Hepatic and Renal Toxicity and Associated Factors Among HIV-Infected Children on Antiretroviral Therapy

A Prospective Cohort Study

BT Tadesse; BA Foster; A Kabeta; F Ayalew; G H/Meskel; D Jerene; E Makonnen; E Aklillu

Disclosures

HIV Medicine. 2019;20(2):147-156. 

In This Article

Abstract and Introduction

Abstract

Objectives: The aim of the study was to investigate the prevalence of renal function and liver enzyme abnormalities among HIV-infected children, changes in prevalence with time on combination antiretroviral therapy (cART), and the factors associated with these abnormalities.

Methods: A prospective cohort study was conducted among HIV-infected children < 18 years old (n= 705) who were on first-line cART. Liver enzymes, renal function, haematology, immunology and virological response were assessed at enrolment and followed bi-annually for 18 months. Liver fibrosis and cirrhosis were assessed using noninvasive markers including the aspartate aminotransferase (AST) to platelet ratio index (APRI) and fibrosis score (FIB-4).

Results: The median age was 12 [interquartile range (IQR) 8–14] years; 53.3% of patients were male. At enrolment, the median cART duration was 3.3 (IQR 1.1–6.1) years; 177 (25.1%) and 83 (11.8%) patients had elevated AST and alanine aminotransferase (ALT), respectively. A tenth of the children had an APRI score > 0.5, suggesting liver fibrosis. Being on a zidovudine (ZDV)- or nevirapine (NVP)-based regimen and having a viral load > 1000 HIV-1 RNA copies/mL were significantly associated with elevated ALT. Twenty-four (3.4%) and 84 (12.1%) patients had elevated creatinine and blood urea nitrogen (BUN), respectively. As cART duration increased by 6 months, median BUN increased by 1.6 [95% confidence interval (CI) 0.4–2.7] mg/dL (P = 0.01); the glomerular filtration rate (GFR) decreased by 35.6 (95% CI 17.7–53.4) mL/min/1.73 m2 (P < 0.0001); and AST and ALT decreased by 1.4 (95% CI 0.4–2.5) IU/L (P = 0.01) and 1.4 (95% CI 0.2–2.6) IU/L (P = 0.01), respectively.

Conclusions: A high prevalence of liver enzyme and renal function abnormalities was observed at enrolment. Decreasing liver enzyme levels during follow-up are possibly reassuring, while the progressive reduction in GFR and the increase in BUN are worrisome and require further study.

Introduction

In 2016, a total of 2.1 million children below the age of 15 years were living with HIV globally, with about 160 000 new HIV infections and 120 000 deaths annually 1. Following the introduction of combination antiretroviral therapy (cART), the number of HIV/AIDS-related deaths has been cut by more than half over the past 5 years.[1] All HIV drugs used in cART are, however, associated with adverse events of varying severity and presentation.[2] Nevertheless, the benefits of cART in reducing the number of AIDS-related deaths and improving quality of life outweigh the risks of adverse events.[1,2]

The liver and kidneys are organ systems commonly affected by both HIV infection and antiretroviral drugs. However, the definition of drug-induced hepatotoxicity or drug-induced liver disease (DILI) in HIV-infected children is controversial, with poorly understood pathophysiological mechanisms. Although alkaline phosphatase and bilirubin elevations could also indicate cholestatic liver diseases, aminotransferase elevations are usually used as markers of liver injury.[3,4] The identification of liver abnormalities requires proper follow-up using markers of liver injury, synthetic function tests and imaging, as appropriate.[5,6] Similarly, the magnitude and pathophysiology of renal function impairment in HIV-infected children remain poorly understood.[7]

HIV infection and cART can be associated with a myriad of clinical and laboratory abnormalities, including elevation of liver enzymes, jaundice, abdominal symptoms, and even fulminant liver failure.[2,8] Studies in adults within the first 3 months of cART initiation showed a relatively low proportion of patients with hepatotoxicity, with a prevalence of 1–2% and an incidence rate of 4–8 cases per 100 person-years. The study also reported no association between hepatotoxicity within the first 3 months of cART and risk of death.[9] In contrast, a study from Ethiopia among HIV-infected adults on treatment reported a much higher elevation (32%) of liver enzymes.[10] In a prospective comparative study, a higher incidence of liver toxicity (30%) was reported in Ethiopian tuberculosis (TB)/HIV-coinfected patients receiving dual anti-TB therapy and cART than in HIV-monoinfected patients on cART only (15.7%).[11,12]

Hepatotoxicity is the most common adverse event in children.[13] Studies report a prevalence of elevated liver enzymes of about 16–20% in children taking cART, which is markedly higher than that in adults.[13–15] Elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are marked during the early months after initiation of cART and resolution is expected with increasing time on cART. A study in Nigeria reported resolution within 3–6 months on cART.[16] The untoward effects of cART on liver function in children are less clear, particularly for children in sub-Saharan Africa, where successful cART scale-up has recently been achieved.

Impaired renal function and other kidney problems can occur among children and adolescents as a consequence of HIV infection. Impairments of kidney function can occur as a result of complex immune-mediated processes, referred to as HIV-associated nephropathy (HIVAN), or can be caused by adverse events associated with cART.[17] Both HIV and cART can compromise renal function in HIV-infected children and adolescents.

The literature on the medium- to long-term side effects of cART in children from sub-Saharan Africa and Asia is sparse. Optimizing treatment of HIV-infected children and adolescents requires a better understanding of the untoward effects of these drugs. A recently initiated cohort study (Ethiopian Pediatric HIV Cohort - EPHIC)[18] collected viral load and clinical laboratory data on children infected with HIV who were receiving cART. The present study investigated the medium- and long-term renal and hepatic effects of cART in children from the EPHIC study.

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