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. 2016 Jan 15;213(2):250-6.
doi: 10.1093/infdis/jiv383. Epub 2015 Jul 14.

Phenotype, Genotype, and Drug Resistance in Subtype C HIV-1 Infection

Anne Derache  1 , Carole L Wallis  2 , Saran Vardhanabhuti  3 , John Bartlett  4 , Nagalingeswaran Kumarasamy  5 , David Katzenstein  1
Affiliations

Phenotype, Genotype, and Drug Resistance in Subtype C HIV-1 Infection

Anne Derache et al. J Infect Dis. .

Abstract

Background: Virologic failure in subtype C is characterized by high resistance to first-line antiretroviral (ARV) drugs, including efavirenz, nevirapine, and lamivudine, with nucleoside resistance including type 2 thymidine analog mutations, K65R, a T69del, and M184V. However, genotypic algorithms predicting resistance are mainly based on subtype B viruses and may under- or overestimate drug resistance in non-B subtypes. To explore potential treatment strategies after first-line failure, we compared genotypic and phenotypic susceptibility of subtype C human immunodeficiency virus 1 (HIV-1) following first-line ARV failure.

Methods: AIDS Clinical Trials Group 5230 evaluated patients failing an initial nonnucleoside reverse-transcriptase inhibitor (NNRTI) regimen in Africa and Asia, comparing the genotypic drug resistance and phenotypic profile from the PhenoSense (Monogram). Site-directed mutagenesis studies of K65R and T69del assessed the phenotypic impact of these mutations.

Results: Genotypic algorithms overestimated resistance to etravirine and rilpivirine, misclassifying 28% and 32%, respectively. Despite K65R with the T69del in 9 samples, tenofovir retained activity in >60%. Reversion of the K65R increased susceptibility to tenofovir and other nucleosides, while reversion of the T69del showed increased resistance to zidovudine, with little impact on other NRTI.

Conclusions: Although genotype and phenotype were largely concordant for first-line drugs, estimates of genotypic resistance to etravirine and rilpivirine may misclassify subtype C isolates compared to phenotype.

Keywords: 2nd NNRTI generation; HIV; first-line failure; genotype/phenotype comparison; subtype C.

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Figures

Figure 1.
Figure 1.
Log values of Stanford genotype scores plotted to log values of Monogram phenotypic fold change, illustrating genotypic and phenotypic correlations for ETR (A), RPV (B), and TDF (C). The circled areas indicate samples that were misclassified as genotypically resistant, although they displayed susceptibility to TDF, ETR, and RPV upon phenotyping. Abbreviations: ETR, etravirine; RPV, rilpivirine; TDF, tenofovir.
See this image and copyright information in PMC

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