Kidney injury biomarkers during exposure to tenofovir-based preexposure prophylaxis.
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ABSTRACT:
SUBMITTER: Nickolas TL
PROVIDER: S-EPMC8102362 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
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Kidney injury biomarkers during exposure to tenofovir-based preexposure prophylaxis.
Nickolas Thomas L TL Barasch Jonathan J Mugwanya Kenneth K KK Branch Andrea D AD Heffron Renee R Wanga Valentine V Mugo Nelly R NR Ronald Allan A Celum Connie C Donnell Deborah D Baeten Jared M JM Wyatt Christina M CM
AIDS (London, England) 20210601 7
We previously reported a higher incidence of non-albumin proteinuria and a small but significant decline in estimated glomerular filtration rate (eGFR) among HIV-negative adults randomized to emtricitabine/tenofovir disoproxil fumarate preexposure prophylaxis (FTC/TDF PrEP) versus placebo. In a nested case--control study among participants randomized to FTC/TDF PrEP, established kidney injury biomarkers measured at 12 months were not significantly different between participants who subsequently ...[more]
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Project description:Despite tremendous promise as a female-controlled HIV prevention strategy, implementation of preexposure prophylaxis (PrEP) among women has been limited, in part because of disparate efficacy results from randomized trials in this population. This review synthesizes existing evidence regarding PrEP efficacy for preventing HIV infection in women and considerations for delivering PrEP to women.In three efficacy trials, conducted among men and women, tenofovir-based oral PrEP reduced HIV acquisition in subgroups of women by 49-79% in intent-to-treat analyses, and by >85% when accounting for PrEP adherence. Two trials did not demonstrate an HIV prevention benefit from PrEP in women, but substantial evidence indicates those results were compromised by very low adherence to the study medication. Qualitative research has identified risk perception, stigma, and aspects of clinical trial participation as influencing adherence to study medication. Pharmacokinetic studies provide supporting evidence that PrEP offers HIV protection in women who are adherent to the medication.Tenofovir-based daily oral PrEP prevents HIV acquisition in women. Offering PrEP as an HIV prevention option for women at high risk of HIV acquisition is a public health imperative and opportunities to evaluate implementation strategies for PrEP for women are needed.
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Project description:Clinical trials of oral preexposure prophylaxis (PrEP) have focused on regimens of tenofovir (TDF) with or without emtricitabine (FTC). However, TDF may be associated with toxicities (renal, bone), and FTC may select for drug resistance. Both are also first-line drugs for HIV treatment. In this review, we discuss agents that might serve as alternatives to TDF/FTC for HIV PrEP.Several drug characteristics are important to consider when selecting agents for PrEP with the most critical being safety, tolerability, adequate penetration into target tissues for prevention of HIV infection, and long-lasting activity with convenient dosing. With these factors in mind, we review five potentially useful agents for PrEP. The first group includes drugs that are already Food and Drug Administration approved (maraviroc, raltegravir) with attributes that make them attractive for PrEP. The second group includes investigational agents with long-lasting activity that are being developed in parenteral form (rilpivirine-long acting, S/GSK1265744, ibalizumab).Future PrEP drugs may give clinicians the flexibility to select agents on the basis of individual patient needs and preferences.
| S-EPMC3732461 | biostudies-other
Project description:BackgroundReproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection.MethodsWe conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly.ResultsOf 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was -49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), -4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). We observed no significant differences in the frequencies of other adverse events.ConclusionsNone of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. (Funded by the National Institutes of Health; VOICE ClinicalTrials.gov number, NCT00705679.).
