Drug Resistance Mutations Against Protease, Reverse Transcriptase and Integrase Inhibitors in People Living With HIV-1 Receiving Boosted Protease Inhibitors in South Africa

Abstract

The South African national combination antiretroviral therapy (cART) roll-out program started in 2006, with over 4.4 million people accessing treatment since it was first introduced. HIV-1 drug resistance can hamper the success of cART. This study determined the patterns of HIV-1 drug-resistance associated mutations (RAMs) in People Living with HIV-1 (PLHIV-1). Receiving first (for children below 3 years of age) and second-line (for adults) cART regimens in South Africa. During 2017 and 2018, 110 patients plasma samples were selected, 96 samples including those of 17 children and infants were successfully analyzed. All patients were receiving a boosted protease inhibitor (bPI) as part of their cART regimen. The viral sequences were analyzed for RAMs through genotypic resistance testing. We performed genotypic resistance testing (GRT) for Protease inhibitors (PIs), Reverse transcriptase inhibitors (RTIs) and Integrase strand transfer inhibitors (InSTIs). Viral sequences were subtyped using REGAv3 and COMET. Based on the PR/RT sequences, HIV-1 subtypes were classified as 95 (99%) HIV-1 subtype C (HIV-1C) while one sample as 02_AG. Integrase sequencing was successful for 89 sequences, and all the sequences were classified as HIV-1C (99%, 88/89) except one sequence classified CRF02_AG, as observed in PR/RT. Of the 96 PR/RT sequences analyzed, M184V/I (52/96; 54%) had the most frequent RAM nucleoside reverse transcriptase inhibitor (NRTI). The most frequent non-nucleoside reverse transcriptase inhibitor (NNRTI) RAM was K103N/S (40/96, 42%). Protease inhibitor (PI) RAMs M46I and V82A were present in 12 (13%) of the sequences analyzed. Among the InSTI major RAM two (2.2%) sequences have Y143R and T97A mutations

Increased acquired protease inhibitor drug resistance mutations in minor HIV-1 quasispecies from infected patients suspected of failing on national second-line therapy in South Africa

“…Even though there is no indication of the patients being administered RAL, three of the patients in our study harbored Y143R mutation in > 20% of the population. Previous studies on HIV-1C have shown major INI mutations at baseline in less than 5% of patients from Ethiopia (T66I, E138K, Q148R, and Q148H) and South Africa (Q148H, T66S, E92G, S147G, T66A, Y143YF and Y143H) [3,5,14]. However, the presence of INI RAMs in minor viral population is deemed not to have any clinical consequences [28].…”

“…Plasma samples were obtained from bPIs suspected of failing patients (as referred by the clinician) from the diagnostic section at the Division of Medical Virology, Stellenbosch University, and the South African National Health Laboratory Services (NHLS), and were collected between March 2017 and February 2018 [5,18]. We excluded patient samples with no previous cART regimen history and patients receiving rstline cART treatment regimens.…”

“…Studies have shown that even in adherent patients, those with pre-existing Y181C mutants have a triple higher risk of virological failure on an efavirenz-based cART regimen [4]. Several studies have shown that minority pre-treatment drug resistance was associated with reduced treatment e cacy for rst-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs), but not for rilpivirine and integrase inhibitors (INIs) [3,5,6]. In contrast, other studies have indicated that in a population with a relatively low prevalence of DRM, the use of deep sequencing to detect minority HIV-1 DRM has limited clinical bene t [7].…”

“…The recommended second-line cART consists of the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine or tenofovir and lamivudine and a ritonavir-boosted (/r) protease inhibitor (PI), usually lopinavir (LPV/r) [9,10]. Earlier study from Sweden and South Africa reported that despite good adherence, there is an increased risk of virological failure in patients with HIV-1C on bPI-based regimens [5,11]. Ex vivo and in vitro experiments also indicated large variations in susceptibility of HIV-1C viruses in the absence of PI resistance-associated mutations (RAMs) [12].…”

Interaction Analysis of Statistically Enriched Mutations Identified in Cameroon Recombinant Subtype CRF02_AG that can Influence the Development of Dolutegravir Drug Resistance Mutations

“…It is well known that diverse subtypes may affect the clinical treatment outcome in patient management (1). In Cameroon, HIV-1 CRF02_AG continues to be the predominant subtype causing infection, with most other strains, including groups N, O and P, circulating in the country and accounting for a smaller proportion of infections (2,3). Previous studies have shown that different HIV subtypes may support different mutational pathways, and this could lead to subtype-based differences in acquiring drug resistance (4)(5)(6).…”