scholarly journals Drivers of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTIs) in nine southern African countries: a modelling study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Julien Riou ◽  
Carole Dupont ◽  
Silvia Bertagnolio ◽  
Ravindra K. Gupta ◽  
Roger D. Kouyos ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Southern Africa ◽  
Transmission Model ◽  
Second Line ◽  
Fragility Index ◽  
Reverse Transcriptase Inhibitors ◽  
First Line ◽  
Nnrti Resistance ◽  
Dynamic Transmission Model ◽  
Hiv 1

Abstract Introduction The rise of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI) threatens antiretroviral therapy's long-term success (ART). NNRTIs will remain an essential drug for the management of HIV-1 due to safety concerns associated with integrase inhibitors. We fitted a dynamic transmission model to historical data from 2000 to 2018 in nine countries of southern Africa to understand the mechanisms that have shaped the HIV-1 epidemic and the rise of pretreatment NNRTI resistance. Methods We included data on HIV-1 prevalence, ART coverage, HIV-related mortality, and survey data on pretreatment NNRTI resistance from nine southern Africa countries from a systematic review, UNAIDS and World Bank. Using a Bayesian hierarchical framework, we developed a dynamic transmission model linking data on the HIV-1 epidemic to survey data on NNRTI drug resistance in each country. We estimated the proportion of resistance attributable to unregulated, off-programme use of ART. We examined each national ART programme's vulnerability to NNRTI resistance by defining a fragility index: the ratio of the rate of NNRTI resistance emergence during first-line ART over the rate of switching to second-line ART. We explored associations between fragility and characteristics of the health system of each country. Results The model reliably described the dynamics of the HIV-1 epidemic and NNRTI resistance in each country. Predicted levels of resistance in 2018 ranged between 3.3% (95% credible interval 1.9–7.1) in Mozambique and 25.3% (17.9–33.8) in Eswatini. The proportion of pretreatment NNRTI resistance attributable to unregulated antiretroviral use ranged from 6% (2–14) in Eswatini to 64% (26–85) in Mozambique. The fragility index was low in Botswana (0.01; 0.0–0.11) but high in Namibia (0.48; 0.16–10.17), Eswatini (0.64; 0.23–11.8) and South Africa (1.21; 0.83–9.84). The combination of high fragility of ART programmes and high ART coverage levels was associated with a sharp increase in pretreatment NNRTI resistance. Conclusions This comparison of nine countries shows that pretreatment NNRTI resistance can be controlled despite high ART coverage levels. This was the case in Botswana, Mozambique, and Zambia, most likely because of better HIV care delivery, including rapid switching to second-line ART of patients failing first-line ART.

scholarly journals Dynamics and drivers of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors in nine African countries

2020 ◽  
Author(s):  
Julien Riou ◽  
Carole Dupont ◽  
Silvia Bertagnolio ◽  
Ravindra Gupta ◽  
Roger D Kouyos ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Survey Data ◽  
Southern Africa ◽  
Hiv Care ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Nnrti Resistance ◽  
Country Level ◽  
Hiv 1

Background. The rise of HIV-1 drug resistance to non-nucleoside reverse-transcriptase inhibitors (NNRTI) is a major problem in countries of southern Africa. Understanding the dynamics and drivers of NNRTI resistance at the country level is of critical importance for planning future antiretroviral therapy (ART) programs. Methods. We collected survey data on pretreatment drug resistance (PDR) to NNRTIs in nine countries of southern Africa from 2000 to 2018. We fitted a dynamic transmission model to key indicators of the local HIV-1 epidemics (HIV-1 prevalence, ART coverage and mortality) and to survey data about NNRTI PDR using a Bayesian hierarchical framework. We estimated two country-level indicators: the proportion of NNRTI PDR that cannot be attributed to ART programmes and the vulnerability to NNRTI PDR within ART programmes. We explored associations between vulnerability to NNRTI PDR and country-level covariates.Findings. The model reliably described the dynamics of HIV-1 and the dynamics of NNRTI PDR in each country. Predicted levels of NNRTI PDR in 2018 ranged between 3.3% (95% credible interval 1.9% to 7.1%) in Mozambique and 25.3% (17.9% to 33.8%) in Eswatini. The main determinant of high NNRTI PDR were the conjunction of high ART coverage and high vulnerability to NNRTI PDR within ART programmes. Heterogeneity in the vulnerability to NNRTI resistance was associated with features of the healthcare financing system at the national level.Interpretation. Between-country comparison shows that NNRTI PDR can be controlled despite high levels of ART coverage, as in Botswana, Lesotho, Mozambique and Zambia, likely because of better adherence, patient management procedures and quality in HIV care service delivery.

