cell membrane. Similar to

influenza hemagglutinin, it was postulated that after binding of

gp120 to CD4, a conformational change is also induced in gp41

that allows gp41 to insert its hydrophobic NH

-terminal into the

target cell membrane. Gp41 has been compared to a "mouse

trap" and a crystallographic analysis of the ectodomanic struc-

ture of gp41 seems to confirm that hypothesis (29). The identi-

fication of crucial amino acid sequences for this process was

used to synthesize peptides that may bind to gp41 within the

domains that are critical for the induction of conformational

changes and that may inhibit membrane fusion.

The HIV Replication Cycle 25

Hoffmann, Kamps, et al.

Fig 3: Inhibition of virus entry of CCR5-utilizing (monocytotropic) and CXCR4-

utilizing (T-cell tropic) HIV isolates by the natural ligands of the chemokine co-

receptors CCR5 and CXCR4.

T20 is the first of several peptides that bind to gp41 and has

been tested in clinical trials for suppressing viral replication

(30). Currently, T20 is available as a therapeutic option for se-

lected patients. One disadvantage of T20 is that it must be taken

intramuscularly rather than as a pill.

Using transfected cell lines, besides CCR5 and CXCR4, other

chemokine receptors, such as CCR3, CCR2, CCR8, CCR9,

STRL33 ("Bonzo"), Gpr 15 ("Bob"), Gpr 1, APJ and ChemR23,

were identified and shown to be used for entry by certain HIV

isolates (31, 32). APJ may represent a relevant co-receptor

within the central nervous system. Despite this broad spectrum

of potentially available co-receptors, CCR5 and CXCR4 seem

to represent the most relevant co-receptors for HIV-1 in vivo.

26 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

The importance of CCR5 as the predominant co-receptor for M-

tropic HIV isolates is underscored by another observation. The

majority of individuals with a genetic defect of CCR5 are re-

sistant to infection with HIV-1 (33). In vitro experiments show

that lymphocytes derived from these individuals are resistant to

HIV-1 infection using M-tropic isolates but not to infection

with T-tropic isolates. Lymphocytes from these individuals do

not express CCR5 on their cell surface and genetically they

have a 32 base pair deletion of the CCR5 gene. Worldwide, a

few patients have been identified that have acquired HIV-1 in-

fection despite a homozygous deletion of the CCR5. As ex-

pected, all of them were infected with CXCR4-using HIV-1

isolates (34). In epidemiologic studies, the allelic frequency of

the CCR5 gene deletion is 10-20% among Caucasians, particu-

larly amongst those of Northern European descent. The fre-

quency of a homozygous individual is about 1% in Caucasians

(35). Studies conducted on African or Asian populations, how-

ever, do not find this 32 basepair deletion of the CCR5, sug-

gesting that this mutation arose after the separation of these

races in evolutionary history.

Individuals that are heterozygous for the 32 bp deletion of the

CCR5 show a decreased expression of CCR5 on the cell surface

and are more frequently encountered within cohorts of long-

term non-progressors compared to patients who have a rapid

progression of disease (35).

In addition to the 32bp deletion of the CCR5, other genetic

polymorphisms, with regard to the chemokine receptors

(CCR2) or their promoters (CCR5), were described. Based on

the occurrence of these polymorphisms within defined patient

cohorts, they were associated with a more rapid or a more fa-

vorable course of disease, depending on the particular polymor-

phism (36, 37).

In patients who have a rapid progression of disease (rapid drop

in CD4

T cell count), virus isolates that use CXCR4 as a pre-

dominant co-receptor tend to be frequently isolated from their

cells, in comparison to patients with a stable CD4

T cell count.

The HIV Replication Cycle 27

Hoffmann, Kamps, et al.

The expression of co-receptors on CD4

lymphocytes depends

on their activation level.

CXCR4 is mainly expressed on naive T cells, whereas CCR5 is

present on activated and effector/memory T cells. During the

early course of HIV-1 infection, predominantly M-tropic HIV-1

isolates are detected. Interestingly, M-tropic HIV-1 isolates are

preferentially transmitted regardless of whether or not the "do-

nor" predominantly harbors T-tropic isolates. At present, it re-

mains unclear whether this "in vivo" preference of M-tropic

HIV-1 isolates is determined by selected transportation of M-

tropic isolates by submucosally located dendritic cells or

whether the local cytokine/chemokine milieu favors the repli-

cation of M-tropic viruses. Recent intriguing studies by Cheng

Meyer et al. suggest that M-tropic HIV-1 viruses are more eas-

ily able to 'hide' from the immune system by replicating in

macrophages, in comparison to T-tropic viruses, thus giving

them a survival advantage in the infected individual.

The blockade of CCR5 therefore seems to represent a promising

target for therapeutic intervention. In vitro, monoclonal anti-

bodies to CCR5 (2D7 and others) are able to block the entry of

CCR5-using HIV isolates into CD4

T cells and macrophages.

Small molecule inhibitors of CCR5 have been designed and are

currently being tested in clinical trials. In vitro studies, as well

as experiments using SCID mice, however, suggest that block-

ade of CCR5-using isolates may alter their tropism towards in-

creased usage of CXCR4.

Small molecule inhibitors like T22, ALX40-4C or AMD3100

are able to inhibit CXCR4 (59, 60) and are also subject to pre-

clinical and clinical trials. Although the therapeutic use of

chemokine receptor blockers seems promising, a lot of ques-

tions still remain unanswered. Chemokine analogs such as

AOP-Rantes do not only inhibit, but also show agonistic activ-

ity and may not bind to CCR5 exclusively. Using knockout

mice it was demonstrated that the absence of CXCR4 or SDF-1

is associated with severe defects in hematopoiesis and in cere-

bellar development (61). Currently, it remains unclear whether

28 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

the blockade of CXCR4 in postnatal or adult individuals may

also affect other organ systems.

Fig 4: HIV life cycle within a CD4

T cell.

Postfusion Events

HIV-1 entry into quiescent T cells is comparable to HIV-1 entry

into activated T cells, but synthesis of HIV-1 DNA remains in-

complete in quiescent cells (38). The conversion of viral RNA

into proviral DNA, mediated by the viral enzyme reverse tran-

scriptase (RT), occurs in the cytoplasm of the target cell and is a

crucial step within the viral replication cycle (see Fig. 4).

Blockade of the RT by the nucleoside inhibitor, zidovudine,

was the first at-tempt to inhibit viral replication in HIV-1 in-

fected patients. To-day, numerous nucleoside, nucleotide and

non-nucleoside RT inhibitors are available for clinical use and

The HIV Replication Cycle 29

Hoffmann, Kamps, et al.

have broadened the therapeutic arsenal substantially since the

mid-eighties.

Reverse transcription occurs in multiple steps. After binding of

the tRNA primers, synthesis of proviral DNA occurs as a mi-

nus-strand polymerization starting at the PBS ("primer binding

site") up to the 5' repeat region as a short R/U5 DNA. The next

step includes degradation of RNA above the PBS by the viral

enzyme RNAase H and a "template switch" of the R/U5 DNA

with hybridization at the R sequence at the 3' RNA end. Now

the full length polymerization of proviral DNA with degrada-

tion of the tRNA is completed. Reverse transcription results in

double-stranded HIV DNA with LTR regions ("long terminal

repeats") at each end.

HIV-1 enters into quiescent T cells and reverse transcription

may result in the accumulation of proviral, non-integrating

HIV-DNA. However, cellular activation is necessary for inte-

gration of the proviral HIV DNA into the host cell genome after

transportation of the pre-integration complex into the nucleus

(38). Cellular activation may occur in vitro after stimulation

with antigens or mitogens, in vivo activation of the immune

system is observed after antigen contact or vaccination or dur-

ing an opportunistic infection. In addition, evidence is emerging

that HIV-1 gp120 itself may activate the infecting cell to en-

hance integration. Besides monocytes, macrophages and mi-

croglial cells, latently infected quiescent CD4

T-cells that

contain non-integrated proviral HIV-DNA represent important

long-living cellular reservoirs for HIV (39). Since natural HIV-

1 infection is characterized by continuing cycles of viral repli-

cation in activated CD4

T-cells, viral latency in these resting

CD4

T-cells likely represents an accidental phenomenon and is

not likely to be important in the pathogenesis of this disease.

This small reservoir of latent provirus in quiescent CD4

T-cells

gains importance, however, in individuals who are treated with

HAART, since the antivirals are unable to affect non-replicating

proviruses and thus the virus will persist in those cells and be

replication competent to supply new rounds of infection, if the

30 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

drugs are stopped. Thus, the existence of this latent reservoir

has prevented HAART from entirely eradicating the virus from

infected individuals.

Cellular transcription factors like NF-kB may also bind to the

LTR regions. After stimulation with mitogens or cytokines, NF-

kB is translocated into the nucleus where it binds to the HIV-

LTR region, thereby initiating transcription of HIV genes.

Transcription initially results in the early synthesis of regulatory

HIV-1 proteins such as tat or rev. Tat binds to the TAR site

("transactivation response element") at the beginning of the

HIV-1 RNA in the nucleus and stimulates transcription and the

formation of longer RNA transcripts. Rev activates the expres-

sion of structural and enzymatic genes and inhibits the produc-

tion of regulatory proteins, therefore promoting the formation of

mature viral particles. The proteins coded for by pol and gag

form the nucleus of the maturing HIV particle; the gene prod-

ucts coded for by env form the gp120 "spikes" of the viral en-

velope. The gp120 spikes of the envelope are synthesized as

large gp160-precursor molecules and are cleaved by the HIV-1

protease into gp120 and gp41. The gag proteins are also derived

from a large 53 kD precursor molecule, from which the HIV-

protease cleaves the p24, p17, p9 and p7 gag proteins. Cleavage

of the precursor molecules by the HIV-1 protease is necessary

for the generation of infectious viral particles, and therefore the

viral protease represents another interesting target for therapeu-

tic blockade (40). The formation of new viral particles is a

stepwise process: a new virus core is formed by HIV-1 RNA,

gag proteins and various pol enzymes and moves towards the

cell surface. The large precursor molecules are cleaved by the

HIV-1 protease, which results in the infectious viral particles

budding through the host cell membrane. During the budding

process, the virus lipid membranes may incorporate various

host cell proteins and become enriched with certain phospho-

lipids and cholesterol. In contrast to T cells, where budding oc-

curs at the cell surface and virions are released into the extra-

cellular space, the budding process in monocytes and macro-

HIV and the Immune System 31

Hoffmann, Kamps, et al.

phages results in the accumulation of virions within cellular

vacuoles.

The replication of retroviruses is error prone and is character-

ized by a high spontaneous mutation rate. On average, re-verse

transcription results in 1-10 errors per genome and per round of

replication. Mutations can lead to the formation of replication-

incompetent viral species, but mutations causing drug resistance

may also accumulate, which, provided that there is selection

pressure under certain antiretroviral drugs and incomplete sup-

pression of viral replication, may be outgrowing.

In addition, viral replication is dynamic and turns over quickly

in infected individuals at an average rate of 10

new virus parti-

cles being produced and subsequently cleared per day. Thus,

within any individual, because of the extensive virus replication

and mutation rates, there exists an accumulation of many

closely related virus variants within the 'population' of viruses,

referred to as a viral "quasispecies". The selection pressure on

mostly the pre-existing mutations may not only be exerted by

certain drugs, but also by components of the immune system,

such as neutralizing antibodies or cytotoxic T cells (CTL).

HIV and the Immune System

The Role of Antigen-Presenting Cells in the Patho-

genesis of HIV Infection

Dendritic cells as prototypes of antigen-presenting cells

Dendritic cells, macrophages and B cells represent the main

antigen-presenting cells of the immune system. Dendritic cells

(DC) are the most potent inducers of specific immune responses

and are considered essential for the initiation of primary anti-

gen-specific immune reactions. DC precursors migrate from the

bone marrow towards the primary lymphatic organs and into the

submucosal tissue of the gut, the genitourinary and the respira-

tory tracts. They are able to pick up and process soluble anti-

32 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

gens and migrate to the secondary lymphatic organs, where they

activate antigen-specific T cells.

DC represent a heterogenous family of cells with different

functional capacities and expression of phenotypic markers,

depending on the local microenvironment and the stage of

maturation. Immature DC have the capacity to pick up and pro-

cess foreign antigens, but do not have great T cell stimulatory

capacities. However, mature DC show a predominant immu-

nostimulatory ability. DC in tissues and Langerhans cells,

which are specialized DC in the skin and mucosal areas, repre-

sent a more immature phenotype and may take up antigen. Once

these DC have taken up the antigen they migrate to the lym-

phoid tissues where they develop a mature phenotype.

The stimulation of CD8

T lymphocytes and the formation of

antigen-specific cytotoxic T-cells (CTL) depend on the presen-

tation of a peptide together with MHC class I antigens. DC may

become infected with viruses, for instance influenza. Viral pro-

teins are then produced within the cytoplasm of the cell, similar

to cellular proteins, then degraded to viral peptides and translo-

cated from the cytosol into the endoplasmatic reticulum, where

they are bound to MHC class I antigens. These peptide-MHC

class I complexes migrate to the DC surface. The number of

specific antigen-MHC class I complexes is usually limited and

must eventually be recognized by rare T cell clones, up to a ra-

tio of 1:100.000 or less. The T-cell receptor (TCR) may display

only a low binding affinity (1 mM or less). The high density of

co-stimulatory molecules on the DC surface, however, enhances

the TCR-MHC:peptide interaction allowing efficient signal-ling

to occur through the T cell and resulting in proliferation (clonal

expansion) of the T cell. Virus-infected cells or tumor cells of-

ten do not express co-stimulatory molecules, and thus may not

be able to induce a clonal expansion of effector cells. This un-

derscores the importance of having a highly specialized system

of antigen-presenting cells, i.e. DC, in operation to prime T

cells to expand and proliferate initially.

HIV and the Immune System 33

Hoffmann, Kamps, et al.

The interaction of dendritic cells and B/T-cells

B- and T-lymphocytes may be regarded as the principle effector

cells of antigen-specific immune responses. However, their

function is under the control of dendritic cells. DC are able to

pick up antigens in the periphery. These antigens are processed

and expressed on the cell surface, together with co-stimulatory

molecules that initiate T cell activation. B cells may recognize

antigen after binding to the B cell receptor. Recognition of anti-

gen by T cells requires previous processing and presentation of

antigenic peptides by DC. T cells express different T cell re-

ceptors (TCR), that may bind to the peptide:MHC class I on the

surface of dendritic cells to allow activation of CD8

T cells, or

to the peptide:MHC class II molecules, to activate CD4

T cells.

The ability of DC to activate T cells also depends on the secre-

tion of stimulatory cytokines such as IL-12, which is a key cy-

tokine for the generation and activation of T

1 and natural killer

(NK-) cells.

Only a few DC and small amounts of antigen are sufficient to

induce a potent antigen-specific T cell response, thus demon-

strating the immunostimulatory potency of DC. The expression

of adhesion molecules and lectins, such as DC-SIGN, support

the aggregation of DC and T cells and promote the engagement

of the T cell receptor (TCR). DC-SIGN is a type C lectin that

has also been shown to bind to lentiviruses such as SIV and

HIV-1 and -2 by interaction of gp120 with carbohydrates. In

vivo, immunohistochemical studies show expression of DC-

SIGN on submucosal and intradermal DC, suggesting an impli-

cation of DC-SIGN in vertical and mucosal transmission of

HIV. The expression of DC-SIGN was shown to enhance the

transmission of HIV to T cells and allows utilization of co-

receptors if their expression is limited. Thus DC-SIGN may be

a mechanism whereby HIV-1 is taken up by DC in the mucosal

tissues. It is then transported by the DC to the lymphoid tissues,

where HIV-1 can then infect all the residing CD4

T cells.

34 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

Lymphatic Tissue as the Site of Viral Replication

Viral replication within the lymphatic tissue is already exten-

sive in the early stages of the disease (42,43). During the initial

phase of HIV-1 infection, there is a burst of virus into the

plasma, followed by a relative decline in viremia. During this

time, a strong HIV-1 specific cytotoxic T cell response is gen-

erated, which coincides with the early suppression of plasma

viremia in most patients. Virions are trapped by the follicular

dendritic cell (FDC) network within the lymphoid tissue.

Macrophages, and activated and quiescent CD4

T cells are the

main targets of infection. During the whole course of infection

with HIV-1, the lymphoid tissue represents the principle site of

HIV-1 replication. The frequency of cells containing proviral

DNA is 5-10x higher in lymphoid tissue than in circulating pe-

ripheral mononuclear cells in the blood, and the difference in

viral replication in lymphoid tissue exceeds that in the periph-

eral blood by about 10-100x. Thus, the virus mainly accumu-

lates in the lymph nodes.

After entry of HIV-1 into a quiescent CD4

T cell and after

completion of reverse transcription, the viral genome is repre-

sented by proviral unintegrated HIV DNA. The activation of

CD4

T cells is necessary for the integration of the HIV DNA

into the host cell genome and is therefore a prerequisite for the

synthesis of new virions. In this regard, the micromilieu of the

lymphoid tissue represents the optimal environment for viral

replication. The close cell-cell contact between CD4

T-cells

and antigen-presenting cells, the presence of infectious virions

on the surface of the FDC, and an abundant production of pro-

inflammatory cytokines such as IL-1, IL-6 or TNFα, promotes

the induction of viral replication in infected cells and augments

viral replication in cells already producing the virus. It should

be noted that both IL-1 and TNFα induce NF-kb which binds to

the HIV-1 LTR to promote proviral transcription. The impor-

tance of an antigen-induced activation of CD4

T cells is un-

derlined by several in vivo and in vitro studies that demonstrate

HIV and the Immune System 35

Hoffmann, Kamps, et al.

an increase of HIV-1 replication in association with a tetanus or

influenza vaccination or an infection with Mycobacterium tu-

berculosis (44). Even though the clinical benefit of vaccination

against common pathogens (e.g. influenza and tetanus) in HIV-

1 infected patients outweighs the potential risk of a temporary

increase in viral load, these studies indicate that in every situa-

tion where the immune system is activated, enhanced viral rep-

lication can also occur.

Patients undergoing HAART demonstrate a dramatic decrease

in the number of productively infected CD4

T cells within the

lymphoid tissue (45). However, in all patients examined so far,

there persists a pool of latently infected quiescent T cells de-

spite successful suppression of plasma viremia (39). It is these

latently infected cells which may give rise to further rounds of

viral replication, if the antiviral drugs are stopped.

During the natural course of HIV-1 disease, the number of

CD4

T cells slowly decreases while plasma viremia rises in

most patients. If sequential analysis of the lymphoid tissue is

performed, progression of the disease is reflected by destruction

of the lymphoid tissue architecture and a decreased viral trap-

ping. Various immunohistological studies indicate that the

paracortex of the lymph nodes represents the primary site where

HIV replication is initiated (42,43). Infection of the surrounding

CD4

T cells, as well as the initiation of T cell activation by

DC, contributes to the spreading of HIV-1 within the lymphoid

environment.

The HLA System and the Immune Response against

HIV

CD8

T cells recognize "their" antigen (peptide) in context with

HLA class I molecules on antigen-presenting cells, whereas

CD4

T cells require the presentation of antigenic peptides in

context with HLA class II molecules. The generation of an HIV

specific immune response is therefore dependent on the indi-

vidual HLA pattern.

36 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

Antigen-presenting cells may bind HIV peptides in different

ways within "grooves" on the HLA class I molecules. There-

fore, CD8

T cells can be activated in an optimal or suboptimal

way or may not be activated at all. Using large cohorts of HIV-

1 infected patients, in whom the natural course of disease (fast

versus slow progression) is known, HLA patterns were identi-

fied that were associated with a slow versus fast disease pro-

gression. These studies suggest that the HLA type could be re-

sponsible for the benign course of disease in about 40% of pa-

tients with a long-term non-progressive course of disease. Ho-

mozygosity for HLA Bw4 is regarded as being protective. Pa-

tients who display heterozygosity at the HLA class I loci are

characterized by a slower progression of immunodeficiency

than patients with homozygosity at these loci (46).

An initial study by Kaslow in 1996 demonstrated that HLA

B14, B27, B51, B57 and C8 are associated with a slow disease

progression; in contrast, the presence of HLA A23, B37 and

B49 were associated with the rapid development of immunode-

ficiency (47).

All patients with HLA B35 had developed symptoms of AIDS

after 8 years of infection.

More recent studies suggest that discordant couples with a

"mismatch" at the HLA class I have a protective effect towards

heterosexual transmission (48).

In vitro studies in HLA B57 positive patients demonstrate that

these patients display HLA B57 restricted CTL directed against

HIV-1 peptides. However it is possible that the identification of

protective HLA alleles or HLA restricted peptides in HIV-1

infected patients with a benign course of disease does not nec-

essarily indicate that the same alleles or peptides are crucial for

the design of a protective vaccine. Kaul and co-workers were

able to show that CD8

T cells from HIV-1 exposed but unin-

fected African women recognize different epitopes than CD8

cells from HIV-1 infected African women (49). This suggests

that the epitopes that the immune system is directed against

HIV and the Immune System 37

Hoffmann, Kamps, et al.

during a natural infection might be different from those that are

protective against infection.

HLA class II antigens are crucial for the development of an

HIV-1 specific CD4

T cell response. Rosenberg (1997) was the

first to show that HIV-1 infected patients with a long-term non-

progressive course of disease had HIV-1 specific CD4

T cells

that could proliferate against HIV-1 antigens (50). The identifi-

cation of protective or unfavorable HLA class II alleles is less

well elaborated on than the knowledge about protective HLA

class I alleles. Cohorts of vertically infected children and HIV-

infected adults demonstrate a protective effect of HLA DR13

(51).

The HIV-specific Cellular Immune Response

In comparison to HIV-1 infected patients with a rapid decline of

CD4

T cells, patients with a long-term non-progressive course

of disease ("LTNP" = long-term non-progressors) have HIV-1-

specific CTL precursors in high numbers and with a broad

specificity towards various HIV-1 proteins. The different ca-

pacities of certain HLA alleles to present viral particles more or

less efficiently and to induce a more or less potent immune re-

sponse may explain why certain HLA alleles are associated

with a more rapid or a slow progressive course of disease (see

above).

Individuals have been described who developed CTL "escape"

mutants after years of stable disease and the presence of a

strong CTL response. The evolution of CTL escape mutants

was associated with a rapid decline in CD4

T cells in these pa-

tients, indicating the protective role of CTL (52).

HIV-specific CTL responses have been detected in HIV-1 ex-

posed but uninfected individuals. Nef-specific CTL have been

identified in HIV-1 negative heterosexual partners of HIV in-

fected patients and env-specific CTL have been found in sero-

negative healthcare workers after exposure to HIV-1 containing

material (needle stick injuries) (54).

