aids and tuberculosis || hiv/aids drugs

Part TwoDrugs

AIDS and Tuberculosis: A Deadly Liaison. Edited by Stefan H.E. Kaufmann and Bruce D. WalkerCopyright � 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32270-1

4HIV/AIDS DrugsRoy M. Gulick

4.1Introduction

Currently, a total of 25 FDA-approved drugs are available for the treatment of HIVinfection (Table 4.1; Figure 4.1). Approved antiretroviral drugs comprise sixmechanistic classes (in chronologic order of development): nucleoside analoguereverse transcriptase inhibitors (NRTI); non-nucleoside reverse transcriptase in-hibitors (NNRTI); protease inhibitors (PI); fusion inhibitors; chemokine receptor(CCR5) antagonists; and integrase inhibitors (see Figure 4.2). Following thesuccessful development of combination antimicrobial treatment regimens for bothtuberculosis (TB) and Gram-negative bacterial infections, strategies for antiretro-viral therapy evolved from monotherapy using single-nucleoside analogues duringthe late 1980s to early 1990s, to two-drug combination therapy using dualnucleoside analogues in the early to mid 1990s, and to three-drug combinationtherapy using dual nucleoside analogues together with an HIV PI or an NNRTI,beginning in the mid to late 1990s. The development of three-drug antiretroviraltherapy led to a marked decrease in HIV-related morbidity and mortality, with anapproximate 60% decrease in HIV-related deaths from 1995 to 1997, and acontinued decline thereafter.Over the past 10 years, effective combination antiretroviral regimens became

more convenient, better tolerated, less toxic, and have demonstrated durablevirologic, immunologic, and clinical responses. The introduction of drugs withactivity against drug-resistant viruses and, in particular, the approval of three newclasses of antiretroviral drugs since 2003 – namely, fusion inhibitors, CCR5antagonists, and integrase inhibitors – allows the design of effective treatmentregimens even for patients with drug-resistant viral variants, and also challenges thecurrent standard paradigms of HIV antiretroviral treatment. The development ofeffective antiretroviral therapy has reduced HIV-related mortality to rates approach-ing that seen in the general population in developed countries [1, 2]. Worldwide, theintersecting epidemics of HIV disease and TB pose challenges for the optimal

j77

AIDS and Tuberculosis: A Deadly Liaison. Edited by Stefan H.E. Kaufmann and Bruce D. WalkerCopyright � 2009 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32270-1

Table4.1FD

A-app

rovedan

tiretrovirald

rugs.

Drugclass/Genericna

me

Abb

reviation

Tradena

me

Year

ofFD

Aapproval

Stan

dard

oraldo

seCon

comita

ntusewith

TBmedications

HIV

reversetran

scriptaseinhibitors

Nucleoside

analogues

zido

vudine

ZDV,

AZT

Retrovir

1987

300mgbid

OK

didanosine

ddI

Videx

1991

400mgqd

Overlappingtoxicity

(peripheral

neu

ropathy)

zalcitabine

ddC

Hivid

1992

(withdraw

n)

Overlappingtoxicity

(peripheral

neu

ropathy)

stavudine

d4T

Zerit

1994

40mgbid

Overlappingtoxicity

(peripheral

neu

ropathy)

lamivudine

3TC

Epivir

1995

300mgqd

OK

abacavir

ABC

Ziagen

1998

600mgqd

OK

tenofovir

TDF

Viread

2001

300mgqd

OK

emtricitabine

FTC

Emtriva

2003

200mgqd

OK

Non

-nucleoside

analogues

nevirapine

NVP

Viram

une

1996

200mgbid

Overlappingtoxicity

(drughepatitis);

sign

ificantdrug-druginteraction(ri-

fampin);increasedvirologicfailu

rerate

delavirdine

DLV

Rescriptor

1997

400mgtid

Sign

ificantdrug–druginteraction(ri-

fampin,rifabutin)–contraindicated

efaviren

zEFV

Sustiva

1998

600mgqd

OK;overlappingtoxicity(drughe

patitis);

dose

adjustmen

tsmay

berequ

ired

etravirine

ETR

Intelence

2008

200mgbid

Overlappingtoxicity

(drughepatitis);

sign

ificantdrug–druginteraction

(rifam

pin)

78j 4 HIV/AIDS Drugs

HIV

protease

inhibitors

Overlappingtoxicity

(drughepatitis),

sign

ificantdrug–druginteraction(ri-

fampin);rifabu

tindo

seadjustmen

trequ

ired

saqu

inavir

SQV

Invirase

1995

1000

mgwithRTV

100mgbid

Seeabove

ritonavir

RTV

Norvir

1996

rarelyusedalon

eSe

eabove

indinavir

IDV

Crixivan

1996

400mgwithRTV10

0mgbid

Seeabove

nelfinavir

NFV

Viracept

1997

1250

mgbid

Seeabove

ampren

avir

APV

Agenerase

1999

(withdraw

n)

lopinavir/riton

avir

LPV/r

Kaletra

2000

400/100mgbidor

800/

200mgqd

Seeabove

atazan

avir

ATV

Reyataz

2003

[300

mgwithRTV10

0mgqd

]or

400mgqd

Seeabove

fosampren

avir

FPV

Lexiva

2003

[700

mgwithRTV20

0mg

bid],[14

00mgwithRTV

100mgqd

],or

1400

mgbid

Seeabove

tipran

avir

TPV

Aptivus

2005

500mgwithRTV20

0mgbid

Seeabove

darunavir

DRV

Prezista

2006

600mgwithRTV10

0mgbid

or80

0mgwithRTV

100mgqd

Seeabove

HIV

entryinhibitors

Fusion

inhibitors

enfuvirtide

ENF,T

-20

Fuzeon

2003

90mgbidby

subcutaneous

injection

OK

CCR5an

tagonists

maraviroc

MVC

Selzen

try

2007

300mgbidor

[150

mgbid

withRTV-con

taining

regimen

s]

Drug–druginteraction(rifam

pin)re-

quiringdo

seadjustmen

t;nodata

with

rifabu

tin

HIV

integraseinhibitors

ralte

gravir

RAL

Isen

tress

2007

400mgbid

Sign

ificantdrug–druginteraction

(rifam

pin)

bid,

twicedaily;q

d,on

cedaily;tid,threetimes

daily.

4.1 Introduction j79

concomitant treatment of both infections. However, both infections may becomanaged effectively, and the expanded arsenal of antiretroviral drugs betteraddresses drug–drug interactions and overlapping toxicities. Moreover, clinicalstrategy trials are under way.

Figure 4.1 Timeline of the FDA approval of antiretroviral drugs,1987–2008. For drug abbreviations, see Table 4.1.

Figure 4.2 The life cycle of HIV and sites of action of the six classes of inhibitor.


4.2Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs)

The eight approved NRTIs are analogues of the native DNA bases, adenine, cytosine,guanine and thymine, with substitutions at the 30 position of the ribose ring(Figure 4.3). The first antiretroviral agent to be approved, in 1987, was zidovudine(azidothymidine; AZT). One of the first studies of antiretroviral therapy was theBW002 study, in which 288 patients with AIDS or symptomatic HIV disease (thenknown as AIDS-related complex or ARC) were enrolled and then randomized toreceive zidovudine 250mg every 4 h around the clock, versus placebo [3]. After amedian of 127 days, only a single patient in the zidovudine arm died, compared to 19patients in the placebo group (p< 0.001). In addition, 24 patients taking zidovudinehad opportunistic infections compared to 45 receiving the placebo (p< 0.001). Sideeffects and toxicities associated with zidovudine were common, and includednausea, neutropenia, and anemia [4]. Subsequent studies showed that zidovudinedoses as low as 300mg per day were as effective but less toxic [5, 6], and 600mg(300mg twice daily) remains the current standard dose. Although, when used asmonotherapy zidovudine demonstrated only short-term benefits, the drug remaineda common component of both two- and three-drug combination regimens. In fact,only recently has zidovudine fallen out of favor among NRTIs due to its gastroin-testinal and hematologic toxicities and associated lipoatrophy (fat loss of the face orextremities) [7].The next three approved NRTIs – didanosine (ddI), zalcitabine (ddC), and stavudine

