The Role of Social Relationships in PrEP Uptake and Use Among Transgender Women and Men Who Have Sex with Men.

Qualitative studies suggest that social relationships play an important role in HIV pre-exposure prophylaxis (PrEP) use, but there have been few quantitative assessments of the role of social relationships in PrEP uptake or adherence. We examined the association between disclosure of study participation or LGBT identity and PrEP use in the 1603 HIV-negative participants enrolled in the iPrEx OLE study. We also evaluated the association between LGBT social group involvement and PrEP use. Study participation disclosure to parents and LGBT identity disclosure to anyone in a participant's social network were associated with greater PrEP uptake. Study participation disclosure to partners was associated with higher probability of having protective PrEP drug concentrations compared [risk difference 0.15 95% CI (0.01, 0.30)]. For each additional type of LGBT organization a participant was involved in, the probability of PrEP uptake and having protective drug concentrations increased by 0.04 [95% CI (0.03, 0.06)] and 0.04 (95% CI (0.02, 0.07)] respectively. Overall, social context was associated with PrEP use in iPrEx OLE, and should be taken into consideration when designing future PrEP implementation programs.

International Sexual Partnerships May Be Shaped by Sexual Histories and Socioeconomic Status.

Exchange sex and higher education were associated with an increased likelihood of international sexual partnerships (ISPs). Exchange sex and older age were associated with an increased likelihood of condomless sex in ISPs. Educational and socioeconomic factors may create unbalanced power dynamics that influence exchange sex and condomless sex in ISPs.

Strong Correlation Between Concentrations of Tenofovir (TFV) Emtricitabine (FTC) in Hair and TFV Diphosphate and FTC Triphosphate in Dried Blood Spots in the iPrEx Open Label Extension: Implications for Pre-exposure Prophylaxis Adherence Monitoring.

Self-reported adherence to pre-exposure prophylaxis (PrEP) has limitations, raising interest in pharmacologic monitoring. Drug concentrations in hair and dried blood spots (DBS) are used to assess long-term-exposure; hair shipment/storage occurs at room temperature. The iPrEx Open Label Extension collected DBS routinely, with opt-in hair collection; concentrations were measured with liquid chromatography/tandem mass spectrometry. In 806 hair-DBS pairs, tenofovir (TFV) hair levels and TFV diphosphate (DP) in DBS were strongly correlated (Spearman coefficient r = 0.734; P < .001), as were hair TFV/DBS emtricitabine (FTC) triphosphate (TP) (r = 0.781; P < .001); hair FTC/DBS TFV-DP (r = 0.74; P < .001); hair FTC/DBS FTC-TP (r = 0.587; P < .001). Drug detectability was generally concordant by matrix. Hair TFV/FTC concentrations correlate strongly with DBS levels, which are predictive of PrEP outcomes.

Streamlining HIV testing for HIV preexposure prophylaxis.

HIV-testing algorithms for preexposure prophylaxis (PrEP) should be optimized to minimize the risk of drug resistance, the time off PrEP required to evaluate false-positive screening results, and costs and to expedite the start of therapy for those confirmed to be infected. HIV rapid tests (RTs) for anti-HIV antibodies provide results in less than 1 h and can be conducted by nonlicensed staff at the point of care. In many regions, Western blot (WB) testing is required to confirm reactive RT results. WB testing, however, causes delays in diagnosis and adds expense. The iPrEx study evaluated the safety and efficacy of daily oral emtricitabine-tenofovir disoproxil fumarate among HIV-seronegative men and transgender women who have sex with men: HIV infection was assessed with two RTs plus WB confirmation, followed by HIV-1 plasma viral load testing. During the iPrEx study, there were 51,260 HIV status evaluations among 2,499 volunteers using RTs: 142 (0.28%) had concordant positive results (100% were eventually confirmed) and 19 (0.04%) had discordant results among 14 participants; 11 were eventually determined to be HIV infected. A streamlined approach using only one RT to screen and a second RT to confirm (without WB) would have had nearly the same accuracy. Discrepant RT results are best evaluated with nucleic acid testing, which would also increase sensitivity.

