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Melanie A. Thompson; Judith A. Aberg; Pedro Cahn; et al.

Society�USA PanelRecommendations of the International AIDS Antiretroviral Treatment of Adult HIV Infection: 2010

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CLINICIAN’S CORNERREVIEW

Antiretroviral Treatment of Adult HIV Infection2010 Recommendations of the International AIDSSociety–USA PanelMelanie A. Thompson, MDJudith A. Aberg, MDPedro Cahn, MDJulio S. G. Montaner, MDGiuliano Rizzardini, MDAmalio Telenti, MD, PhDJose M. Gatell, MD, PhDHuldrych F. Günthard, MDScott M. Hammer, MDMartin S. Hirsch, MDDonna M. Jacobsen, BSPeter Reiss, MD, PhDDouglas D. Richman, MDPaul A. Volberding, MDPatrick Yeni, MDRobert T. Schooley, MD

SUCCESSFUL ANTIRETROVIRAL

therapy (ART) is associated withdramatic decreases in AIDS-defining conditions and their as-

sociated mortality. Expansion of treat-ment options and evolving knowledgerequire revision of guidelines for the ini-tiation and long-term management ofART in adults with HIV infection.

Since the 2008 International AIDSSociety–USA ART guidelines,1 new datahave emerged regarding timing oftherapy, optimal regimen choices, andmonitoring. There are also issues of spe-cial relevance to circumstances such aspregnancy, hepatitis virus coinfec-tions, kidney disease, cardiovasculardisease, and primary HIV infection.

Analyses of clinical trials and epide-miologic cohorts have shed light on therole of ART in mitigating serious non-AIDS events associated with uncon-trolled HIV replication. Newer drugs arebetter understood in terms of efficacy,toxicity, and potential uses. New dataalso suggest a role for ART in the pre-vention of HIV transmission.

METHODSThe panel was convened in 1995 to de-velop evidence-based recommenda-tions for ART for HIV-infected adults indeveloped-world settings.2 Members are

appointedby InternationalAIDSSociety–USA according to clinical and researchexpertise. Current panel members do notparticipate in pharmaceutical market-ing or promotional activities (eg, speak-ers’ bureaus, industry satellites) duringtenure on the panel. The current panelconvened in January 2010 and metweekly in person or by teleconference.Data published or presented in specificscientific meetings since the last report1

CME available online atwww.jamaarchivescme.comand questions on p 357.

Author Affiliations are listed at the end of this article.Corresponding Author: Melanie A. Thompson, MD,131 Ponce de Leon Ave NE, Ste 130, Atlanta, GA30308 ([email protected]).

Context Recent data regarding the consequences of untreated human immunodefi-ciency virus (HIV) infection and the expansion of treatment choices for antiretroviral-naive and antiretroviral-experienced patients warrant an update of the International AIDSSociety–USA guidelines for the use of antiretroviral therapy in adults with HIV infection.

Objectives To provide updated recommendations for management of HIV-infected adults, using antiretroviral drugs and laboratory monitoring tools available inthe international, developed-world setting. This report provides guidelines for whento initiate antiretroviral therapy, selection of appropriate initial regimens, patient moni-toring, when to change therapy, and what regimens to use when changing.

Data Sources and Study Selection A panel with expertise in HIV research andclinical care reviewed relevant data published or presented at selected scientific con-ferences since the last panel report through April 2010. Data were identified througha PubMed search, review of scientific conference abstracts, and requests to antiret-roviral drug manufacturers for updated clinical trials and adverse event data.

Data Extraction and Synthesis New evidence was reviewed by the panel. Rec-ommendations were drafted by section writing committees and reviewed and editedby the entire panel. The quality and strength of the evidence were rated and recom-mendations were made by full panel consensus.

Conclusions Patient readiness for treatment should be confirmed before initiation ofantiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4cell count �500/µL, for all symptomatic patients, and those with specific conditions andcomorbidities. Therapy should be considered for asymptomatic patients with CD4 cellcount �500/µL. Components of the initial and subsequent regimens must be individu-alized, particularly in the context of concurrent conditions. Patients receiving antiretro-viral treatment should be monitored regularly; treatment failure should be detected andmanaged early, with the goal of therapy, even in heavily pretreated patients, being HIV-1RNA suppression below commercially available assay quantification limits.JAMA. 2010;304(3):321-333 www.jama.com

©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, July 21, 2010—Vol 304, No. 3 321



were considered (eFigure, available athttp://www.jama.com). Data on file andpersonal communications were not con-sidered except for data and safety moni-toring board reports and US Food andDrug Administration alerts.

For identification of evidence, onemember (P.A.V.) conducted a PubMedsearch of reports published since the lastupdate. Search terms were HIV and an-tiretroviral, limited to humans, clinicaltrials, meta-analyses, randomized con-trolled trials, reviews, English, and adult,and yielded 582 citations. Of those, 194citations were selected for review, elimi-nating those not relevant to adult care inresource-rich settings. Section teamsidentified abstracts from scientific con-ferences. Drug manufacturers were askedto provide published or presented dataon updated clinical trials and adverseevents for their products.

Section team leaders (J.A.A., P.C.,J.S.G.M., G.R., and A.T.) summarizedsection consensus for group review anddiscussion. The quality and strengthof the evidence were rated for eachrecommendation (eBox). Final recom-mendationswereby fullpanel consensus.

WHEN TO STARTEstablished HIV-1 Infection

Deciding to start ART requires weigh-ing the benefits of treatment on mor-bidity and mortality against its risks, in-cluding toxicity, resistance, druginteractions, and the costs and incon-venience of lifelong treatment. Sus-tained viral suppression restores andpreserves immunologic function, de-creasing opportunistic diseases andmortality. The patient must be readyand willing to adhere to lifelongtherapy. Advances in ART continue toshift the therapeutic risk-benefit bal-ance to earlier treatment. Improve-ments in potency, toxicity and toler-ability, and pill burden allow for durableviral suppression for most patients.

The risks associated with ART havedecreased, whereas concerns regardingthe risks of long-standing untreated vi-remia have increased. Uncontrolled HIVreplication and immune activation leadto a chronic inflammatory state, result-

ing in end-organ damage and comorbidconditions not previously thought to beassociated with HIV infection. Severalstudies have shown that the life span ofthose with HIV infection still falls shortof that of the general population, evenathigherCD4cell counts.3-6 This life spandecrease is related to serious, non-AIDSevents attributed to chronic immune ac-tivation and the potentially permanentimmune damage associated with pro-longed immune depletion. In several datasets,3-8 non-AIDS events were associ-ated with elevated levels of viral repli-cation and markers of immune activa-tion and coagulation (including D-dimer,interleukin 6, or high-sensitivity C-reactive protein). Mortality from non-AIDS events now exceeds that of AIDS-defining opportunistic diseases inindividuals receiving effective ART.9-11

The strength of evidence support-ing initiation of therapy increases asCD4 cell count decreases. In a cohortof 17 517 asymptomatic HIV-infectedpersons, initiating ART at a CD4 cellcount greater than 500/µL decreasedmortality by 94%, and initiating it at aCD4 cell count between 351 and 500/µLdecreased mortality by 69%, althoughthe numbers of deaths were low in bothgroups. The majority of deaths werefrom non-AIDS conditions.10 In ananalysis of 62 760 persons in 12 co-horts, reduction in death was 23% and45% for those beginning therapy witha CD4 cell count greater than 500/µLand 350 to 500/µL, respectively.12