(d4T) – became known as the �d-drugs� and, while similarly effective virologically tozidovudine, they were associated with peripheral neuropathy and pancreatitis. Dual-nucleoside regimens of zidovudine and either didanosine or zalcitabine demon-strated clinical benefits over monotherapy regimens [8–10], and quickly became thestandard of care in the early tomid 1990s. In contrast, the combination of zidovudineand stavudine (two thymidine analogues) was antagonistic and caused declines inCD4 cell counts [11]. Ongoing concerns about both antiretroviral activity and toxicityled to thewithdrawal of zalcitabine in 2006, while high rates of lipoatrophy associatedwith stavudine have caused a major decline in its use. Didanosine continues to beused today in a once-daily enteric-coated formulation that must be taken whilefasting. The overlapping drug toxicity of peripheral neuropathy complicates theconcomitant use of d-drugs and TB drugs.The development of the fifth NRTI, lamivudine (3TC), and its use in combination

with zidovudine, was a notable step forward in antiretroviral therapy. Lamivudine is apotent agent with activity against both HIV and hepatitis B virus and little, if any,associated toxicity. Unfortunately, complete HIV drug-resistance is conferred by asingle amino acid substitution in reverse transcriptase at position 184 (M184V,methionine ! valine). The combination of zidovudine þ lamivudine demonstrat-ed potent, durable virologic activity [12, 13], and these two drugs ultimately wereapproved as a coformulated pill in 1997, the first of several popular coformulatedagents that reduced the pill count and improved the convenience of antiretroviraltherapy regimens (Table 4.2).

4.2 Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs) j81

Figu

re4.3

Structureof

thenu

cleosidesandcorrespo

ndingnu

cleoside

analog

ueHIV

reversetranscrip

tase

inhibitors

(NRTIs).


Abacavir, a guanosine analogue, is a potent antiretroviral drug that demonstratedsimilar virologic but superior CD4 responses, compared to zidovudine, when eachwas used as part of a three-drug regimen [14]. Abacavir is associated with ahypersensitivity reaction in 5–8% of patients; this is a life-threatening toxicity thatmay be greatly decreased (if not eliminated) by the use of a genetic screening test forHLA-B�5701 and avoiding the drug in patients with this genetic marker [15]. Initiallythought to be free of other side effects, abacavir use recently was associated withmyocardial infarction in two large retrospective studies [16, 17], although this findingrequires further confirmation. Additionally, ACTG study 5202 included a head-to-head comparison of abacavir/lamivudine and tenofovir/emtricitabine, each com-bined with efavirenz in treatment-na€ıve subjects with pre-treatment HIV RNA levels>100 000 copies/mL, found that the time to virologic failure was significantly shorterwith the abacavir-containing regimen [18]. Currently, abacavir is available as acoformulation with lamivudine alone and as part of a three-drug formulation withzidovudine and lamivudine (Table 4.2).Tenofovirwas approved in 2001 on the basis of its potent antiretroviral activity [19],

and more recently was approved for the treatment of hepatitis B virus infection. Thetoxicity of tenofovir is limited to an uncommon renal toxicity–proximal renal tubulardysfunction (Fanconi�s-like syndrome) that is characterized by glycosuria, hypopho-sphatemia, proteinuria, and elevated serum creatinine. The pharmacokineticssupport once-daily dosing of tenofovir. Tenofovir was coformulated with the eighthapproved NRTI, emtricitabine (a drug that is similar to lamivudine in terms ofvirologic activity, lack of toxicity and drug resistance, but with a longer intracellularhalf-life), and the coformulation was approved as a once-daily dual-nucleosidecomponent in 2004. In 2006, a three-drug coformulation of tenofovir þ emtricita-bine þ efavirenz became the first one-pill, once-daily antiretroviral regimen forHIVinfection, and remains among preferred first-line regimens today [20, 21].In summary, NRTIs remain a component of most antiretroviral drug regimens

today, although their diverse toxicities, which are thought to be due mitochondrial

Table 4.2 Approved coformulated antiretroviral drugs.

Generic names Abbreviation Tradename

Year of FDAapproval

Standard oral dose

zidovudineþ lamivudine ZDV/3TC Combivir 1997 300/150mg bidabacavirþ zidovudineþ lamivudine

ABC/ZDV/3TC Trizivir 2000 300/150/300mg bid

lopinavirþ ritonavir LPV/RTV Kaletra 2000 400/100mg bid or800/200mg qd

abacavirþ lamivudine ABC/3TC Epzicom 2004 600/300mg qdtenofovirþ emtricitabine TDF/FTC Truvada 2004 300/200mg qdtenofovirþ emtricitabineþ efavirenz

TDF/FTC/EFV Atripla 2006 300/200/600mg qd

stavudineþ lamivudineþnevirapine

d4T/3TC/NVP Triomune a 40/150/200mg bid

aGeneric formulation, not FDA-approved for use in the U.S.bid, twice daily; qd once daily.

4.2 Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs) j83

toxicity, limit the use of some members of the class. Of notable concern is theoverlapping toxicity of peripheral neuropathy that is common with some NRTIs(e.g., didanosine, stavudine) and someTBdrugs (e.g., isoniazid). In recent years, less-toxic, convenient once-daily coformulated NRTIs have become the standard of care.The lack of drug–drug interactions between NRTIs and TB drugs makes NRTIs anexcellent choice for inclusion in antiretroviral regimens for the concomitant therapyof HIV infection and TB. Triple NRTI regimens are less potent than NNRTI-basedregimens [22], and are used uncommonly in developed countries. Quadruple NRTIregimens have shown promise, but limited data are available to support theirwidespread use [23]. Hence, most commonly, two NRTIs are used with an NNRTIin the setting of concomitant HIV and TB infections.

4.3Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Whilst the NNRTIs also inhibit the HIV reverse transcriptase enzyme, they bind tothe enzyme at a site remote from the active site where the NRTIs bind, and havediverse, unrelated structures (Figure 4.4). The NNRTIs are potent antiretroviraldrugs and, despite their unrelated structures, share common toxicities of rash andhepatic transaminase elevations. They are metabolized by the cytochrome P450enzyme system, so that drug–drug interactions with other hepatically metabolizeddrugs (including anti-TB drugs) are common occurrences. Drug resistance developseasily to most NNRTIs, and concerns about increasing transmitted NNRTI-resis-tance in the community exist [24].The first NNRTI to be approved, in 1996, was nevirapine. Although potent, a

single amino acid substitution in reverse transcriptase at position 181 (Y181C,

Figure 4.4 Structure of the non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs).


tyrosine ! cytosine) within the NNRTI binding site is enough to confer, rapidly,complete resistance [25]. An early study of three-drug therapy with zidovudine þdidanosine þ nevirapine was conducted in patients with prior NRTI experience, butthe virologic effect was modest [26]. A subsequent investigation of the same three-drug therapy in treatment-na€ıve patients was one of the first studies to show that amajority of patients could achieve maximal and durable virologic suppression [27].Subsequent studies demonstrated elevations of hepatic transaminases, with rashoccurring more commonly (and surprisingly) in patients with higher CD4 cellcounts. A 10-fold increase was identified in women with CD4 cell counts >250ml�1,and a sixfold increase inmenwithCD4 cell counts >400ml�1, compared to thosewithlower CD4 cell counts [28]. Nevertheless, the generic coformulated combination ofstavudine þ lamivudine þ nevirapine is likely the most commonly used regimenworldwide, although ongoing concerns remain regarding the toxicity of bothnevirapine and stavudine. The use of a nevirapine-based regimen with concomitanttreatment for TB is complicated both by an unfavorable drug–drug interaction withrifampin, that reduces nevirapine concentrations by 20–58%, as well as overlappinghepatotoxicity [20]. One prospective South African study identified inferior virologicresponses in HIV-infected patients taking concomitant nevirapine-containing anti-retroviral and TB treatment compared to patients taking nevirapine-containingantiretroviral treatment without TB [29].The second approved NNRTI, delavirdine, requires three-times daily dosing, has

suboptimal potency, and is used rarely. Because of unfavorable drug–drug interac-tions with rifamycins that lead to marked decreases in delavirdine concentrations,concomitant use is contraindicated [20].The thirdNNRTI to be approved, in 1998,was efavirenz. In a seminal Phase III study

(the 006 study), 450 treatment-na€ıve patients were randomized to receive zidovudinelamivudine þ indinavir (control arm), zidovudine þ lamivudine þ efavirenz, or aNRTI-sparing arm of efavirenz þ indinavir [30]. At 48 weeks, the two NRTIs þefavirenz arm proved superior virologically, well-tolerated and convenient, and ledthis combination rapidly to become the standard of care for antiretroviral therapyduring the late 1990s. As above, the one-pill, once-daily coformulation of tenofovir þlamivudine þ efavirenz is recommended among preferred initial antiretroviral

Table 4.3 Recommended initial antiretroviral regimens: Two NRTIs þ [NNRTI or PI].

