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Introduction: Randomized trials of new agents for HIV pre-exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well-characterized adherence-efficacy relationship for F/TDF to back-calculate the (non-PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a nove PrEP agent and estimate comparative efficacy (to counterfactual bHIV). Methods: The DISCOVER trial (ClinicalTrials.gov: NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non-inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0.47, 95% CI: 0.19 to 1.15). Tenofovir diphosphate (TFV-DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian mode with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV Results: There were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person-years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV-negative controls, 5% of the person-time years had low, 9% had medium and 86% had high TFV-DP levels. A non-informative prior distribution for counterfactual bHIV, combined with the prior for TFV-DP level-efficacy relationship, yielded a posterior counterfactual bHIV of 3.4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1.9 to 5.9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV. Conclusions: Based on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non-PrEP control group in randomized, active-controlled PrEP trials that include a F/TDF-comparator group. Keywords: counterfactual; PrEP; clinical trial design; tenofovir alafenamide; tenofovir disoproxil fumarate; Bayesian inference, 1 | INTRODUCTION HIV pre-exposure prophylaxis (PrEP) with oralemtricitabine and tenofovir disoproxil fumarate (F/TDF) is safe and highly effective for HIV prevention, when taken as directed in diverse at-risk populations [...]

: Introduction: Randomized trials of new agents for HIV pre‐exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well‐characterized adherence‐efficacy relationship for F/TDF to back‐calculate the (non‐PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV). Methods: The DISCOVER trial (ClinicalTrials.gov: NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non‐inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0·47, 95% CI: 0·19 to 1.15). Tenofovir diphosphate (TFV‐DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian model with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV. Results: There were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person‐years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV‐negative controls, 5% of the person‐time years had low, 9% had medium and 86% had high TFV‐DP levels. A non‐informative prior distribution for counterfactual bHIV, combined with the prior for TFV‐DP level‐efficacy relationship, yielded a posterior counterfactual bHIV of 3·4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1·9 to 5·9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV. Conclusions: Based on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non‐PrEP control group in randomized, active‐controlled PrEP trials that include a F/TDF‐comparator group., INTRODUCTION HIV pre‐exposure prophylaxis (PrEP) with oralemtricitabine and tenofovir disoproxil fumarate (F/TDF) is safe and highly effective for HIV prevention, when taken as directed in diverse at‐risk populations with rare [...]

A randomized, open-label, multicenter study was conducted to evaluate the therapeutic switch to a single-tablet formulation of efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF) among virologically suppressed, HIV-1--infected subjects. Eligible subjects on stable antiretroviral therapy (ART) with HIV-1 RNA less than 200 copies per milliliter for 3 months or more were stratified by prior protease inhibitor (PI)- or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy and randomized (2:1) to EFV/FTC/TDF or to stay on their baseline regimen (SBR). Patient-reported measures were quality of life (QOL; SF-36 [version 2]), treatment adherence (visual analogue scale), preference of medication (POM), perceived ease of the regimen for condition (PERC), and a 20-item HIV symptom index. Overall, 203 subjects were randomized to EFV/FTC/TDF and 97 to SBR. Fifty-three percent of subjects had previously received a PI-based regimen; 47% an NNRTI-based therapy. Throughout the study, SF-36 summary scores did not differ significantly from baseline, regardless of previous ART or treatment allocation. Adherence was 96% or more in both groups at baseline and all subsequent study visits. At study conclusion, the EFV/FTC/TDF regimen was considered easier to follow than prior regimens by 97% and 96% of subjects previously receiving PI-based and NNRTI-based therapies, respectively. Overall, 91% of subjects switched to EFV/FTC/TDF indicated a preference over their prior therapy. Switching to EFV/FTC/ TDF was associated with transient worsening/emergence of dizziness and sustained improvements in several other HIV-related symptoms. In conclusion, switching virologically suppressed, HIV-1--infected subjects from PI-based or NNRTI-based regimens to EFV/FTC/TDF was associated with maintained QOL and treatment adherence, and improved ease of use and treatment satisfaction. DOI: 10.1089/apc.2009.0259

The steady-state pharmacokinetics of lopinavir/ritonavir (LPV/r) and tenofovir during multiple-dose administration relative to administration of LPV/r and tenofovir disoproxil fumarate (TDF) is discussed. It was seen that higher tenofovir exposures did not result in any evidence of alterations in the safety profile for TDF and in the pharmacokinetic study.

This was a 36-day, open-label, fixed-sequence, multipledose drug interaction study in 23 healthy subjects to evaluate the effects of multiple doses of tenofovir disoproxil fumarate on the single-dose pharmacokinetics of [...]

Adefovir and tenofovir are nucleotide analogs that undergo renal secretion by the human renal organic anion transporter. The pharmacokinetics of tenofovir and adefovir following the administration of tenofovir disoproxil fumarate [...]