Data from prospective observationalcohorts and clinical trials demonstrateworse outcomes among patients who be-gin receiving ART at CD4 cell counts lessthan 350/µL or who have symptomaticHIV disease.1 Among 24 444 patientsfrom 18 cohorts, there was no addi-tional benefit from initiating therapy atCD4 cell counts of 451 to 550/µL com-pared with 351 to 450/µL. However, thisanalysis included only persons who be-gan receiving ART at less than 550/µL.13 A randomized trial addressing thetiming of initiation of therapy is underway. Indicators of rapid progression ofdisease, such as high HIV-1 RNA andrapid CD4 cell count decline, are recog-

nized as reasons to initiate ART regard-less of CD4 cell count.1 Older age is alsoassociated with higher risk of AIDS andnon-AIDS-related deaths. Pregnantwomen should be treated at least by thesecond trimester and therapy contin-ued after birth.5,10,14-18

Special Considerations

HIV increases the risk of liver-relatedmortality in those with hepatitis B virus(HBV).19 Hepatitis B infection should notbe treated with lamivudine or emtricit-abine alone. If tenofovir is contraindi-cated, entecavir should be added.20 Thedurability of entecavir is compromisedby previous HBV treatment failure withregimens including emtricitabine or la-mivudine.21 Flares of hepatocellular in-flammation may occur when therapywith agents active against HBV is dis-continued or when HBV resistance to la-mivudine or emtricitabine emerges in pa-tients receiving these agents withouttenofovir or entecavir.22,23 If ART mustbe interrupted, patients should be closelymonitored for HBV reactivation.24

Patients with HIV–hepatitis C virus(HCV) coinfection progress to end-stage liver disease more rapidly than doHCV monoinfected patients.25 Clear-ance of HCV is associated with regres-sion of liver fibrosis and a reduced riskof ART-related hepatotoxicity.26 In onestudy, abacavir with ribavirin was as-sociated with a reduced rate of sus-tained HCV virologic response.27 Zido-vudine, didanosine, and stavudine haveoverlapping hematologic and hepatictoxicities with current HCV therapy.25

Patients with HCV coinfection are at in-creased risk of hepatotoxicity, and cer-tain ART regimens may require dose ad-justment (see “Monitoring” section).Current HCV therapy has a higherprobability of sustained HCV viro-logic response with HCV genotype 2 or3; therefore, for patients with a highCD4 cell count and no imperative to be-gin ART, HCV treatment before ARTmay avoid cumulative drug toxicity anddrug interactions.28

Renal disease ranges from HIV-asso-ciated nephropathy, to HIV-associatedimmune complex kidney disease, to

ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION

322 JAMA, July 21, 2010—Vol 304, No. 3 (Reprinted) ©2010 American Medical Association. All rights reserved.



thrombotic microangiopathy. In 5 cross-sectional cohort studies, 5.5% of pa-tients had stages 3 to 5 chronic kidneydisease (estimated glomerular filtrationrate [eGFR] �60 mL/min for more than3 months). Older patients, blacks, per-sons with lower CD4 nadirs, and thosewith diabetes or hypertension have ahigher risk of developing chronic kid-ney disease.29,30 Albuminuria and eGFRless than 60 mL/min per 1.73 m2 are in-dependently associated with an in-creased risk of cardiovascular events.31

Tenofovir is associated with a decreasein GFR and tubular dysfunction; both in-dinavir (about 4% of patients)32 andatazanavir33 (uncommonly) are associ-ated with nephrolithiasis. All nRTIs ex-cept abacavir may require dose adjust-ments according to the GFR.

Uncontrolled HIV infection is asso-ciated with increased cardiovascularrisk.34 In a multivariate analysis involv-ing 70 357 (487 HIV-infected and69 870 HIV-uninfected) subjects, el-evated high-sensitivity C-reactive pro-tein and HIV were independently as-sociated with acute myocardialinfarction. With both risk factors, acutemyocardial infarction risk increasedgreater than 4-fold.35 There were strongassociations between overall mortal-ity or cardiovascular disease and spe-cific biomarkers. Although ART re-duces the level of these biomarkers, theyremain elevated compared with thoseof HIV-uninfected individuals. Theclinical utility of these biomarkers forinitiation or monitoring therapy isunknown. Modifiable cardiovascularrisk factors should be aggressivelyaddressed in all persons with HIVinfection.

In a randomized controlled trial ofwhen to initiate ART for patients with ac-tive opportunistic infections (exclud-ing tuberculosis [TB]), early initiation(median, 12 days after presentation) re-duced death or AIDS progression by 50%compared with beginning ART after thecompletion of opportunistic infectiontreatment.36 A South African random-ized controlled trial including patientswith TB and HIV demonstrated that ini-tiating ART within 2 months of begin-

ning tuberculosis treatment decreasedmortality by 56% compared with initi-ating ART after completion of TB treat-ment.37 Immune reconstitution inflam-matory syndromes occurred more oftenwith early therapy, but no changes inART were needed and no deaths were re-lated to immune reconstitution inflam-matory syndromes. Consideration mustbe given to the potential for drug inter-actions among therapies for opportunis-tic infections and ART.38,39

Patients who present with sympto-matic primary HIV infection mayprogress more rapidly than those whopresent without symptoms.40,41 Anti-retroviral therapy reduces the ex-tremely high viral loads in primaryinfection and may reduce transmis-sion.42,43 For patients presenting withasymptomatic primary infection, thereare insufficient data for a recommen-dation on whether to treat immedi-ately or defer; however, an analysis of3019 seroconverters showed a 78% re-duction in mortality when ART was ini-tiated rather than delayed.12

Antiretroviral therapy reduces HIVtransmission.44 Widespread use of ARTduring pregnancy has nearly elimi-nated mother-to-child transmission inthe developed world.45,46 A meta-analysis concluded that ART also de-creases the risk of HIV transmission touninfected partners in HIV-serodiscor-dant heterosexual couples,43 and a co-hort study of 3381 heterosexual sero-discordant couples showed a 92%reduction in transmission when ART wasused by the infected partner.47 Anothercohort study showed a strong associa-tion between increased ART coverage,decreased community plasma viral load,and decreased HIV incidence among in-jection drug users.48 Some mathematicmodels suggest that more aggressive ARTcoverage could reduce the incidence ofnew HIV infections49-51; some field dataalso support this.42,52

Recommendations

Patient readiness for treatment is a keyconsiderationwhendecidingwhentoini-tiate ART. There is no CD4 cell countthreshold at which initiating therapy

is contraindicated (BIIa). Initiation oftherapy is recommended (TABLE 1) forsymptomaticpatientswithestablisheddis-ease, regardless of CD4 cell count (AIa),and for asymptomatic individuals withCD4 cell counts less than or equal to500/µL(AIafor�350/µL,AIIafor�500/µL). Treatment should be consideredfor asymptomatic individuals with CD4cell counts greater than 500/µL (CIII).Therapy is recommended regardless ofCD4 cell count in the following settings:increased risk of disease progression as-sociated with a rapid decline in CD4 cellcount(ie,�100/µLperyear)oraplasmaHIV-1 RNA level greater than 100 000copies/mL1 (AIIa); older than 60 years(BIIa); pregnancy (at least by the secondtrimester)(AIa);orchronicHBVorHCVcoinfection (BIIa), although for patientswithHCVgenotype2or3andhighCD4cell counts, anattempt toeradicateHCVmay be undertaken before ART is initi-ated(BIII);HIV-associatedkidneydisease(BIIa), avoidingdrugswithpotential ad-verseeffectsonthekidney(tenofovir, in-dinavir, atazanavir), if possible (AIIa)53;high cardiovascular risk (BIIa), modifi-ableriskfactorsforcardiovasculardiseaseshouldbeaggressivelymanaged(AIa);op-portunistic infections, includingtubercu-losis, with attention to drug interactionsandthepotential for immunereconstitu-tion inflammatorysyndromes(AIa); andsymptomatic primary HIV infection topreventrapidprogression,topreserveim-munefunction,andtolimitongoingtrans-mission from this high-risk population(BIIa).42 Once initiated, ART should becontinued,exceptinthecontextofaclini-cal trial (AIa).Therapyshouldbeconsid-ered where there is a heightened risk ofHIVtransmission(ie,HIV-serodiscordantcouples)(BIIa),withoutsupplantingtra-ditionalpreventionapproaches.Risk re-duction counseling should be a routinepart of care at each patient-clinicianinteraction.54

