Abstract
BackgroundDeep sequencing could improve understanding of HIV treatment failure and viral population dynamics. However, this tool is often inaccessible in low- and middle-income countries.ObjectivesTo determine the genetic patterns of resistance emerging in West African HIV-1 subtypes during first-line virological failure, and the implications for future antiretroviral options.Patients and methodsParticipants were selected from a Nigerian cohort of people living with HIV who had failed first-line ART and subsequently switched to second-line therapy. Whole HIV-1 genome sequences were generated from first-line virological failure samples with Illumina MiSeq. Mutations detected at ≥2% frequency were analysed and compared by subtype.ResultsHIV-1 sequences were obtained from 101 participants (65% female, median age 30 years, median 32.9 months of nevirapine- or efavirenz-based ART). Thymidine analogue mutations (TAMs) were detected in 61%, other core NRTI mutations in 92% and NNRTI mutations in 99%. Minority variants (<20% frequency) comprised 18% of all mutations. K65R was more prevalent in CRF02_AG than G subtypes (33% versus 7%; P = 0.002), and ≥3 TAMs were more common in G than CRF02_AG (52% versus 24%; P = 0.004). Subtype G viruses also contained more RT cleavage site mutations. Cross-resistance to at least one of the newer NNRTIs, doravirine, etravirine or rilpivirine, was predicted in 81% of participants.ConclusionsExtensive drug resistance had accumulated in people with West African HIV-1 subtypes, prior to second-line ART. Deep sequencing significantly increased the detection of resistance-associated mutations. Caution should be used if considering newer-generation NNRTI agents in this setting.
Highlights
ART in low- and middle-income countries is often provided without routine viral load monitoring or drug resistance testing
Infrequent monitoring may delay the recognition of virological failure and this problem may be compounded by restricted access to second-line regimens
This finding has not been replicated in similar analyses in sub-Saharan Africa, which found no association between baseline minority variants and first-line ART outcomes.[12,13,14]
Summary
ART in low- and middle-income countries is often provided without routine viral load monitoring or drug resistance testing. Most of the literature on HIV drug resistance is derived from partial pol gene Sanger sequencing technology.[3,8,9] Studies in high-income countries with predominantly subtype B infections have shown that deep sequencing can identify more mutations than standard methods, but it is unclear whether this technology produces additional information that is clinically useful.[10] For example, a European case–control study reported that the presence of minority drug-resistant variants prior to ART was associated with increased odds of first-line treatment failure.[11] But this finding has not been replicated in similar analyses in sub-Saharan Africa, which found no association between baseline minority variants and first-line ART outcomes.[12,13,14] it is not known whether minority variants present at first-line treatment failure are likely to influence the susceptibility to subsequent ART regimens. Deep sequencing could improve understanding of HIV treatment failure and viral population dynamics. This tool is often inaccessible in low- and middle-income countries
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