Drug Resistance and Coreceptor Usage in HIV Type 1 Subtype C-Infected Children Initiating or Failing Highly Active Antiretroviral Therapy in South Africa

Abstract

HIV-1 drug resistance monitoring in resource-poor settings is crucial due to limited drug alternatives. Recent reports of the increased prevalence of CXCR4 usage in subtype C infections may have implications for CCR5 antagonists in therapy. We investigated the prevalence of drug resistance mutations and CXCR4 coreceptor utilization of viruses from HIV-1 subtype C-infected children. Fifty-one children with virological failure during highly active antiretroviral therapy (HAART) and 43 HAART-naive children were recruited. Drug resistance genotyping and coreceptor utilization assessment by phenotypic and genotypic methods were performed. At least one significant drug resistance mutation was present in 85.4% of HAART-failing children. Thymidine analogue mutations (TAMs) were detected in 58.5% of HAART-failing children and 39.0% had ‡ 3 TAMs. CXCR4 (X4) or dual (R5X4)/mixed (R5, X4) (D/M)-tropic viruses were found in 54.3% of HAART-failing and 9.4% of HAARTnaive children ( p < 0.0001); however, the HAART-failing children were significantly older ( p < 0.0001). In multivariate logistic regression, significant predictors of CXCR4 usage included antiretroviral treatment, older age, and lower percent CD4 + T cell counts. The majority of genotypic prediction tools had low sensitivity ( £ 65.0%) and high specificity ( ‡ 87.5%) for predicting CXCR4 usage. Extensive drug resistance, including the high percentage of TAMs found, may compromise future drug choices for children, highlighting the need for improved treatment monitoring and adherence counseling. Additionally, the increased prevalence of X4/D/M viruses in HAARTfailing children suggests limited use of CCR5 antagonists in salvage therapy. Enhanced genotypic prediction tools are needed as current tools are not sensitive enough for predicting CXCR4 usage.

Tackling virological failure in HIV-infected children living in Africa

“…A high prevalence of drug-resistance mutation occurs in untreated, HIV infected infants, reaching 32% in Senegal [97] and 85.4% in South Africa [98], although prevalence was much lower at 4.9% in Cameroon [99]. Longer exposure to failing regimens increased the rate of TAM, which can compromise subsequent second-line treatments [97].…”

Monophylogenetic HIV-1C epidemic in Ethiopia is dominated by CCR5-tropic viruses–an analysis of a prospective country-wide cohort

“…Previously, X4-tropic strains have been reported to be very rare in HIV-1C infection, even in the later stage of disease [9–11]. Some recent studies from South Africa and India also showed predominance of R5 strains in treatment naïve as well as experienced HIV-1C infected patients [12], although a South African study reported predominance of X4 strains in treatment experienced children [13]. More recently, a higher incidence of X4-tropic HIV-1C were described in patients with advanced immunodeficiency from South Africa, India and Botswana, respectively [14–17].…”

High-Sequence Diversity and Rapid Virus Turnover Contribute to Higher Rates of Coreceptor Switching in Treatment-Experienced Subjects with HIV-1 Viremia

“…[25][26][27] Since the frequency of coreceptor switching is influenced by both HIV-1 subtype 28,29 and host CCR5 genotype, [30][31][32] both viral and host factors must contribute. Coreceptor switching is less frequent in subtype C HIV-1 infection 29,33 but the frequency increases [34][35][36] following antiretroviral therapy (ART), as it does in subtype B infection. 17,37 Subjects heterozygous for the CCR5 D32 mutation tend to have lower viral loads 38,39 but earlier emergence of R5X4 or X4 variants, 32 suggesting that entry fitness and selective pressure to use CXCR4 are influenced by CCR5 density.…”