Daily Oral Tenofovir Disoproxil Fumarate Research Articles

EE281 Cost-Effectiveness of Every Two Month Cabotegravir Long-Acting (CAB-LA) for Pre-Exposure Prophylaxis (PREP) Compared with Daily Oral Tenofovir Disoproxil Fumarate (TDF)/ Emtricitabine (FTC) As Prep to Prevent HIV-1 in the UK

EE281 Cost-Effectiveness of Every Two Month Cabotegravir Long-Acting (CAB-LA) for Pre-Exposure Prophylaxis (PREP) Compared with Daily Oral Tenofovir Disoproxil Fumarate (TDF)/ Emtricitabine (FTC) As Prep to Prevent HIV-1 in the UK

Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial

Injectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study. The HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094. Of the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation. Long-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance. Division of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

Pregnancy and neonatal safety outcomes of timing of initiation of daily oral tenofovir disoproxil fumarate and emtricitabine pre-exposure prophylaxis for HIV prevention (CAP016): an open-label, randomised, non-inferiority trial

The safety of tenofovir disoproxil fumarate and emtricitabine as pre-exposure prophylaxis (PrEP) in pregnant women not living with HIV is uncertain. We aimed to compare pregnancy and neonatal outcomes in women exposed and not exposed to PrEP during pregnancy. In this single-site, open-label, randomised, non-inferiority trial in Durban, South Africa, we evaluated pregnancy and neonatal outcomes in pregnant women aged 18 years or older, not living with HIV, and at 14-28 weeks' gestation at the time of enrolment. Eligible participants were randomly assigned (1:1) using a computer-generated permuted block (block size of ten) randomisation list to immediate initiation or deferred initiation of PrEP until breastfeeding cessation. Participants in the immediate PrEP group received a monthly supply of once daily oral tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg. Participants in the deferred PrEP group received standard of care for HIV prevention. The primary outcomes were the occurrence of preterm live birth (<37 weeks gestational age) and very preterm birth (<34 weeks gestational age) determined by menstrual dating, low birthweight (<2500 g), very low birthweight (<1500 g), stillbirth (≥20 weeks gestational age), and small for gestational age (birthweight less than the tenth percentile). Post-natal safety outcomes will be reported elsewhere. We used binomial regression models to estimate risk differences and two-sided 90% CIs. Immediate PrEP was non-inferior to deferred PrEP if the upper bound of the 90% CI of the risk difference was less than the upper predefined non-inferiority margin for preterm birth (7·5%), very preterm birth (2·6%), low birthweight (5·5%), very low birthweight (1·2%), stillbirth (1·0%), and small for gestational age (3·7%). All outcomes were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT3227731. Between Sept 25, 2017, and Dec 6, 2019, we screened 693 women, of whom 540 were randomly assigned to immediate PrEP (n=271) or deferred PrEP (n=269). The median gestational age was 19 weeks (IQR 15-23 for immediate PrEP and 16-23 for deferred PrEP). The risk difference between the immediate PrEP group and the deferred PrEP group for preterm birth was -4·7% (90% CI -10·7 to 1·2; immediate PrEP was non-inferior), for very preterm birth was 0·6% (-3·4 to 4·6; upper limit exceeded the non-inferiority margin), for low birthweight was 2·5% (-1·6 to 6·6; upper limit exceeded the non-inferiority margin), for very low birthweight was 0% (-1·4 to 1·4; upper limit exceeded the non-inferiority margin), for stillbirth was 1·2% (-1·5 to 3·8; upper limit exceeded the non-inferiority margin), and for small for gestational age was 0·9% (-1·2 to 2·9; immediate PrEP was non-inferior). In our study, PrEP was not associated with preterm birth or small for gestational age infants. Our data support the use of tenofovir disoproxil fumarate and emtricitabine in pregnancy and our reassuring findings can be used to allay safety concerns among pregnant women. South African Medical Research Council and Gilead Sciences.

