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. 2008;300(5):555-570 (doi:10.1001/jama.300.5.555)JAMAScott M. Hammer; Joseph J. Eron, Jr; Peter Reiss; et al.

Society USA PanelRecommendations of the International AIDSAntiretroviral Treatment of Adult HIV Infection: 2008

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CLINICIANS CORNERSPECIAL COMMUNICATION

Antiretroviral Treatment of Adult HIV Infection2008 Recommendations of the InternationalAIDS SocietyUSA PanelScott M. Hammer, MD

Joseph J. Eron Jr, MD

Peter Reiss, MD, PhD

Robert T. Schooley, MDMelanie A. Thompson, MD

Sharon Walmsley, MD

Pedro Cahn, MD

Margaret A. Fischl, MD

Jose M. Gatell, MD, PhD

Martin S. Hirsch, MD

Donna M. Jacobsen, BS

Julio S. G. Montaner, MD

Douglas D. Richman, MD

Patrick G. Yeni, MD

Paul A. Volberding, MD

THE FIELD OF ANTIRETROVIRAL

therapy continues to evolverapidly, and, to maintain thehighest possible standard of

care, treatment guidelines must con-tinually be refined to assist the com-plex decision-making process. For a dis-ease that has been transformed fromalmost uniformly fatal to manageableover decades, the impact of treatmentdecisions is substantial. Treatment can

provide durable virologic, immuno-logic, and clinical benefits while mini-mizing toxicities and drug resistance,

and potentially allow for a normal lifespan.

The rationale for the current up-date of the 2006 International AIDS So-

CME available online atwww.jamaarchivescme.comand questions on p 596.

Context The availability of new antiretroviral drugs and formulations, including drugsin new classes, and recent data on treatment choices for antiretroviral-naive and -ex-perienced patients warrant an update of the International AIDS SocietyUSA guide-lines for the use of antiretroviral therapy in adult human immunodeficiency virus (HIV)infection.

Objectives To summarize new data in the field and to provide current recommen-dations for the antiretroviral management and laboratory monitoring of HIV infec-tion. This report provides guidelines in key areas of antiretroviral management: whento initiate therapy, choice of initial regimens,patient monitoring, when to changetherapy,and how best to approach treatment options, including optimal use of recently ap-proved drugs (maraviroc, raltegravir, and etravirine) in treatment-experienced pa-tients.

Data Sources and Study Selection A 14-member panel with expertise in HIVresearch and clinical care was appointed. Data published or presented at selected sci-entific conferences since the last panel report (August 2006) through June 2008 wereidentified.

Data Extraction and Synthesis Data that changed the previous guidelines were

reviewed by the panel (according to section). Guidelines were drafted by section writ-ing committees and were then reviewed and edited by the entire panel. Recommen-dations were made by panel consensus.

Conclusions Newdata and considerations support initiating therapy before CD4 cellcount declines to less than 350/L. In patients with 350 CD4 cells/L or more, thedecision to begin therapy should be individualized based on the presence of comor-bidities, risk factors for progression to AIDS and non-AIDS diseases, and patient readi-ness for treatment. In addition to the prior recommendation that a high plasma viralload (eg, 100 000 copies/mL) and rapidly declining CD4 cell count (100/L peryear) should prompt treatment initiation, active hepatitis B or C virus coinfection, car-diovascular disease risk, and HIV-associated nephropathy increasingly prompt earliertherapy. The initial regimen must be individualized, particularly in the presence of co-morbid conditions, but usually will include efavirenz or a ritonavir-boosted proteaseinhibitor plus 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine orabacavir/lamivudine). Treatment failure should be identified and managed promptly,

with the goal of therapy, even in heavily pretreated patients, being an HIV-1 RNAlevel below assay detection limits.

JAMA. 2008;300(5):555-570 www.jama.com

Author Affiliations are listed at the end of this ar-ticle.Corresponding Author: Scott M. Hammer, MD, Di-vision of Infectious Diseases, ColumbiaUniversityCol-lege of Physiciansand Surgeons,630 W 168th St,NewYork, NY 10032 ([email protected]).

2008 American Medical Association. All rights reserved. (Reprinted) JAMA,August 6, 2008Vol 300, No. 5 555

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cietyUSA (IAS-USA) antiretroviraltreatment recommendations1 is basedon (1) the recent approval of 3 novelagents: maraviroc, a CC chemokine re-ceptor 5 (CCR5) antagonist; raltegra-vir, an integrase strand transfer inhibi-tor; and etravirine, a second-generationnonnucleoside reverse transcriptase in-hibitor (NNRTI); (2) new data that bet-ter inform the choice of drugs for ini-

tial therapy and the management oftreatment failure; and (3) new patho-genetic insights into the role of hu-man immunodeficiency virus (HIV) indisease processes previously consid-ered nonAIDS-related conditions.

These guidelines are built on theprecept of pathogenesis- and evidence-based individualization of therapy in

highly resourced settings. Conse-quently, they are most applicable todeveloped and selected mid-leveleconomies. However, the core prin-ciple underlying these guidelines,namely pathogenesis-directed therapy

with regimens designed to achieve fullvirologic suppression with minimaltoxicity and maximal simplicity, isapplicable to the developing world.Progress with antiretroviral rolloutin the developing world is encourag-ing,2 but recent advances in the highlyresourced world need to be adaptedand translated to the developingworld to realize these benefits. Thus,these guidelines can be viewed in 2contextsproviding direct, practicaladvice to caregivers in the developedworld and serving as an advocacy tool

to help close HIV treatment gapsbetween high and low socioeconomicsettings.

METHODS

The volunteer panel was first convenedbythe IAS-USA in 19953 to develop evi-dence-based recommendations for an-tiretroviral therapy in adult HIV infec-tion in developed world settings.

After a planned partial rotation, thepanel reconvened in February 2008.The panel met in person and electroni-

cally to consider data produced sinceits 2006 report. A MEDLINE search wasconducted (P.A.V.) to identify rel-evant studies. All manufacturers of ap-proved or expanded-access antiretro-viral drugs werecontacted for publishedor publicly presented data pertaining totheir product(s). Data on file, unpub-lished observations, personal commu-nications, and other such informationwas notconsidered exceptfor public re-leases of data and safety monitoringboard reports. Where recommenda-

tions have not changed, reference tosupporting evidence is available in theprevious report.1 Each panel memberwas assigned to 1 or more writingteams, and section leaders (J.J.E., P.R.,R.T.S., M.A.T., and S.W.) prepareddrafts as previously described.1

The quality and strength of the evi-dence were rated according to a scale

(BOX).1 Clinical recommendations weremade by panel consensus.

WHEN TO STARTANTIRETROVIRAL THERAPY

Established HIV-1 Infection

The primary goal of antiretroviraltherapy is to increase disease-free sur-vival through maximal suppression ofviral replication and preservation of im-munologic function. The optimal tim-ing of initiation of antiretroviral therapydepends on consideration of these ben-efits in balance with the risks of drugtoxicity, potential emergence of viral re-sistance, and the understanding thatHIV infection is a chronic disease re-quiring continuous therapy, usuallyover the course of decades.

Although the benefits of beginning

antiretroviral therapy at CD4cell countsabove 200/Larewell documented, pre-vious recommendations were influ-enced by the perceived need to mini-mize drug toxicity and preservetherapeuticoptions for subsequentregi-mens.1 Although these remain crucialconcerns, as treatment options have in-creased and the risks of untreated vi-remia are better appreciated, the risk-benefit ratio is shifting toward earliertreatment.

The substantial toxicity and inconve-

nience of early regimens dampened en-thusiasm for starting therapy at higherCD4 cell counts. However, newer regi-mens are potent, durable, and lesstoxic.4-10 Fixed-dose combinations withlong half-lives andritonavir-boosted pro-tease inhibitors(PIs)have simplifiedregi-mens, improved pharmacokinetics andtreatment response,11 enhanced adher-ence to therapy,12 and slowed the emer-gence of resistance.11,13,14

New data demonstrate the increasedrelative burden of non-AIDS diseases in

HIV-infected persons and require theirinclusion in the definition of HIV dis-easeprogression.15-21 Clinical trial andob-servationalcohort dataindicatethatevenat high CD4 cell counts, uncontrolledHIV replication and immune activationare strongly associated with the devel-opment of diseases not traditionally as-sociatedwithHIVinfection, such asnon-

Box. Strength of

Recommendation and

Quality of Evidence

Rating Scale

Strength of Recommendation

A: Strong evidence to support therecommendation

B: Moderate evidence to supportthe recommendation

C: Insufficient evidence to sup-port the recommendation

Quality of Evidence

Ia: Evidence from 1 or more ran-domized, controlled clinical trialspublished in the peer-reviewed lit-erature

Ib: Evidence from 1 or more ran-domized, controlled clinical trials

presented in abstract form at peer-reviewed scientific meetings

IIa: Evidence from nonrandom-ized clinical trials or cohort orcase-control studies published inthe peer-reviewed literature

IIb: Evidence from nonrandom-ized clinical trials or cohort orcase-control studies presented inabstractform at peer-reviewed sci-entific meetings

III: Recommendationbased on thepanels analysis of the accumu-lated available evidence

ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION

556 JAMA,August 6, 2008Vol 300, No. 5(Reprinted) 2008 American Medical Association. All rights reserved.



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AIDS cancers (including lung, anal, andheadand neckcancersand Hodgkin lym-phoma)22-24 and end-organ damage, in-cluding cardiovascular,25 hepatic,26 andrenal27,28 dysfunction. A large multico-hort survival analysis among antiretro-

viral-naive persons with CD4cell countsof more than 350/L demonstrated in-creased mortality even at high CD4 cellcountscompared with thegeneral popu-lation.29 The risk of developing nonAIDS-defining cancersis higher when theCD4 cell count is less than 500/L for 1year or more.30 Markers of inflamma-tion (eg, interleukin 6) and coagulation(eg, D dimer) are strong predictors ofmortality,evenat higherCD4cell counts,and are tightly correlated with plasmaHIV-1 RNA levels.31-33 In addition,main-taining CD4 cell counts of more than