Two NRTIs NNRTI PI

Preferred TDF/FTC EFV ATVþRTVDRVþRTVFPVþRTV bidLPV/RTV

Alternative ABC/3TC NVP ATVddIþ [FTC or 3TC] FPVZDV/3TC FPVþRTV qd

SQV/RTV

For drug abbreviations, see Tables 4.1 and 4.2.bid, twice daily; qd once daily.

4.3 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) j85

regimens [20, 21] (Table 4.3), and this combination has become the most commonlyprescribed initial regimen inmany countries today. Efavirenz is associatedwith centralnervous system toxicities (e.g., vivid dreams, somnolence) in about 50% of patients,although these symptoms tend to diminish over several weeks [31]; rashmay occur inabout 10% of patients, and hepatotoxicity in about 8%. As with nevirapine, a singleamino acid substitution in reverse transcriptase confers resistance to efavirenz. Anantiretroviral regimen with two NRTIs and efavirenz is commonly used with con-comitant TB treatment, although there is potential for overlapping hepatotoxicity andbecause of a drug–drug interaction with rifampin, the optimal dose of efavirenz (600versus 800mg daily) is not known [20]. A prospective study found similar virologicoutcomes in patients treated with efavirenz-based regimens either with or withoutconcomitant TB treatment [29].The fourth NNRTI, etravirine, was approved in 2008 and is the most recently

introduced antiretroviral drug. Etravirine is the first NNRTI with demonstratedactivity against NNRTI-resistant viral strains. The Phase III DUET studies includedpatients with prior NRTI, NNRTI, and PI treatment experience, and constructed anoptimized background regimen that included the protease inhibitor darunavir alongwith a choice of NRTIs and/or enfuvirtide. The patients were then randomized toreceive etravirine, or not [32, 33]. At 48 weeks, 40% of the group with the optimizedbackground alone and 61% of the group with an optimized background andetravirine had HIV RNA suppressed to <50 copiesml�1. This led to the approvalof etravirine for treatment-experienced patients. However, etravirine is contraindi-cated with concomitant rifampin because of a significant drug–drug interaction [20].In summary, NNRTIs are potent, convenient, and generally well tolerated. Hence,

NNRTI-based regimens are the most commonly used antiretroviral regimens world-wide. However, ongoing concerns regarding transmitted NNRTI-drug resistanceexist, while drug–drug interactions with rifamycins and overlapping hepatotoxicitycomplicate the concomitant use ofNNRTI-based antiretroviral therapywith TB drugs.

4.4HIV Protease Inhibitors

TheHIVPIs were designed as peptidomimetic compounds to bind in the active site ofthe protease enzyme, and were the most potent antiretroviral agents described whenthey entered clinical development during the early 1990s. As a class, the PIs havecomplicated structures (Figure 4.5) and are associated with some class toxicities, suchas transaminase elevations. Some PIs are also associated with lipohypertrophy andhyperlipidemia. The PIs are metabolized by the cytochrome P450 hepatic enzymesystem, and drug–drug interactions are a common occurrence. For example, rifampindecreases the concentrations of all PIs by >75% and their concomitant use is contra-indicated, although rifabutin can be substitutedwith careful dose adjustment [20]. Theprotease inhibitor ritonavir is themostpotent inhibitor of theCYP3A4enzyme isoformeverdescribed; it isusedroutinely at lowdoses to�boost� the levelsof theotherHIVPIs,allowing once- or twice-daily dosing with improved pharmacokinetic properties.


The first three PIs to be approved were saquinavir, ritonavir and indinavir, duringlate 1995-early 1996. Approval was on the basis of landmark studies that paved theway for the development of effective antiretroviral therapy regimens that subse-quently led to dramatic reductions in HIV-related morbidity and mortality [34]. The

Figure 4.5 Structures of the HIV protease inhibitors (PIs).

4.4 HIV Protease Inhibitors j87

first study to show that an HIV PI-containing regimen led to notable clinical effectsincluded 1090 patients with CD4 cell counts<100mm�3, all of whom received none,one, or two NRTIs and then were randomized to add the PI, ritonavir, or matchingplacebo [35]. After a median follow-up of 29 weeks, 22% of the patients receivingritonavir compared to 38%of those receiving placebo had anAIDS-defining illness ordied (p< 0.001). Thus, ritonavir use was associated with a near-50% reduction inclinical events over the short term.The 035 Study was the first to utilize an effective three-drug combination

antiretroviral therapy for the treatment of HIV infection [36]. In this pilot study,97 zidovudine-experienced patients were enrolled and randomized to receive zido-vudine þ lamivudine, indinavir alone, or the three-drug combination of zidovudinelamivudine þ indinavir. At 24 weeks, 0% (zidovudine þ lamivudine) versus 43%(indinavir monotherapy) versus 90% (three drugs) of the patients had HIV RNA<50 copiesml�1. The ACTG 320 Study tested a similar strategy in 1146 zidovudine-experienced patients who received zidovudine þ lamivudine with randomizedindinavir or placebo [37]. After a median follow-up of 38 weeks, AIDS or deathoccurred in 11% (two drugs) versus 6% (three drugs) of patients (p< 0.001). Thus,the indinavir-based regimen was associated with a 50% reduction in clinical events.These two studies defined zidovudine þ lamivudine þ indinavir as the standard ofcare HIV treatment in the mid-1990s.Unfortunately, the initial three PIs had limitations based on their bioavailability

and potency (saquinavir), tolerability (ritonavir), and convenience (indinavir). Con-sequently, additional studies were conducted with newer PIs which includednelfinavir (approved in 1997), amprenavir (1999), and lopinavir/ritonavir (2000).Nelfinavir demonstrated virologic activity [38], was better tolerated (toxicity waslimited to diarrhea in ca. 15–20%of patients), andmore convenient in that it could betaken with food; these benefits led to its widespread use in three-drug combinations.Amprenavir also was potent and reasonably well tolerated, but had a high pill count,which limited its acceptance.The first coformulated PI was lopinavir/ritonavir. Early Phase II studies showed

not only its potency when combined with NRTIs in treatment-na€ıve patients [39], butalso its significant activity in patientswhohad experienced prior virologic failurewhenreceiving other PIs [40]. The coformulation improved convenience over other PIs, anda head-to-head study showed that a lopinavir/ritonavir-based regimen was superior toa nelfinavir-based regimen [41]. On this basis, lopinavir/ritonavir was recommendedas a preferred PI in antiretroviral treatment guidelines [20, 21] (Table 4.3), although theside effects of diarrhea and hyperlipidemia were well recognized.In a more recent head-to-head study, ACTG 5142, a total of 757 patients were

randomized to receive two NRTIs together with either lopinavir or efavirenz, or anNRTI-sparing arm of efavirenz þ lopinavir/ritonavir. Although virologic superiorityof the efavirenz-based regimen was demonstrated, there were significantly betterCD4 responseswith the lopinavir-based regimens, and less drug resistance followingvirologic failure with the two NRTI þ lopinavir/ritonavir regimen [42]. Surprisinglyin this study, efavirenzwas associatedwithmore lipoatrophy than lopinavir/ritonavir,particularly when used with stavudine or zidovudine [43]. Currently, both lopinavir/


ritonavir- and efavirenz-based regimens are recommended among preferred initialantiretroviral regimens in U.S. treatment guidelines [20, 21] (Table 4.3), and both areused commonly internationally.Having recognized the convenience, tolerability, and toxicity challenges of the prior