| S-EPMC4341965 | biostudies-literature
Project description:OBJECTIVES:Pregnancy is a time of increased HIV acquisition risk and pregnancy reduces concentrations of antiretrovirals used for treatment. We assessed whether pregnancy lowers concentrations of tenofovir (TFV) and tenofovir-diphosphate (TFV-DP) among HIV-uninfected women using oral preexposure prophylaxis (PrEP). METHODS:We analyzed data from an open-label PrEP study, comparing concentrations of TFV in plasma and TFV-DP in dried blood spots (DBS) among 37 pregnant women and 97 nonpregnant women. Analyses controlled for adherence from daily electronic monitoring. RESULTS:The average plasma concentration of TFV among pregnant women was 34.7 ng/ml with 22.2 average recorded doses over the prior month versus 86.5 ng/ml with 23.1 doses among nonpregnant women. After controlling for adherence, TFV concentrations were 58% lower among pregnant women, a statistically significant difference of -50.4 ng/ml (95% CI -68.3 to -32.5). The average TFV-DP concentration was 450.3 fmol/punch among pregnant women and 636.7 fmol/punch among nonpregnant women. This difference was not statistically significant after adjusting for adherence; however, among those with quantifiable TFV-DP, concentrations were 27% lower during pregnancy [-202 fmol/punch (95% CI -384 to -19)]. Among participants with samples before and during pregnancy, there were significant decreases during pregnancy, controlling for adherence: -28.1 ng/ml TFV (95% CI -52.3 to -4.0) and -289.2 fmol/punch TFV-DP (95% CI -439.0 to -139.3). CONCLUSION:Consistent with studies among HIV-infected women on ART, we found TFV and TFV-DP concentrations were lower during pregnancy. There is no established TFV concentration threshold to achieve HIV prevention. Additional pharmacokinetic studies and studies of PrEP efficacy in pregnancy are needed.
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Project description:ObjectiveWe developed Healthy Families-PrEP to support perinatal women to use HIV prevention strategies.DesignSingle-arm study to evaluate PrEP use among pregnant women exposed to the intervention.MethodsWe offered safer conception counselling, including TDF/FTC as PrEP with adherence support (Healthy Families-PrEP) for women planning for pregnancy in South Africa with a partner with HIV or unknown serostatus. Women completed pregnancy and HIV testing quarterly and were followed for 1 year or until pregnancy end. For those initiating PrEP, electronic pillcap data and plasma were collected. We described PrEP adherence by proportion of days with pillcap openings and proportion of women with detected (≥10ng/ml) plasma tenofovir.ResultsFrom November 2017 to January 2020, 326 women with median age 24 years [interquartile range (IQR) 22-27] enrolled. Partner HIV-serostatus was unknown by 316 (97%). Over 3204 person-months of follow-up, 56 women became pregnant. Twenty-six women used PrEP during pregnancy and opened pillcaps on a mean of 53.1% [95% confidence interval (CI) 46.9-59.3%] of days. Plasma tenofovir was detected among 25, 15.4, and 12.5% of women providing samples during months 0-3, 4-6, and 7-9. No HIV seroconversions were observed.ConclusionWe observed low-pregnancy incidence. Counselling may have encouraged delayed pregnancy plans; some women may have exaggerated pregnancy plans to enroll. About half of pregnant women used PrEP and took over half of doses by pillcap. Fewer than 25% had tenofovir detected, likely reflecting pregnancy-related pharmacokinetics and adherence challenges. High interest in pregnancy PrEP use highlights the need to optimize adherence support and prevention choice.
| S-EPMC11902610 | biostudies-literature
Project description:ObjectiveTo evaluate the effects of HIV preexposure prophylaxis (PrEP) with tenofovir disoproxial fumurate (TDF)/emtricitabine (FTC) on kidney function and kidney tubular health.DesignThe Iniciativa Profilaxis Pre-Exposicion open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. This study included 123 iPrEx-OLE participants who demonstrated PrEP adherence.MethodsWe compared estimated glomerular filtration rate calculated using serum creatinine (eGFRcr), serum cystatin C (eGFRcys), and in combination (eGFRcr-cys), and a panel of 14 urine biomarkers reflecting kidney tubular health before and 6 months after PrEP initiation.ResultsAt baseline, mean eGFRcr, eGFRcys, and eGFRcr-cys were 108.3, 107.0, and 111.1 ml/min per 1.73 m, respectively. Six months after PrEP initiation, eGFRcr declined by -4% (95% CI: -5.7 to -2.4%), eGFRcys declined by -3.3% (95% CI: -8.3 to 1.9%), and eGFRcr-cys declined by -4.1% (95% CI: -7.5 to -0.7%). From the urine biomarker panel, α1-microglobulin and β2-microglobulin increased by 22.7% (95% CI: 11.8--34.7%) and 14.1% (95% CI: -6.1 to 38.6%), whereas chitinase-3-like 1 protein and monocyte chemoattractant protein-1 decreased by -37.7% (95% CI: -53.0 to -17.3%) and -15.6% (95% CI: -31.6 to 4.2%), respectively. Ten of the 14 urine biomarkers, including albumin, had estimated changes of less than 12% with wide confidence intervals.ConclusionSix months of PrEP with TDF/FTC was associated with decreases in eGFRcr and eGFRcys. We also observed for the first time changes in flour of 14 urine biomarkers reflecting kidney tubular health. These findings demonstrate that PrEP has direct effects on eGFR and the proximal tubule.