500/L may result in a normal life ex-pectancy through the prevention of ir-reversible immune damage associatedwith prolonged immune activation.34

Althoughnot designedto address theissue of when to initiate therapy, re-cent evidence from the Strategic Man-agement of Antiretroviral Therapy(SMART) trial supports the hypoth-esis that uncontrolled viral replicationcarries an increased risk of morbidityand mortality at all CD4 strata.35 In thistrial, opportunistic diseases and death

occurred at higher rates when therapywasinterrupted than when therapy wascontinuous, even with CD4 cell countsof more than 350/L. At high CD4 cellcounts, these outcomes were associ-ated with HIV-1 RNA levels above 400copies/mL. The risks of cardiovascu-lar, hepatic, and renal complicationsalso were higher in the drug interrup-tion group than in the continuous vi-ral suppression group.36When therapywas reinstituted, risk decreased but didnot return to baseline.37 In a subset of

patients who were antiretroviral-naive or not currently receiving therapy,those in the deferred therapy group hadan increased rate of serious non-AIDSevents compared with those in the im-mediate group who began treatmentwith CD4 cell counts of more than 350/L.38 These results demonstrate a strongrelationship between uncontrolled HIV

replication and multiple nonAIDS-defining diseases that substantiallyaffect both quality and length of life,even at CD4 cell counts of more than350/L. Treatment for all infected per-sons with HIV-related symptoms and

for all asymptomatic HIV-infected per-sons with CD4 cell counts at or less than200/L has been a consistent recom-mendation.1 Additionally, longitudi-nal cohort studies and randomizedclinical trials have shown that thosewho begin therapy with CD4 cell countsbetween 200/L and350/Lhave lowerrates of AIDS-defining diseases anddeath and are more likely to achievemaximal suppression of virus replica-tion and higher CD4 cell counts thanthose who begin therapy at lower CD4cell levels.19,34,39-52 Although not all per-

sons with higher CD4 cell counts areappropriate candidates for treatment,these data support the benefit oftherapy, especially when other comor-bidities or risk factors for HIV diseaseprogression exist. In particular, high vi-ral load(ie,100000copies/mL), rapidCD4 cell count decline (100/L peryear), hepatitis B or C virus (HBV orHCV) coinfection, HIV-associated ne-phropathy (HIVAN), and risk factorsfor non-AIDS diseases, particularly car-diovascular diseases, merit consider-

ation of initiation of therapy indepen-dent of CD4 cell counts.

Other benefits of antiretroviraltherapy include decrease of mother-to-child HIV transmission53 and poten-tial reduction of HIV transmissionamong adults.54 Because antiretroviraltherapy can decrease HIV transmis-sion in the setting of couples with dis-cordant HIV status,55,56 considerationshould be given to initiation of therapyin the HIV-seropositive partner butshould not supplant traditional pre-

vention methods. Risk reduction coun-seling should be a routine part of careand reinforced at each clinician-patient interaction.

Primary HIV-1 Infection

Although knowledge continues toevolve regarding the pathogenesis ofprimary HIVinfection,no definitive evi-

dence has emerged that supports rou-tine initiation of antiretroviral therapyin primary HIV infection.

Recommendations

The patients readiness for treatmentshould always be assessed when con-sidering initiation of therapy. Therapyis recommended (TABLE1) for all pa-

tients with symptomatic establishedHIV disease (rating A1a in the Box) af-ter appropriate counseling. For asymp-tomatic individuals, therapy should beinitiated before the CD4 cell count de-creases to less than 350/L (AIIa,AIIb).At present, there are no definitive ran-domized clinical trial data to define aspecific CD4 cell count threshold of350/L or more for beginning therapy.Therefore, in this group, decisionsshould be based on comorbidities, riskof disease progression (including risk

of non-AIDS diseases), and patient will-ingness and estimated ability to ad-here to long-term treatment. Rapid de-cline in CD4 cell count (ie, 100/Lper year), a plasma HIV-1 RNA levelgreater than 100 000 copies/mL, andriskfactors for cardiovascular and othernon-AIDS diseases are indicators thatfavor earlier therapy (AIIa, AIIb). Risk

Table 1.Recommendations for InitiatingAntiretroviral Therapy in Treatment-NaiveAdults With Established HIV-1 Infectiona

MeasureRecommendation

(Rating)

Symptomatic HIVdisease

Antiretroviral therapyrecommended

(AIa)Asymptomatic HIV

diseaseCD4 cell count350/L

Antiretroviral therapyrecommended(AIIa, AIIb)

CD4 cell count350/L

Antiretroviral therapyshould beindividualized (seeWhen to Startsection of text)(AIIa, AIIb)b

Abbreviation: HIV, human immunodeficiency virus.a In nonpregnant adults only. For all individuals, regardless

of whether they are receiving treatment, intensive coun-seling to prevent secondary transmission is recom-mended.

bConsiderations include highviral load(100000HIV RNAcopies/mL),rapiddeclinein CD4cellcount (100/L per

year),high riskof cardiovasculardisease, activehepatitisB or C virus coinfections, or presence of HIV-associatednephropathy.





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factors for cardiovascular disease, suchas hypertension, hyperlipidemia, dia-betes, and tobacco use, should be ag-gressively managed in all patients. Al-though controlled clinical trials havenot directly addressed whether earlier

initiationof antiretroviral therapymightreduce cardiovascular or other nonAIDS-related disease risks, it is clear thatthe risk is higher when viral replica-tion is uncontrolled. Patient readi-ness, drug interactions,adherencechal-lenges, toxicities, and costs should beconsidered when determining whetherto initiate therapy at higher CD4 cellcounts,recognizing thattreatment mustbe sustained. There is no upper CD4cell limit for starting therapy when 1or more of these considerations arepresent. An individual risk-benefit as-

sessment is appropriate in such cir-cumstances. Clinicians should followroutine screening recommendationsformalignancies, implementing earlierscreening when risk factors warrant it.Because infected individuals continueto be identified at an advanced stage ofdisease, implementing routine volun-tary HIV testing and counseling usingrapid testing technology is importantfor the earlier identification and treat-ment of HIV infection.

WHAT TO STARTRecent Data: Choice of InitialRegimen

The initial selection of an antiretroviralregimen depends on the drug suscepti-bility of the individual patients HIV.Transmission of resistant variantsin de-veloped countries ranges from 5% to20%.57,58 The selection is additionally in-fluenced by factors like pill burden, fre-quency of dosing, anticipated tolerabil-ity, comorbid conditions, andshort- andlong-term adverse event profiles. Poten-

tial for emergence of resistance duringtherapy and subsequent treatment op-tions may also affect thedesign of an ini-tial regimen.

PI vs NNRTI Comparisons. AIDSClinical Trials Group (ACTG) studyA5142 compared 3 initial regimens in757patients:efavirenz plus2 nRTIs,rito-navir-boosted lopinavir (lopinavir/r)plus

2 nRTIs, and efavirenz plus lopinavir/rwithout nRTIs. Efavirenz plus 2 nRTIsled to a longer time to virologic failureanda lower rate of virologic failure thanlopinavir/r plus 2 nRTIs (24% vs 37%,respectively).59 Eighty-ninepercent ofpa-

tients initiating efavirenz plus 2 nRTIshad HIV RNA levels of less than 50 cop-ies/mL at 96 weeks compared with 77%of those initiating lopinavir/r plus 2nRTIs. The CD4 cell count increases at96 weeks were greater in patients tak-inglopinavir/r plus 2 nRTIsthan in thosetaking efavirenzplus 2 nRTIs(287/L vs230/L, respectively). Grade 3 or 4 di-arrhea and triglyceride changes oc-curred more often in the group takinglopinavir/r plus 2 nRTIs, whereas lipaseelevations of this severity were morecommon with efavirenzplus 2 nRTIs. In-

creases in mediantotal cholesterol,nonhigh-density lipoproteincholesterol,andhigh-density lipoprotein cholesterollev-els were similar in the 2 nRTI-contain-ing groups, whereasincreases in triglyc-eride levels were lower with efavirenzplus 2 nRTIs.60 Fat loss was most pro-nounced when efavirenz was combinedwith stavudine or zidovudine. There isno evidence that efavirenz combinedwith nonthymidine nRTIs is associatedwith lipoatrophy.61

NNRTI-Based Regimens.The viro-

logic response of regimens containingefavirenz plus 2 nRTIs is durable59,62,63

andconsistent acrossviral load andCD4cell count strata.64 Ina retrospectivestudyexamining the activity of efavirenz plus2 nRTIs across broad CD4 and HIV RNAstrata,timeto virologicfailuredidnotdif-fer for patients with pretreatment viralloadsabove 300 000 RNAcopies/mLandCD4 cell counts of less than 50/Lcom-pared with all other patients.65 Al-though sample sizes were limited, pa-tients with baseline HIV RNA levels of

more than 750 000 copies/mL hadsimi-lar treatment responses.PI-Based Regimens (TABLE 2). Inan

open-label, randomized study, fosam-prenavir/r twice daily wasnoninferiortolopinavir/r twice daily.13 Treatmentresponsesweresimilar forthosewith viralloadsof at leastvs lessthan 100 000 cop-ies/mL andacross CD4cell countstrata.

Virologic failures were uncommon(6%-7%) and no major PI resistanceassociated mutations were observed.

