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Clinical implications of fixed-dose coformulations ofantiretrovirals on the outcome of HIV-1 therapy

Josep M. Llibrea, Jose R. Arribasb, Pere Domingoc, Josep M. Gatelld,

Fernando Lozanoe, Jose R. Santosa, Antonio Riverof, Santiago Morenog,

Bonaventura Cloteta, the Spanish Group for FDAC Evaluation

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aLluita Contra la ScHospital Sant PauSofıa, Cordoba, an

Correspondence to08916 Badalona,

Tel: +34 9349788Received: 2 Febru

DOI:10.1097/QAD

ISSN

The substitution by generic equivalents of some of the drugs included in fixed-doseantiretroviral coformulations (FDACs) poses the potential risk of disrupting thesecombinations and administering the components separately in order to incorporatethe new generic drug, which offers a more competitive sales price. This may represent astep backwards in the advances achieved in simplicity and adherence to therapy, posingan increased risk of selective noncompliance of some of the separately administereddrug substances. Available antiretroviral drugs must be administered for life in theaffected individuals – both children and adults. The FDACs represent a significantadvance in the simplification of antiretroviral therapy, facilitating adherence to com-plex and chronic treatments, and contributing to a quantifiable improvement in patientquality of life. These drug coformulations reduce the risk of treatment error, areassociated with a lower risk of hospitalization, and can lessen the possibility of covertmonotherapy in situations of selective noncompliance. Thus, FDACs can reduce the riskof selection of HIV-1 resistances, which not only adversely affect the treatment optionsof the individual patient but also constitute a public health problem, and furtherincrease the cost and complexity of therapy. With the exception of those cases requiringdose adjustments, the preferential use of FDACs should be recommended for thetreatment of HIV-1 infection in those situations when the agents included in thecoformulation are drugs of choice.

� 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

AIDS 2011, 25:1683–1690

Keywords: AIDS, antiretroviral treatment, combined treatment, fixed-dosecombinations, human immunodeficiency virus infection, recommendation

Introduction

HIV-1 infection causes gradual destruction of hostcellular immunity, and persistent activation of the entire

ippincott Williams & Wilkins. Unau

IDA Foundation, University Hospital Germans Tr, Barcelona, dHospital Clinic, IDIBAPS, Barcelod gHospital Ramon y Cajal, Madrid, Spain.

Josep M. Llibre, Fundacio Lluita contra la SIDA, HSpain.

87; e-mail: jmllibre.fls.germanstrias@gencat.catary 2011; revised: 12 May 2011; accepted: 7 Ju

.0b013e3283499cd9

0269-9370 Q 2011 Wolters Kluwer Hea

immune system and associated nonspecific inflammatorymechanisms. It is a world pandemic, one of the mainpublic health problems worldwide since the late 20thcentury, and also probably the most significant success

thorized reproduction of this article is prohibited.

ias i Pujol, Badalona, bHospital Universitario La Paz, Madrid,na, eHospital Universitario de Valme, Sevilla, fHospital Reina

ospital Universitari Germans Trias i Pujol, Ctra de Canyet s/n,

ne 2011.

lth | Lippincott Williams & Wilkins 1683

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story in modern medicine [1–5]. Antiretroviral drugsadministered in effective combinations persistentlysuppress HIV-1 replication, allow gradual recovery ofthe CD4þ T-lymphocyte counts, and reduce patientmorbidity and mortality [6–8]. In sum, these treatmentsare able to revert the ominous prognosis of HIV-1 diseaseand restore patient survival and quality of life to almostnormal longevity, with a radical change in the clinicalspectrum of the illness [2,9,10]. Likewise, the control ofHIV-1 replication drastically reduces the risk oftransmission to the general population, and avoids verticaltransmission to the offspring of infected mothers [11–16].

Antiretroviral therapy (ART) represents one of thestrategies with favorable cost–efficacy ratios in the health-care systems of the Western world [5,17–21]. Theconsensus guides on ART developed in different countriesby government organizations and national and inter-national scientific societies are continuously subjected torevision – updating and optimizing the ideal timing forstarting therapy, the optimum first-choice combinations,and many other aspects related to ART [22–27].

It presently can be firmly stated that in countries withuniversal public healthcare coverage and free access toART, HIV-1 infection detected on time is a treatablechronic disease allowing patients to lead lives similar in allaspects to those of noninfected persons, includingoccupational activity [1].