38 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

The presence of a CTL response does not only correlate with

the suppression of plasma viremia during the initial phase of

HIV infection. Patients who underwent structured therapy inter-

ruptions, especially when HAART was initiated early following

infection, demonstrated the appearance of HIV-specific CTL

during the pauses.

However, it is still unclear in most patients who exhibit a potent

temporary CTL response, why this CTL response diminishes

later on. The appearance of viral "escape" mutants might ex-

plain why previously recognized epitopes are no longer immu-

nodominant.

The nef protein may downregulate HLA class I antigens and

therefore counteract the recognition of infected cells by CTL. In

addition, the majority of infected individuals do show detect-

able CTL responses. It is unclear why they are unable to control

the virus. Interestingly, CTL from HIV-infected patients shows

a lack of perforin and an immature phenotype, even though the

ability to secrete chemokines and cytokines is not impaired. It is

possible that the CTL in most HIV-1 infected individuals, al-

though detectable, may be functionally defective, and thus un-

able to completely clear the virus. CD8

T cells may also be-

come HIV infected, although this was not demonstrated for

HIV-specific CD8

T cells. It is unclear, whether CD8

T cells

might temporarily express CD4 and which chemokine co-

receptors mediate infection of these CD8

T cells.

In addition to the cytotoxic activities directed against HIV-

infected cells, CD8

T cells from HIV-1 infected patients ex-

hibit a remarkable soluble HIV-1 inhibitory activity that inhibits

HIV-1 replication in autologous and allogeneic cell cultures

(55). Despite multiple efforts, the identity of this inhibitory ac-

tivity ("CAF") has not been clarified, although chemokines,

such as MIP-1α, MIP-1ß, RANTES (24), IL-16 (56), the che-

mokine MDC (57) and defensins, may account for at least some

of the inhibition.

HIV and the Immune System 39

Hoffmann, Kamps, et al.

The T

1/T

2 Immune Response

Depending on the secretion pattern of cytokines, CD4

T cells

may be differentiated into T

1 and T

2 cells. T

1 CD4

T cells

primarily produce interleukin-2 (IL-2) and IFNγ, which repre-

sent the cytokines that support the effector functions of the im-

mune system (CTL, NK-cells, macrophages). T

2 cells pre-

dominantly produce IL-4, IL-10, IL-5 and IL-6, which represent

the cytokines that favor the development of a humoral immune

response. Since T

1 cytokines are critical for the generation of

CTLs, an HIV-1-specific T

1 response is regarded as being a

protective immune response. Studies on HIV-exposed but non-

infected individuals have shown, that following in vitro stimu-

lation with HIV-1 env antigens (gp120/gp160) and peptides, T

cells from these individuals secrete IL-2 in contrast to non-

exposed control persons (58). Similar studies were undertaken

in healthcare workers after needlestick injuries and in newborns

from HIV-infected mothers. Although these observations may

indicate that a T

1-type immune response is potentially protec-

tive, it should be considered that similar immune responses

might also have been generated after contact with noninfectious

viral particles and therefore do not necessarily imply a means of

protection against a replication-competent virus.

HIV-1-specific Humoral Immune Responses

The association between an HIV-1 specific humoral immune

response and the course of disease is less well characterized. A

slow progression of immunodeficiency was observed in patients

with high titers of anti-p24 antibodies (63), persistence of neu-

tralizing antibodies against primary and autologous virus (64),

and lack of antibodies against certain gp120 epitopes (62).

Long-term non-progressors with HIV tend to have a broad neu-

tralizing activity towards a range of primary isolates and show

persistence of neutralizing antibodies against autologous virus.

At present, it is unclear whether the presence of neutralizing

antibodies in LTNP represents part of the protection or whether

40 Pathogenesis of HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

it merely reflects the integrity of a relatively intact immune

system. Individuals that have a substantial risk for HIV-1 infec-

tion, but are considered "exposed, non-infected", by definition

represent individuals with a lack of a detectable antibody re-

sponse to HIV-1. This definition implies that a systemic hu-

moral immune response may not represent a crucial protective

mechanism. It has been shown that these individuals may dem-

onstrate a local (mucosal) IgA response against HIV-1 proteins

that are not detected by the usual antibody testing methods (65,

66). Thus, local IgA, rather than systemic IgG, may be associ-

ated with protection against HIV-1 infection. There is also some

evidence that some anti-HIV-1 antibodies can enhance the in-

fection of CD4

T cells.

A number of old and recent studies have shown that neutraliz-

ing antibodies do exist in HIV-1 infected individuals; however,

they seem to lag in time. That is, individuals will develop neu-

tralizing antibodies to their own viruses with time, however, by

the time these antibodies develop, the new viruses circulating in

the individual's plasma will become resistant to neutralization,

even though the older ones are now sensitive to the current an-

tibodies in the patient's serum. Thus, the antibody response ap-

pears to be hitting a 'moving' target, allowing viruses to escape

continuously. Further knowledge gained on understanding the

mechanisms of humoral escape will likely lead to potential new

therapies.

Improved knowledge and understanding of the pathophysio-

logic mechanisms during the course of HIV-1 infection have

not only contributed to the development of antiretroviral treat-

ment strategies, but have given rise to new therapeutic ap-

proaches, such as cytokine therapies, e.g., IL-2 and therapeutic

vaccination. However, the most important challenge and thus,

the demand for a better understanding of the immunopatho-

genesis of HIV-1 infection, remains the development of a pro-

tective vaccine, which is urgently needed to interrupt the epi-

demic especially in countries of the Subsahara and Southeast

Asia.

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Hoffmann, Kamps, et al.

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Introduction 47

Hoffmann, Kamps, et al.

Chapter 2: Acute HIV-1 Infection

Marcus Altfeld and Bruce D. Walker

Introduction

Acute HIV-1 infection presents in 40 – 90 % of cases as a tran-

sient symptomatic illness, associated with high levels of HIV-1

replication and an expansive virus-specific immune response.

With 14,000 new cases per day worldwide, it is an important

differential diagnosis in cases of fever of unknown origin,

maculopapular rash and lymphadenopathy.

The diagnosis of acute infection is missed in the majority of

cases, as other viral illnesses (“flu”) are often assumed to be the

cause of the symptoms, and there are no HIV-1-specific anti-

bodies detectable at this early stage of infection. The diagnosis

therefore requires a high degree of clinical suspicion, based on

clinical symptoms and history of exposure, in addition to spe-

cific laboratory tests (detection of HIV-1 RNA or p24 antigen

and negative HIV-1 antibodies) confirming the diagnosis.

An accurate early diagnosis of acute HIV-1 infection is impor-

tant, as patients may benefit from therapy at this early stage of

infection (see below), and infection of sexual partners can be

prevented.

Signs and Symptoms

After an incubation period of a few days to a few weeks, most

cases present with an acute flu-like illness. The most common

symptoms (see Table 1) are fever, maculopapular rash, oral ul-

cers, lymphadenopathy, arthralgia, pharyngitis, malaise, weight

loss, aseptic meningitis and myalgia. In a recently published

study by Hecht et al., fever (80 %) and malaise (68 %) had the

highest sensitivity for clinical diagnosis of acute HIV-1 infec-

tion, whereas loss of weight (86 %) and oral ulcers (85 %) had

48 Acute HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

the highest specificity. In this study, the symptoms of fever and

rash (especially in combination), followed by oral ulcers and

pharyngitis had the highest positive predictive value for diagno-

sis of acute HIV-1 infection. In another study by Daar et al.,

fever, rash, myalgia, arthralgia and night sweats were the best

predictors for acute HIV-1 infection.

Table 1: Main symptoms of acute HIV-1 infection

Symptom Frequency Odds ratio (95% CI)

Fever 80% 5.2 (2.3-11.7)

Rash 51% 4.8 (2.4-9.8)

Oral ulcers 37% 3.1 (1.5-6.6)

Arthralgia 54% 2.6 (1.3-5.1)

Pharyngitis 44% 2.6 (1.3-5.1)

Loss of appetite 54% 2.5 (1.2-4.8)

Weight loss > 2.5 kg 32% 2.8 (1.3-6.0)

Malaise 68% 2.2 (1.1-4.5)

Myalgia 49% 2.1 (1.1-4.2)

Fever and rash 46% 8.3 (3.6-19.3)

From: Hecht FM et al. Use of laboratory tests and clinical symptoms for

identification of primary HIV infection. AIDS 2002, 16: 1119-1129

The symptomatic phase of acute HIV-1 infection lasts between

7 – 10 days, and rarely longer than 14 days. The severity and

duration of symptoms has prognostic implications, as severe

and prolonged symptoms are associated with more rapid disease

progression. The nonspecific nature of the symptoms poses a

great challenge to the clinician and underlines the importance of

a detailed history of exposure.

Diagnosis

The diagnosis of acute HIV-1 infection is based on the detec-

tion of HIV-1 replication in the absence of HIV-1 antibodies, as

these are not yet present at this early stage of infection. Differ-

ent tests are available for diagnosis of acute HIV-1 infection.

Diagnosis 49

Hoffmann, Kamps, et al.

The most sensitive tests are based on detection of plasma HIV-1

RNA.

In a recently published study, all assays for HIV-1 RNA that

were tested (branched chain DNA, PCR and GenProbe) had a

sensitivity of 100 %, but occasionally (in 2 – 5 % of cases) led

to false positive results. False positive results from these tests

are usually below 2,000 copies HIV-1 RNA per ml plasma, and

therefore far below the high titers of viral load normally seen

during acute HIV-1 infection (in our own studies on average 13

x 10

copies HIV-1 RNA/ml with a range of 0.25 – 95.5 x 10

copies HIV-1 RNA/ml). Repetition of the assay for HIV-1 RNA

from the same sample with the same test led to a negative result

in all false positive cases. Measurement of HIV-1 RNA from

duplicate samples therefore results in a sensitivity of 100 %

with 100 % specificity. In contrast, detection of p24 antigen has

a sensitivity of only 79 % with a specificity of 99.5 – 99.96 %.

The diagnosis of acute HIV-1 infection must be subsequently

confirmed with a positive HIV-1 antibody test (seroconversion)

within the following weeks.

During acute HIV-1 infection, there is frequently a marked de-

crease of CD4+ cell count, which later increases again, but usu-

ally does not normalize to the initial levels. In contrast, the

CD8

cell count rises initially, which may result in a

CD4

/CD8

ratio of < 1. Infectious mononucleosis is the most

important differential diagnosis. Hepatitis, influenza, toxoplas-

mosis, syphilis and side effects of medications may also be con-

sidered.

In summary, the most important step in the diagnosis of acute

HIV-1 infection is to include it in the differential diagnosis. The

clinical suspicion of an acute HIV-1 infection then merely re-

quires performance of an HIV-1 antibody test and possibly re-

peated testing of HIV-1 viral load, as shown in the algorithm in

Figure 1 (adapted from Hecht et al., AIDS 2002).

50 Acute HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

Figure 1

Treatment

The goal of antiretroviral therapy during acute HIV-1 infection

is to reduce the number of infected cells, preserve HIV-1-

specific immune responses and possibly lower the viral set

point in the long term. Several studies in recent years have

shown that treatment of acute HIV-1 infection allows long-term

viral suppression, leads to preservation and even increase of

HIV-1-specific T helper cell responses and allows for the con-

servation of a very homogeneous virus population.

First studies in patients who were treated during acute HIV-1

infection and subsequently went through structured treatment

interruptions show that the HIV-1-specific immune response

References 51

Hoffmann, Kamps, et al.

could be boosted in these patients. Most patients were subse-

quently able to discontinue therapy and experienced at least

temporal control of viral replication, with viral set points re-

maining below 5,000 copies/ml for more than 3 years in some

patients. However, in a number of individuals viral load re-

bounded to higher level during longer follow-up, requiring the

initiation of therapy.

The long-term clinical benefit of early initiation of therapy has

not been demonstrated yet. It is also not known how long the

period between acute infection and initiation of therapy can be

without losing immunological, virological and clinical benefit.

In view of all these unanswered questions, patients with acute

HIV-1 infection should be treated in controlled clinical trials. If

this is not possible, the option of standard first-line treatment

should be offered and discussed. Usually, treatment continues

for at least a year, followed by structured treatment interrup-

tions within the framework of controlled studies. It is important

during counseling to clearly indicate the lack of definitive data

on clinical benefit and to address the risks of antiretroviral ther-

apy and treatment interruptions, including drug toxicity, devel-

opment of resistance, acute retroviral syndrome during viral

rebound and HIV-1 transmission and superinfection during

treatment interruptions.

References

1. Rosenberg ES Altfeld M, Poon SH, et al. Immune control of HIV-1 after

early treatment of acute infection. Nature 2000, 407:523-6.

http://amedeo.com/lit.php?id=11029005

2. Kahn JO and Walker BD. Acute HIV type 1 infection. New Eng J Med

1998, 339:33-9.

3. Altfeld M, Rosenberg ES, Shankarappa R, et al. Cellular Immune Re-

sponses and Viral Diversity in Individuals Treated during Acute and Early

HIV-1 Infection. J Exp Med 2001, 193:169-180.

http://amedeo.com/lit.php?id=11148221

4. Hecht FM, Busch MP, Rawal B, et al. Use of laboratory tests and clinical

symptoms for identification of primary HIV infection. AIDS 2002, 16:1119-

1129. http://amedeo.com/lit.php?id=12004270

52 Acute HIV-1 Infection

HIV Medicine 2003 – www.HIVMedicine.com

5. Yeni PG, et al. Antiretroviral treatment for adult HIV infection in 2002:

updated Recommendations of the International AIDS Society-USA Panel.

JAMA 2002, 288:222-235. http://jama.ama-

assn.org/issues/v288n2/ffull/jst20002.html

6. Daar E Little S, Pitt J, et al. Diagnosis of primary HIV-1 infection. Ann

Intern Med 2001, 134:25-29. http://amedeo.com/lit.php?id=11187417

7. The PRN Notebook – Special Edition February 2002: Primary HIV-1 In-

fection. (http://www.prn.org)

1. Perspective 53

Hoffmann, Kamps, et al.

Chapter 3: HIV Therapy 2003

1. Perspective

Christian Hoffmann

The development of antiretroviral therapy has been one of the

most dramatic progressions in the history of medicine. Few

other areas have been subject to such fast- and short-lived

trends. Those who have experienced the rapid developments of

the last few years have been through many ups and downs:

The early years, from 1987-1990, brought great hope and the

first modest advances using monotherapy (Volberding et al.

1990, Fischl et al. 1990). But, by the time the results of the

Concorde Study had arrived (Hamilton et al. 1992, Concorde

1994), both patients and clinicians had plunged into a depres-

sion that was to last for several years. Zidovudine was first

tested on humans in 1985, and introduced as a treatment in

March 1987 with great expectations. Initially, at least, it did not

seem to be very effective. The same was true for the nucleoside

analogs zalcitabine, didanosine and stavudine, introduced be-

tween 1991 and 1994. The lack of substantial treatment options

led to a debate that lasted for several years about which nucleo-

side analogs should be used, when, and at what dose. One such

question was: Should the alarm clock be set to go off during the

night for a sixth dose of zidovudine?

Many patients, who were infected during the early and mid-80s,

began to die. Hospices were established, as well as more and

more support groups and ambulatory nursing services. One be-

came accustomed to AIDS and its resulting death toll. There

was, however, definite progress in the field of opportunistic in-

fections (OI) – cotrimoxazole, pentamidine, ganciclovir, for-

scarnet and fluconazole saved many patients’ lives, at least in

the short-term. Some clinicians started to dream of a kind of

“mega-prophylaxis”. But the general picture was still tainted by

54 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

an overall lack of hope. Many remember the somber, almost

depressed mood of the IX

World AIDS Conference in Berlin,

in June 1993. Between 1989 and 1994, morbidity and mortality

rates were hardly affected.

Then, in September 1995, the preliminary results of the Euro-

pean-Australian DELTA Study (Delta 1995) and the American

ACTG 175 Study (Hammer et al. 1996) attracted attention. It

became apparent that combination therapy with two nucleoside

analogs was more effective than monotherapy. Indeed, the dif-

ferences made on the clinical endpoints (AIDS, death) were

highly significant. Both studies demonstrated that it was poten-

tially of great importance to immediately start treatment with

two nucleoside analogs, as opposed to using the drugs “sequen-

tially”.

This was by no means the final breakthrough. By this time, the

first studies with protease inhibitors (PIs), a completely new

drug class, had been ongoing for several months. PIs had been

designed in the lab using the knowledge of the molecular

structure of HIV and protease – their clinical value was initially

uncertain. Preliminary data, and many rumors, were already in

circulation. In the fall of 1995, a fierce competition started up

between three companies: Abbott, Roche and MSD. The li-

censing studies for the three PIs, ritonavir, saquinavir and indi-

navir, were pursued with a great amount of effort, clearly with

the goal of bringing the first PI onto the market. The monitors

of these studies in the different companies “lived” for weeks at

the participating clinical sites. Deep into the night, case report

files had to be perfected and thousands of queries answered. All

these efforts led to a fast track approval, between December

1995 and March 1996, for all three PIs – first saquinavir, fol-

lowed by ritonavir and indinavir – for the treatment of HIV.

Many clinicians (including the author) were not really aware at

the time of what was happening during these months. AIDS

remained ever present. Patients were still dying, as only a rela-

tively small number were participating in the PI trials – and

very few were actually adequately treated by current standards.

1. Perspective 55

Hoffmann, Kamps, et al.

Doubts remained. Hopes had already been raised too many

times in the previous years by alleged miracle cures. Early in

January 1996, other topics were more important: palliative

medicine, treatment of CMV, MAC and AIDS wasting syn-

drome, pain management, ambulatory infusion therapies, even

euthanasia.

In February 1996, during the 3

Conference on Retroviruses

and Opportunistic Infections (CROI) in Washington, many

caught their breath as Bill Cameron reported the first data from

the ABT-247 Study during the latebreaker session. The audito-

rium was absolutely silent. Riveted, listeners heard that the

mere addition of ritonavir oral solution decreases the frequency

of death and AIDS from 38 % to 22 % (Cameron et al. 1998).

These were sensational results in comparison to everything else

that had been previously published!

But for many, the combination therapies that became widely

used from 1996 onwards, still came too late. Some severely ill

patients with AIDS managed to recover during these months,

but, even in 1996, many still died. Although the AIDS rate in

large centers had been cut in half between 1992 and 1996

(Brodt et al. 1997), in smaller centers roughly every fifth patient

died in this year.

However, the potential of the new drugs was slowly becoming

apparent, and the World AIDS Conference in Vancouver a few

months later, in June 1996, was like a big PI party. Even regular

news channels reported in great depth on the new “AIDS cock-

tails”. The strangely unscientific expression “highly active

antiretroviral therapy” (HAART) began to spread irreversibly.

Clinicians were only too happy to become infected by this en-

thusiasm.

By this time, David Ho, Time magazine’s “Man of the Year” in

1996, had shed light on the hitherto completely misunderstood

kinetics of HIV with his breakthrough research (Ho et al. 1995,

Perelson et al. 1996). A year earlier, Ho had already initiated

the slogan “hit hard and early”, and almost all clinicians were

56 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

now taking him by his word. With the new knowledge of the

incredibly high turnover of the virus and the relentless daily

destruction of CD4+ T cells, there was no longer any consid-

eration of a “latent phase” – and no life without antiretroviral

therapy. In many centers almost every patient was treated with

HAART. Within only three years, from 1994-1997, the propor-

tion of untreated patients in Europe decreased from 37 % to

barely 9 %, whilst the proportion of HAART patients rose from

2 % to 64 % (Kirk et al. 1998).

Things were looking good. By June 1996, the first non-

nucleoside reverse transcriptase inhibitor, nevirapine, was li-

censed, and a third drug class introduced. Nelfinavir, another

PI, had also arrived. Most patients seemed to tolerate the drugs

well. 30 pills a day? No problem, if it helps. And how it helped!

The number of AIDS cases was drastically reduced. Within

only four years, between 1994 and 1998, the incidence of AIDS

in Europe was reduced from 30.7 to 2.5 per 100 patient years –

i.e. to less than a tenth. The reduction in the incidence of several

feared OIs, particularly CMV and MAC, was even more dra-

matic. HIV ophthalmologists had to look for new areas of work.

The large OI trials, planned only a few months before, faltered

due to a lack of patients. Hospices, which had been receiving

substantial donations, had to shut down or reorientate them-

selves. The first patients began to leave the hospices, and went

back to work; ambulatory nursing services shut down. AIDS

wards were occupied by other patients.

In 1996 and 1997 some patients began to complain of an in-

creasingly fat stomach, but was this not a good sign after the

years of wasting and supplementary nutrition? Not only did the

PIs contained lactose and gelatin, but the lower viremia was

thought to use up far less energy. It was assumed that, because

patients were less depressed and generally healthier, they would

eat more. At most, it was slightly disturbing that the patients

retained thin faces. However, more and more patients also be-

gan to complain about the high pill burden.

1. Perspective 57

Hoffmann, Kamps, et al.

In June 1997, the FDA published the first warning about the

development of diabetes mellitus associated with the use of PIs

(Ault 1997). In February 1998, the CROI in Chicago finally

brought home the realization among clinicians that protease

inhibitors were perhaps not as selective as had long been be-

lieved. One poster after the next, indeed whole walls of pictures

showed fat abdomens, buffalo humps, thin legs and faces. A

new term was introduced at the beginning of 1998, which

would influence the antiretroviral therapy of the years to come:

lipodystrophy. And so the old medical wisdom was shown to

hold true even for HAART: all effective drugs have side effects.

The actual cause of lipodystrophy remained completely unclear.

Then, in early 1999, a new hypothesis emerged from the Neth-

erlands: “mitochondrial toxicity”. It has become a ubiquitous

term in HIV medicine today.

The dream of eradication (and a cure), still widely hoped for in

the beginning, eventually had to be abandoned, too. Mathemati-

cal models are evidently not suitable for predicting what will

really happen. In 1997, it was still estimated that viral suppres-

sion, with a maximum duration of three years, was necessary;

after this period, it was predicted that all infected cells would

presumably have died. Eradication was the magic word. At

every conference since then, the duration of three years has

been adjusted upwards. Nature is not so easy to predict, and

newer studies came to the sobering conclusion that HIV re-

mains detectable in latent infected cells, even after long-term

suppression. To date, nobody knows how long these latent in-

fected cells survive, and whether even a small number of them

would be sufficient for the infection to flare up again as soon as

treatment is interrupted. Finally, during the Barcelona World

AIDS Conference, experts in the field admitted to bleak pros-

pects for eradication. The most recent estimates for eradication

of these cells were approximately 50-70 years. One thing is

certain: HIV will not be curable for at least the next 10 years.

