Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2021 May;24(5):e25744.
doi: 10.1002/jia2.25744.

Using the adherence-efficacy relationship of emtricitabine and tenofovir disoproxil fumarate to calculate background hiv incidence: a secondary analysis of a randomized, controlled trial

David V Glidden  1   2 , Moupali Das  3 , David T Dunn  4 , Ramin Ebrahimi  3 , Yongwu Zhao  3 , Oliver T Stirrup  4 , Jared M Baeten  3 , Peter L Anderson  5
Affiliations
Randomized Controlled Trial

Using the adherence-efficacy relationship of emtricitabine and tenofovir disoproxil fumarate to calculate background hiv incidence: a secondary analysis of a randomized, controlled trial

David V Glidden et al. J Int AIDS Soc. 2021 May.

Abstract

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.

Keywords: Bayesian inference; PrEP; clinical trial design; counterfactual; tenofovir alafenamide; tenofovir disoproxil fumarate.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Bayesian estimates of posterior efficacy distributions for F/TAF and F/TDF. F/TAF, co‐formulated emtricitabine and tenofovir alafenamide; F/TDF, co‐formulated emtricitabine and tenofovir disoproxil fumarate. F/TAF, co‐formulated emtricitabine and tenofovir alafenamide; F/TDF, co‐formulated emtricitabine and tenofovir disoproxil fumarate.
Figure 2
Figure 2
Estimates of counterfactual bHIV by the adherence‐efficacy method under varying assumptions and corresponding efficacy estimates.
Figure 3
Figure 3
Comparing Counterfactual Estimates of Background Placebo HIV Incidence. *Based on Centers for Disease Control and Prevention (CDC) surveillance data [42]. BL, baseline; F/TAF, co‐formulated emtricitabine and tenofovir alafenamide; F/TDF, co‐formulated emtricitabine and tenofovir disoproxil fumarate.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587–99. - PMC - PubMed
    1. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367:399–410. - PMC - PubMed
    1. Molina JM, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, et al. On‐demand preexposure prophylaxis in men at high risk for HIV‐1 infection. N Engl J Med. 2015;373:2237–46. - PubMed
    1. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Pre‐exposure prophylaxis to prevent the acquisition of HIV‐1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open‐label randomised trial. Lancet. 2016;387:53–60. - PMC - PubMed
    1. Marcus JL, Hurley LB, Hare CB, Nguyen DP, Phengrasamy T, Silverberg MJ, et al. Preexposure prophylaxis for HIV prevention in a large integrated health care system: adherence, renal safety, and discontinuation. J Acquir Immune Defic Syndr. 2016;73:540–6. - PMC - PubMed

Publication types

Associated data