<b>BACKGROUND: </b>Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use.<b>METHODS: </b>Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing.<b>RESULTS: </b>Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 [57%]), compared with the TDF arm (1 of 19 [5.3%]; P = .01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment.<b>CONCLUSIONS: </b>These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.
<b>Importance: </b>Tenofovir disoproxil fumarate (TDF) use has been associated with declines in the estimated glomerular filtration rate (eGFR) when used as part of antiretroviral treatment by persons with human immunodeficiency virus (HIV) type 1, but limited data are available for risk when used as preexposure prophylaxis (PrEP) for HIV-1 prevention.<b>OBJECTIVE: </b>To determine whether TDF-based PrEP causes eGFR decline in HIV-1-uninfected adults.<b>Design, Setting, and Participants: </b>A per-protocol safety analysis of changes in eGFR in the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF and emtricitabine (FTC)-TDF PrEP among heterosexual HIV-1-uninfected members of serodiscordant couples in Kenya and Uganda. The trial was conducted from 2008 to 2012.<b>Main Outcomes and Measures: </b>Predefined outcomes of this analysis were mean eGFR change and a 25% or greater eGFR decline from baseline. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.<b>RESULTS: </b>Of 4640 participants in the once-daily TDF (n = 1548), FTC-TDF (n = 1545), or placebo (n = 1547) groups, 63% were men. At enrollment, median age was 35 years (range, 18-64 years), and mean eGFR was 130 mL/min/1.73 m². During a median follow-up of 18 months (interquartile range 12-27 months), mean within-group eGFR change from baseline was +0.14 mL/min/1.73 m² for TDF, -0.22 mL/min/1.73 m² for FTC-TDF, and +1.37 mL/min/1.73 m² for placebo, translating into average declines in eGFR attributable to PrEP vs placebo of -1.23 mL/min/1.73 m² (95% CI, -2.06 to -0.40; P = .004) for TDF and -1.59 mL/min/1.73 m² (95% CI, -2.44 to -0.74; P < .001) for FTC-TDF. The difference in mean eGFR between PrEP and placebo appeared by 1 month after randomization, was stable through 12 months, and then appeared to wane thereafter. The respective proportions of persons who developed a confirmed 25% or greater eGFR decline from baseline by 12 and 24 months was 1.3% and 1.8% for TDF and 1.2% and 2.5% for FTC-TDF, and these frequencies were not statistically different from the confirmed decline in the placebo group (0.9% and 1.3% by 12 and 24 months, respectively).<b>Conclusions and Relevance: </b>In this large randomized, placebo-controlled trial among heterosexual persons, with median follow-up of 18 months and maximum follow-up of 36 months, daily oral TDF-based PrEP resulted in a small but nonprogressive decline in eGFR that was not accompanied by a substantial increase in the risk of clinically relevant (≥25%) eGFR decline.<b>Trial Registration: </b>clinicaltrials.gov Identifier: NCT00557245.
Importance: 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. OBJECTIVE: To assess pregnancy incidence and outcomes among women using PrEP during the periconception period. Design, Setting, and Participants: 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. INTERVENTIONS: 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. Main Outcomes and Measures: Pregnancy incidence, birth outcomes (live births, pregnancy loss, preterm birth, congenital anomalies), and infant growth. RESULTS: 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 [<i>P</i> = .22 vs placebo]), and 8.8 among those assigned FTC+TDF (incidence difference, −1.3; 95%CI, −4.1 to 1.5 [<i>P</i> = .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%; <i>P</i> = .16) and was 27.7% for those receiving TDF alone (difference vs placebo, −4.6%; 95%CI, −18.1% to 8.9%; <i>P</i> = .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%; <i>P</i> = .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. Conclusions and Relevance: 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. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
OBJECTIVE: To evaluate preexposure prophylaxis (PrEP) efficacy for HIV-1 prevention among women using depot medroxyprogesterone acetate (DMPA) for contraception and men whose HIV-1-infected partners use DMPA.
DESIGN: Secondary analysis of data from a randomized placebo-controlled trial of daily oral tenofovir and emtricitabine/tenofovir PrEP among heterosexual Kenyan and Ugandan HIV-1 serodiscordant couples.
METHODS: PrEP efficacy for HIV-1 prevention was compared among HIV-1-uninfected women using DMPA versus no hormonal contraception and among HIV-1 uninfected men whose HIV-1-infected female partners used DMPA versus no hormonal contraception.