PIs, atazanavir was developed and approved in 2003 as a once-daily PI withoutsignificant lipid increases, and performed favorably when compared with an efavir-enz-based regimen [44]. One unique laboratory abnormality – an increased indirectbilirubin (Gilbert�s-like syndrome) – is due to atazanavir inhibiting the uridine 50-diphospho-glucuronosyl-transferase (UGT) 1A1 enzyme; the drug has few other sideeffects. The addition of ritonavir boosting improves the pharmacokinetic profile ofatazanavir, althoughsomeof the lipidbenefits appear tobe lost.Atazanavir þ ritonavircompared favorably with lopinavir/ritonavir in both the CASTLE study of 883 treat-ment-na€ıvepatients [45],andalsoanotherstudyof358PI-experiencedpatients [46].Theresults of these studies supported the addition of atazanavir þ ritonavir to the list ofpreferred protease inhibitors in treatment guidelines [20, 21] (Table 4.3).Fosamprenavir is a pro-drug of amprenavir with reduced pill count that was

approved in 2003 and subsequently prompted the withdrawal of amprenavir (withthe exception of the liquid formulation) from the market. In the KLEAN study, 878treatment-na€ıve patients who took NRTIs and were randomized to fosamprenavirþ ritonavir- or lopinavir/ritonavir-based regimens did comparably well [47], sup-porting the use of samprenavir þ ritonavir as a preferred PI in the treatmentguidelines [20, 21] (Table 4.3).Although patients who experienced virologic failure on potent PI-containing

regimens in clinical trials often showed few PI-associated mutations, other patientsdeveloped numerous mutations; consequently, additional compounds were soughtthat would demonstrate activity against PI-resistant viral strains. The two mostrecently approved HIV PIs (tipranavir in 2005 and darunavir in 2006) share theproperty of virologic activity against PI-resistant strains. Each has been approved forthe treatment of PI-experienced patients and, importantly, these PIs are not routinelycross-resistant to one another.Tipranavir was approved based on the results of the Phase III RESIST studies in

which 1483 treatment-experienced patients were enrolled and their backgroundregimen optimized on the basis of treatment history and drug resistance testing.Patients were then randomized to receive either tipranavir or placebo [48]. Thetipranavir regimen performed significantly better, with 23% of patients having HIVRNA<50 copiesml�1 at week 48 compared to 10% of those on placebo (p< 0.0001).Tipranavir is associated with hepatic transaminase elevations and some importantdrug–drug interactions, including its contraindication with the use of etravirine.Darunavir was tested in a similar way in the Phase II/III POWER studies which

included 596 treatment-experienced patients who received an optimized backgroundregimen, with or without darunavir [49, 50]. Ultimately, darunavir at the standarddose led to 39–53% of patients with HIV RNA <50 copiesml�1 at 48 weeks,compared to 7–18% in the placebo arm (p< 0.001). More recently, darunavir wastested in patients in earlier stages of HIV disease. Darunavir þ ritonavir wascompared to lopinavir-ritonavir in 595 PI-experienced, lopinavir/na€ıve patients in

4.4 HIV Protease Inhibitors j89

the TITANstudy [51], and in 689 treatment-na€ıve patients in theARTEMIS study [52].In both studies, the darunavir regimen performed similar virologically to thelopinavir regimen, with darunavir having fewer liver function test and lipid abnor-malities, fewer discontinuations for diarrhea in the treatment-experienced study, andfewer gastrointestinal side effects and treatment-related discontinuations in thetreatment-na€ıve study. These data support the use of darunavir-based antiretroviraltherapy among the preferred initial treatment choices [20, 21] (Table 4.3).In summary, HIV PIs constituted the backbone for the first potent three-drug

combination antiretroviral regimens for the effective treatment of HIV disease.Limitations of convenience, tolerability, toxicity, and drug resistance have beenovercome with the development of newer members of this drug class. However,drug–drug interactions and overlapping toxicities such as hepatotoxicity complicatetheir use with concomitant TB medications. The high cost of PIs also creates achallenge for their routine use in resource-poor settings.

4.5Newer Classes: Entry Inhibitors and Integrase Inhibitors

Drugs with new mechanisms of action would be expected to show activity againstHIVstrains that are resistant to the conventional classes of drugs, such as the NRTIs,NNRTIs, and PIs.

4.5.1Entry Inhibitors

The first member of a new class of antiretroviral drugs to be approved for almost adecade, in 2003, was the fusion inhibitor, enfuvirtide (envelope fusion viral peptide,T-20). HIV entry is a three-step process: (1) HIV recognizes its target cell through thebinding of HIV outer membrane glycoprotein (gp) 120 to the CD4 receptor; thisbinding induces a conformational change in gp 120 allowing (2) binding of gp 120 tothe coreceptor or chemokine receptor (either CCR5 or CXCR4). This, in turn, inducesa second HIV outer membrane glycoprotein (gp 41) to insert in the cell membrane,anchoring the viral particle to theCD4 cell (3a). This is followedby a folding of gp 41 onitself in a coil-on-coil interaction (3b) that, in turn, allows fusion of the viralmembraneand the CD4 cell membrane (3d) [53] (Figure 4.6). Enfuvirtide is a small peptide thatbinds to gp41 and prevents membrane fusion. Although the landmark Phase IIITORO studies demonstrated potent virologic activity of enfuvirtide in treatment-experiencedpatients [54, 55], enfuvirtide (a peptide) requires twice-daily subcutaneousdosing, is costly, and therefore is used only rarely today.The second inhibitor of HIVentry to be approved, in 2007, wasmaraviroc. This is a

CCR5 antagonist that binds not to a viral target but rather to the CC-chemokinereceptor 5 (CCR5) on the surface of the host CD4 cell (Figure 4.6). In binding CCR5,maraviroc prevents entry of R5, but not of X4 viruses [56]. In theMOTIVATE studies,1049 treatment-experienced patients with documented R5 viruses (only) using a


tropismassay optimized their background regimens on the basis of treatment historyand drug-resistance testing, and then were randomized to receive either maraviroc(at one of two doses) or matching placebo [57]. In total, 46% of the maraviroc twice-daily recipients compared to 17% of placebo recipients had HIV RNA <50 copiesml�1 at week 48 (p< 0.001). Sincemaraviroc was the first antiretroviral drug to targeta host immune cell receptor, concerns about immune effects or unusual toxicitieshave been raised. In patients congenitally lacking the CCR5 receptor, there aredemonstrable immune effects, e.g. increasedmorbidity andmortality followingWestNile Virus infection [58]. However, no excess hepatic toxicity, unusual infections ormalignancies were associated with maraviroc use in the MOTIVATE studies, incontrast to other investigational CCR5 antagonists [59, 60]. Of note, the Food andDrug Administration (FDA) required that all study subjects who received a CCR5antagonist in a clinical trial be followed for clinical events for five years. The use ofCCR5 antagonists in developing countries represents amajor challenge due to a needfor the viral tropism assay. The concomitant treatment of TB and HIV with amaraviroc-containing regimen is also complicated by a significant drug–druginteraction, whereby rifampin cause a >60% decrease in maraviroc concentrationsthat would necessitate the maraviroc dose to be adjusted. At present, no data areavailable regarding any interactions of maraviroc with rifabutin [20].

4.5.2Integrase Inhibitors

The most recently approved member of a new class of drugs was the strand transferintegrase inhibitor, raltegravir. The HIV integrase enzyme catalyzes three steps of

HIV Entry Mechanism

3c. FusionComplete

1. CD4Attachment

3b. coil-coilinteraction

CXCR4CCR5

gp120

3a. Anchorage

CD4

2. Co-receptorinteraction

Cell

HIV

HIV

HIV

HIV

HIV

gp41

gp41

HIV

ChemokineReceptorInhibitors

FusionInhibitors

R5 or X4

Figure 4.6 Mechanism of action of the HIV entry inhibitors.

