Research Article: First-line HIV treatment failures in non-B subtypes and recombinants: a cross-sectional analysis of multiple populations in Uganda

Date Published: January 22, 2019

Publisher: BioMed Central

Author(s): Art F. Y. Poon, Emmanuel Ndashimye, Mariano Avino, Richard Gibson, Cissy Kityo, Fred Kyeyune, Immaculate Nankya, Miguel E. Quiñones-Mateu, Eric J. ARTS.

http://doi.org/10.1186/s12981-019-0218-2

Abstract

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.

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.

This is the largest database of first-line treatment failures (documentclass[12pt]{minimal}
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begin{document}$$n=1724$$end{document}n=1724) in Uganda to date, with a predicted statistical power of 80% to detect subtype associations at an odds ratio of documentclass[12pt]{minimal}
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begin{document}$$ge 1.2$$end{document}≥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.

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.

The online version of this article (10.1186/s12981-019-0218-2) contains supplementary material, which is available to authorized users.

Partial Text

East Africa was one of the first regions in the world to experience high rates of HIV infection [1]. In 1990, for instance, some antenatal clinics in Uganda recorded adult HIV prevalences among women exceeding 30% [2]. Currently, the adult prevalence of HIV in Uganda is about 7.1% [3]. Increasing the coverage of combination antiretroviral therapy in Uganda is a crucial public health objective to not only reduce HIV-related morbidity and mortality, but also to prevent the onward transmission of HIV by reducing plasma viral loads [4, 5]. However, the enormous genetic diversity of the HIV-1 subtypes has been a persistent concern for antiretroviral treatment, especially in low- and middle-income countries like Uganda with multiple prevalent subtypes [6]. Antiretroviral drugs have generally been developed and tested on HIV subtype B [7], which is the predominant subtype in North America and western Europe [8]. HIV-1 infections in Uganda are predominated by subtypes A and D [9], with a low frequency of subtype C that is the predominant subtype in southern Africa. In addition, recombinants of subtypes A and D have historically been observed in about 10% to 30% of HIV infections sampled in Uganda [10, 11]. Based on a phylogenetic analysis of dated HIV sequences, subtype A likely migrated into Uganda around the 1950s before subtype D entered about a decade afterwards [12]. To date, subtype A HIV-1 infections are more prevalent in the east and north regions of Uganda, while subtype D dominates in the west and south of this small country [13].

This study represents the largest database of first-line treatment failures in Uganda to date, drawing from every available study cohort associated with the JCRC. In a previous cross-sectional study of a clinical HIV database in Uganda, we reported a statistical association between HIV subtype D infections and treatment failures on second-line and salvage therapies (documentclass[12pt]{minimal}
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begin{document}$$n=843$$end{document}n=843) [33], which are generally associated with higher failure rates than first-line therapies [34]. Furthermore, suboptimal modification of drug regimens in second-line and salvage therapies may allow substantial virus replication to amplify incipient differences among HIV-1 subtypes. In this study, we observed limited evidence for significant variation with respect to genotype susceptibility scores and plasma viral loads among HIV-1 subtypes within the first-line treatment failures. We acknowledge some insurmountable limitations in this retrospective cross-sectional study of all available records of first-line treatment failures in the JCRC databases. For instance, matched baseline and failure samples or duration of treatment were not available for the majority of cases, which would have permitted a longitudinal analysis of these populations. Moreover, our Bayesian network analysis was limited to the documentclass[12pt]{minimal}
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begin{document}$$n=1750$$end{document}n=1750 (42%) records with complete information on drug regimens and sampling region.

 

Source:

http://doi.org/10.1186/s12981-019-0218-2

 

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