HIV-1 drug resistance in the iPrEx preexposure prophylaxis trial.

BACKGROUND: The iPrEx study demonstrated that combination oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) as preexposure prophylaxis (PrEP) protects against HIV acquisition in men who have sex with men and transgender women. Selection for drug resistance could offset PrEP benefits. METHODS: Phenotypic and genotypic clinical resistance assays characterized major drug resistant mutations. Minor variants with FTC/TDF mutations K65R, K70E, M184V/I were measured using 454 deep sequencing and a novel allele-specific polymerase chain reaction (AS-PCR) diagnostic tolerant to sequence heterogeneity. RESULTS: Control of primer-binding site heterogeneity resulted in improved accuracy of minor variant measurements by AS-PCR. Of the 48 on-study infections randomized to FTC/TDF, none showed FTC/TDF mutations by clinical assays despite detectable drug levels in 8 participants. Two randomized to FTC/TDF had minor variant M184I detected at 0.53% by AS-PCR or 0.75% by deep sequencing, only 1 of which had low but detectable drug levels. Among those with acute infection at randomization to FTC/TDF, M184V or I mutations that were predominant at seroconversion waned to background levels within 24 weeks after discontinuing drug. CONCLUSIONS: Drug resistance was rare in iPrEx on-study FTC/TDF-randomized seroconverters, and only as low-frequency minor variants. FTC resistance among those initiating PrEP with acute infection waned rapidly after drug discontinuation. Clinical Trials Registration.NCT00458393.

Syphilis predicts HIV incidence among men and transgender women who have sex with men in a preexposure prophylaxis trial.

BACKGROUND: Syphilis infection may potentiate transmission of human immunodeficiency virus (HIV). We sought to determine the extent to which HIV acquisition was associated with syphilis infection within an HIV preexposure prophylaxis (PrEP) trial and whether emtricitabine/tenofovir (FTC/TDF) modified that association. METHODS: The Preexposure Prophylaxis Initiative (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily FTC/TDF or placebo. Syphilis prevalence at screening and incidence during follow-up were measured. Hazard ratios for the effect of incident syphilis on HIV acquisition were calculated. The effect of FTC/TDF on incident syphilis and HIV acquisition was assessed. RESULTS: Of 2499 individuals, 360 (14.4%) had a positive rapid plasma reagin test at screening; 333 (92.5%) had a positive confirmatory test, which did not differ between the arms (FTC/TDF vs placebo, P = .81). The overall syphilis incidence during the trial was 7.3 cases per 100 person-years. There was no difference in syphilis incidence between the study arms (7.8 cases per 100 person-years for FTC/TDF vs 6.8 cases per 100 person-years for placebo, P = .304). HIV incidence varied by incident syphilis (2.8 cases per 100 person-years for no syphilis vs 8.0 cases per 100 person-years for incident syphilis), reflecting a hazard ratio of 2.6 (95% confidence interval, 1.6-4.4; P < .001). There was no evidence for interaction between randomization to the FTC/TDF arm and incident syphilis on HIV incidence. CONCLUSIONS: In HIV-seronegative MSM, syphilis infection was associated with HIV acquisition in this PrEP trial; a syphilis diagnosis should prompt providers to offer PrEP unless otherwise contraindicated.

Preferences for PrEP modalities among gay, bisexual, and other men who have sex with men from Brazil, Mexico, and Peru: a cross-sectional study.