RESULTS: Of 4747 HIV-1 serodiscordant couples, 901 HIV-1-uninfected women used DMPA at some point during follow-up, 1422 HIV-1-uninfected women used no hormonal contraception, 1568 HIV-1-uninfected men had female partners who used DMPA, and 2626 men had female partners who used no hormonal contraception. PrEP efficacy estimates for HIV-1 prevention, compared with placebo, were similar among women using DMPA and those using no hormonal contraception (64.7 and 75.5%, adjusted interaction P = 0.65). Similarly, for men whose female partners used DMPA, PrEP efficacy did not differ from men whose partners used no hormonal contraception (90.0 versus 81.7%, adjusted interaction P = 0.52).
CONCLUSION: PrEP is efficacious for HIV-1 prevention among women using DMPA and men whose partners use DMPA, suggesting PrEP could mitigate the potential increased HIV-1 acquisition and transmission risks that have been associated with DMPA use. Women at risk for HIV-1 choosing DMPA could maintain this contraceptive method and add PrEP to achieve prevention of unintended pregnancy and HIV-1.
BACKGROUND: For women at risk of HIV-1, effective contraception and effective HIV-1 prevention are global priorities. Methodology: In a clinical trial of pre-exposure prophylaxis (PrEP) for HIV-1 prevention in HIV-1-serodiscordant couples, we estimated the effectiveness of hormonal contraceptives (oral contraceptive pills, injectable depot medroxyprogesterone acetate, and hormonal implants) for pregnancy prevention relative to no contraception among 1785 HIV-1-uninfected women followed up to 36 months. We compared the effectiveness of each method among women assigned PrEP versus placebo. Contraception was not required for participation, but was offered on-site and was recorded monthly; incident pregnancy was determined by monthly urine testing. RESULTS: For women using no contraception, overall pregnancy incidence was 15.4% per year. Women reporting oral contraceptive use had comparable pregnancy incidence to women using no contraception, and this lack of contraceptive effectiveness was similar for those assigned PrEP and placebo (17.7 and 10.0% incidence per year, respectively; <i>P</i>-value for difference in effect by PrEP use = 0.24). Women reporting injectable contraception had reduced pregnancy incidence compared to those reporting no contraception, which did not differ by arm (PrEP 5.1%, placebo 5.3% per year; <i>P-</i>value for difference = 0.47). Contraceptive effectiveness was highest among women using implants (pregnancy incidence < 1% per year in both arms). CONCLUSION: PrEP had no adverse impact on hormonal contraceptive effectiveness for pregnancy prevention. As seen previously in similar populations, women reporting contraceptive pill use had little protection from pregnancy, possibly due to poor adherence. Injectable or implantable hormonal contraception and PrEP provide effective prevention for pregnancy and HIV-1. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
<b>BACKGROUND: </b>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.<b>METHODS: </b>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.<b>FINDINGS: </b>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.<b>INTERPRETATION: </b>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.<b>Funding: </b>Bill & Melinda Gates Foundation and US National Institutes of Health.
BACKGROUND: Daily oral antiretroviral preexposure prophylaxis (PrEP) is a promising strategy for prevention of HIV-1 acquisition. Three clinical trials demonstrated PrEP efficacy; however, two PrEP trials among women did not find protection against HIV-1. One hypothesis proposed for these divergent results is that PrEP efficacy may be reduced in populations with higher HIV-1 incidence. METHODS: Using data from the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral tenofovir (TDF) and emtricitabine/tenofovir (FTC/TDF) PrEP among heterosexual HIV-1 serodiscordant couples from Kenya and Uganda, we assessed PrEP efficacy among subgroups at higher risk for HIV-1 acquisition, including subgroups of women with high HIV-1 incidence. RESULTS: The overall placebo arm HIV-1 incidence was 2.0 per 100 person-years. Among higher risk subgroups, placebo arm HIV-1 incidence ranged from 3.9 to 6.6 per 100 person-years. In all subgroups, PrEP was protective against HIV-1 acquisition, with efficacy point estimates ranging from 64 to 84%. Among subgroups of women with placebo-arm HIV-1 incidence more than 5.0, efficacy estimates ranged from 64 to 84%. Monthly visit attendance for PrEP refills and tenofovir detection in plasma were high. CONCLUSION: Among higher-risk subgroups in the Partners PrEP Study, including groups solely of higher-risk women, both TDF alone and combined FTC/TDF PrEP had consistently high efficacy for HIV-1 protection. PrEP, when used with high adherence, is a highly effective prevention strategy for higher risk heterosexuals. Prioritizing PrEP for persons at high risk of HIV-1 will maximize its prevention impact. (PsycInfo Database Record (c) 2021 APA, all rights reserved)
ANTECEDENTES: La profilaxis preexposición con antirretrovirales es un enfoque prometedor para la prevención del virus de la inmunodeficiencia humana tipo 1 (VIH-1) en la población heterosexual.