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Project description:Multiple doses of tenofovir disoproxil fumarate (TDF) together with emtricitabine is effective for HIV preexposure prophylaxis (PrEP). TDF is converted to tenofovir (TFV) in circulation, which is subsequently cleared via tubular secretion by organic ion transporters (OATs; OAT1 and OAT3). Using in vitro kinetic parameters for TFV and the OAT1 and OAT3 inhibitor probenecid, a bottom-up physiologically-based pharmacokinetic model was successfully developed for the first time that accurately describes the probenecid-TFV interaction. This model predicted an increase in TFV plasma exposure by 60%, which was within 15% of the observed clinical pharmacokinetic data, and a threefold decrease in renal cells exposure following coadministration of a 600 mg TDF dose with 2 g probenecid. When compared with multiple-dose regimens, a single-dose probenecid-boosted TDF regimen may be effective for HIV PrEP and improve adherence and safety by minimizing TFV-induced nephrotoxicity by reducing TFV accumulation in renal cells.
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Project description:ImportanceEmtricitabine and tenofovir disoproxil fumarate (F/TDF) for HIV preexposure prophylaxis (PrEP) is highly effective in cisgender men who have sex with men (MSM) when adherence is high (>4 doses/week). Real-world effectiveness and adherence with F/TDF for PrEP in cisgender women is less well characterized.ObjectiveTo characterize the effectiveness of F/TDF for PrEP and its relationship with adherence in cisgender women.Design, setting, and participantsData were pooled from 11 F/TDF PrEP postapproval studies conducted in 6 countries that included 6296 cisgender women aged 15 to 69 years conducted from 2012 to 2020. HIV incidence was evaluated according to adherence level measured objectively (tenofovir diphosphate concentration in dried blood spots or tenofovir concentration in plasma; n = 288) and subjectively (electronic pill cap monitoring, pill counts, self-report, and study-reported adherence scale; n = 2954) using group-based trajectory modeling.ExposuresF/TDF prescribed orally once a day. HIV incidence was analyzed in subgroups based on adherence trajectory.Main outcomes and measuresHIV incidence.ResultsOf the 6296 participants, 46% were from Kenya, 28% were from South Africa, 21% were from India, 2.9% were from Uganda, 1.6% were from Botswana, and 0.8% were from the US. The mean (SD) age at PrEP initiation across all studies was 25 (7) years, with 61% of participants being younger than 25 years. The overall HIV incidence was 0.72 per 100 person-years (95% CI, 0.51-1.01; 32 incident HIV diagnoses among 6296 participants). Four distinct groups of adherence trajectories were identified: consistently daily (7 doses/week), consistently high (4-6 doses/week), high but declining (from a mean of 4-6 doses/week and then declining), and consistently low (less than 2 doses/week). None of the 498 women with consistently daily adherence acquired HIV. Only 1 of the 658 women with consistently high adherence acquired HIV (incidence rate, 0.13/100 person-years [95% CI, 0.02-0.92]). The incidence rate was 0.49 per 100 person-years (95% CI, 0.22-1.08) in the high but declining adherence group (n = 1166) and 1.27 per 100 person-years (95% CI, 0.53-3.04) in the consistently low adherence group (n = 632).Conclusions and relevanceIn a pooled analysis of 11 postapproval studies of F/TDF for PrEP among cisgender women, overall HIV incidence was 0.72 per 100 person-years; individuals with consistently daily or consistently high adherence (4-6 doses/week) to PrEP experienced very low HIV incidence.