WHAT TO STARTSelecting an initial regimen has long-standingconsequencesforfuturetherapy.The initial regimen should be individu-alized according to resistance testing re-sultsandpredictedvirologicefficacy, tox-





icity and tolerability,pill burden,dosingfrequency,drug-druginteractions,comor-bidities,andpatientandpractitionerpref-erence. In theabsenceofoverridingcon-siderations,costandaffordabilityshouldalsobeconsidered.Currentevidencesup-ports the combination of 2 nRTIs and apotent third agent from another class(BOX). Fixed-dose formulations andonce-daily regimens are generally pre-ferred for initial therapy. The eTablepresents a summary of selected clinicaltrial results in treatment-naive patients.

Nucleoside and Nucleotide ReverseTranscriptase Inhibitors

Tenofovir has activity against both HIV-1and HBV and a long intracellular half-life. Potent viral suppression and CD4cell count increases occur when tenofo-vir and emtricitabine are used with athird agent. Alternative nRTIs are pre-ferred over dose-adjusted tenofovir forpatients with renal dysfunction.55 Teno-fovir concentrations can be increased bysome protease inhibitors (PIs), and stud-ies have suggested a greater risk of re-nal dysfunction when tenofovir is used

in PI-based regimens.56-58 Tenofovir isavailable in fixed-dose, once-daily for-mulations with emtricitabine and withemtricitabine plus efavirenz.

HLA-B*5701testingidentifiespersonsat high risk for abacavir hypersensitiv-ity.59,60 In theAIDSClinicalTrialsGroupstudyA5202, inferiorvirologicresponseswereobservedwithabacavirpluslamivu-dine compared with tenofovir plus em-tricitabine insubjectswithbaselineHIV-RNA levels greater than 100 000 copies/mL. Abacavir plus lamivudine also wasassociated with more lipid abnormali-ties.61,62 The Data Collection on AdverseEvents of Anti-HIV Drugs study, a largemultinationalobservationalcohort,foundthat recent, current,orcumulativeuseofabacavir predicted an increased risk ofmyocardial infarction,anassociationnotobservedwithtenofovir.63,64 Thisriskwasaccentuated inparticipantswhohadpre-existingcardiovascularriskfactors.Incon-trast, in a pooled analysis of 52 clinicaltrials involving more than 9500 partici-pantswhoreceivedabacavir,noincreasedriskofmyocardial infarctionwasfound.65

Thus,noconsensushasyetbeenreached

on either the association or a possiblemechanism.66

Lamivudineandemtricitabineareeachwell tolerated and select for the M184Vmutation, which confers high-level re-sistance to both drugs but enhances theactivity of tenofovir. Both are activeagainst HBV but should only be used incombination with a second HBV-activedrug when treating HIV-HBV coin-fected patients. The role of zidovudinein initial regimens is limited by toler-ability issues, as well as increased risk forlipodystrophy and hyperlipidemia com-pared with tenofovir.1 Stavudine and di-danosine are not recommended for ini-tial therapy because of increased toxicityof each.1 Combination regimens includ-ing 3 or 4 nRTIs alone are not recom-mended because of suboptimal viro-logic activity and increased toxicity.1,67

Nonnucleoside ReverseTranscriptase Inhibitors

Several studies have shown consis-tently high and sustained rates of viralsuppression with efavirenz in the initialregimen.1,68 Efavirenz was virologicallysuperior to ritonavir-boosted lopinavir(lopinavir/r)69,70 and comparable toatazanavir/r61,62 and raltegravir.71 In AIDSClinical Trials Group A5142 and 2 otherstudies, lopinavir/r showed better CD4cell count responses and less drug resis-tance after virologic failure than efavi-renz.69,72,73 Efavirenz is associated withrash and central nervous system ad-verse effects and should not be used dur-ing the first trimester of pregnancy or inwomen of childbearing age trying to con-ceive or not using effective and consis-tent contraception.17 Efavirenz is an in-ducer of cytochrome P450, and potentialdrug interactions are an important con-sideration. Baseline genotypic testing isimportant when considering nonnucleo-side reverse transcriptase inhibitor(NNRTI) use. Primary NNRTI resis-tance ratesvary fromapproximately8.1%in the United States to 2.3% inEurope.74-76

Nevirapinewasnoninferior toatazana-vir/r (each combined with tenofovir plusemtricitabine) in a randomized con-trolled trial restricted to women and men

Table 1. Recommendations for Initiating Antiretroviral Therapy (ART) in Treatment-NaiveAdults With HIV-1 Infection Who Are Ready to Begin Therapya

Measure Recommendation Rating

Specific conditions ART is recommended regardlessof CD4 cell count

Symptomatic HIV disease AIa

Pregnant women AIa

HIV-1 RNA �100 000 copies/mL AIIa

Rapid decline in CD4 cell count,�100/µL per year

AIIa

Active hepatitis B or C virus coinfection BIIa, AIIa

Active or high risk for cardiovasculardisease

BIIa

HIV-associated nephropathy BIIa

Symptomatic primary HIV infection BIIa

Risk for secondary HIV transmission ishigh, eg, serodiscordant couples

BIIa

Asymptomatic, CD4 cell count �500/µL ART is recommended

CD4 cell count �350/µL AIa

CD4 cell count 350-500/µL AIIa

Asymptomatic, CD4 cell count �500/µL ART should be considered,unless patient is an elitecontroller (HIV-1 RNA �50copies/mL) or has stable CD4cell count and low-levelviremia in the absence of ART

CIII

Abbreviation: HIV, human immunodeficiency virus.aDetails, cautions, considerations, and supporting data1,3-18,20-52 are described in the text. Ratings are described in the

eBox (http://www.jama.com).





with CD4 cell counts less than 250/µLand 400/µL, respectively.77 Nevirapinewas similar virologically to lopinavir/r(again, each with tenofovir/emtricita-bine) in a randomized trial of 500 Afri-

can women with CD4 cell counts lessthan 200/µL.78 However, drug discon-tinuation because of adverse events washigher among nevirapine recipi-ents.79,80 Serious hepatic events have been

described within the first several weeksof initiation of nevirapine-based therapybut are less frequent if nevirapine is re-stricted to pretreatment CD4 cell countsless than 250/µL (women) or less than

Box. Recommended Components of the Initial Antiretroviral Regimena

Dual nRTI ComponentRecommended

Tenofovir/emtricitabine

Availableasfixed-dosecombinationaloneandwithefavirenz

Once daily

Low genetic barrier to resistance (emtricitabine)

Renal dysfunction, decreased bone mineral densityassociated with tenofovir influence choice

AlternativeAbacavir/lamivudine

Available as fixed-dose combination

Once daily

Weaker antiviral efficacy in treatment-naive patients withbaseline HIV-1 RNA �100 000 copies/mL than tenofovir/emtricitabine

Low genetic barrier (lamivudine)

Need to screen for HLA-B*5701b to reduce risk of aba-cavir hypersensitivity

Abacavir may be associated with increased cardiovascularrisk

Key Third AgentRecommended

Efavirenzb

NNRTI class

Available in fixed-dose combination with tenofovir/emtricitabine, which has become standard-of-care com-parator regimen in most clinical trials