Vaginal microbial shifts are unaffected by oral pre-exposure prophylaxis in South African women

Vaginal microbiota have been shown to be a modifier of protection offered by topical tenofovir in preventing HIV infection in women, an effect not observed with oral tenofovir-based pre-exposure prophylaxis (PrEP). It remains unclear whether PrEP can influence the vaginal microbiota composition. This study investigated the impact of daily oral tenofovir disoproxil fumarate in combination with emtricitabine for PrEP on the vaginal microbiota in South African women. At baseline, Lactobacillus iners or Gardnerella vaginalis dominant vaginal communities were observed in the majority of participants. In cross sectional analysis, vaginal microbiota were not affected by the initiation and use of PrEP. Longitudinal analysis revealed that Lactobacillus crispatus-dominant “cervicotypes 1 (CT1)” communities had high probability of remaining stable in PrEP group, but had a higher probability of transitioning to L. iners-dominant CT2 communities in non-PrEP group. L. iners-dominant communities were more likely to transition to communities associated with bacterial vaginosis (BV), irrespective of PrEP or antibiotic use. As expected, BV-linked CTs had a higher probability of transitioning to L. iners than L. crispatus dominant CTs and this shift was not associated with PrEP use.

A new paradigm for antiretroviral delivery: long-acting cabotegravir and rilpivirine for the treatment and prevention of HIV.

Purpose of reviewCabotegravir (CAB) and rilpivirine (RPV) is the first long-acting injectable antiretroviral therapy (ART) option approved for virologically suppressed adults with HIV-1. In addition, long-acting CAB is a promising agent for HIV preexposure prophylaxis (PrEP). This review focuses on phase 3 clinical trial results and implementation considerations for these long-acting ART and PrEP strategies.Recent findingsLong-acting CAB and RPV administered every 4 weeks demonstrated noninferiority to oral ART through week 96 in both the ATLAS and FLAIR studies, whereas ATLAS-2M found similar efficacy through 96 weeks when the long-acting injectable ART was administered every 8 weeks instead of every 4 weeks. For prevention, two phase 3 trials were stopped early due to fewer incident HIV infections in participants receiving long-acting CAB every 8 weeks compared with daily oral tenofovir disoproxil fumarate–emtricitabine for PrEP. The long-acting therapies were well tolerated across all clinical trials.SummaryClinical trial results support the use of long-acting CAB for HIV PrEP and long-acting CAB and RPV as a switch strategy for adults with HIV-1 who are first virologically suppressed with oral ART. Implementation challenges persist, and data are urgently needed in populations who may benefit most from long-acting therapy, including adolescents, pregnant individuals, and those with barriers to medication adherence.

Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women

BackgroundSafe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection.MethodsWe conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate–emtricitabine (TDF–FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection.ResultsThe intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF–FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF–FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified.ConclusionsCAB-LA was superior to daily oral TDF–FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.)

HIV-1 genetic diversity to estimate time of infection and infer adherence to preexposure prophylaxis.

To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for preexposure prophylaxis (PrEP) and relate infection with adherence patterns. We used the diversity structure of the virus population at the first HIV RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10-25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median = 47 [IQR = 35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90-95% adherence in two, 55% adherence in one, and nonadherence in three. We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%.

BHIVA/BASHH guidelines on the use of HIV pre-exposure prophylaxis (PrEP) 2018.

We aim to provide evidence-based guidance on best clinical practice in the provision, monitoring and support of pre-exposure prophylaxis (PrEP) for the prevention of HIV acquisition. The guidelines include: (i) Guidance on risk assessment prior to PrEP; (ii) Baseline assessment; (iii) Dosing schedules; (iv) Monitoring; (v) Supporting adherence; (vi) Buying generic PrEP; and (vii) Cost-effectiveness. The guidelines are aimed at clinical professionals directly involved in, and responsible for, HIV prevention, and at community advocates and organisations responsible for supporting HIV prevention strategies in those at risk of HIV acquisition. A detailed review of the evidence base is included in Section 4. Sections 5 to 7 are intended to offer practical guidance in risk assessment, starting PrEP, ongoing management while on PrEP and stopping PrEP.

The Pre-Exposure Prophylaxis-Stigma Paradox: Learning from Canada's First Wave of PrEP Users.

