Optimization of pediatrics antiretroviral treatment outcomes among HIV infected children in Ethiopia

Abstract: Ending the HIV/AIDS epidemic by 2030 is a global agenda. To meet this global goal, having safe and effective antiretroviral therapy is a key requirement. In Ethiopia, the safety and efficacy of combination antiretroviral therapy in HIV infected pediatric population is poorly studied. In this thesis, I aimed at understanding the short- and long-term safety and efficacy of antiretroviral therapy among HIV infected children in Ethiopia. Clinical and laboratory data were recorded for a total of 870 HIV infected children in two parallel cohorts – EPDOS and EPHIC projects. We first investigated the burden and correlates of pretreatment drug resistance (PDR) in Paper I. We observed that the overall rate of PDR was 14%. All cases with PDR had resistance to NNRTIs while ~9% harbored resistance solely to NNRTIs and ~5% harbored resistance to both NNRTIs and NRTIs. No resistance was observed to protease inhibitors. In Paper II, among children who were followed for 48 weeks following initiation of treatment, we assessed virologic outcome of children at one year of cART initiation using Cox Proportional Hazards Model. In total, 94/110 (85.5%) achieved virological suppression to undetectable levels during the first year of treatment. Thirty-six (31.9%) experienced virologic rebound. Tenofovir-containing cART regimen and absence of PDR were associated with higher virologic suppression. In Paper III, we explored burden and correlates of HIV drug resistance among children who failed treatment. Overall, 81% (73/90) of successfully genotyped participants had resistant mutations. From these, 69% (62/90) harbored dual drug class resistance. Strikingly, 42% of the participants harbored resistance to all four NRTIs recommended for second line use in the setting. Longer duration of cART and any regimen changes were associated with occurrence of drug resistance mutations. In Paper IV, we investigated the long term renal and hepatic toxicities associated with antiretroviral therapy among cART experienced children. At study enrolment, 177(25.1%) and 83(11.8%) had high aspartate aminotransferase and alanine aminotransferase (ALT), respectively. Zidovudine or nevirapine containing regimens and viral load >1000 copies/mL were associated with elevated ALT. Twenty-four (3.4%) and 84(12.1%) of the children had elevated creatinine and blood urea nitrogen (BUN), respectively. A progressive increment in BUN and decrement in GFR were observed during the follow up period. Both AST and ALT exhibited a decreasing trend. In Paper V, we compared the prevalence and correlates of dyslipidemia between cART naïve and experienced HIV infected children. Dyslipidemia was more common among cART experienced (70.2%) than naïve (58.1%) HIV infected children (p=0.03). Higher proportion of low HDLc (40.2% versus 23.4%, p=0.006) and hypertriglyceridemia (47.2% versus 35.8%, p= 0.02) was observed among cART experienced HIV infected children as compared to naïve. No difference was observed in the proportion of total hypercholesterolemia and high LDLc levels between the groups. Undernutrition was associated with more dyslipidemia in the cART naïve group (p=0.01). In conclusion, we showed that a high proportion of children with HIV infection in resource-limited settings do achieve virologic suppression during the first year of treatment initiation. We also confirmed that HIV drug resistance is a major cause of virologic treatment failure in children with limited virologic monitoring. On the other hand, the burden of PDR is low but predicts virologic outcome. Adverse events associated with cART are the major challenges for meeting the global UNAIDS targets in 2020 and 2030. The findings call for targeted monitoring and treatment of children in resource-limited settings.