Low genetic barrier

Major psychiatric illness, first trimester of pregnancy, orintention to become pregnant influences choice

Atazanavir/rb

PI/r class

Once daily

Widely prescribed when PI/r is chosen for initial therapy

Leaves options for future regimens

Less lipidogenic potential than lopinavir/r

Hyperbilirubinemia, need for acid-reducing agents, andrisk of nephrolithiasis influence choice

Darunavir/rc

PI/r class

Once daily in treatment-naive patients

Limited experience in treatment-naive patients, pres-ence of other options in most naive patients, and effi-

cacyinpatientswithtreatmentexperience,andmultidrug-resistant virus influence choice

Raltegravirc

INSTI class (only 1 FDA approved at present time)

Twice daily

Low drug interaction potential

Rapid decline in HIV-1 RNA slope after initiation

Low genetic barrier

Limited experience in naive patients, presence ofother options in most naive patients, and efficacy intreatment-experienced patients with multidrug-resistant virus influence choice

AlternativesLopinavir/r

PI/r class

Extensive clinical experience

Comparator PI/r in many trials

Only PI coformulated with ritonavir (heat stable)

Can be given once daily in naive patients

Potential for hyperlipidemia and gastrointestinaladverse effects influences choice

Fosamprenavir/r

PI/r class

Profile similar to lopinavir/r

May be useful when other initial PI/r not toleratedMaraviroc

CCR5 antagonist class

Targets host protein (viral coreceptor)

Need to perform viral tropism assay before use

Limited clinical experience in treatment-naive patients

Strategically, may be more useful in treatment-experienced patients or when primary (transmitted)drug resistance is present but viral population shouldbe exclusively receptor 5

Abbreviations: CCR5, CC chemokine receptor 5; FDA, Food andDrug Administration; HIV, human immunodeficiency virus; INSTI,integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse tran-scriptase inhibitor; nRTI, nucleoside or nucleotide analogue reversetranscriptase inhibitor; PI, protease inhibitor; /r, ritonavir boosted.aDetails, cautions, considerations, and supporting data1,17,55-105 aredescribed in the text.bBased on extensive clinical experience.cBased on antiviral efficacy and tolerability comparable to that of keythird agents but more limited experience in treatment-naive patients.





400/µL (men).81 Patients who experi-enced CD4 cell count increases to lev-els above these thresholds with unde-tectable viremia as a result of previousART safely switched to nevirapinetherapy.82 The efficacy in initial therapyof etravirine, a newer NNRTI, has not yetbeen reported.

Protease Inhibitors

Atazanavir/r has greater virologic activ-ity than unboosted atazanavir when com-bined with 2 nRTIs.83 Once-dailyatazanavir/r and twice-daily lopina-vir/r, both combined with tenofovir plusemtricitabine, showed similar virologicand CD4 cell count responses at 48 and96 weeks.84,85 The hyperbilirubinemia,scleral icterus, or frank jaundice associ-ated with atazanavir exposure is not ac-companied by hepatic transaminase el-evations but is more frequent withritonavir boosting. Nephrolithiasis hasoccurred uncommonly with atazana-vir, with or without ritonavir,33 and theeGFR may decrease when atazanavir iscombined with tenofovir.86 Unboostedatazanavir should not be used with te-nofovir.87 Atazanavir requires acidic gas-tric pH for dissolution. Thus, concomi-tant use of drugs that increase gastric pH,suchasantacids,H2antagonists, andpar-ticularly proton-pump inhibitors, mayimpair absorption of atazanavir and com-promise its activity.88

Darunavir/r once daily was comparedwith standard doses of lopinavir/r (onceor twicedaily),eachincombinationwithtenofovirplusemtricitabine.At48weeks,darunavir/rwasnoninferior to lopinavir/r,butvirologicresponserateswere lowerin the lopinavir/r arm among subjectswith baseline HIV-1-RNA levels greaterthan 100 000 copies/mL. At 96 weeks,darunavir/rwasvirologically superior tolopinavir/r.89 Grade2to4adverseevents,primarily diarrhea, were more frequentinthelopinavir/rarm.90Darunavir/riscon-sidered by many as less attractive in ini-tial therapybecause it isparticularlyuse-ful for patients with PI-resistant virus.

Lopinavir/r demonstrates lower viro-logic efficacy but better CD4 responseand fewer emergent resistance muta-tions than efavirenz.69,72,73 For initial

therapy, once-daily and twice-daily lopi-navir/r in combination with tenofovirplus emtricitabine achieved compa-rable rates of plasma HIV-1-RNA levelsless than 50 copies/mL at 48 weeks,91

with similar rates of moderate to severedrug-related diarrhea. Other major ad-verse effects of lopinavir/r include insu-lin resistance and hyperlipidemia.

Twice-dailyfosamprenavir/randlopin-avir/r, both administered with abacavirplus lamivudine,hadcomparableratesofvirologicsuppressionandadverseeventsat48and144weeks.92Once-dailyvstwice-dailyfosamprenavir/rdidnotdifferinratesof virologic suppression.93

Saquinavir/r was compared with lopi-navir/r, both with tenofovir plus emtri-citabine, resulting in rates of viral sup-pression at 48 weeks of about 65% foreach regimen; however, the statisticalpower of this study was limited by smallsample size and short length of follow-up.94 Triglyceride levels were higher inthe lopinavir/r arm. Although this waspossibly a class effect, the Food and DrugAdministration has issued a warning ofa potential risk for QT-interval prolon-gation with saquinavir/r.95

Hepatictransaminaseelevationscanoc-cur with any of the above regimens,96

especially in patients with underlyingliver disease. Cumulative exposure toindinavir/r, lopinavir/r, and fosampren-avir/r(butnotsaquinavir/r)hasalsobeenassociated with an increased risk of car-diovascularevents.63,64,97 Ifpossible, thesedrugsarebestavoidedinpatientswithel-evatedcardiovascularrisk.Dataconcern-ing cardiovascular risk associated withatazanavir/r or darunavir/r are pending.

Integrase Strand Transfer Inhibitors

Raltegravirandefavirenz,eachcombinedwithtenofovirandemtricitabine,showedsimilarhighvirologicefficacyduring192weeks.71,98,99 Raltegravir is well toleratedand has a favorable lipid and drug inter-action profile; however, it is dosed twicedailyandhasarelatively lowgeneticbar-rierforselectionofresistancemutations.100

Raltegravir is considered by some as lessattractive for initial therapy because it isparticularlyuseful forpatientswithdrug-resistant virus.

Entry InhibitorsThe CC chemokine receptor 5 (CCR5)inhibitor maraviroc was compared withefavirenz, both in combination with zi-dovudinepluslamivudine,in633subjectswithCCR5-tropicvirusandnoevidenceof resistance to the study drugs.101 At 48weeks, HIV-1 RNA less than 50 copies/mL was achieved in 65% and 69% ofmaraviroc and efavirenz recipients, re-spectively. The results did not meetprespecifiedcriteria fornoninferiority formaraviroc.Through48weeks,morepar-ticipantsdiscontinuedmaravirocbecauseof lack of efficacy (11.9% and 4.2%, re-spectively),whereasfewerparticipantsdis-continuedmaravirocbecauseof toxicity(4.2%and13.6%, respectively).Follow-upresults at96weeksdemonstrateddu-rableresponsesinbothgroups.102Reanaly-sisof theresultswithamoresensitivetro-pism assay or with a genotype-basedapproach suggested that the differencesbetween treatment arms could be attrib-uted to misclassification of tropism insomepatientsby theolderassay.101,103-105

IfonlysubjectswithR5virusatentrywereconsidered, maraviroc appeared similartoefavirenz inantiretroviralactivity.Ma-ravirochasnotbeenevaluatedextensivelywith other nRTI backbones in initialtherapy.