Atazanavir/r was also noninferior tolopinavir/r at 48 weeks in an open-label study. Fewer patients in either

group achieved an HIV RNAlevel oflessthan 50 copies/mL if their baseline HIVRNA level was at least 100 000 copies/mL.Patients with lower CD4cell countsappeared to respond less well to lopi-navir/r. The percentage changes in totalcholesterol and triglyceride (but notlow- or high-density lipoprotein cho-lesterol) levels were greater in the lopi-navir/r group.66

Darunavir/r was comparedwithlopi-navir/r at 48 weeks in a randomized,open-label study.68 Lopinavir/r could beadministered once (25% of patients)

or twice daily; only 2% initiated treat-ment with the tabletformulation of lopi-navir/r. Thedarunavir/r dose was800mg/100 mg once daily, not the currentlyapproved dose of 600 mg/100 mg twicedaily for treatment-experienced pa-tients. The differencebetween groups inresponse to less than 50 HIV-1 RNAcop-ies/mL at 48 weeksfavoring thedaruna-vir regimenmet criteria for noninferior-ity but not for superiority. In the HIVRNA stratum of 100 000 copies/mL orgreater, the response in the darunavir/r

group was superior to that in the lopi-navir/r group. Differences between thegroups appeared to be driven by the re-sponse in patients who received lopina-vir/r oncedaily. No patients acquired ma-jor PI resistance mutations. Saquinavir/rwas also noninferior to lopinavir/r in arandomized, open-label study.67

Use of the soft-gel formulation oflopinavir/r, which will soon no longerbe available, complicates the interpre-tation of the aforementioned studies. Arandomized, open-label study com-

pared once-daily vs twice-daily lopina-vir/r combined with tenofovir and em-tricitabine.69 An 8-week comparativetrial of soft-gel capsuleswith tablets wasembedded in the overall trial, al-though all patients received the tabletformulation after 8 weeks. The once-daily group was noninferior to thetwice-daily group, in contrast with the





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comparative study of lopinavir/r andda-runavir/r, and no substantial differ-ences in treatment responses were seenbetween HIV RNA strata (100 000and100 000 copies/mL). There wereno differences in tolerability or ad-

verse events.In a smaller randomized study, therewere fewer virologic failures andless re-

sistance emergence with atazanavir/r(300 mg/100 mg once daily) than withunboosted atazanavir (400 mg oncedaily), both combined with 2 nRTIs.Differences in the median changes inlipids were small.70

Since the previous guidelines, once-daily fosamprenavir, 1400 mg,withrito-navir, 100 mg, was approved for use in

treatment-naive patients, although com-parative data are limited. A small ran-domized trial comparing fosamprena-vir/r with atazanavir/r once daily, bothwith fixed-dosecombination tenofovir/emtricitabine, found no substantial dif-

ferences between the groups.

71

Dual nRTI Components. Dual nRTIsremain the backbone of most initial

Table 2.Selected Comparative Studies of Ritonavir-Boosted Protease Inhibitors a

SourceNo. of

Patients

No. of Patients With50 HIV RNA

Copies/mL at 48 wk, % Comments

Eron et al,13 2006 (KLEAN)b 878 Similar results in viral load ( or 100000 copies/mL) andCD4 strata

Similar adverse events

Fosamprenavir, 700 mg twice daily ritonavir, 100 mg twice daily

66

Lopinavir, 400 mg twice daily ritonavir,100 mg twice daily c

65

Molina et al,66 2008 (CASTLE)d 883 Percentage with 50 HIV RNA copies/mL was 8%-9% less ineach treatment group in stratum with 100000copies/mL; no substantial differences between groups ineither viral load stratum

Decreased response to lopinavir in lower CD4 strataHyperbilirubinemia more common with atazanavirNausea, diarrhea, elevated total cholesterol and triglyceride

levels more common with lopinavir

Atazanavir, 300 mg once daily ritonavir, 100 mg once daily

78

Lopinavir, 400 mg once daily ritonavir,100 mg once dailyc

76

Walmsley et al,67 2007 (GEMINI)d 337 Results by viral load strata not reportedMore diarrhea and greater increases in triglycerides with

ritonavir-boosted lopinavir

Saquinavir, 1000 mg twice daily ritonavir, 100 mg twice daily

65

Lopinavir, 400 mg twice daily ritonavir,100 mg twice daily c

64

Clumeck et al,68 2007 (ARTEMIS)d 689 Most received capsule formulation of lopinavir; 25% usedlopinavir once daily

Treatment response was lower in both groups in stratum wit h100 000 HIV RNA copies/mL; in this stratum, darunavirwas superior (P .05)

Diarrhea less frequent and mean triglyceride levels lower withdarunavir

Darunavir, 800 mg once daily ritonavir, 100 mg once daily

84

Lopinavir, 400 mg twice daily ritonavir,100 mg twice daily or lopinavir, 800mg once daily ritonavir, 200 mgonce daily

78

Gathe et al,69 2008 (M05-730) 664 No significant difference between groups by viral load strata( or 100000 HIV RNA copies/mL) or CD4 strata

No substantial differences in tolerability or laboratory adverseevents

Lopinavir, 800 mg once daily ritonavir,200 mg once daily

77

Lopinavir, 400 mg twice daily ritonavir,100 mg twice daily

76

Abbreviation: HIV, human immunodeficiency virus.a In each study, noninferiority of the comparator group (listed first) was established.bAll patients received fixed-dose combination abacavir/lamivudine, 600 mg/300 mg once daily.c Capsule formulation of lopinavir/ritonavir.dAll patients received fixed-dose combination tenofovir/emtricitabine, 300 mg/200 mg once daily.





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regimens. Extensive data support in-clusion of lamivudine or emtricita-bine as 1 of the 2 nRTIs. Tenofovir/emtricitabine and abacavir/lamivudinearetaken once daily. Long-term data fortenofovir/emtricitabine support its use

in initial therapy,

61-63

although indi-viduals with underlying renal dysfunc-tion or requiring other nephrotoxicagents may be at increased risk of re-nal toxicity. Modest decreases in bonedensity have been observed,63 and hy-pophosphatemia can occur.72 The long-term impact of tenofovir on bone me-tabolism, phosphate metabolism,73 andrenal function needs further evalua-tion. Tenofovir, emtricitabine, and efa-virenz are coformulated in a single pilltaken once daily.

Abacavir/lamivudine is currently being

compared with tenofovir/emtricitabinein a randomized, blinded, 96-week clini-cal trial of 688 treatment-naive pa-tients.10 Bothdual-nRTIcombinations arepaired withonce-dailylopinavir/r. At the48-weekprimary end-pointanalysis,68%of patients receiving abacavir/lamivu-dine and 67% of those receiving tenofo-vir/emtricitabine had HIV RNA levels ofless than 50 copies/mL. In the stratumwithscreeningviral loads of100 000 cop-ies/mL or greater, 63% and 65% of pa-tientshadHIVRNA levelsbelow 50 cop-

ies/mL in the abacavir and tenofovirgroups, respectively; confirmed viro-logic failure occurred in 12% and 11%,respectively, of the patients over 48weeks. Median changes in triglycerideand low-density lipoprotein cholesterollevelswere greater in theabacavir group.

In contrast with these results, the on-going ACTG A5202 study of approxi-mately 1800 treatment-naive patientscomparing the same 2 dual-nRTI com-binations, in conjunction with a com-parison of efavirenzwithatazanavir/r, was

modified when a data and safety moni-toring board interim review noted ahigher rate of virologic failure in pa-tients with screening viral loads of100 000 copies/mL or higher in theaba-cavir/lamivudine group than in the te-nofovir/emtricitabine group. The esti-mated hazard ratio for cumulativevirologicfailurein thisstratum was2.33

(95% confidence interval [CI], 1.46-3.72; P=.0003) (http://www.aactg.org/news_results.asp).

A large,collaborativecohortstudy in-vestigated the association of nRTI usewith subsequent myocardial infarc-

tion.

74,75

After controlling for numer-ous factors, an increased risk of myo-cardial infarction associated withrecentabacavir or didanosine use (relativerates, 1.90 [95% CI, 1.47-2.45] and 1.49[95% CI, 1.14-1.95], respectively) wasdemonstrated. Cumulative exposurewas not predictive, and those who hadnot taken abacavir or didanosine for 6months or more did not have an in-creased risk. The overall absolute riskwas small but was greatest in those athighest risk of myocardial infarction,based on traditional cardiovascular risk

factors. Although an association hasbeen demonstrated in this study, cau-sation is not established.

Other Initial Combinations. TheACTG A5142 study included an nRTI-sparing groupof efavirenz,600 mg onced a i l y , w i t h l o p i n a v i r , 5 3 3 m g / ritonavir, 133 mg, twice daily59 that hada time to virologic failure similar to efa-virenz plus 2 nRTIsin the overall analy-sis, although in the stratum of 100 000HIV RNAcopies/mL or greater, thetimeto virologic failure was shorter. Limb-

fatincrease wasgreatest in the efavirenz/lopinavir/r group, laboratory toxicitywasmore common(predominantly be-cause of rises in triglyceridelevels), andemergence of resistance was more fre-quent than in the 2 nRTI groups.

Initial PI monotherapy has also beenevaluated in a small, randomized, open-label study comparing lopinavir/r alonewithlopinavir/r pluszidovudine and la-mivudine in patients with baseline vi-ral loads below 100 000 copies/mL.76

Fewer patients receiving PI mono-

therapy achieved HIV RNA levels be-low the limit of detection, and a greaternumber receiving PI monotherapy hademergence of PI resistance mutations,suggesting that this approach shouldcurrently be considered suboptimal.

In another randomized, open-labelstudy of 114 patients, 4 nRTIs (zido-vudine, lamivudine, abacavir, and te-

nofovir) had similar antiretroviral ac-tivity as efavirenz plus zidovudine andlamivudine; 68% and 67% had HIVRNA levels of less than 50 copies/mLat 48 weeks, respectively.77

N e w D r u g C l a s s e s i n I n i t i a l

Therapy. Raltegravir, an integrasestrand transfer inhibitor,78 was ap-proved in 2007 for use in highly treat-ment-experienced patients.79,80 It wascompared with efavirenz in treatment-naive patients in a randomized, par-tially blinded trial in which patients re-ceived 1 of 4 doses of raltegravir (100,200, 400, or 600 mg twice daily) or efa-virenz, each combined with tenofovirand lamivudine. At 48 weeks, the pro-portions of individuals whohad an HIVRNA level of less than 50 copies/mLwere similar among the 5 groups, rang-

ing from 83% to 88%.81 Phase 3 stud-iescomparing raltegravir, 400 mg twicedaily, with efavirenz once daily, eachpaired with 2 nRTIs, are under way.

