HIV Drug Resistance Mutations in Non-B Subtypes After Prolonged Virological Failure on NNRTI-Based First-Line Regimens in Sub-Saharan Africa

Antimalarial resistance surveillance in sub-Saharan Africa is often constrained by logistical and financial challenges limiting its breadth and frequency. At two sites in Ghana, we have piloted a streamlined sample pooling process created immediately by sequential addition of positive malaria cases at the time of diagnostic testing. This streamlined process involving a single tube minimized clinical and laboratory work and provided accurate frequencies of all known drug resistance mutations after high-throughput targeted sequencing using molecular inversion probes. Our study validates this method as a cost-efficient, accurate and highly-scalable approach for drug resistance mutation monitoring that can potentially be applied to other infectious diseases such as tuberculosis.

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Prevalence and Evolution of Low Frequency HIV Drug Resistance Mutations Detected by Ultra Deep Sequencing in Patients Experiencing First Line Antiretroviral Therapy Failure

PLoS ONE ◽

10.1371/journal.pone.0086771 ◽

2014 ◽

Vol 9 (1) ◽

pp. e86771 ◽

Cited By ~ 31

Author(s):

Marie-Anne Vandenhende ◽

Pantxika Bellecave ◽

Patricia Recordon-Pinson ◽

Sandrine Reigadas ◽

Yannick Bidet ◽

...

Keyword(s):

Drug Resistance ◽

Antiretroviral Therapy ◽

Deep Sequencing ◽

Low Frequency ◽

Resistance Mutations ◽

Therapy Failure ◽

First Line ◽

Hiv Drug Resistance ◽

Drug Resistance Mutations

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Scale-up of antiretroviral treatment in sub-Saharan Africa is accompanied by increasing HIV-1 drug resistance mutations in drug-naive patients

AIDS ◽

10.1097/qad.0b013e32834bbbe9 ◽

2011 ◽

Vol 25 (17) ◽

pp. 2183-2188 ◽

Cited By ~ 50

Author(s):

Avelin F. Aghokeng ◽

Charles Kouanfack ◽

Christian Laurent ◽

Eugenie Ebong ◽

Arrah Atem-Tambe ◽

...

Keyword(s):

Drug Resistance ◽

Antiretroviral Treatment ◽

Scale Up ◽

Sub Saharan Africa ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Drug Naïve ◽

Sub Saharan ◽

Hiv 1

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Accumulation of HIV Drug Resistance Mutations in Patients Failing First-Line Antiretroviral Treatment in South Africa

AIDS Research and Human Retroviruses ◽

10.1089/aid.2011.0136 ◽

2012 ◽

Vol 28 (2) ◽

pp. 171-175 ◽

Cited By ~ 51

Author(s):

Kim C.E. Sigaloff ◽

Tina Ramatsebe ◽

Raquel Viana ◽

Tobias F. Rinke de Wit ◽

Carole L. Wallis ◽

...

Keyword(s):

South Africa ◽

Drug Resistance ◽

Antiretroviral Treatment ◽

Resistance Mutations ◽

First Line ◽

Hiv Drug Resistance ◽

Drug Resistance Mutations

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An apparent paradox: resistance mutations in HIV-1 DNA predict improved virological responses to antiretroviral therapy

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz264 ◽

2019 ◽

Vol 74 (10) ◽

pp. 3011-3015 ◽

Cited By ~ 1

Author(s):

Anna Maria Geretti ◽

Adam Abdullahi ◽

Olga Mafotsing Fopoussi ◽

Laura Bonnett ◽

Victoire Fokom Defo ◽

...

Keyword(s):

Viral Load ◽

Virological Failure ◽

Dna Sequences ◽

Sub Saharan Africa ◽

Resistance Mutations ◽

First Line ◽

Second Line Therapy ◽

Apparent Paradox ◽

Sub Saharan ◽

Hiv 1

Abstract Background In sub-Saharan Africa, detecting resistance-associated mutations (RAMs) at failure of first-line ART with two NRTIs plus an NNRTI predicts improved virological responses to second-line therapy with two NRTIs plus a ritonavir-boosted PI (PI/r). This indicates residual NRTI activity in the presence of RAMs, although additional factors may contribute to the effect. Objectives The aim of this study was to investigate the influence of pre-existing RAMs on the outcomes of maintenance monotherapy with ritonavir-boosted darunavir within a randomized trial in Cameroon. Methods RAMs were detected in HIV-1 DNA using PBMCs collected at initiation of darunavir/ritonavir monotherapy. Adherence was assessed by pill count and visual analogue scale (VAS). Predictors of virological failure (confirmed or last available viral load >400 copies/mL) were explored by logistic regression analysis. Trial name = MANET (NCT02155101). Results After NNRTI-based therapy, participants (n = 81) had received PI/r-based therapy for a median of 3.2 years and had a confirmed viral load <60 copies/mL and a median CD4 count of 466 cells/mm3. NRTI and NNRTI RAMs were detected in 39/60 (65.0%) and 41/60 (68.3%) HIV-1 DNA sequences, respectively. Over 48 weeks of monotherapy, 16/81 (19.8%) patients experienced virological failure. After adjusting for age, HIV-1 DNA load, adherence by VAS and RAM status, virological failure was less likely with higher VAS-measured adherence (adjusted OR 0.04, 95% CI 0.01–0.37; P = 0.004) and detectable HIV-1 DNA RAMs (adjusted OR 0.15, 95% CI 0.03–0.82; P = 0.028). Conclusions Pre-existing NRTI and NNRTI RAMs are associated with improved virological responses to NRTI-sparing ART in sub-Saharan Africa, indicating a predictive effect that is independent of residual NRTI activity.