Instead of eradication, it has become more realistic to consider

the lifelong management of HIV infection as a chronic disease

58 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

in the future, similar to diabetes mellitus. This means, however,

that drugs have to be administered over many years, which

demands an enormous degree of discipline from patients. Those

who are familiar with the management of diabetes understand

the challenges that patients and clinicians have to face and how

important it will be to develop better combinations in the com-

ing years. Hardly anyone will have the discipline and ability,

both mentally and physically, to take the currently available

pills several times daily at fixed times for the next ten, twenty

or even thirty years. But, presumably, this will not be necessary.

There will be new and improved treatment regimens. Once-

daily regimens are coming; maybe even twice-weekly.

At the same time, the knowledge of the risks of antiretroviral

therapy has changed the approach of many clinicians towards

treatment over the last three years. By the year 2000, many

strict recommendations from previous years were already being

revised. “Hit HIV hard, but only when necessary” is now heard

more than “hit hard and early” (Harrington and Carpenter

2000). The simple question of “when to start?” is now being

addressed at long symposia. It is often a question that requires

great sensitivity.

Despite all the skepticism, it is important not to forget what

HAART can do. HAART can often achieve miracles! Crypto-

sporidia and Kaposi's sarcoma simply disappear; PML may

even be cured completely; secondary prophylaxis for CMV can

be stopped; and above all: patients feel significantly better, even

if some activists and AIDS counselors still do not want to admit

this.

This also means, however, that many younger clinicians in

Western countries who entered into HIV medicine at the end of

the 90s often no longer know what AIDS really means. AIDS

for them is an accident, whose damage can be fixed. They did

not experience the "stone age" of AIDS.

HIV clinicians are well advised, perhaps more than other clini-

cians, to remember the "stone age", whilst still keeping an open

1. Perspective 59

Hoffmann, Kamps, et al.

mind for new approaches. Those, who are strictly opposed to

the interruption of treatment, and insistent on particular sche-

mata of treatment, are not only overlooking the realities of

treatment, but also losing touch. Those, who do not make an

effort to broaden their knowledge several times a year at differ-

ent conferences, will not be able to provide adequate treatment

for their patients in a field that changes direction at least every

two to three years. Those, who adhere strictly to evidence-based

HIV medicine, and only treat according to guidelines, quickly

become outdated. HIV medicine is ever changing. Treatment

guidelines remain just guidelines. They are often out of date by

the time of publication. There are no laws set in stone. How-

ever, those, who confuse therapeutic freedom with random

choices and assume that data and results coming from basic re-

search can be ignored, are also missing the point. Individualized

treatment is not random treatment. In addition, it cannot be

stressed enough, that clinicians are also responsible for the

problem of bad compliance. Even if many experienced clini-

cians have come to disregard this: every patient has the right to

know why he is taking which therapy or, indeed, why it has

been omitted.

HIV remains a dangerous and cunning opponent. Patients and

clinicians must tackle it together. The following describes how

this can be done.

References

1. Ault A. FDA warns of potential protease-inhibitor link to hyperglycaemia.

Lancet 1997, 349:1819.

2. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity in-

duced by nucleoside-analogue reverse-transcriptase inhibitors is a key

factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy.

Lancet 1999, 354:1112-5. http://amedeo.com/lit.php?id=10509516

3. Brodt HR, Kamps BS, Gute P, et al. Changing incidence of AIDS-defining

illnesses in the era of antiretroviral combination therapy. AIDS 1997,

11:1731-8. http://amedeo.com/lit.php?id=9386808

4. Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-

controlled trial of ritonavir in advanced HIV-1 disease. Lancet 1998,

351:543-9. http://amedeo.com/lit.php?id=9492772

60 HIV Therapy 2003

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5. Concorde: MRC/ANRS randomised double-blind controlled trial of imme-

diate and deferred zidovudine in symptom-free HIV infection. Lancet

1994, 343:871-81. http://amedeo.com/lit.php?id=7908356

6. Consensus Statement on Antiretroviral Treatment for AIDS in Poor

Countries by Individual Members of the Faculty of Harvard University.

2001. http://hiv.net/link.php?id=182

7. Delta: a randomised double-blind controlled trial comparing combinations

of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-

infected individuals. Lancet 1996, 348: 283-91.

http://amedeo.com/lit.php?id=8709686

8. Gulick RM, Mellors JW, Havlir D, et al. 3-year suppression of HIV viremia

with indinavir, zidovudine, and lamivudine. Ann Intern Med 2000, 133:35-

9. http://amedeo.com/lit.php?id=10877738

9. Hamilton JD, Hartigan PM, Simberkoff MS, et al. A controlled trial of early

versus late treatment with zidovudine in symptomatic HIV infection. N

Engl J Med 1992, 326:437-43. http://amedeo.com/lit.php?id=1346337

10. Hammer SM, Katzenstein DA, Hughes MD et al. A trial comparing nu-

cleoside monotherapy with combination therapy in HIV-infected adults

with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med

1996, 335:1081-90. http://amedeo.com/lit.php?id=8813038

11. Harrington M, Carpenter CC. Hit HIV-1 hard, but only when necessary.

Lancet 2000, 355:2147-52. http://amedeo.com/lit.php?id=10902643

12. Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995, 333:450-1.

13. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M.

Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.

Nature 1995, 373:123-6. http://amedeo.com/lit.php?id=7816094

14. Kirk O, Mocroft A, Katzenstein TL, et al. Changes in use of antiretroviral

therapy in regions of Europe over time. AIDS 1998, 12: 2031-9.

http://amedeo.com/lit.php?id=9814872

15. Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-98:

the EuroSIDA study. Lancet 2000, 356:291-6.

http://amedeo.com/lit.php?id=11071184.

16. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1

dynamics in vivo: virion clearance rate, infected cell life-span, and viral

generation time. Science 1996, 271:1582-6.

http://amedeo.com/lit.php?id=8599114

17. Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asympto-

matic HIV infection. A controlled trial in persons with fewer than 500 CD4-

positive cells per cubic millimeter. N Engl J Med 1990, 322:941-9.

http://amedeo.com/lit.php?id=1969115

2. Overview of Antiretroviral Drugs 61

Hoffmann, Kamps, et al.

2. Overview of Antiretroviral Drugs

Christian Hoffmann

Table 2.1: Antiretroviral agents

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Trade name Abb. Drug Manufacturer

Combivir

AZT+3TC GSK

Epivir

3TC Lamivudine GSK

Hivid

ddC Zalcitabine Roche

Retrovir

AZT Zidovudine GSK

Trizivir

AZT+3TC+ABC GSK

Videx

ddI Didanosine BMS

Viread

TDF Tenofovir Gilead

Zerit

d4T Stavudine BMS

Ziagen

ABC Abacavir GSK

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Rescriptor

DLV Delavirdine Pfizer

Sustiva

, Stocrin

EFV Efavirenz BMS

Viramune

NVP Nevirapine Boehringer

Ingelheim

Protease Inhibitors (PIs)

Agenerase

APV Amprenavir GSK

Crixivan

IDV Indinavir MSD

Fortovase

SQV-SGC Saquinavir soft gel Roche

Invirase

SQV-HGC Saquinavir hard gel Roche

Kaletra

LPV Lopinavir/ Ritonavir Abbott

Norvir

RTV Ritonavir Abbott

Viracept

NFV Nelfinavir Roche

Three classes of antiretroviral agents are currently available for

the treatment of HIV infection: nucleoside and nucleotide ana-

logs (NRTIs), non-nucleoside reverse transcriptase inhibitors

(NNRTIs) and protease inhibitors (PIs). Some 20 drug products

have been licensed, including formulations of both individual

and combined antiretroviral agents. The fusion inhibitor T-20

was launched in March 2003 as the prototype of a fourth drug

class. A number of other drugs and new classes of drugs are in

62 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

the pipeline and expected to be licensed in the next years. Re-

search is also focusing on immunomodulatory approaches with

vaccines or cytokines (interferons, interleukins).

The following overview will deal mainly with the individual

antiretroviral agents and their specific features and problems.

Common combinations are described in the chapter on “How to

start HAART?”.

Nucleoside Analogs (“nukes”, NRTIs)

Mechanism of action

Nucleoside analogs (slang: “nukes”) are also referred to as nu-

cleoside reverse transcriptase inhibitors. Their target is the HIV

enzyme reverse transcriptase. Acting as alternative substrates or

“false building blocks“, they compete with physiological nu-

cleosides, differing from these only by a minor modification in

the sugar (ribose) molecule. The incorporation of nucleoside

analogs aborts DNA synthesis, as phosphodiester bridges can

no longer be built to stabilize the double strand.

Nucleoside analogs are converted to the active metabolite only

after endocytosis, whereby they are phosphorylated to triphos-

phate derivatives. AZT and d4T are thymidine analogs, ddC and

3TC are cytidine analogs. A combination of AZT and d4T

would be senseless, since both drugs compete for the same

bases; this also applies to ddC and 3TC. ddI is an inosine ana-

log, which is converted to dideoxyadenosine; abacavir is a gua-

nine analog. There is a high degree of cross-resistance between

nucleoside analogs (see also the chapter on “Resistance“).

Nucleoside analogs are important components of almost all

combination regimens. They are potent inhibitors of HIV repli-

cation, and are rapidly absorbed when taken orally. However,

they can cause a wide spectrum of side effects, encompassing

myelotoxicity, lactic acidosis, polyneuropathy and pancreatitis.

Complaints include fatigue, headache and a variety of gastroin-

testinal problems such as abdominal discomfort, nausea, vom-

iting and diarrhea. Although lipodystrophy was initially linked

2. Overview of Antiretroviral Drugs 63

Hoffmann, Kamps, et al.

exclusively to treatment with protease inhibitors, numerous dis-

orders of lipid metabolism (especially lipoatrophy) are now also

attributed to nucleoside analogs (Galli et al. 2002).

Most side effects are probably related to mitochondrial toxicity,

first described in 1999 (Brinkmann et al. 1999). Mitochondrial

function also requires nucleosides. The metabolism of these

important organelles is disrupted by the incorporation of false

nucleosides, leading to mitochondrial degeneration. More re-

cent clinical and scientific data indicates that there are probably

significant differences between individual drugs with regard to

mitochondrial toxicity.

Nucleoside analogs are eliminated mainly by renal excretion

and do not interact with drugs that are metabolized by hepatic

enzymes. There is therefore little potential for interaction. How-

ever, substances such as ribavirin may decrease the intracellular

phosphorylation of AZT or d4T in vitro (Piscitelli et Galliciano

2001).

Individual agents: Special features and problems

Abacavir (Ziagen

) is a potent and mostly well-tolerated nu-

cleoside analog with good CNS penetration. One drawback to

the use of abacavir is the occurrence of the hypersensitivity re-

action (HSR), which is not yet fully understood. HSR occurs in

approximately 4-5% of patients, almost always (93%) within

the first six weeks of treatment. Every treating physician should

be familiar with this syndrome, which can be fatal in individual

cases, especially after rechallenge (see Management of Side

Effects). The combination of strongly worded warnings con-

tained in the package insert and the often unspecific symptoms

of the HSR poses a constant challenge to the patient-physician

relationship. Several reports were published in 2002 suggesting

that patients with HLA type B5701 may be genetically predis-

posed and at higher risk than others (Mallal et al. 2002, Heth-

erington et al. 2002). Apart from HSR, abacavir seems to have

an otherwise favorable long-term profile, especially in terms of

mitochondrial toxicity (Carr et al. 2002).

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AZT – Zidovudine (Retrovir

) was the first antiretroviral

agent to be put on the market, in 1987. In the first few years, it

was administered in doses that were too high, which led to sig-

nificant myelotoxicity and brought the drug into somewhat of

disrepute. Even with the standard doses given today, monitoring

of blood count is obligatory. Long-term treatment almost al-

ways increases MCV. Initial gastrointestinal complaints may

present a short-term problem. AZT seems to have a more favor-

able profile with regard to long-term toxicity. Lack of neuro-

toxicity and good CNS penetration are important advantages of

this drug, which has remained the cornerstone of many HAART

regimens and transmission prophylaxis.

ddC - Zalcitabine (Hivid

) was investigated closely in the

double nuke studies of the early to mid-nineties. It has since

been marginalized due to the relatively frequent development of

peripheral neuropathy, the three times daily dosing requirement,

and lack of data in the HAART era. At the present time, ddC is

by far the least used nucleoside analog. Stomatitis is a side ef-

fect that is relatively specific for ddC. Although a twice daily

dose now seems possible (Moyle and Gazzard 1998), increased

competition from newer nucleoside analogs may mean that this

substance will disappear from antiretroviral therapies.

ddI – Didanosine (Videx

) is a nucleoside analog that has been

well investigated and shown good efficacy in numerous ran-

domized studies. The introduction of acid-resistant tablets in

2000, to replace the chewable tablets used for many years, has

done much to improve tolerability. ddI remains one of the most

important components of many HAART regimens. ddI was

shown to be more potent than AZT, even with regard to disease

progression in the ACTG 175 Study (Hammer et al. 1996), con-

firming results of an earlier study (Kahn et al. 1992). After fail-

ure with AZT, ddI is probably more effective than d4T (Havlir

et al. 2001). Gastrointestinal complaints are typical and rela-

tively frequent side effects. Pancreatitis, a less common but also

typical adverse effect, may be fatal in individual cases and is

possibly dose-related. Special caution should be given to the

2. Overview of Antiretroviral Drugs 65

Hoffmann, Kamps, et al.

combination with d4T and hydroxyurea (Havlir at al. 2001).

The advantage to the use of ddI of simple once daily dosing,

which is possible due to the long intracellular half-life, is coun-

terbalanced by the need to take the drug under fasting condi-

tions.

d4T – Stavudine (Zerit

) was the second thymidine analog to

be introduced after AZT. On initiation of therapy it is often

better tolerated than AZT, producing less gastrointestinal side-

effects and limited myelotoxicity. It is definitely just as effec-

tive and was for many years the most frequently prescribed

antiretroviral agent. Recently, focus on long-term toxicity rather

than efficacy has revealed that d4T seems to be associated with

more problems than other nucleoside analogs. It increases the

risk of lactic acidosis and hyperlactacidemia, especially in com-

bination with ddI or 3TC (Gerard et al. 2000, Miller at al. 2000,

Mokrzycki et al. 2000, John et al. 2001). There has also been

concern over recent reports of progressive neuromuscular

weakness. 22 of 25 patients (7 fatal cases), presenting with

symptoms similar to the Guillain-Barré syndrome and with hy-

perlactacidemia, had received d4T, 11 of these d4T+ddI (Mar-

cus et al. 2002). Lipodystrophy is probably also more frequent

with d4T. In a German cohort the risk of lipoatrophy had dou-

bled after one year of treatment (Mauss et al. 2002); in a Swiss

cohort it had tripled after two years (Bernasconi et al. 2002).

Other data, with one exception (Bogner et al. 2001), points in

the same direction (Chene et al. 2002).

Even more significant than the data from cohort studies is the

publication of the first studies showing the positive effect on

lipoatrophy of discontinuation of d4T (and replacement with

other nukes): In a randomized study from Australia, in which

111 lipoatrophic patients on stable HAART had d4T or AZT

replaced either with abacavir or not, most benefit was seen in

the d4T group (Carr et al. 2002). The effect at 24 weeks, how-

ever, was still very moderate. The increased subcutaneous fat

tissue detectable by dexa scan was not visible clinically. It may

therefore take years, as the authors concluded, for lipoatrophy

66 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

to visibly improve after discontinuation of d4T. A positive ef-

fect, albeit once again weak, has been described in two further

d4T-replacement studies (John et al. 2002, McGomsey et al.

2002). Thus, bearing resistance patterns in mind, in patients on

d4T with severe lipoatrophy, the drug should be replaced, opti-

mally with abacavir. There is, however, no assurance for reso-

lution of lipoatrophy, and, above all, great patience is required.

3TC – Lamivudine (Epivir

) is a very well tolerated nucleo-

side analog. This substance is frequently used, as it is a compo-

nent of both Combivir and Trizivir. Its main disadvantage is

rapid development of resistance, and a single point mutation

(M184V) is sufficient for loss of effectiveness. Since resistance

is likely to develop after only a few weeks, 3TC has practically

no effect as monotherapy. Thus, treatment with 3TC as the only

nucleoside analog component of a combination is considered

problematic. As the M184V mutation seems to impair viral fit-

ness, however, continuation of 3TC therapy following this mu-

tation may make good sense (Miller et al. 2002).

3TC is also effective against hepatitis B viruses. Once daily

dosing appears to be feasible (Sension et al. 2002). In the US,

3TC has already been approved as the first once-daily nucleo-

side analog.

Tenofovir (Viread

) acts as a false building block similarly to

nucleoside analogs, targeting the enzyme reverse transcriptase.

However, in addition to the pentose and nucleic base it is

monophosphorylated, and is therefore referred to as a nucleo-

tide analog. The more accurate description of the substance is

tenofovir DF (disoproxil fumarate), which is a phosphonate

from which the phosphonate component is only removed by a

serum esterase and which is activated intracellularly in two

phosphorylation steps (Robbins et al. 1998).

After the first nucleotide analog adefovir was abandoned in

HIV therapy due to weak antiviral activity and severe side ef-

fects (and is now being further developed in lower doses as the

hepatitis B medication Hepsera

), tenofovir has shown mark-

2. Overview of Antiretroviral Drugs 67

Hoffmann, Kamps, et al.

edly improved tolerability and would also appear to be more

potent. In the 902 Study, in which tenofovir versus placebo was

added to HAART, tenofovir decreased viral load by 0.62 log

after 48 weeks (Schooley et al. 2002). The 903 Study was a

double-blind study in which treatment-naive patients were

given tenofovir or d4T (in addition to the backbone regimen

with 3TC and efavirenz). Preliminary results showed at least

equivalent potency (Staszewski et al. 2002). Tolerability was

higher in the tenofovir group, especially with regard to polyneu-

ropathy and fat redistribution. This is consistent with in vitro

data, which shows that phosphorylated tenofovir has a low af-

finity for mitochondrial polymerases (Suo 1998).

Despite all the positive reports, long-term data on tenofovir are

not yet available. In combination with ddI, there are increased

levels of ddI, which could lead to increased toxicity (Kearney et

al. 2002); a daily dose reduction of ddI to 250 mg is probably

necessary. On the other hand, since tenofovir is eliminated re-

nally, interactions with substances metabolized in the liver are

rare. Longterm, the possibility of cumulative nephrotoxicity

needs to be clarified.

Efficacy – Which nuke backbone is best?

All classical HAART regimens contain two nucleoside analogs

as the “backbone” of treatment. For many years, numerous

studies, especially before the introduction of PIs and NNRTIs,

concentrated on the optimal combination of two nucleoside

analogs.

There are probably no great differences. Although data has been

contradictory, this is probably due to different study settings

and frequently heterogeneous patient populations. There seems

only to be consensus that ddC-containing nuke combinations

are slightly less potent. A meta-analysis of several randomized

studies has shown that AZT+ddI is more potent than AZT+ddC

(HTCG 1999). Similarly, in patients pretreated with monother-

apy, AZT+3TC was superior to AZT+ddC (Bartlett et al. 1996).

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AZT+3TC or d4T+ddI?

A great deal of data is now available comparing the two most

frequent combinations – AZT+3TC and d4T+ddI. In the French

Albi Trial, d4T+ddI was clearly more effective than AZT+3TC.

However, it was later shown that d4T+ddI significantly caused

more frequent lipoatrophy (Molina et al. 1999, Chene et al.

2002), and following failure of d4T+ddI, AZT resistance was

found to be equal or more than that with AZT+3TC (Picard et

al. 2001). The combination with indinavir also showed a posi-

tive trend in favor of d4T+ddI over AZT+3TC (Eron et al.

2000).

These results, however, were not confirmed in another study

(Carr et al. 2000). Similarly, no difference in efficacy was

found between d4T+ddI, AZT+3TC and d4T+3TC, whether in

combination with nevirapine or indinavir (Foudraine et al.

1998, Squire et al. 2000, French et al. 2002).

Although ACTG 384, the ultimate large study dealing with this

issue has yet to be completed, the pendulum seems to have

swung in favor of AZT+3TC. Preliminary results, presented

recently at the World AIDS Conference in Barcelona (Robbins

et al. 2002, Shafer et al. 2002), were puzzling: AZT+3TC is

virologically superior to d4T+ddI, although only in combination

with efavirenz; a combination with nelfinavir shows no added

benefit. A plausible explanation has yet to be given.

Summary of nuke backbones

To date, the results of efficacy studies remain inconclusive and

do not provide a mandate for the choice of one particular com-

bination over another. Treatment can thus be adapted to the

particular needs of each patient.

Choice of one of the three combinations AZT+3TC, AZT+ddI

or d4T+3TC is nearly always appropriate. In view of recent

studies on lactic acidosis and lipoatrophy, the combination of

d4T+ddI should be carefully considered and monitored.

2. Overview of Antiretroviral Drugs 69

Hoffmann, Kamps, et al.

Other combinations such as AZT+ABC, d4T+ABC,

ABC+3TC, or ddI+3TC also seem acceptable, but are not as

well supported by clinical data. ddI+3TC may also produce less

favorable results than AZT+3TC or d4T+3TC, as was suggested

by the ACTG 306 Study (Kuritzkes et al. 1999).

Combinations such as AZT+d4T, ddC+3TC, d4T+ddC and

ddI+ddC should definitely be avoided. It has also been shown

that constant changing of the nuke backbone with the goal of

preventing development of resistance has no positive effect and

probably only confuses the patient (Molina et al. 1999).

Non-Nucleoside Reverse Transcriptase Inhibitors

(NNRTIs)

Mechanism of action and efficacy

As with the nucleoside analogs, the target enzyme of NNRTIs is

reverse transcriptase. NNRTIs were first described in 1990. In

contrast to the NRTIs, they are not “false” building blocks, but

rather bind directly and non-competitively to the enzyme, at a

position in close proximity to the substrate-binding site for nu-

cleosides. The resulting complex blocks the catalyst-activated

binding site of the reverse transcriptase, which can thus bind

fewer nucleosides, and polymerization is slowed down signifi-

cantly. In contrast to NRTIs, NNRTIs do not require activation

within the cell.

The three currently available NNRTIs – nevirapine, delavirdine

and efavirenz – were introduced between 1996 and 1998. Hav-

ing only limited potency as individual agents, they were ini-

tially regarded somewhat skeptically. Although studies such as

the INCAS Trial or Protocol 0021II clearly demonstrated the

superiority of triple therapy with nevirapine or delavirdine

compared to double nuke therapy (Conway et al. 2000), the

“rise” of the NNRTIs was rather hesitant, and did not receive

the media attention given to that of the PIs.

