Deep sequencing of HIV-1 reveals extensive subtype variation and drug resistance after failure of first-line antiretroviral regimens in Nigeria

Abstract

Background Deep sequencing could improve understanding of HIV treatment failure and viral population dynamics. However, this tool is often inaccessible in low- and middle-income countries. Objectives To 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 methods Participants 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. Results HIV-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. Conclusions Extensive 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.

Evaluating Barriers to Viral Suppression among People with HIV in Santiago, Dominican Republic

“…27 Other treatment regimens that are being evaluated for low-income countries to improve adherence and tolerability, and limit pill burden include long-acting injectable cabotegravir-rilpivirine which has shown on modeling studies to be cost-effective in PWH with an HIV VL of more than 1000 copies/mL but there is concern for potentially inducing integrase inhibitor resistance. 24,28 This paper complements the literature to help characterize common barriers to HIV care among people living with HIV in the DR and the greater Caribbean region. Risk factors for non-adherence to ART found in other urban regions of the DR (Santo Domingo and Puerto Plata) included heavy alcohol use, having children and perceptions of less social support.…”

“…Patients who are on second-line regimens are more likely to be at risk for virologic failure due to existing difficulties with ART adherence and possibly undiagnosed drug resistance. 22 – 24 Other contributing factors include the greater pill burden, more complicated dosing schedules, and higher rates of adverse effects known to be associated with PI-based regimens. 25 , 26 Access to genotype testing is limited for PWH in the DR, and ART regimens are frequently changed based on HIV disease progression, lack of viral suppression and the availability of medications in the hospital pharmacy.…”

“…27 Other treatment regimens that are being evaluated for low-income countries to improve adherence and tolerability, and limit pill burden include long-acting injectable cabotegravir-rilpivirine which has shown on modeling studies to be cost-effective in PWH with an HIV VL of more than 1000 copies/mL but there is concern for potentially inducing integrase inhibitor resistance. 24 , 28 …”

“…32 Haitian patients constituted about 10% of our study population and had a slightly higher (though not statistically significant) rate of having a detectable viral load. 24 Among those that reported being Dominican we did not assess if they were of Haitian descent. Additional research and interventions are needed to better address the structural racism that persons of Haitian descent face and its impact on their HIV care.…”

Characterization of a novel HIV-1 circulating recombinant form, CRF91_cpx, comprising CRF02_AG, G, J, and U, mostly among men who have sex with men

“…There are limited available sequencing data, and the available sequences are mostly partial sequences derived from molecular epidemiology studies focusing on drug resistance analyses. Previous studies showed that subtype G and CRF02_AG were the predominant HIV-1 strains in Nigeria, although the transmission of CRF06_cpx was also observed [ 30 , 31 , 32 , 33 , 34 , 35 ]. The co-circulation of these strains could have potentially resulted in the generation of the CRF91_cpx strain.…”