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Title: HIV-1 transmission linkage in an HIV-1 prevention clinical trial

Abstract

HIV-1 sequencing has been used extensively in epidemiologic and forensic studies to investigate patterns of HIV-1 transmission. However, the criteria for establishing genetic linkage between HIV-1 strains in HIV-1 prevention trials have not been formalized. The Partners in Prevention HSV/HIV Transmission Study (ClinicaITrials.gov NCT00194519) enrolled 3408 HIV-1 serodiscordant heterosexual African couples to determine the efficacy of genital herpes suppression with acyclovir in reducing HIV-1 transmission. The trial analysis required laboratory confirmation of HIV-1 linkage between enrolled partners in couples in which seroconversion occurred. Here we describe the process and results from HIV-1 sequencing studies used to perform transmission linkage determination in this clinical trial. Consensus Sanger sequencing of env (C2-V3-C3) and gag (p17-p24) genes was performed on plasma HIV-1 RNA from both partners within 3 months of seroconversion; env single molecule or pyrosequencing was also performed in some cases. For linkage, we required monophyletic clustering between HIV-1 sequences in the transmitting and seroconverting partners, and developed a Bayesian algorithm using genetic distances to evaluate the posterior probability of linkage of participants sequences. Adjudicators classified transmissions as linked, unlinked, or indeterminate. Among 151 seroconversion events, we found 108 (71.5%) linked, 40 (26.5%) unlinked, and 3 (2.0%) to have indeterminate transmissions. Ninemore » (8.3%) were linked by consensus gag sequencing only and 8 (7.4%) required deep sequencing of env. In this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner, illustrating the relevance of these methods in the design of future HIV-1 prevention trials in serodiscordant couples. A hierarchy of sequencing techniques, analysis methods, and expert adjudication contributed to the linkage determination process.« less

Authors:
 [1];  [2];  [2];  [2];  [2];  [2];  [2]
  1. Los Alamos National Laboratory
  2. UNIV OF WASHINGTON
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
971651
Report Number(s):
LA-UR-09-06451; LA-UR-09-6451
TRN: US201004%%234
DOE Contract Number:  
AC52-06NA25396
Resource Type:
Journal Article
Journal Name:
PLOS Medicine
Additional Journal Information:
Journal Name: PLOS Medicine
Country of Publication:
United States
Language:
English
Subject:
59; ALGORITHMS; CLINICAL TRIALS; DESIGN; GENES; GENETICS; PLASMA; PROBABILITY; RNA; STRAINS

Citation Formats

Leitner, Thomas, Campbell, Mary S, Mullins, James I, Hughes, James P, Wong, Kim G, Raugi, Dana N, and Scrensen, Stefanie. HIV-1 transmission linkage in an HIV-1 prevention clinical trial. United States: N. p., 2009. Web.
Leitner, Thomas, Campbell, Mary S, Mullins, James I, Hughes, James P, Wong, Kim G, Raugi, Dana N, & Scrensen, Stefanie. HIV-1 transmission linkage in an HIV-1 prevention clinical trial. United States.
Leitner, Thomas, Campbell, Mary S, Mullins, James I, Hughes, James P, Wong, Kim G, Raugi, Dana N, and Scrensen, Stefanie. Thu . "HIV-1 transmission linkage in an HIV-1 prevention clinical trial". United States. https://www.osti.gov/servlets/purl/971651.
@article{osti_971651,
title = {HIV-1 transmission linkage in an HIV-1 prevention clinical trial},
author = {Leitner, Thomas and Campbell, Mary S and Mullins, James I and Hughes, James P and Wong, Kim G and Raugi, Dana N and Scrensen, Stefanie},
abstractNote = {HIV-1 sequencing has been used extensively in epidemiologic and forensic studies to investigate patterns of HIV-1 transmission. However, the criteria for establishing genetic linkage between HIV-1 strains in HIV-1 prevention trials have not been formalized. The Partners in Prevention HSV/HIV Transmission Study (ClinicaITrials.gov NCT00194519) enrolled 3408 HIV-1 serodiscordant heterosexual African couples to determine the efficacy of genital herpes suppression with acyclovir in reducing HIV-1 transmission. The trial analysis required laboratory confirmation of HIV-1 linkage between enrolled partners in couples in which seroconversion occurred. Here we describe the process and results from HIV-1 sequencing studies used to perform transmission linkage determination in this clinical trial. Consensus Sanger sequencing of env (C2-V3-C3) and gag (p17-p24) genes was performed on plasma HIV-1 RNA from both partners within 3 months of seroconversion; env single molecule or pyrosequencing was also performed in some cases. For linkage, we required monophyletic clustering between HIV-1 sequences in the transmitting and seroconverting partners, and developed a Bayesian algorithm using genetic distances to evaluate the posterior probability of linkage of participants sequences. Adjudicators classified transmissions as linked, unlinked, or indeterminate. Among 151 seroconversion events, we found 108 (71.5%) linked, 40 (26.5%) unlinked, and 3 (2.0%) to have indeterminate transmissions. Nine (8.3%) were linked by consensus gag sequencing only and 8 (7.4%) required deep sequencing of env. In this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner, illustrating the relevance of these methods in the design of future HIV-1 prevention trials in serodiscordant couples. A hierarchy of sequencing techniques, analysis methods, and expert adjudication contributed to the linkage determination process.},
doi = {},
journal = {PLOS Medicine},
number = ,
volume = ,
place = {United States},
year = {2009},
month = {1}
}