Since then, both randomized and large cohort studies have

demonstrated that NNRTIs are extremely effective in combina-

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HIV Medicine 2003 – www.HIVMedicine.com

tion with nucleoside analogs. The immunological and virologi-

cal potency of NNRTIs is at least equivalent to that of PIs

(Friedl et al. 2001, Staszewski et al. 1999, Torre et al. 2001). In

contrast to PIs, however, the clinical effect has not yet been

proven, as the studies that led to licensing of NNRTIs all used

surrogate markers. Nevertheless, the simple dosage and the

overall good tolerability have led nevirapine and efavirenz to

become important components of HAART regimens, which are

often even ranked above those containing PIs. While the manu-

facturers of nevirapine and efavirenz compete for market domi-

nation, delavirdine has lost relevance (a situation which is un-

likely to change).

To date, no controlled study provides clear evidence that one

NNRTI is more potent than another. A small, randomized pilot

study from Spain demonstrated no significant differences be-

tween nevirapine and efavirenz (Nunez et al. 2002). However,

several cohort studies indicate the superiority of efavirenz. In an

Italian study, treatment failure on nevirapine was 2.08 times

more likely than on efavirenz (Cozzi-Lepri et al. 2002), and in

the Euro-SIDA study this factor was 1.75 (Phillips et al. 2001).

Such analyses should be interpreted with caution, as extremely

heterogeneous patient groups, with varying previous treatments,

were studied. This was recently underlined by the eagerly

awaited results of the 2NN Study ("The Double Non-

Nucleoside Study"). 2NN is the first large-scale randomized

trial directly comparing nevirapine and efavirenz-containing

regimens in HAART-naive patients. The trial showed that nevi-

rapine and efavirenz were comparable with respect to virologi-

cal and immunological efficacy after 48 weeks of therapy.

However, nevirapine and efavirenz have distinctive adverse

event profiles which should be considered in the choice of these

drugs (see below).

In the case of both NNRTIs, efficacy and toxicity probably cor-

relate with plasma levels (Veldkamp et al. 2001, Marzolini et al.

2001, Gonzalez et al 2002). Nevirapine and efavirenz are me-

tabolized by cytochrome P450 enzymes (Miller et al. 1997).

2. Overview of Antiretroviral Drugs 71

Hoffmann, Kamps, et al.

Nevirapine is an inductor, whereas efavirenz is both an inductor

and an inhibitor of the cytochrome P450 isoenzyme. The com-

bination of efavirenz with saquinavir or lopinavir leads to

strong interactions that require dose adjustments.

Individual agents: Special features and problems

The most significant problem with NNRTIs is resistance, with a

high risk of cross-resistance. One point mutation on position

103 (K103N) of the hydrophobic binding site is sufficient to

eliminate an entire class of drug. Point mutations may occur

very rapidly. Resistance has even been described in maternal

transmission prophylaxis, in mothers who had taken nevirapine

only once during delivery (Eshleman et al. 2002). Thus,

NNRTI-containing regimens are vulnerable – and waiting too

long to switch therapy during insufficient suppression of viral

load almost certainly leads to complete resistance.

The side effects of nevirapine and efavirenz are quite different,

and should be considered in the choice of regimen.

Nevirapine (Viramune

) was the first licensed NNRTI. In rare

cases, it may cause serious hepatic toxicity. To prevent allergic

reactions, the currently recommended dosage regimen is 200

mg qd for 2 weeks, followed by 200 mg bid thereafter. During

the first 8 weeks, biweekly monitoring of liver function tests is

recommended. A rash develops in 15-20 % of cases and leads

to discontinuation in 7% of patients (Miller et al. 1997). In the

case of an isolated rash or isolated elevation of transaminases

(up to five times the upper limit of normal), treatment may usu-

ally be continued. However, treatment should be discontinued

in the case of a rash with even slightly elevated transaminases

(>2-fold of norm). Patients with chronic hepatitis are probably

at a higher risk (Sulkowski et al. 2000). Similarly, there seems

to be a correlation with plasma levels (Gonzalez et al. 2002). It

is important to note that hepatic toxicity may occur even after

several months (Sulkowski et al. 2002).

In contrast, nevirapine has a good lipid profile. In the Atlantic

Study, in which nevirapine was tested against lamivudine and

72 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

indinavir, with all groups on a d4T+ddI backbone, those re-

ceiving nevirapine showed favorable lipid changes for choles-

terol and triglycerides. Astonishingly, there was an increase in

HDL (Van der Valk et al. 2001), demonstrated also in the

Spanish Lipnefa Study (Fisac et al. 2002). These effects are un-

doubtedly positive. Whether they will have clinical relevance

over time, remains to be seen.

Efavirenz (Sustiva

, Stocrin

) was the third NNRTI to be ap-

proved and the first in which it was demonstrated that NNRTIs

were at least as effective as PIs (Staszewski et al. 1999). The

long half-life allows for once-daily dosing. With the approval of

a new 600 mg capsule, dosage has been reduced to a single cap-

sule per day.

Efavirenz may cause mild CNS side effects and should there-

fore be taken in the evening. These disorders usually include

morning dizziness and somnolence; nightmares may also occur.

The side effects probably correlate with high plasma levels

(Marzolini et al. 2001). In one study, after four weeks of treat-

ment with efavirenz, 66 % of patients complained of dizziness,

48 % of abnormal dreams, 37 % of somnolence and 35 % of

insomnia. Although these symptoms seem to resolve with fur-

ther treatment (frequencies of these complaints at 24 weeks was

only 13 %, 18 %, 13 % and 7 %, respectively), patients must be

warned of these potential side effects (Fumaz et al. 2002). To

date, little is known of the effect on driving. We recommend

that efavirenz should not be prescribed to patients during ex-

amination periods, to pilots or crane operators. Patients with

impaired concentration should avoid potentially hazardous ac-

tivities such as driving or operating heavy machinery (see pack-

age insert). Efavirenz is contraindicated in pregnancy. Lipids

are not as favorably affected as with nevirapine (Hoffmann et

al. 2000), but hepatotoxicity is less frequent.

Delavirdine (Rescriptor

): Due to a high pill burden and the

required three times daily dosing, delavirdine is currently rarely

prescribed, although it is likely to be approximately as effective

as nevirapine and efavirenz (Wood et al. 1999, Conway 2000).

2. Overview of Antiretroviral Drugs 73

Hoffmann, Kamps, et al.

The need for prescription should be carefully considered. In

1999, an application for licensure in Europe was rejected due to

insufficient efficacy data.

Protease Inhibitors (PIs)

Mechanism of action and efficacy

The HIV protease cuts the viral gag-pol polyprotein into its

functional subunits. Inhibition of the protease, preventing pro-

teolytic splicing and maturation, leads to the release of virus

particles which are unable to infect new cells. With knowledge

of the molecular structure of the protease encoded by the virus,

the first protease inhibitors were designed in the early nineties;

these substances were modified in such a way, that they fit ex-

actly into the enzyme active site of the HIV protease (detailed

reviews: Deeks 1997, Somadossi 1999, Eron 2001).

Since 1995, protease inhibitors have revolutionized the treat-

ment of HIV infection (see also the chapter on “History”). At

least three large studies with clinical endpoints proved the effi-

cacy of indinavir, ritonavir and saquinavir (Hammer et al. 1997,

Cameron et al. 1998, Stellbrink et al. 2000). Even if in recent

years PIs have demonstrated a series of drawbacks, they remain

an essential component of HAART, especially for treatment-

experienced patients.

As with the NNRTIs, there has been intense pharmaceutical

company competition to establish which PI has superior effi-

cacy. However, comparative studies have failed to demonstrate

clear superiority of one protease inhibitor over any other.

Two exceptions have to be mentioned: the hard gel capsule

saquinavir-HGC and ritonavir. A large retrospective analysis

has shown the relative benefit of indinavir when compared to

saquinavir-HGC. There was significantly less virologic failure

in patients taking indinavir (Fätkenheuer et al. 1997). In the

Euro-SIDA cohort there was even a clinical benefit of indinavir

when compared to saquinavir hard gel capsules (Kirk et al.

2001). Saquinavir was subsequently “rescued” mainly by

74 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

boosting (see below), but also by the development of soft gel

capsules with improved resorption. A small, randomized study

showed no differences between indinavir, saquinavir soft gel

capsules, ritonavir, nelfinavir and amprenavir, when combined

with abacavir (McMahon et al. 2001). Similarly, the CHEESE

Study found no differences between saquinavir-SGC and indi-

navir (Cohen et al. 1999).

In the case of ritonavir, the main problem is poor tolerability. In

an open-label randomized trial with three groups, although no

major differences could be shown between ritonavir/saquinavir

and indinavir-containing regimens, but there was a definite un-

favorable trend for patients on ritonavir, due not to virologic

failure but to frequent discontinuation because of side effects

(Katzenstein et al. 2000).

Boosted PI regimens are presumably more effective. Lopina-

vir/r in combination with d4T/3TC was shown to reduce viral

load more effectively than nelfinavir-containing HAART. After

one year in the double-blind M98-863 Study, 67 % versus 52 %

had a viral load below 50 copies/ml (Walmsley et al. 2002).

Individual agents: Special features and problems

Apart from gastrointestinal side effects and high pill burden, all

PIs used in long-term therapy can be implicated in lipodystro-

phy and dyslipidemia (see also the chapter on “Lipodystrophy”;

review in Graham 2000). Smaller randomized studies have

shown that elevation of lipid levels is more pronounced in rito-

navir-containing regimens than with saquinavir or nelfinavir

(Roge et al. 2001, Wensing et al. 2001). In addition, there may

be significant drug interactions with ritonavir and with boosted

regimens. Sexual dysfunction has also been attributed to PIs

(Schrooten et al. 2001), although data is inconclusive (Lalle-

mand et al. 2002).

There is a high degree of cross-resistance between protease in-

hibitors, which was described even before PIs were put on the

market (Condra et al. 1995; see also the chapter on “Resis-

tance”). All PIs are inhibitors of the CYP3A4 system and inter-

2. Overview of Antiretroviral Drugs 75

Hoffmann, Kamps, et al.

act with numerous other drugs. Ritonavir is by far the strongest

inhibitor, saquinavir probably the weakest.

Amprenavir (Agenerase

) – As an unboosted PI, the sub-

stance is hardly acceptable today due to the high pill burden

(8 pills BID). Important side effects include gastrointestinal

disorders and, in contrast to other PIs, occasional rashes.

Whether the incidence of lipodystrophy and dyslipidemia is

reduced as compared with other PIs has yet to be proven (Noble

et al. 2000). The resistance profile of the drug is particularly

interesting, as it only partially overlaps with that of other PIs. It

is to be expected that Agenerase

will be removed from the

market as soon as the follow-on drug fos-amprenavir is avail-

able. This could lead to serious competition for lopinavir in the

area of salvage therapy.

Indinavir (Crixivan

) has been shown to be a very effective PI

in numerous studies; it is probably the most extensively tested

(Gulick et al. 1997, Hammer et al. 1997). The large amount of

data is currently the most important argument in favor of this

drug. Low protein binding (60 %) seems to allow better CNS

penetration than with other PIs (Martin et al. 1999). Whether

this is clinically significant remains to be seen.

There are, however, a number of problems associated with indi-

navir. First, it causes nephrolithiasis in approximately 5-10 % of

patients and thus requires good hydration (at least 1.5 liters

daily). Patients with a history of nephrolithiasis or renal insuffi-

ciency should therefore not receive indinavir. Secondly, in the

unboosted form, indinavir must be taken three times daily in

fasting conditions, a form of dosing that is currently unaccept-

able. Finally, the minimal inhibitory concentration is often

reached as soon as 8 hours after administration.

Unboosted twice-daily dosing is not possible. A trial using 2 x

1200 mg indinavir (3 tablets BID) in 87 patients had to be

stopped because of 36 % versus 9 % treatment failures in the

study group with twice-daily dosing (Haas et al. 2000). For this

reason, indinavir is increasingly being used in combination with

76 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

boosting doses of ritonavir. Such boosting may, however, pres-

ent some problems due to side effects (Gatell et al. 2000, Harley

et al. 2001, Shulman et al. 2002). In the MaxCmin1 Trial the

drop-out rate in the indinavir group was clearly higher than

among patients receiving saquinavir (Gerstoft et al. 2002).

There are relatively frequent mucocutaneous side effects, remi-

niscent of retinoid therapy: alopecia, dry skin and lips, ingrown

nails. Some patients may also develop asymptomatic hyperbili-

rubinemia.

Lopinavir/Ritonavir (Lopinavir/r, Kaletra

) is the newest PI

and the first to contain a fixed booster dose of ritonavir, which

may increase concentrations of lopinavir by more than 100-fold

(Sham et al. 1998). Lopinavir has the highest genetic barrier of

all PIs (6-8 cumulative PI resistance mutations are probably

necessary for treatment failure), and it has surprising efficacy in

salvage therapy. However, use in early treatment is controver-

sial, and to date it has also not been shown whether lopinavir is

the most effective PI for treatment-naive patients. It is probably

superior to nelfinavir (and also atazanavir), but as yet there is

no data for boosted PIs such as indinavir, saquinavir or ampre-

navir. Dyslipidemia appears to be a significant problem with

lopinavir therapy.

Nelfinavir (Viracept

) was the fourth PI to be put on the mar-

ket and was for a long time one of the most frequently used PIs.

Although it is also licensed for the (initially developed) dose of

3 x 3 capsules, nelfinavir may be taken twice daily in the dose

of 2 x 5 capsules. Boosting with ritonavir does not lead to sig-

nificant improvement in plasma levels.

The most frequent side effect of nelfinavir is diarrhea, which

may be quite severe. The antiretroviral potency of nelfinavir is

weaker than that of boosted PIs (Walmsley et al. 2002). In the

large Agouron 511 Study which led to licensing, 61 % of pa-

tients (with an AZT+3TC backbone) showed blood levels under

50 copies/ml at 48 weeks (Saag et al. 2001). The substance has

a good resistance profile. The D30N primary mutation for nel-

finavir reduces viral fitness (Martinez et al. 1999) and does not

2. Overview of Antiretroviral Drugs 77

Hoffmann, Kamps, et al.

influence the efficacy of other PIs. Unfortunately however,

other mutations, which in contrast can jeopardize the success of

later regimens, also occur frequently. A new formulation ena-

bling a reduction to 2 x 2 capsules daily is in development,

which may reverse the recent downward trend in sales of nelfi-

navir due to strong competition.

Ritonavir (Norvir

) was the first PI for which efficacy was

proven with clinical endpoints (Cameron et al. 1998). Due to its

poor tolerability (gastrointestinal complaints, perioral paresthe-

sias), ritonavir is generally no longer used as a single PI. How-

ever, when used to boost other protease inhibitors, the ritonavir

dose can be reduced to 2 x 100 mg, whereby toleration is vastly

improved. Ritonavir is a potent inhibitor of the cytochrome

P450 pathway with a great potential for interactions with other

drugs; thus, many drugs are contraindicated for concomitant

administration with ritonavir. Metabolic disorders are probably

more frequent than with other PIs. Caution should generally be

exercised in patients with impaired liver function. It is impor-

tant to inform patients that ritonavir capsules must be stored at

cool temperatures, which can become a problem during long

trips.

Saquinavir (Invirase

and Fortovase

) is the only PI which is

available in two formulations: a hard gel capsule (Invirase

saquinavir-HGC) and a soft gel capsule (Fortovase

or saquina-

vir-SGC). The soft gel capsules have a greatly improved bio-

availability and therefore a superior antiviral activity, which

was demonstrated in a pilot study in naive patients (Mitsuyasu

et al. 1998). However, in the era of boosting with ritonavir, this

distinction is probably less relevant (see below).

Saquinavir was the first PI to be licensed in December 1995 for

HIV therapy. Although rare serious side effects can occur, the

main adverse reactions are relatively mild gastrointestinal com-

plaints, which are more frequent with the soft gel capsules (Ku-

rowski et al. 2002). Saquinavir is otherwise well tolerated. In

the MaxCmin1 Trial, the drop-out rate was significantly lower

when compared to the indinavir group (Gerstoft et al. 2002).

78 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

Why “boost” PI regimens?

Ritonavir is a very potent inhibitor of the isoenzyme 3A4, a

subunit of the cytochrome P450 hepatic enzyme system, and

small doses of ritonavir lead to increased plasma levels (boost-

ing) of almost all PIs (Kempf et al. 1997). Indeed, nelfinavir is

the only drug for which boosting with ritonavir is not recom-

mended, as plasma levels do not rise significantly (Kurowski et

al. 2002).

The interaction between ritonavir and the other PIs simplifies

the daily regimen by reducing the number of pills to be taken

every day. Some PIs can now be used in twice-daily regimens.

Recent trials are investigating the possibility of once-daily

dosing. Boosting also aims to intensify therapy; due to the ele-

vated plasma levels, boosted indinavir or amprenavir seem to be

effective against resistant viral strains (Condra et al. 2000).

There is, however, a high degree of variability of boosted

plasma levels among individuals. Therapeutic drug monitoring

is therefore recommended (Burger et al. 2002). In addition to

achieving elevated trough levels of the boosted drug, which

prevents plasma levels from dropping below the minimal in-

hibitory concentration, ritonavir also increases peak levels,

which may lead to more side effects.

Saquinavir/ritonavir is the most-studied booster combination

regimen. Due to the low oral bioavailability of saquinavir, this

combination was tested very early on. Plasma levels of saqui-

navir can be increased 20-fold by ritonavir. Studies have shown

that the booster combination 400/400 (= 400 mg saquinavir plus

400 mg ritonavir, both twice daily) is virologically the most

effective (Cameron et al. 1999). In patients already taking

saquinavir, boosting may have only moderate effects (Smith et

al. 2001). Boosting of saquinavir in the better tolerated

1000/100 combination has recently been licensed.

When boosting saquinavir, it is worth considering using Invi-

rase

instead of Fortovase

. In a recently published study (Ku-

rowski et al. 2002), boosted levels of saquinavir were even

2. Overview of Antiretroviral Drugs 79

Hoffmann, Kamps, et al.

higher for Invirase

, which is also better tolerated with respect

to gastrointestinal complaints than the subsequently developed

Fortovase

. Interestingly, Invirase

is nearly twice as expensive

as Fortovase

– an issue that the manufacturer Hoffmann-La

Roche might well have to address in the near future, if, as can

be expected, it comes under pressure from patient advocacy

groups.

Table 2.2: Well investigated boosted PI regimens

Dose in mg Pills/day Comment

Saquinavir/

Ritonavir

2 x 1000/100 2 x 6 Officially licensed for boosting

Saquinavir/

Ritonavir

2 x 400/400 2 x 6 Good efficacy, but problematic

due to increased rate of side

effects

Indinavir/

Ritonavir

2 x 800/100 2 x 3 Higher rate of nephrolithiasis (?)

Indinavir/

Ritonavir

2 x 400/400 2 x 5 Good pharmacokinetic data

Lopinavir/

Ritonavir

2 x 400/100 2 x 3

Only fixed combination in one

capsule

Nelfinavir/

Ritonavir

Not recommended

Saquinavir/

Nelfinavir

3 x 600/750 3 x 6 Only well documented booster

combination without ritonavir, but

too many pills three times a day

Amprenavir/

Ritonavir

2 x 600/100 2 x 5 FDA approved

The combination of indinavir/ritonavir is also well investi-

gated. There is good pharmacokinetic data for the 800/100 dose

(Van Heeswijk et al. 1999). In a smaller pilot study with this

combination, however, results showed nephrolithiasis in 19/57

patients (Voigt et al. 2001). The 400/400 dose presumably in-

duces less renal side effects. The combination of indina-

vir/ritonavir seems to be associated with an increased risk of

side effects. In studies such as BEST or NICE, switching from

indinavir to indinavir/ritonavir was shown to have a slightly

80 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

higher rate of side effects and drop-outs (Gatell et al. 2000,

Harley et al. 2001, Shulman et al. 2002).

Lopinavir/ritonavir is to date the only fixed booster combina-

tion therapy available in one capsule (see above). There is good

data for amprenavir/ritonavir, especially for salvage therapy

(Condra 2000, Duval et al. 2002). The FDA approved once

daily dosing for this combination in 2002.

Boosted PIs are probably equivalent with regard to anti-HIV

potency, although only sparse clinical data is as yet available. In

the randomized MaxCmin1 Trial, efficacy of saquinavir and

indinavir was comparable. The drop-out rate in the indinavir

group was significantly higher, and was probably due to a

higher incidence of side effects (Gerstoft et al. 2002). Results

are expected to be published soon of a second trial, the

MaxCmin2 Study, in which both treatment-naive and treatment-

experienced patients were randomized to receive either saqui-

navir/ritonavir or lopinavir/r. Interim analyses have shown that

both combinations have good efficacy and exhibit no great dif-

ferences (Dragstedt et al. 2002). Publication of the final data is

expected in the third quarter of 2003.

Plasma levels even of well-boosted PIs seem to decrease with

duration of treatment. After 10 months, saquinavir levels had

dropped by 40 % in six patients (Gisolf et al. 2000). Plasma

levels must therefore be monitored for all booster combinations,

especially in patients with underlying liver disease, as the extent

of interaction is unpredictable and dose adjustments may be

required.

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86 HIV Therapy 2003

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74. Moyle GJ, Gazzard BG. Finding a role for zalcitabine in the HAART era.

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tunistic infections. N Engl J Med 2001, 344:984-96.

80. Raboud JM, Rae S, Vella S, et al. Meta-analysis of two randomized con-

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combined zidovudine, didanosine, and nevirapine therapy in patients with

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83. Roge BT, Katzenstein TL, Gerstoft J. Comparison of P-triglyceride levels

among patients with HIV on randomized treatment with ritonavir, indinavir

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84. Saag MS, Tebas P, Sension M, et al. Randomized, double-blind com-

parison of two nelfinavir doses plus nucleosides in HIV-infected patients

(Agouron study 511). AIDS 2001, 15:1971-8.

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85. Schooley RT, Ruane P, Myers RA, et al. Tenofovir DF in antiretroviral-

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86. Schrooten W, Colebunders R, Youle M, et al. Sexual dysfunction associ-

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87. Sension MG, Bellos NC, Johnson J, et al. Lamivudine 300 mg QD versus

continued lamivudine 150 mg BID with stavudine and a protease inhibitor

in suppressed patients. HIV Clin Trials 2002, 3:361-70.

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88. Shafer R, Robbins G, Smeaton L, et al. Antiretroviral strategies in naive

HIV+ subjects: comparison of 4-drug versus sequential 3-drug regimens

(ACTG 384). Abstract LbOr20B, XIV International AIDS Conference

2002, Barcelona, Spain.