4.5 Newer Classes: Entry Inhibitors and Integrase Inhibitors j91

integration: (1) formation of the double-stranded viral DNA complex; (2) the 30-processing of the DNA; and (3) transport and insertion of the viral DNA into the hostcell DNA in a process called �strand transfer� [61] (Figure 4.7). Raltegravir wasapproved in 2007 on the basis of demonstrating significant virologic activity in thebenchmark studies of 699 treatment-experienced patients in the BENCHMRKstudies, whereby 62% of raltegravir versus 33% of placebo recipients had HIV RNA<50 copiesml�1 at 48 weeks (p< 0.001) [62]. However, the majority of patients whoexperienced virologic failure also developed drug resistance to raltegravir [63].Raltegravir also was compared to efavirenz, both in combination with NRTIs, in aPhase II study of treatment-na€ıve patients and demonstrated comparable virologicsuppression rates with 85–95% of patients having HIV RNA <50 copiesml�1

through 48 weeks [64, 65]. Raltegravir demonstrated a side-effect profile similar tothat of placebo in all of these studies. Whilst raltegravir is metabolized by glucur-onidation, concomitant administration with rifampin causes a 40–60% decrease inraltegravir concentrations, thus complicating the concomitant treatment of TB [20].In summary, drugs with newmechanisms of action, such as HIV entry inhibitors

and integrase inhibitors, have demonstrated significant virologic activity in patientswith resistance to NRTIs, NNRTIs, and PIs. Consequently, new drugs have revolu-tionized the goals andmanagement of treatment-experienced patients, setting a newstandard of virologic response: HIV RNA levels suppressed to <50 copiesml�1 [20,21]. Unfortunately, these newer drugs are limited by their higher cost, the need forparenteral administration of enfuvirtide the restriction of activity to R5 virus (only)and the need for the tropism assay, in the case of maraviroc, and a low barrier toresistance for raltegravir. Significant drug–drug interactions of maraviroc or ralte-gravir with rifampin also further complicate the use of these drugs.

2In-DependintProcessingof 3'Ends

1Assembly on Viral DNA in aNucleoprotein Complex

Gap Repall

MatureProvirus

NuclearEntry

Viral DNA Synthesis

X

3aTargetDNA

Binding3b

ConcertedTarget DNACleavage

and joining

Strand TransferInhibitors

Nuclear Membrane

Figure 4.7 Mechanism of action of the HIV integrase inhibitors.


4.6Newer Strategies

While current combination antiretroviral therapy regimens are highly effective, theirlimitations of convenience, tolerability, toxicity, drug–drug interactions and activityagainst drug-resistant viral strains continue to prompt the search for new strategiesand newer antiretroviral agents. The current preferred initial therapy for HIVinfection is a regimen consisting of two NRTIs in combination with an NNRTI ora ritonavir-boosted PI [20, 21] (Table 4.3), on the basis of results from largerandomized, comparative clinical trials [7, 14, 30, 41, 45, 47]. Studies comparingpreferred NNRTI-based regimens with PI regimens have demonstrated distinctbenefits to both strategies [42, 44], and support either approach.Newer strategies for treatment-na€ıve patients include some novel approaches. All-

NRTI regimens have the potential to avoid drug–drug interactions, particularly withthe hepatically metabolized NNRTIs and PIs and TB drugs. However, three-NRTIregimens are less potent than NNRTI-based regimens [22], while four-NRTI regi-mens have not yet been studied extensively [23] and could have toxicity problems oftheir own. An NRTI-sparing approach to avoid NRTI-related toxicities also has beenexplored, typically consisting of an NNRTI together with a ritonavir-boosted PI.However, these regimens have been associated with toxicity [30] and/or increasedrates of drug resistance at virologic failure [42], continue to have significantdrug–drug interaction issues, and have not been adopted widely.Newer compounds may challenge the existing drugs and treatment paradigms

(Table 4.4).When combinedwith dualNRTIs, an investigationalNNRTI – rilpivirine –showed comparable virologic responses to efavirenz but was associated with fewerrashes and central nervous system toxicity in a Phase II study for up to 96 weeks [66].Rilpivirine is currently under investigation in large Phase III studies. Rilpivirine isalso available in an investigational nanoparticle formulation with a prolonged drug

Table 4.4 Investigational antiretroviral agents in clinical development (partial list only).

Stage ofdevelopment

NRTIs NNRTIs PIs Entryinhibitors

Integraseinhibitors

Maturationinhibitors

Phase III rilpivirine vicriviroc elvitegravirPhase II apricitabine BILR-355 ibalizumab bevirimat

dexelvucitabine UK-453,061 PRO 140Phase I/II amdoxovir IDX-899 HGS004 GSK

compoundsMPC-9055

elvucitabine RDEA-806 PRO 542Phase I PPL-100 PF-232798 INH-1001

SPI-256 SCH-532706TBR 652TRI-1144

4.6 Newer Strategies j93

half-life that allows dosing as infrequently as once a month [67]. Additional newerformulations of antiretroviral agents may allow infrequent dosing of antiretroviraltherapy.Newer drugs approved for treatment-experienced patients also may offer benefits

to treatment-na€ıve patients as part of combination regimens. For example, darunavirwas non-inferior virologically to lopinavir/ritonavir and had fewer side effects [52].Maraviroc was non-inferior to efavirenz as part of a three-drug regimen for the HIVRNA<400 copiesml�1 endpoint, but not for<50 copiesml�1 [68], although tropismassay sensitivity most likely played a role. A raltegravir-based regimen had compa-rable virologic responses to an efavirenz-based regimen over 96 weeks, and astatistically significantly more rapid time to virologic suppression [64, 69]; similarlydesigned Phase III raltegravir studies provided similar preliminary results [65].With the development of these newer agents in treatment-na€ıve patients, new

potentially paradigm-shifting strategies could be tested that could spare severalclasses of drugs. For example, the combination of a PIwith an integrase inhibitor or aCCR5 antagonist could spare both NRTIs and NNRTIs. Similarly, a standardcombination regimen of NRTIs and an NNRTI could be used first and then, afterregimen failure, a new regimen consisting of a PI with an integrase inhibitor or aCCR5 antagonist could be used. This would define a sequence of two fully potentantiretroviral therapy regimens with distinct mechanisms of action and nonover-lapping drug resistance profiles, although drug–drug interactions (including thosewith TB medications) would complicate these new approaches. Consequently, pilotstudies investigating such possibilities are currently in progress.For patients with significant treatment experience, the current guidelines recom-

mend reviewing the treatment history, performing drug-resistance testing, anddesigning a regimen with two (or preferably three) fully active agents in the nextregimen [20, 21]. A number of investigational compounds in existing classes(NRTIs, NNRTIs, PIs), in newer approved classes (CCR5 antagonists, integraseinhibitors), or in investigational classes (CD4 attachment inhibitors, CXCR4antagonists, maturation inhibitors) have demonstrated activity against drug-resistant viruses, andmay be particularly useful for treatment-experienced patientsif they are proved safe and effective (Table 4.4). Today, the �pipeline� for newantiretroviral agents appears full.

4.7Concomitant Treatment of HIV Infection and Tuberculosis

The current guidelines emphasize that the treatment of HIV-infected patients withactive TB should follow the same principles as for HIV-infected patients withoutTB [20]. Although the optimum time to start antiretroviral therapy in patients withactive TB is not known, a number of clinical trials are under way [70]. Neither arethe optimal antiretroviral regimens to treat HIV-infected patients with TB known,although NRTI combinations that do not cause peripheral neuropathy (e.g.,abacavir/lamivudine, tenofovir/emtricitabine, or zidovudine/lamivudine), in


combination with a NNRTI withmanageable drug interactions and a lower potentialfor overlapping hepatotoxicity (e.g., efavirenz), have demonstrated virologic out-comes that are not different from those in treated HIV-infected patients withoutTB [29]. The treatment of HIV and TB can be successfully managed, and theintegration of care and treatment for both infections is clearly critical. In addition,clinical trials are in progress that will continue to define the optimal strategies forconcomitant treatment [70].

4.8Conclusions

The development of effective antiretroviral therapy changed the natural history ofHIV disease, with dramatic decreases in morbidity and mortality worldwide. Today,the life expectancy of HIV-infected people receiving treatment is approaching that ofthe general population. With effective treatment, HIV has been transformed into achronic, manageable disease; consequently, more convenient, more tolerable andless-toxic medications are critical for long-term adherence and clinical responses.More recently, the development of new drugs in existing classes with activity againstdrug-resistant virus (e.g., NNRTIs, PIs), and of drugswith newmechanisms of action(HIV entry inhibitors, integrase inhibitors), has offered greatly improved treatmentoptions for individuals with treatment experience and/or drug-resistant viral strains.Newer compounds and strategies continue to be tested and will ensure furtherprogress in the field. The concomitant treatment of HIV infection and TB iscomplicated by overlapping drug toxicities, drug–drug interactions, and the incon-venience of multidrug regimens. However, effective comanagement strategies arepossible, and clinical trials are either planned or underway to ensure further progressin this area.

