Suchergebnisse

IntroductionVaginal tenofovir (TFV) 1% gel may reduce incident HIV‐1 and herpes simplex virus 2 infection. Pregnancy may increase risk of HIV acquisition, and incident HIV in pregnancy potentiates perinatal HIV transmission. Our objective was to investigate the safety and pharmacokinetics of seven days of TFV 1% vaginal gel in term and near‐term pregnancy.MethodsNinety‐eight healthy pregnant women, stratified to a term cohort followed by a near‐term cohort, were enrolled into a 2:1 randomized, double‐blinded, placebo‐controlled trial. Women received TFV or placebo gel for seven consecutive days with pharmacokinetic sampling on days 0 and 6. Maternal and cord blood were collected at delivery. Primary end points included laboratory and genital adverse events, adverse pregnancy and neonatal outcomes, and maternal TFV levels.ResultsMost adverse events were grade 1 and none of the grade 3 or 4 adverse events were related to study product. There was no significant difference in safety end points between the two pregnancy cohorts (p=0.18); therefore, their data were combined. Primary safety end point rates were similar for mothers randomized to the TFV gel vs placebo arm (72.7 and 68.8%, p=0.81). The same was true for newborns in the TFV gel vs placebo arms (4.5% vs 6.3%, p=0.66). All women randomized to TFV had quantifiable serum levels within eight hours of dosing, with low overall median (interquartile range) day 0 and day 6 peak values (3.8 (2.0 to 7.0) and 5.8 (2.6 to 9.4) ng/mL, respectively).ConclusionsDaily TFV 1% vaginal gel use in term and near‐term pregnancy appears to be safe and produces low serum drug levels.

IntroductionIn the Microbicide Trial Network MTN‐003 (VOICE) study, a Phase IIB pre‐exposure prophylaxis trial of daily oral or vaginal tenofovir (TFV), product adherence was poor based on pharmacokinetic (PK) drug detection in a random subsample. Here, we sought to compare behavioural and PK measures of adherence and examined correlates of adherence misreporting.MethodsWe included participants with PK and behavioural data from VOICE random subsample. Behavioural assessments included face‐to‐face interviews (FTFI), audio computer‐assisted self‐interviewing (ACASI) and pharmacy‐returned product counts (PC). TFV concentrations <0.31 ng/mL in plasma (oral group) and <8.5 ng/swab in vaginal group were defined as "PK non‐adherent." Logistic regression models were fit to calculate the combined predictive ability of the behavioural measures as summarized by area under the curve (AUC). Baseline characteristics associated with over‐reporting daily product use relative to PK measures was assessed using a Generalized Linear Mixed Model.ResultsIn this random adherence cohort of VOICE participants assigned to active products, (N=472), PK non‐adherence was 69% in the oral group (N=314) and 65% in the vaginal group (N=158). Behaviourally, ≤10% of the cohort reported low/none use with any behavioural measure and accuracy was low (≤43%). None of the regression models had an AUC >0.65 for any single or combined behavioural measures. Significant (p<0.05) correlates of over‐reporting included being very worried about getting HIV and being unmarried for the oral group; whereas for the vaginal group, being somewhat worried about HIV was associated with lower risk of over‐reporting.ConclusionsPK measures indicated similarly low adherence for the oral and vaginal groups. No behavioural measure accurately predicted PK non‐adherence. Accurate real‐time measures to monitor product adherence are urgently needed.Trial registration: ClinicalTrials.gov identifier: NCT00705679

AbstractIntroductionTenofovir‐based oral pre‐exposure prophylaxis is currently approved for HIV prevention; however, adherence in women has been low. A vaginal gel containing tenofovir (TFV) demonstrated partial protection to HIV but protection was not confirmed in additional studies. Vaginal rings offer user‐controlled long‐acting HIV prevention that could overcome adherence and protection challenges. TFV may also help prevent herpes simplex virus type 2 acquisition when delivered intravaginally. We evaluated the pharmacokinetics, safety, adherence and acceptability of a 90‐day TFV ring.MethodsBetween January and June 2019, Microbicide Trials Network (MTN)‐038 enrolled 49 HIV‐negative participants into a phase 1, randomized (2:1) trial comparing a 90‐day ring containing 1.4 grams (g) TFV to a placebo ring. TFV concentrations were quantified in plasma, cervicovaginal fluid (CVF), rectal fluid and cervical tissue, and TFV‐diphosphate (TFV‐DP) in cervical tissue. Used rings were analysed for residual TFV. Safety was assessed by adverse events (AEs); acceptability and adherence by self‐report.ResultsMean age was 29.5; 46 identified as cisgender‐female and three gender non‐conforming. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs in the TFV versus placebo arms (p = 0.41); no grade ≥3 AEs were reported. Geometric mean TFV concentrations increased through day 34 in CVF/rectal fluid and day 59 in plasma, but declined across compartments by day 91. Geometric mean TFV‐DP tissue concentrations exceeded the 1000 fmol/mg target through day 56, but fell to 456 fmol/mg at day 91. Among 32 rings returned at the end of the study, 13 had no or low (<0.1 g) residual TFV. Residual TFV did not differ by socio‐demographics, sexual activity, Nugent Score or vaginal microbiota. Most participants reported being fully adherent to ring use: 85% and 81% in the TFV and placebo arms, respectively (p = 1.00). A majority of participants reported liking the ring (median 8 on a 10‐point Likert scale) and reported a high likelihood of using the ring in the future, if effective (median 9).ConclusionsThe 90‐day TFV ring was well‐tolerated, acceptable and exceeded target cervical tissue concentrations through day 56, but declined thereafter. Additional studies are needed to characterize the higher release from TFV rings in some participants and the optimal duration of use.

AbstractIntroductionVaginal rings are a promising approach to provide a woman‐centred, long‐acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV‐1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three‐month rings with different DPV dosages, compared with the monthly DPV ring.MethodsFrom December 2017 to October 2018, MTN‐036/IPM‐047 enrolled 49 HIV‐negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three‐month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow‐up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model.ResultsThere were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs in the extended duration versus monthly ring arms (p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervical tissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at all times, with no product discontinuations/outages) with no differences between the monthly versus three‐month rings. Most participants found the ring acceptable (median = 8 on 10‐point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms (p = 0.01 and p = 0.15 respectively).ConclusionsThe extended duration DPV rings were well‐tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three‐month DPV rings for HIV prevention.