High levels of pre‐treatment HIV drug resistance and treatment failure in Nigerian children

Abstract

IntroductionPre-treatment HIV drug resistance (PDR) is an increasing problem in sub-Saharan Africa. Children are an especially vulnerable population to develop PDR given that paediatric second-line treatment options are limited. Although monitoring of PDR is important, data on the paediatric prevalence in sub-Saharan Africa and its consequences for treatment outcomes are scarce. We designed a prospective paediatric cohort study to document the prevalence of PDR and its effect on subsequent treatment failure in Nigeria, the country with the second highest number of HIV-infected children in the world.MethodsHIV-1-infected children ≤12 years, who had not been exposed to drugs for the prevention of mother-to-child transmission (PMTCT), were enrolled between 2012 and 2013, and followed up for 24 months in Lagos, Nigeria. Pre-antiretroviral treatment (ART) population-based pol genotypic testing and six-monthly viral load (VL) testing were performed. Logistic regression analysis was used to assess the effect of PDR (World Health Organization (WHO) list for transmitted drug resistance) on subsequent treatment failure (two consecutive VL measurements >1000 cps/ml or death).ResultsOf the total 82 PMTCT-naïve children, 13 (15.9%) had PDR. All 13 children harboured non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations, of whom seven also had nucleoside reverse transcriptase inhibitor resistance. After 24 months, 33% had experienced treatment failure. Treatment failure was associated with PDR and a higher log VL before treatment initiation (adjusted odds ratio (aOR) 7.53 (95%CI 1.61–35.15) and 2.85 (95%CI 1.04–7.78), respectively).DiscussionPDR was present in one out of six Nigerian children. These high numbers corroborate with recent findings in other African countries. The presence of PDR was relevant as it was the strongest predictor of first-line treatment failure.ConclusionsOur findings stress the importance of implementing fully active regimens in children living with HIV. This includes the implementation of protease inhibitor (PI)-based first-line ART, as is recommended by the WHO for all HIV-infected children <3 years of age. Overcoming practical barriers to implement PI-based regimens is essential to ensure optimal treatment for HIV-infected children in sub-Saharan Africa. In countries where individual VL or resistance testing is not possible, more attention should be given to paediatric PDR surveys.

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

“…Additionally, we compared the profile of the DRMs in two Pretreatment drug resistance in cell-free RNA occurring above 20% frequency is known to be a strong predictor of early virological failure in children. 48,49 In this study, the signature DRM associated with ART were not observed in cell-free RNA at baseline. Although University database, we found that a few DRM associated with specific ART regimen were found at a higher frequency in drugexposed subjects infected with HIV-1C and a few other DRM identified through the present study were not found.…”

“…Pretreatment drug resistance in cell‐free RNA occurring above 20% frequency is known to be a strong predictor of early virological failure in children . In this study, the signature DRM associated with ART were not observed in cell‐free RNA at baseline.…”

“…17,49 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- preparations available in developing countries, 55 genetic polymorphisms in the genes coding for the drug transporter proteins, and nutritional status are known to play a substantial role in achieving optimal therapeutic drug levels. We previously reported that in adherent children of southern India, nevirapine failed to reach optimal physiological levels during the initial dose escalation period (48). Findings such as this raise concerns regarding the prevalence of nonadherence in an NNRTI-containing ART regimen.…”

Polymorphisms and drug resistance analysis of HIV-1 isolates from patients on first line antiretroviral therapy (ART) in South-eastern Nigeria

“…There is however comparatively little available data from less developed countries where non-B subtypes predominate. In Nigeria where the epidemic is largely driven by non-B subtypes, reports on HIV drug resistance and polymorphisms [12][13][14][15][16][17][18][19][20][21] have primarily focused on resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) while resistance to Protease inhibitors (PI) remain understudied. Since the commencement of ART program in Nigeria in 2001, government has collaborated with some donor agencies such as Global Fund to Fight AIDS, Tuberculosis, and Malaria and US President's Emergency Plan for AIDS Relief (PEPFAR) to scale up its ART clinics.…”

The Clinical Implications of Pretreatment Drug Resistance—A Moving Target

“…The impact of PDR on the response to a first-line regimen has been difficult to quantify as resistance testing prior to initiating ART is used to guide therapy in high-resource regions. However, there have been at least 13 studies in which a first-line NNRTI-based ART regimen was initiated either according to public health guidelines [5][6][7][8][9][10][11][12][13][14][15] or a clinical trial protocol [16,17] and for which stored samples were available to assess the impact of pretreatment DRMs on virological success. These studies included about 340 persons with PDR.…”