88 HIV Therapy 2003

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89. Sham HL, Kempf DJ, Molla A, et al. ABT-378, a highly potent inhibitor of

the HIV protease. Antimicrob Agents Chemother 1998, 42:3218-24.

http://amedeo.com/lit.php?id=9835517

90. Shulman N, Zolopa A, Havlir D, et al. virtual inhibitory quotient predicts

response to ritonavir boosting of indinavir-based therapy in HIV-infected

patients with ongoing viremia. Antimicrob Agents Chemother 2002,

46:3907-3916. http://amedeo.com/lit.php?id=12435695

91. Smith D, Hales G, Roth N, et al. A randomized trial of nelfinavir, ritonavir,

or delavirdine in combination with saquinavir-SGC and stavudine in

treatment-experienced HIV-1-infected patients. HIV Clin Trials 2001,

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92. Sommadossi JP. HIV protease inhibitors: pharmacologic and metabolic

distinctions. AIDS 1999, 13 Suppl 1: S29-40.

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93. Squires KE, Gulick R, Tebas P, et al. A comparison of stavudine plus

lamivudine versus zidovudine plus lamivudine in combination with indina-

vir in antiretroviral naive individuals with HIV infection: selection of thymi-

dine analog regimen therapy (START I). AIDS 2000, 14: 1591-600.

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94. Staszewski S, Gallant J, Pozniak AL, et al. Efficacy and saefty of tenofo-

vir disoproxil fumarate versus stavudine when used in combination with

lamivudine and efavirenz in HIV-1 infected patients naive to antiretroviral

therapy: 48-week interim results. Abstract LB17, XIV International AIDS

Conference 2002, Barcelona, Spain.

95. Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus

zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zi-

dovudine and lamivudine in the treatment of HIV-1 infection in adults.

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96. Stellbrink HJ, Hawkins DA, Clumeck N, et al. Randomised, multicentre

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untreated or minimally pretreated hiv-infected patients. Clin Drug Invest

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97. Stellbrink HJ, van Lunzen J, Westby M, et al. Effects of interleukin-2 plus

highly active antiretroviral therapy on HIV-1 replication and proviral DNA

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98. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity

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99. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepa-

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therapy: role of hepatitis C and B infections. Hepatology 2002, 35:182-9.

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100. Suo Z, Johnson KA. Selective inhibition of HIV-1 reverse transcriptase by

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21. http://amedeo.com/lit.php?id=11590519

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103. Van Heeswijk RP, Veldkamp AI, Hoetelmans RM, et al. The steady-state

plasma pharmacokinetics of indinavir alone and in combination with a low

dose of ritonavir in twice daily dosing regimens in HIV-1-infected indi-

viduals. AIDS 1999, 13: F95-9. http://amedeo.com/lit.php?id=10513637

104. Veldkamp AI, Weverling GJ, Lange JM, et al. High exposure to nevira-

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HIV-1-infected individuals. AIDS 2001; 15: 1089-95.

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105. Voigt E, Wickesberg A, Wasmuth JC, et al. First-line ritonavir/indinavir

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106. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfina-

vir for the initial treatment of HIV infection. N Engl J Med 2002, 346:2039-

46. http://amedeo.com/lit.php?id=12087139

107. Wensing AM, Reedijk M, Richter C, Boucher CA, Borleffs JC. Replacing

ritonavir by nelfinavir or nelfinavir/saquinavir as part of HAART leads to

an improvement of triglyceride levels. AIDS 2001, 15:2191-3.

108. Wood R, Hawkins DA, Moyle G, et al. Second placebo-controlled study in

naive individuals confirms the role of delavirdine in highly active antiretro-

viral, protease-sparing treatment. Abstract 624. 6th CROI 1999, Chicago,

USA. http://www.retroconference.org/99/abstracts/624.htm

ART 2003/2004: The Horizon and Beyond

This overview focuses on drugs already well advanced in de-

velopment. In view of the large number of substances currently

being tested, it does not claim to be complete. Some products

are about to be licensed and have been available through ex-

panded access programs. At least four are likely to be approved

within the next one to two years: d4T XR, emtricitabine, fos-

90 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

amprenavir, atazanavir. The new entry-inhibitor T-20 has been

approved in the US in March 2003.

New nukes

Stavudine (Zerit

) will soon be available as d4T XR (extended

release) in a capsulated once-daily formulation (75 mg and 100

mg). The formulation is stable, does not accumulate and seems

to cause less polyneuropathy, possibly due to lower peak levels.

In the BMS 099 Study, d4T XR was tested double-blind (in

combination with lamivudine and efavirenz) against the stan-

dard dose of 2 x 40 mg stavudine daily. At 24 weeks, there were

no differences in efficacy (CD4+ cell count, viral load) and

safety (Pollard et al. 2002). d4T XR was approved by the FDA

on December 31, 2002.

Emtricitabine (Coviracil

, FTC) is a cytidine analog which

was developed by Triangle. It has a very long half-life (once-

daily dosing with 200 mg) and biochemically resembles lami-

vudine. In vitro, it was more effective than lamivudine, but this

has not been confirmed in humans (Delehanty et al. 1999). Its

advantage over lamivudine is questionable since its efficacy is

also completely impaired with the M184V point mutation.

Newer data from the FTC-301 Trial might lead to drug approval

in 2003 (Saag et al. 2002): In this double-blind, randomized

study, emtricitabine and stavudine, both in combination with

didanosine and efavirenz, were compared in 571 treatment-

naive patients. The study was stopped after a mean follow-up of

42 weeks. After this period, the probability for virologic failure

after one year, estimated by Kaplan-Meier curve, was 14 % in

the stavudine group versus 6 % in patients receiving emtrici-

tabine; the study investigators considered the difference great

enough to prematurely end the trial. Toxicity was also higher in

the stavudine group. In the Montana Study, the good tolerability

of a once-daily combination with emtricitabine, didanosine and

efavirenz seems to be confirmed (Molina et al. 2001). After the

acquisition of Triangle by Gilead, the development of a fixed

2. Overview of Antiretroviral Drugs 91

Hoffmann, Kamps, et al.

combination of emtricitabine and tenofovir in one single tablet

is planned.

DAPD (Amdoxovir) is a guanine analog developed by Trian-

gle. DAPD is converted in vivo to the highly potent DXG. It is

currently being tested in Phase I/II studies (Corbett et al. 2001).

DAPD is effective against zidovudine/lamivudine-resistant vi-

ruses, including viruses with an insertion at codon 69, which

confers multi-resistance against all nucleoside analogs. Sensi-

tivity seems reduced in the presence of mutations such as K65R

and L74V (Chong et al. 2002, Mewshaw et al. 2002). In cell

cultures the drug has synergistic effects with the fusion inhibitor

T-20, which could be useful in the future (Trembley et al.

2002). Equally pleasing is its good efficacy against hepatitis B

viruses. Reports on possible lens anomalies are less satisfying.

Although the association with DAPD is not yet certain, the

company was immediately required by the FDA to study this

issue further before continuation of trials.

A look into the lab – Experiments in cell cultures have shown

that DPC 817, a new oral cytidine analog from BMS with a

long half-life, is very effective in the presence of zi-

dovudine/lamivudine resistance mutations (Schinazi et al.

2002). The same appears to be true for ACH-126,443 (Beta-L-

Fd4C), an enantiomer of DPC 817, developed by Achillion

Pharmaceuticals. It would appear to allow once-daily dosing

and also to be effective against multi-resistant HIV strains and

against hepatitis B viruses. Phase IB studies in HIV infected

patients are being performed for both drugs. There was similar

news of BCH-13520, a drug by Shire BioChem Inc. In this

case, however, first reports of resistance mutations (Q15M and

the insertion at codon 69) have been published (Bethell et al.

2002). MIV-301 (Alovudine, FLT) is a thymidine analog,

which was initially tested in the 80s but abandoned at the time,

mainly due to myelotoxicity. MIV-301 could be celebrating a

comeback, as it seems to have excellent efficacy against nuke-

resistant viruses (Kim et al. 2001).

92 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

Out of sight, out of mind: The following drugs are currently

not being pursued, as they are either too toxic or have poor effi-

cacy:

Adefovir dipivoxil (bis POM PMEA) from Gilead Sciences

dOTC (BCH-10652) from BioChem Pharma

FddA (Beta-fluoro-ddA, Lodenosine

) from US Bioscience

Lobucavir from BMS

New NNRTIs

Even more than with any other drug class, the industry has the

following motto: If one cannot come up with a new drug that is

at least effective against efavirenz- and nevirapine-resistant vi-

ruses, one might as well not continue with the research. “Me-

too” drugs are not needed. In the meantime various drugs have

already been abandoned; the road to approval is especially long

and hard for NNRTIs, even though they are relatively cheap to

develop. Many of the drugs featured below will therefore not

reach market development.

TMC 125 is a new second generation NNRTI. It is effective

against both wild-type viruses and viruses with almost all of the

classical NNRTI mutations (such as K103N, Y181C). In a

Phase IIB study, in which 16 patients on stable ART mostly

with several NNRTI mutations were treated with 900 mg TMC

125 BID for 7 days, the viral load dropped by a median 0.9 log,

and in some cases up to 1.7 log (Gazzard et al. 2002, Sankatsing

et al. 2002). Even after this timepoint, viral load continued to

decrease. TMC 125 was well tolerated. The half-life is long,

and the drug is metabolized in the liver. Although first pharma-

cokinetic data indicates unfavorable interactions with PIs (espe-

cially indinavir and saquinavir), TMC 125 appears to be devel-

oping into a strong and promising drug, with a high genetic bar-

rier.

DPC 083 is a second generation NNRTI, which is also said to

be effective against NNRTI-resistant viruses. In a Phase II

study, in which the drug was tested in two doses of 100 and 200

2. Overview of Antiretroviral Drugs 93

Hoffmann, Kamps, et al.

mg qd in patients with NNRTI treatment failure (viral load >

1000 copies/ml), 4/10 patients who, based on the resistance pro-

file, received DPC 083 as the only effective drug, achieved a

viral load of < 400 copies/ml (Ruiz et al. 2002). However, the

data from this study was unsatisfactory. There was no data on

resistance mutations in these patients, and no clear dose effect

with regard to both effectiveness and side effects. In a previous

“early” Phase III study, which had compared three different

doses of DPC 083 double-blind (50 mg, 100 mg, 200 mg) in

some 100 treatment-naive patients, the effect against wild-type

viruses was comparable to that of efavirenz. The side effects

seemed to be less.

GW420867X is a quinoxaline-NNRTI from GlaxoSmithKline,

which has been shown to be quite effective in vivo in combina-

tion with zidovudine and lamivudine (Arasteh et al. 2001). It

has good CNS penetration and would probably be a candidate

for once-daily dosing (Thomas et al. 2000). As monotherapy,

GW420867X decreased viral load by 1.5 log after 8 days, and

there were no differences mong the various doses investigated

(50 mg, 100 mg, 200 mg). The side effects – neurological, gas-

trointestinal, hepatic – resemble the typical NNRTI complaints;

rash was uncommon. However, cross-resistance seems to exist

to nevirapine and efavirenz, and it is to be expected that devel-

opment will be stopped.

Capravirine (AG1549, previously S-1153) is a relatively well-

advanced NNRTI, which was initially developed by Shionogi

Pharmaceuticals (Fujiwara et al. 1998) and subsequently sold to

Agouron. Capravirine is effective in vivo even against viruses

with the K103N mutation (Wolfe et al. 2001) and was therefore

a hopeful candidate in the battle against NNRTI-resistant vi-

ruses. After animal studies in dogs showed an unusually high

rate of vasculitis after higher doses, Agouron stopped all Phase

II/III clinical trials last year. Safety evaluations have now

shown that capravirine does not cause such side effects in hu-

mans (Hawley et al. 2002), and in the meantime development

will continue. The dose will probably be set at 2 x 700 mg/day.

94 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

Emivirine (EMV, MKC-442, Coactinon) is an NNRTI which

requires twice-daily dosing and has good tolerability (Szczech

et al. 2000). The main side effects are nausea and the efavirenz-

typical dizziness. In a study of patients with relatively low

treatment experience, efficacy was good; 82 % of patients had a

viral load below 400 copies/ml at 16 weeks, on a combination

of stavudine, didanosine and emivirine (Johnson et al. 1999).

Unfortunately, the drug seems to be a “me-too” product. There

are no differences when compared to the other NNRTIs, and

significant cross-resistance (Jeffrey et al. 1999, McCreedy et al.

1999) and PI-interactions (Blum et al. 1998) exist. Further de-

velopment seems uncertain; the FDA has deemed the available

data insufficient for approval.

Out of sight, out of mind - The following NNRTIs are cur-

rently not being pursued, as they are either too toxic or have

poor efficacy:

Calanolide A from Sarawak MediChem Pharmaceu-

ticals

Atevirdine from Upjohn

Loviride from Janssen Pharmaceuticals

HBY-097 from Hoechst-Bayer

PNU142721 from Pharmacia & Upjohn

New protease inhibitors (PIs)

Fos-amprenavir (GW433908) is a calcium phosphate-ester of

amprenavir with better solubility and resorption than the parent

compound. It is generally well tolerated, and patients would

have to take either 2 x 1 or 1 x 2 pills daily when fos-

amprenavir is boosted with ritonavir. This compares favorably

with the unacceptable 8 pills bid of standard amprenavir dos-

age.

In the NEAT Study (APV30001), fos-amprenavir is currently

being compared with nelfinavir in treatment-naive patients

(Rodriguez et al. 2002). 251 patients were randomized open-

label to fos-amprenavir or nelfinavir, with a nuke backbone of

2. Overview of Antiretroviral Drugs 95

Hoffmann, Kamps, et al.

lamivudine and abacavir. Preliminary 24-week data shows that

54 % versus 40 % of patients (ITT) reached an undetectable

viral load. The difference in efficacy was more pronounced in

patients with a high viral load. There was also less diarrhea in

the fos-amprenavir group. As a potent inductor of amprenavir

metabolism, efavirenz can significantly lower plasma levels.

This does not happen when fos-amprenavir is boosted with rito-

navir, as a study recently demonstrated (Wire et al. 2002): 32

healthy volunteers received one dose of fos-amprenavir with

either 100 mg ritonavir bid, 100 mg ritonavir bid plus efavirenz,

or 200 mg ritonavir bid plus efavirenz. Overall, the outcomes

were similar. In brief: efavirenz does not change anything if

ritonavir is given in addition to fos-amprenavir. Even 100 mg

ritonavir significantly influences plasma levels; 200 mg neither

cause more side effects nor achieve further increases in plasma

levels, although lipid levels may increase slightly.

Atazanavir (Reyataz

) is a once-daily PI with a favorable lipid

profile (Robinson et al. 2000) and an antiviral potency which

seems comparable to that of nelfinavir (Squires et al. 2001,

Cahn et al. 2001). The 400 mg dose is currently being tested in

phase III studies (Piliero et al. 2002). Recently, data from a

large study comparing atazanavir with efavirenz (with

AZT+3TC as the nuke backbone) was presented (Squires et al.

2002). There were no differences with regard to virological re-

sponse. However, the proportion of patients with < 50 copies/ml

was very low in both groups, which is likely to be a methodo-

logical problem in this (probably too large) trial. Lipid levels

were clearly better in the atazanavir than in the efavirenz group.

The primary resistance-conferring mutation for this drug seems

to be 150L; this mutation does not interfere with sensitivity to

other PIs (including amprenavir) and may possibly even im-

prove it. Interestingly, amprenavir selects for another mutation

exactly at this codon – 150V; the drug thus seems to select on a

different basis than amprenavir (Colonno et al. 2002).

Based on the available data, atazanavir could become a good

option for initial therapy. The drug is already available in an

96 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

expanded access program and will probably be approved in

2003.

Increases in bilirubin levels seem to be a frequent problem. The

mechanism for this resembles that of the Gilbert syndrome (and

the increased levels with indinavir); there are increased levels of

indirect bilirubin due to reduced conjugation in the liver. Al-

though to date no serious hepatic disorders have been described,

liver function should be monitored.

Studies of drug interactions in healthy volunteers have shown

that rifabutin does not significantly influence atazanavir levels.

In contrast, efavirenz may lower plasma levels due to enzyme

induction, probably through induction of CYP3A4 (Preston et

al. 2002). Concomitant therapy with efavirenz will therefore

require an increased dose of atazanavir. Adding 200 mg of rito-

navir when giving efavirenz can diminish this effect, presuma-

bly also counteracting any favorable effects on lipid levels.

Tipranavir is the first non-peptide protease inhibitor and shows

good efficacy against PI-resistant viruses (Larder et al. 2000).

In a study of 41 patients previously treated with at least two PIs,

tipranavir still showed efficacy in 35 patients (Schwartz et al.

2002). Only the combination of the V82T and L33 point muta-

tions led to a reduction in sensitivity. Oral bioavailability of

tipranavir is not very good, and it always requires ritonavir

boosting (inhibition of the CYP3A4 system), as a trial in 113

HIV negative volunteers has shown. Ritonavir increases Cmax

at least 4-fold and Cmin at least 20-fold.

Mozenavir (DMP-450) is a cyclic PI with good solubility,

which was initially developed by Dupont and has now been

sold to Triangle. The required dose will probably enable manu-

facture of a single pill (Sierra-Madero 2001). A disadvantage of

the drug is its short half-life. As with indinavir, three daily

doses will probably be necessary; the resistance profile is also

similar. In a small Phase I/II study in 50 patients, virological

efficacy was comparable to indinavir. Fortunately, the longer

QT-intervals, which had occurred in dogs, were not observed.

2. Overview of Antiretroviral Drugs 97

Hoffmann, Kamps, et al.

Numerous other PIs are already in early clinical trials. Exam-

ples include the drugs TMC 114 and TMC 126 from Tibotec,

which should be effective especially against PI-resistant vi-

ruses. First Phase II trials are ongoing

References: New Nukes, NNRTIs, PIs

1. Arasteh K, Wood R, Muller M, et al. GW420867X administered to HIV-1-

infected patients alone and in combination with lamivudine and zi-

dovudine. HIV Clin Trials 2001, 2:307-16.

http://amedeo.com/lit.php?id=11590533

2. Bethell RC, Allard B, De Muys JM, et al. BCH-13520, a new heterosub-

stituted nucleoside analogue, is an effective inhibitor of drug-resistant

HIV-1. Abstract 386, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13340.htm

3. Blum MR, Moxham CP, Kargl DJ, et al. A pharmacokinetic interaction

evaluation of MKC-442 and nelfinavir in healthy male and female volun-

teers. Abstract 12380, 12th International AIDS Conference 1998, Ge-

neva, Switzerland.

4. Cahn P, Percival L, Phanuphak P, et al. Phase II 24-week data from

study AI424-008: Comparative results of BMS-232632, stavudine, lami-

vudine as HAART for treatment-naive HIV-infected patients. Abstract 5,

1st IAS Conference on HIV Pathogenesis and Treatment 2001, Buenos

Aires, Argentina.

5. Chong Y, Borroto-Esoda K, Furman PA, Schinazi RF, Chu CK. Molecular

mechanism of DAPD/DXG against zidovudine- and lamivudine-drug re-

sistant mutants: a molecular modelling approach. Antivir Chem Chemo-

ther 2002, 13:115-28. http://amedeo.com/lit.php?id=12238529

6. Colonno RJ, Friborg J, Rose RE, Lam E, Parkin N. Identification of amino

acid substitutions correlated with reduced atazanavir susceptibility in pa-

tients treated with atazanavir-containing regimens. Antiviral Ther 2002,

7:S4. Abstract 4.

7. Corbett AH, Rublein JC. DAPD. Curr Opin Investig Drugs 2001, 2:348-53.

http://amedeo.com/lit.php?id=11575703

8. Delehanty J, Wakeford C, Hulett L, et al. A phase I/II randomized, con-

trolled study of FTC versus 3TC in HIV-infected patients. Abstract 16, 6th

CROI 1999, Chicago, USA.

9. Fujiwara T, Sato A, el-Farrash M, et al. S-1153 inhibits replication of

known drug-resistant strains of HIV-1. Antimicrob Agents Chemother

1998, 42:1340-5. Original-Artikel

http://aac.asm.org/cgi/content/full/42/6/1340?view=full&pmid=9624472

10. Gazzard B, Pozniak A, Arasteh K, et al.TMC125, A next-generation

NNRTI, demonstrates high potency after 7 days therapy in treatment-

experienced HIV-1-infected individuals with phenotypic NNRTI resis-

tance. Abstract 4, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/14022.htm

98 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

11. Hawley P, Diniz-Piraino S, Paxton W. et al. Absence of risk of vasculitis

in a hiv population taking capravirine-results of an active monitoring plan.

Abstract TuPeB4549. XIV International AIDS Conference 2002, Barce-

lona, Spain

12. Jeffrey S, Corbett J, Bacheler L. In vitro NNRTI resistance of recombinant

HIV carrying mutations observed in efavirenz treatment failures. Abstract

110, 6th CROI Chicago 1999, USA.

13. Johnson D, Sanne I, Baraldi E, et al. A phase II, open-label study to

evaluate the antiviral activity, safety, and tolerability of emivirine (EMV,

MKC-442) and stavudine + didanosine. Abstract 502, 39th ICAAC 1999,

San Francisco, USA.

14. Kim EY, Vrang L, Oberg B, Merigan TC. Anti-HIV type 1 activity of 3'-

fluoro-3'-deoxythymidine for several different multidrug-resistant mutants.

AIDS Res Hum Retroviruses 2001, 17:401-7.

http://amedeo.com/lit.php?id=11282008

15. Larder BA, Hertogs K, Bloor S, et al. Tipranavir inhibits broadly protease

inhibitor-resistant HIV-1 clinical samples. AIDS 2000, 14:1943-8.

http://amedeo.com/lit.php?id=10997398

16. McCallister S, Sabo J, Galitz L, Mayers D. An open-label steady state

investigation of the pharmacokinetics of tipranavir and ritonavir and their

effects on cytochrome P-450 (3A4) activity in normal healthy volunteers

(BI 1182.5). Abstract 434, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13434.htm

17. McCreedy B, Borroto-Esoda K, Harris J, et al. Genotypic and phenotypic

analysis of HIV-1 from patients receiving therapy containing two NRTIs in

combination with the NNRTI, emivirine (MKC-442). Abstract 1173, 39th

ICAAC 1999, San Francisco, USA.

18. Mewshaw JP, Myrick FT, Wakefield DA, et al. Dioxolane guanosine, the

active form of the prodrug diaminopurine dioxolane, is a potent inhibitor of

drug-resistant HIV-1 isolates from patients for whom standard nucleoside

therapy fails. J Acquir Immune Defic Syndr 2002, 29:11-20.

http://amedeo.com/lit.php?id=11782585

19. Molina J, Perusat S, Ferchal F, et al. Once-daily combination therapy with

emtricitabine, didanosine and efavirenz in treatment-naive HIV-infected

adults: 64-week follow-up of the ANRS 091 trial. Abstract 321, 8th CROI

2001, Chicago, USA.

