Pre-Treatment Integrase Inhibitor Resistance and Natural Polymorphisms among HIV-1 Subtype C Infected Patients in Ethiopia

Abstract

Dolutegravir-based antiretroviral therapy (ART) has been scaled up in many developing countries, including Ethiopia. However, subtype-dependent polymorphic differences might influence the occurrence of HIV-drug-resistance mutations (HIVDRMs). We analyzed the prevalence of pre-treatment integrase strand transfer inhibitor (INSTI) HIVDRMs and naturally occurring polymorphisms (NOPs) of the integrase gene, using plasma samples collected as part of the national HIVDR survey in Ethiopia in 2017. We included a total of 460 HIV-1 integrase gene sequences from INSTI-naïve (n = 373 ART-naïve and n = 87 ART-experienced) patients. No dolutegravir-associated HIVDRMs were detected, regardless of previous exposure to ART. However, we found E92G in one ART-naïve patient specimen and accessory mutations in 20/460 (4.3%) of the specimens. Moreover, among the 288 integrase amino acid positions of the subtype C, 187/288 (64.9%) were conserved (<1.0% variability). Analysis of the genetic barrier showed that the Q148H/K/R dolutegravir resistance pathway was less selected in subtype C. Docking analysis of the dolutegravir showed that protease- and reverse-transcriptase-associated HIVDRMs did not affect the native structure of the HIV-1 integrase. Our results support the implementation of a wide scale-up of dolutegravir-based regimes. However, the detection of polymorphisms contributing to INSTI warrants the continuous surveillance of INSTI resistance.

Prevalence of HIV-1 Natural Polymorphisms and Integrase-Resistance-Associated Mutations in African Children

“…The Sanger method does not detect drug-resistance minority variants below 20% of the virus population. The most frequently reported major INI RAMs include codons T66A/I/K, E92G/Q, F121Y, Y143C/H/R/S, S147G, Q148H/R/K, N155H, and R263K [ 1 , 13 , 26 ], while accessory RAMs and other mutations have been largely reported in recent studies from SSA [ 21 , 22 , 23 , 24 , 25 , 27 ]. The prevalence of both major and accessory mutations in the ART-naïve population is very low (0.5%) and likely results from cases of transmitted INI resistance and the cumulative natural occurrence of mutations without selective drug pressure [ 4 , 26 , 28 ].…”

“…Nine accessory INI-resistance mutations were found in this study, among which L74I/M, T97A, and E157Q, were identified most frequently. These mutations were observed in Cameroon and Ethiopia [ 24 , 27 ], and L74M/I and M50I have been reported in the untreated population. Although many reports have shown that accessory INI-resistance mutations (including naturally occurring polymorphisms) do not compromise the effectiveness of INI-based regimens [ 29 , 30 ], other studies have revealed that several mutations can act synergistically or additively to decrease drug susceptibility [ 31 , 32 ]; for instance, the combination of L74M and G163R associated with T79A, has been reported by Abram et al as further reducing susceptibility to RAL and/or EVG in the absence of primary INI-resistance mutations.…”

“…The second most common mutation was E157Q in those sequences, a polymorphic mutation that was weakly selected in RAL-treated patients and in vitro with EVG. E157Q was the most common polymorphic accessory mutation detected in an Ethiopian analysis, and natural polymorphisms were present in 1–10% of untreated individuals, depending on the subtype [ 27 ]. It has been shown that E157Q decreases RAL susceptibility five-fold and EVG two-fold [ 33 ].…”

HIV-1 drug resistance in people on dolutegravir-based ART: Collaborative analysis of cohort studies

“…We defined two HIV drug resistance outcomes: the level of resistance to DTG and the presence of known drug resistance mutations (DRMs). The Stanford HIV Database version 9•0 and the Stanford HIVdb algorithm 27 were used to categorise drug resistance levels as susceptible (score below 10), potential low (10)(11)(12)(13)(14), low (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29), intermediate or high (>60). The same approach was used to assess resistance to all other antiretroviral drugs, whereby drug resistance to tenofovir alafenamide (not covered by the Stanford algorithm) was considered equal to tenofovir resistance.…”

Increasing trend of transmitted integrase inhibitor resistance in a cohort of antiretroviral therapy-naive people living with HIV

“…INSTI polymorphisms that may decrease susceptibility to INSTIs are not infrequent; 3 for instance, mutations like G163R/K are polymorphic in subtype F viruses but can also be non-polymorphic when considering other HIV-1 subtypes; 4 however, if alone, they have little impact on INSTI activity. 5–7 …”