Background: Pre-exposure prophylaxis (PrEP) scale-up is urgent to reduce new HIV cases among gay, bisexual, and other men who have sex with men (MSM) in Latin America. Different PrEP modalities may increase PrEP uptake and adherence, especially among young MSM. Objectives: To assess preferences for PrEP modalities among MSM from Brazil, Mexico, and Peru. Design: Cross-sectional web-based study (March-May 2018) targeting MSM through advertisements on Grindr, Hornet, and Facebook. We included MSM aged ⩾ 18 years and who reported HIV-negative status. Methods: We assessed preferences for PrEP modalities with the following question: 'Considering that all following PrEP modalities were available, which one would you prefer considering a scale from 1 to 3 (1 = most preferred): daily oral PrEP, event-driven PrEP (ED-PrEP), and long-acting injectable PrEP'. We assessed factors associated with each most preferred PrEP modality per country using multivariable logistic regression models. Results: A total of 19,457 MSM completed the questionnaire (Brazil: 58%; Mexico: 31%; Peru: 11%); median age was 28 years [interquartile range (IQR): 24-34]. Overall, injectable PrEP was the most preferred modality [42%; 95% confidence interval (CI): 41-43], followed by daily PrEP (35%; 95% CI: 34-35), and ED-PrEP (23%; 95% CI: 23-24). In multivariable models, preferring injectable PrEP was associated with PrEP awareness in all three countries, while PrEP eligibility only in Brazil. Preferring daily PrEP was associated with younger age and lower income in Brazil and Mexico, and lower education only in Brazil. The odds of preferring ED-PrEP were lower among MSM aware and eligible for PrEP in Brazil and Mexico. Conclusions: Long-acting injectable PrEP was the preferred PrEP modality among MSM in Brazil, Mexico, and Peru, especially those aware and eligible for PrEP. Public health interventions to increase PrEP modalities literacy and availability in Latin America are urgent especially among MSM of young age, lower income, and lower education.

Same-day initiation of oral pre-exposure prophylaxis among gay, bisexual, and other cisgender men who have sex with men and transgender women in Brazil, Mexico, and Peru (ImPrEP): a prospective, single-arm, open-label, multicentre implementation study.

BACKGROUND: Although gay, bisexual, and other cisgender men who have sex with men (MSM) and transgender women have the highest HIV burden in Latin America, pre-exposure prophylaxis (PrEP) implementation is poor. We aimed to assess the feasibility of same-day oral PrEP delivery in Brazil, Mexico, and Peru. METHODS: Implementation PrEP (ImPrEP) was a prospective, single-arm, open-label, multicentre PrEP implementation study conducted in Brazil (14 sites), Mexico (four sites), and Peru (ten sites). MSM and transgender women were eligible to participate if they were aged 18 years or older, HIV-negative, and reported one or more prespecified criteria. Enrolled participants received same-day initiation of daily oral PrEP (tenofovir disoproxil fumarate [300 mg] coformulated with emtricitabine [200 mg]). Follow-up visits were scheduled at week 4 and quarterly thereafter. We used logistic regression models to identify factors associated with early loss to follow-up (not returning after enrolment), PrEP adherence (medication possession ratio ≥0·6), and long-term PrEP engagement (attending three or more visits within 52 weeks). This study is registered at the Brazilian Registry of Clinical Trials, U1111-1217-6021. FINDINGS: From Feb 6, 2018, to June 30, 2021, 9979 participants were screened and 9509 were enrolled (Brazil n=3928, Mexico n=3288, and Peru n=2293). 543 (5·7%) participants were transgender women, 8966 (94·3%) were cisgender men, and 2481 (26·1%) were aged 18-24 years. There were 12 185·25 person-years of follow-up. 795 (8·4%) of 9509 participants had early loss to follow-up, 6477 (68·1%) of 9509 were adherent to PrEP, and 5783 (70·3%) of 8225 had long-term PrEP engagement. Transgender women (adjusted odds ratio 1·60, 95% CI 1·20-2·14), participants aged 18-24 years (1·80, 1·49-2·18), and participants with primary education (2·18, 1·29-3·68) had increased odds of early loss to follow-up. Transgender women (0·56, 0·46-0·70), participants aged 18-24 years (0·52, 0·46-0·58), and those with primary education (0·60, 0·40-0·91) had lower odds of PrEP adherence. Transgender women (0·56, 0·45-0·71), participants aged 18-24 years (0·56, 0·49-0·64), and those with secondary education (0·74, 0·68-0·86) had lower odds of long-term PrEP engagement. HIV incidence was 0·85 per 100 person-years (95% CI 0·70-1·03) and was higher for transgender women, participants from Peru, those aged 18-24 years, Black and mixed-race participants, and participants who were non-adherent to PrEP. INTERPRETATION: Same-day oral PrEP is feasible for MSM and transgender women in Latin America. Social and structural determinants of HIV vulnerability need to be addressed to fully achieve the benefits of PrEP. FUNDING: Unitaid, WHO, and Ministries of Health in Brazil, Mexico, and Peru. TRANSLATIONS: For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