References

1 Lohse, N., Hansen, A.B., Pedersen, G.,Romberg, G., Gestalt, J., Sorensen, H.T.,Viet, M. and Nobel, N. (2007) Survival ofpersons with and without HIV infection inDenmark, 1995–2005. Ann. Intern. Med.,146, 87–95.

2 Bhaskaran, K., Hamouda, O., Sannes, M.,Boufassa, F., Johnson, A.M., Lambert, P.C.,Porter, K., CASCADE Collaboration (2008)Changes in the risk of death after HIVseroconversion compared with mortality inthe general population. JAMA, 300, 51–59.

3 Fischl, M.A., Richman, D.D., Grieco,M.H., Gottlieb, M.S., Volberding, P.A.,

Laskin, O.L., Leedom, J.M. et al. (1987) Theefficacy of azidothymidine (AZT) in thetreatment of patientswithAIDSandAIDS-related complex. A double-blind, placebo-controlled trial. N. Engl. J. Med., 317,185–191.

4 Richman, D.D., Fischl, M.A., Grieco,M.H., Gottlieb, M.S., Volberding, P.A.,Laskin, O.L., Leedom, J.M. et al. (1987) Thetoxicity of azidothymidine (AZT) in thetreatment of patientswithAIDSandAIDS-related complex. A double-blind, placebo-controlled trial. N. Engl. J. Med., 317,192–197.

References j95

5 Collier, A.C., Bozzette, S., Coombs, R.W.,Causey, D.M., Schoenfeld, D.A., Spector,S.A., Pettinelli, C.B. et al. (1990) A pilotstudy of low-dose zidovudine in humanimmunodeficiency virus infection. N.Engl. J. Med., 323, 1015–1021.

6 Volberding, P.A., Lagakos, S.W., Koch,M.A., Pettinelli, C., Myers, M.W., Booth,D.K., Balfour, H.H. Jr et al. (1990)Zidovudine in asymptomatic humanimmunodeficiency virus infection. Acontrolled trial in persons with fewer than500 CD4-positive cells per cubicmillimetre. The AIDS Clinical TrialsGroup of the National Institute of Allergyand Infectious Diseases. N. Engl. J. Med.,322, 941–949.

7 Gallant, J.E., DeJesus, E., Arribas, J.R.,Pozniak, A.L., Gazzard, B., Campo, R.E.,Lu, B. et al., Study 934 Group (2006)Tenofovir DF, emtricitabine, and efavirenzvs. zidovudine, lamivudine, and efavirenzfor HIV. N. Engl. J. Med., 354, 251–260.

8 Hammer, S.M., Katzenstein, D.A.,Hughes, M.D., Gundacker, H., Schooley,R.T., Haubrich, R.H., Henry, W.K. and theAIDS Clinical Trials Group Study 175Study Team (1996) A trial comparingnucleoside monotherapy withcombination therapy in HIV-infectedadults with CD4 cell counts from 200 to500 per cubic millimetre. N. Engl. J. Med.,335, 1081–1090.

9 Delta Coordinating Committee (1996)Delta: a randomised double-blindcontrolled trial comparing combinationsof zidovudine plus didanosine orzalcitabine with zidovudine alone inHIV-infected individuals. Lancet, 348,283–291.

10 Saravolatz, L.D., Winslow, D.L., Collins,G., Hodges, J.S., Pettinelli, C., Stein, D.S.,Markowitz, N. and the Investigators for theTerry Beirn Community Programs forClinical Research on AIDS (1996)Zidovudine alone or in combination withdidanosine or zalcitabine in HIV-infectedpatients with the acquiredimmunodeficiency syndrome or fewer

than 200CD4 cells per cubicmillimetre.N.Engl. J. Med., 335, 1099–1106.

11 Havlir, D.V., Tierney, C., Friedland, G.H.,Pollard, R.B., Smeaton, L., Sommadossi,J.P., Fox, L. et al. (2000) In vivo antagonismwith zidovudine plus stavudinecombination therapy. J. Infect. Dis., 182,321–325.

12 Bartlett, J.A., Benoit, S.L., Johnson, V.A.,Quinn, J.B., Sepulveda, G.E., Ehmann,W.C., Tsoukas, C. and the North AmericanHIV Working Party (1996) Lamivudineplus zidovudine compared withzalcitabine plus zidovudine in patientswith HIV infection. A randomized,double-blind, placebo-controlled trial.Ann. Intern. Med., 125, 161–172.

13 Eron, J.J., Benoit, S.L., Jemsek, J.,MacArthur, R.D., Santana, J., Quinn, J.B.,Kuritzkes, D.R. and the North AmericanHIVWorking Party (1995) Treatment withlamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4þcells per cubic millimetre.N. Engl. J. Med.,333, 1662–1669.

14 DeJesus, E., Herrera, G., Teofilo, E.,Gerstoft, J., Buendia, C.B., Brand, J.D.,Brothers, C.H. and the CNA30024 StudyTeam (2004) Abacavir versus zidovudinecombined with lamivudine and efavirenz,for the treatment of antiretroviral-naiveHIV-infected adults. Clin. Infect. Dis., 39,1038–1046.

15 Mallal, S., Phillips, E., Carosi, G., Molina,J.M., Workman, C., Tomazic, J., J€agel-Guedes, E. and the PREDICT-1 StudyTeam (2008) HLA-B�5701 screening forhypersensitivity to abacavir. N. Engl. J.Med., 358, 568–579.

16 Sabin, C.A., Worm, S.W., Weber, R., Reiss,P., El-Sadr,W.,Dabis, F., DeWit, S. and theD:A:D Study Group (2008) Use ofnucleoside reverse transcriptase inhibitorsand risk of myocardial infarction in HIV-infected patients enrolled in the D:A:Dstudy: a multi-cohort collaboration. Lancet,371, 1417–1426.

17 Strategies for Management of Anti-Retroviral Therapy/INSIGHT; DAD Study


Groups (2008) Use of nucleoside reversetranscriptase inhibitors and risk ofmyocardial infarction in HIV-infectedpatients. AIDS, 22, F17–F24

18 Sax, P., Tierney, C., Collier, A., Fischl, M.,Godfrey, C., Jahed, N. et al. (2008) ACTG5202: shorter time to virologic failure (VF)with abacavir/lamivudine (ABC/3TC) thantenofovir/emtricitabine (TDF/FTC) as partof combination therapy in treatment-na€ıvesubjects with screening HIV RNA�100,000 c/ml. InProgramsandAbstractsof the XVII International AIDSConference, Mexico City, August 3–8,abstract #THAB0303.

19 Schooley, R.T., Ruane, P., Myers, R.A.,Beall, G., Lampiris, H., Berger, D., Chen,S.S., Miller, M.D. and the Study 902 Team(2002) Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study.AIDS, 16, 1257–1263.

20 Panel on Clinical Practices for theTreatment of HIV Infection. Guidelinesfor the use of antiretroviral agents inHIV-infected adults and adolescents.www.aids.info.org. November 3, 2008update.

21 Hammer, S.M., Eron, J.J. Jr, Reiss, P. et al.(2008) Antiretroviral treatment of adultHIV infection: 2008 recommendations ofthe International AIDSSociety-USApanel.JAMA, 300, 555–570.

22 Gulick, R.M., Ribaudo, H.J., Shikuma,C.M., Lustgarten, S., Squires, K.E., Meyer,W.A. 3rd, Acosta, E.P. and the AIDSClinical Trials Group Study A5095 Team(2004) Triple-nucleoside regimens versusefavirenz-containing regimens for theinitial treatment of HIV-1 infection. N.Engl. J. Med., 350, 1850–1861.

23 Moyle, G.,Higgs, C., Teague, A.,Mandalia,S., Nelson,M., Johnson,M., Fisher,M. andGazzard, B. (2006) An open-label,randomized comparative pilot study of asingle-class quadruple therapy regimenversus a 2-class triple therapy regimen forindividuals initiating antiretroviraltherapy. Antivir. Ther., 11, 73–78.

24 Weinstock, H.S., Zaidi, I., Heneine, W.,Bennett, D., Garcia-Lerma, J.G., Douglas,J.M. Jr, LaLota, M. et al. (2004) Theepidemiology of antiretroviral drugresistance among drug-na€ıve HIV-1-infected persons in 10 US cities. J. Infect.Dis., 189, 2174–2180.

