Development of HIV drug resistance and therapeutic failure in children and adolescents in rural Tanzania

Abstract

Objective:To investigate the prevalence and determinants of virologic failure and acquired drug resistance-associated mutations (DRMs) in HIV-infected children and adolescents in rural Tanzania.Design:Prospective cohort study with cross-sectional analysis.Methods:All children 18 years or less attending the paediatric HIV Clinic of Ifakara and on antiretroviral therapy (ART) for at least 12 months were enrolled. Participants with virologic failure were tested for HIV-DRM. Pre-ART samples were used to discriminate acquired and transmitted resistances. Multivariate logistic regression analysis identified factors associated with virologic failure and the acquisition of HIV-DRM.Results:Among 213 children on ART for a median of 4.3 years, 25.4% failed virologically. ART-associated DRM were identified in 90%, with multiclass resistances in 79%. Pre-ART data suggested that more than 85% had acquired key mutations during treatment. Suboptimal adherence [odds ratio (OR) = 3.90; 95% confidence interval (CI) 1.11–13.68], female sex (aOR = 2.57; 95% CI 1.03–6.45), and current nonnucleoside reverse transcriptase inhibitor-based ART (aOR = 7.32; 95% CI 1.51–35.46 compared with protease inhibitor-based) independently increased the odds of virologic failure. CD4+ T-cell percentage (aOR = 0.20; 0.10–0.40 per additional 10%) and older age at ART initiation (aOR = 0.84 per additional year of age; 95% CI 0.73–0.97) were protective (also in predicting acquired HIV-DRM). At the time of virologic failure, less than 5% of the children fulfilled the WHO criteria for immunologic failure.Conclusion:Virologic failure rates in children and adolescents were high, with the majority of ART-failing children harbouring HIV-DRM. The WHO criteria for immunologic treatment failure yielded an unacceptably low sensitivity. Viral load monitoring is urgently needed to maintain future treatment options for the millions of African children living with HIV.

Viral evolution in the cell‐associated HIV‐1 DNA during early ART can lead to drug resistance and virological failure in children

“…The emergence of DRM in the plasma RNA leading to virological failure in children was reported previously although these DRMs were absent at baseline . Using paired NGS sequencing of the cell‐associated DNA at baseline and at month six after ART, we present the most credible evidence for the emergence of the drug‐resistant virus during early ART resulting in virological failure.…”

“…The viral variants containing drug‐resistance mutations (DRMs) may have been transmitted to a newly infected individual before treatment initiation or may have evolved spontaneously in a chronically infected individual . The minority drug‐resistant viral variants can evolve upon ART initiation even if the preexisting DRMs were not detectable and can eventually impact treatment response …”

Validation of a self‐report adherence measurement tool among a multinational cohort of children living with HIV in Kenya, South Africa and Thailand

“…While viral load monitoring is becoming more routine in many LMIC and can be useful for identifying non-adherence, this strategy cannot determine whether viral non-suppression is due to adherence (as well as what type of adherence issues), drug resistance or some combination. Available data suggest drug resistance, particularly for older and more treatment experienced children, is increasingly common in LMIC [39][40][41]. The frequency of treatment interruptions in this cohort as measured by MEMS â highlights the potential risk for developing drug resistance with particular non-adherent behaviours.…”

Strengthening HIV therapy and care in rural Tanzania affects rates of viral suppression

“…Overall, studies conducted in Tanzania reported a prevalence of virological failure ranging from 19% to 61% and an over 75% prevalence of HIV-DRM. 10,[22][23][24][25] Several factors may have contributed to the observed virological efficacy of ART in our setting. First, unlike many other HIV treatment programmes in resource-limited settings, the CDCI is reasonably well staffed with physicians specifically dedicated to HIV treatment outcome in rural Tanzania JAC HIV treatment and care, including HIV specialists who continuously provide mentorship for capacity building to local medical practitioners.…”