Search

Background: Dolutegravir (DTG) is a cornerstone of global antiretroviral (ARV) therapy (ART) due to its high efficacy and favorable tolerability. However, limited data exist regarding the risk of emergent integrase strand transfer inhibitor (INSTI) drug-resistance mutations (DRMs) in individuals receiving DTG-containing ART. Methods: We performed a PubMed search using the term “Dolutegravir”, last updated 18 December 2023, to estimate the prevalence of VF with emergent INSTI DRMs in people living with HIV (PLWH) without previous VF on an INSTI who received DTG-containing ART. Results: Of 2131 retrieved records, 43 clinical trials, 39 cohorts, and 6 cross-sectional studies provided data across 6 clinical scenarios based on ART history, virological status, and co-administered ARVs: (1) ART-naïve PLWH receiving DTG plus two NRTIs; (2) ART-naïve PLWH receiving DTG plus lamivudine; (3) ART-experienced PLWH with VF on a previous regimen receiving DTG plus two NRTIs; (4) ART-experienced PLWH with virological suppression receiving DTG plus two NRTIs; (5) ART-experienced PLWH with virological suppression receiving DTG and a second ARV; and (6) ART-experienced PLWH with virological suppression receiving DTG monotherapy. The median proportion of PLWH in clinical trials with emergent INSTI DRMs was 1.5% for scenario 3 and 3.4% for scenario 6. In the remaining four trial scenarios, VF prevalence with emergent INSTI DRMs was ≤0.1%. Data from cohort studies minimally influenced prevalence estimates from clinical trials, whereas cross-sectional studies yielded prevalence data lacking denominator details. Conclusions: In clinical trials, the prevalence of VF with emergent INSTI DRMs in PLWH receiving DTG-containing regimens has been low. Novel approaches are required to assess VF prevalence with emergent INSTI DRMs in PLWH receiving DTG in real-world settings.

Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) rarely leads to virological failure (VF) and drug resistance in integrase strand transfer inhibitor (INSTI)-naïve persons living with HIV (PLWH). As a result, limited data are available on INSTI-associated drug resistance mutations (DRMs) selected by DTG-containing ART regimens. Methods: We reviewed studies published through July 2023 to identify those reporting emergent major INSTI-associated DRMs in INSTI-naïve PLWH receiving DTG and those containing in vitro DTG susceptibility results using a standardized assay. Results: We identified 36 publications reporting 99 PLWH in whom major nonpolymorphic INSTI-associated DRMs developed on a DTG-containing regimen and 21 publications containing 269 in vitro DTG susceptibility results. DTG-selected DRMs clustered into four largely non-overlapping mutational pathways characterized by mutations at four signature positions: R263K, G118R, N155H, and Q148H/R/K. Eighty-two (82.8%) viruses contained just one signature DRM, including R263K (n = 40), G118R (n = 24), N155H (n = 9), and Q148H/R/K (n = 9). Nine (9.1%) contained ≥1 signature DRM, and eight (8.1%) contained just other DRMs. R263K and G118R were negatively associated with one another and with N155H and Q148H/K/R. R263K alone conferred a median 2.0-fold (IQR: 1.8–2.2) reduction in DTG susceptibility. G118R alone conferred a median 18.8-fold (IQR:14.2–23.4) reduction in DTG susceptibility. N155H alone conferred a median 1.4-fold (IQR: 1.2–1.6) reduction in DTG susceptibility. Q148H/R/K alone conferred a median 0.8-fold (IQR: 0.7–1.1) reduction in DTG susceptibility. Considerably higher levels of reduced susceptibility often occurred when signature DRMs occurred with additional INSTI-associated DRMs. Conclusions: Among INSTI-naïve PLWH with VF and treatment emergent INSTI-associated DRMs, most developed one of four signature DRMs, most commonly R263K or G118R. G118R was associated with a much greater reduction in DTG susceptibility than R263K.

Background: As the relentless coronavirus disease-2019 (COVID-19) pandemic continues to spread across Africa, Botswana could face challenges maintaining the pathway towards control of its HIV epidemic. Objective: Utilising the Spectrum GOALS module (GOALS-2021), the 5-year outcomes from the implementation of the Treat All strategy were analysed and compared with the original 2016 Investment Case (2016-IC) projections. Future impact of adopting the new Joint United Nations Programme on HIV/AIDS (UNAIDS) Global AIDS Strategy (2021–2026) targets and macroeconomic analysis estimating how the financial constraints from the COVID-19 pandemic could impact the available resources for Botswana’s National HIV Response through 2030 were also considered. Method: Programmatic costs, population demographics, prevention and treatment outputs were determined. Previous 2016-IC data were uploaded for comparison, and inputs for the GOALS, AIM, DemProj, Resource Needs and Family Planning modules were derived from published reports, strategic plans, programmatic data and expert opinion. The economic projections were recalibrated with consideration of the impact of the COVID-19 pandemic. Results: Decreases in HIV infections, incidence and mortality rates were achieved. Increases in laboratory costs were offset by estimated decreases in the population of people living with HIV (PLWH). Moving forward, young women and others at high risk must be targeted in HIV prevention efforts, as Botswana transitions from a generalised to a more concentrated epidemic. Conclusion: The Treat All strategy contributed positively to decreases in new HIV infections, mortality and costs. If significant improvements in differentiated service delivery, increases in human resources and HIV prevention can be realised, Botswana could become one of the first countries with a previously high-burdened generalised HIV epidemic to gain epidemic control, despite the demands of the COVID-19 pandemic.