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Patterns of acquired HIV-1 drug resistance mutations and predictors of virological failure in Moshi, northern Tanzania

10.1101/2020.04.21.052902 ◽

2020 ◽

Author(s):

Shabani Ramadhani Mziray ◽

Happiness H Kumburu ◽

Hellen B Assey ◽

Tolbert B Sonda ◽

Michael J Mahande ◽

...

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Virological Failure ◽

Health Concern ◽

Resistance Mutations ◽

Hiv Drug Resistance ◽

Drug Resistance Mutations ◽

Northern Tanzania ◽

Hiv Drugs ◽

Hiv 1

AbstractDrug resistance is a public health concern. Profiles of HIV drug resistance mutations (HIVDRM) and virological failure (VF) are not extensively studied in Tanzania. This study aimed to determine HIVDRM and predictors of VF in HIV-infected individuals failing first-line HIV drugs in Moshi, northern Tanzania. A case-control study was conducted at KCMC, Mawenzi, Pasua and Majengo health facilities with HIV-care and treatment clinics in Moshi from October, 2017 to August, 2018. Cases and controls were HIV-infected individuals with VF and viral suppression (VS) respectively. HIV-1 reverse transcriptase and protease genes were amplified and sequenced. Stanford University’s HIV drug resistance database and REGA HIV-1 Subtyping tool 3.0 determined HIVDRM and HIV-1 subtypes respectively. Odds ratios with 95% confidence intervals investigated predictors of VF. P-value <5% was considered statistically significant. A total of 124 participants were recruited, of whom 63 (50.8%) had VF and 61 (49.2%) had VS. Majority (66.1%) were females. Median [IQR] age and duration on ART were 45 [35-52] years and 72 [48-104] months respectively. Twenty five out of 26 selected HIV-1 RNA samples from cases were successively sequenced. Twenty four samples (96%) had at least one major mutation conferring resistance to HIV drugs, with non-nucleoside reverse transcriptase inhibitor (NNRTI) associated mutations as the majority (92%). Frequent NNRTI resistance mutations were K103N (n=11), V106M (n=5) and G190A (n=5). Prevalent nucleoside reverse transcriptase inhibitors mutations were M184V (n=17), K70R (n=7) and D67N (n=6). Dual-class resistance was observed in 16 (64%) samples. Thirteen samples (52%) had at least one thymidine analogue-associated resistance mutation (TAM). Three samples (12%) had T69D mutation with at least 1 TAM. Age was independently associated with VF [aOR 0.94 (0.90-0.97) p<0.001]. In conclusion, HIV drug resistance is common among people failing antiretroviral therapy and resistance testing will help to guide switching of HIV drugs.

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Lower prevalence of drug resistance mutations at first-line virological failure to first-line therapy with atripla vs. tenofovir + emtricitabine/lamivudine + efavirenz administered on a multiple tablet therapy

AIDS ◽

10.1097/qad.0000000000000424 ◽

2014 ◽

Vol 28 (17) ◽

pp. 2531-2539 ◽

Cited By ~ 16

Author(s):

José L. Blanco ◽

Julio S.G. Montaner ◽

Vincent C. Marconi ◽

Maria M. Santoro ◽

Ariel E. Campos-Loza ◽

...

Keyword(s):

Drug Resistance ◽

Virological Failure ◽

Lower Prevalence ◽

Resistance Mutations ◽

First Line ◽

Drug Resistance Mutations ◽

First Line Therapy ◽

Line Therapy

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Accumulation of HIV-1 drug resistance after continued virological failure on first-line ART in adults and children in sub-Saharan Africa

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkw218 ◽

2016 ◽

Vol 71 (10) ◽

pp. 2918-2927 ◽

Cited By ~ 49

Author(s):

T. Sonia Boender ◽

Cissy M. Kityo ◽

Ragna S. Boerma ◽

Raph L. Hamers ◽

Pascale Ondoa ◽

...

Keyword(s):

Drug Resistance ◽

Virological Failure ◽

Sub Saharan Africa ◽

First Line ◽

Adults And Children ◽

Sub Saharan ◽

Hiv 1

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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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