Lower pre-ART intra-participant HIV-1 pol diversity may not be associated with virologic failure in adults.

TitleLower pre-ART intra-participant HIV-1 pol diversity may not be associated with virologic failure in adults.
Publication TypeJournal Article
Year of Publication2018
AuthorsKearney MF, Spindler J, Wiegand A, Shao W, Haubrich R, Riddler S, Lalama CM, Hughes MD, Coffin JM, Mellors JW
JournalPLoS One
Volume13
Issue1
Paginatione0190438
Date Published2018
ISSN1932-6203
KeywordsCase-Control Studies, CD4 Lymphocyte Count, Drug Resistance, Viral, Genes, pol, Genetic Variation, HIV Infections, HIV-1, Humans, Polymerase Chain Reaction, Viral Load
Abstract

BACKGROUND: Identifying pre-ART factors associated with the emergence of HIV-1 drug resistance is critical for optimizing strategies to prevent virologic failure. A previous study reported that lower pre-ART HIV-1 pol diversity was associated with higher risk of virologic failure in HIV-1-infected children. To investigate this association in adults, we measured HIV-1 diversity with deep sequencing in pre-ART samples from adults with well-characterized virologic outcomes in a study (A5142) of initial ART conducted by the AIDS Clinical Trials Group (ACTG).

METHODS: We identified 22 cases in ACTG A5142 who experienced virologic failure with drug resistance mutations in RT and 44 matched controls who did not experience virologic failure. cDNA was synthesized from plasma HIV-1 RNA. Each cDNA molecule was tagged with a unique primer ID and RT codons 41-103 were amplified and deep sequenced. Sequences with the same tag were aligned and a consensus was generated to reduce PCR and sequencing errors. Diversity was calculated by measuring average pairwise distance (APD) of the consensus sequences. An exact conditional logistic regression model with percent APD as the risk factor estimated the odds ratio for VF and the corresponding 95% confidence interval.

RESULTS: Consensus single-genome sequences and diversity estimates of pol were obtained for pre-ART samples from 21 cases and 42 controls. The median (IQR) pre-ART percent APD was 0.71 (0.31-1.13) in cases and 0.58 (0.32-0.94) in controls. A possible trend was found for higher diversity being associated with greater risk of virologic failure in adults (OR = 2.2 per one percent APD increase, 95% CI = [0.8, 7.2]; p = 0.15).

CONCLUSIONS: This study in adults suggests there is a positive association between higher pre-ART pol diversity and the risk of virologic failure in adults rather than an inverse relationship reported in children.

DOI10.1371/journal.pone.0190438
Alternate JournalPLoS ONE
PubMed ID29370196
PubMed Central IDPMC5784902
Grant ListUM1 AI069494 / AI / NIAID NIH HHS / United States
R35 CA200421 / CA / NCI NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States
UM1AI106701 / NH / NIH HHS / United States
U01 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States