Recent HIV infection and annualized HIV incidence rates among sexual and gender minorities in Brazil and Peru (ImPrEP seroincidence study): a cross-sectional, multicenter study.

Background: HIV incidence estimation is critical for monitoring the HIV epidemic dynamics and the effectiveness of public health prevention interventions. We aimed to identify sexual and gender minorities (SGM) with recent HIV infections, factors associated with recent HIV infection, and to estimate annualised HIV incidence rates. Methods: Cross-sectional multicentre study in HIV testing services in Brazil and Peru (15 cities). Inclusion criteria: 18+ years, SGM assigned male at birth, not using pre-/post-exposure prophylaxis. We identified recent HIV infection using the Maxim HIV-1 LAg-Avidity EIA assay as part of a recent infection testing algorithm (RITA). Annualized HIV incidence was calculated using the UNAIDS/WHO incidence estimator tool. Multivariable logistic regression models were used to estimate factors associated with recent HIV infection. Trial registration: NCT05674682. Findings: From 31-Jan-2021 to 29-May-2022, 6899 individuals participated [Brazil: 4586 (66.5%); Peru: 2313 (33.5%)]; 5946 (86.2%) cisgender men, 751 (10.9%) transgender women and 202 (2.9%) non-binary/gender diverse. Median age was 27 (IQR: 23-34) years. HIV prevalence was 11.4% (N = 784/6899); 137 (2.0%) SGM were identified with recent HIV infection. The overall annualized HIV incidence rate was 3.88% (95% CI: 2.86-4.87); Brazil: 2.62% (95% CI: 1.78-3.43); Peru: 6.69% (95% CI: 4.62-8.69). Participants aged 18-24 years had higher odds of recent HIV infection compared to those aged 30+ years in both countries. Interpretation: Our results highlight the significant burden of HIV epidemic among SGM in large urban centres of Brazil and Peru. Public health policies and interventions to increase access to effective HIV prevention methods such as PrEP are urgently needed in Latin America. Funding: Unitaid, WHO (Switzerland), Ministry of Health from Brazil and Peru.

Factors associated with long-term HIV pre-exposure prophylaxis engagement and adherence among transgender women in Brazil, Mexico and Peru: results from the ImPrEP study.