With the emergence of daily oral tenofovir disoproxil fumarate and emtricitabine-based pre-exposure prophylaxis (PrEP) use in Canada, questions have emerged concerning the impacts of this HIV prevention tool on gay men's social and sexual lives. We conducted small focus groups and individual qualitative interviews with 16 gay men in Toronto who were part of the ‘first wave’ of Canadian PrEP users. Participants were on PrEP for at least one year as part of a demonstration project (November 2014–June 2016). These participants accessed PrEP before regulatory approval by Health Canada in February 2016. The mean age of participants was 37.6 years (SD 11.02); 94% completed secondary education, and 69% were white. Sex-stigma emerged as a complex theme in men's accounts of PrEP use across three overlapping domains: (1) PrEP-related stigma, including discussions of concealment and stigma from friends, family, and sexual partners, (2) PrEP as a perceived tool for combating HIV-related stigma, where some men said that they no longer discussed HIV status with sexual partners, and (3) PrEP as illuminating structural stigma, where it was attributed to unmasking stigma related to sex and sexuality. For some participants, PrEP has allowed for liberating sex and a self-described return to normalcy—normal, exciting, pleasurable sex that was no longer reliant on condom use. Paradoxically, some men said that PrEP use both led them to experience stigmatizing reactions within their social and sexual networks, while also helping to remove stigma, shame, and fear related to HIV, sexuality, and sex with gay men living with HIV.

Safety of oral tenofovir disoproxil fumarate-based HIV pre-exposure prophylaxis use in lactating HIV-uninfected women

ABSTRACTIntroduction: In settings where HIV is prevalent in heterosexual populations, pregnancy and postpartum breastfeeding periods can be associated with substantial HIV acquisition risk. Pre-exposure prophylaxis (PrEP) with daily oral tenofovir disoproxil fumarate (TDF)/emtricitabine is an attractive HIV prevention option for women who are lactating but data are limited on its safety during the lactation period.Areas covered: We provide a concise synthesis and summary of current evidence on the safety of TDF-based PrEP during breastfeeding. We conducted a review, searching Pubmed database and major PrEP conferences for primary studies with TDF-based PrEP exposure during postpartum breastfeeding.Expert opinion: TDF-based oral PrEP is an effective female-controlled HIV prevention option. There is evidence supporting the safety of TDF use for infant outcomes during breastfeeding in antiretroviral treatment regimens for HIV and hepatitis B virus, and more limited, but consistently safe, data from use of TDF as PrEP. The potential for risk is arguably outweighed for at-risk individuals by HIV prevention benefits, including indirect protection to the infant as a result of preventing HIV in the breastfeeding mother. As PrEP delivery is scaled up in heterosexual populations in high HIV prevalence settings and for at-risk persons in other settings, implementation science studies can provide a framework to increase the accrual of safety, acceptability, and use data related to PrEP during lactation.

Reversibility of Glomerular Renal Function Decline in HIV-Uninfected Men and Women Discontinuing Emtricitabine-Tenofovir Disoproxil Fumarate Pre-Exposure Prophylaxis.

Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis (PrEP) use is associated with a small but statistically significant decline in estimated glomerular filtration rate (eGFR). We investigated the reversibility of eGFR decline among HIV-uninfected adults discontinuing PrEP. Data were from the Partners PrEP Study, a randomized trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among African HIV-uninfected men and women with baseline creatinine clearance ≥60 mL/min. Serum creatinine was measured quarterly while on-study medication and at month 1 and 2 after discontinuation. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration Equation. A total of 3924 individuals had a poststudy drug serum creatinine measurement after the scheduled drug discontinuation (1271 for TDF, 1308 for FTC-TDF, and 1345 for placebo); 65% were men, median age was 35 (range 18-64) years. Median time on study drug was 33 (interquartile range 25-36) months overall, and 36 months (interquartile range 30-36) for TDF and FTC-TDF. Mean eGFR at the last on-treatment visit was 129 mL·min·1.73 m for TDF and 128 mL·min·1.73 m for FTC-TDF versus 131 mL·min·1.73 m for placebo (2-3 mL·min·1.73 m mean decline for PrEP versus placebo, P ≤ 0.01), and this difference reversed by 4 weeks after drug discontinuation (mean eGFR at the first postdrug visit: 130 mL·min 1.73 m in all groups). More than 96% of participants had a confirmed >75% eGFR rebound to baseline level by 8 weeks after drug discontinuation, with similar proportions across treatment groups. In this large, placebo-controlled study of TDF-based PrEP, the small reduction in mean eGFR associated with PrEP reversed within weeks after discontinuation.