| S-EPMC10951736 | biostudies-literature
Project description:Background:Antiretroviral drugs have been associated with changes in lipids, fat mass and dat distribution. Tenofovir disoproxil fumarate (TDF) has been shown to have a more favorable metabolic profile than other drugs in its class. However, the metabolic effects of TDF in preexposure prophylaxis (PrEP) are unknown. Methods:We evaluated the effects of TDF/emtricitabine (FTC) on lipids and body composition in a blinded, placebo-controlled PrEP trial. Participants enrolled in a metabolic subcohort (N = 251, TDF/FTC; N = 247, placebo) consented to fasting lipid panels, dual-energy X-ray absorptiometry scans for body composition, and pharmacologic testing of drug metabolites at baseline and every 24 weeks thereafter. Results:Lean body mass was stable and unaffected by TDF/FTC. Body weight increased in both groups but was lower on TDF/FTC through week 72. This difference was explained by lower fat accumulation on TDF/FTC. The net median percent difference (standard error, P value) for TDF/FTC vs placebo at week 24 was -0.8% (0.4%, P = .02), +0.3% (0.4%, P = .46), and -3.8% (1.4%, P = .009) for total, lean, and fat mass, respectively. There was no apparent differential regional fat accumulation on TDF/FTC. Decreases in cholesterol, but not triglycerides, were seen in TDF/FTC participants, with detectable drug levels compared to placebo. Conclusions:TDF/FTC for PrEP showed cholesterol reductions and appeared to transiently suppress the accumulation of weight and body fat compared to placebo. There was no evidence of altered fat distribution or lipodystrophy during daily oral TDF/FTC PrEP. Clinical Trials Registration:NCT00458393.
| S-EPMC6051460 | biostudies-literature
Project description:BackgroundHIV preexposure prophylaxis (PrEP) using daily oral tenofovir-disoproxil-fumarate/emtricitabine (TDF/FTC) is effective for preventing HIV acquisition, but concerns remain about its potential kidney toxicity. This study examined kidney function in individuals using PrEP in real-world clinical settings.SettingDemonstration project in 2 sexually transmitted infection clinics and a community health center.MethodsWe evaluated kidney function among men who have sex with men and transgender women taking tenofovir-disoproxil-fumarate/emtricitabine PrEP for up to 48 weeks. Serum creatinine and urine dipstick for protein were obtained at 12-week intervals. Kidney function was estimated using creatinine clearance (CrCl) (Cockcroft-Gault) and estimated glomerular filtration rate (eGFR) (CKD-EPI).ResultsFrom October 2012 to January 2014, we enrolled 557 participants (median age 33). Mean creatinine increased from baseline to week 12 by 0.03 mg/dL (4.6%) (P < 0.0001); mean CrCl decreased by 4.8 mL/min (3.0%) (P < 0.0001). These changes remained stable through week 48 (P = 0.81, P = 0.71 respectively). There were 75/478 (15.7%) participants who developed worsening proteinuria at week 12 compared with baseline (P < 0.0001), and this percent remained stable through week 48 (P = 0.73). Twenty-five participants (5.1%) developed new-onset eGFR <70 mL/min/1.73 m; independent predictors of this outcome were age ≥40 years (OR 3.79, 95% CI: 1.43 to 10.03) and baseline eGFR <90 mL/min/1.73 m (OR 9.59, 3.69-24.94).ConclusionsIn a demonstration setting, daily tenofovir-disoproxil-fumarate/emtricitabine PrEP leads to reduced CrCl and eGFR; however, these eGFR changes are based on very small changes in serum creatinine and seem to be nonprogressive after the first 12 weeks. Future studies are needed to understand the prognostic significance of these small changes.
| S-EPMC5762266 | biostudies-literature