20. Piliero P, Cahn C, Pantaleo G, et al. Atazanavir: A Once-Daily Protease

Inhibitor with a Superior Lipid Profile: Results of Clinical Trials Beyond

Week 48. Abstract 706, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13827.htm

21. Pollard R, Ive P, Farthing C, et al. Stavudine XR vs stavudine IR as part

of potent antiretroviral combination therapy: 24-week safety and antiviral

efficacy. Abstract 411, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13559.htm

22. Preston S, Piliero P, O'Mara E, et al. Evaluation of steady-state interac-

tion between atazanavir and efavirenz. Abstract 443, 9th CROI 2002, Se-

attle, USA. http://63.126.3.84/2002/Abstract/13543.htm

2. Overview of Antiretroviral Drugs 99

Hoffmann, Kamps, et al.

23. Robinson BS, Riccardi KA, Gong YF, et al. BMS-232632, a highly potent

HIV protease inhibitor that can be used in combination with other avail-

able antiretroviral agents. Antimicrob Agents Chemother 2000, 44:2093-

2099. Original-Artikel:

http://aac.asm.org/cgi/content/full/44/8/2093?view=full&pmid=10898681

24. Rodriguez-French A, Nadler J, and the Neat Study Team. The NEAT

Study: GW433908 efficacy and safety in anti-retroviral therapy naive

subjects, preliminary 24-week results. Abstract H-166, 42th ICAAC 2002,

San Diego, USA.

25. Ruiz N, Nusrat R, Lauenroth-Mai E, et al. Study DPC 083-203, a phase II

comparison of 100 and 200 mg once-daily DPC 083 and 2 NRTIs in pa-

tients failing a NNRTI-containing regimen. Abstract 6, 9th CROI 2002,

Seattle, USA. http://63.126.3.84/2002/Abstract/13700.htm

26. Saag M, Cahn P, Raffi F, et al. A randomized, double-blind, multicenter

comparison of emtricitabine QD to stavudine BID. Abstract LB1, 42nd

ICAAC 2002, San Diego, USA.

27. Sankatsing S, Weverling G, van't Klooster G, et al. TMC125 monotherapy

for 1 week results in a similar initial rate of decline of HIV-1 RNA as ther-

apy with a 5-drug regimen. Abstract 5, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13427.htm

28. Schinazi RF, Mellors J, Bazmi H, et al. DPC 817: a cytidine nucleoside

analog with activity against zidovudine- and lamivudine-resistant viral

variants. Antimicrob Agents Chemother 2002, 46:1394-401.

http://amedeo.com/lit.php?id=11959574

29. Schwartz R, Kazanjian P, Slater L. Resistance to tipranavir is uncommon

in a randomized trial of tipranavir/ritonavir in multiple PI-failure patients

(BI 1182.2). Abstract 562, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13757.htm

30. Sierra-Madero J. Antiviral activity, safety and phamacokinetics of moze-

navir (DMP 450), a novel cyclic urea protease inhibitor, in combination

with d4t and 3tc in treatment-naïve hiv-1 infected patients (study DMP-

102). Abstract 2, 1st IAS Conference on HIV Pathogenesis and Treat-

ment 2001, Buenos Aires, Argentina.

31. Squires K, Gatell J, Piliero P, et al. AI424-007: 48-week safety and effi-

cacy results from a phase II study of a once-daily HIV-1 protease inhibi-

tor, BMS-232632. Abstract 15, 8th CROI 2001, Chicago, USA.

32. Squires KE, Thiry A, Giordano M, for the AI424-034 International Study

Team. Atazanavir QD and efavirenz QD with fixed-dose ZDV+3TC:

Comparison of antiviral efficacy and safety through wk 24 (AI424-034).

Abstract H-1076, 42nd ICAAC 2002, San Diego, USA.

33. Szczech GM, Furman P, Painter GR, et al. Safety assessment, in vitro

and in vivo, and pharmacokinetics of emivirine, a potent and selective

nonnucleoside reverse transcriptase inhibitor of HIV type 1. Antimicrob

Agents Chemother 2000, 44:123-30.

http://amedeo.com/lit.php?id=10602732

100 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

34. Thomas S, Cass L, Prince W, Segal M. Brain and CSF entry of the novel

non-nucleoside reverse transcriptase inhibitor, GW420867X. Neuroreport

2000, 11:3811-5. http://amedeo.com/lit.php?id=11117496

35. Tremblay C, Poulain D, Hicks JL, et al. T-20 and DAPD have synergistic

in vitro anti-HIV interactions. Abstract 393, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13137.htm

36. Wire MB, Ballow C, Preston S, et al. An assessment of plasma amprena-

vir pharmacokinetics following administration of two GW433908 and rito-

navir regimens in combination with efavirenz in healthy adult subjects

(APV10010). Abstract 443, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13503.htm

37. Wolfe P, Hawley P, Boccia G, et al. Safety and efficacy of capravirine

versus placebo in HIV-infected patients failing a NNRTI-containing regi-

men: results of a phase II, double blind, placebo controlled trial. Abstract

323, 8th CROI 2001, Chicago, USA.

http://www.retroconference.org//2001/abstracts/abstracts/abstracts/323.ht

Entry inhibitors

There are three crucial steps for entry of HIV into the CD4+ T

cell:



binding of HIV to the CD4 receptor (“attachment” – target

of attachment inhibitors),



binding to co-receptors (target of co-receptor antagonists),

and finally



fusion of virus and cell (target of fusion inhibitors).

All three drug classes are currently summarized as entry in-

hibitors. Even if the antiviral effects of the drugs now being

tested are not overwhelming, the availability of new drugs with

different mechanisms of action could open up new possibilities

for the treatment of HIV infection.

Attachment inhibitors

BMS-806 is an “early” attachment inhibitor, which, independ-

ently of co-receptors, binds to HIV gp120 specifically and re-

versibly, and so prevents the attachment of HIV to CD4+ T-

lymphocytes (Lin et al. 2002). It has oral bioavailability with

low plasma protein binding and could probably be taken in

2. Overview of Antiretroviral Drugs 101

Hoffmann, Kamps, et al.

tablet form. Animal studies have shown good tolerability. There

is hope that there might be an additive, perhaps even synergistic

effect with other entry inhibitors. Enthusiasm about this drug

have been slightly dampened by the demonstration that differ-

ent HIV isolates have shown differences in sensitivity to BMS

806, indicating potential rapid development of resistance.

Pro-542 is a soluble antibody-like fusion protein, which also

prevents attachment of HIV to CD4+ T-lymphocytes by binding

to gp120. Phase I studies have shown good tolerability, and vi-

ral load decreased even after a single infusion (Jacobson et al.

2000). Pro-542 has already been tested in children (Shearer et

al. 2000). In the SCID mouse model, Pro-542 has shown re-

markable efficacy (Franti et al. 2002). However, the impractical

route of administration (infusion) must be improved.

Co-receptor antagonists

SCH-C is a CCR5-receptor antagonist with oral bioavailability

and a potent in vitro activity against numerous HIV isolates

(Strizki et al. 2001). In healthy volunteers, side effects such as

arrhythmias (longer QT-interval) occurred mainly at higher

doses. This problem appears to be absent with low dosage, and

the FDA has given the go-ahead for further development. A

pilot study in 12 HIV patients, who received SCH-C for 10 days

(the dose was significantly reduced to 2 x 25 mg/daily) showed

that all 10 patients had a decrease in viral load of more than 0.5

log, and 4 patients of more than 1.0 log (Reynes et al. 2002).

This effect persisted even a few days after completion of ther-

apy. However, viral escape mutants have already been de-

scribed for SCH-C, which are cross-resistant to other CCR5-

receptor antagonists (Riley et al. 2002, Xu et al. 2002). SCH-D

is claimed to be more potent and better tolerated than SCH-C,

and therefore seems to have better chances for further develop-

ment (Chen et al. 2002). However, first reports have described

development of resistance, probably via changes in the HIV env

gene.

102 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

Pro-140 is a CCR5-antagonist, which acts as a monoclonal an-

tibody (Trkola et al. 2001). In animal studies (SCID mouse

model), single doses of the drug achieved significant and dose-

related reductions in viral load. (Franti et al. 2002). Clinical

data is still lacking, and there is no information on tolerability.

AMD-3100 is a CXCR4-receptor antagonist as is T-22. Results

to date could be described as discouraging. In a complicated

study with 12 patients, who received a continuous infusion over

10 days, no reduction of viral load occurred. In addition, a vari-

ety of side effects such as thrombocytopenia, orthostasis and

arrhythmias were experienced (Hendrix et al. 2002). However,

AMD-3100 appears to be effective against CXCR4-receptor-

tropic viruses (Schols et al. 2002, van Rij et al. 2002). The one

patient who exclusively harbored such a virus population was

the only one to show a decrease in viral load by 0.87 log after

11 days, and 1.34 log after 18 days. Resistance mutations have

been described both for AMD-3100 and T-22. Whether devel-

opment of AMD-3100 will be pursued is uncertain. Follow-on

drugs, possibly for oral administration, are apparently being

studied.

Fusion inhibitors

T-20 (Enfuvirtide, Fuzeon

): Hardly a day goes by without

mention of T-20 in the media, and every other patient asks him-

or herself and the physician, why he or she is not yet receiving

the “new drug”. T-20 is the prototype of fusion inhibitors. It is a

relatively large peptide, comprised of 36 amino acids, and must

therefore be given by subcutaneous injection like insulin. It

binds to an intermediate structure of the HIV gp41-protein,

which appears during entry of HIV into the target cell, i.e. dur-

ing fusion.

In one of the first studies with T-20, HIV patients were given

different doses intravenously as monotherapy. There was a

dose-related effect, and with the higher dose of 2 x 100 mg per

day, median viral load was reduced by almost 2 log (Kilby et al.

1998). Because of the impracticability of twice-daily infusion,

2. Overview of Antiretroviral Drugs 103

Hoffmann, Kamps, et al.

the first study using subcutaneous application was initiated

shortly afterwards. 78 highly treatment-experienced patients

received T-20 in addition to stable HAART – either via an in-

sulin pump or twice-daily subcutaneously (Kilby et al. 2002).

Again, positive dose-related effects on viral load were shown in

both groups. However, maximal suppression was lower than

with infusions, and the maximum decrease was 1.6 log. More

importantly, the effect was short-lived; after 28 days, in most

cases viral load had returned to baseline levels. The main side

effects in this study were reactions (mostly mild) at the injec-

tion site.

Long-term evaluations have shown that the drug is also well

tolerated over longer periods of time (Lalezari et al. 2000). In

the T20-205 Study, 70 patients, mostly PI-experienced, re-

ceived 2 x 50 mg T-20 subcutaneously daily for 48 weeks. Only

few patients discontinued treatment prematurely due to side

effects. After 48 weeks, a constant effect on viral load was still

evident in at least one third of patients, but it became evident

that T-20 was of more benefit to patients who received other

new drugs for HAART at initiation of T-20. In the first Phase II

study (T20-206) for which 48-week data is available, the strat-

egy was therefore changed: 71 NNRTI-naive patients received

different doses of T-20 in addition to a new ART regimen (Lal-

ezari et al. 2002). In this study, the additional effect of T-20 was

weaker, but still present, although the study was not intended to

show differences between the individual groups. Nevertheless,

this study demonstrated that the simple addition of T-20 to an

otherwise unchanged treatment regimen would not be that bene-

ficial. Approximately two thirds of the T-20 patients in this

study had local reactions (mostly mild) at the injection site. T-

20 was generally well tolerated.

The preliminary and actually unexpected good data from the

first Phase III studies led to considerable media attention for T-

20 during the summer of 2002 (Henry et al. 2002, Clotet et al.

2002). TORO 1 (“T-20 versus optimized regimen only”, previ-

ously T20-301 Study) enrolled 491 patients in North America

104 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

and Brazil. Patients were randomized 2:1 to receive 2 x 90 mg

T-20 subcutaneously or not, on an optimized HAART regimen

(Henry et al. 2002). Almost all patients were heavily pre-treated

and harbored multiresistant viruses at entry. Again, the results

were astounding: The addition of T-20 clearly reduced viral

load compared to the optimized therapy “only”. At 24 weeks,

the reduction of viral load was 1.70 log in the T-20group, com-

pared to 0.76 log in the controls – a surprising difference of

0.93 log. In TORO 2 (T20-302), the same design was tested in

504 patients in Europe and Australia (Clotet et al. 2002). The

difference at 24 weeks was 1.43 versus 0.65 log – still a differ-

ence of 0.78 log.

Summary, evaluation and prospects of T-20: Patients with a

well-controlled viral load or who still have options with “classi-

cal” HAART would probably not require T-20 immediately.

For salvage therapy, however, the drug seems to be quite useful.

It must be stressed, however, that even in this setting wonders

cannot be achieved, the antiviral effect after one year being just

about one log. Although there is still no data from studies with

clinical endpoints, patients who currently have no other treat-

ment options might benefit clinically from this drug.

T-20 has been approved in the US in March 2003. The drug will

presumably not be available for all patients immediately, as

there are considerable logistical problems that still need to be

solved in manufacturing. According to Roche, this is one of the

most complicated drugs that the company has ever manufac-

tured: 106 steps are necessary for synthesis. This will presuma-

bly translate into high product pricing; one can thus expect that

the cost of a T-20-containing HAART regimen will be double

that of one without.

T-20 is certainly not as sensational as it has been portrayed over

the last 12 months. From a medical point of view, it is a major

breakthrough that this mechanism of action for inhibiting viral

replication actually works. A combination of different entry

inhibitors, which would hopefully act synergistically, both with

2. Overview of Antiretroviral Drugs 105

Hoffmann, Kamps, et al.

each other and with HAART, will likely inhibit HIV replication

more efficiently than traditional HAART.

T-1249 is the second fusion inhibitor to be developed and is

possibly more promising than T-20. T-1249 is a peptide that

binds to the hairpin-structure of the HIV envelope protein gp41

and consequently prevents fusion of the viral and host cell

membranes. The drug has favorable pharmacokinetics with a

once-daily dose as well as activity against T-20-resistant viruses

(Lambert et al. 1999). So far data is available from a Phase I/II

study (Eron et al. 2001, Gulick et al. 2002). 72 heavily pre-

treated HIV patients received T-1249 as monotherapy subcuta-

neously for 14 days, in doses ranging from 6.25 mg to 50 mg

per day (as a once- or twice-daily dose). A dose-related reduc-

tion of viral load was observed (maximum reduction – 1.4 log

with the 50 mg dose), with the plateau not yet reached. 40 % of

patients experienced a local reaction at the injection site; one

patient developed grade 4 neutropenia. Whether the one patient

who acquired a rash with fever had a hypersensitivity reaction

is still unclear. Selection of T-1249-resistant isolates is possible

in vitro.

Integrase inhibitors

The integrase is one of the three key enzymes encoded by the

HIV pol gene. This enzyme is involved in integration of viral

DNA into the host genome (Nair 2002). Integrase inhibitors

differ from entry inhibitors as they do not prevent entry of the

virus into the cell. Although human cells probably do not have

an integrase, the development of new and effective drugs in this

class is proving difficult, and progress is slow (Debyser et al.

2002). A good number of drugs have appeared over the last

years, only to disappear again just as quickly.

S-1360, which was developed by Shionogi/Glaxo, shows initial

promising data (Yoshinaga et al. 2002). In vitro (using an MTT

assay), S-1360 is effective against a variety of isolates, includ-

ing all NRTI- and PI-resistant mutants. There seems to be syn-

ergy with zidovudine, lamivudine, nevirapine and nelfinavir. In

106 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

animal studies (mice, rats, dogs), the drug has so far shown lit-

tle toxicity. The molecule is small, so that oral dosing is likely

to be possible. The drug was well tolerated in healthy volun-

teers (Fujiwara 2002).

Merck has also been working on integrase inhibitors. After

some difficulties, the first prototypes are now ready for testing

in clinical trials (Hazuda 2002). A new class, the naphthyridine-

7-carboxamides, shows good oral bioavailability. L-870812 and

L-870810 are currently the most promising drugs in this class.

In an animal model in SIV-infected monkeys, viral load de-

creased in 4 of 6 animals by more than one log. Phase I trials

were started based on this data.

References: Entry inhibitors, integrase inhibitors

1. Chen Z, Hu B, Huang W. HIV-1 mutants less susceptible to SCH-D, a

novel small-molecule antagonist of CCR5. Abstract 396, 9

CROI 2002,

Seattle, USA. http://63.126.3.84/2002/Abstract/13946.htm

2. Clotet B, Lazzarin A, Cooper D, et al. Enfuvirtide (T-20) in combination

with an optimized background (OB) regimen vs. OB alone in patients with

prior experience resistance to each of the three classes of approved

antiretrovirals in Europe and Australia. Abstract LbOr19A, XIV Interna-

tional AIDS Conference 2002, Barcelona, Spain.

3. Debyser Z, Cherepanov P, Van Maele B, et al. In search of authentic

inhibitors of HIV-1 integration. Antivir Chem Chemother 2002, 13:1-15.

http://amedeo.com/lit.php?id=12180645

4. Eron J, Merigan T, Kilby M, et al, for the T1249-101 Study Group. A 14-

day assessment of the safety, pharmacokinetics, and antiviral activity of

T-1249, a peptide inhibitor of membrane fusion. Abstract 14, 8th CROI

2001, Chicago, USA.

5. Franti M, Nagashima K, Maddon P, et al. The CCR5 co-receptor inhibitor

PRO 140 effectively controls established HIV-1 infection in vivo. Abstract

403, 9

CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13641.htm

6. Franti M, O’Neill T, Maddon P, et al. PRO 542 (CD4-IgG2) has a pro-

found impact on HIV-1 replication in the Hu-PBL-SCID mouse model. Ab-

stract 401, 9

CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13664.htm

7. Fujiwara T. Phase 1 multiple oral dose safety and pharmacokinetic study

of S-1360, an HIV integrase inhibitor with healthy volunteers. Abstract

TuPeB4431, XIV International AIDS Conference 2002, Barcelona, Spain.

8. Franti M, O’Neill T, Maddon P, et al. PRO 542 (CD4-IgG2) has a pro-

found impact on HIV-1 replication in the hu-PBL-SCID mouse model. Ab-

2. Overview of Antiretroviral Drugs 107

Hoffmann, Kamps, et al.

stract 401, 9

CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13664.htm

9. Gulick R, Eron J, Bartlett JA, et al. Complete analysis of T1249-101:

Safety, pharmacokinetics, and antiviral activity of T-1249, a peptide in-

hibitor of HIV membrane fusion. Abstract H-1075, 42nd ICAAC, San Di-

ego, USA.

10. Hazuda D. Integrase inhibitors. Abstract MoOrA137, XIV International

AIDS Conference 2002, Barcelona, Spain.

11. Hendrix C, Collier AC, Lederman M, et al. AMD-3100 CXCR4 receptor

blocker fails to reduce HIV viral load by > 1 log following 10-day continu-

ous infusion. Abstract 391, 9

CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13704.htm

12. Henry K, Lalezari J, O'Hearn M, et al. Enfuvirtide (T-20) in combination

with an optimized background (OB) regimen vs. OB alone in patients with

prior experience resistance to each of the three classes of approved

antiretrovirals in North America and Brazil. Abstract LbOr19B, XIV Inter-

national AIDS Conference 2002, Barcelona, Spain.

13. Jacobson JM, Lowy I, Fletcher CV, et al. Single-dose safety, pharmacol-

ogy, and antiviral activity of the HIV type 1 entry inhibitor PRO 542 in

HIV-infected adults. J Infect Dis 2000, 182:326-329.

http://amedeo.com/lit.php?id=10882617

14. Kilby JM, Hopkins S, Venetta TM, et al. Potent suppression of HIV-1

replication in humans by T-20, a peptide inhibitor of gp41-mediated virus

entry. Nat Med 1998, 4:1302-1307.

http://amedeo.com/lit.php?id=9809555

15. Kilby JM, Lalezari JP, Eron JJ, et al. The safety, plasma pharmacokinet-

ics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide in-

hibitor of gp41-mediated virus fusion, in HIV-infected adults. AIDS Res

Hum Retroviruses 2002, 18:685-93.

http://amedeo.com/lit.php?id=12167274

16. Lalezari J, Cohen C, Eron J, and the T20-205 study group. Forty eight

week analysis of patients receiving T-20 as a component of multidrug

salvage therapy. Abstract LbPp116, XIII International AIDS Conference

2000, Durban, South Africa.

17. Lalezari J, DeJesus E, Northfelt D, et al. A week 48 assessment of a

randomized, controlled, open-label phase II trial (T20-206) evaluating 3

doses of T-20 in PI-experienced, NNRTI-naïve patients infected with HIV-

1. Abstract 418, 9th CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/13592.htm

18. Lambert DM, Zhou J, Medinas R, et al. HIV-1 isolates from patients

treated with T-20 are sensitive to the second generation fusion inhibitor

T1249. Antiviral Ther 1999, 4 (suppl 1):8.

19. Lin PF, Guo K, Fridell R, et al. Identification and characterization of a

novel inhibitor of HIV-1 entry - II: Mechanism of Action. Abstract 10, 9th

CROI 2002, Seattle, USA. http://63.126.3.84/2002/Abstract/14126.htm

108 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

20. Lin PF, Robinson B, Gong YF, et al. Identification and characterization of

a novel inhibitor of HIV-1 entry - I: virology and resistance. Abstract 9, 9th

CROI 2002, Seattle, USA. http://63.126.3.84/2002/Abstract/14125.htm

21. Nair V. HIV integrase as a target for antiviral chemotherapy. Rev Med

Virol 2002, 12:179-93.

22. Reynes J, R. Rouzier R, Kanouni T. SCH C: safety and antiviral effects of

a CCR5 receptor antagonist in HIV-1- infected subjects. Abstract 1, 9

CROI 2002, Seattle, USA. http://63.126.3.84/2002/Abstract/14090.htm

23. Riley J, Wojcik L, Xu S, Strizki J. Genotypic and phenotypic analysis of in

vitro generated HIV-1 escape isolates to the CCR5 antagonist SCH-C.

