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

Glidden, David V.; Das, Moupali; Dunn, David; Ebrahimi, Ramin; Zhao, Y; Stirrup, Oliver; Baeten, Jared M.; Anderson, Peter L.

doi:10.1002/jia2.25744

Cited by 13 publications

(14 citation statements)

References 37 publications

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“…Importantly, the rigour of clinical trial evaluation largely mitigates the concern of different quality of ascertainment in comparisons based on external studies. This complements other approaches to bridging from placebo data in the same high‐incidence populations [35–38].…”

Section: Discussionmentioning

confidence: 79%

Counterfactual estimation of efficacy against placebo for novel PrEP agents using external trial data: example of injectable cabotegravir and oral PrEP in women

et al. 2023

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Introduction:Multiple antiretroviral agents have demonstrated efficacy for human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP). As a result, clinical trials of novel agents have transitioned from placebo-to active-controlled designs; however, active-controlled trials do not provide an estimate of efficacy versus no use of PrEP. Counterfactual placebo comparisons using other data sources could be employed to provide this information. Methods: We compared the active-controlled study (HPTN 084) of injectable cabotegravir (CAB-LA) versus daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) among women from seven countries in Africa to three external, contemporaneous randomized HIV prevention trials from which we constructed counterfactual placebo estimates. We used direct standardization via analysis weights to achieve the same distribution of person-years between the external study and HPTN 084, across strata predictive of HIV risk (country and selected risk covariates). We estimated prevention efficacy against a counterfactual placebo to provide information on the use of CAB-LA and FTC/TDF compared to no intervention. We compared the counterfactual placebo findings for FTC/TDF to previous placebo-controlled trials, adjusted for observed adherence to daily pills. Results: Distribution of age and baseline prevalence of gonorrhoea and chlamydia were similar among matched counterfactual placebo and observed HPTN 084 arms after standardization. Counterfactual estimates of CAB-LA versus placebo in all three settings showed a consistent risk reduction of 93%-94%, with lower bounds of the confidence intervals above 72%. Observed adherence (quantifiable tenofovir in plasma) in HPTN 084 was 54%-56%, and estimated efficacy of daily oral FTC/TDF against a counterfactual placebo was consistent with a predicted risk reduction of 39%-40% for this level of daily pill use. Conclusions: Counterfactual placebo rates of HIV acquisition derived from external trial data in similar locations and time can be used to support estimates of placebo-based efficacy of a novel HIV prevention agent. External trial data must be standardized to be representative of the clinical trial cohort testing the novel HIV prevention agent, accounting for confounders.

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Section: Discussionmentioning

confidence: 79%

Counterfactual estimation of efficacy against placebo for novel PrEP agents using external trial data: example of injectable cabotegravir and oral PrEP in women

et al. 2023

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“…However, it requires an estimate of background HIV incidence for persons not taking either a proven PrEP product or the trial medication. Previously described approaches for estimating this counterfactual incidence parameter apply a Bayesian approach with estimates from historic research data on emtricitabine/tenofovir disoproxil fumarate effectiveness [ 32 , 45 ] or use the correlation between incidence of rectal gonorrhea and HIV to estimate the number of HIV infections that would have been observed in the absence of PrEP [ 46 ]. However, neither of these approaches makes use of population-based data, and they are therefore subject to bias to the extent that trial participants are dissimilar to persons among whom these assumptions are based.…”

Section: Discussionmentioning

confidence: 99%

“…Alternative trial designs for future HIV prevention products have been the topic of many recent meetings [27][28][29] and publications [25,[30][31][32][33]. One of these alternative approaches is to compare the incidence in those receiving the investigational medication to the incidence in a counterfactual group (ie, a hypothetical contemporary group of persons with similar risk characteristics who would be eligible for the PrEP treatment, but who were not taking PrEP).…”

Section: Introductionmentioning

confidence: 99%

Estimating HIV Incident Diagnoses Among Men Who Have Sex With Men Eligible for Pre-exposure Prophylaxis but Not Taking It: Protocol and Feasibility Assessment of Data Sources and Methods