Individually replacing a drug with a usually less expensivegeneric equivalent is a generally accepted practice whendrug protection by patent rights runs out. However, inthe Western world the introduction of generic equiva-lents of some of the drugs included in fixed-doseantiretroviral coformulations (FDACs), or of genericequivalents presumed to have characteristics similar tothose of some of the drugs included in FDACs [likeemtricitabine (FTC) and lamivudine (3TC)], poses thepotential risk of disrupting these combinations andadministering the components separately in order toincorporate the new generic drug which offers a morecompetitive sales price. This may represent a stepbackwards in the advances achieved in simplicity andadherence to therapy, with an additional risk of selectivenoncompliance of some of the separately administereddrugs, treatment failure, and selection of HIV-1 variantsresistant to antiretroviral agents [28–31].

On the contrary, local approval in certain centers orcountries of the possibility of disrupting FDACs mayimply significant healthcare disparities with access todifferent levels of excellence in ART, administered on thebasis of economy-oriented criteria depending on thegeographical area of residency.

The present study reviews the existing knowledge on theimportance of FDACs in ART.

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Implications of long-term antiretroviraltreatment

Whereas the cure is still seemingly impossible for aretroviral infection, ART must be administered for life inthe affected individuals [32]. Success of ART requiresconstant patient adherence to treatment regimens that areoften complex and with possible adverse effects over theshort and long term.

The evaluation of different controlled treatment inter-ruption strategies failed to demonstrate clinical benefits,and treatment interruption moreover was found to beassociated with an increase in opportunistic diseases andother disorders associated with the proinflammatory statederived from uncontrolled HIV-1 replication [4,33–35].Therefore, it is likewise not possible to reduce theeconomical cost or toxicity of ART by administering itintermittently [36,37].

Unlike other treatable chronic conditions (e.g. arterialhypertension, type 2 diabetes mellitus or hypercholester-olemia), in which the ultimate control achieved afterseveral years depends on the total period of time for whichthe patient has undergone correct treatment, irregularadherence to ART for only a few weeks may lead todefinitive loss of efficacy of the treatment provided,selection of resistance to the drugs administered, and evencross-resistance to other drugs which the patient has notreceived [13,38]. For this reason, the long-term morbidityand mortality of HIV-1 infection does not only depend on‘average’ adherence over the entire course of ART, but onthe resistance selected during the periods of patientnoncompliance [39]. This represents one of the mostdifficult aspects to control in the chronic management ofthis disease.

Antiretroviral drug resistance implies loss of treatmentoptions, requires more complex, expensive and toxicrescue therapies, and can be transmitted [38,40]. Atpresent, 10–14% of the treated population in Europe isinfected with HIV-1 strains resistant to some antiretroviralagents [41–43].

Optimized virological control of the HIV-1-infectedpopulation therefore ultimately results in a lesser risk oftransmission of resistant strains, and thus better responserates in recently infected individuals who start ART [40].For this reason, once effective ART is made freelyavailable and at no cost, sustained patient adherence tosuch treatment is the key factor for preventing failure.

Factors related to adherence toantiretroviral therapy

Long-term adherence to ART is of utmost importancefor long-term outcomes and has been extensively

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investigated for years. The presence of psychiatricproblems, active substance abuse, poverty, low edu-cational level, comorbidities, frequency of doses, numberof tablets, and short-term or long-term toxicity of ARTare all significantly related to inadequate adherence[23,25,44]. Not surprisingly, adherence and type oftreatment were the modifiable factors most stronglyassociated with survival [45,46].

It should be stressed that not only the percentage ofmissed doses is important, but also the suboptimaladherence patterns involved. In effect, treatment inter-ruptions (defined as more than 2 days without taking anydrug) have a greater impact upon virological responsethan occasional failure to take a dose, depending on theregimen involved [39,47]. On the contrary, improvedadherence results in lower associated global economicalcosts, and is also significantly associated with a lower riskof hospitalization [19].

For this reason, all HIV units worldwide have focused onimproving adherence to ART, with implication of thenursing personnel, psychologists and pharmacists of thedifferent centers in the effort. Likewise, in the differentconsensus documents on ART, the chapter addressing theoptimization of treatment compliance has becomeparticularly important [23–25].