Maraviroc, a CCR5 antagonist ap-proved in 2007 for use in treatment-experienced patients, has antiretrovi-ral activity only in patients with HIV-1variants that exclusively use the CCR5coreceptor (termed R5 viruses). Mara-viroc wascompared with efavirenz,eachcombined with zidovudine/lamivu-dine, in a randomized, double-blind,

phase 3 study in treatment-naive pa-tients with R5 virus.82 At 48 weeks,69.3% and 65.3% of patients achieveda viral load of less than 50 copies/mLin the efavirenz and the maravirocgroups, respectively; the prespecifiedcriterion for noninferiority wasnot met.

Recommendations

Two nRTIs plus either efavirenz (AIa)or a PI/r (AIa, AIb) are recommendedfor initial therapy (TABLE3). Simplic-ity of therapy, pill number, tolerabil-

ity, desire for pregnancy, drug interac-tions, primary drug resistance, andcomorbid conditions are likely to in-fluence thechoice between these 2 rec-ommended options. Efavirenz is notrecommended for women in thefirst tri-mester of pregnancy or who are con-templating pregnancy (AIIa). Treat-ment for patients with transmitted drug





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resistance should be guided by resis-tance test results (BIIa, BIIb). Nevira-pine is an alternative to efavirenz whenan NNRTI-based regimenis desiredandthe CD4 cell count is less than 250/Land400/Lin women andmen, respec-

tively (AIa).Of the ritonavir-boosted PIs, recom-mended components include lopina-vir/r (AIa), atazanavir/r (AIb), fosam-prenavir/r (AIa), darunavir/r (AIb), orsaquinavir/r (AIb). Choice of PI/r is in-fluenced by factors such as frequency

of dosing, pill number, coformula-tion, need for refrigeration, adverseeffect profile, concomitant medica-tions, comorbid illnesses, presence ofprimary drug resistance, and cost.

Lopinavir/r has been the most ex-

tensively studied ritonavir-boosted PIand served as the comparator for mostclinical trials of other ritonavir-boosted PIs. It is the only coformu-lated boosted PI option, and the com-bination tablet does not requirerefrigeration. It may be given once (BIa,

AIb) or twice (AIa, AIb) daily in treat-ment-naive patients, may be the mostlikely to cause diarrhea, and may havethe greatest negative effect on triglyc-eride levels.

Once-daily ritonavir-boostedatazana-

vir (AIb) has similar activity to lopina-vir/r, with fewer gastrointestinal ad-verse effects, a more favorable lipidprofile, anda lower pill burden.66 Coad-ministration with acid-reducing agentsmust be donecautiously.86,87 Fosampre-navir/r may be given twice daily (AIa)13

Table 3.Recommended Components of Initial Antiretroviral Therapy and Considerations for Choosing a Regimen

Component Considerations for Choice Major Toxic Effects and Cautions

Nucleoside reverse transcriptase inhibitors a

Tenofovir/emtricitabineb,c Well toleratedEfficacy superior to zidovudine/lamivudine4,62

and similar to stavudine/lamivudine

63

Available as a once-daily fixed dose

Baseline renal function should be evaluatedbefore initiating tenofovir

Reduce dose or avoid in patients with renaldysfunction

Abacavir/lamivudined Noninferior to tenofovir/emtricitabine in 1 trial10

May have less activity in patients with viral load100000 HIV RNA copies/mL83

Available as a once-daily fixed dose

Hypersensitivity syndrome in 5% to 8% ofpersons (risk associated with HLA-B*5701genotype)

Risk reduced with HLA-B*5701 screening84,85

May be associated with increased risk ofmyocardial infarction74,75

Nonnucleoside reverse transcriptase inhibitorse

Efavirenz Standard-of-care comparator in many trialsAvailable as a once-daily fixed dose with

tenofovir/emtricitabine

Central nervous system toxicity may be limitingPotentially teratogenic in first trimester of

pregnancyAssociated with lipoatrophy when given with

thymidine reverse transcriptase inhibitors60

Ritonavir-boosted protease inhibitors f

Lopinavir Substantial clinical trial data and phase 4experience supporting efficacy

Heat-stable tablet1 or 2 doses per day for treatment-naive

patients

Gastrointestinal adverse effectsHyperlipidemia, especially hypertriglyceridemia

Atazanavir Noninferior to ritonavir-boosted lopinavirLess hyperlipidemia and diarrhea66

Once-daily dosing

Hyperbilirubinemia (UGT1A1-28 alleles andT3435C polymorphism in MDR1gene)

Occasionally associated with nephrolithiasisAcid-reducing agents decrease atazanavir

concentrations; proton pump inhibitorsshould be used cautiously

Fosamprenavir Noninferior to ritonavir-boosted lopinavir13

Once-daily or twice-daily dosing possible; morerobust data with twice-daily dose

Similar adverse effect profile to ritonavir-boostedlopinavir

Rash

Darunavir Noninferior to ritonavir-boosted lopinavir andsuperior in those with viral load 100000HIV RNA copies/mL

Less nausea, lower triglyceride levels68

800 mg 100 mg ritonavir once daily

Rash

Saquinavir Noninferior to ritonavir-boosted lopinavir, with

lower triglyceride levels.67Twice-daily dosing

High pill burden

Abbreviation: HIV, human immunodeficiency virus.a Zidovudine/lamivudine is considered an alternative (see When to Start section of text).bA baseline urinalysis and estimation of creatinine clearance or glomerular filtration rate for assessment of renal function are recommended.27 All patients receiving tenofovir should

be observed for development of renal dysfunction.c Or lamivudine.d Or emtricitabine.e Nevirapine (in women with 250 CD4 cells/L and men with 400 CD4 cells/L) is considered an alternative (see What to Start section of text).fSubstantial clinical trial data exist for ritonavir-boosted lopinavir as initial antiretroviral therapy, including data on long-term outcomes. Each of the other ritonavir-boosted protease

inhibitorshas beencomparedwith ritonavir-boosted lopinavirbut not withone another. Choice of ritonavir-boosted protease inhibitor should be individualized (seeWhat to Startsection of text).





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or once daily with either 200 or 100 mgof ritonavir (BIa). Withtwice-daily dos-ing, the adverse effect profile and lipideffects aresimilar to lopinavir/r.13 Twice-daily saquinavir/r (AIb) was alsononin-ferior to twice-daily lopinavir/r,67 with

lessdiarrhea andmore favorable triglyc-eride changes.Once-daily darunavir/r (AIb) is also

well tolerated, with similar activity tolopinavir/r.68 At present, the formula-tion of darunavir studied in the phase3 trial is not available. Using daruna-vir/r in initial therapy must be bal-anced against its proven efficacy in pa-tients with multidrug-resistant virus.Debate exists whether darunavir shouldb e u s e d i n p a t i e n t s w i t h d r u g -susceptible virus or should be re-served for patients with primary or ac-

quired drug resistance.88-91

Unboosted PIs are not recom-mended. However, consideration oftheir use arises in highly selected cir-cumstances; eg, in individuals who arenot candidates for NNRTI-basedtherapy or who have intoleranceor con-traindications to ritonavir. Atazana-vir, fosamprenavir, and, in some cases,nelfinavir are candidates to consider,but a non-PI, non-NNRTIbased regi-men such as raltegravir plus 2 nRTIs isanother alternative, pending results of

phase 3 studies.Recommended nRTIs in the initial

regimen are the fixed-dose combina-tions tenofovir/emtricitabine (AIa) orabacavir/lamivudine (AIa). Data pub-lished or presented since the 2006 pub-lication of these guidelines continue tosupport the efficacy and safety of teno-fovir/emtricitabine. The recently re-ported association of abacavir with anincreased risk of myocardial infarc-tion should be considered in patientswith known or high risk of cardiovas-

cular disease. The diminished viro-logic efficacy of abacavir/lamivudinecompared with tenofovir/emtricita-bine (each in combination with efavi-renz or atazanavir/ritonavir) in pa-tients with viral loads of more than100 000 copies/mL reported in 1 ran-domized study should also be consid-ered. The data are as yet insufficient,

however, to remove abacavir as a rec-ommended nRTI component of initialtherapy.

Zidovudine/lamivudine twice daily isan alternative dual-nRTI component(AIa), although the gastrointestinal and

central nervous system adverse effectsand associations with lipoatrophy andanemia make thischoice less desirable.

The quadruple nRTI combination ofabacavir/lamivudine/zidovudine/tenofovir (BIIa)77 may be considered inspecial circumstances, such as coad-ministration with tuberculosis therapyor when comorbid conditions man-date treatment with other medica-tions that have substantial drug inter-a c t i on s w i t h N N R T Is a n d P I s .Lopinavir/r plus efavirenz (AIa)59 alsomay be considered to avoid nRTI use,

although lipid abnormalities are com-mon. Currently, initial therapy withraltegravir should be considered onlyin highly selected circumstances (BIa).Use of maraviroc (CIb) or PI/r mono-therapy (CIa) for initial therapy is notcurrently recommended.

PATIENT MONITORING

Considerations

Recommendations for the initialworkup of newly diagnosed HIV-infected persons have not changed sub-

stantially except that baseline geno-typic testing for resistance should beperformed in all treatment-naive pa-tients regardless of estimated durationof infection.92 Baseline and periodicCD4 cell counts andplasmaHIV-1 RNAmeasurements guide timing of initialtherapy. Presence of HBV or HCV in-fection, evidence of HIVAN, or cardio-vascular riskmayalsoinfluence therapyinitiation and regimen and, therefore,should be assessed.