INTRODUCTION: The HIV epidemic continues to disproportionately impact Latin-American transgender women (TGW). We assessed factors associated with long-term pre-exposure prophylaxis (PrEP) engagement and adherence among TGW enrolled in the Implementation of PrEP (ImPrEP) study, the largest PrEP demonstration study in Latin America. METHODS: HIV-negative TGW aged ≥18 years reporting 1+eligibility criteria in the 6 months prior to enrolment (e.g. sex partner known to be living with HIV, condomless anal sex [CAS], transactional sex or having a sexually transmitted infection [STI]) who could safely take PrEP were enrolled. Follow-up visits were conducted at 4 weeks and then quarterly. We conducted logistic regression to identify factors associated with long-term PrEP engagement (3+ follow-up visits in 52 weeks) and complete self-reported adherence (no missed pills in the past 30 days) during follow-up. For both outcomes, we constructed multivariable models controlling for country, socio-demographics, sexual behaviour, substance use, STIs and self-reported adherence at 4 weeks (long-term engagement outcome only). RESULTS: From March 2018 to June 2021, ImPrEP screened 519 TGW, enrolled 494 (Brazil: 190, Mexico: 66 and Peru: 238) and followed them for 52 weeks. At baseline, 27.5% of TGW were aged 18-24 years, 67.8% were mixed-race and 31.6% had >secondary education. Most, 89.9% reported CAS, 61.9% had >10 sex partners and 71.9% reported transactional sex. HIV incidence was 1.82 cases per 100 person-years (95% confidence interval [CI]: 0.76-4.38). Almost half of TGW (48.6%) had long-term PrEP engagement, which was positively associated with reporting complete adherence at week 4 (aOR:2.94 [95%CI:1.88-4.63]) and was inversely associated with reporting CAS with unknown-HIV partner (aOR:0.52 [95%CI:0.34-0.81]), migration (aOR:0.54 [95%CI:0.34-0.84]), and being from Mexico (aOR:0.28 [95%CI:0.14-0.53]). Self-reported adherence was associated with TGW aged >34 (aOR:1.61 [95%CI:1.10-2.34]) compared to those aged 25-34 and those with >secondary education (aOR:1.55 [95%CI:1.10-2.19]) and was lower among TGW from Peru (aOR:0.29 [95%CI:0.21-0.41]) or reporting PrEP-related adverse effects (aOR:0.63 [95%CI:0.42-0.92]). CONCLUSIONS: Although TGW were willing to enrol in ImPrEP, long-term PrEP engagement and complete self-reported adherence were limited, and HIV incidence remained relatively high. A successful HIV prevention agenda should include trans-specific interventions supporting oral PrEP and exploring long-acting PrEP strategies for TGW.

Brief Report: Cocaine Use and Pre-exposure Prophylaxis: Adherence, Care Engagement, and Kidney Function.

BACKGROUND: Concomitant use of cocaine and HIV pre-exposure prophylaxis (PrEP) raises important clinical questions around adherence, retention in care, and renal toxicity. METHODS: We assessed the associations of confirmed cocaine use with PrEP adherence (both ascertained through objective measures), care engagement, and renal function in the iPrEx open-label extension. Cocaine use was measured in scalp hair samples and categorized as light (500-3000 pg/mg) and moderate to heavy (>3000 pg/mg). PrEP adherence in the first 3 months was measured through plasma tenofovir concentrations. Disengagement from PrEP care was defined as a gap in follow-up greater than 4 months. Serum creatinine was assessed at baseline and quarterly visits. RESULTS: Of the 400 participants included in this analysis, 90% were men who have sex with men, 10% transgender women, 74% Hispanic/Latino; 21% tested positive for cocaine use in the last 3 months. In adjusted analysis, light cocaine use [adjusted odds ratio 2.10 (95% confidence interval: 1.07 to 4.14)] and moderate to heavy use [adjusted odds ratio 2.32 (1.08 to 5.00)] were associated with greater odds of having plasma tenofovir concentrations below the level of quantitation. Participants with moderate to heavy use had a nearly 3-fold higher rate of disengagement from PrEP care compared with nonusers (adjusted hazard ratio 2.90 [1.48 to 5.66]). We found no statistically or clinically significant differences in creatinine clearance and serum creatinine between participants who tested positive for cocaine and those who did not. CONCLUSIONS: Cocaine use decreases PrEP adherence and care engagement. Comprehensive approaches are needed to reduce cocaine use and enhance engagement along the PrEP care continuum.

Impact of Estimated Pre-Exposure Prophylaxis (PrEP) Adherence Patterns on Bone Mineral Density in a Large PrEP Demonstration Project.