Low Risk of Proximal Tubular Dysfunction Associated With Emtricitabine-Tenofovir Disoproxil Fumarate Preexposure Prophylaxis in Men and Women.

Tenofovir disoproxil fumarate (TDF) is associated with proximal tubular dysfunction (tubulopathy) when used in the treatment of human immunodeficiency virus (HIV) infection. We evaluated whether TDF causes tubulopathy when used as HIV preexposure prophylaxis (PrEP) and whether tubulopathy predicts clinically relevant decline (≥25%) in the estimated glomerular filtration rate (eGFR). A subgroup analysis of the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF, alone or with emtricitabine (FTC), in HIV-uninfected African men and women (Clinicaltrials.gov NCT00557245). Tubulopathy was assessed in concurrently obtained urine and serum samples at the 24-month or last on-treatment visit, predefined as ≥2 of the following: tubular proteinuria, euglycemic glycosuria, increased urinary phosphate, and uric acid excretion. Of 1549 persons studied (776 receiving FTC-TDF, 773 receiving placebo), 64% were male, and the median age was 37 years. Over a median 24 months of study-drug exposure, the frequency of tubulopathy was 1.7% for FTC-TDF versus 1.3% for placebo (odds ratio, 1.30; 95% confidence interval, .52-3.33; P = .68); Tubulopathy occurred in 2 of 52 persons (3.8%) with versus 3 of 208 (1.4%) without ≥25% eGFR decline (adjusted odds ratio, 1.39; .10-14.0; P > .99). Daily oral FTC-TDF PrEP was not significantly associated with tubulopathy over the course of 24 months, nor did tubulopathy predict clinically relevant eGFR decline.

Bone Mineral Density Changes Among Young, Healthy African Women Receiving Oral Tenofovir for HIV Preexposure Prophylaxis.

Background:Limited data exist on effect of tenofovir disoproxil fumarate (TDF) when used for preexposure prophylaxis (PrEP) on bone mineral density (BMD) in HIV-negative women. We evaluated the effect of daily oral TDF and emtricitabine/TDF compared with placebo on BMD among women enrolled in an HIV-1 PrEP trial.Methods:HIV-uninfected women in Uganda and Zimbabwe had BMD measurements of lumbar spine (LS) and total hip (TH) by dual-energy x-ray absorptiometry at baseline and every 24 weeks for 48 weeks of active treatment and for 48 weeks after discontinuation of study medication. Plasma tenofovir levels were assessed every 12 weeks for the first 48 weeks.Results:Of 518 women enrolled, 432 had dual-energy x-ray absorptiometry results at baseline and week 48. In the primary analysis, no significant differences in percent BMD change in hip or spine between arms observed, likely because of low product adherence. Among the subset with tenofovir detection in 75%–100% of plasma samples, the mean percent BMD change from baseline to week 48 in the LS was 1.4% lower for TDF or emtricitabine/TDF recipients than for placebo (P = 0.002) and TH BMD was 0.9% lower (P = 0.018). BMD changes from end of active treatment to 48 weeks were significantly greater in the active arm participants compared with placebo participants with a net difference of approximately +0.9% at the LS (P = 0.007) and +0.7% (P = 0.003) at the TH.Conclusions:TDF-containing oral PrEP resulted in small but significant reversible decreases in hip and spine BMD among young African women.

Single-agent tenofovir versus combination emtricitabine plus tenofovir for pre-exposure prophylaxis for HIV-1 acquisition: an update of data from a randomised, double-blind, phase 3 trial

Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP. We did a randomised, double-blind, placebo-controlled three-group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov, number NCT00557245. 4410 (99·6%) of 4427 couples received tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0·71 cases per 100 person-years) and 21 were in those assigned emtricitabine plus tenofovir disoproxil fumarate (0·48 cases per 100 person-years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtricitabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio [HR] 0·67, 95% CI 0·39-1·17; p=0·16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0·15, 95% CI 0·06-0·37; p<0·0001) and 93% for the emtricitabine plus tenofovir disoproxil fumarate group (0·07, 0·02-0·23; p<0·0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups. These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women. Bill & Melinda Gates Foundation and US National Institutes of Health.