Sullivan¹,

Hall²,

Bradley³

et al. 2023

JMIR Res Protoc

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Background HIV incidence estimates are published each year for all Ending the HIV Epidemic (EHE) counties, but they are not stratified by the demographic variables highly associated with risk of infection. Regularly updated estimates of HIV incident diagnoses available at local levels are required to monitor the epidemic in the United States over time and could contribute to background incidence rate estimates for alternative clinical trial designs for new HIV prevention products. Objective We describe methods using existing, robust data sources within areas in the United States to reliably estimate longitudinal HIV incident diagnoses stratified by race and age categories among men who have sex with other men (MSM) eligible for pre-exposure prophylaxis (PrEP) but not taking it. Methods This is a secondary analysis of existing data sources to develop new estimates of incident HIV diagnoses in MSM. We reviewed past methods used to estimate incident diagnoses and explored opportunities to improve these estimates. We will use existing surveillance data sources and population sizes of HIV PrEP-eligible MSM estimated from population-based data sources (eg, US Census data and pharmaceutical prescription databases) to develop metropolitan statistical area–level estimates of new HIV diagnoses among PrEP-eligible MSM. Required parameters are number of new diagnoses among MSM, estimates of MSM with an indication for PrEP, and prevalent PrEP use including median duration of use; these parameters will be stratified by jurisdiction and age group or race or ethnicity. Preliminary outputs will be available in 2023, and updated estimates will be produced annually thereafter. Results Data to parameterize new HIV diagnoses among PrEP-eligible MSM are available with varying levels of public availability and timeliness. In early 2023, the most recent available data on new HIV diagnoses were from the 2020 HIV surveillance report, which reports 30,689 new HIV infections in 2020, and 24,724 of them occurred in an MSA with a population of ≥500,000. Updated estimates for PrEP coverage based on commercial pharmacy claims data through February 2023 will be generated. The rate of new HIV diagnoses among MSM can be estimated from new diagnoses within each demographic group (numerator) and the total person-time at risk of diagnosis for each group (denominator) by metropolitan statistical area and year. To estimate time at risk, the person-time of individuals on PrEP or person-time after incident HIV infection but before diagnosis should be removed from stratified population size estimates of the total number of person-years with indications for PrEP. Conclusions Reliable, serial, cross-sectional estimates for rates of new HIV diagnoses for MSM with PrEP indications can serve as benchmark community estimates of failures of HIV prevention and opportunities to improve services and will support public health epidemic monitoring and alternative clinical trial designs. International Registered Report Identifier (IRRID) DERR1-10.2196/42267

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“…Conversely, high adherence to PrEP translates to high efficacy. In trials such as iPrEX, its open-label extension (iPrEX OLE), and the Partners Demonstration Project, PrEP with FTC/TDF successfully prevented HIV infection in up to 100% of participants if taken at least four times a week [ 6 , 32 – 34 ].…”

Section: Efficacy Of Ftc/taf and Ftc/tdfmentioning

confidence: 99%

Clinical Considerations in the Selection of Preexposure Prophylaxis for HIV Prevention in Canada

Knox

Pilarski

Dhunna

et al. 2022

Canadian Journal of Infectious Diseases and Medical Microbiolog

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According to the Public Health Agency of Canada, approximately 62,050 people were living with HIV in Canada in 2018, and of those, 13% were undiagnosed. Currently, no single strategy provides complete protection or is universally effective across all demographic groups at risk for HIV. However, HIV preexposure prophylaxis (PrEP) is the newest HIV prevention strategy that shows promise. To date, two products have received an indication for PrEP by Health Canada: emtricitabine/tenofovir disoproxil fumarate (Truvada®; FTC/TDF) and emtricitabine/tenofovir alafenamide (Descovy®; FTC/TAF). Despite the high efficacy of these PrEP intervention methods, access to PrEP in Canada remains low. Identifying and addressing barriers to PrEP access, especially in high-risk groups, are necessary to reduce HIV transmission in Canada. While guidelines published by the Center for Disease Control and Prevention (CDC) include FTC/TAF information, the efficacy of FTC/TAF for PrEP has not yet been considered in Canada’s clinical practice guidelines. Thus, the current paper reviews data regarding the use of FTC/TDF and FTC/TAF for PrEP, which may be useful for Canadian healthcare providers when counseling and implementing HIV prevention methods. The authors highlight these data in relation to various at-risk populations and review ongoing clinical trials investigating novel PrEP agents. Overall, FTC/TDF PrEP is effective for many populations, including men who have sex with men, transgender women, heterosexuals with partners living with HIV, and people who use drugs. While there is fewer data reported on the efficacy of FTC/TAF to date, recent clinical trials have demonstrated noninferiority of FTC/TAF in comparison to FTC/TDF. Notably, as studies have shown that FTC/TAF maintains renal function and bone mineral density to a greater extent than FTC/TDF, FTC/TAF may be a safer option for patients experiencing renal and/or bone dysfunction, for those at risk of renal and bone complications, and for those who develop FTC/TDF-related adverse events.

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

Cited by 13 publications

References 37 publications

Counterfactual estimation of efficacy against placebo for novel PrEP agents using external trial data: example of injectable cabotegravir and oral PrEP in women

Counterfactual estimation of efficacy against placebo for novel PrEP agents using external trial data: example of injectable cabotegravir and oral PrEP in women

Estimating HIV Incident Diagnoses Among Men Who Have Sex With Men Eligible for Pre-exposure Prophylaxis but Not Taking It: Protocol and Feasibility Assessment of Data Sources and Methods

Clinical Considerations in the Selection of Preexposure Prophylaxis for HIV Prevention in Canada

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