Bayesian estimation of HIV acquisition dates for prevention trials

Accurate timing estimates of when participants acquire HIV in HIV prevention trials are necessary for determining antibody levels at acquisition. The Antibody-Mediated Prevention (AMP) Studies showed that a passively administered broadly neutralizing antibody can prevent the acquisition of HIV from a neutralization-sensitive virus. We developed a pipeline for estimating the date of detectable HIV acquisition (DDA) in AMP Study participants using diagnostic and viral sequence data. Using a Bayesian strategy that combines three streams of data (REN [rev/vpu/env/Δnef] sequence, GP [gag/Δpol] sequence, and diagnostic) where their 95% credible intervals overlap based on pre-specified criteria and decision rules. We evaluated the performance of our AMP pipeline using PacBio viral sequence data from 41 participants across two prospective acute HIV acquisition cohort studies, FRESH and RV217, with twice-weekly sampling. These cohort studies enrolled young women in South Africa and men and women in Kenya and Thailand, respectively, with a high likelihood of HIV acquisition. In evaluating performance, "true DDA" was the center of bounds between last-negative and first-positive RNA diagnostic tests (median time 4 days, range 2-7 days); bias was the mean difference between estimated and true DDA. Using diagnostic data alone yielded timing estimates with a bias of 2.4 days and root mean square error (RMSE) of 7.9 days. These results were improved using sequence + diagnostic data (bias 1.5 days, RMSE 6.9 days), as well as by restricting sequence-based estimation to samples from ≤5 weeks post-DDA (bias 0.2 days, RMSE 7.8 days).IMPORTANCEIn HIV prevention trials, accurate timing estimates of when individual participants acquire HIV can be used to estimate antibody levels at the time of acquisition, which is useful for projecting antibody levels needed for prevention. The results we report here suggest that if sequence-based estimation of acquisition timing is used in future clinical trials of combination broadly neutralizing antibody (bnAb) regimens or multispecific bnAbs for HIV prevention, a sampling frequency of at least monthly is needed. Moreover, in the samples analyzed here, we observed less bias in sequence-based timing estimation for samples taken <5 weeks post-DDA. This observation is consistent with the timing of immune-driven selective pressures that may negatively impact the power to detect acquisition sieve effects.

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Publication Details

Journal
mBio
Published
2025-09-09
DOI
https://doi.org/10.1128/mbio.01881-25
Citations
2
Primary Topic
HIV Research and Treatment
Type
article
Field-Weighted Citation Impact
2.07
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article

Bayesian estimation of HIV acquisition dates for prevention trials

Kevin P. Delaney, James P. Ludwig, Michal Juraska, Yunda Huang et al.
2 citations
mBio
HIV Research and Treatment
2.07
article

Bayesian estimation of HIV acquisition dates for prevention trials

Kevin P. Delaney, James P. Ludwig, Michal Juraska, Yunda Huang, Kamini Gounder, Anna Yssel, Bruce D. Walker, Raabya Rossenkhan, Bette Korber, Jan Phillipus Lourens Labuschagne, Dylan H. Westfall, Shelley N. Facente, Daniel Muema, Paul T. Edlefsen, Allan C. deCamp, Craig A. Magaret, Wenjie Deng, David Matten, Thumbi Ndung’u, Carolyn E. Williamson, Eduard Grebe, Ewelina Kosmider, Tanmoy Bhattacharya A, Leigh Anne Eller, Fred Sawe, Erika Rudnicki, Lawrence Corey, Bryan T. Mayer, Morgane Rolland, Sorachai Nitayaphan, Merlin L. Robb, Peter B. Gilbert, Lindsay Nicole Carpp, Elena E. Giorgi, Daniel B. Reeves, Krista L. Dong, M. Busch, John Hural, James I. Mullins, Danica Shao
article en
2 citations

Abstract

Accurate timing estimates of when participants acquire HIV in HIV prevention trials are necessary for determining antibody levels at acquisition. The Antibody-Mediated Prevention (AMP) Studies showed that a passively administered broadly neutralizing antibody can prevent the acquisition of HIV from a neutralization-sensitive virus. We developed a pipeline for estimating the date of detectable HIV acquisition (DDA) in AMP Study participants using diagnostic and viral sequence data. Using a Bayesian strategy that combines three streams of data (REN [rev/vpu/env/Δnef] sequence, GP [gag/Δpol] sequence, and diagnostic) where their 95% credible intervals overlap based on pre-specified criteria and decision rules. We evaluated the performance of our AMP pipeline using PacBio viral sequence data from 41 participants across two prospective acute HIV acquisition cohort studies, FRESH and RV217, with twice-weekly sampling. These cohort studies enrolled young women in South Africa and men and women in Kenya and Thailand, respectively, with a high likelihood of HIV acquisition. In evaluating performance, "true DDA" was the center of bounds between last-negative and first-positive RNA diagnostic tests (median time 4 days, range 2-7 days); bias was the mean difference between estimated and true DDA. Using diagnostic data alone yielded timing estimates with a bias of 2.4 days and root mean square error (RMSE) of 7.9 days. These results were improved using sequence + diagnostic data (bias 1.5 days, RMSE 6.9 days), as well as by restricting sequence-based estimation to samples from ≤5 weeks post-DDA (bias 0.2 days, RMSE 7.8 days).IMPORTANCEIn HIV prevention trials, accurate timing estimates of when individual participants acquire HIV can be used to estimate antibody levels at the time of acquisition, which is useful for projecting antibody levels needed for prevention. The results we report here suggest that if sequence-based estimation of acquisition timing is used in future clinical trials of combination broadly neutralizing antibody (bnAb) regimens or multispecific bnAbs for HIV prevention, a sampling frequency of at least monthly is needed. Moreover, in the samples analyzed here, we observed less bias in sequence-based timing estimation for samples taken <5 weeks post-DDA. This observation is consistent with the timing of immune-driven selective pressures that may negatively impact the power to detect acquisition sieve effects.

mBioVol. 16(10)
National Health Laboratory Service (ZA), South African Medical Research Council (ZA), Henry M. Jackson Foundation (US), Santa Fe Institute (US), Virginia Department of Health (US), Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), Infectious Disease Research Institute (US), Los Alamos National Laboratory (US), Howard Hughes Medical Institute (US), University of Cape Town (ZA), University of California, San Francisco (US), University of Washington (US), Stellenbosch University (ZA), Centre for the AIDS Programme of Research in South Africa (ZA), United States Army Medical Research Directorate - Africa (KE), Ragon Institute of MGH, MIT and Harvard (US), Pacific Research Institute (US), Fred Hutch Cancer Center (US), Jackson Foundation (US), New Mexico Consortium (US), Armed Forces Research Institute of Medical Science (TH), National Center for HIV/AIDS Viral Hepatitis STD and TB Prevention (US), Vitalant (US), Africa Health Research Institute (ZA), Wellcome Centre for Infectious Diseases Research in Africa (ZA), Berkeley Public Health Division (US), Institute of Infection and Immunity (CA), University College London (GB), University of San Francisco (US), Walter Reed Army Institute of Research (US), University of California, Berkeley (US)
Openalex Percentile: Top 12%
HIV Research and Treatment
2.07
DOIOpen Access PDFOpenAlex
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