Vermund, SH

Walker, AS

PubMed

UCL Discovery

The Journal of Infectious DiseasesE D I T O R I A L C O M M E N T A R YUse of Pharmacokinetic Data in Novel Analyses toDetermine the Effect of Topical Microbicides asPreexposure Prophylaxis Against HIV InfectionSten H. Vermund1 and A. Sarah Walker21Vanderbilt Institute for Global Health and Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee; and 2MRC Clinical Trials Unit, University College London,United Kingdom(See the major article by Dai et al on pages 335–42.)Keywords. microbicide; biostatistical methods; pre-exposure prophylaxis; HIV; pharmacokinetics; tenofovir; clinical trials.In this issue of The Journal of InfectiousDiseases, Dai et al reexamine theVOICE trial (MTN 003), whose primarystudy outcomes failed to indicate thattopical tenofovir, oral tenofovir, or oraltenofovir/emtricitabine protect womenagainst human immunodeﬁciency virustype 1 (HIV) infection [1]. The VOICEtrial had collected extensive plasma teno-fovir levels, enabling the investigators toexamine protocol drug adherence withan objective measure [2]. Hence, the in-tent-to-treat analyses were adjusted byDai et al, using 2 deﬁnitions based on de-tecting tenofovir in plasma either (1) atleast once during follow-up or (2) at 3months of follow-up [1]. For the gelarm only, analyses that adjusted for base-line predictors of HIV infection risk re-sulted in a reversal of the negative trialresults, with an adjusted relative risk forHIV infection prevention of 0.53 (95%conﬁdence interval, .29–.97) amongwomen with tenofovir ever detected and0.40 (95% conﬁdence interval, .16–.98)among women with tenofovir detectedat 3 months, compared with women inthe placebo arm. (We presume that theadjusted relative risk would be similar ifnonadherent women were the compari-son group, but this is not presented.)Given the ability of these adjusted modelsto present as-treated or per-protocolanalysis with substantially reduced con-founding, the conclusion of no effectwas reversed, with a strong suggestionthat the topical preexposure prophylaxis(PrEP) worked to protect gel users,when the gel was actually used. The bio-logical marker was not successful in pre-dicting nonadherence in the 2 oral drugarms.The debate between the merits of intent-to-treat and as-treated or per-protocolanalyses are familiar to clinical trialsmethodologists [3]. Abandoning therandomized design inherent in intent-to-treat analyses introduces potentiallyunmeasured confounding; in the case oforal or topical PrEP, the baseline HIV in-fection risk could differ between womenusing PrEP and women not using it. Ifrisky behaviors or higher-risk sexual con-tacts were more frequent among thewomen who were not using the product,then the product could look efﬁcacious,but this would really merely be a markerof lower risk exposure in the treatedgroup. Hence, randomized clinical trialsaiming to show superiority should notrely on as-treated or per-protocol analy-ses except as secondary data analyses toinform future work. In contrast, for non-inferiority trials, per-protocol or as-treatedanalyses can be informative, even giventheir potential biases.The use of a biological indicator by Daiet al as a ﬁrm measure of protocol adher-ence is valuable for a host of studies inwhich the product is being used bystudy participants and the administrationof the product is therefore not in the con-trol of the investigators. The VOICEstudy was notable for many ﬁeld researchinsights. First, many of the women in thetrial were disingenuous, stating that theywere using the product when they werenot. Social response bias was thereforelikely, with some individuals telling thehealthcare workers what they thoughtthat the workers wanted to hear about ad-herence. This may have been a major fac-tor in the motivations of VOICE trialparticipants. Many women feared PrEPside effects but did not want to risk alien-ating VOICE study staff. In addition, adesire to receive study-related remunera-tions may have led some women to signup for the trial without having any ﬁrmintention of actually using the product.Analogous concerns may have beenfactors in the negative results of theFEM-PrEP and the FACTS trials of topi-cal PrEP, both of which suggested nobeneﬁt of tenofovir-based microbicideuse in HIV infection prevention but hadvery poor adherence among participants;Received and accepted 8 June 2015; published online 29June 2015.Correspondence: S. H. Vermund, Vanderbilt Institute forGlobal Health and Department of Pediatrics, Vanderbilt Univer-sity School of Medicine, Nashville, TN 37203 (sten.vermund@vanderbilt.edu).The Journal of Infectious Diseases® 2016;213:329–31© The Author 2015. Published by Oxford University