BackgroundRoll-out of Integrase Strand Transfer Inhibitors (INSTIs) such as dolutegravir for HIV combination antiretroviral therapy (cART) in sub-Saharan Africa necessitates the development of affordable HIV drug resistance (HIVDR) assays targeting the Integrase gene. We optimised and evaluated an in-house integrase HIV-1 drug resistance assay (IH-Int) and compared it to a commercially available assay, ViroSeq™ Integrase Genotyping kit (VS-Int) amongst HIV-1 clade C infected individuals.MethodsWe used 54 plasma samples from treatment naïve participants and one plasma sample from a patient failing INSTI based cART. Specimens were genotyped using both the VS-Int and IH-Int assays. Stanford HIV drug resistance database were used for integrase resistance interpretation. We compared the major and minor resistance mutations, pairwise nucleotide and amino-acid identity, costs and assay time.ResultsAmong 55 specimens tested with IH-Int, 53 (96.4%) successfully amplified compared to 45/55 (81.8%) for the VS-Int assay. The mean nucleotide and amino acid similarity from 33 paired sequences was 99.8% (SD ± 0.30) and 99.8% (SD ± 0.39) for the IH-Int and VS-Int assay respectively. The reagent cost/sample were 32 USD and 147 USD for IH-Int and VS-Int assay, respectively. All sequenced samples were confirmed as HIV-1 subtype C.ConclusionsThe IH-Int assay had a high amplification success rate and high concordance with the commercial assay. It is significantly cheaper compared to the commercial assay. Our assay has the needed specifications for routine monitoring of participants on Dolutegravir based regimens in Botswana.

Background: Short-term mortality rates among patients with HIV receiving antiretroviral therapy (ART) in sub-Saharan Africa are higher than those recorded in high-income countries, but systematic long-term comparisons have not been made because of the scarcity of available data. We analysed the effect of the implementation of Botswana's national ART programme, known as Masa, from 2002 to 2010. Methods: The Masa programme started on Jan 21, 2002. Patients who were eligible for ART according to national guidelines had their data collected prospectively through a clinical information system developed by the Botswana Ministry of Health. A dataset of all available electronic records for adults (≥18 years) who had enrolled by April 30, 2010, was extracted and sent to the study team. All data were anonymised before analysis. The primary outcome was mortality. To assess the effect of loss to follow-up, we did a series of sensitivity analyses assuming varying proportions of the population lost to follow-up to be dead. Findings: We analysed the records of 126 263 patients, of whom 102 713 had documented initiation of ART. Median follow-up time was 35 months (IQR 14–56), with a median of eight follow-up visits (4–14). 15 270 patients were deemed lost to follow-up by the end of the study. 63% (78 866) of the study population were women; median age at baseline was 34 years for women (IQR 29–41) and 38 years for men (33–45). 10 230 (8%) deaths were documented during the 9 years of the study. Mortality was highest during the first 3 months after treatment initiation at 12·8 deaths per 100 person-years (95% CI 12·4–13·2), but decreased to 1·16 deaths per 100 person-years (1·12–1·2) in the second year of treatment, and to 0·15 deaths per 100 person-years (0·09–0·25) over the next 7 years of follow-up. In each calendar year after the start of the Masa programme in 2002, average CD4 cell counts at enrolment increased (from 101 cells/μL [IQR 44–156] in 2002, to 191 cells/μL [115–239] in 2010). In each year, the proportion of the total enrolled population who died in that year decreased, from 63% (88 of 140) in 2002, to 0·8% (13 of 1599) in 2010. A sensitivity analysis assuming that 60% of the population lost to follow-up had died gave 3000 additional deaths, increasing overall mortality from 8% to 11–13%. Interpretation: The Botswana national HIV/AIDS treatment programme reduced mortality among adults with HIV to levels much the same as in other low-income or middle-income countries. Funding: The African Comprehensive HIV/AIDS Partnerships.

Monitoring the effectiveness of global antiretroviral therapy scale-up efforts in resource-limited settings is a global health priority, but is complicated by high rates of losses to follow-up after treatment initiation. Determining definitive outcomes of these lost patients, and the effects of losses to follow-up on estimates of survival and risk factors for death after HAART, are key to monitoring the effectiveness of global HAART scale-up efforts.A cohort study comparing clinical outcomes and risk factors for death after HAART initiation as reported before and after tracing of patients lost to follow-up was conducted in Botswana's National Antiretroviral Therapy Program. 410 HIV-infected adults consecutively presenting for HAART were evaluated. The main outcome measures were death or loss to follow-up within the first year after HAART initiation. Of 68 patients initially categorized as lost, over half (58.8%) were confirmed dead after tracing. Patient tracing resulted in reporting of significantly lower survival rates when death was used as the outcome and losses to follow-up were censored [1-year Kaplan Meier survival estimate 0.92 (95% confidence interval, 0.88-0.94 before tracing and 0.83 (95% confidence interval, 0.79-0.86) after tracing, log rank P

Clinical observations suggest that HIV-1 infection causes higher anemia rates in patients in southern Africa than in those in the United States. To explore this difference we performed a cross-sectional exploratory study on the effect of HIV-1 infection on hematopoiesis in Botswana by examining hematological presentation, HIV disease state, hematopoietic progenitor cell number, and circulating viral levels in HIV-infected patients and HIV-uninfected controls. We found significant associations between CD34and CD4cell counts in HIV-positive patients. Significant relationships were also seen between the CD34CD4cell population and hemoglobin levels, as well as colony-forming ability. These associations, however, were not seen in uninfected controls. Circulating viral p24 levels were found to correlate significantly with CD34cell count, CD34CD4cell count, and colony-forming ability. These results demonstrate a direct association between HIV-1 infection in southern Africa and hematopoietic progenitor cell health. [ABSTRACT FROM AUTHOR]