Bone mineral density (BMD) declines due to tenofovir-containing pre-exposure prophylaxis (PrEP) have varied among PrEP demonstration projects, potentially related to variable adherence. Characterization of BMD changes in highly adherent individuals, estimated via tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS), can assist clinicians when counseling patients. Cisgender men who have sex with men and transwomen in the optional dual-energy X-ray absorptiometry (DXA) substudy of a large, international, open-label PrEP demonstration project, the iPrEx-open-label extension (OLE) study underwent DXA scans and DBS collection every 24 weeks, with average weekly dosing adherence patterns (2, 4, and 7 doses/week) estimated from validated TFV-DP cut-offs. The mean percent BMD change was estimated in strata of average weekly adherence by using a linear mixed-effects model to calculate the BMD decline in highly adherent individuals on PrEP for the first time. DXA/DBS data were available for 254 individuals over a median of 24 weeks in iPrEx-OLE from June 2011 to December 2013. The percent decline in spine BMD was monotonically associated with strata of increasing average weekly adherence (p < .001 trend); the p value for trends using hip BMD measurements was .07. Individuals with estimated daily adherence experienced a 1.2% decrease in spine BMD and a 0.5% drop in hip BMD. In highly adherent PrEP users, we found a lower-than-expected drop in BMD when compared with previous studies. This drop is likely not clinically significant for most PrEP users. However, for those at the highest risk of fracture who plan prolonged PrEP use, alternate PrEP strategies could be considered.

Transgender Women in Clinical Trials of Pre-Exposure Prophylaxis.

Lessons were learned with trans women who participated (as volunteers and investigators) in trials of HIV pre-exposure prophylaxis (PrEP). Trans women are not men. Compared with men who have sex with men, trans women trial participants were more likely to be involved with transactional sex, had more sexual partners, and were less likely to have PrEP medications detected in blood. Trans women define themselves differently in different cultures. One best practice is to ask at least 2 gender questions: sex assigned at birth and current gender. More information is needed to fully situate PrEP efficacy for trans women, including analysis of drug-drug interactions between PrEP medications and feminizing hormones and PrEP drug penetration into neovaginal tissues. Including trans women in studies is helpful only if their participation is specifically reported, as could occur in a table of baseline characteristics of the enrolled cohort. Gender-affirming care is important to foster appropriate uptake and use of PrEP. Such care includes use of preferred pronouns and names, safety to use the bathroom of choice, and access to gender-affirming hormone therapy and surgery. The consistent finding that PrEP works when taken across diverse populations having diverse practices related to gender, sexual intercourse, and hormone use provides a basis for offering PrEP to people at substantial risk of acquiring HIV although some subgroups may not have been fully represented in trials. Nonetheless, specific PrEP implementation science for trans women (and men) is essential to develop best practices for PrEP delivery and use.

The Safety of Tenofovir-Emtricitabine for HIV Pre-Exposure Prophylaxis (PrEP) in Individuals With Active Hepatitis B.

BACKGROUND: Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) prevents HIV infection. The safety and feasibility of HIV PrEP in the setting of hepatitis B virus (HBV) infection were evaluated. METHODS: The Iniciativa Profilaxis Pre-Exposición study randomized 2499 HIV-negative men and transgender women who have sex with men to once-daily oral FTC/TDF versus placebo. Hepatitis serologies and transaminases were obtained at screening and at the time PrEP was discontinued. HBV DNA was assessed by polymerase chain reaction, and drug resistance was assessed by population sequencing. Vaccination was offered to individuals susceptible to HBV infection. RESULTS: Of the 2499 participants, 12 (0.5%; including 6 randomized to FTC/TDF) had chronic HBV infection. After stopping FTC/TDF, 5 of the 6 participants in the active arm had liver function tests performed at follow-up. Liver function tests remained within normal limits at post-stop visits except for a grade 1 elevation in 1 participant at post-stop week 12 (alanine aminotransferase = 90, aspartate aminotransferase = 61). There was no evidence of hepatic flares. Polymerase chain reaction of stored samples showed that 2 participants in the active arm had evidence of acute HBV infection at enrollment. Both had evidence of grade 4 transaminase elevations with subsequent resolution. Overall, there was no evidence of TDF or FTC resistance among tested genotypes. Of 1633 eligible for vaccination, 1587 (97.2%) received at least 1 vaccine; 1383 (84.7%) completed the series. CONCLUSIONS: PrEP can be safely provided to individuals with HBV infection if there is no evidence of cirrhosis or substantial transaminase elevation. HBV vaccination rates at screening were low globally, despite recommendations for its use, yet uptake and efficacy were high when offered.