scholarly journals Patterns of HIV-1 Drug Resistance After First-Line Antiretroviral Therapy (ART) Failure in 6 Sub-Saharan African Countries: Implications for Second-Line ART Strategies

2012 ◽  
Vol 54 (11) ◽  
pp. 1660-1669 ◽  
Author(s):  
R. L. Hamers ◽  
K. C. E. Sigaloff ◽  
A. M. Wensing ◽  
C. L. Wallis ◽  
C. Kityo ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Second Line ◽  
First Line ◽  
African Countries ◽  
Sub Saharan ◽  
Hiv 1

scholarly journals 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

2020 ◽  
Author(s):  
Adetayo Emmanuel Obasa ◽  
Anoop T Ambikan ◽  
Soham Gupta ◽  
Ujjwal Neogi ◽  
Graeme Brendon Jacobs
Keyword(s):  
South Africa ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Second Line ◽  
Viral Quasispecies ◽  
Resistance Mutations ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Drug Resistance Mutations ◽  
Hiv 1

Abstract Background: 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. 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 suspected of failing on the South African national second-line cART regimen with bPIs.Methods: During 2017 and 2018, 67 patient samples were selected, of which 56 samples were successfully analyzed. 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.Results: Statistically significantly (p<0.001) higher PI RAMs were observed in minor viral quasispecies (25%; 14/56) compared to nucleoside reverse transcriptase inhibitors (11%; 6/56), non-nucleoside reverse transcriptase inhibitors (9%; 5/56) and integrase inhibitor RAM (4%; 2/56). 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.Conclusions: HTS-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.

scholarly journals Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase

2020 ◽  
Author(s):  
Mark Siedner ◽  
Michelle Moorhouse ◽  
Brioni Simmons ◽  
Tulio de Oliveira ◽  
Richard Lessells ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Treatment Initiation ◽  
World Health ◽  
Integrase Inhibitors ◽  
Resistance Mutations ◽  
First Line ◽  
Nnrti Resistance ◽  
The Impact ◽  
Hiv 1

Abstract Background: Little is known about the impact of pre-treatment drug resistance (PDR) to non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the efficacy of second generation integrase inhibitors, now the standard of care drug class for HIV-1 treatment globally.Methods: We conducted next-generation sequencing on stored plasma specimens from the ADVANCE trial collected prior to treatment initiation. Our primary outcome was 96-week virologic success, defined as achievement of a viral load < 1000 copies/mL from 12 weeks, < 200 copies/mL from 24 weeks, and < 50 copies/mL from 48 through 96 weeks. We estimated the impact of PDR, defined by the presence of drug resistance on the World Health Organization (WHO) mutation list, on virologic outcomes in the entire cohort, and stratified by EFV-based versus DTG-based regimens. In sensitivity analyses, we allowed virologic failure with re-suppression, assessed FDA 48 and 96-week Snapshot outcomes, and considered minority resistance mutations (5–20% frequency).Results: Of 1,053 trial participants, 873 (83%) had plasma available and successful sequencing completed. Of these, 288 (33%) were randomized to an EFV-based regimen and 585 (67%) were randomized to a DTG-based regimen. Fourteen percent (122/873) had at least one WHO-defined mutation, of which over 98% (120/122) had NNRTI mutations. NRTI mutations were rare (20/873, 2%). Rates of virologic suppression were significantly lower in those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001). This phenomenon was consistent for both EFV-based (60% [12/20] versus 86% [214/248], P = 0.002) and DTG-based ART (61/92 [66%] versus 84% [391/465] P < 0.001, P for interaction by regimen 0.49). In multivariable models adjusted for clinical characteristics and treatment adherence, PDR strongly predicted failure [adjusted OR 0.38 (0.23–0.61), P < 0.001]. Although suppression rates were greater when allowing for non-consecutive visits with failure, PDR significantly predicted greater risk of failure for both regimens in all outcome definitions. We found no effect of mutations at frequencies 5–20% on any of our outcomes.Interpretation: NNRTI resistance prior to treatment initiation is associated with failure of integrase inhibitor-containing first-line regimens. These results portend high rates of first-line treatment failure in sub Saharan Africa, where circulating NNRTI resistance is common.

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