Dataset Information

HIV disease progression among women following seroconversion during a tenofovir-based HIV prevention trial.

ABSTRACT:

Background

Little is known regarding HIV disease outcomes among individuals who become infected with HIV while receiving antiretroviral medications for prevention. We compared HIV disease parameters among women who seroconverted while receiving tenofovir-containing oral or vaginal pre-exposure prophylaxis (PrEP) to placebo.

Methods

Participants with HIV seroconversion in a randomized placebo-controlled trial of oral tenofovir, oral tenofovir/emtricitabine, and vaginal tenofovir gel (MTN-003) were followed in a longitudinal cohort study (MTN-015). The effect of oral and vaginal tenofovir-containing PrEP on HIV disease progression was compared to placebo using linear mixed effects and Cox proportional hazard models, as appropriate. Additional analyses were performed to compare the outcomes among participants with detectable tenofovir or emtricitabine in plasma at the first quarterly visit in MTN-003.

Results

A total of 224 participants were included in the analysis; 93% from South Africa and 94% clade C virus. No differences in HIV RNA at steady state or the trajectory over 12 months were observed for each active arm compared to placebo; tenofovir gel recipients had higher CD4+ T cell counts (722 vs 596 cells/mm3; p = 0.02) at 90 days after estimated HIV seroconversion and higher average rates of change over 12 months compared to placebo (-181 vs -92 cells/mm3 per year; p = 0.08). With a median follow-up of 31 months, no significant differences were observed for time to CD4+ T cell count ?350 cells/mm3, or the composite endpoint of CD4+ T cells ?350 cells/mm3, initiation of antiretroviral therapy or death for each active arm compared to placebo. Additionally, there were no significant differences in the HIV RNA or CD4+ T cell counts at baseline, the change to month 12, or any disease progression outcomes among participants with oral drug detected and no oral drug detected compared to placebo.

Conclusions

No clinically significant differences in HIV seroconversion outcomes were observed among women randomized to tenofovir-containing oral or vaginal PrEP regimens, however low overall adherence limits the generalizability of these findings.

SUBMITTER: Riddler SA

PROVIDER: S-EPMC5489164 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

HIV disease progression among women following seroconversion during a tenofovir-based HIV prevention trial.

Riddler Sharon A SA Husnik Marla M Ramjee Gita G Premrajh Anamika A Tutshana Bomkazi Onini BO Pather Arendevi A Siva Samantha S Jeenarain Nitesha N Nair Gonasagrie G Selepe Pearl P Kabwigu Samuel S Palanee-Phillips Thesla T Panchia Ravindre R Mhlanga Felix F Levy Lisa L Livant Edward E Patterson Karen K Elharrar Vanessa V Balkus Jennifer J

PloS one 20170628 6

<h4>Background</h4>Little is known regarding HIV disease outcomes among individuals who become infected with HIV while receiving antiretroviral medications for prevention. We compared HIV disease parameters among women who seroconverted while receiving tenofovir-containing oral or vaginal pre-exposure prophylaxis (PrEP) to placebo.<h4>Methods</h4>Participants with HIV seroconversion in a randomized placebo-controlled trial of oral tenofovir, oral tenofovir/emtricitabine, and vaginal tenofovir ge ...[more]

PMID: 28658251

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Project description:ObjectivesThe objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women.DesignThis was a phase 2, randomized, double-blind, placebo-controlled trial.SettingThe study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria.ParticipantsWe enrolled 936 HIV-negative women at high risk of HIV infection into this study.InterventionParticipants were randomized 1:1 to once daily use of 300 mg of TDF or placebo.Outcome measuresThe primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2.ResultsStudy participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03-1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved.ConclusionDaily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study.

Project description:BackgroundDaily oral emtricitabine (FTC, F)/tenofovir disoproxil fumarate (TDF) combination is approved for HIV pre-exposure prophylaxis (PrEP) in men and women. Tenofovir alafenamide fumarate (TAF) is a newer, more potent prodrug of tenofovir (TFV), and in combination with FTC, has recently been approved for prevention of HIV through rectal transmission.MethodsThis Phase I, prospective, interventional, randomized study was conducted in three clinical sites: PROFAMILIA, Santo Domingo, Dominican Republic; University of Pittsburgh and Eastern Virginia Medical School. We assessed the multi-compartmental pharmacokinetics (primary outcome) and safety (secondary outcome) among HIV uninfected women randomized to F/TDF (200mg/300mg) or F/TAF (200mg/25mg; F/TAF25) (n=24) in a single dose phase (SDP) and F/TDF, F/TAF (200mg/10mg; F/TAF10), or F/TAF25 (n=75) in a multiple dose (14 daily doses) phase (MDP). We described PK parameters in plasma, peripheral blood mononuclear cells (PBMCs), and cervicovaginal (CV) and rectal fluids and tissues. ClinicalTrials.gov #NCT02904369, completed.FindingsRecruitment for the study began on 5 October 2016. The first participant was enrolled on 6 October 2016 and the last participant completed the study 21 November 2017.PlasmaTFV concentrations area under curve (AUC) were ~20 fold lower following F/TAF versus F/TDF. TFV-diphosphate (TFV-DP) AUC concentrations in PBMCs were 7-fold higher with F/TAF25 versus F/TDF. Median TFV-DP concentrations in vaginal tissue (4hours post last dose) were approximately 6-fold higher with F/TAF25 versus F/TDF. TFV and TFV-DP were lower with F/TAF versus F/TDF in rectal tissue. Concentrations of FTC and FTC-triphosphate (FTC-TP) were similar across matrices and treatment arms. Gastrointestinal adverse events (AEs) occurred more frequently in F/TDF users (44.0%) than in either F/TAF group (11.5 and 12.0%).InterpretationF/TAF was safe and well-tolerated. TFV-DP concentrations were higher in PBMCs and similar or higher (4h post dose) in female genital tract tissues for F/TAF versus F/TDF. High FTC and FTC-TP concentrations in all compartments support the potential of F/TAF as a new PrEP combination for women.

Dataset Information

HIV disease progression among women following seroconversion during a tenofovir-based HIV prevention trial.

Background

Methods

Results

Conclusions

Publications

HIV disease progression among women following seroconversion during a tenofovir-based HIV prevention trial.

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