The use of fixed-dose drug combinations:the model represented by other treatablechronic diseases

A reduction in the number of different containers andmedicines which the patient must control, and in thenumber of daily doses and tablets, results in improvedadherence to therapy in chronic diseases requiringcombined treatments [48]. Such reduction lessens therisk of error and the possibility of incomplete adherenceto the regimen due to selective noncompliance.

As an example, most patients with arterial hypertensionrequire combined treatments involving several drugs.Consequently, the American Society of Hypertensionfavors the use of fixed-dose drug combinations (FDCs) asa practical need to improve adherence in chronictreatments, reducing the risk of error in followingtherapy [48].

An infectious disease requiring prolonged treatment is anexample much more similar to HIV-1 infection, and inthis sense tuberculosis has been the closest model. The useof FDC not only affords convenience and improvesadherence but also prevents the patient from self-administering monotherapy with any of the individualdrugs – thereby avoiding the selection of resistance [49].For many years, the scientific societies working on the

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treatment of tuberculosis have actively promoted the useof FDCs of antituberculous drugs, and have requested theauthorities and even stimulated the drug companies toincrease their production and diffusion [50,51]. Even inthose situations when dose adjustments may be required,the use of a FDC is recommended, associated with thedrug supplement needed for dose adjustment, with a viewto avoiding covert monotherapy and the selection ofresistance, which represent a genuine public healthcareproblem. The WHO and the International UnionAgainst Tuberculosis and Lung Disease presently recom-mend the use of FDCs as an additional measure toguarantee optimum treatment and avoid the selection andspread of drug-resistant strains of Mycobacterium tuberculosis[52] – designing specific programs to ensure that theseFDCs are of high quality in their manufacture.

A recent meta-analysis has evaluated the efficacy of FDCsin nine randomized studies on the treatment ofdifferent diseases, such as hypertension (n¼ 4), tubercu-losis (n¼ 2), diabetes mellitus (n¼ 2) and HIV-1 infection(n¼ 1). Lastly, the use of FDCs afforded a 26% reductionin the risk of treatment noncompliance with respect toadministration of the same drugs separately [relative risk(RR) 0.74; 95% confidence interval (CI) 0.69–0.80,P< 0.0001] [53]. There is therefore no doubt that FDCsimprove adherence to therapy in chronic illnesses thatrequire combined treatments – though there is stilluncertainty regarding the magnitude of such improve-ment and its impact upon therapeutic efficacy [54].

The use of fixed-dose antiretroviralcoformulations in HIV-1 infection

Research by the pharmaceutical industry has contributedto improve adherence to ART, by lowering the daily pillcount, and developing drugs with pharmacokinetic/dynamic characteristics that allow once-daily adminis-tration, as well as dosing in FDACs.

Different studies have demonstrated patient preferencefor treatments involving a single daily dose and as fewtablets as possible [30,55]. A recent meta-analysis of 11controlled clinical trials (involving a total of 3029 patients)has confirmed that adherence is greater with single dailydosing regimens than with two daily doses (P¼ 0.003)[30]. Likewise, many studies have reported improvedoverall quality of life and better adherence to therapy inpatients who are able to simplify their ART to a singledaily tablet – retaining the same virological andimmunological efficacy [30,31,56,57]. This improvementhas been documented independently of whether thepatients were receiving treatment based on non-nucleo-side reverse transcriptase inhibitors (NNRTIs) or proteaseinhibitors [31]. Such findings have been documented inpatients receiving efavirenz (EFV), tenofovir (TDF), and

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Table 1. Plasma and intracellular elimination half-lives (t1/2) of theHIV-1 nucleoside and non-nucleoside reverse transcriptaseinhibitors, integrase inhibitors, and protease inhibitors used in fixed-dose coformulations.

Drug Plasma t1/2 (h) Intracellular t1/2 (h)a

Zidovudine 1.1 7Lamivudine (3TC) 5–7 16–22Emtricitabine (FTC) 8.2–10 39Abacavir 1.5–2.5 12–26Tenofovir (TDF) 17 >60Efavirenz 40–55 –Nevirapine 25–30 –Elvitegravir/ritonavir 11.2 –Elvitegravir/cobicistatb 5.9–9.1 –Lopinavir/ritonavir 5–6 –Atazanavir/ritonavirc 15.7 –Atazanavir/cobicistatd 16.7 –

Data from [23,25,62,63].aIntracellular t1/2 usually refers to the active metabolites of the drug.bDepending on the use of 100 or 150 mg of cobicistat, respectively.cAdministered as a 300 mg/100 mg dosing; unboosted atazanavir hasa serum t1/2 of 7 h.dUsing an atazanavir/cobicistat dosing of 300/150 mg.