Press forthe Infectious Diseases Society of America. This is an OpenAccess article distributed under the terms of the CreativeCommons Attribution-NonCommercial-NoDerivs licence(http://creativecommons.org/licenses/by-nc-nd/4.0/), whichpermits non-commercial reproduction and distribution of thework, in any medium, provided the original work is notaltered or transformed in any way, and that the work isproperly cited. For commercial re-use, contact journals.permissions@oup.com. DOI: 10.1093/infdis/jiv336EDITORIAL COMMENTARY • JID 2016:213 (1 February) • 329in the face of participating women choos-ing not to adhere to product use in highproportions, the ability of the study to ad-dress the original research question of bi-ological efﬁcacy was compromised [4, 5].In contrast, women in stable couplesrelationships in the Partners PrEP andTDF1/TDF2 studies and at-risk womenin rural South Africa in the CAPRISA004 study had adherence rates with PrEP(oral or topical, depending upon the trial)that were high enough to demonstrate de-ﬁnitive efﬁcacy [6–8]. Among men whohave sex with men, several trials and obser-vational studies demonstrated overall trialproduct efﬁcacy and effectiveness [9–12].In the context of this entire body of work[13], the ﬁndings of Dai et al are more eas-ily interpreted: although women who ad-hered to PrEP may have been differentfrom women who did not, the weight ofthe evidence from the VOICE trial is thatthe products worked to prevent HIV infec-tion among women who used PrEP.Whether or not subjects should bepresented with their own adherence dataduring the trial, to motivate adherence, isdebatable [1, 14, 15]. On one hand, adher-ence can be improved. On the other hand,transient so-called white-coat adherencemay be nurtured when a subject knowsthat a biological sample will be obtainedat the time of a visit. In the PrEP ﬁeld,adherence is so critical to the biologicalbeneﬁts that one might advocate for mon-itoring and feedback for new, untestedproducts but focus on more-practicaloperational research on products andinterventions, including behavioral inter-ventions to encourage adherence, whosebeneﬁts have been conﬁrmed in the con-text of high adherence [16]. The value ofbiological surrogates for measuring treat-ment adherence at the trial’s end, however,is indisputable. A negative trial result at-tributable to nonadherence has far differ-ent clinical and public health implicationsthan a negative trial result due to failure ofthe product to produce the intended ther-apeutic or preventive effect!The biostatistical approaches taken byDai et al were built upon a reasonableassumption, known as the “exclusion re-striction” assumption in the causal litera-ture. Speciﬁcally, if, among those with nopharmacological evidence of adherence,it is possible to adjust for many con-founders such that their risk is indistin-guishable from those on placebo, then,under speciﬁc assumptions, adjustmentfor these confounders should also enablethe efﬁcacy of the product in those whotook it to be estimated. Dai et al showedthat they could sufﬁciently adjust for suchconfounding for a tenofovir gel productbut not for oral tenofovir/emtricitabineor oral tenofovir alone. Data from otherstudies can be used to infer that the nulleffect for the oral formulations after thisadjustment is plausibly due to the phar-macological measure itself, that is, thatthe biological surrogate means somethingdifferent in the oral prophylaxis groups,compared with the topical gel group. Infuture trials, it might not be possible todistinguish genuine lack of efﬁcacy, evenamong adherers, from issues involvingthe use of the biological surrogate. Atleast to some degree, the success of themethod thus relies on already knowingwhat answer to expect.The future of topical PrEP is likely tobe as microbicides whose adherence chal-lenges are far less than those of currentproducts, which require a high degree ofprotocol adherence. The current trials ofnonnucleoside reverse-transcriptase in-hibitor (NNRTI) prophylaxis use a long-acting dapivirine-containing vaginalring that must be replaced once monthly,which, it is hoped, will be a less complexapproach than daily or coitally dependentself-dosing. Two phase 3 trials are in pro-gress, with efﬁcacy results expected in2016: MTN-020 (ASPIRE) and IPM 027(The Ring Study) [17, 18].High efﬁcacy ishoped for, since drug resistance might beexpected in breakthrough infections afterNNRTI monotherapy prophylaxis. Ifhighly efﬁcacious, a monthly ring couldbe a vital preventive tool for women,more popular and deployable on a publichealth scale than PrEP methods for thosewho require more-intensive engagement,especially in sub-Saharan African regionswith