Recommendations

Fixed-dose combinations are recom-mendedwhenpossible for convenience.Tenofovir plus emtricitabine is the rec-ommended nRTI combination in initialtherapy(A1a). If tenofovirplusemtricit-abinecannotbeused, abacavirplus lam-ivudine may be used as an alternativewhen HLA B*5701 testing results arenegative,keepinginmindabacavir’slowerefficacy at high viral loads (AIa) and itspossible association with increased car-diovascular risk (AIIa).Zidovudinepluslamivudine should be reserved for in-stancesinwhichneithertenofovirnoraba-cavircanbeused.Threeor4nRTIsaloneare not recommended for initial therapy(AIa).Efavirenz(AIa),atazanavir/r(AIa),darunavir/r (AIa), or raltegravir (AIa) isrecommendedas thethirdcomponentofaninitial regimen.Moreevidenceisavail-able for efavirenz and atazanavir/r than





fordarunavir/rorraltegravir.Lopinavir/r,fosamprenavir/r,andmaravirocarealter-native third-component choices (AIa).Neither saquinavir/r nor unboosted PIs,including atazanavir, are recommendedforinitialtherapy(BIa).Nevirapineshouldbe used as an alternative initial therapyonly with pretreatment CD4 cell countsless than 250/µL (women) or less than400/µL(men)(BI).Considerationsforini-tial therapy inpatientswithspecific con-ditions are summarized in TABLE 2.

MONITORINGEffectivetherapyshouldresultinsuppres-sion to less than 50 copies/mL (poly-merase chain reaction) or 75 copies/µL(branchedDNA)by24weeks, regardlessof previous treatment experience. Fre-quent HIV-1 RNA monitoring is recom-mended during the first year of ART todetect failure.106 Testing of HIV-1 RNAshould be repeated 2 to 8 weeks afterinitiation, every 4 to 8 weeks until sup-pressed,andthenevery3to4months forat least the first year. CD4 cell countsshould be monitored at least every 3 to 4months after initiation of therapy, espe-ciallyamongpatientswithcountslessthan200/µL,todeterminetheneedforcontinu-ing opportunistic infection prophy-laxis.107,108 InaEuroSIDAstudy,patientswhomaintainedstableandfullysuppres-sive ART for 1 year had a low chance ofexperiencing treatment failure in theen-suingmonths.109Therefore,onceviralrep-lication is suppressed,monitoring inter-valsmaybeextendeduptoevery6monthsamongpatientswhoremainvirologicallysuppressed and have CD4 cell countsgreater than350/µL.Morefrequentmon-itoring is required for patients who havechanged therapy because of virologicfailure.110

Changesinassaymethodologymayre-sult in detectable viral load in individu-als with previously undetectable vire-mia.111,112Detectionartifactshavealsobeenattributed to specific plasma processingpractices.113Newassaysmaysoonbeavail-able with a lower limit of 20 copies/mL;however, the clinical implications of vi-remia between 20 and 50 copies/mL arenot yet clear. Confirmed viral load re-bound on 2 separate tests at least 2 to 4

weeksapartshouldpromptacarefulevalu-ation of regimen tolerability, drug-druginteractions, and patient adherence.

The prevalence of transmitted drugresistance varies in resource-rich soci-eties from 8% to 16%.75,76,114 Baseline ge-

Table2. Initial Antiretroviral Therapy (ART) and Considerations in Patients With Specific Conditionsa

Condition

Regimen Components

ConsiderationsPossible

Backbone Drugs Third AgentHigh athero-

scleroticcardio-vascularrisk

Emtricitabine, lamivu-dine, tenofovir

Efavirenz,nevirapine,atazanavir/r,raltegravir

Initiation of ART, regardless of CD4 cellcount, is recommended.34

If possible avoid abacavir, fosamprenavir/rindinavir/r, lopinavir/r because of anassociated increased risk of cardio-vascular events.63,97

Chronic kid-ney dis-ease

Abacavir,b emtricita-bine, lamivudine;avoid tenofovir(glomerular andtubular toxicity),atazanavir,and indinavir(nephrolithiasis)

Efavirenz,raltegravir,nevirapine,maraviroc,PI/r

Initiate ART regardless of CD4 cell count(BIIa).

Avoid potentially nephrotoxic drugs (AIIa).53

When potentially nephrotoxic drugs mustbe used, monitor renal function closely.

For patients with reduced estimated glo-merular filtration rate, dose adjustmentfor drugs with renal metabolism (emtri-citabine, lamivudine, tenofovir,maraviroc) should be considered.

Chronic HBVinfection

Emtricitabine, lamivu-dine, tenofovir. Use2 HBV-activedrugs. Do not useabacavir orabacavir/lamivudine alonefor treatment ofHBV in coinfectedpatients.

Efavirenz,raltegravir, PI/rshould be moni-tored for hepa-totoxicity.

Avoid nevirapineexcept forwomen withCD4 �250/µLand men with�400/µL.

Maraviroc should beused withcaution inpatients with liverdisease.

ART that includes tenofovir/emtricitabineshould be used irrespective of CD4cell count20 (BIIa).

Monitor alanine aminotransferase afterART initiation and after withdrawal ofsuppressive therapy.22-24

In patients with moderate to severe liverimpairment, dose adjustment fordrugs metabolized by the liver shouldbe considered.

Alcohol should be avoided.

Chronic HCVinfectionrequiringtherapy

Emtricitabine, lamivu-dine, tenofovir

Efavirenz, raltegravir,PI/r should bemonitored forhepatotoxicity.

Avoid nevirapine ex-cept for womenwith CD4 �250/µL and men with�400/µL.

Maraviroc should beused with cau-tion in patientswith liver disease.

ART should generally be initiated first in allpatients with HCV coinfection regard-less of CD4 cell count to slow liver dis-ease progression (BIIa), except possi-bly in patients with HCV genotype 2 or3 infection and a high CD4 cell count,for whom current HCV therapy has ahigher probability of a sustained viro-logic response26,28 (BIII).

Avoid zidovudine, didanosine, zalcitabine,and stavudine, as well as abacavir. 25,27

Alcohol should be avoided by all coin-fected patients.

Pregnantwomen

Complete recommendations for the use ofantiviral therapy in pregnant women areavailable at http://www.aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf, and http://www.europeanaidsclinicalsociety.org/guidelines.asp.17,18

ART is recommended to prevent thetransmission of the virus to the fetusor infant (AIa).

Efavirenz should generally be avoided,especially in the first trimester of preg-nancy (teratogenic effect).

Opportunisticinfections,includingtubercu-losis

Any, according to the“What to Start”section

Choice of agent willbe influenced bydrug interac-tions, especiallywith rifampinand rifabutin.