Abstract 397, 9

CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/12846.htm

24. Schols D, Claes S, De Clerq E, et al. AMD-3100, a CXCR4 antagonist,

reduced HIV viral load and X4 virus levels in humans. Abstract 2, 9

CROI 2002, Seattle, USA. http://63.126.3.84/2002/Abstract/13443.htm

25. Shearer W, Israel R, Starr S, et al., for the PACTG Protocol 351 Study

Team. Recombinant CD4-IgG2 in HIV type 1-infected children: phase 1/2

study. J Infect Dis 2000, 182:1774-1779.

http://amedeo.com/lit.php?id=11069253

26. Strizki JM, Xu S, Wagner NE, et al. SCH-C (SCH 351125), an orally

bioavailable, small molecule antagonist of the chemokine receptor CCR5,

is a potent inhibitor of HIV-1 infection in vitro and in vivo. Proc Natl Acad

Sci U S A 2001, 98:12718-12723. Original-Artikel:

http://www.pnas.org/cgi/content/full/98/22/12718

27. Trkola A, Ketas TJ, Nagashima KA, et al. Potent, broad-spectrum inhibi-

tion of HIV type 1 by the CCR5 monoclonal antibody PRO 140. J Virol

2001, 75:579-88. Original-Artikel:

http://jvi.asm.org/cgi/content/full/75/2/579?view=full&pmid=11134270

28. van Rij RP, Visser JA, Naarding M, et al. In vivo evolution of X4 HIV-1

variants in the natural course of infection coincides with reduced sensitiv-

ity to CXCR4 antagonists. Abstract 395, 9

CROI 2002, Seattle, USA.

http://63.126.3.84/2002/Abstract/12981.htm

29. Xu S, Wojcik L, Strizki J. Antagonism of the CCR5 Receptor by SCH-C

leads to elevated beta-chemokine levels and receptor expression in

chronically treated PBMC cultures. Abstract 398, 9

CROI 2002, Seattle,

USA. http://63.126.3.84/2002/Abstract/12848.htm

30. Yoshinaga T, Sato A, Fujishita T, Fujiwara T. S-1360: in vitro activity of a

new HIV-1 integrase inhibitor in clinical development. Abstract 8, 9

CROI 2002, Seattle, USA.

http://www.retroconference.org//2002/Abstract/13161.htm

2. Overview of Antiretroviral Drugs 109

Hoffmann, Kamps, et al.

Immunotherapy and its Relevance in Practice

In recent years, in addition to “conventional” ART, immuno-

logical treatment strategies have been investigated to an in-

creasing extent (reviews in: Mitsuyasu 2002, Sereti et Lane

2001). Increasing numbers of studies are being published on

approaches with interleukin-2 or hydroxyurea. All of these

therapies still lack proof of clinical benefit. Some important

approaches are nevertheless addressed briefly below.

Interleukin-2

Interleukin-2 (IL-2, aldesleukin, Proleukin

) is a cytokine that

is produced by activated T cells and leads to proliferation and

cytokine production by T cells, B cells and NK cells (review in:

Paredes et al. 2002). It has been employed in oncology for

years. IL-2 was already used in the early nineties, either intra-

venously or as a continuous infusion in HIV infected patients

(Wood et al. 1993). It is now usually administered subcutane-

ously.

The most important effect of IL-2 in HIV medicine is the rise in

CD4+ and CD8+ T cells, which in individual cases may be

quite impressive (Kovacs et al 1996). Several randomized

studies have consistently demonstrated significant increases in

CD4+ T cells. After administration of IL-2, CD45RO+ memory

cells initially increase, followed by naive CD45RA+ T cells.

The life span of CD4+ and CD8+ T cells may also be increased.

IL-2 is usually given in doses of 2 x 4.5 million I.E. subcutane-

ously over 5 days, in cycles 6-8 weeks apart (Davey et al. 2000,

Losso et al. 2000, Abrams et al. 2002, Lelezari et al. 2000,

Hengge et al. 1998). Daily treatment with a low dose has also

been investigated (review in: Smith 2001). After 24 to 48

weeks, increases in CD4+ cell count were 100-250 cells higher

in the IL-2 group than in the controls. Viral load was usually

unaffected by IL-2.

Unfortunately, the activation of T cells had no influence on vi-

ral reservoirs. Although the initial hope was that IL-2 could be

110 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

used to purge virus in the reservoirs and thereby “wash out”

latently infected cells from the body, (Chun et al. 1999), it is

now clear that this does not occur. In the German COSMIC

Study, 56 patients with more than 350 CD4+ T cells/µl on

HAART were randomized to receive IL-2 or placebo. Although

IL-2 led to a normalization of CD4+ cell count in significantly

more patients, IL-2 did not influence viral replication, proviral

DNA nor latently infected cells (Stellbrink et al. 1998, Stell-

brink et al. 2002).

In all larger studies, the combination of IL-2 with HAART has

so far demonstrated to be relatively safe. Nevertheless: the drug

has considerable side effects; fever, chills and sometimes severe

flu-like symptoms with myalgias are usually dose-limiting. The

side effects are the result of the IL-2-induced release of cytoki-

nes and invariably resolve 2-3 days after the last dose.

Paracetamol, rest and intake of electrolyte-rich solutions may be

helpful. The side effects, which are more severe than with inter-

feron, cannot be suppressed completely. Some researchers

question the rationale of IL-2 treatment, arguing that it might

just be the practice of lab cosmetics (“T cells ok, patient sick”).

In addition, doubts have been expressed with regard to the

quality of the immune response. Are the CD4+ T cells gener-

ated by IL-2 of the same quality as “normal” CD4+ T lympho-

cytes, and – more importantly – do the increases really prevent

AIDS? Do patients really have clinical benefit from these diffi-

cult IL-2 treatments? Little is also known about the long-term

use of IL-2 – the longest study performed to date lasted three

years (Gougeon et al. 2001).

Answers to these questions were expected from ESPRIT and

SILCAAT, the two ongoing multinational studies. Both were

intended to clarify over several years whether IL-2 has bona

fide clinical benefits. ESPRIT (http://www.espritstudy.org) is a

randomized study in which around 4,000 patients with at least

300 CD4+ T cells/µl are being treated. SILCAAT

(http://www.silcaat.com) enrolled patients with 50-299 CD4+ T

cells/µl and a viral load of < 10,000 copies/ml. 2,000 patients

2. Overview of Antiretroviral Drugs 111

Hoffmann, Kamps, et al.

were to be observed, initially for four years. After enrolment of

1,957 patients in 137 centers in 11 countries, the study was un-

fortunately stopped in October 2002, although the results of

SILCAAT (patients with low CD4+ cells!) would have been of

great importance for physicians and patients. The decision to

halt the study was probably a business decision: SILCAAT was

becoming too expensive for the manufacturer Chiron. While the

company is now trying to license the product with currently

available data (which might prove difficult), the scientific

committee under the leadership of Clifford Lane opposed the

discontinuation of the trial. Attempts are currently being made

to redirect the study into an academic investigation, so that data

from this important trial will not be lost.

The NIH-sponsored ESPRIT study will continue for the time

being.

All in all, IL-2 must still be viewed skeptically based on the

available data. In our opinion, only a few patients potentially

qualify for therapy with IL-2. These are patients with no immu-

nological response, patients whose CD4+ counts remain below

100/µl despite good viral suppression over longer periods of

time.

Hydroxyurea (Litalir

)

Hydroxyurea is an old chemotherapeutic agent with relatively

low toxicity, which is still being used today in hematology

(mostly in chronic myelogenous leukemia). It inhibits DNA

synthesis via the ribonucleotide reductase, and leads to an intra-

cellular shortage of deoxynucleotide triphosphates. A synergis-

tic effect on HIV replication in combination with didanosine

was demonstrated in 1994.

A randomized, double-blind study from Switzerland attracted

attention in 1998 (Rutschmann et al. 1998). The investigators

had treated 144 patients with hydroxyurea or placebo in addi-

tion to d4T+ddI. After 12 weeks, 54 % of hydroxyurea-treated

patients demonstrated a viral load below 200 copies/ml com-

pared to 28 % in the placebo group. Was this the discovery of a

112 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

new, cheaper option for HIV treatment? In the light of these

seemingly exciting results, the fact that the CD4+ T cell in-

crease in the hydroxyurea group was only 28 versus 107 cells/µl

in the placebo group had to be tolerated. Hydroxyurea was even

more in fashion after publication of the “Berlin-Patient”: a pa-

tient, who had been treated with hydroxyurea in addition to

indinavir and didanosine during acute infection, had stopped all

therapy after a few months and subsequently showed no detect-

able plasma viremia (Lisziewicz et al. 1999). Was this unex-

pected outcome due to hydroxyurea? Several smaller studies

from the US and Argentina seemed to confirm these positive

results, seen primarily in combination with didanosine (Hellin-

ger et al. 2000, Lori et al. 1999, Rodriguez et al. 2000). Many

treating physicians added the drug to ART, and even children

received hydroxyurea. Many already dreamed of a cheap com-

bination of ddI+HU for Africa.

These initial hopes subsided quite rapidly. Although the drug is

usually well tolerated, the combination with didanosine and sta-

vudine in particular seemed problematic. Data from early 2000

reported an additive effect, with a frequency of polyneuropathy

of almost 30/100 patient years (Moore et al. 2000). The ACTG

5025 Study (Havlir et al. 2001), in which hydroxyurea was

evaluated as a “stabilizer” of successful therapy (stable unde-

tectable viral load), led to the temporary demise of this drug in

HIV therapy. Three deaths on the combination of ddI+d4T

(+IDV) due to pancreatitis, all in the hydroxyurea group, were

reported. There was also a higher rate of treatment failure in

patients receiving hydroxyurea, probably due to toxicity rather

than to virological failure. The risk of pancreatitis on didano-

sine seems to be four times higher in combination with hy-

droxyurea (Moore et al. 2001). Randomized studies also failed

to show an effect in primary infection: obviously, further Ber-

lin-patients cannot simply be “reproduced”, at least not for hy-

droxyurea (Zala et al. 2002).

In October 1999, BMS received a warning from the FDA for

having too enthusiastically promoted hydroxyurea for HIV

2. Overview of Antiretroviral Drugs 113

Hoffmann, Kamps, et al.

therapy (http://hiv.net/link.php?id=164). We think that hy-

droxyurea should not be used outside clinical trials.

Interferon

The antiretroviral effect of interferon has been known for years

(Milvan 1996). The effect of 3 million I.E. daily s.c. is ca. 0.5-1

log (Haas et al. 2000). Higher dosing may pronounce the effect

further (Hatzakis et al. 2001). The antiviral effect of interferon

was initially not investigated in more depth because of the sub-

cutaneous delivery route and its side effects. There have re-

cently been indications that the drug may be useful for salvage

therapy. Pegylated interferons now allow for weekly admini-

stration, and improved efficacy with the pegylated drug is an-

ticipated in analogy to the studies in the setting of hepatitis C

infection. Schering-Plough is currently involved in trying to

license the product. However, there have been setbacks, as with

IL-2, and a pivotal multinational study in highly treatment-

experienced patients was aborted in October 2002 due to insuf-

ficient recruitment.

Other immunotherapies

The prototype of therapeutic vaccination already suffered dis-

aster years ago. Remune

, a therapeutic vaccine comprised of

an envelope-depleted (gp120) virus, which was developed by a

team headed by Jonas Salk, although indeed immunogenic,

does not seem to provide any clinical benefit (i.e., prolongation

of life and delay of disease progression). A large trial was inter-

rupted prematurely in May 1999 as no benefit had been demon-

strated for study participants. More than 2500 patients had

taken part for a mean of 89 weeks in this multinational study,

which was designed to evaluate the addition of Remune

HAART. In addition to the lack of clinical benefit not even ad-

vantages with respect to CD4+ cell count or viral load could be

shown (Kahn et al. 2000). The product is now probably obso-

lete, even though there have been dubious reports, mainly from

Thailand, claiming that some effect exists.

114 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

G-CSF and GM-CSF have frequently been used in HIV pa-

tients. G-CSF (granulocyte colony-stimulating factor or fil-

grastim) significantly reduces bacterial infections in HIV pa-

tients with neutropenia (Kuritzkes et al. 1998). G-CSF also sig-

nificantly improved survival in patients with CMV retinitis, al-

though the mechanisms were unclear (Davidson 2002). No ef-

fect on HIV viral load could be shown. GM-CSF (granulocyte-

macrophage colony-stimulation factor or sargramostim) showed

a slight effect on viral load in two double-blind randomized

studies (Skowron et al. 1999, Brites et al. 2000). However, such

approaches cannot be recommended outside of clinical studies.

Whether any clinical benefit exists remains unclear.

Cyclosporine A (Sandimmune

) – Immune activation may

lead to increased HIV replication, and an attractive treatment

hypothesis has been to suppress the immune system in an at-

tempt to slow down viral replication. This is the rationale be-

hind studies investigating the use of cyclosporine A. The drug is

normally used for prophylaxis of transplant rejection after allo-

genic organ transplantation. Between 1997 and 1999, 28 HIV

patients were recruited to receive cyclosporine A 4 mg/kg or

placebo daily for 12 weeks, with or without antiretroviral ther-

apy (two nucleoside analogs; Calabrese et al. 2002). The results

are easily summarized: cyclosporine A had no effect on CD4+

or CD8+ count, nor on expression of activation markers such as

CD38 or HLA-DR. Cyclosporine A therefore probably has no

future in the therapy of chronically infected HIV patients.

Whether, and how, cyclosporine A might improve treatment of

acute HIV infection needs to be clarified in further studies. Use

of both immunosuppressants (CsA) and immunostimulants (IL-

2) in this setting shows the clear discrepancy between scientific

knowledge and hope.

Mycophenol (Cellcept

) follows a concept similar to that of

hydroxyurea and cyclosporine A. Mycophenol inhibits the in-

osine monophosphate (IMP) dehydrogenase and is normally

used for prophylaxis of acute transplant rejection in patients

with allogeneic kidney, heart or liver transplantations, as well as

2. Overview of Antiretroviral Drugs 115

Hoffmann, Kamps, et al.

for some autoimmune diseases. Inhibition of lymphocyte prolif-

eration and reduction of target cells should theoretically inhibit

replication of HIV. First reports from small cohorts of patients

seem to demonstrate an effect on viral load in some cases (Mar-

golis et al. 2002, Press et al. 2002). Whether this will be con-

firmed by randomized trials seems uncertain.

Cannabinoids have no effect. A neatly designed study, in

which patients could either smoke marijuana or receive TCH

(dronabinol, Marinol

) or placebo in addition to HAART,

showed no effects on lymphocyte subpopulations or lympho-

cyte function after three weeks (Bredt et al. 2002).

Interleukin-12 – IL-12 stimulates T lymphocytes and NK cells

to generate a Th1-type immune response. In a randomized

Phase I study with rhIL-12 100 ng/kg 2 x/week, the drug was

well tolerated but had no effect on lymphocyte subpopulations,

antigen-specific immune response or viral load (Jacobson et al.

2002). Further development is therefore uncertain. The same

would appear to be true for interleukin-10 (Angel et al. 2000).

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6. Brites C, Gilbert MJ, Pedral-Sampaio D, et al. A randomized, placebo-

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12. Emery S, Abrams DI, Cooper DA, et al. The evaluation of subcutaneous

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13. Gougeon ML, Rouzioux C, Liberman I, et al. Immunological and virologi-

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14. Haas DW, Lavelle J, Nadler JP, et al. A randomized trial of interferon

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17. Hellinger JA, Iwane MK, Smith JJ, et al. A randomized study of the safety

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18. Hengge UR, Goos M, Esser S, et al. Randomized, controlled phase II trial

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1 immunogen, an immunologic modifier, administered to patients infected

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21. Kovacs JA, Vogel S, Albert JM, et al. Controlled trial of interleukin-2 infu-

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22. Kuritzkes DR, Parenti D, Ward DJ, et al. Filgrastim prevents severe neu-

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23. Lafeuillade A, Hittinger G, Chadapaud S, et al. The HYDILE trial: efficacy

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terleukin-2 in combination with HAART in HIV+ patients: a randomized

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25. Lisziewicz J, Rosenberg E, Lieberman J, et al. Control of HIV despite the

discontinuation of antiretroviral therapy. N Engl J Med 1999, 340:1683-4.

26. Lori F, Jessen H, Lieberman J, et al. Treatment of HIV infection with hy-

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voir. J Infect Dis 1999, 180: 1827-32.

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27. Lori F, Malykh A, Cara A, et al. Hydroxyurea as an inhibitor of HIV-type 1

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28. Losso MH, Belloso WH, Emery S, et al. A randomized, controlled, phase

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29. Margolis DM, Kewn S, Coull JJ, et al. The addition of mycophenolate

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pletion of intracellular deoxyguanosine triphosphate and a decrease in

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infection: ACTG 068. Antivir Ther 1996; 1: 77-88.

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36. Rizzardi GP, Harari A, Capiluppi B, et al. Treatment of primary HIV-1

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38. Rutschmann OT, Opravil M, Iten A, et al. A placebo-controlled trial of

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120 HIV Therapy 2003

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3. Goals and Principles of Therapy

Christian Hoffmann

In the flood of monthly evaluations - including CD4+ count,

viral load, routine laboratory, genotypic and phenotypic resis-

tance testing, and drug plasma levels - the ultimate goal of

antiretroviral therapy should always be borne in mind:

To prolong the patient’s life,

while maintaining the best possible quality

of health and life.

This paradigm suggests that not only opportunistic infections

and malignancies, but also side effects of therapy, should be

prevented. Ideally, antiretroviral treatment should have little or

no influence on daily life. Even if a high CD4+ count and a low

viral load are useful therapeutic goals, the patient’s condition is

at least as significant as such laboratory results! Patients, too,

often lose focus on what really matters. The response to the

doctor’s query: "How are you?" is often accompanied by a

glance toward the CD4+ count result on the chart: "That’s what

I’d like to know from you!". It may therefore indeed be useful

to reflect upon – alone or with the patient – what one realisti-

cally wants to achieve.

Success and Failure of Treatment

Both success and failure of treatment can be evaluated with dif-

fering criteria – virological, immunological or clinical. Of these,

the earliest indicator is virological success or failure (decrease

or increase in viral load). This is followed, often a little later, by

immunological treatment success or failure (rise or fall in

CD4+ cell count). Clinical treatment failure usually becomes

apparent only much later – first the lab values deteriorate, then

3. Goals and Principles of Therapy 121

Hoffmann, Kamps, et al.

the patient! On the other hand, success of treatment may be

seen much earlier; many patients suffering from constitutional

symptoms rapidly improve on HAART. In the Swiss Cohort,

the incidence of opportunistic infections after only three months

on HAART was reduced from 15.1 to 7.7 per 100 patient years

(Ledergerber et al. 1999). For clinical treatment success, in par-

ticular in the prevention of AIDS, immunological success is

probably at least as important as virological success (Grabar et

al. 2000, Piketty et al. 2001).

Virological treatment success and failure

Virological treatment success is usually understood as a viral

load decrease to below the level of detection of 50 copies/ml.

This is based on the understanding that, the more rapid and

complete the decrease in viral load, the longer the therapeutic

effect (Kempf et al. 1998, Powderly et al. 1999, Raboud et al.

1998). In the INCAS Trial, the relative risk for treatment failure

(defined here as an increase to > 5,000 copies/ml) in patients

who had reached a viral load < 20 copies/ml was 20 times lower

than in those who had never reached a level below 400 cop-

ies/ml (Raboud et al. 1998). On HAART, viral load declines in

two phases (see also the chapter on "Monitoring"); there is an

initial very rapid decrease in the first weeks, followed by a

slower phase, in which plasma viremia is reduced only slowly.

A decrease to below the level of detection should be reached by

3-4 months; in cases of very high baseline viral load this may

take 4 or 5 months. A viral load above the level of detection

after 6 months of treatment is generally seen as failure. The

same is true if a rebound in viral load is confirmed by a second

determination after a short interval. In such cases, improve-

ments in therapy (e.g. compliance, change in the regimen)

should soon be considered.

The cut-off point of 50 copies/ml is arbitrary. It is based on the

currently available assays for measurement of viral load.

Whether 60 copies/ml are indeed worse than 30 copies/ml and

indicate a lesser success of treatment has not yet been proven At

122 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

these low levels, methodological inaccuracies must be taken

into account. A single viral load rebound ("blip") to low levels

(up to 1000 copies/ml) is often irrelevant (see below).

A viral load "below the level of detection" of 50 copies/ml

means just that – no more, no less. Numerous studies indicate

that replication and therefore development of resistance can

continue even with an undetectable virus load. 50 viral cop-

ies/ml indicate that 5 liters of blood contain 250,000 viruses; in

addition, even more actively replicating viruses are present in

the lymphatic organs. Thus, theoretically, measurable viremia,

even at very low levels, may possibly translate to a higher risk

of resistance in the long-term. Perhaps there is indeed a relevant

difference between 100 and 10 copies/ml with regard to risk for

developing resistance. But we just don’t know yet.

The good news: Morbidity and mortality may be lowered even

if the viral load is not decreased below the level of detection

(Mezzaroma et al. 1999, Deeks et al. 2000, Grabar et al. 2000).

This should be borne in mind when treating patients who have

only a limited number of treatment options. In such cases, it

may be useful to abandon viral load as a measure for success. In

patients with multiresistant viruses, virological success may not

be possible; here, stabilizing the CD4+ count should be of top

priority. Patients often remain immunologically stable for rela-

tively long periods of time, even with insufficient viral suppres-

sion.

The most important risk factors for virological treatment failure

are extensive pre-treatment with antiretroviral drugs (pre-

existing resistance mutations) and non-compliance (review:

Deeks et al. 2000). Whether viral load and CD4+ count at base-

line really play a role has not yet been proven conclusively; in

several cohorts no influence was detected (Cozzi Lepri et al.

2001, Phillips et al. 2001, Le Moing et al. 2002; see also the

chapter "When to start HAART".)

3. Goals and Principles of Therapy 123

Hoffmann, Kamps, et al.

How long does virological treatment success last?

Little is known about how long treatments remain effective.

Following the six years during which HAART has been em-

ployed, a surprisingly high number of adequately treated pa-

tients still have viral loads below the level of detection, even

after this time span. One of the few trials with a longer follow-

up period studied 336 antiretroviral-naive patients who had

reached a viral load below 50 copies/ml within 24 weeks (Phil-

lips et al. 2001). After 3.3 years, the risk of viral rebound was

relatively high at 25.3 %. More detailed analysis showed that a

large proportion of the patients experiencing viral rebound had

actually interrupted HAART. True virological failure was only

seen in 14 patients, which corresponds to a risk of 5.2 % after

3.3 years. Most importantly, the risk of virological failure de-

creased significantly with time. Thus, if treatment is not inter-

rupted, viral load may remain below the level of detection for

many years.

"Blips" – Do they mean virological failure?

