Abstract
BackgroundHIV-1C has been shown to have a greater risk of virological failure and reduced susceptibility towards boosted protease inhibitors (bPIs), a component of second-line combination antiretroviral therapy (cART) in South Africa. This study entailed an evaluation of HIV-1 drug resistance-associated mutations (RAMs) among minor viral populations through high-throughput sequencing genotypic resistance testing (HTS-GRT) in patients on the South African national second-line cART regimen receiving bPIs.MethodsDuring 2017 and 2018, 67 patient samples were sequenced using high-throughput sequencing (HTS), of which 56 samples were included in the final analysis because the patient’s treatment regimen was available at the time of sampling. All patients were receiving bPIs as part of their cART. Viral RNA was extracted, and complete pol genes were amplified and sequenced using Illumina HiSeq2500, followed by bioinformatics analysis to quantify the RAMs according to the Stanford HIV Drug Resistance Database.ResultsStatistically significantly higher PI RAMs were observed in minor viral quasispecies (25%; 14/56) compared to non-nucleoside reverse transcriptase inhibitors (9%; 5/56; p = 0.042) and integrase inhibitor RAM (4%; 2/56; p = 0.002). The majority of the drug resistance mutations in the minor viral quasispecies were observed in the V82A mutation (n = 13) in protease and K65R (n = 5), K103N (n = 7) and M184V (n = 5) in reverse transcriptase.ConclusionsHTS-GRT improved the identification of PI and reverse transcriptase inhibitor (RTI) RAMs in second-line cART patients from South Africa compared to the conventional GRT with ≥20% used in Sanger-based sequencing. Several RTI RAMs, such as K65R, M184V or K103N and PI RAM V82A, were identified in < 20% of the population. Deep sequencing could be of greater value in detecting acquired resistance mutations early.
Highlights
HIV-1 subtype C (HIV-1C) has been shown to have a greater risk of virological failure and reduced susceptibility towards boosted protease inhibitors, a component of second-line combination antiretroviral therapy in South Africa
The Nucleoside reverse transcriptase inhibitors (NRTI), Non-nucleoside reverse transcriptase inhibitors (NNRTI) and Integrase inhibitors (INI) Resistance-associated mutations (RAM) were observed among 25% (14/56), 57% (32/56), 50% (28/56) and 7% (4/56), respectively
Significantly higher protease inhibitor (PI) RAMs (25%; 14/56) were observed only in the minor viral quasispecies compared to NNRTI (9%; 5/56; p = 0.042) and INI RAM (4%; 2/56; p = 0.002)
Summary
HIV-1C has been shown to have a greater risk of virological failure and reduced susceptibility towards boosted protease inhibitors (bPIs), a component of second-line combination antiretroviral therapy (cART) in South Africa. Increased identification of pre-treatment minority drug resistance mutations (DRMs) compared to Sanger-based sequencing genotypic resistance testing (GRT) was reported from both resource-rich and resource-limited settings [2, 3]. The role of minority drug-resistant variants and their clinical consequences in the failure of combination antiretroviral therapy (cART) is debatable [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. Data on acquired minority mutations on treatment-failure patients are limited
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