HIV pre-exposure prophylaxis in men who have sex with men and transgender women: a secondary analysis of a phase 3 randomised controlled efficacy trial.

BACKGROUND: For maximum effect pre-exposure prophylaxis should be targeted to the subpopulations that account for the largest proportion of infections (population-attributable fraction [PAF]) and for whom the number needed to treat (NNT) to prevent infection is lowest. We aimed to estimate the PAF and NNT of participants in the iPrEx (Pre-Exposure Prophylaxis Initiative) trial. METHODS: The iPrEx study was a randomised controlled efficacy trial of pre-exposure prophylaxis with coformulated tenofovir disoproxil fumarate and emtricitabine in 2499 men who have sex with men (MSM) and transgender women. Participants aged 18 years or older who were male at birth were enrolled from 11 trial sites in Brazil, Ecuador, Peru, South Africa, Thailand, and the USA. Participants were randomly assigned (1:1) to receive either a pill with active pre-exposure prophylaxis or placebo, taken daily. We calculated the association between demographic and risk behaviour during screening and subsequent seroconversion among placebo recipients using a Poisson model, and we calculated the PAF and NNT for risk behaviour subgroups. The iPrEx trial is registered with ClinicalTrials.gov, NCT00458393. FINDINGS: Patients were enrolled between July 10, 2007, and Dec 17, 2009, and were followed up until Nov 21, 2010. Of the 2499 MSM and transgender women in the iPrEx trial, 1251 were assigned to pre-exposure prophylaxis and 1248 to placebo. 83 of 1248 patients in the placebo group became infected with HIV during follow-up. Participants reporting receptive anal intercourse without a condom seroconverted significantly more often than those reporting no anal sex without a condom (adjusted hazard ratio [AHR] 5·11, 95% CI 1·55-16·79). The overall PAF for MSM and transgender women reporting receptive anal intercourse without a condom was 64% (prevalence 60%). Most of this risk came from receptive anal intercourse without a condom with partners with unknown serostatus (PAF 53%, prevalence 54%, AHR 4·76, 95% CI 1·44-15·71); by contrast, the PAF for receptive anal intercourse without a condom with an HIV-positive partner was 1% (prevalence 1%, AHR 7·11, 95% CI 0·70-72·75). The overall NNT per year for the cohort was 62 (95% CI 44-147). NNTs were lowest for MSM and transgender women self-reporting receptive anal intercourse without a condom (NNT 36), cocaine use (12), or a sexually transmitted infection (41). Having one partner and insertive anal sex without a condom had the highest NNTs (100 and 77, respectively). INTERPRETATION: Pre-exposure prophylaxis may be most effective at a population level if targeted toward MSM and transgender women who report receptive anal intercourse without a condom, even if they perceive their partners to be HIV negative. Substance use history and testing for STIs should also inform individual decisions to start pre-exposure prophylaxis. Consideration of the PAF and NNT can aid in discussion of the benefits and risks of pre-exposure prophylaxis with MSM and transgender women. FUNDING: National Institute of Allergy and Infectious Diseases and the Bill & Melinda Gates Foundation.