Beyond clinical trials: Cross-sectional associations of combination antiretroviral therapy with reports of multiple symptoms and non-adherence among adolescents in South Africa

This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0. RESEARCH Beyond clinical trials: Cross-sectional associations of combination antiretroviral therapy with reports of multiple symptoms and non-adherence among adolescents in South Africa H P M Natukunda,1,2 MPhil; L D Cluver,2,3 DPhil; E Toska,2,4 DPhil; V Musiime,5,6 PhD; A R Yakubovich,2 MSc Pathology Department, Medical Research Council, Harwell Institute, UK Department of Social Policy and Intervention, University of Oxford, UK 3 Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa 4 AIDS and Society Research Unit, Centre for Social Science Research, Faculty of Humanities, University of Cape Town, South Africa 5 Department of Paediatrics and Child Health, College of Health Sciences, Makerere University, Kampala, Uganda 6 Joint Clinical Research Centre, Kampala, Uganda 1 2 Corresponding author: H P M Natukunda () Background. Studies investigating symptoms associated with combination antiretroviral therapy (cART) use among adolescents in resource-limited settings are rare beyond clinical trials. Identifying adolescents at risk of non-adherence is imperative for HIV/AIDS programming and controlling the epidemic in this key population. Objective. To examine which cART regimens were associated with reports of multiple symptoms and past-week non-adherence in a large community-traced sample of HIV-positive adolescents in South Africa (SA). Methods. A total of 1 175 HIV-positive ART-experienced adolescents aged 10 - 19 years attending 53 health facilities in the Eastern Cape Province, SA, were interviewed in 2014 - 2015. Ninety percent (n=1 059) were included in the study. Adolescents who reported no medication use and those with unclear or missing data were excluded from further analysis, resulting in a sample for analysis of n=501. Outcomes were reports of multiple symptoms (three or more symptoms in the past 6 months) and past-week ART non-adherence (<95% correct doses in the past week). Multivariable logistic regression analyses controlled for sociodemographic and HIV-related covariates in Stata 13/IC. Results. Of the adolescents included, 54.3% were female. The median age was 14 (interquartile range 12 - 16) years, and 66.5% were vertically infected. The prevalence of multiple symptoms was 59.7% (95% confidence interval (CI) 55.3 - 63.9). Independent of covariates, stavudine (d4T)-containing cART regimens and the fixed-dose combination of tenofovir (TDF) + emtricitabine (FTC) + efavirenz (EFV) were associated with more reports of multiple symptoms (adjusted odds ratio (aOR) 3.38; 95% CI 1.19 - 9.60 and aOR 2.67; 95% CI 1.21 5.88, respectively). Lopinavir/ritonavir (LPV/r)-containing regimens were associated with fewer reports of multiple symptoms (aOR 0.47; 95% CI 0.21 - 1.04). For EFV-based regimens, adolescents on d4T + lamivudine (3TC) + EFV were more likely to report multiple symptoms than those on TDF + FTC + EFV or those on abacavir (ABC) + 3TC + EFV (aOR 3.26; 95% CI 1.01 - 10.52, aOR 2.86; 95% CI 1.35 - 6.05 and aOR 1.08; 95% CI 0.64 - 1.82, respectively). However, only TDF + FTC + EFV cART was associated with lower levels of non-adherence among participants (aOR 0.44; 95% CI 0.21 - 0.93). Conclusions. Rates of multiple symptoms among HIV-positive ART-experienced adolescents were high. d4T-containing regimens and TDF + FTC + EFV were associated with more reports of multiple symptoms, whereas LPV/r-containing regimens were associated with fewer reports. However, adolescents on TDF + FTC + EFV were the most adherent subgroup. These findings support the World Health Organization-recommended discontinuation of d4T use, but also underscore the dilemma faced by clinicians when choosing between lowtoxicity regimens and those that promote ART adherence, particularly among HIV-positive adolescents. S Afr Med J 2017;107(11):965-975. DOI:10.7196/SAMJ.2017.v107i11.12405 Globally, adolescents aged 10 - 19 years are the only age group in which AIDS-related deaths are increasing, and AIDS is now the leading cause of adolescent death in Africa.[1] Combination antiretroviral therapy (cART) increases long-term survival and wellbeing of people living with HIV,[2] but requires diligent lifetime adherence of ~87 - 95%.[3] However, cART has also been associated with toxicities in clinical trials. Low adherence rates are common among HIV-positive adolescents and rates have been shown to worsen over time,[4,5] but more research is needed to understand what drives adolescent non-adherence to cART, particularly in subSaharan Africa. Side-effects of cART are important both with regard 965 to quality of life and as potential predictors of non-adherence. In clinical practice, symptoms associated with cART use and symptoms of opportunistic infections in HIV or other illnesses can easily be confused. Symptoms commonly listed in the literature as sideeffects of cART include skin rash, fatigue/tiredness, nausea/vomiting, diarrhoea/stomach ache, insomnia/bad dreams, headache, fever, dry mouth and dizziness.[6-9] Evidence on cART-related symptoms among adolescents is very limited, particularly in sub-Saharan Africa, where a >90-fold increase in cART access has occurred in the past decade. [10] Most studies reporting cART-related outcomes focus on adults or younger children (<14 years) or include very few children.[4,7,11-17] November 2017, Vol. 107, No. 11 RESEARCH In younger children, observational studies and randomised controlled trials (RCTs) comparing nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-based and non-nucleotide reverse transcriptase inhibitor (NNRTI)-based regimens have found no major differences in toxicity profiles,[15,17-19] including in children with prior nevirapine (NVP) exposure.[20] In Uganda, 23% of children aged <18 years reported mild to moderate symptoms, and in Rwanda, 33% of children aged <15 reported cART-related symptoms, 9% of whom required treatment modification. However, these studies did not specify which regimens/regimen components were likely to be associated with the reported symptoms.[8,21] Studies in high-income countries have shown zidovudine (AZT)-based regimens to be safer than stavudine (d4T)-based regimens,[9] and lopinavir/ritonavir (LPV/r)-based regimens to be safe and effective in HIV-infected children.[22,23] Studies in adults report cough, fever, peripheral neuropathy, skin rash, pruritus, diarrhoea and dizziness to be common among participants on AZT- and d4T-based cART, with higher prevalences in participants on AZT-based regimens than in those on d4T-based regimens.[14,24] RCTs and systematic reviews in adults in high-income countries have also shown efavirenz (EFV)based regimens to be associated with more symptoms than nonEFV-based regimens.[7,25] To date, no study has examined associations between cART regimens and reports of multiple symptoms among HIV-positive adolescents. C (...truncated)