25 Richman, D.D., Havlir, D., Corbeil, J.,Looney, D., Ignacio, C., Spector, S.A.,Sullivan, J. et al. (1994) Nevirapineresistance mutations of humanimmunodeficiency virus type 1 selectedduring therapy. J. Virol., 68, 1660–1666.

26 D�Aquila, R.T., Hughes, M.D., Johnson,V.A., Fischl, M.A., Sommadossi, J.P., Liou,S.H., Timpone, J. and the NationalInstitute of Allergy and InfectiousDiseases AIDS Clinical Trials GroupProtocol 241 Investigators (1996)Nevirapine, zidovudine, and didanosinecomparedwith zidovudine and didanosinein patients with HIV-1 infection, Arandomized, double-blind, placebo-controlled trial. Ann. Intern. Med., 124,1019–1030.

27 Montaner, J.S., Reiss, P., Cooper, D., Vella,S., Harris,M., Conway, B.,Wainberg,M.A.et al. (1998) A randomized, double-blindtrial comparing combinations ofnevirapine, didanosine, and zidovudinefor HIV-infected patients: the INCAS(Italy, The Netherlands, Canada andAustralia Study) Trial. JAMA, 279,930–937.

28 Baylor, M.S. and Johann-Liang, R. (2004)Hepatotoxicity associated with nevirapineuse. J. Acquir. Immune Defic. Syndr., 35,538–539.

29 Boulle, A., Van Cutsem, G., Cohen, K.,Hilderbrand,K.,Mathee, S., Abrahams,M.et al. (2008) Outcomes of nevirapine- andefavirenz-based antiretroviral therapywhen coadministered with rifampicin-based antitubercular therapy. JAMA, 300,530–539.

30 Staszewski, S., Morales-Ramirez, J.,Tashima, K.T., Rachlis, A., Skiest, D.,Stanford, J., Stryker, R. et al. (1999)Efavirenz plus zidovudine and

References j97

lamivudine, efavirenz plus indinavir, andindinavir plus zidovudine and lamivudinein the treatment of HIV-1 infection inadults, Study 006 Team. N. Engl. J. Med.,341, 1865–1873.

31 Clifford, D.B., Evans, S., Yang, Y., Acosta,E.P., Goodkin, K., Tashima, K., Simpson,D. et al. (2005) Impact of efavirenz onneuropsychological performance andsymptoms in HIV-infected individuals.Ann. Intern. Med., 143, 714–721.

32 Madruga, J.V., Cahn, P., Grinsztejn, B.,Haubrich, R., Lalezari, J., Mills, A., Pialoux,G. and the DUET-1 study group (2007)Efficacy and safety of TMC125 (etravirine)in treatment-experienced HIV-1-infectedpatients in DUET-1: 24-week results from arandomised, double-blind, placebo-controlled trial. Lancet, 370, 29–38.

33 Lazzarin, A., Campbell, T., Clotet, B.,Johnson, M., Katlama, C., Moll, A.,Towner, W. and the DUET-2 study group(2007) Efficacy and safety of TMC125(etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-weekresults from a randomised, double-blind,placebo-controlled trial. Lancet, 370,39–48.

34 Palella, F.J. Jr, Delaney, K.M., Moorman,A.C., Loveless, M.O., Fuhrer, J., Satten,G.A., Aschman, D.J. and Holmberg, S.D.(1998) Declining morbidity and mortalityamong patients with advanced humanimmunodeficiency virus infection.N. Engl. J. Med., 338, 853–860.

35 Cameron, D.W., Heath-Chiozzi, M.,Danner, S., Cohen, C., Kravcik, S.,Maurath, C., Sun, E. and The AdvancedHIVDisease Ritonavir StudyGroup (1998)Randomised placebo-controlled trial ofritonavir in advanced HIV-1 disease.Lancet, 351, 543–549.

36 Gulick, R.M., Mellors, J.W., Havlir, D.,Eron, J.J., Gonzalez, C., McMahon, D.,Richman,D.D. et al. (1997) Treatmentwithindinavir, zidovudine, and lamivudine inadults with human immunodeficiencyvirus infection and prior antiretroviraltherapy. N. Engl. J. Med., 337, 734–739.

37 Hammer, S.M., Squires, K.E., Hughes,M.D., Grimes, J.M., Demeter, L.M.,Currier, J.S., Eron, J.J. Jr, and the AIDSClinical Trials Group 320 Study Team(1997) A controlled trial of two nucleosideanalogues plus indinavir in persons withhuman immunodeficiency virus infectionand CD4 cell counts of 200 per cubicmillimeter or less. N. Engl. J. Med., 337,725–733.

38 Saag,M.S., Tebas, P., Sension,M., Conant,M., Myers, R., Chapman, S.K., Anderson,R., Clendeninn, N., and the ViraceptCollaborative Study Group (2001)Randomized, double-blind comparison oftwo nelfinavir doses plus nucleosides inHIV-infected patients (Agouron study511). AIDS, 15, 1971–1978.

39 Murphy, R.L., Brun, S., Hicks, C., Eron,J.J., Gulick, R., King, M., White, A.C. Jr.et al. (2001) ABT 378/ritonavir plusstavudine and lamivudine for thetreatment of antiretroviral-naive adultswith HIV-1 infection: 48-week results.AIDS, 15, F1–F9.

40 Benson, C.A., Deeks, S.G., Brun, S.C.,Gulick, R.M., Eron, J.J., Kessler, H.A.,Murphy, R.L. et al. (2002) Safety andantiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleosidereverse-transcriptase inhibitors in humanimmunodeficiency virus type 1-infectedprotease inhibitor-experienced patients.J. Infect. Dis., 185, 599–607.

41 Walmsley, S., Bernstein, B., King, M.,Arribas, J., Beall, G., Ruane, P., Johnson,M. and the M98-863 Study Team (2002)Lopinavir-ritonavir versus nelfinavir forthe initial treatment of HIV infection.N. Engl. J. Med., 346, 2039–2046.

42 Riddler, S.A., Haubrich, R., DiRienzo,A.G., Peeples, L., Powderly, W.G.,Klingman, K.L., Garren, K.W. and theAIDS Clinical Trials Group Study A5142Team (2008) Class-sparing regimens forinitial treatment of HIV-1 infection.N. Engl. J. Med., 358, 2095–2106.

43 Haubrich, R.H., Riddler, S., DiRienzo, G.,Komarow, L., Powderly, W.G., Klingman,


K., Garren, K.W., et al., and the AIDSClinical Trials Group (ACTG) A5142 StudyTeam (2009) Metabolic outcomes in arandomized trial of nucleoside,nonnucleoside and protease inhibitor-sparing regimens for initial HIVtreatment, AIDS, 23,1109–18.

44 Squires, K., Lazzarin, A., Gatell, J.M.,Powderly, W.G., Pokrovskiy, V., Delfraissy,J.F., Jemsek, J. et al. (2004) Comparison ofonce-daily atazanavir with efavirenz, eachin combinationwithfixed-dose zidovudineand lamivudine, as initial therapy forpatients infected with HIV. J. Acquir.Immune Defic. Syndr., 36, 1011–1019.

45 Molina, J.M., Andrade-Villanueva, J.,Echevarria, J., Chetchotisakd, P., Corral, J.,David, N., Moyle, G. and the CASTLEStudy Team (2008) Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination withtenofovir and emtricitabine, formanagement of antiretroviral-naive HIV-1-infected patients: 48 week efficacy andsafety results of the CASTLE study. Lancet,372, 646–655.

46 Johnson,M.,Grinsztejn, B., Rodriguez,C.,Coco, J., DeJesus, E., Lazzarin, A.,Lichtenstein, K. et al. (2005) Atazanavirplus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencingmultiplevirological failures. AIDS, 19, 685–694.

47 Eron, J.J. Jr, Yeni, P., Gathe, J. Jr, Estrada,V., DeJesus, E., Staszewski, S., Lackey, P.and the KLEAN study team (2006) TheKLEAN study of fosamprenavir-ritonavirversus lopinavir-ritonavir, each incombinationwith abacavir-lamivudine, forinitial treatment of HIV infection over 48weeks: a randomised non-inferiority trial.Lancet, 368, 476–482.

