HIV-1 antiretroviral drug resistance patterns in patients failing NNRTI-based treatment: results from a national survey in South Africa

Steegen, Kim; Bronze, Michelle; Papathanasopoulos, Maria A.; Zyl, Gert van; Goedhals, Dominique; Variava, Ebrahim; Macleod, W. Bentley; Sanne, Ian; Stevens, Wendy; Carmona, Sergio

doi:10.1093/jac/dkw358

Cited by 41 publications

(47 citation statements)

References 36 publications

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“…The K103N mutation occurred at a higher frequency in patients receiving AZT plus 3TC or ABC plus 3TC than in those receiving TDF plus 3TC, and 3TC plus d4T. The high rate of K103N RAM is also well documented and has been observed in several previous studies − ( Bronze et al, 2012;Steegen et al, 2017). The group receiving AZT plus 3TC or ABC plus 3TC showed the highest rates of NNRTI mutations such as P225H, V106M, E138A/G/K/Q, G190A/S, and Y188L occurred most frequently in patients receiving AZT plus 3TC or ABC plus 3TC.…”

Section: Discussionsupporting

confidence: 55%

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

et al. 2020

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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

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Section: Discussionsupporting

confidence: 55%

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

et al. 2020

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“…The prevalence of RPV-resistant isolates ranges from 4 to 10% in individuals who are treatment naive (26)(27)(28)(29)(30)(31)(32)(33) to 42 to 72% in individuals with viremia during non-RPVcontaining ART (34)(35)(36)(37)(38)(39)(40)(41). Three clinical studies evaluated the efficacy of RPV-containing regimens compared to EFV-containing regimens in treatment-naive individuals (the ECHO, THRIVE, and STaR trials), all of which identified multiple RPV-associated resistance mutations that arose in subjects on RPV-containing ART (42,43).…”

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confidence: 99%

Long-Acting Rilpivirine (RPV) Preexposure Prophylaxis Does Not Inhibit Vaginal Transmission of RPV-Resistant HIV-1 or Select for High-Frequency Drug Resistance in Humanized Mice

Melody

Roy

Kline

et al. 2020

J Virol

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As a long-acting formulation of the nonnucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as preexposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice. Vaginal challenges of wild-type (WT), Y181C, and Y181V HIV-1 were performed in mice left untreated or after RPV PrEP. Plasma viremia was measured for 7 to 10 weeks, and single-genome sequencing was performed on plasma HIV-1 RNA in mice infected during PrEP. RPV LA significantly prevented vaginal transmission of WT HIV-1 and Y181C HIV-1, which is 3-fold resistant to RPV. However, it did not prevent transmission of Y181V HIV-1, which has 30-fold RPV resistance in the viruses used for this study. RPV LA did delay WT HIV-1 dissemination in infected animals until genital and plasma RPV concentrations waned. Animals that became infected despite RPV LA PrEP did not acquire new RPV-resistant mutations above frequencies in untreated mice or untreated people living with HIV-1, and the mutations detected conferred low-level resistance. These data suggest that high, sustained concentrations of RPV were required to inhibit vaginal transmission of HIV-1 with little or no resistance to RPV but could not inhibit virus with high resistance. HIV-1 did not develop high-level or high-frequency RPV resistance in the majority of mice infected after RPV LA treatment. However, the impact of low-frequency RPV resistance on virologic outcome during subsequent antiretroviral therapy still is unclear. IMPORTANCE The antiretroviral drug rilpivirine was developed into a long-acting formulation (RPV LA) to improve adherence for preexposure prophylaxis (PrEP) to prevent HIV-1 transmission. A concern is that RPV LA will not inhibit transmission of drug-resistant HIV-1 and may select for drug-resistant virus. In female humanized mice, we found that RPV LA inhibited vaginal transmission of WT or 3-fold RPV-resistant HIV-1 but not virus with 30-fold RPV resistance. In animals that became infected despite RPV LA PrEP, WT HIV-1 dissemination was delayed until genital and plasma RPV concentrations waned. RPV resistance was detected at similar low frequencies in untreated and PrEP-treated mice that became infected. These results indicate the importance of maintaining RPV at a sustained threshold after virus exposure to prevent dissemination of HIV-1 after vaginal infection and low-frequency resistance mutations conferred low-level resistance, suggesting that RPV resistance is difficult to develop after HIV-1 infection during RPV LA PrEP.

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“…MJ4 expression vector was used as a wild-type control. Virus inocula were standardized to produce a luminescence of 1×10 4 to 1×10 5 relative light units (RLU) after 48 h of incubation with HEK293T cells in drug-free medium. The fold-change (FC) difference in inhibitory concentration-50 (IC 50 ) relative to the wild-type control was calculated for each patient-derived pseudovirus.…”

Section: Phenotypic Drug Susceptibility Analysismentioning

confidence: 99%

“…After two consecutive VL tests >1,000 copies/ml, patients were switched to a protease inhibitor (PI)-based second-line regimen. Patients failing an NNRTI-based first-line regimen with genotypic drug resistance mutations typically present with M184V/I, K65R, and/or thymidine analogue mutations (TAMs) and K103N, V106M/A and/or Y181C as the most prevalent NRTI and NNRTI mutations, respectively [5]. However, several studies have observed that 16%-71% of patients with viral breakthrough are able to re-suppress on the same NNRTI-based regimen after adherence intensification [6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

HIV-1 re-suppression on a first-line regimen despite the presence of phenotypic drug resistance

et al. 2020

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We have previously reported on HIV-1 infected patients who fail anti-retroviral therapy but manage to re-suppress without a regimen change despite harbouring major drug resistance mutations. Here we explore phenotypic drug resistance in such patients in order to better understand this phenomenon. Patients (n = 71) failing a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, but who subsequently re-suppressed on the same regimen, were assessed for HIV-1 genotypic drug resistance through Sanger sequencing. A subset (n = 23) of these samples, as well as genotypically matched samples from patients who did not re-suppress (n = 19), were further assessed for phenotypic drug resistance in an in vitro single cycle assay. Half of the patients (n = 36/71, 51%) harboured genotypic drug resistance, with M184V (n = 18/36, 50%) and K103N (n = 16/36, 44%) being the most prevalent mutations. No significant difference in the median time to re-suppression (31-39 weeks) were observed for either group (p = 0.41). However, re-suppressors with mutant virus rebounded significantly earlier than those with wild-type virus (16 vs. 33 weeks; p = 0.014). Similar phenotypic drug resistance profiles were observed between patients who re-suppressed and patients who failed to re-suppress. While most remained susceptible to stavudine (d4T) and zidovudine (AZT), both groups showed a reduced susceptibility to 3TC and NNRTIs. HIV-1 infected patients on an NNRTI-based regimen can achieve viral re-suppression on the same regimen despite harbouring viruses with genotypic and phenotypic drug resistance. However, re-suppression was less durable in those with resistance, reinforcing the importance of appropriate regimen choices, ongoing viral load monitoring and adherence counselling.

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HIV-1 antiretroviral drug resistance patterns in patients failing NNRTI-based treatment: results from a national survey in South Africa

Cited by 41 publications

References 36 publications

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

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

Long-Acting Rilpivirine (RPV) Preexposure Prophylaxis Does Not Inhibit Vaginal Transmission of RPV-Resistant HIV-1 or Select for High-Frequency Drug Resistance in Humanized Mice

HIV-1 re-suppression on a first-line regimen despite the presence of phenotypic drug resistance

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