Monitoring Treatment Response

Effective therapy should generally re-sult in at least a 10-fold (1.0 log10) de-crease in HIV-1 RNA copies/mL in thefirstmonthandsuppression to less than50 copies/mL by 24 weeks, dependingon pretreatment viral load.1 OnceHIV-1RNA suppression is confirmed, itshould be assessed at regular intervals

(eg, every 3 or 4 months).1 Isolated epi-sodes of low-level viremia (blips) arenot predictive of subsequent virologicfailure, but consistent elevations tomore than 50 copies/mL meet a strictdefinition of virologic failure. Con-

firmed viral load rebound shouldprompt a careful evaluation of regi-men tolerability, drug-drug interac-tions, and patient adherence. CD4 cellcounts should generally be assessed inconcert with viral load. Once CD4 cellcounts are consistently at least 350/L, however, less frequent monitor-ing of CD4 cell count (ie, every 6months) is reasonable if the viral loadremains suppressed.

Resistance Testing

Updated IAS-USAguidelines for the use

of antiretroviral drug resistance test-ing have been published.92 For treat-ment failure with HIV-1 RNA levels ofmore than 500 to 1000 copies/mL, re-sistance testing is essential and shouldbe performed while the patient is tak-ing the failing regimen.92

Tropism

Human immunodeficiency virus 1 re-quires a second receptor, either CCR5or CX chemokine receptor 4 (CXCR4),to enter CD4 cells. Virus may exclu-

sively use either CCR5 (R5 virus) orCXCR4 (X4 virus) or may use both re-ceptors (dual-tropic). Human immu-nodeficiency virus 1 variants within aninfected individual may be R5 only, X4only, or a mixture of R5, X4, and dual-tropic variants (so-called dual-/mixed-tropic populations). Most transmittedvariants are R5, and R5 virus predomi-nates early in the course of infection.The CCR5 antagonist maraviroc inhib-its R5 virus and can provide added vi-rologic activity in patients with R5 vi-

rus

93

; it has little or no activity inpatients with dual-/mixed- or X4-tropic virus.94 Thus, assessment of tro-pism prior to use of maraviroc is es-sential.92,95

Monitoring for Treatment Toxicity

When balancing the risks and benefitsassociated with a particular treat-





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ment, it is important to realize that car-diovascular, hepatic, and renal compli-cations may not only reflect drugtoxicity butmay also be associated withuncontrolled HIV replication.36-39 Ap-propriate clinical and laboratory as-

sessment of relevant comorbid condi-tions should be performed beforeinitiating treatment and during follow-up. For example, cardiovascular dis-ease risks should be assessed by avail-able algorithms. The Framingham riskalgorithm may be the most appropri-ate, although it can underestimate car-diovascular disease risk in the settingof HIV infection.96 Guidelines for theprevention and management of meta-bolic complications in HIVinfection areavailable.97

Assessment of renal function should

be made beforeinitiationandduring useof tenofovir, allowing avoidance, dosemodification, or timely substitution ofthe drug when appropriate.27

HLA-B*5701 Screening

The Prospective Randomized Evalua-tion of DNA Screening in a ClinicalTrial (PREDICT) study demonstratedthe clinical value of prospective HLA-B*5701 screening to identify patientsat risk of abacavir-associated hypersen-sitivity reaction (HSR).84 Those screen-

ing negative for HLA-B*

5701 rarely de-velop immunologically confirmedabacavir HSR; approximately 50% ofHLA-B*5701positive patients de-velopimmunologically confirmed HSRwhen given abacavir. Thus, HLA-B*5701positive patientsshould not re-ceive abacavir. When a patient screensnegative for HLA-B*5701, this shouldnot replace careful follow-up becauseclinically diagnosed forms of abacavirHSR may still occur in such patients,albeit infrequently.

Therapeutic Drug Monitoring

The clinical role of therapeutic drugmonitoring remains controversial, andno definitive data have emerged sincethe last edition of the guidelines onwhich to base a clear-cut recommen-dation.98-100 When available with as-says performed by a quality-assured

laboratory,101 therapeutic drug moni-toring of PIs and NNRTIs may be se-lectively useful in pregnant wom-en,102,103 children,104,105 andpatientswithrenal or liver failure106-108; to poten-tially minimize overexposure and ad-

verse effects

108-110

; when managing po-tential drug-drug interactions99; or invirologic failure in the absence of re-sistance when adherence is thought tobe excellent.

Recommendations

The goal of antiretroviral therapy is toreduce and maintain a plasma HIV-1RNA level of less than 50 copies/mL,regardless of previous treatment expe-rience.PlasmaHIV-1 RNAlevelsshouldbe monitored frequently when treat-ment is initiated or changed for viro-

logic failure (eg, at 2, 4, 8, and every 4weeks thereafter) (AIIa)until it reacheslevels below the assay detection lim-its, and regularly thereafter (eg, 3-4times per year [BIII]). Once the viralload is suppressed for an extended pe-riod and CD4 cell counts are stable at350/L or more, twice-yearly CD4 cellcounts are reasonable (CIII).

Baseline genotypic testing for resis-tance should be performed in all treat-ment-naive patients (AIIa and, in casesof confirmed virologic failure, AIa). Re-

sistance testing should also be consid-ered after a new regimen is introducedif the trajectory of HIV-1 RNA reduc-tion is not optimal, as archived muta-tions may emerge (AII). Appropriate as-sessment of comorbid conditions andmonitoring for toxicity should be per-formed before initiating treatment andduring follow-up (eg, for hyperlipid-emia, cardiovascular risk, renal func-tion,andhepatic transaminases) andmaybe partly dependent on the regimen.When possible, patients should be

screened for the HLA-B*

5701 haplo-type if being considered for abacavir(AIa);those screeningpositiveshouldnotreceive the drug (AIa). Those screeningnegative can generally takeabacavir, butbecause rare cases of abacavir HSR mayoccur in such patients, clinical vigi-lance for suspected abacavir HSR re-mains appropriate (AIa).

Assessment of viral tropism is rec-ommended prior to use of maraviroc(AIb). Therapeuticdrug monitoring forPIs and first-generation NNRTIs is notrecommended as part of routine care(CIII).

WHEN TO CHANGEAND WHAT TO CHANGE

Changing for Reasons of Toxicity

or Convenience

The principles for modifying a regimensuccessful in suppressing HIV have notchanged.1 Single-agent switches to de-crease toxicity, avoid adverse drug in-teractions, or improve convenience andadherence are possible providedthe po-tency of the regimen is maintained andsubsequent drug interactions are man-agedappropriately.111-115 Switching to PI/r

monotherapyis notrecommended, giventhe increased rates of low-level vire-mia,116 unlessother options arenotavail-able (BI). Caution must be taken inswitching to nevirapine in women withCD4 cell counts ofmore than 250/Landin men with CD4 cell counts of morethan400/L,although studies have sug-gested that the risks of hypersensitivityand hepatotoxicity are lower than havebeenreported in antiretroviral-naive in-dividuals who startnevirapine withsimi-lar CD4 cell counts (BII).117,118 Changes

because of toxicity should not be madeprematurely, as many early drug-related adverse effects subside with time.However, persistent adverse effects maycompromise adherence and lead to re-sistance.

Recommendations. Replacing singleagents to reduce toxicity or drug inter-actions or to improve convenience andadherence is acceptable provided theregimen potencyis maintained andsub-sequent adverse drug interactions areavoided (AIIa). Prior treatment his-

tory andresults of prior resistance test-ing should be reviewed. Close moni-toring of HIV-1 RNA level after such aswitch can help ensure that virologicsuppression is maintained.

Changing for Virologic Failure

Viral load suppression to less than 50copies/mLis now achievable in the ma-





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jority of patients with virologic fail-ure, even those with multidrug-resistant HIV.89,90,93,119-123

The selection of a new regimenshould take into consideration historyof drug exposure, current andprior ge-

notypic or phenotypic resistance pat-terns, tolerability, other prescribeddrugs with interaction potential, andreasons for failure and should includeexpert advice when possible. At least 2(and ideally 3) fully activedrugs shouldbe included, and using drugs from atleast 1 new class should be consid-ered.

First-Line Failure of NNRTI-BasedRegimens. There is no advantage tomaintaining an NNRTI to which resis-tance has emerged. The failure of anagent should be recognized early and

discontinued so that additional muta-tions to theNNRTI anddual-nRTI com-ponents do not emerge to compro-mise other compounds in the class.

First-line NNRTI failures are typi-cally treated with 2 active nRTIs plus aPI/r. If such a regimen cannot be con-structed, including etravirine or anagent in a new class, such as raltegra-vir or maraviroc (if virus is pure R5),can be considered if adequately sup-ported by other active drugs in the regi-men. Although etravirine retains activ-

ity in the setting of fewer than 3 NNRTImutations and does not appear to be af-fected by K103N,124 it will need to besupported by at least 1 fully active nRTIanda PI/r. Etravirine with 2 nRTIsaloneis not recommended [BI].

First-Line Failure of PI/r Regimens.As with NNRTI-based regimens, fail-ure should be detected early and mu-tations identified. For many patients,resistance to the PI may not haveemerged, allowing the same drug or an-other PI/r to be used next. For virus

with some degree of PI resistance, a PI/rwith activity against resistant strains,such as lopinavir/r, darunavir/r, or ti-pranavir/r, should be considered.In thissetting, darunavir/r is likely to be moreactive than lopinavir/r88 and may bemore tolerable than tipranavir/r. If notpreviously used, an NNRTI may be in-cluded, provided that drug interac-

tions are considered. Whenever pos-sible, 2 fully active nRTIs should beincluded. If the combined potency isuncertain, including an agent from anew class, such as an integrase strandtransfer inhibitor or a CCR5 antago-

nist (if R5 virus can be confirmed bytropism assay), should be considered.With virologic failure of either an

NNRTI- or a PI/r-based initial regi-men, decisions should be individual-ized with respect to the number of newdrugs and new drug classes used in thereplacement combination. For early fail-ures, strategic sequencing of PIs shouldbe considered. For example, for a vi-rus that is fully susceptible to all PIs,there is no virologic advantage to usingdarunavir/r or tipranavir/r over lopina-vir/r or atazanavir/r.125

Recommendations. Virologic fail-ure with an initial NNRTI- or PI-basedregimen should be treated early with atleast 2, andideally 3, fully active drugs.For NNRTI failures, the new combina-tion shouldinclude, if possible,an agentfrom a new class (AIa), most com-monly a PI/r. With NNRTI failure, etra-virine may be a useful component of anew regimen if there are fewer than 3NNRTI-associated mutations, but itmust be supported by a potent combi-nation of other drugs that should in-

clude a PI/r (AIa). Depending on thedrug resistance profile and optionsavailable, inclusion of an agent from an-other new drug class (raltegravir, an in-tegrase inhibitor, or maraviroc, a CCR5antagonist) should be considered(BIII).