Pre-exposure prophylaxis does not affect the fertility of HIV-1-uninfected men.

There is a paucity of data on the effect of antiretroviral medications on male fertility. Couples affected by HIV-1 often have fertility intentions, and antiretroviral medications, as both treatment of HIV-1-infected persons and pre-exposure prophylaxis (PrEP) for uninfected persons, are part of peri-conception risk reduction. Within a randomized, placebo-controlled trial of daily oral tenofovir disoproxil fumarate (TDF) and combination emtricitabine (FTC)/TDF PrEP for HIV-1 prevention conducted among heterosexual HIV-1-serodiscordant couples, we assessed the impact of TDF and FTC/TDF use on male fertility, measured as incident pregnancy in female partners of men assigned to PrEP vs. placebo. Of the 2962 HIV-1-uninfected men partners, 986 were randomized to TDF, 1013 to FTC/TDF, and 963 to placebo. The overall pregnancy incidence in their HIV-1-infected female partners was 12.9 per 100 person-years and did not differ significantly across the study arms (13.2 TDF, 12.4 FTC/TDF, 13.2 placebo). The frequency of live births, pregnancy losses, and gestational age at birth or loss was also statistically similar in the three randomization groups. TDF and FTC/TDF, when used as PrEP by HIV-1-uninfected men, did not adversely affect male fertility or pregnancy outcomes.

Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial.

Antiretroviral preexposure prophylaxis (PrEP), using tenofovir disoproxil fumarate (TDF) and combination emtricitabine/tenofovir disoproxil fumarate (FTC+TDF), is efficacious for prevention of human immunodeficiency virus (HIV) acquisition. PrEP could reduce periconception HIV risk, but the effect on pregnancy outcomes is not well defined. To assess pregnancy incidence and outcomes among women using PrEP during the periconception period. Randomized trial among 1785 HIV-serodiscordant heterosexual couples (the Partners PrEP Study) in which the female partner was HIV uninfected that demonstrated that PrEP was efficacious for HIV prevention, conducted between July 2008 and June 2013 at 9 sites in Kenya and Uganda. Daily oral TDF (n = 598), combination FTC+TDF (n = 566), or placebo (n = 621) through July 2011, when PrEP demonstrated efficacy for HIV prevention. Thereafter, participants continued receiving active PrEP without placebo. Pregnancy testing occurred monthly and study medication was discontinued when pregnancy was detected. Pregnancy incidence, birth outcomes (live births, pregnancy loss, preterm birth, congenital anomalies), and infant growth. A total of 431 pregnancies occurred. Pregnancy incidence was 10.0 per 100 person-years among women assigned placebo, 11.9 among those assigned TDF (incidence difference, 1.9; 95% CI, -1.1 to 4.9 [P = .22 vs placebo]), and 8.8 among those assigned FTC+TDF (incidence difference, -1.3; 95% CI, -4.1 to 1.5 [P = .39 vs placebo]). Before discontinuation of the placebo treatment group in July 2011, the occurrence of pregnancy loss (96 of 288 pregnancies) was 42.5% for women receiving FTC+TDF compared with 32.3% for those receiving placebo (difference for FTC+TDF vs placebo, 10.2%; 95% CI, -5.3% to 25.7%; P = .16) and was 27.7% for those receiving TDF alone (difference vs placebo, -4.6%; 95% CI, -18.1% to 8.9%; P = .46). After July 2011, the frequency of pregnancy loss (52 of 143 pregnancies) was 37.5% for FTC+TDF and 36.7% for TDF alone (difference, 0.8%; 95% CI, -16.8% to 18.5%; P = .92). Occurrence of preterm birth, congenital anomalies, and growth throughout the first year of life did not differ significantly for infants born to women who received PrEP vs placebo. Among HIV-serodiscordant heterosexual African couples, differences in pregnancy incidence, birth outcomes, and infant growth were not statistically different for women receiving PrEP with TDF alone or combination FTC+TDF compared with placebo at conception. Given that PrEP was discontinued when pregnancy was detected and that CIs for the birth outcomes were wide, definitive statements about the safety of PrEP in the periconception period cannot be made. These results should be discussed with HIV-uninfected women receiving PrEP who are considering becoming pregnant. clinicaltrials.gov Identifier: NCT00557245.