MÉTODOS: Se realizó un ensayo aleatorio de la terapia antirretroviral oral para su uso como profilaxis preexposición entre las parejas heterosexuales VIH-1 serodiscordantes de Kenia y Uganda. La pareja VIH-1 seronegativos en cada pareja se le asignó al azar a uno de tres regímenes de estudio - tenofovir una vez al día (TDF), la combinación de tenofovir-emtricitabina (TDF-FTC), o placebo - y siguió mensual de hasta 36 meses. Al inicio del estudio, los socios del VIH-1 seropositivos no eran elegibles para la terapia antirretroviral, de acuerdo con las directrices nacionales. Todas las parejas recibieron servicios de VIH-1 de tratamiento y prevención estándar.
Resultados: Se incluyó a 4.758 parejas, de los cuales 4747 se siguieron: 1.584 asignados aleatoriamente a TDF, 1579 a TDF-FTC, y 1584 con el placebo. Para el 62% de las parejas que siguió, la pareja VIH-1 seronegativos era masculino. Entre los participantes VIH-1 seropositivos, el recuento promedio de CD4 fue de 495 células por milímetro cúbico (rango intercuartil, 375-662). Un total de 82 infecciones por VIH-1 se produjo en los participantes seronegativos durante el estudio, 17 en el grupo TDF (incidencia, 0,65 por 100 personas-año), 13 en el grupo TDF-FTC (incidencia de 0,50 por 100 personas-año), y 52 en el grupo placebo (incidencia, 1,99 por 100 personas-año), lo que indica una reducción relativa del 67% en la incidencia de VIH-1 con TDF (95% intervalo de confianza [IC] del 44 a 81; p <0,001) y del 75% con TDF-FTC (IC del 95%, 55-87; P <0,001). Los efectos protectores de TDF-FTC y TDF solo contra el VIH-1 no fueron significativamente diferentes (P = 0,23), y los dos medicamentos del estudio redujeron significativamente la incidencia del VIH-1 entre hombres y mujeres. La tasa de eventos adversos graves fue similar en todos los grupos de estudio. Se encontraron ocho participantes que recibieron tratamiento activo que han sido infectadas con el VIH-1 al inicio del estudio, y entre estos ocho, resistencia antirretroviral desarrollaron en dos durante el estudio.
CONCLUSIONES: Oral TDF y TDF-FTC ambos protegen contra la infección VIH-1 en los hombres y mujeres heterosexuales. (Financiado por la Fundación Bill y Melinda Gates;. Número Partners PrEP ClinicalTrials.gov, NCT00557245).
Preexposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone reduces the risk of human immunodeficiency virus (HIV) acquisition. Understanding the risk of antiretroviral resistance selected by PrEP during breakthrough infections is important because of the risk of treatment failure during subsequent antiretroviral use.
METHODS:
Within the largest randomized trial of FTC/TDF versus TDF as PrEP, plasma samples were tested for HIV with resistance mutations associated with FTC (K65R and M184IV) and TDF (K65R and K70E), using 454 sequencing.
RESULTS:
Of 121 HIV seroconverters, 25 received FTC/TDF, 38 received TDF, and 58 received placebo. Plasma drug levels in 26 individuals indicated PrEP use during or after HIV acquisition, of which 5 had virus with resistance mutations associated with their PrEP regimen. Among those with PrEP drug detected during infection, resistance was more frequent in the FTC/TDF arm (4 of 7 [57%]), compared with the TDF arm (1 of 19 [5.3%]; P = .01), owing to the FTC-associated mutation M184IV. Of these cases, 3 had unrecognized acute infection at PrEP randomization, and 2 were HIV negative at enrollment.
CONCLUSIONS:
These results suggest that resistance selected by PrEP is rare but can occur both with PrEP initiation during acute seronegative HIV infection and in PrEP breakthrough infections and that FTC is associated with a greater frequency of resistance mutations than TDF.
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
