HIV-1 integrase resistance associated mutations and the use of dolutegravir in Sub-Saharan Africa: A systematic review and meta-analysis

Abstract

As sub-Saharan Africa (SSA) countries are transitioning to dolutegravir (DTG)-based ART, baseline data are required for optimal monitoring of therapeutic response. In this frame, we sought to generate up-to-date evidence on the use of integrase-strand transfer inhibitors (INSTI) and associated drug resistance mutations (DRMs) within SSA. In this systematic review and meta-analysis, we included randomized and non-randomized trials, cohort-studies, cross-sectional studies, and case-reports published on INSTI or integrase DRMs in SSA. We included studies of patients exposed to DTG, raltegravir (RAL) or elvitegravir (EVG). Primary outcomes were “the rate of virological control (VC:<50copies/ml)” and “the presence of DRMs” on INSTI-based regimens among patients in SSA. We synthesised extracted data using subgroup analysis, and random effect models were used where appropriate. Additional analyses were conducted to assess study heterogeneity. We identified 1,916 articles/citations through database searches, of which 26 were included in the analysis pertaining to 5,444 patients (mean age: 37±13 years), with 67.62% (3681/5444) female. Specifically, 46.15% (12/26) studies focused on DTG, 26.92% (7/26) on RAL, 23.08% (6/26) on both DTG and RAL, and 3.85% (1/26) on EVG. We found an increasing use of DTG overtime (0% before 2018 to 100% in 2021). Median treatment duration under INSTI-based regimens was 12 [9–36] months. Overall, the rate of VC was 88.51% [95%CI: 73.83–97.80] with DTG vs. 82.49% [95%CI: 55.76–99.45] and 96.55% [95%CI: 85.7–100.00] with RAL and EVG, respectively. In univariate analysis, VC with DTG-containing vs. other INSTI-regimens was significantly higher (OR = 1.44 [95%CI: 1.15–1.79], p = 0.0014). Among reported DRMs at failure, the only DTG resistance-mutations were G118R and R263K. In SSA, DTG presents a superiority effect in VC compared to other INSTIs. Nonetheless, the early detection of INSTI-DRMs calls for sentinel surveillance for a successful transition and a sustained efficacy of DTG in SSA. PROSPERO Registration Number: CRD42019122424.

Comprehensive Analysis of HIV-1 Integrase Resistance-Related Mutations in African Countries

“…To evaluate the conservation degree in INSTI-DRMs and polymorphisms of HIV-IN amino acidic sequences in SSA over time, we conducted a chronological analysis of the overall contribution of the entire study population. The dataset was divided into two time periods, 1983–2007 (3491 samples) vs. 2008–2023 (4415 samples), with consideration given to the time before and after approval of INSTI-based treatment regimens [ 13 ], and the amino acidic sequences were first aligned and compared to the reference strain B (HXB2) and then compared to each other ( Figure 2 ).…”

Optimising HIV drug resistance testing laboratory networks in Kenya: insights from systems engineering modelling

“…As noted previously, despite marked enthusiasm for dolutegravir-containing regimen use in LMICs, DR will be an enduring concern. DR to dolutegravir is already emerging,9 41–45 and because it remains unclear what regimens should be used in cases of dolutegravir resistance, the use of DRT is only going to increase as surveillance for dolutegravir resistance intensifies in LMICs. Though the maximum potential DRT demand rate (14.6%) modelled in our scenario 2 is highly improbable to occur in LMICs in the foreseeable future, there is a pressing need for a substantial increase in centralised and POC DRT capacity to cope with the likely upsurge in DRT demand.…”

HIV transmission dynamics and population-wide drug resistance in rural South Africa

“…ART guidelines currently recommend a combination of DTG, 3TC, and TDF as the first-line regimen for all eligible adults, adolescents, and children aged >10 26 , 27 . While the WHO has endorsed DTG-based ART as the preferred first-line regimen, understanding the patterns of NRTI and NNRTI antiretroviral resistance in both ART-naïve and ART-experienced patients remains crucial.…”