ART should be initiated as soon as pos-sible in patients with opportunisticinfections, including tuberculosis, withattention to drug interactions and thepotential for immune reconstitutioninflammatory syndromes (AIa).36,37 Druginteractions likely to require dose ad-justments; consult drug interactiondosing references (http://www.hiv-druginteractions.org, and http://hivinsite.ucsf.edu/insite?page=ar-00-02.38,39

Abbreviations: ART, antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; PI, protease inhibitor; /r, ritonavirboosted.

aDetails, cautions, considerations, and supporting data are described in the text. Levels of evidence are described in theeBox (available at http://www.jama.com).

b In HLA B*5701–negative patients; has been associated with increased risk of myocardial infarction. Lower efficacy inpatients with �100 000 copies/mL of HIV RNA at baseline (see text).





notypic testing is recommended for alltreatment-naive patients.81 For con-firmed virologic failure, resistance test-ing is essential and should be per-formed while the patient is receiving thefailing regimen, when possible. If thetrajectory of HIV-1 RNA reduction isnot optimal after a new regimen, ar-chived mutations or minority variantsmay emerge. Minority variants not de-tected by current resistance testing havebeen associated with an increased riskof virologic failure; however, the as-say thresholds that identify patients atgreatest risk of experiencing poor out-comes have not been defined.40,115-119

Tropism testing before use of a CCR5antagonist is essential because this classhas no activity against CX chemokinereceptor 4 or dual-tropic viruses.101 Im-provement in tropism assay method-ology may further facilitate the clini-cal use of CCR5 antagonists.101,120

The frequency of monitoring for ARTtoxicity depends on the known toxici-ties of specific drugs and underlying co-morbidities. Monitoring may occur every2 to 8 weeks after initiation of therapy,decreasing to every 6 to 12 months af-ter stabilization of HIV disease.108,121

Assessment of renal function shouldoccur before initiation and during ART,in particular when tenofovir is used, al-lowing avoidance, dose modification, ortimely substitution of another drug whenappropriate.

Therecommendationsandalgorithmsof the National Osteoporosis Founda-tion122 and the World Health Organiza-tionfractureriskassessmenttool123,124 areuseful for theassessmentof riskandpre-vention of osteoporotic fractures; how-ever,thesetoolshavenotbeenspecificallyvalidatedintheHIV-infectedpopulation.Vitamin D deficiency is common in thesetting of HIV infection and may be as-sociated with ART use.125 Monitoring ofvitamin D levels may be of benefit.125-127

Hepatic,cardiovascular,andrenalcom-plicationsmaybeassociatedwithuncon-trolledHIVreplication.Clinicalandlabo-ratory assessment of relevant comorbidconditions should be performed beforeinitiationoftreatmentandduringfollow-up.108,121 Cardiovascular disease risk

shouldbeassessedbyavailable tools.TheFramingham risk algorithm may be themostappropriatebutmayunderestimatecardiovascular disease risk in the settingofHIVinfection.128Guidelinesforthepre-vention and management of metaboliccomplicationsandnoninfectiouscomor-biditiesinHIVinfectionareavailable.108,121

Therapeutic drug monitoring re-mains controversial.129 When assays areperformed by a quality-assured labora-tory, monitoring of PI and NNRTI lev-els may be useful in pregnant women,children, and patients with renal or liverimpairment to minimize overexposureand adverse effects, manage potentialdrug-drug interactions, or evaluate vi-rologic failure in the absence of resis-tance. As stated, HLA-B*5701 screen-ing can identify patients at risk forabacavir-associated hypersensitivity.59

Recommendations

PlasmaHIV-1RNAlevelsshouldbemoni-tored frequentlywhen treatment is initi-atedorchangedforvirologicfailure(AIIa)until they decrease below detection lim-its and regularly thereafter (BIII). Oncetheviral load is suppressed forayearandCD4 cell counts are stable at 350/µL orgreater,viral loadandCD4cellcountscanbemonitoredatintervalsofupto6monthsin patients with dependable adherence(CIII). Baseline genotypic testing for re-sistance should be performed in alltreatment-naive patients (AIIa) and incasesofconfirmedvirologic failure(AIa).HLA-B*5701haplotypescreeningshouldbeperformedinanypatientforwhomaba-cavir is considered (AIa). Assessment ofviraltropismisrecommendedbeforeusingmaraviroc(AIa).Therapeuticdrugmoni-toringisnotrecommendedinroutinecare;however, selectedpatientsmightbenefitfrom this intervention (CIII).

WHEN TO CHANGEAND WHAT TO CHANGEChanging for Virologic Failure

The virologic goal of treatment for first-andmultiple-regimen failure is toachieveaplasmaHIV-1RNAlevelbelowthe limitof detection of the most sensitive assaysavailable. With the availability of newdrugs and regimens, this goal now is

achievable, even in most patients withmultiregimen failure.130-132 Reasons forvi-ral rebound after complete suppres-sion, such as poor adherence, drug-drug interactions, concurrent infections,and recent vaccinations, should be con-sidered before the regimen is changed.Testing for an isolated detectable viralload should be repeated to exclude mea-surement error or self-resolving low-level viremia.1 Stage of HIV disease,nadir and current CD4 cell count, co-morbidities, treatment history, currentand previous drug resistance tests, andconcomitant medications with poten-tial for interactions should be consid-ered when the new regimen is de-signed. Ideally3,but at least2, fully activedrugs should be included and drugs fromnew classes should be considered. Thetoxicities of stavudine, didanosine, andto a lesser extent zidovudine make theiruse problematic, and they should be usedonly when options are limited.

Initial Failure of NNRTI-BasedRegimens. Once failure has been con-firmed, an NNRTI-containing regimenshouldbediscontinuedassoonaspossibletominimizetheselectionofadditionalmu-tations. Initial NNRTI failures tradition-allyhavebeentreatedwith2activenRTIsplus a PI/r, but raltegravir, maraviroc,andetravirinenowprovideadditionalop-tions.According topotencyandhighge-neticbarrier, theinclusionofaPI/rshouldbe considered whenever possible, butwhen not possible, an agent from a newclass should be considered. Treatment-experiencedpatients receivingetravirineanddarunavir/rplusanoptimizedback-ground regimen had better virologic re-sponsesthanthosereceivingplaceboplusbackground regimen, with comparabletolerability at 48 weeks.133

Initial Failure of PI/r Regimens. Re-sistance to the PI/r component does notalways emerge when regimen failure isdetected, allowing the same drug or an-other in the PI class to be used in the nextregimen. For early failures, strategic se-quencing of PIs should be considered. Ifsome degree of PI resistance exists, da-runavir/r is likely to be preferred overlopinavir/r or tipranavir/r because of itssuperior tolerability and toxicity pro-





file, as well as problematic drug interac-tions associated with tipranavir/r.1 If notpreviously used, an NNRTI may be in-cluded, provided that potential drug in-teractions are considered. Whenever pos-sible, a new antiretroviral regimen shouldcontain at least 2 fully active drugs.

Multidrug (Including PI and NNRTI)Resistance. In this setting, 3 active drugs,including new classes of agents (inte-grase strand transfer inhibitors or entryinhibitors), should be used. Individualswith multidrug-resistant virus usuallybenefit from a PI/r with activity againstresistant strains, such as darunavir/r ortipranavir/r. Etravirine can be paired withdarunavir/r (but not tipranavir/r) andmay be of value, depending on the num-ber of NNRTI mutations present. Enfu-virtide may be an option if no other newclass can be used, despite the inconve-nience of subcutaneous injection and in-jection site reactions. Dual-boosted PIsare not recommended.134 Lamivudine oremtricitabine is sometimes included tomaintain the M184V mutation and de-crease viral fitness, but there is no newevidence to support this approach. An-other theoretically beneficial strategy isto use zidovudine to prevent the emer-gence of the K65R mutation in the pres-ence of thymidine analogue mutationswhen using tenofovir in patients inwhom nRTI-containing regimens are fail-ing. However, no clinical benefit has beenshown for this approach.135

Changes for Toxicity, Tolerability,or Convenience

Single-agent switches to decrease tox-icity,avoiddruginteractions,or improveconvenienceandadherencearepossible,provided the potency of the regimen ismaintained and drug interactions aremanaged. Although some studies haveshownmaintenanceofvirologicsuppres-sion with PI/r monotherapy as a simpli-fication strategy,136 other studies haveshown higher rates of failure, especiallyin the central nervous system,137 thanwith a combination including 2 nRTIplus a PI/r.138,139 Therefore, PI/r mono-therapy is not recommended, except inexceptional circumstances when otherdrugs cannot be considered for reasons

oftoxicity/tolerability.Delayingswitcheswhen adverse effects persist may affectadherence and facilitate the emergenceof resistance.