FTC or 3TC in a single dose but administered separately,and who changed to a single FDAC with the samecompounds [56]. On the contrary, adherence to ARTandpercentage of virological response were also greater with aregimen involving a single tablet once daily, in a cohort ofmarginally housed patients with baseline factors thatmade adherence particularly problematic [29]. Indeed,patients receiving TDF, FTC and EFVas one pill daily aremore likely to maintain the regimen after 1 year thanpatients receiving the same regimen as two pills a day [58].Thus, simplicity importantly affects outcomes of chronictherapies. The risk factors associated in multivariateanalysis with ART modification during the first year oftreatment were months since HIV-1 diagnosis, existenceof prior AIDS-defining conditions, and not receiving acoformulated ART [58,59].

In fact, the massive use of FDACs has been correlated toan increase in regimen persistence and a decrease in theprevalence of antiretroviral drug resistance mutations inthe period 2003–2008, and even to a decrease in thosemutations specifically related to the drugs included insuch combinations (K65R and M184V/I), although acausal relationship has not been established [59,60]. Thus,FDACs, by preventing partial noncompliance and hiddenmonotherapy, could reduce the risk of development ofHIV-1 drug resistance.

Moreover, patients who received their ART as a once-daily single-tablet regimen were significantly more likelyto be highly adherent to therapy and were associated witha lower risk of hospitalization compared to patients ontwo or more pills per day regimens, even though the studycould not assess causality [61].

Pairs of nucleoside reverse transcriptaseinhibitors coformulated in fixed-doseantiretroviral coformulations: importanceof pharmacokinetic homogeneity of theincluded drugs

When a FDAC is designed, it must meet a series ofcriteria in order to ensure its long-term efficacy. Thecoformulated drugs must not present similar or additivetoxicities or require individual dose adjustments, and theirpharmacokinetic profile must be concordant. This lattercondition refers not only to frequency of administrationbut also to the elimination half-life (t1/2), which is apivotal factor when the patient fails to take some doses orinterrupts ART. Nucleoside reverse transcriptase inhibi-tor (NRTI) efficacy is correlated to the intracellular levelsof the drug (Table 1) [23,25,62–64]. The plasma andintracellular t1/2 values of FTC are significantly longerthan those of 3TC, and more concordant with those ofTDF and EFV in the existing coformulation. This point is

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extremely important for avoiding the selection of resistantmutants in every ART interruption, since the t1/2 valuesof the three drugs are overlapped, thus avoiding sequentialterminal monotherapy when the concentrations of themdrop to below the IC50 of HIV-1, when resistant mutantsare easily selected.

Emtricitabine and 3TC have similar chemical structures,are administered once a day, act on the same target, selectthe same resistance pathways, and offer similar efficacy intreatment-naıve patients. As a result, both drugs areconsidered to be interchangeable in some ART guides[23,24]. Thus, even though the table of preferredantiretroviral regimens lists the exact combination usedin pivotal trials in which efficacy has been demonstrated, afootnote states that 3TC may substitute for FTC or viceversa [23]. Nevertheless, there are some differencesbetween 3TC and FTC that should be taken intoconsideration. The IC50 of HIV-1 is usually about 11times greater for 3TC than for FTC, though the clinicalrelevance of this fact has not been confirmed, since theplasma or intracellular levels of the drug remain far abovethe mentioned concentration [65,66]. On the contrary,FTC-triphosphate offers greater (about nine times)efficacy than 3TC-triphosphate in incorporation duringRNA-dependent viral DNA synthesis catalyzed byreverse transcriptase [67]. All this would result in agreater maximum polymerization rate and greater affinityfor FTC. In fact, in vitro, appearance of the M184V/Imutant occurs earlier in cultures with 3TC than withFTC [68].

