Abstract:
Botswana has over the years reported a rise in cases of HIV-associated drug resistance to
all four available drug classes. This multi-class drug resistance is associated with virologic failure and increased disease progression, which significantly reduces antiretroviral drug (ARV) choices,especially in settings with limited treatment options. This highlights the need to monitor the emergence and spread of drug resistance, to avoid selection of ineffective ART regimens. This study therefore sought to determine the prevalence of multi-class drug resistance and determine if second generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) [Doravirine (DOR), Etravarine (ETR) and Rilpivirine (RPV)] and entry inhibitors [Maraviroc (MVC), Enfuvirtide (T20) and Fostemsavir (FTR)] can be used as alternative therapy for individuals with multi-class drug resistance. Four approaches were used to analyze a total of 7473 HIV sequences: (i) the Stanford HIV drug resistance database to evaluate multi-class drug resistance and resistance to DOR, ETR and RPV; (ii) computational evaluation of MVC resistance by determining CXCR4
coreceptor usage using geno2pheno, webPSSM and the 11/25 rule; (iii) using the 2023 IAS mutations update to determine T20 resistance; and (iv) determining FTR resistance by probing previous studies that published FTR-resistance associated mutations. The proportions of drug resistance mutations (DRMs) were estimated using binomial exact methods. Predictors of multi drug resistance were determined using the univariate and multivariate logistic regression hazard models. The prevalence of multi-class drug resistance (MDR) was 682/7473 (9.1%: 95 % CI; 8.3-9.6). High prevalence of resistance to second generation NNRTIs was observed within the MDR group at the following rates: 79.3%, 63.6 % and 67.1% for RPV, ETR, and DOR, respectively.For entry inhibitors, 7.9% (31/391) CXCR4 coreceptor usage was observed, indicating low prevalence of MVC resistance. A total of 113/626 (18.1%) MDR variants presented FTR resistance. T20 resistance was observed in 313/623 (50.2%) of MDR variants. ART experience, virologic failure at viral load of >400 copies/mL and being male were significantly associated with
developing MDR. This study reports high resistance to second generation NNRTIs and T20 which reduces their potential use as alternative therapy for people living with HIV who harbor MDR variants in Botswana. In contrast, low prevalence of FTR and MVC resistance allows for their potential use as alternative therapy for MDR individuals, although genotypic testing prior to use of these drugs would be necessary in order to avoid selection of ineffective ARV regimens.