Multidrug (Including PI and NNRTI)

Resistance

In this setting, 3 active drugs, includ-ing new classes of agents wheneverpossible, should be used. Individualswith treatment failure and multidrug-

resistant virus usually benefit from aPI/r with activity against resistants t r a i ns , s u c h a s d a r u n a v i r / r o rtipranavir/r.90,119 Etravirine can bepaired with darunavir/r but nottipranavir/r12 6 and may be of valuedepending on the number of NNRTImutations. One or more drugs drawnf r o m n e w e r c l a s s e s s h o u l d b e

included, such as raltegravir or mara-viroc (if R5 virus is confirmed).93,122,123

Enfuvirtide may be of value despitethe inconvenience of subcutaneousinjection and the associated injectionsite reactions.127 There is no convinc-

ing evidence for the use of 2 PI/rs(double PI boosting).128 There is nonew information on the role of con-tinuing lamivudine (or emtricitabine)to maintain the M184V mutation tomodulate viral fitness.

Recently Approved Agents

Particularly Useful in

Multidrug-Experienced Patients

Raltegravir. Patients with triple classresistant HIV were randomized to re-ceive raltegravir, 400 mg twice daily, orplacebo in addition to optimized back-

ground therapy in 2 phase 3 trials(TABLE 4).122,123 Human immunodefi-ciency virus 1 RNA levels of less than50 copies/mL occurred in 65% of pa-tients taking raltegravir and in 31% inthe control groups. Virologic re-sponses were greater in the subgroupof patients with lower baseline HIV-1RNA levels, higher baseline CD4 cellcounts, andwho hadmoreactiveagentsin the optimized background therapy.There were nonstatistically signifi-cantly increased numbers of cancers in

patients randomized to receive activedrug (relative risk at 48 weeks,1.5; 95%CI, 0.5-6.3). It is unclear whether thisimbalance is drug related or reflects an-ticipated complications in an ad-vanced patient population. Raltegra-vir resistance remains under study butappears to involve a minimum of 2 mu-tations along 1 of 2 pathways of the in-teg r ase enzy m e (Q1 4 8 H / K / R o rN155H).129 Raltegravir is a potent agentfor patients with multidrug resis-tance, but given its relatively low ge-

netic barrier to resistance, it needs tobe supported by other agents.Maraviroc.Maraviroc was evalu-

ated in triple classexperienced pa-tients with R5 virus in 2 phase 3 stud-ies (Table 4).93 The mean HIV-1 RNAchange from baseline in the placebogroup was0.78 log10 copies/mL com-pared with1.68 log10copies/mL with





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once-daily maraviroc and1.84 log10copies/mL with twice-daily maravi-roc. Maraviroc has not been associ-ated with an increasedincidence of ma-lignancy, but the question has beenraised withanother investigational drug

in this class, vicriviroc, so careful phase4 follow-up is ongoing. Resistance tomaraviroc typically occurs throughemergence of X4 or dual-/mixed-tropic virus preexistent in the viralpopulation; a second mechanism in-volves mutations developing in gp120of HIV-1 that permit the virusto use theCCR5 receptor in thepresence of boundmaraviroc.

Etravirine. Etravirine was evalu-ated in treatment-experienced pa-tients in 2 parallel trials in which pa-tients received etravirine, 200 mg twice

daily, or matching placebo withdaruna-

vir/r and optimized backgroundtherapy.120,121,130 At 48weeks, 65% of pa-tients randomized to etravirine, com-pared with 39% to 40% randomized toplacebo, had HIV-1 RNA levels of lessthan 50 copies/mL. More active agents

in the optimized background therapyproduced greater response rates. Thepresence of 3 or more NNRTI muta-tions was associated with a poor viro-logic response.124 Most data for thisagent have been derived from the trialsin which it was combined with daruna-vir/r and other active agents, so its usein other combinations needs to be con-sidered cautiously.

Recommendations. The treatmentgoal of suppression of HIV-1 RNAto lessthan 50 copies/mL in treatment-experienced patients, introduced in the

last report,1 has been strengthened by

recent advances (AIa). Regimens shouldinclude at least 2, and ideally 3, fullyactive agents (AIa), and at least 1 newclass should be included (AIa). Expertadvice should guide therapy for pa-tients with multidrug resistance (BIII).

Ritonavir-boosted PIs with activityagainst resistant viruses (darunavir/r ortipranavir/r) often are the foundationsof a new regimen. Adding raltegravirprovides a potent agent from a newclass.Raltegravir hasa relativelylow ge-netic barrier to resistance and, thus,needs to be protected by the additionof other agents to prevent virologicbreakthrough (AIa).

Etravirine can be an important ad-junct to a new regimen if no or only 1or 2 NNRTI-associated resistance mu-tations are present (AIa), and it must

be supported by a potent backbone (eg,

Table 4.Selected Trials of Newly Available Drugs in Antiretroviral-Experienced Patients

Class and Drug

Pivotal Trials inMultidrug-Resistant

Patients Entry Criteria Randomization Outcomes Comments

Integrase inhibitor:raltegravir

BENCHMRK-1(n = 352)122

BENCHMRK-2(n = 351)123

Multidrug resistanceHIV RNA1000

copies/mLAny CD4 cell count

Optimizedbackgroundtherapy raltegravir orplacebo (2:1 ratio)

HIV RNA50copies/mL atweek 48:60%-65%(raltegravir) vs31%-34%(control)

CD4 cell countsincreased98-120/L

(raltegravir) vs40-49/L (control)

Most frequentadverse eventsgastrointestinal;not increased vsplacebo

Relative risk ofmalignancyincreased vsplacebo;significance

uncertain

CCR5 antagonist:maraviroc

Motivate-1 (n = 601)93

Motivate-2 (n = 475)93Multidrug resistanceR5-tropicHIV RNA5000

copies/mLAny CD4 cell count

Optimizedbackgroundtherapy placebo ormaraviroc oncedaily or maraviroctwice daily (1:2:2ratio)

HIV RNA50copies/mL atweek 48: 45.5%(maraviroc, oncedaily) and 43.2%(maraviroc, twicedaily) vs 16.7%(control)

CD4 cell countsincreased 116/L(maraviroc, oncedaily) and 124/L(maraviroc, twicedaily) vs 61/L(control)

Need to performtropism assayprior to use

No increase inmalignancy

Most commonadverse events:diarrhea, nausea,fatigue, andheadache; similarto placebo

NNRTI: etravirine DUET-1 (n = 612)120

DUET-2 (n = 489)121

HIV RNA5000

copies/mL1 NNRTI mutation3 PI mutationsAny CD4 cell count

Ritonavir-boosted

darunavir

optimizedbackgroundtherapy etravirine orplacebo

HIV RNA50

copies/mL atweek 48:60%-61%(etravirine) vs39%-41%(control)

CD4 cell countsincreased94-103/L(etravirine) vs72-74/L (control)

Fully active only if

fewer than 3resistance-associatedmutations; activitynot compromisedby isolated K103Nmutation

Most data are basedon combined usewith darunavir

Abbreviation: HIV, human immunodeficiency virus; NNRTI, nonnucleoside reverse transcriptase inhibitor.





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a boosted PI such as darunavir/r). Etra-virine should not be used with tiprana-vir/r because of drug-drug interac-tions (AII).

For individuals with R5 virus, ma-raviroccan provide another active agent

from a new class (AIa). Tropism shouldbe assessed whencontemplating the useof maraviroc(AIa). Concerns about thelimited sensitivity of the tropism as-says in excluding the presence of X4 vi-rus are being addressed by the devel-opment and availability of moresensitive assays. Maraviroc is espe-cially important to consider if the PI/rcomponent of the regimen is compro-mised by PI resistance.

Despite its inconvenience, enfu-virtide remains an important agent forpersons with multidrug-resistant vi-

rus, especially those with greater com-promise of the PI component.

The nRTIs are often included in newr eg i m ens fo r hi g hl y tr eatm ent-experienced patients but typically pro-vide only partial, adjunctive activity,given the frequent presence of drugclass cross-resistance as a result of priordrug exposure. Their use as adjuncts isrecommended in situations where re-sidual antiretroviral activity is thoughtto be present and tolerance is good(BIa).

ANTIRETROVIRAL THERAPYIN SPECIAL POPULATIONS

In at least 3 circumstances, special con-sideration should be given to initia-tion of therapy.

HIV-Infected Persons With

or at Risk of Specific Opportunistic

Diseases and Coinfections

The presence of coinfections, or a highrisk of certain opportunistic diseases,can provide a strong rationale for ear-

lier initiation of therapy. Liver diseasea s s o c i a t e d w i t h H B V a n d H C Vprogresses more rapidly in HIV-1coinfected populations thanin those in-fected with HBV or HCV alone. Liverdisease progression is slower in HIV/HCV-coinfected patients receiving ef-fective antiretroviraltherapy.131 Therapyfor HCV (eg, peginterferon alfa plus

ribavirin) is limited by toxicity, adher-ence challenges, and limited efficacy,particularly with HCV genotype 1 and4 infection. Therefore, initiation of an-tiretroviral therapy, regardless of CD4cell countin those coinfected with HCV

genotypes 1 and 4, in those with geno-types 2 or 3 who do not tolerate therapy,or in persons who do not clear virus de-spite a course of anti-HCV therapymight substantially reduce the rate ofprogression of liver disease.

