Decreased Tenofovir Diphosphate Concentrations in a Transgender Female Cohort: Implications for Human Immunodeficiency Virus Preexposure Prophylaxis.
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ABSTRACT:
SUBMITTER: Cottrell ML
PROVIDER: S-EPMC7188232 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
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Decreased Tenofovir Diphosphate Concentrations in a Transgender Female Cohort: Implications for Human Immunodeficiency Virus Preexposure Prophylaxis.
Cottrell Mackenzie L ML Prince Heather M A HMA Schauer Amanda P AP Sykes Craig C Maffuid Kaitlyn K Poliseno Amanda A Chun Tae-Wook TW Huiting Erin E Stanczyk Frank Z FZ Peery Anne F AF Dellon Evan S ES Adams Jessica L JL Gay Cindy C Kashuba Angela D M ADM
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20191101 12
Feminizing hormone therapy (FHT) may interact with human immunodeficiency virus preexposure prophylaxis (PrEP). We found that transgender women who took FHT exhibited a 7-fold lower rectal tissue ratio of PrEP's active metabolites vs competing deoxynucleotides compared to cisgender women and men (P = .03) that inversely correlated with estradiol (ρ = -0.79; P < .05). Thus, FHT may negatively impact PrEP efficacy. Clinical Trials Registration . NCT02983110. ...[more]
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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.
| S-EPMC6061961 | biostudies-literature
Project description:BackgroundEffective concentrations of antiretrovirals in the female genital tract (FGT) are critical for suppression of viral shedding or effective preexposure prophylaxis. The disposition of tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in the FGT have been previously described. Despite widespread use, however, lamivudine triphosphate (3TC-TP) exposure in the FGT is unknown. Depot medroxyprogesterone acetate (DMPA) and vaginal dysbiosis have been implicated in increased risk of human immunodeficiency virus (HIV) acquisition, but whether they alter TFV-DP or 3TC-TP exposure, and therefore compromise prevention efficacy, is unknown.MethodsFifty premenopausal women living with HIV in Kampala, Uganda, and receiving daily tenofovir disoproxil fumarate/lamivudine were recruited. Ectocervical biopsies were obtained for quantification of TFV-DP and 3TC-TP using liquid chromatography-mass spectrometry. 16S ribosomal RNA gene sequencing was performed on DNA extracted from vaginal swabs. Wilcoxon rank-sum was used to test for differences between contraceptive groups.Results3TC-TP concentrations were on average 17-fold greater than TFV-DP concentrations in cervical tissues. TFV-DP concentrations in cervical biopsies were 76% greater in DMPA users compared with women using nonhormonal contraception (n = 23 per group). Abundance of Lactobacillus in vaginal swabs was correlated with 3TC-TP concentrations in cervical tissues.ConclusionsWe found that TFV-DP concentrations were significantly greater in DMPA users compared with women using nonhormonal contraception, suggesting that prevention efficacy is unlikely to be compromised by DMPA use. Similar to reports of FTC-TP, 3TC-TP exposure was significantly greater than TFV-DP in cervical tissue and was correlated with abundance of Lactobacillus. These data support lamivudine as an option for preexposure prophylaxis.Clinical trials registrationNCT03377608.
| S-EPMC7146007 | biostudies-literature
Project description:BackgroundDaily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration.MethodsParticipant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models.ResultsAround 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (∼90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (∼7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels.ConclusionsUsing the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved.
| S-EPMC10139701 | biostudies-literature
Project description:ObjectivesWomen likely require higher adherence than men to preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for similar efficacy. Pharmacologic metrics of adherence predict efficacy better than self-report, but expected drug levels (adherence benchmarks) must be established using directly observed therapy. We sought to evaluate whether tenofovir hair concentrations differ between women and men receiving directly observed TDF/FTC.MethodsWe assessed tenofovir hair concentrations in HIV-uninfected volunteers randomized to receive 100%, 67%, or 33% of daily dosing of TDF/FTC for 12 weeks (DOT-DBS, NCT02022657). Hair samples were collected at dosing weeks 4, 8, and 12 and every 3 weeks during a 12-week washout. Tenofovir concentrations in the proximal 1.5 cm of hair (representing ∼6 weeks of exposure) were analyzed using liquid chromatography/tandem mass spectrometry. Linear regression was used to model tenofovir hair concentrations in terms of sex, doses over the prior 6 weeks, and number of days since last dose.ResultsA total of 264 hair samples were analyzed from 23 female and 24 male participants. Female participants had similar tenofovir hair concentrations to men (estimated fold-difference 0.92, 95% CI 0.75-1.13, P = 0.43). The estimated fold-difference in tenofovir levels for female versus male participants did not appreciably change when age (0.93, 95% CI 0.76-1.15), weight (0.89, 95% CI 0.71-1.11), or race/ethnicity (0.95, 95% CI 0.77-1.17) were added to the model.ConclusionWomen and men have similar adherence benchmarks for tenofovir in hair samples. As pharmacokinetic metrics are increasingly used for PrEP monitoring, these findings provide guidance for assessing adherence via hair concentrations.