Assessing the clinical relevance of these minor differencesin vivo in the context of triple regimens is not simple.Nevertheless, in a randomized, double-blind trialcomparing 3TC with FTC together with nevirapine

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Antiretroviral coformulations in HIV treatment Llibre et al. 1687

(or EFV) and stavudine, and which included 468 naivepatients, the M184V/I mutation rate (associated to highresistance to both drugs) was lower with FTC than with3TC (30 vs. 65% of the virological failures with availablegenotype, P¼ 0.01) [66] – though in contrast thevirological failure rate was greater with FTC than with3TC (12.8 vs. 7.3%, P¼ 0.046) [69].

An in-vitro study involving HIV-1 strains resistant toantiretrovirals without the M184V/I mutation but withthymidine-analog mutations (TAMs), K65R, Q151M orL74I/V, showed cross-resistance to both drugs to besimilar in the presence of the K65R, Q151M or L74I/Vmutations, though in the presence of TAMs the impactupon phenotypic resistance of FTC was greater than on3TC (P< 0.001) [70]. However, it is not common inclinical practice to find these mutations without havingselected M184V/I.

On the contrary, retrospective analysis of episodes ofvirological failure revealed a significantly higher resistancerate in regimens with TDF/3TC than with TDF/FTC[71,72]. Interestingly the K65R mutation has beenreported in trials in which TDF was combined with 3TC[73], but not with FTC (both used with EFV) [74].

Replacing 3TC with FTC has been shown not to beinferior in a clinical trial, whereas the opposite situation,that is, replacing FTC with 3TC, has not been evaluated[75].

Therefore, although the molecules are similar, 3TC andFTC have differential pharmacokinetic characteristicsthat do not allow us to rule out the possibility of differentresistance rates in the event of virological failure, andthe efficacy of replacing FTC with 3TC (particularly inthe context of FDAC) remains uncertain. Thus, untiladequate studies are carried out, such replacement shouldbe avoided in view of the potential risk involved.

Positioning of the scientific societies andofficial organisms in consensus documentsregarding the use of fixed-doseantiretroviral coformulations

The following FDACs are now available: zidovudine/3TC, zidovudine/3TC/ABC, ABC/3TC, TDF/FTC,EFV/TDF/FTC, and lopinavir/ritonavir. New cofor-mulations are in the pipeline [74,75].

The North American guides on ART, the CDC, theFDA, and the NIH consider that fixed-dose coformula-tions offer an important advantage, and that among otherfactors, the number of tablets and the frequency of dosingare elements on which the choice of ART is to be based[23]. They likewise specifically recommend the use of

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pairs of coformulated NRTIs (TDF/FTC or ABC/3TC).In turn, the European AIDS Clinical Society specificallyrecommends the use of these coformulations [24], in thesame way as the British guides [26]. The Spanish guidesinclude an important chapter on the simplification ofART [25], recommending the adoption of once-dailyregimens whenever possible (level A, maximum level ofevidence from randomized studies). Likewise, wheneverpossible, nucleosides should be coformulated as prefer-ential treatment regimen (level A). The IAS – USA alsorecommends pairs of NRTIs in coformulation (TDF/FTC or ABC/3TC) in starting therapy [27].

Conclusion

Fixed-dose antiretroviral coformulations represent asignificant advance in the simplification of ART,facilitating adherence to chronic treatments, and con-tributing to a quantifiable improvement in patient qualityof life. The drug coformulations may reduce the risk oftreatment error and consequently the possibility offunctional monotherapy in situations of selective non-compliance. They therefore may reduce the risk ofdeveloping HIV-1 resistance to antiretrovirals. Resistancenot only adversely affects the treatment options of theindividual patient as well as its cost and complexity, but istransmissible and constitutes a public health concern.Patients receiving ART as a once-daily single-tabletregimen are significantly more likely to be highlyadherent to therapy and have a lower risk of hospital-ization. With the exception of those cases in which doseadjustment is required, the preferential use of FDACsshould be recommended for the treatment of HIV-1infection in those situations in which the agentsincluded in the coformulation are drugs of choice.Thus, both the authorities and the drug industry mustmaximize efforts to preserve the use of FDACs when theintroduction of a generic equivalent to any of the drugsin the coformulation poses the risk of disrupting thefixed combination and separate administration. How-ever, for the sake of the ART budget, as soon as allcomponents of currently available FDACs becomeavailable as generics, FDACs built with them shouldbe pursued.