In HBV coinfection, treatment forHIV should be considered at any CD4cell count. A number of HIV drugs (te-nofovir, emtricitabine, lamivudine) alsoareappropriate for HBVtherapyandcanbeused in initial HIV regimens for HBV-coinfected patients.

The timing of antiretroviral therapy

in those presenting with HIV-1 infec-tion and an acute opportunistic infec-tion was recently examined.132 In HIV-1infected persons presenting with asubset of treatable opportunistic infec-tions, 6-month morbidity and mortal-ity were reduced in those in whom an-tiretroviral therapy was initiated closerto thetime of presentation than in thosein whom therapy was delayed. Thisstudy excluded patients with tubercu-losis; thus, the optimal approach tostarting antiretroviral therapy in those

withimmunologically advanced HIVin-fection andtuberculosis remains an areaof active investigation.

HIV-Associated Nephropathy

Abnormal kidney function is found inup to 3 0 % o f H I V- i nfected per -sons.133,134 Proteinuric renal disease ismore common in persons of African de-scent and persons with diabetes, hy-pertension, HCV infection, family his-tory of kidney disease, CD4 cell countof less than 200/L, or HIV-1 RNA level

of more than 4000 copies/mL.

27,133

An-tiretroviral therapy can improve renalfunction in HIVANand may slow, if notstop, its progression.135-137 Observa-tional studies suggest that antiretrovi-ral therapy may prevent HIVAN, as itsprevalence has decreased in the era ofhighly active therapy.136 Uncontrolledviral replication is associated with the

development of non-AIDSdiseases, andrenal disease is more prevalent in un-treated HIV infection.27,35,36

Pregnant Women

Antiretroviral therapy for pregnant

women with detectable HIV-1 RNA isindicated to improve the health of themother and to prevent transmission ofHIV-1 to the fetus or infant. Antiretro-viral therapy should not be deferred inwomen in their first trimester of preg-nancy if they arecandidates for therapy,irrespective of pregnancy status. Com-plete recommendations for antiretro-viral treatment during pregnancyshould be used to guide therapy.53

Recommendations

Human immunodeficiency virus infec-

tion treatment may be consideredat anyCD4 cell count for persons coinfectedwith HCV genotypes 1a, 1b, or4 to slowthe progression of liver disease (AIIa,AIIb). Therapy should also be consid-ered for those with HCV genotypes 2or 3 who donot clear virus with therapyor who cannot tolerate HCV treat-ment (AIIa, AIIb).

Active HBV coinfection shouldpromptconsideration of initiation of an-tiretroviral therapy, irrespective of CD4cell count, since earlier therapy might

reduce the rate of liver disease progres-sion (AIIa). Early antiretroviral therapywith at least 2 agents that are activeagainst HBV will likely have a benefi-cial impact on liver disease and re-duce the rate of evolution of drug-resistant HBV variants. Tenofovir andeither emtricitabine or lamivudine arepreferred for initial treatment of HBVin coinfection. The activity of ente-cavir against HIV has not yet been con-firmed in clinical trials; therefore, itshould not be substituted for an active

nRTI for the treatment of HIV.

138

Persons with HIVAN should beginantiretroviral therapy (AIIa, AIIb) assoon as renal disease is diagnosed.27

Drugs with potential nephrotoxicityshould be avoided in persons with re-nal abnormalities, if possible. Whenpo-tentially nephrotoxicdrugslikeatazana-vir (nephrolithiasis) and tenofovir





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(renal tubular disorders) are used, re-nal function should be monitoredclosely.

CONCLUSIONS

The 21 years since zidovudine was ap-proved for the treatment of HIV infec-tion have witnessed remarkable ad-vances in the understanding of diseasepathogenesis,translation of that knowl-edge into practical therapeutics, con-tinued discovery of complications ordisease states associatedwith HIVor itstreatment that increase the complex-ity of management, anda dynamic drugdevelopment process that hasled to thecurrent availability of more than 30 in-dividual drugs and fixed-dose combi-nations to treat HIV infection.

Despite theseadvances,disease man-

agement remains challenged by toxici-ties, maintenance of adherence, clini-cal manifestations related to both thedrugs and the HIV infection itself, andthe threat of drug resistance. Sustain-ability and expansion of the progressachieved will depend on maintaininga robust drugdevelopment pipelineandthe ability to deliver effective therapyand monitoring tools to the worlds af-fected populations. With creativity andpolitical will, the progress and indi-vidualized approach to antiretroviral

therapy evident in the developed worldcan be adapted to the public health ap-proach in the developing world, where90% of the worlds HIV-infected popu-lation lives.

Author Affiliations: Columbia University College ofPhysicians and Surgeons, New York, New York (DrHammer); University of North Carolina at Chapel Hill(Dr Eron); Academic Medical Center, University ofAmsterdam, Amsterdam, the Netherlands (Dr Reiss);University of California San Diego, La Jolla (DrSchooley); AIDS Research Consortium of Atlanta,Atlanta, Georgia (Dr Thompson); University ofToronto, Toronto, Ontario, Canada (Dr Walmsley);Hospital Juan Fernandez/University of Buenos AiresMedical School and Fundacion Huesped, BuenosAires, Argentina (Dr Cahn); University of Miami,

Miami, Florida (Dr Fischl); University of Barcelona,Barcelona, Spain (Dr Gatell); Harvard Medical School,Boston, Massachusetts (Dr Hirsch); InternationalAIDS SocietyUSA (Ms Jacobsen) and University ofCalifornia San Francisco and San Francisco VeteransAffairs Medical Center (Dr Volberding), San Fran-cisco; University of British Columbia, Vancouver, Brit-ish Columbia, Canada (Dr Montaner); University ofCalifornia San Diego and Veterans Affairs San DiegoHealthcare System, San Diego (Dr Richman); andHopital Bichat-Cl aude Bernard and Xavier BichatMedical School, Paris, France (Dr Yeni).

Author Contributions: Study concept and design:Hammer,Eron, Reiss, Schooley, Thompson, Walmsley,Cahn, Fischl, Gatell, Hirsch, Jacobsen, Montaner,Richman, Yeni, Volberding.Acquisition of data: Hammer, Eron, Schooley,Volberding.Analysis and interpretation of data:Hammer, Eron,Reiss, Schooley, Thompson, Cahn, Gatell, Hirsch,Montaner, Richman, Yeni, Volberding.

Drafting of the manuscript: Hammer, Eron, Reiss,Schooley,Thompson, Walmsley, Cahn,Fischl, Gatell,Hirsch, Jacobsen, Richman, Yeni, Volberding.Critical revision of the manuscript for important in-tellectual content:Hammer, Eron, Reiss, Schooley,Thompson,Walmsley, Cahn,Gatell, Hirsch,Montaner,Richman, Yeni, Volberding.Obtained funding:Jacobsen.Administrative, technical, or material support:Hammer, Schooley, Jacobsen, Yeni.Studysupervision:Hammer, Eron,Cahn, Gatell,Hirsch,Jacobsen, Montaner, Volberding.Financial Disclosures:Dr Hammerreportsthathe hasserved as a scientific advisor to Boehringer Ingel-heim, Bristol-Myers Squibb, Merck, Pfizer, Progen-ics, Schering, Shire, TaiMed Biologics, and Tibotec-Virco; hasreceiveda clinicaltrialresearchcontract fromMerck; and has served on a data and safety monitor-ing board for Bristol-Myers Squibb. Dr Eron reports

that he was the principal investigator on research grantsto University of North Carolina from Boehringer In-gelheim, GlaxoSmithKline, Merck, and Panacos; hasserved as a consultant to Avexa, Bristol-Myers Squibb,GlaxoSmithKline, Merck, Monogram,Panacos, Pfizer,Tibotec, and Tobira; and was on the speakers bu-reaus for or received honorarium from Bristol-MyersSquibb, Merck, Roche, and Tibotec. Dr Reiss reportsthat he has served on advisory boards and/or speak-ers bureaus forand/or received research grantsfromBoehringerIngelheim, Bristol-Myers Squibb, GileadSci-ence, GlaxoSmithKline, Hoffmann, LaRoche, Merck,Pfizer, Theratechnologies, and Tibotec. Dr Schooleyreports that hehas servedas a consultant toAchillion,Anadys, Ardea, Gilead, GlaxoSmithKline, ImQuest,In-hibitex, Koronis, Merck, Monogram, Myriad, Pfizer,TaiMed, Tanox, Tibotec, Tobira, and Vertex; has re-ceived grant support from Merck and Chimerix; andhas had stock options for Achillion and Monogram.