Simplification

Itmaybedesirabletoswitchtoanequallyeffective regimen with fewer drugs orlower pill burden. Not all switches, evenwithadrugfromanewclass,aresuccess-ful because the activity of the accompa-nying drugs in the regimen is a keydeterminant of outcome. Continuinglopinavir/r was virologically better thanswitching to raltegravir in patients withextensiveprevious3-classARTexperienceandpre-existingnRTIresistance.140 Withraltegravir, it is important to maintain astrongARTbackbone,usually includingaPI/r.Twosmallerstudies foundthatral-tegravir was safe, well tolerated, and vi-rologically similar when substituted forenfuvirtide in patients with multidrug-resistant HIV-1.141,142

Once-dailydarunavir800mg/ritonavir100mgwasnoninferiortotwice-dailyda-runavir 600 mg/ritonavir 100 mg in anopen-labelstudyintreatment-experiencedpatients.143 Dual therapy strategies in-tendedto takeadvantageofdrug interac-tions such as the combination of un-boostedatazanavirandraltegravirarestillexperimental andarenot recommendedforclinicalpractice.Forpatientswithvi-rologic suppression who were receivingaboostedorunboostedPI-basedregimen,switchingtoaonce-dailyregimencontain-ing atazanavir provided better mainte-nance of virologic suppression, compa-rablesafety,andimprovedlipidsthrough48 weeks compared with continued un-modified therapy.144

Treatment interruptions should beavoided.1 Interruptions, suchas those forplanned surgeries or severe toxicities inpatients without options for switching,shouldconsider thedifferenthalf-livesofthe regimen components; drugs shouldbediscontinuedinastaggeredmanner(ora PI/r temporarily substituted) when anNNRTI is a component.145

Recommendations

Maintenance of regimen potency is theobjective when switching ART regi-

mens. Virologic failure of an initial regi-men (confirmed measurable viremia)should be identified and treated as earlyas possible with at least 2 fully activedrugs (AIa) to avoid the accumulationof resistance mutations. For NNRTI fail-ures, the new combination usuallyshould include a PI/r or an agent from anew class (AIa) if a PI/r is not possible.Etravirine may be a useful component ofa new regimen for NNRTI failure butmust be supported by a potent combi-nation including a PI/r (AIa). Depend-ing on the resistance profile and op-tions available, inclusion of agents fromnew drug classes (raltegravir or maravi-roc) should be considered (BIIb). Mono-therapy with a PI/r should be avoided un-less other drugs cannot be considered forreasons of toxicity/tolerability (AIa).

Design of a new regimen should con-sider previous drug exposure, previ-ous resistance profile, drug interac-tions, and history of intolerance/toxicity (CIII). Treatment interruptionsshould be avoided, except in the con-text of controlled clinical trials (AIa).Elective treatment interruptions shouldconsider the different half-lives of theregimen components, with stopping thedrugs in a staggered manner when anNNRTI is a component (CIII).

CONCLUSIONS ANDFUTURE DIRECTIONSIncreasing evidence that insidious dam-age occurs during “asymptomatic” HIVinfection underscores the potential ben-efit of ART, even when the risk of tradi-tionalAIDS-definingdiseases isrelativelylow.Theprominenceofnon-AIDSeventsas a major cause of morbidity and mor-tality in those with ongoing HIV replica-tionsuggeststhatearlyARTinitiationmayfurther improve thequalityandlengthoflife forpersons livingwithHIV.Thestra-tegicuseofnewerdrugscan improvetol-erability, as well as provide durable andpotentviralsuppressionininitialandsub-sequent therapy.

However, far too many HIV-infectedpersonspresent formedicalcarewithad-vanced disease, both in wealthy andresource-limitedsettings.Universal vol-untary HIV testing, comprehensive pre-





ventionservices,andearly linkagetocareandtreatmentarenecessarytoensurethatadvances inARTaremadeavailabledur-ingearlierdiseasestages.AdvancesinARThaveshownthatAIDS,astraditionallyde-fined,canbeprevented.Oneof thegreat-estchallenges is that full implementationof these guidelines will require address-ing social andstructuralbarriers todiag-nosis and care, as well as the pervasivestigmaanddiscriminationassociatedwithan HIV diagnosis.

Author Affiliations: AIDS Research Consortium of At-lanta, Atlanta, Georgia (Dr Thompson); University ofCalifornia San Diego, La Jolla (Dr Schooley); New YorkUniversity School of Medicine, New York (Dr Aberg);Hospital Juan Fernandez/University of Buenos AiresMedical School and Fundacion Huesped, Argentina(Dr Cahn); Hospital Clinic-IDIBAPS, University ofBarcelona, Barcelona, Spain (Dr Gatell); UniversityHospital Zurich, Division of Infectious Diseases andHospital Epidemiology, University of Zurich, Zurich,Switzerland (Dr Günthard); Columbia University Col-lege of Physicians and Surgeons, New York, New York(Dr Hammer); Harvard Medical School, Boston, Mas-sachusetts (Dr Hirsch); International AIDS Society–USA, San Francisco, California (Ms Jacobsen); BC-Centre for Excellence in HIV/AIDS, Providence HealthCare and University of British Columbia, Vancouver,Canada (Dr Montaner); Academic Medical Center, Uni-versity of Amsterdam, Amsterdam, the Netherlands(Dr Reiss); University of California San Diego and Vet-erans Affairs San Diego Healthcare System (Dr Rich-man); Luigi Sacco Hospital, Milan, Italy (Dr Riz-zardini); University Hospital of Lausanne, Lausanne,Switzerland (Dr Telenti); University of California SanFrancisco and San Francisco Veterans Affairs MedicalCenter (Dr Volberding); and Hopital Bichat-Claude Ber-nard and Xavier Bichat Medical School, Paris, France(Dr Yeni).Author Contributions: Study concept and design:Thompson, Aberg, Cahn, Rizzardini, Telenti, Gatell,Günthard, Hammer, Hirsch, Jacobsen, Reiss, Richman,Volberding, Yeni, Schooley.Acquisition of data: Thompson, Aberg, Cahn,Rizzardini, Telenti, Hammer, Volberding, Schooley.Analysis and interpretation of data: Thompson, Aberg,Cahn, Montaner, Rizzardini, Telenti, Gatell, Günthard,Hammer, Hirsch, Reiss, Richman, Volberding, Yeni,Schooley.Drafting of the manuscript: Thompson, Aberg, Cahn,Rizzardini, Telenti, Günthard, Hirsch, Jacobsen, Reiss,Richman, Volberding, Schooley.Critical revision of the manuscript for important in-tellectual content: Thompson, Aberg, Cahn, Montaner,Rizzardini, Telenti, Gatell, Günthard, Hammer, Hirsch,Reiss, Richman, Volberding, Yeni, Schooley.Obtained funding: Jacobsen, Volberding.Administrative, technical, or material support:Montaner, Günthard, Hammer, Jacobsen, Volberding.Study supervision: Thompson, Cahn, Telenti, Hammer,Hirsch, Jacobsen, Schooley.Financial Disclosures: Dr Thompson reported receivingresearch grants awarded to AIDS Research Consor-tium of Atlanta from Abbott Laboratories, Avexa,Boehringer Ingelheim Pharmaceuticals, Bristol-MyersSquibb,GlaxoSmithKline,GileadSciences,GeoVax,Kat-ketsuken, Koronis Pharmaceuticals, Merck ResearchLaboratories, Myriad, Ora-Sure, Panacos Pharmaceu-ticals (now Myriad), Pfizer, Progenics Pharmaceuti-cals, Roche Laboratories, Roche Molecular Systems,Serono, Theratechnologies Tibotec Therapeutics, TobiraTherapeutics, Trimeris, and VaxGen; has served on the