48 Hicks, C.B., Cahn, P., Cooper, D.A.,Walmsley, S.L., Katlama, C., Clotet, B.,Lazzarin, A. and the RESIST investigatorgroup (2006)Durable efficacy of tipranavir-ritonavir in combination with anoptimized background regimen ofantiretroviral drugs for treatment-experienced HIV-1-infected patients at 48

weeks in the Randomized Evaluation ofStrategic Intervention in multi-drugresistant patients with Tipranavir(RESIST) studies: an analysis of combineddata from two randomised open-labeltrials. Lancet, 368, 466–475.

49 Katlama, C., Esposito, R., Gatell, J.M.,Goffard, J.C., Grinsztejn, B., Pozniak, A.,Rockstroh, J. and the POWER 1 studygroup (2007) Efficacy and safety ofTMC114/ritonavir in treatment-experienced HIV patients: 24-week resultsof POWER 1. AIDS, 21, 395–402.

50 Haubrich, R., Berger, D., Chiliade, P.,Colson, A., Conant, M., Gallant, J. et al.(2007) Week 24 efficacy and safety ofTMC114/ritonavir in treatment-experienced HIV patients: POWER 2.AIDS, 21, F11–18.

51 Madruga, J.V., Berger, D., McMurchie, M.,Suter, F., Banhegyi, D., Ruxrungtham, K.,Norris, D. and the TITAN study group(2007) Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients inTITAN: a randomised controlled phase IIItrial. Lancet, 370, 49–58.

52 Ortiz, R., Dejesus, E., Khanlou, H.,Voronin, E., van Lunzen, J., Andrade-Villanueva, J., Fourie, J. et al. (2008)Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir intreatment-naive HIV-1-infected patients atweek 48. AIDS, 22, 1389–1397.

53 Moore, J.P. and Doms, R.W. (2003) Theentry of entry inhibitors: a fusion ofscience andmedicine. Proc. Natl Acad. Sci.USA, 100, 10598–10602.

54 Lalezari, J.P., Henry, K., O�Hearn, M.,Montaner, J.S., Piliero, P.J., Trottier, B.,Walmsley, S. and the TORO 1 StudyGroup(2003) Enfuvirtide, an HIV-1 fusioninhibitor, for drug-resistant HIV infectionin North and South America. N. Engl. J.Med., 348, 2175–2185.

55 Lazzarin,A.,Clotet, B.,Cooper,D., Reynes,J., Arast�eh, K., Nelson,M., Katlama, C. andthe TORO2StudyGroup (2003) Efficacy of

References j99

enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia.N. Engl. J. Med., 348, 2186–2195.

56 Dorr, P., Westby, M., Dobbs, S., Griffin, P.,Irvine, B., Macartney, M., Mori, J. et al.(2005) Maraviroc (UK-427,857), a potent,orally bioavailable, and selective small-molecule inhibitor of chemokine receptorCCR5 with broad-spectrum anti-humanimmunodeficiency virus type 1 activity.Antimicrob. Agents Chemother., 49,4721–4732.

57 Gulick, R.M., Lalezari, J., Goodrich, J.,Clumeck, N., DeJesus, E., Horban, A.,Nadler, J. et al. (2008) Maraviroc forpreviously treated patients with R5 HIV-1infection.N. Engl. J. Med., 359, 1429–1441.

58 Glass, W.G., McDermott, D.H., Lim, J.K.,Lekhong, S., Yu, S.F., Frank, W.A., Pape, J.et al. (2006) CCR5 deficiency increases riskof symptomatic West Nile virus infection.J. Exp. Med., 203, 35–40.

59 Nichols, W.G., Steel, H.M., Bonny, T.,Adkison, K., Curtis, L., Millard, J., Kabeya,K. and Clumeck, N. (2008) Hepatotoxicityobserved in clinical trials of aplaviroc(GW873140). Antimicrob. AgentsChemother., 52, 858–865.

60 Gulick, R.M., Su, Z., Flexner, C., Hughes,M.D., Skolnik, P.R., Wilkin, T.J., Gross, R.and the AIDS Clinical Trials Group 5211Team (2007) Phase 2 study of the safetyand efficacy of vicriviroc, a CCR5inhibitor, in HIV-1-Infected, treatment-experienced patients. J. Infect. Dis., 196,304–312.

61 Hazuda, D.J., Felock, P., Witmer, M.,Wolfe, A., Stillmock, K., Grobler, J.A.,Espeseth, A. et al. (2000) Inhibitors ofstrand transfer that prevent integrationand inhibit HIV-1 replication in cells.Science, 287, 646–650.

62 Steigbigel, R.T., Cooper, D.A., Kumar,P.N., Eron, J.J., Schechter, M., Markowitz,M., Loutfy, M.R. and the BENCHMRKStudy Teams (2008) Raltegravir withoptimized background therapy forresistant HIV-1 infection. N. Engl. J. Med.,359, 339–354.

63 Cooper, D.A., Steigbigel, R.T., Gatell, J.M.,Rockstroh, J.K., Katlama, C., Yeni, P.,Lazzarin, A. and the BENCHMRK StudyTeams (2008) Subgroup and resistanceanalyses of raltegravir for resistant HIV-1infection. N. Engl. J. Med., 359, 355–365.

64 Markowitz, M., Nguyen, B.Y., Gotuzzo, E.,Mendo, F., Ratanasuwan, W., Kovacs, C.,Prada, G. and the Protocol 004 Part IIStudy Team (2007) Rapid and durableantiretroviral effect of the HIV-1 Integraseinhibitor raltegravir as part of combinationtherapy in treatment-naive patients withHIV-1 infection: results of a 48-weekcontrolled study. J. Acquir. Immune Defic.Syndr., 46, 125–133.

65 Lennox, J., Dejesus, E., Lazzarin, A.,Pollard, R., Madruga, J., Zhao, J. et al.(2008) STARTMRK, A Phase III study ofthe safety & efficacy of raltegravir (RAL)-based vs. efavirenz (EFV)-basedcombination therapy in treatment-naiveHIV-infected patients. In Program andAbstracts of the 48th InternationalConference on Antimicrobial Agents andChemotherapy (ICAAC) and theInfectious Diseases Society of America(IDSA) 46thAnnualMeeting,Washington,DC, October 25–28, Abstract H-896a.

66 Santoscoy, M., Cahn, P., Gonzalez, C.,Hao,W., Pozniak, A., Shalit, P., Vanveggel,S., Boven, K. et al. (2008) TMC278(rilpivirine), a next-generation NNRTI,demonstrates long-term efficacy andtolerability in ARV-na€ıve patients: 96-weekresults of study C204. In Programs andAbstracts of the XVII International AIDSConference, Mexico City, August 3–8,abstract #TUAB0103.

67 Baert, L.,van�t Klooster, G., Dries, W.,François, M., Wouters, A., Basstanie, E.,Iterbeke, K., et al. (2009) Development of along-acting injectable formulation withnanoparticles of rilpivirine (TMC 278) forHIV treatment, Eur. J. Pharm. Biopharm.,72, 502–508.

68 Saag, M., Ive, P., Heera, J., Tawadrous, M.,DeJesus, E., Clumeck, N., Cooper, D. et al.(2007) Amulticenter, randomized, double-


blind, comparative trial of a novel CCR5antagonist, maraviroc versus efavirenz,both in combination with Combivir(zidovudine [ZDV]/lamivudine [3TC]), forthe treatment of antiretroviral naivesubjects infected with R5 HIV-1: week 48results of the MERIT study. In Programsand Abstracts of the 4th InternationalAIDS Conference on Pathogenesis,Treatment, and Prevention, Sydney,Australia, July 22–25, abstract #WESS104.

69 Markowitz, M., Nguyen, B.-Y., Gotuzzo,E., Mendo, F., Ratanasuwan, W., Kovacs,C., Wan, H. et al. (2008) Sustained

antiretroviral efficacy of raltegravir aspart of combination ART in treatment-naive HIV-1 infected patients: 96-weekdata. In Programs and Abstracts of theXVII International AIDS Conference,Mexico City, August 3–8, abstract#TUAB0102.

70 Blanc, F.X., Havlir, D.V., Onyebujoh, P.C.,Thim,S.,Goldfeld,A.E. andDelfraissy, J.F.(2007) Treatment strategies for HIV-infected patients with tuberculosis:ongoing and planned clinical trials.J. Infect. Dis., 196 (Suppl. 1), S46–S51

References j101

aids and tuberculosis || hiv/aids drugs

Documents