Patterns of drug resistance mutations after failure of first-line NNRTI-based antiretroviral therapy in Western India

Background: Until 2019, first-line antiretroviral therapy (ART) in Southern Africa consisted of one non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTI). As a response to the increasing level of NNRTI resistance, these drugs are being replaced by dolutegravir (DTG), an integrase inhibitor with a high barrier to resistance. Patients failing an NNRTI-based regimen might therefore start DTG-based therapy with preexisting NRTI resistance, potentially jeopardizing the long-term success of DTG-based ART. We performed a systematic review and meta-analysis to quantify the prevalence of NRTI drug resistance mutations (DRMs) in patients failing NNRTI-based ART in Southern Africa. Methods: We searched several bibliographic databases, including Embase and Medline, from inception to May 2019 to identify studies reporting NRTI DRMs observed among adult HIV-positive patients experiencing virological failure on first-line NNRTI-based regimens in countries of Southern Africa. After screening titles and abstracts, two independent reviewers assessed full manuscripts of potentially eligible studies and extracted data. We developed a hierarchical logistic meta-regression model to synthesize the effect of different ART regimen on the emergence of NRTI and NNRTI DRMs across studies, accounting for ART duration and study-specific effects. Analyses were performed in a Bayesian framework using the rstan package in R.Results: Of 7,579 studies, 3,247 were duplicates and 4,135 were excluded after initial screening. After assessing 194 full-texts, we included 15 studies with 17 study samples and 2,432 individuals from South Africa (13 studies), Mozambique (1), Botswana (1), Lesotho (1) and Zambia (1). We analyzed the dynamics of nine NRTI DRMs by ART regimen. Baseline levels of DRMs were low, ranging from 0.2% to 7.8%. The use of emtricitabine/lamivudine was associated with development of high levels of the M184V/I mutation (1.2% at baseline vs. 64% after 3 years on treatment). When emtricitabine/lamivudine was combined with tenofovir disoproxil fumarate, a substantial increase in the K65R mutation (0.8% at baseline vs. 69.5% after 3 years) was observed. We also analyzed the dynamics of seven NNRTI DRMs after 3 years. With a prevalence of 45.6% after 3 years of efavirenz, K103 was the most prevalent NNRTI resistance mutation, followed by V106 (35.5% after 3 years of efavirenz) and Y181 (14.7% after 3 years of nevirapine).Interpretation: In patients failing first-line ART in Southern Africa, the prevalence of NRTI DRM is high, suggesting that a substantial proportion of patients failing NNRTI-based regimen will switch to DTG-based regimen with non-working NRTIs. This could potentially impair the long-term efficacy of DTG-introduction in Southern Africa.

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HIV Drug Resistance Mutations Detection by Next-Generation Sequencing during Antiretroviral Therapy Interruption in China

Pathogens ◽

10.3390/pathogens10030264 ◽

2021 ◽

Vol 10 (3) ◽

pp. 264

Author(s):

Miaomiao Li ◽

Shujia Liang ◽

Chao Zhou ◽

Min Chen ◽

Shu Liang ◽

...

Keyword(s):

Drug Resistance ◽

Next Generation Sequencing ◽

Antiretroviral Therapy ◽

Detection Threshold ◽

Next Generation ◽

Resistance Mutations ◽

Hiv Drug Resistance ◽

Drug Resistance Mutations ◽

Therapy Interruption ◽

Generation Sequencing

Patients with antiretroviral therapy interruption have a high risk of virological failure when re-initiating antiretroviral therapy (ART), especially those with HIV drug resistance. Next-generation sequencing may provide close scrutiny on their minority drug resistance variant. A cross-sectional study was conducted in patients with ART interruption in five regions in China in 2016. Through Sanger and next-generation sequencing in parallel, HIV drug resistance was genotyped on their plasma samples. Rates of HIV drug resistance were compared by the McNemar tests. In total, 174 patients were included in this study, with a median 12 (interquartile range (IQR), 6–24) months of ART interruption. Most (86.2%) of them had received efavirenz (EFV)/nevirapine (NVP)-based first-line therapy for a median 16 (IQR, 7–26) months before ART interruption. Sixty-one (35.1%) patients had CRF07_BC HIV-1 strains, 58 (33.3%) CRF08_BC and 35 (20.1%) CRF01_AE. Thirty-four (19.5%) of the 174 patients were detected to harbor HIV drug-resistant variants on Sanger sequencing. Thirty-six (20.7%), 37 (21.3%), 42 (24.1%), 79 (45.4%) and 139 (79.9) patients were identified to have HIV drug resistance by next-generation sequencing at 20% (v.s. Sanger, p = 0.317), 10% (v.s. Sanger, p = 0.180), 5% (v.s. Sanger, p = 0.011), 2% (v.s. Sanger, p < 0.001) and 1% (v.s. Sanger, p < 0.001) of detection thresholds, respectively. K65R was the most common minority mutation, of 95.1% (58/61) and 93.1% (54/58) in CRF07_BC and CRF08_BC, respectively, when compared with 5.7% (2/35) in CRF01_AE (p < 0.001). In 49 patients that followed-up a median 10 months later, HIV drug resistance mutations at >20% frequency such as K103N, M184VI and P225H still existed, but with decreased frequencies. The prevalence of HIV drug resistance in ART interruption was higher than 15% in the survey. Next-generation sequencing was able to detect more minority drug resistance variants than Sanger. There was a sharp increase in minority drug resistance variants when the detection threshold was below 5%.

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