Absence of HIV-1 Drug Resistance Mutations Supports the Use of Dolutegravir in Uganda

Abstract

To screen for drug resistance and possible treatment with Dolutegravir (DTG) in treatment-naive patients and those experiencing virologic failure during first-, second-, and third-line combined antiretroviral therapy (cART) in Uganda. Samples from 417 patients in Uganda were analyzed for predicted drug resistance upon failing a first- (N = 158), second- (N = 121), or third-line [all 51 involving Raltegravir (RAL)] treatment regimen. HIV-1 pol gene was amplified and sequenced from plasma samples. Drug susceptibility was interpreted using the Stanford HIV database algorithm and SCUEAL was used for HIV-1 subtyping. Frequency of resistance to nucleoside reverse transcriptase inhibitors (NRTIs) (95%) and non-NRTI (NNRTI, 96%) was high in first-line treatment failures. Despite lack of NNRTI-based treatment for years, NNRTI resistance remained stable in 55% of patients failing second-line or third-line treatment, and was also at 10% in treatment-naive Ugandans. DTG resistance (n = 366) was not observed in treatment-naive individuals or individuals failing first- and second-line cART, and only found in two patients failing third-line cART, while 47% of the latter had RAL- and Elvitegravir-resistant HIV-1. Secondary mutations associated with DTG resistance were found in 2%-10% of patients failing third-line cART. Of 14 drugs currently available for cART in Uganda, resistance was readily observed to all antiretroviral drugs (except for DTG) in Ugandan patients failing first-, second-, or even third-line treatment regimens. The high NNRTI resistance in first-line treatment in Uganda even among treatment-naive patients calls for the use of DTG to reach the UNAIDS 90:90:90 goals.

Variability in HIV-1 Integrase Gene and 3′-Polypurine Tract Sequences in Cameroon Clinical Isolates, and Implications for Integrase Inhibitors Efficacy

“…The fact that only 0.6% of samples analyzed had INSTIs major RAMs suggests that there will be a lesser likelihood of resistance to INSTIs in Cameroon and that INSTIs will be effective for HIV-infected Cameroonians. Similar trends were observed in other countries in Africa [13,34,[43][44][45], Asia [46][47][48][49][50][51], Europe [52][53][54], and South America [55] where studies showed a low frequency of INSTIs major RAMs.…”

Resistance in Patients Failing Integrase Strand Transfer Inhibitors: A Call to Replace Raltegravir With Dolutegravir in Third-Line Treatment in South Africa

“…The third signature RAL mutation, Q148R, which is commonly observed in subtype B, was only observed once in this study. The R263K mutation was not observed in our cohort, which was also reported by Argentinian and Ugandan studies [7, 8]. Cross-resistance to DTG remains limited to 6% in RAL-exposed individuals, which is also consistent with the Ugandan findings (4%) [7], but this is substantially lower compared with the findings from the Argentinian cohort (32%), where poor adherence was reported by most patients [8].…”

“…These results are lower than those observed in Argentina where 72% of heavily treated patients presented with RAL and/or EVG resistance after a median of 22.5 months of RAL exposure [8]. Our findings are more similar to those from a Ugandan cohort of 51 patients failing RAL-based TLART where 47% of patients presented with RAL and/or EVG resistance [7]. The prevalence of HIV-1 subtypes differs globally and among studies reporting INSTI resistance: HIV-1 subtype B/F and B predominated in the Argentinian cohort versus A, D, and A/D in Uganda and subtype C in our study.…”

“…In South Africa 78% to 83% of patients obtain virological suppression on TLART [4–6]. A study from Uganda reported prevalence of INSTI resistance in RAL-based third-line failures at 47% (24 of 51) with RAL and/or elvitegravir (EVG) resistance and 4% (2 of 51) with DTG resistance [7]. Whereas an Argentinian survey reported 72% of patients (41 of 57) on RAL-based salvage ART presented with RAL and/or EVG resistance and 32% presented with with intermediate (29%) to high-level (2%) DTG cross-resistance [8], data from Botswana show that only 4 of 20 (20%) patients failing DTG-based salvage regimens had INSTI resistance [3].…”

Integrase strand transfer inhibitor (INSTI)-resistance mutations for the surveillance of transmitted HIV-1 drug resistance

“…This is not surprising because INSTIs have been primarily used in upper-income countries that have a lower prevalence of non-subtype B viruses, [37][38][39][40][41] with relatively small numbers of reports of INSTI resistance emanating from low-and middle-income countries. 42,43 WHO's 2018 ARV guidelines recommend the use of dolutegravir as preferred first-line ART. 5,6 It is expected that the new regimen will be adopted widely in many regions of the word, including settings with non-B subtype and where programmatic challenges, such as ARV drug stockouts, might result in the emergence of INSTI resistance and eventually its transmission.…”