Dr Thompson reports that she has received researchgrantsfor AIDS Research Consortium of AtlantafromAbbott, Avexa, Boehringer Ingelheim, Bristol-MyersSquibb, GlaxoSmithKline, Gilead, Koronis, Merck, Pa-nacos,Pfizer, Progenics, Roche,Serono, TaiMed, Ther-atechnologies, and Tibotec; has spoken at events spon-soredby GlaxoSmithKlineand Serono; and has servedas a consultant to or was on the scientific advisoryboards for GlaxoSmithKline, Gilead, Panacos, Pfizer,Progenics, Serono, and Tibotec. Dr Walmsley reportsthat shehas servedon advisory boardsand/or speak-ers bureaus for Abbott, Bristol-Myers Squibb, Boe-hringer Ingelheim, GileadSciences, GlaxoSmithKline,Merck, Pfizer, Roche, and Tibotec. Dr Cahn reportsthathe hasreceived feesfor consultancy, speaking en-gagements, scientific advisory board membership,and/or research grants from Abbott, Avexa, Boe-h r i n g e r I n g e l h e i m , B r i s t o l - My e r s S q u i b b,GlaxoSmithKline, Hoffmann LaRoche, Merck, Pfizer,

Pharmasset, Schering-Plough, and Tibotec. Dr Fischlreports thatshe has receivedresearch grants fromAb-b o t t L a b o r a t o r i e s , B r i s t o l - M y e r s S q u i b b ,GlaxoSmithKline, Merck, Progenics Pharmaceuticals,and Cytheris and has served on advisory boards forMerck and Progenics Pharmaceuticals. Dr Gatell re-ports that he has received honoraria for speaking orparticipating in advisory boardsor research grantsfromAbbott, Boehringer Ingelheim, Bristol-Myers Squibb,Gilead, GlaxoSmithKline,Idenix,Janssen, MSD, Pfizer,Roche, Tibotec, and Tobira. Dr Hirsch reports that hehasservedon data safety monitoringboardsfor Merck

and TaiMed Biologics. Dr Montaner reports that hehas receivedgrants from, served anadvisorto, or spo-kenat eventssponsored by Abbott, Argos Therapeu-tics, Bioject Inc, Boehringer Ingelheim, Bristol-MyersSquibb, Gilead Sciences, GlaxoSmithKline, Hoff-mann-La Roche, Janssen-Ortho, MerckFrosst, Pana-cos, Pfizer, Schering, Serono Inc, TheraTechnologies,Tibotec, andTrimeris. Dr Richman reports that he hasserved as a consultant to Anadys Pharmaceuticals,

Biota, Bristol-Myers Squibb,Boehringer Ingelheim, Gi-lead Sciences, Idenix, KoronisPharmaceuticals,Merck,MonogramBiosciences, Pfizer, Roche, and Tobira. DrYeni reports that he has received grants and researchsupport from Bristol-Myers Squibb, GlaxoSmithKline,Merck, Roche, and Tibotec and has served as a con-s u l t a n t t o B r i s t o l - M y e r s S q u i b b , G i l e a d ,GlaxoSmithKline, Merck, and Tibotec. Dr Volberdingreports that he hasservedon scientific advisoryboardsfor Bristol-Myers Squibb, Gilead, Merck, Pfizer, andSchering; has participated as a member of an end-point adjudication committee of Schering for an on-going clinical trial; hasprovidedexpert testimonyin alawsuit against Abbott Laboratories; and has re-ceived an unrestricted educational grant fromGlaxoSmithKline-Italy. TheIAS-USA hasreceivedgrantsfor selected continuing medical education activities thatarepooled (ie, no singlecompanysupports anysingleeffort) from Abbott Laboratories, Boehringer Ingel-heim, Bristol-Myers Squibb, Gilead Sciences,GlaxoSmithKline, Merck, Pfizer, Roche, and Tibotec.No other disclosures were reported.Funding/Support:This work was funded by the IAS-USA. Panel members servein volunteer capacities (ie,are not compensated). No private sector or govern-ment funding contributed to this work.Role ofthe Sponsor: The IAS-USA determinedthe needfor updated recommendations, selected the panelmembers, and provided administrative oversight andfinancial support.Additional Contributions: We thank Brian G. Gaz-zard, MD, FRCP, Chelsea and Westminster Hospital,London, England; Michael S. Saag, MD,University ofAlabama at Birmingham; Mauro Schechter, MD, PhD,Universidade Federal do Rio de Janeiro, Rio de Ja-neiro,Brazil; andCharles C. J. Carpenter, MD,BrownUniversity School of Medicine, Providence, RhodeIs-land; for helpful comments; and Michelle Tayag, BS,who was compensated as an employee of the IAS-

USA, for administrative support.

REFERENCES

1. Hammer SM, Saag MS, Schechter M, et al. Treat-ment for adult HIV infection: 2006 recommenda-tions of the International AIDS SocietyUSA panel.JAMA. 2006;296(7):827-843.2. Braitstein P, Brinkhof MW, Dabis F, et al. Mortal-ity of HIV-1-infected patients in the first year of an-tiretroviral therapy: comparison between low-income and high-income countries. Lancet. 2006;367(9513):817-824.3. Carpenter CCJ,Fischl MA,Hammer SM,et al.An-tiretroviral therapy for HIV infection in 1996: recom-mendations of an international panel. JAMA. 1996;276(2):146-154.4. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir

DF, emtricitabine, and efavirenz vs zidovudine, lam-ivudine, and efavirenz for HIV.N Engl J Med. 2006;354(3):251-260.5. Dube MP, Komarow L, Mulligan K, et al. Long-term body fat outcomes in antiretroviral-naive par-ticipantsrandomized to nelfinaviror efavirenzor bothplus dual nucleosides: dual x-ray absorptiometry re-sults from A5005s, a substudy of Adult Clinical TrialsGroup 384. J Acquir Immune Defic Syndr. 2007;45(5):508-514.6. Nelson MR, Katlama C, Montaner JS, et al. Thesafety of tenofovir disoproxil fumarate for the treat-





15/17

ment ofHIV infectionin adults: thefirst 4 years. AIDS.2007;21(10):1273-1281.7. Podzamczer D, Ferrer E, Sanchez P, et al. Less li-poatrophyand betterlipidprofile withabacavir as com-pared to stavudine: 96-week results of a randomizedstudy. J Acquir Immune Defic Syndr. 2007;44(2):139-147.8. De WitS, Sabin CA, Weber R, etal. Incidenceandrisk factors for new onset diabetes mellitus in HIV in-

fected patients: theD:A:D study. Diabetes Care. 2008;31(6):1224-1229.9. Riedel DJ, GeboKA, Moore RD,LucasGM. A ten-yearanalysis of the incidence andrisk factors for acutepancreatitis requiring hospitalization in an urban HIVclinical cohort. AIDS Patient Care STDS. 2008;22(2):113-121.10. SmithK, FineD, Patel P,et al. Efficacyandsafetyof abacavir/lamivudine compared to tenofovir/emtricitabinein combinationwith once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. Pre-sented at: 15th Conference on Retroviruses andOpportunistic Infections; February 3-6, 2008; Bos-ton, MA. Abstract 774.11. Wood E,HoggRS,Yip B,Moore D,HarriganPR,MontanerJS. Superior virological responseto boostedprotease inhibitor-based highly active antiretroviraltherapy in an observational treatment programme. HIVMed. 2007;8(2):80-85.

12. Bangalore S, Kamalakkannan G, Parkar S, MesserliFH. Fixed-dosecombinationsimprovemedicationcom-pliance: a meta-analysis. Am J Med. 2007;120(8):713-719.13. EronJ Jr, Yeni P,Gathe J Jr,et al.TheKLEANstudyof fosamprenavir-ritonavir versus lopinavir-ritonavir,eachin combination withabacavir-lamivudine, for ini-tial treatment of HIV infection over 48 weeks: a ran-domised non-inferiority trial. Lancet. 2006;368(9534):476-482.14. Kempf DJ, King MS, Bernstein B, et al. Incidenceof resistance in a double-blind study comparing lopi-navir/ritonavir plus stavudine and lamivudine to nel-finavir plusstavudine andlamivudine.J Infect Dis. 2004;189(1):51-60.15. Palella FJ, Baker RK, Moorman AC, et al. Mor-tality in the highly active antiretroviral therapy era:changing causesof death anddisease in theHIV out-patient study. J Acquir Immune Defic Syndr. 2006;

43(1):27-34.16. May M, Sterne JA, Sabin C, et al. Prognosis ofHIV-1-infected patients up to 5 years after initiationof HAART:collaborative analysis of prospectivestudies.AIDS. 2007;21(9):1185-1197.17. SmitC, Geskus R, Walker S, et al.Effective therapyhas altered the spectrum of cause-specific mortalityfollowing HIV seroconversion. AIDS. 2006;20(5):741-749.18. ReislerRB, HanC, BurmanWJ, Tedaldi EM,NeatonJD. Grade 4 events are as important as AIDS eventsin the era of HAART. J Acquir Immune Defic Syndr.2003;34(4):379-386.19. Neaton J, Grund B. Earlier initiation of antiretro-viral therapy in treatment-naive patients: implica-tions of results of treatment interruption trials. CurrOpin HIV/AIDS. 2008;3:112-117.20. Lau B, Gange SJ, Moore RD. Risk of non-AIDS-relatedmortalitymay exceedrisk of AIDS-relatedmor-

talityamong individuals enrollinginto carewith CD4

countsgreater than 200cells/mm3.J Acquir ImmuneDefic Syndr. 2007;44(2):179-187.21. PhillipsA. Morbidityand mortalityin theHAARTera. Presented at: 15th Conference on Retrovirusesand OpportunisticInfections;February 3-6, 2008;Bos-ton, MA. Abstract 8.22. Grulich AE,Van Leeuwen MT,FalsterMO, VajdicCM. Incidence of cancers in people with HIV/AIDScompared with immunosuppressed transplant recipi-ents: a meta-analysis. Lancet. 2007;370(9581):59-67.

23. Long JL, Engels EA, Moore RD, Gebo KA. Inci-denceand outcomes of malignancy in theHAARTerain an urban cohort of HIV-infected individuals.AIDS.2008;22(4):489-496.24. Patel P, Hanson DL, Sullivan PS, et al. Incidenceof types of canceramongHIV-infectedpersons com-pared withthe generalpopulation in theUnitedStates,1992-2003. Ann Intern Med. 2008;148(10):728-736.

25. Friis-Mller N, Reiss P, SabinCA, et al;D:A:D StudyGroup.Classof antiretroviral drugsand therisk ofmyo-cardial infarction. N Engl J Med. 2007;356(17):1723-1735.26. Weber R, Sabin CA, Friis-Mller N. Liver-relateddeaths in persons infected with the human immuno-deficiency virus: the D:A:D Study. Arch Intern Med.2006;166(15):1632-1641.27. Gupta SK, Eustace JA, Winston JA, et al. Guide-lines for the management of chronic kidney diseasein HIV-infectedpatients: recommendationsof theHIVMedicine Association of the Infectious Diseases So-ciety of America. Clin Infect Dis. 2005;40(11):1559-1585.28. Choi AI, Rodriguez RA, Bacchetti P, BertenthalD, Volberding PA, OHare

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