Short Communication: High Rates of Thymidine Analogue Mutations and Dual-Class Resistance Among HIV-Infected Ugandan Children Failing First-Line Antiretroviral Therapy

Abstract

HIV-infected children are at high risk of acquiring drug-resistant viruses, which is of particular concern in settings where antiretroviral drug options are limited. We aimed to assess resistance patterns and predict viral drug susceptibility among children with first-line antiretroviral therapy (ART) failure in Uganda. A cross-sectional analysis of children switching ART regimens due to first-line failure was performed at three clinical sites in Uganda. HIV-RNA determination and genotypic resistance testing on all specimens with HIV-RNA >1,000 copies/ml were performed. Major drug resistance mutations were scored using the 2011 International Antiviral Society-USA list. The Stanford algorithm was used to predict drug susceptibility. At the time of switch, 44 genotypic resistance tests were available for 50 children. All children harbored virus with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance [95% confidence interval (CI) 92-100%] and NRTI resistance was present in 98% (95% CI 88-100%). Forty-six percent (95% CI 30-61%) of children harbored ≥2 thymidine analog mutations. M184V was identified as the only NRTI mutation in 27% (95% CI 15-43%). HIV susceptibility to NRTIs, with the exception of tenofovir, was reduced in ≥60% of children. Ugandan children experiencing first-line ART failure in our study harbored high rates of dual-class and accumulated HIV drug resistance. Methods to prevent treatment failure, including adequate pediatric formulations and alternative second-line treatment options, are urgently needed.

High levels of virological failure with major genotypic resistance mutations in HIV-1-infected children after 5 years of care according to WHO-recommended 1st-line and 2nd-line antiretroviral regimens in the Central African Republic

“…[16,20,21,23–25,27,28,30–37,79–92] Furthermore, the frequency of therapeutic failure seems quite higher when NNRTI-based regimens are used in 1st-line treatment, [82] ranging from 12% to 98% [16,20,21,24,33,37,38,79–82,84,87,88,92,93] than when PI-based regimen are used, ranging from 26% to 44%. [83,86,87,89,91] …”

“…[8,14–25] Thus, recent studies in African children receiving 1st-line antiretroviral treatment according to the treatment guidelines of the World Health Organization (WHO) for resource-limited countries have reported generally high degrees of virological failure depending in part on treatment duration, ranging from 6% in Kwazulu-Natal (South Africa), [26,27] 15% in Cape Town (South Africa), [28] 17% [29] to 44% [30] in Ghana, 26% in Uganda, [31] 29% in Rwanda, [32] 34% in Kenya, [33] 35% in Ivory Coast, [16] 40% in the Central African Republic, [23] 53% in rural Cameroon, [34] 55% in Senegal, [24] 56% in Togo, [25] 58% in Tanzania [35,36] to 61% in Mali. [37] In addition, circulating virus resistant to at least 1 antiretroviral drug could be detected very frequently in 61% [33] to 98% [38] of children with a detectable viral load while receiving antiretroviral treatment. Moreover, the problem of perinatally infected adolescents has recently emerged.…”

Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

“…were associated with the appearance of HIV-1 drug-resistant genotypes (68,69). The concordance between first-line treatment failures and drug resistance in HICs is generally greater than 95% (65).…”

Tackling virological failure in HIV-infected children living in Africa

“…A better response to second-line treatment occurs when the patient resistance profile is known before switching therapy [100]. Studies show a high rate (96.5%) of NRTI and NNRTI (98.6%) resistanceassociated mutations [100] in children failing first-line treatment in Uganda; similarly, in another study, a high rate of NNRTI (95%) and NRTI (98%) resistance-associated mutations were also observed [101] with the proportion of TAMs much higher than reported among children in other African countries [84,[102][103][104].…”