| S-EPMC6330141 | biostudies-literature
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:BackgroundEfforts to end the human immunodeficiency virus (HIV) epidemic may be threatened if limited preexposure prophylaxis (PrEP) resources are funneled from tenofovir disoproxil fumarate with emtricitabine (TDF/FTC) to tenofovir alafenamide with emtricitabine (TAF/FTC) without proportional clinical benefits.MethodsThe study population was patients at a Boston community health center who were assigned male sex at birth, aged ≥18 years, and prescribed TDF/FTC for PrEP in the 12 months before TAF/FTC approval (October 2019). We determined the frequency of switching to TAF/FTC in the 12 months after approval, including clinically indicated switching (ie, creatinine clearance <60 mL/minute or reduced bone density), potentially unnecessary switching (ie, no indications for switching and no cardiovascular risk factors), and potentially harmful switching (ie, no indications for switching and either obesity or dyslipidemia).ResultsOf 2892 TDF/FTC users, mean age was 38 years, 96.0% were cisgender men, and 78.9% were white. A total of 343 (11.9%) switched to TAF/FTC. Based on documented renal, bone, and cardiovascular risk factors, we identified 24 (7.0%) with clinically indicated switching, 271 (79.0%) with potentially unnecessary switching, and 48 (14.0%) with potentially harmful switching. When indications for switching additionally included hypertension, diabetes, and creatinine clearance 60-70 mL/minute, 27.1% of switching was clinically indicated.ConclusionsFew who switched to TAF/FTC had documented indications for switching, although some appear to have been switched in anticipation of indications developing. As generic TDF/FTC is further discounted, provider education and patient decision aids are needed to facilitate selection of PrEP medications that is both clinically sound and cost-effective.
| S-EPMC8496521 | biostudies-literature
Project description:BackgroundTenofovir alafenamide fumarate (TAF) was promoted as a safer alternative to tenofovir disoproxil fumarate (TDF) for human immunodeficiency virus oral preexposure prophylaxis (PrEP). It is unknown if switching from TDF to TAF translates to improved renal function. We used electronic health record (EHR) data to assess changes in creatinine-estimated glomerular filtration rate (eGFR) after switching from TDF to TAF.MethodsWe conducted a retrospective cohort study using EHR data from Kaiser Permanente Southern California. We identified individuals who switched from TDF to TAF between October 2019 and May 2022 and used time-varying propensity score matching to identify controls who were on TDF ("nonswitchers"). We then used Bayesian longitudinal modeling to compare differences in eGFR between switching and nonswitching scenarios.ResultsAmong 5246 eligible individuals, we included 118 TDF to TAF switchers and 114 nonswitchers. Compared to nonswitchers, switchers had older age of starting TDF but similar body weights at index date. A higher proportion of switchers were White, on Medicare or Medicaid, and had dyslipidemia at index date. Switching to TAF was associated with a higher eGFR compared to staying on TDF in 3-15 months post-switch, but the differences were not statistically significant (eg, month 9 difference: 1.27 [95% credible interval, -1.35 to 3.89]). While most of the estimated changes showed eGFR increase associated with switching, most were <2 eGFR units. Sensitivity analyses to address missingness or nonadherence showed similar results.ConclusionsSwitching from TDF to TAF for PrEP was associated with a nonsignificant increase in eGFR. Findings need to be confirmed using larger cohorts.
| S-EPMC10863550 | biostudies-literature
Project description:ObjectiveTo understand perspectives on and preferences for preexposure prophylaxis (PrEP) for pregnant individuals who are at risk for human immunodeficiency virus (HIV) infection.MethodsIn this qualitative study, we purposively sampled and conducted in-depth interviews with pregnant participants at risk of HIV infection (indicated by a recent sexually transmitted infection [STI]) from a U.S. urban obstetrics clinic. Interview questions focused on perceived HIV risk, knowledge and perceptions of PrEP, and preferences for different PrEP formulations. We coded data using deductive and inductive codes, created matrices to explore patterns in findings, and wrote memos to interpret emergent themes.ResultsTwenty patients were enrolled. Median age of the participants was 24 years (interquartile range 19-26 years), 95.0% were African American, 65.0% were high school graduates, and 70.0% had unplanned pregnancies. Participants had low knowledge of PrEP and most saw themselves at low to no risk of HIV acquisition, despite their recent STI. Further, participants' low HIV risk perception and medication safety concerns reduced PrEP acceptability. Moreover, very few had discussed PrEP with their obstetrician-gynecologists (ob-gyns) during antenatal care, which further affected perceived acceptability. However, participants who did discuss PrEP with their ob-gyns had favorable perceptions of it. These participants indicated that they would choose a formulation based on individual preferences, which were largely shaped by perceived ease of use, acceptability, and prior experience with other medication regimens.ConclusionObstetrician-gynecologists may play an important role in increasing pregnant individuals' knowledge of and access to PrEP during pregnancy among those who are at risk of HIV acquisition. To maximize uptake and adherence during this time, PrEP formulations should be tailored to individual preferences. Prevention of HIV during this critical life transition is important not only for the long-term health and well-being of pregnant individuals and their infants, but to the plan to end the HIV epidemic in the United States by 2030.
| S-EPMC9627543 | biostudies-literature
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.
| S-EPMC4705855 | biostudies-other
Project description:Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection.We 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.Of 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.None 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