the highest incidence of HIV infec-tion [19]. (For anal sexual exposuresamong men or women, a depot topicalring approach is not likely to be feasible.)Statistical methods like those presentedhere by Dai et al may well be needed togain the most value from ongoing studiesand are most welcome in this complexHIV prevention research arena.NotePotential conﬂict of interest. Both authors:No reported conﬂicts. Both authors have submit-ted the ICMJE Form for Disclosure of PotentialConﬂicts of Interest. Conﬂicts that the editorsconsider relevant to the content of the manu-script have been disclosed.References1. Dai J, Hendrix C, Richardson B, et al. Pharmacolog-ical measures of treatment adherence and risk ofHIV infection in the VOICE study. J Infect Dis2016; 213:335–42.2. Marrazzo JM, Ramjee G, Richardson BA, et al. Te-nofovir-based preexposure prophylaxis for HIV in-fection among African women. N Engl J Med 2015;372:509–18.3. Shrier I, Steele RJ, Verhagen E, Herbert R, RiddellCAKaufman JS. Beyond intention to treat: what isthe right question? Clin Trials 2014; 11:28–37.4. Van Damme L, Corneli A, Ahmed K, et al. Preexpo-sure prophylaxis for HIV infection among Africanwomen. N Engl J Med 2012; 367:411–22.5. Rees H, Delany-Moretlwe S, Baron D, et al. FACTS001 phase III trial of pericoital tenofovir 1% gel forHIV prevention in women [abstract 26LB]. Present-ed at: Conference on Retroviruses and Opportunis-tic Infections, Seattle, Washington, 2015.6. Baeten JM, Donnell D, Ndase P, et al. Antiretroviralprophylaxis for HIV prevention in heterosexualmen and women. N Engl J Med 2012; 367:399–410.7. Thigpen MC, Kebaabetswe PM, Paxton LA, et al.Antiretroviral preexposure prophylaxis for hetero-sexual HIV transmission in Botswana. N Engl JMed 2012; 367:423–34.8. Abdool Karim Q, Abdool Karim S, Frohlich JA,et al. Effectiveness and safety of tenofovir gel, an an-tiretroviral microbicide, for the prevention of HIVinfection in women. Science 2010; 329:1168–74.9. Grant RM, Lama JR, Anderson PL, et al. Preexpo-sure chemoprophylaxis for HIV prevention inmen who have sex with men. N Engl J Med 2010;363:2587–99.10. Grant RM, Anderson PL, McMahan V, et al. Uptakeof pre-exposure prophylaxis, sexual practices, andHIV incidence in men and transgender womenwho have sex with men: a cohort study. Lancet In-fect Dis 2014; 14:820–9.11. Molina JM, Capitant C, Charreau I, et al. On de-mand PrEP with oral TDF-FTC in MSM: Resultsof the ANRS Ipergay trial [abstract 23LB]. Presentedat: Conference on Retroviruses and OpportunisticInfections, Seattle, Washington, 2015.12. Gafos M, Dolling D, Desai M, et al. Sexual behaviourproﬁle of gay and other men who have sex with menenrolled in the PROUD Pre-exposure Prophylaxis330 • JID 2016:213 (1 February) • EDITORIAL COMMENTARYOpen-label Pilot Study in England [abstractOA07.03]. Presented at: R4P Conference, CapeTown, South Africa, 2014.13. Baeten J, Celum C. Systemic and topical drugs forthe prevention of HIV infection: antiretroviral pre-exposure prophylaxis. Annu Rev Med 2013;64:219–32.14. Koester KA, Liu A, Eden C, et al. Acceptability ofdrug detection monitoring among participantsin an open-label pre-exposure prophylaxis study.AIDS Care 2015; doi:10.1080/09540121.2015.1039958.15. Emerson SS, Fleming TR. Adaptive methods: telling“therestofthestory”. JBiopharmStat2010;20:1150–65.16. van der Straten A, Mayo A, Brown ER, et al. Percep-tions and experiences with the VOICE AdherenceStrengthening Program (VASP) in the MTN-003trial. AIDS Behav 2015; 19:770–83.17. Microbicides Trials Network. ASPIRE–A study toprevent infection with a ring for extended use:phase III safety and effectiveness study of the dapivir-ine ring. http://www.mtnstopshiv.org/news/studies/mtn020/backgrounder. Accessed 3 June 2015.18. International Partnership for Microbicides. The ringstudy. http://www.ipmglobal.org/the-ring-study.Accessed 3 June 2015.19. Vermund SH, Sheldon EK, Sidat M. Southern Afri-ca: the highest priority region for HIV preventionand care interventions. Curr HIV/AIDS Rep 2015;12:191–5.EDITORIAL COMMENTARY • JID 2016:213 (1 February) • 331

Use of Pharmacokinetic Data in Novel Analyses to Determine the Effect of Topical Microbicides as Preexposure Prophylaxis Against HIV Infection.

Sten H. Vermund

A. Sarah Walker

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The Journal of Infectious Diseases

Use of Pharmacokinetic Data in Novel Analyses to Determine the Effect of Topical Microbicides as Preexposure Prophylaxis Against HIV Infection

Use of Pharmacokinetic Data in Novel Analyses to Determine the Effect of Topical Microbicides as Preexposure Prophylaxis Against HIV Infection.

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