High-Level Cross-Resistance to Didanosine Observed in South African Children Failing an Abacavir- or Stavudine-Based 1st-Line Regimen

Abstract

BackgroundThe knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure.MethodsA retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions.ResultsChildren were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%).ConclusionAnalysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens.

High Prevalence of Abacavir-associated L74V/I Mutations in Kenyan Children Failing Antiretroviral Therapy

“…However, study authors were unable to assess the predicted efficacy of second-line regimens due to the lack of HIVDR data. As L74 mutations have been associated with continued AZT and tenofovir disoproxil fumarate (TDF) susceptibility 6 and even AZT hypersusceptibility of uncertain clinical significance, 10 there may be benefits to utilize AZT or TDF as second-line choices after failure on ABC-containing regimens rather than the reverse (ABC in the second line after failure on an AZT-containing regimen).…”

“…One study in South Africa found high frequency of drug resistance mutations (DRMs) after ABC exposure in children, with virologic failure (VF) referred for resistance testing. 6 Our study describes the prevalence and characteristics associated with RT DRMs at position L74 among children found to be failing ART as part of a national survey in Kenya.…”

Antiretroviral agents in pre-exposure prophylaxis: emerging and advanced trends in HIV prevention

“…Moreover, another study was carried out in South Africa to investigate the cross‐resistance of RPV. It is proved that RPV resistance is strongly correlated to K103N mutation . In a pharmacokinetic study of SSAT040 TMC278LA of RPV resistance, plasma sample of an unexpected seroconverter in the 300‐mg arm was collected and assessed.…”

A farewell to didanosine: harm reduction and cost savings by eliminating use of didanosine

“…Additional concerns include that ddI may not actually be virologically active in most second-line patients, due to prevalence of L74V and other known resistance mutations in NRTI-experienced patients, some having been only recently discovered. 22–25 Evidence that continued use of ddI in a failing regimen may select for mutations that are associated with cross-resistance to other NRTIs, such as the Q151M complex and T69 insertion, has been described and could support discontinuation of the drug in patients currently receiving it. 26–28 These considerations should be viewed in the context of resource-limited settings using a public health approach to ART regimen selection without the benefit of patient-level genotyping.…”