Acknowledgements

Members of the Spanish Group for FDAC Evaluation alsoinclude Antonio Antela (Complejo Hospitalario Uni-versitario, Santiago de Compostela, Spain), Jose Lopez-Aldeguer (Hosp Univ La Fe, Valencia, Spain), Jose Molto(Lluita contra la SIDA Fndn, Univ Hosp Germans Trias iPujol, Badalona, Spain), Celia Miralles (Hosp Xeral,Vigo, Spain), Enrique Ortega (Hosp General Univ,

horized reproduction of this article is prohibited.

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Valencia, Spain), Piedad Arazo (Hosp. Univ. MiguelServet, Zaragoza, Spain), and Melcior Riera andConcepcion Villalonga (Hosp Son Dureta, Palma deMallorca, Spain).

Conflicts of interestJ.M.L. has received funding for research or payment forconferences or participation on advisory boards fromAbbott, Boehringer-Ingelheim, Bristol-Myers Squibb,Gilead Sciences, GlaxoSmithKline, Jansen-Cilag, MerckSharp & Dohme, Pfizer, Roche, Tibotec and ViiVHealthcare.

J.R.A. has received consulting fees, speaker fees or grantsupport from Merck, Abbott, Tibotec, Janssen, Gilead,GSK, Pfizer, Biogen, Avexa, BMS.

P.D. has received funding for research or payment forconferences or participation on advisory boards fromAbbott Laboratories, Bristol-Myers Squibb, BoehringerIngelheim, Gilead Sciences, GlaxoSmithKline, JanssenCilag, Merck Sharp & Dohme, Pfizer, Roche andViiV Healthcare.

J.M.G. has received funding for research or paymentfor conferences or participation on advisory boardsfrom Boehringer-Ingelheim, Merck Sharp & Dohme,Janssen, Tibotec, Abbott, Tobira, Gilead and ViiVHealthcare.

F.L. has received funding for research or payment forconferences or participation on advisory boards fromAbbott Laboratories, Bristol-Myers Squibb, BoehringerIngelheim, Gilead Sciences, GlaxoSmithKline, JanssenCilag, Merck Sharp & Dohme, Pfizer, Roche and ViiVHealthcare.

J.R.S. has received funding for research or payment forconferences or participation on advisory boards fromAbbott, Bristol-Myers Squibb, Gilead Sciences, Glaxo-SmithKline, and Jansen.

J.L.-A. has received funding for research or payment forconferences or participation on advisory boards fromAbbott, Boehringer-Ingelheim, Gilead Sciences, Glaxo-SmithKline, Merck Sharp & Dohme, Pfizer, Roche,Tibotec and ViiV Healthcare.

C.M. has received funding for research or payment forconferences or participation on advisory boards fromAbbott, Bristol-Myers Squibb, Boehringer-Ingelheim,Gilead Sciences, GlaxoSmithKline, Merck Sharp &Dohme, Pfizer, Roche, Tibotec and ViiV Healthcare.

E.O. has received funding for research or payment forconferences or participation on advisory boards fromAbbott, Bristol-Myers Squibb, Boehringer-Ingelheim,

pyright © Lippincott Williams & Wilkins. Unautho

Gilead Sciences, GlaxoSmithKline, Merck Sharp &Dohme, Pfizer, Roche, Tibotec and ViiV Healthcare.

P.A. has received funding for research or payment forconferences or participation on advisory boards fromAbbott, Bristol-Myers Squibb, Boehringer-Ingelheim,Gilead Sciences, GlaxoSmithKline, Pfizer, Jansen andViiV Healthcare.

S.M. has received funding for research or payment forconferences or participation on advisory boards fromAbbott, Boehringer-Ingelheim, Bristol-Myers Squibb,Gilead Sciences, GlaxoSmithKline, Jansen-Cilag, MerckSharp & Dohme, Pfizer, Roche, Tibotec and ViiVHealthcare.

B.C. has served during the past 2 years as a consultant onadvisory boards or participated in speakers’ bureaus orconducted clinical trials with Boehringer-Ingelheim,Abbott, GlaxoSmithKline, Gilead, Janssen, Merck,Shionogi and ViiV.

J.M.L. ideated and drafted the manuscript. All authorsreviewed and approved the final document.

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