TY - JOUR
T1 - First-line HIV treatment failures in non-B subtypes and recombinants
T2 - A cross-sectional analysis of multiple populations in Uganda
AU - The Ugandan Drug Resistance Study Team
AU - Poon, Art F.Y.
AU - Ndashimye, Emmanuel
AU - Avino, Mariano
AU - Gibson, Richard
AU - Kityo, Cissy
AU - Kyeyune, Fred
AU - Nankya, Immaculate
AU - Quiñones-Mateu, Miguel E.
AU - ARTS, Eric J.
AU - Paton, Nicholas I.
AU - Walker, Sarah
AU - Hoppe, Anne
AU - de Wit, Tobias F.Rinke
AU - Sigaloff, Kim C.E.
AU - Hamers, Raph
AU - Boender, T. Sonia
AU - Boerma, Ragna S.
AU - Ondoa, Pascale
AU - Nijboer, Marloes
AU - Kroeze, Stefanie
AU - Inzaule, Seth
AU - Mutuluuza, Cissy Kityo
AU - Akanmu, Alani Sulaimon
N1 - Funding Information: This study was supported by grants from the National Institutes of Health (AI49170, AI36219 and AI‑71747), the Case Western Reserve University/ University Hospitals Center for AIDS Research (P30 AI036219), the Canadian Institutes of Health Research (CIHR BOP‑149562, PJT‑155990 and PJT‑156178), and in part by the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI‑131). EN was supported by a Queen Elizabeth II Diamond Jubilee Scholarship (Western University DLI O19375892122). AFYP was supported by a CIHR New Investigator Award (FRN‑130609). Publisher Copyright: © 2019 The Author(s).
PY - 2019/1/22
Y1 - 2019/1/22
N2 - Background: Our understanding of HIV-1 and antiretroviral treatment (ART) is strongly biased towards subtype B, the predominant subtype in North America and western Europe. Efforts to characterize the response to first-line treatments in other HIV-1 subtypes have been hindered by the availability of large study cohorts in resource-limited settings. To maximize our statistical power, we combined HIV-1 sequence and clinical data from every available study population associated with the Joint Clinical Research Centre (JCRC) in Uganda. These records were combined with contemporaneous ART-naive records from Uganda in the Stanford HIVdb database. Methods: Treatment failures were defined by the presence of HIV genotype records with sample collection dates after the ART start dates in the JCRC database. Drug resistances were predicted by the Stanford HIVdb algorithm, and HIV subtype classification and recombination detection was performed with SCUEAL. We used Bayesian network analysis to evaluate associations between drug exposures and subtypes, and binomial regression for associations with recombination. Results: This is the largest database of first-line treatment failures ( $$n=1724$$ n = 1724 ) in Uganda to date, with a predicted statistical power of 80% to detect subtype associations at an odds ratio of $$\ge 1.2$$ ≥ 1.2. In the subset where drug regimen data were available, we observed that use of 3TC was associated with a higher rate of first line treatment failure, whereas regimens containing AZT and TDF were associated with reduced rates of failure. In the complete database, we found limited evidence of associations between HIV-1 subtypes and treatment failure, with the exception of a significantly lower frequency of failures among A/D recombinants that comprised about 7% of the population. First-line treatment failure was significantly associated with reduced numbers of recombination breakpoints across subtypes. Conclusions: Expanding access to first-line ART should confer the anticipated public health benefits in Uganda, despite known differences in the pathogenesis of HIV-1 subtypes. Furthermore, the impact of ART may actually be enhanced by frequent inter-subtype recombination in this region.
AB - Background: Our understanding of HIV-1 and antiretroviral treatment (ART) is strongly biased towards subtype B, the predominant subtype in North America and western Europe. Efforts to characterize the response to first-line treatments in other HIV-1 subtypes have been hindered by the availability of large study cohorts in resource-limited settings. To maximize our statistical power, we combined HIV-1 sequence and clinical data from every available study population associated with the Joint Clinical Research Centre (JCRC) in Uganda. These records were combined with contemporaneous ART-naive records from Uganda in the Stanford HIVdb database. Methods: Treatment failures were defined by the presence of HIV genotype records with sample collection dates after the ART start dates in the JCRC database. Drug resistances were predicted by the Stanford HIVdb algorithm, and HIV subtype classification and recombination detection was performed with SCUEAL. We used Bayesian network analysis to evaluate associations between drug exposures and subtypes, and binomial regression for associations with recombination. Results: This is the largest database of first-line treatment failures ( $$n=1724$$ n = 1724 ) in Uganda to date, with a predicted statistical power of 80% to detect subtype associations at an odds ratio of $$\ge 1.2$$ ≥ 1.2. In the subset where drug regimen data were available, we observed that use of 3TC was associated with a higher rate of first line treatment failure, whereas regimens containing AZT and TDF were associated with reduced rates of failure. In the complete database, we found limited evidence of associations between HIV-1 subtypes and treatment failure, with the exception of a significantly lower frequency of failures among A/D recombinants that comprised about 7% of the population. First-line treatment failure was significantly associated with reduced numbers of recombination breakpoints across subtypes. Conclusions: Expanding access to first-line ART should confer the anticipated public health benefits in Uganda, despite known differences in the pathogenesis of HIV-1 subtypes. Furthermore, the impact of ART may actually be enhanced by frequent inter-subtype recombination in this region.
KW - Drug resistance
KW - HIV-1 subtypes
KW - Recombination
KW - Sub-Saharan Africa
KW - Treatment failure
UR - http://www.scopus.com/inward/record.url?scp=85060270127&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85060270127&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30670037
U2 - https://doi.org/10.1186/s12981-019-0218-2
DO - https://doi.org/10.1186/s12981-019-0218-2
M3 - Article
C2 - 30670037
SN - 1742-6405
VL - 16
JO - AIDS research and therapy
JF - AIDS research and therapy
IS - 1
M1 - 3
ER -