Tenofovir-Based HIV Pre-Exposure Prophylaxis

HIV pre-exposure prophylaxis (PrEP) with daily oral tenofovir disoproxil fumarate (TDF) or TDF–emtricitabine (FTC) has been shown to be effective against sexual and injection-drug related HIV acquisition in four out of six large clinical trials. This article reviews the pharmacology of TDF and FTC as it relates both to PrEP efficacy and the emergence of viral resistance, summarizes the six trials and the inherent challenges to PrEP they highlighted, and proposes some future areas for further exploration.

Randomized Trial of Clinical Safety of Daily Oral Tenofovir Disoproxil Fumarate Among HIV-Uninfected Men Who Have Sex With Men in the United States

To evaluate the clinical safety of daily tenofovir disoproxil fumarate (TDF) among HIV-negative men who have sex with men. Randomized, double-blind, placebo-controlled trial. Participants were randomized 1:1:1:1 to immediate or delayed study drug (TDF, 300 mg orally per day, or placebo). Four hundred healthy HIV-uninfected men who have sex with men reporting anal sex with another man within the previous 12 months enrolled in Atlanta, Boston, and San Francisco. HIV serostatus, clinical and laboratory adverse events (AEs), adherence (pill count, Medication Event Monitoring System, and self-report), and sexual and other sociobehavioral data were assessed at 3-month intervals for 24 months. Primary outcomes were clinical safety, assessed by incidence of AEs and laboratory abnormalities. Study drug was initiated by 373 (93%) participants (186 TDF and 187 placebo), of whom 325 (87%) completed the final study visit. Of 2428 AEs reported among 334 (90%) participants, 2366 (97%) were mild or moderate in severity. Frequencies of commonly reported AEs did not differ significantly between TDF and placebo arms. In multivariable analyses, back pain was more likely among TDF recipients (P = 0.04); these reports were not associated with documented fractures or other objective findings. There were no grade ≥3 creatinine elevations; grades 1 and 2 creatinine increases were not associated with TDF receipt. Estimated percentage of study drug doses taken was 92% by pill count and 77% by Medication Event Monitoring System. Seven seroconversions occurred: 4 on placebo and 3 among delayed arm participants not yet on study drug. Daily oral TDF was well tolerated, with reasonable adherence. No significant renal concerns were identified.

HIV prevention research in a resource-limited setting: the experience of planning a trial in Cambodia

On Aug 13 2004 all work was stopped and never resumed on a study being prepared in Cambodia to determine whether daily oral tenofovir disoproxil fumarate was safe and effective in preventing the sexual transmission of HIV infection. The study was to have been a randomised double-blind trial that recruited 960 HIV-negative women engaged in sex work to receive either 300 mg of tenofovir disoproxil fumarate once daily or an identical placebo for 12 months. Trial development was suspended in response to a statement from the Cambodian Prime Minister. Before the statement concerns about the trial had been raised by a group representing women engaged in sex work in Cambodia. There has since been much commentary about the trial and its surrounding issues through the media and the internet. The commentary asserted that: the trial was purely motivated by the commercial interests of a pharmaceutical company the drug had not been adequately assessed before it was proposed as a possible prevention agent affected communities were inadequately consulted during study preparations the researchers would not be providing participants with safe sex counselling and condoms during the trial to increase HIV incidence recruitment practices would not adequately incorporate informed consent and medical treatment for trial-related injury and HIV care for seroconverters would not be available to participants. Along with this commentary the researchers were accused of engaging or intending to engage in practices that were inconsistent with the standards of research ethics. To better inform public discussion we provide our perspective on the design and development stages of the trial focusing particularly on issues raised by commentators. (excerpt)