Blips are transient increases in viral load. They occur in 20-40%

of patients and have been shown to be associated with a higher

level of viral replication. Blips often worry both patients and

clinicians. Strictly speaking, if one defines virological success

as < 50 copies/ml, blips signify treatment failure. However, in-

creasing data indicates that blips seem to have no consequences

in the medium-term, and do not necessarily indicate immuno-

logical or even clinical treatment failure (Havlir et al. 2001,

Moore et al. 2002, Sklar et al. 2002). This is true both for pa-

tients on first-line therapy and for highly treatment-experienced

patients. However, longer follow-up is still required to exclude

that patients with occasional blips are at more risk of develop-

ing resistance. In at least one recent analysis, the risk for treat-

ment failure after 18 months was approximately doubled

(Greub et al. 2002). Following presently available data, blips

should not necessitate an immediate change of therapy. They

can and should, however, raise the opportunity for a conversa-

124 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

tion with the patient on the subject of compliance. It should be

noted that viral load may also temporarily increase after immu-

nizations (Kolber et al. 2002).

Immunological treatment failure and success

Immunological treatment success is generally defined as an in-

crease in the CD4+ cell count. A more precise definition for

immunological treatment success does not currently exist. De-

pending on the study, increases by 50, 100 or 200 CD4+ T

cells/µl or increases to above 200 or 500 CD4+ T cells/µl are

defined as success. Failure is usually described as the absence

of an increase or decrease in the CD4+ T cell count in patients

receiving HAART.

Prediction of a rise in CD4+ count in patients on HAART is

difficult as there is significant individual variation. As with the

decrease in viral load, the increase in CD4+ count occurs in two

phases. After a first, usually rapid increase over the first three to

four months, further increases are considerably less pro-

nounced. In a prospective study involving some 1,000 patients,

CD4+ count in the first three months increased by a median of

21.2 CD4+ T cells/µl per month; in the following months the

increase was only 5.5 CD4+ T cells/µl (Le Moing et al. 2002).

There is inconclusive data as to whether lower CD4+ counts at

baseline result in a slower increase. However, normalization of

the CD4+ count (> 500 /µl) appears to be less likely and/or

takes longer, if the CD4+ count was low at initiation of therapy

(Kaufmann et al. 2002, Valdez et al. 2002). Immunological

treatment success is not necessarily linked to maximal viral

suppression; even partial suppression may lead to improvement

in the CD4+ T cell count (Kaufmann et al. 1998, Mezzaroma et

al. 1999). Neither is the level of initial viral load significant;

what seems to be crucial is that the viral load remains lower

than before treatment (Deeks et al. 2002).

3. Goals and Principles of Therapy 125

Hoffmann, Kamps, et al.

Discordant response

Failure to achieve one or two of the therapeutic goals – clinical,

immunological and virological - is referred to as a discordant

response. Some patients may have virological treatment success

without an immunological improvement, continuing to have a

very low CD4+ T cell count despite undetectable viral load

(Piketty et al. 1998, Renaud et al. 1999, Gabran et al. 2000,

Piketty et al. 2001). Conversely, HAART may be immunologi-

cally extremely effective and induce significant increases in the

CD4+ count, while the viral load remains detectable. The fre-

quencies of such discordant responses are outlined in the table

below.

Table 3.1: Prospective cohort studies, treatment response*

Response to HAART Piketty et al.

n = 150

Grabar et al.

n = 2236

Virological and immunological response 60 % 48 %

Discordant: only immunological response 19 % 19 %

Discordant: only virological response 9 % 17 %

No treatment response 12 % 16 %

* Immunological response: rise in CD4+ T cells > 100/µl after 30 months

(Piketty et al. 2001) or > 50/µl after 6 months (Grabar et al. 2000). Virological

response: continually at least 1 log below baseline or < 500 copies/ml (Piketty

et al. 2001) or < 1000 copies/ml (Grabar et al. 2000).

Immunological response is often moderate in comparison to

virological response, particularly in older patients. With in-

creasing age, the immune system becomes less capable of re-

generating, probably due to thymus degeneration (Lederman et

al. 2000). Various studies have demonstrated that the probabil-

ity of not achieving a rise in CD4+ count increases with patient

age and with progressive decrease in thymus size as detected by

CT (Goetz et al. 2001, Marimoutou et al. 2001, Piketty et al.

2001, Teixera et al. 2001, Viard et al. 2001).

126 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

Practical considerations in dealing with viral load and

CD4+ count



Viral load, since it can be directly affected, is the most im-

portant parameter in treatment monitoring.



If possible, use only one type of assay (in the same lab) –

keep in mind that there is considerable methodological

variability (up to half a log)!



Virological success should be monitored one month after

initiation or modification of HAART.



Viral load should be below 50 copies/ml after 3 months

(with high initial viral load, after 6 months at the latest) – if

it is not, check for the cause!



The greater the decrease in viral load, the more durable the

response to treatment.



Transient, low-level increases in viral load (blips) are often

of no significance – but VL should be remonitored at short

intervals (after 2-4 weeks).



The older the patient, the likelier a discordant response (low

viral load with no significant increase in CD4+ count).



In contrast to viral load, increase in CD4+ T cells, i.e. im-

munological success, is difficult to influence. CD4+ T cells

are probably more predictive of the individual risk for

AIDS.



Once CD4+ count is above 400-500/µl, controls can be per-

formed less frequently. Keep in mind that with higher

CD4+ counts, values may vary considerably from one

measurement to the next (which may cause the patient ei-

ther a false sense of euphoria or unnecessary concern).

3. Goals and Principles of Therapy 127

Hoffmann, Kamps, et al.

Clinical treatment success and failure

Clinical treatment success is dependent on virological and im-

munological therapeutic success. In individual patients, clinical

response is not always easy to assess. After all, there is no way

to show what might have occurred if treatment had not been

started. As an asymptomatic patient cannot feel any better, it

may be difficult to find good arguments to continue treatment in

the presence of side effects, which, at least temporarily, may

affect the quality of life.

Clinical success is almost always evaluated via clinical end-

points (AIDS-defining illnesses, death), although the improve-

ment on HAART in a patient with considerable constitutional

symptoms should also be seen as clinical success. With regard

to risk of disease progression, immunological response is at

least as important as virological response (Table 3.2).

Table 3.2: Risk of progression, as defined by immunological and virological

treatment response. See previous table caption for definitions. 95 % confi-

dence interval in parentheses.

Grabar et al. 2000 Piketty et al. 2001

CD4+ T cells at baseline (median) 150 73

Relative risk Relative risk

Virological and immunological re-

sponse

Immunological response only 1.6 (1.0-2.5) 6.5 (1.2-35.8)

Virological response only 2.0 (1.3-3.1) 9.7 (1.6-58.4)

No treatment response 3.4 (2.3-5.0) 51.0 (11.3-229.8)

The degree of virological response is also of great importance.

In the Swiss Cohort, 6.6 % of patients with a viral load con-

stantly below the level of detection suffered AIDS or died after

30 months. In contrast, AIDS or death occurred in 9.0 % of pa-

tients with viral rebound, and in 20.1 % of those whose viral

load never became undetectable (Ledergerber et al. 1999). The

importance of a complete and sustained virological treatment

response for clinical success has also been reported in other co-

horts (Salzberger et al. 1999, Thiebaud et al. 2000).

128 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

Clinical failure is usually defined as development of an AIDS-

associated condition or death. However, illness is not always

indicative of clinical treatment failure. A good example is the

immune reconstitution syndrome, where a pre-existing, sub-

clinical infection becomes apparent during the first weeks fol-

lowing initiation of antiretroviral therapy. On the other hand, if

a patient suffers serious side effects or even dies as a result of

them, this should also be seen as treatment failure.

What can be achieved today?

Every HIV clinician sees the remarkable strides made possible

by HAART reflected in his or her own patients (Table 3.3). In

many areas, the incidence of AIDS has been reduced to less

than a tenth (Mocroft et al. 2000). Today, in many Western

countries, almost all AIDS cases occur in patients who are not

being treated with antiretroviral therapy – usually because they

are unaware of their infection. The mortality rate has declined

to levels far below that of even a few years ago (Mocroft et al.

2002).

Table 3.3: Patient case (female, 41 years) demonstrating advances in treat-

ment due to HAART*

CD4+ T cells Viral load

Feb 95 AZT+ddC 23 (4 %) NA

Nov 96

AIDS: Toxoplasmosis, MAC,

Candida esophagitis

12 (1 %) 815.000

Feb 97 d4T+3TC+SQV 35 (8 %) 500

June 97 stopped HAART due to polyneu-

ropathy

July 97 AZT+3TC+IDV 17 (4 %) 141.000

Mar 98 147 (22 %) < 50

Mar 99 AZT+3TC+IDV+NVP 558 (24 %) 100

Mar 00 942 (31 %) < 50

Mar 02 1132 (33 % ) < 50

* Excellent immune reconstitution despite initially severe immunodeficiency and

several AIDS-defining illnesses. All primary/secondary prophylaxes (MAC,

Toxoplasmosis, PCP) have now been discontinued.

3. Goals and Principles of Therapy 129

Hoffmann, Kamps, et al.

Data from prospective, controlled studies on this dramatic

change is still relatively sparse, there being few randomized

trials with clinical endpoints (Hammer et al. 1997, Cameron et

al. 1998, Stellbrink et al. 2000). The results seen in these stud-

ies, which led to licensing of PIs, were also relatively modest,

due their design. In a multi-center trial, 1,090 clinically ad-

vanced patients received ritonavir liquid formulation or placebo

in addition to their ongoing treatment. Probability of AIDS and

death with a follow-up of 29 weeks was 21.9 % in the ritonavir

arm and nearly double (37.5 % ) in the placebo arm (Cameron

et al. 1998). In the SV14604 Study, the largest study of its kind

to date, involving 3,485 patients, the frequency of AIDS and

death was reduced by about 50 % in the group receiving

AZT+ddC+saquinavir hard gel, compared to the groups on dual

therapy (Stellbrink et al. 2000).

Due to the success of antiretroviral therapy, the number of

clinical endpoints that occur is fortunately now extremely low.

As a result, the duration of any contemporary study to prove

clinical benefit of one combination over another would have to

be very long. Only rarely will such investigations be undertaken

in the future (Raffi et al. 2001).

SILCAAT, a large multi-center study that had enrolled around

2,000 patients with less than 300 CD4+ T cells/µl was termi-

nated in October 2002 because the number of clinical endpoints

reached was too low to enable adequate detection of any differ-

ences.

With regard to opportunistic infections and malignancies, the

effect of HAART is equally apparent on their clinical course as

on their incidence. Illnesses such as cryptosporidiosis or PML

can be cured, while Kaposi's sarcoma can resolve completely

without specific therapy. Prophylaxis of pneumocystis, toxo-

plasma, CMV or MAC can usually be safely withdrawn. These

effects are discussed in more detail in the corresponding chap-

ters.

130 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

Table 3.4: Decline in morbidity and mortality in large cohorts

Where? (n) Patients (Period) Mortality

(/100 py)

Morbidity

(/100 py)

Palella

1998

USA (1255) < 100 CD4+ T

cells/µl

(1/94-6/97)

29.4 → 8.8 21.9 → 3.7*

Leder-

gerber

1999

Switzerland

(2410)

6 months before

versus 3 months

after HAART (9/95-

12/97)

15.1 → 7.7

Mocroft

2000

Europe

(7331)

All (94-98) NA

30.7 → 2.5

Mocroft

2002

Europe

(8556)

All (94-01)

15.6 → 2.7

* MAC, PCP, CMV. Mortality/Morbidity each per 100 py = patient years

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3. Goals and Principles of Therapy 135

Hoffmann, Kamps, et al.

Eradication – Is it Feasible?

At this point in time, eradication of HIV in the sense of a cure is

unrealistic. Although as late as 1997, many still dreamt of

eradication, leading researchers now incline towards pessimism.

The problem lies in the pool of latently infected CD4+ T cells,

which probably comprise a lifelong reservoir. The half-life of

this reservoir is 44 months, and, according to recent estimates,

eradication could take 60-73 years (Finzi et al. 1999). Even af-

ter years of sufficient viral suppression to below 20-50 cop-

ies/ml, cellular viral transcription still takes place (Dornadula et

al. 1999, Furtado et al. 1999, Zhang et al. 1999, Sharkey et al.

2000). This holds in particular for blood cells, but also applies

to lymph nodes and sperm (Lafeuillade et al. 2001, Nunnari et

al. 2002). Different methods have been used to attempt to flush

out these latent reservoirs (IL-2, hydroxyurea, OKT), but all

have failed (Kulkosky et al. 2002, Pomerantz et al. 2002). At

the last World AIDS Conference, Bob Siliciano painted a bleak

picture of the situation (Siliciano 2002): Eradication is not pos-

sible with currently available drugs. The reservoirs cannot be

eliminated. Latently infected cells differ from uninfected cells

only in one minute detail, which is hardly detectable with pres-

ent methods and cannot be specifically targeted. Flushing out

the reservoirs or even just the complete elimination of memory

cells is either unsuccessful, too toxic, or far too dangerous.

Hopefully, future chapters can be dedicated to this issue.

Other Important Aspects of HAART

Besides the goals described above – virological, immunological

and clinical treatment success – several other aspects need to be

considered. Although not primary goals of HAART, they are

nevertheless extremely important: cost reduction; prevention;

and improving compliance – a constant challenge for every HIV

clinician.

136 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

Reduction of costs

Antiretroviral therapies are expensive. Single drugs cost be-

tween $250 and $1000 per month, depending on the drug and

the country where it is prescribed. Even within drug classes,

astonishing differences exist. In some countries, Crixivan

relatively cheap, at roughly half the price of Agenerase

. A

combination regimen with Trizivir

and Kaletra

adds up to at

least $2,000 per month. As a health care provider, it is therefore

important to have an idea of costs and to question the pricing

policy of some pharmaceutical companies. For example, why

does boosted Invirase

cost nearly twice as much as boosted

Fortovase

in Germany?

Despite such high costs, the positive effect of HAART remains

unquestioned. Reliable estimates assume an expenditure of

between $13,000 and $23,000 per additional QUALY (quality-

adjusted year of life; Freedberg et al. 2001) – relatively cheap in

comparison to many other therapies. HAART can avoid expen-

sive treatment of opportunistic infections, hospital and patient

care costs. In one German study, between 1997 and 2001, total

annual outgoings per patient decreased from €35,865 to

€24,482 (Stoll et al. 2002). Many patients are able to work

again, resulting in an overall economic reduction of costs

(Sendi et al. 1999).

As HAART is expensive, when treatment is being changed, ei-

ther merely to reduce pill burden or due to concern over long-

term toxicity, it is justified to ask a patient to first use up exist-

ing stocks. Privately insured patients are obviously appreciative

of this, but even patients on state health insurance should be

made aware of drug costs – not to cause guilt feelings or to

transfer insufficiencies of the health care system to the patient,

but rather to create an awareness of the value of this treatment.

Initially, only one box of tablets should be prescribed, even if,

for example, one box of Retrovir

prescribed at the standard

dose – 15 years after licensing! – still only lasts for 20 days.

Only by this approach can one avert a patient being left with

3. Goals and Principles of Therapy 137

Hoffmann, Kamps, et al.

many drugs should intolerance occur. Prescribing more than

three months of drugs at a time should be avoided.

Prevention

The lower the viral load, the less infectious is the patient. A

prospective study of 415 HIV-discordant couples in Uganda

showed that of 90 new infections over a period of up to 30

months, none occurred from an infected partner with a viral

load below 1500 copies/ml. The risk of infection increased with

every log of viral load by a factor of 2.45 (Quinn et al. 2000). In

a study from Thailand of 493 patients, this factor was 1.81 –

and here no case of infection was recorded below 1094 cop-

ies/ml (Tovanabutra 2002). Within limits, HAART can thus

serve as a preventive measure (Hosseinipur et al. 2002).

Most patients are interested in knowing: "Do I still need to use a

condom?". The answer is: "Yes!". Studies have shown that the

decrease of viral load in plasma and seminal fluid is roughly

parallel and that a decrease of several logs in plasma after sev-

eral months may also be seen in semen (Liuzzi et al. 1999).

Although the same seems to be true for the vaginal and anorec-

tal mucosa, individual risk remains difficult to estimate

(Lampinen et al. 2000, Cu-Uvin et al. 2000). Furthermore, viral

load levels in blood and other body fluids do not always corre-

late with one another (see also the chapter on "Monitoring").

In recent years the preventive effects of HAART seem to have

led to an increase in risk behaviour. Calculations have shown

that an increase in risk behaviour of only 10 % would offset the

effects of HAART (Blower et al. 2001, Law et al. 2001). In the

French PRIMO Cohort, so-called risk contacts of patients in-

creased from 5 % to 21 % between 1998 and 2001 (Desquilbet

et al. 2002). Small syphilis endemics among HIV infected indi-

viduals are now being reported in every major city in the USA

and Europe. Of equal concern is the increasing data on trans-

mission of multiresistant viruses.

138 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

Compliance as a goal of therapy

Compliance is the Achilles heel of antiretroviral therapy. Non-

compliance is a main, if not the most important, factor in treat-

ment failure. Insufficient plasma drug levels and partial sup-

pression of viral load are the conditions under which resistance

can develop.

Compliance is defined as consent and acceptance of a treatment

regimen by the patient. In the mid-90s a newer, more politically

correct term was adopted – "adherence". This term describes

both clinician and patient working together to achieve a treat-

ment concept acceptable for both, and emphasizes, quite cor-

rectly, that not only the patient may be responsible for treatment

failure. Adherence includes all factors that influence staying on

a regimen, in terms of "acceptability". Whichever term is used,

two facts remain:

If 5 % of drugs are not taken, treatment success becomes

precarious.

Clinicians usually overestimate the compliance of their pa-

tients.

"Risk patients" for non-compliance include not only individuals

with substance or alcohol abuse or those experiencing side ef-

fects. Studies on compliance have identified both patients with

depression or younger age as being particularly at risk (Murri et

al. 2001, Frank 2002). Positive factors are physician experience,

confidence of the patient in the positive effects of HAART, and

social support. Race, sex or stage of disease do not seem to be

relevant. The individual’s view of disease and health, accep-

tance of modern medicine and fear of side effects are further

considerations. However, all of these factors vary greatly, and

in the end compliance is difficult to predict in individual cases

(Lerner et al. 1998).

The importance of taking drugs regularly has been demon-

strated in numerous studies in recent years. In one study of 99

patients, in which compliance was evaluated by way of an elec-

tronic monitoring system, the rate of treatment failure was only

3. Goals and Principles of Therapy 139

Hoffmann, Kamps, et al.

22 % in patients with a level of compliance of at least 95 %

(95 % of doses taken). Failure rates in patients with 80-94 % or

< 80 % compliance were 61 % and 80 %, respectively. In this

study, 41 % of patients were misjudged by their treating clini-

cians with regard to compliance. Nurses seemed to have a better

understanding of their patients, judging incorrectly in only 30 %

of cases (Paterson et al. 2000). The importance of compliance is

also demonstrated by the successes reported in patients with

directly observed therapy (DOT). A DOT study performed in

one of Florida’s correctional facilities showed 100 % of sub-

jects with a viral load < 400 copies/ml at 48 weeks, compared

with 81 % in an unmonitored control group in the general

population (Fischl et al. 2001).

Non-compliance not only leads to virological failure. It also has

immunological consequences. In an analysis of two prospective

studies, patients with a compliance of 100 %, 80-99 % and 0-

79 % experienced reductions in viral load by 2.77, 2.33 and

0.67 log after one year. At the same time, the CD4+ cell count

rose by 179, 159 and 53, respectively (Mannheimer 2002).

Furthermore, non-compliance not only affects CD4+ count and

viral load, but also has clinical effects. In a Spanish study, pa-

tients who did not take more than 10 % of their drugs had a

four-fold increase in mortality risk (Garcia 2002). This data has

been confirmed in other studies (Maher et al. 1999, Hogg et al.

2000). Hospital stays are also less frequent in patients with high

compliance (Paterson et al. 2000). In addition, it should be con-

sidered that the risk of transmission of resistant viruses is in-

creased by non-compliant patients.

The basic mechanisms for development of resistance should be

explained to patients. One must emphasize that, in contrast with

other chronic illnesses, resistance mutations do not disappear

once they have developed. Diabetes and hypertension make ef-

fective examples: whereas these diseases may "tolerate" forget-

ting the occasional tablet, HIV is different – here even short-

term lapses can have irreversible consequences. Patients have to

be made aware of this unusual feature of HIV disease. Coop-

140 HIV Therapy 2003

HIV Medicine 2003 – www.HIVMedicine.com

eration with special treatment discussion groups offered by

various support organizations can be useful.

If compliance remains low

Despite all our efforts, some patients will not be able to im-

prove their compliance. Physicians and other health care pro-

viders are advised not to take this personally or to feel offended

should a patient not want to participate in the advances of medi-

cine. Even if it may be difficult to accept others’ views on life

and treatment, tolerance and acceptance should remain funda-

mental to the interactions of all health care providers with their

patients. Some providers, especially those who treat selective

patient populations in university settings, sometimes forget the

reality of routine medical practice. Rigidly upholding the prin-

ciples of modern medicine usually doesn’t help here, and put-

ting patients under pressure achieves even less.

The question of whether non-compliant patients should con-

tinue to be treated with antiretroviral therapy is not always easy

to address. On the one hand, there are patients who benefit even

from suboptimal therapy; on the other hand, drugs are expen-

sive and should not be prescribed too readily. When resources

are limited, available drugs should be used prudently. One

should also be beware of criminal dealings: there have recently

been several reports of patients who had deals with pharmacies

in order to receive other drugs (methadone, etc.), or even

money, in exchange for their prescriptions (black sheep are

ubiquitous!). Prescriptions have to be documented in the patient

chart. Where there are good reasons to doubt the compliance or

honesty of a patient, plasma drug levels can be determined.

3. Goals and Principles of Therapy 141

Hoffmann, Kamps, et al.

Twelve tips to improve compliance

Every patient should receive a written (legible!) treatment

plan, which should be reviewed at the end of the visit. It

should include a telephone number to call in case of prob-

lems or questions.

Patient and clinician should agree on the treatment plan.

The patient's concerns or critical questions should be dis-

cussed.

The patient should have the impression that the treatment

regimen was not randomly chosen, but tailored to his/her

individual needs.

The explanation of a new or modified treatment plan takes

time, and should not be rushed – all questions should be an-

swered.

The reasons why compliance is so important should be ex-

plained. It makes sense to repeat such conversations – they

should not only take place when initiating or modifying

treatment, but should be part of routine care.

Possible side effects should be explained, as well as what

can be done to alleviate them.

Support groups and other types of assistance should be

utilized and offered.

It is important to tell the patient to come back if any prob-

lems are encountered with HAART – it is better to solve

them together than have the patient try to deal with them

alone at home.

The patient should know that the treatment regimen must be

taken in its entirety ("Last month I left out the big tablets").

10.

Prescriptions should be documented, in order to get a rough

idea of compliance. Irregularities should be addressed

openly.

11.

Especially during the early phases of therapy, the patient

should be informed of treatment success as seen by reduc-

tion of viral load and rise in CD4+ count.

12.

Treat depression!

Duesbergians