scientific advisory boards or as a clinical trial designconsultant for Chimerix, GeoVax, GlaxoSmithKline,Panacos Pharmaceuticals, Progenics Pharmaceuti-cals, and Tibotec Therapeutics; has received hono-raria for scientific lectures from GlaxoSmithKline andSerono; and has served on data and safety monitor-ing boards for Tibotec Therapeutics. Dr Aberg reportedserving as a scientific advisor to Abbott Laboratories,Boehringer Ingelheim Pharmaceutical, Gilead Sci-ences, GlaxoSmithKline, Merck, Pfizer, Theratech-nologies, Tibotec Therapeutics, and ViiV Healthcare;has received grants and research support from GileadSciences, GlaxoSmithKline, Merck, Pfizer, Schering-Plough, Theratechnologies, Tibotec Therapeutics, VircoLab, and Wyeth; and has received honoraria fromAbbott Laboratories, Bristol-Myers Squibb, and GileadSciences. Dr Cahn reported serving on the advisoryboards for Avexa, Gilead Sciences, GlaxoSmithKline,Myriad Genetics, Merck, Pfizer, Pharmasset, Schering-Plough, and Tibotec Therapeutics; has served as aninvestigator for Avexa, Boehringer Ingelheim Phar-maceuticals, Gilead Sciences, GlaxoSmithKline, Merck,Pfizer, Pharmasset, Roche Laboratories, Schering-Plough, and Tibotec Therapeutics; and has receivedhonoraria for speaking engagements from AbbottLaboratories, Bristol-Myers Squibb, Boehringer Ingel-heim, GlaxoSmithKline, Merck, Pfizer, and TibotecTherapeutics. Dr Montaner reported receiving researchgrants from, and served as an ad hoc advisor or con-sultant to, Abbott Laboratories, Argos Therapeutics,Boehringer Ingelheim Pharmaceuticals, Bristol-MyersSquibb, Cato Research Canada, ConjuChem Biotech,Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche,Johnson & Johnson, Merck Canada, Merck Frosst Labo-ratories, Pfizer Canada, Serono, Theratechnologies, andTibotec Pharmaceuticals and has served on an end-point adjudication committee for Schering-Plough. DrRizzardini reported receiving research grants fromGilead Sciences and Merck Sharp & Dohme. Dr Telentireported receiving research grants or honoraria for lec-tures from Abbott Laboratories, Boehringer Ingel-heim Pharmaceuticals, Bristol-Myers Squibb, andGlaxoSmithKline. Dr Gatell reported receiving researchgrants or honoraria for serving on advisory boards orfor lectures from Abbott Laboratories, Boehringer Ingel-heim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sci-ences, Janssen, Merck Sharpe & Dohme, Pfizer,GlaxoSmithKline, Roche Laboratories, Theratechnolo-gies, Tibotec Therapeutics, Tobira Therapeutics, andVirco Lab. Dr Günthard reported serving as a consul-tant and medical advisor for Abbott Laboratories,Bristol-Myers Squibb, Boehringer Ingelheim Pharma-ceuticals, Gilead Sciences, GlaxoSmithKline, Pfizer,Tibotec Therapeutics, and ViiV Healthcare and hasreceived unrestricted research and educational grantsfrom Abbott Laboratories, Bristol-Myers Squibb, GileadSciences, Merck Sharp & Dohme, and Pfizer. Dr Ham-mer reported serving on a scientific or clinical advi-sory boards for Merck, Progenics Pharmaceuticals,TaiMed Biologics, Tibotec Therapeutics, and Wyeth;has received clinical research contracts from Merck;and has served on data and safety monitoring boardsand committees for Bristol-Myers Squibb and on theboard of directors of SIGA Pharmaceuticals. Dr Hirschreported serving on data and safety monitoring boardsfor Merck and TaiMed Biologics. Dr Reiss reported serv-ing as a scientific advisor to Boehringer Ingelheim Phar-maceuticals, Bristol-Myers Squibb, Gilead Sciences,GlaxoSmithKline, Merck, Theratechnologies, TibotecTherapeutics, and Tobira Therapeutics; has served ondata and safety monitoring boards and endpoint adju-dication committees for Tibotec Therapeutics; hasreceived honoraria for speaking engagements at sci-entific conferences from Boehringer Ingelheim Phar-maceuticals, Bristol-Myers Squibb, Gilead Sciences,GlaxoSmithKline, and Theratechnologies; and hasreceived research support from Gilead Sciences, ViiVHealthcare, and Boehringer Ingelheim Pharmaceuti-

cals. Dr Richman reported being a consultant to Ana-dys Pharmaceuticals, Biota, Boehringer Ingelheim Phar-maceuticals, Bristol-Myers Squibb, Chimerix, Gen-Probe, Gilead Sciences, Idenix Pharmaceuticals, KoronisPharmaceuticals, Merck, Monogram Biosciences,Myriad Genetics, Pfizer, Roche, Theraclone Sciences,and Tobira Therapeutics; has served on an endpointadjudication committee for Schering-Plough; has beenthe recipient of a research grant from Merck; and hasbeen a stock options holder of Chimerix and IdenixPharmaceuticals. Dr Volberding reported serving ondata and safety monitoring boards for Merck andTaiMed Biologics and on an endpoint adjudication com-mittee for Schering-Plough; has provided paid experttestimony for commercial firms; has served on scien-tific or clinical advisory boards for Bristol-Myers Squibb,Gilead Sciences, GlaxoSmithKline, Pfizer, and TobiraTherapeutics; and has been the recipient of servicegrants for, or held contracts from, GlaxoSmithKline Italy.Dr Yeni reported receiving scientific grants from AbbottLaboratories, Bristol-Myers Squibb, Gilead Sciences,GlaxoSmithKline, Pfizer, Merck, and Roche Labora-tories. Dr Schooley reported serving as a consultantto Achillion Pharmaceuticals, Anadys Pharmaceuticals,Ardea Biosciences, Gilead Sciences, GlaxoSmithKline,Inhibitex, iTherX, Johnson & Johnson, LabCorp,Merck, Myriad Biosciences, Pfizer, TaiMed Biologics,Tanox, Tobira Therapeutics, Vertex Pharmaceuticals,and Vical; has received grants from Gilead Sciencesand Pfizer; and has stock options for Achillion Phar-maceuticals.Funding/Support: This work was funded by the In-ternational AIDS Society–USA. Panel members servein volunteer capacities (ie, are not compensated). Noprivate sector or government funding was used to sup-port the effort. The International AIDS Society–USAhas received grants for selected CME activities (un-related to guidelines development) from AbbottLaboratories, Boehringer Ingelheim Pharmaceuticals,Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline,Merck, Pfizer, Roche Laboratories, Tibotec Therapeu-tics, and ViiV Healthcare. Grants are pooled such thatno single company supports any single effort.Role of the Sponsor: The International AIDS Society–USA determined the need for updated recommenda-tions, selected the panel members, and provided ad-ministrative oversight and financial support.Online-Only Material: The eTable, eBox, and eFig-ure are available at http://www.jama.com.Additional Contributions: We thank Michelle TayagValderama, BS, who was compensated as an em-ployee of the International AIDS Society–USA, for ad-ministrative support.

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Tratamiento antiretroviral en adultos con infeccion VIH J.A.M.A. 2010