Improved liver function, but progressive kidney damage, among children on antiretroviral therapy in Ethiopia

Among HIV-positive children with liver and kidney abnormalities, liver enzyme abnormalities improved while kidney function progressively deteriorated the longer the children were on antiretroviral therapy (ART). With the exception of nevirapine, the specific ART regimen did not have a significant effect on changes in liver enzymes or kidney function.

These findings from the Ethiopian Paediatric HIV Cohort, a multi-centre prospective longitudinal study, were published in HIV Medicine.

Both HIV infection and antiretroviral drugs affect the liver and kidneys. However, the precise mechanisms of drug-induced liver toxicity or disease and kidney function damage in HIV-infected children are poorly understood. Among children on ART, liver toxicity is the most common adverse event, with approximately one in five children on ART having raised liver enzymes.

Glossary

alanine aminotransferase (ALT)

An enzyme found primarily in the liver. Alanine aminotransferase may be measured as part of a liver function test. Abnormally high blood levels of ALT are a sign of liver inflammation or damage from infection or drugs.

creatinine

Breakdown product of creatine phosphate in muscle, usually produced at a fairly constant rate by the body (depending on muscle mass). As a blood test, it is an important indicator of the health of the kidneys because it is an easily measured by-product of muscle metabolism that is excreted unchanged by the kidneys.

enzyme

A protein which speeds up a chemical reaction.

fibrosis

Scarring of the liver – the development of hard, fibrous tissue. See also ‘cirrhosis’, which is more severe scarring.

paediatric

Of or relating to children.

There is a paucity of literature on the medium- and long-term effects of ART in children from sub-Saharan Africa and Asia. Limited paediatric treatment options underscore the critical need for a better understanding of the adverse effects of antiretrovirals.

The authors undertook a study to look at the prevalence of kidney and liver abnormalities and the pattern of changes over time among HIV-positive children. In 2015 and 2016 children under 18 years of age on first-line ART were enrolled in the cohort in six established HIV/AIDS centres throughout Ethiopia.

Liver enzymes (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)), kidney function (creatinine and blood urea nitrogen (BUN)), complete blood count, immunology (CD4 count and percentage) and viral load were assessed at enrolment and followed up every six months for 18 months.

Liver fibrosis and cirrhosis were assessed using non-invasive markers comprising AST to platelet ratio score (APRI) and fibrosis score (FIB-4).

A total of 705 of the children (90%) enrolled had at least one measurement for kidney and liver function tests over the 18-month prospective follow-up while 450 children had all four tests. The median age was 12 (interquartile range 8-14) years and just over half were male. The median time on ART was 3.3 (interquartile range 1.1-6.1) years.

At enrolment, a quarter of the children had elevated liver enzyme test results and 10% with an APRI score > 0.5 suggesting liver fibrosis.

Being younger, (p = 0.008), on ART for a shorter time (p = 0.02), on a zidovudine- or nevirapine-based regimen (p = 0.001) and having a viral load >1000 copies/mL (p = 0.03) were significantly associated with elevated liver enzymes. This continued for the first six months and then normalised.

There was no statistically significant link with kidney function or liver enzyme abnormalities among children co-infected with either hepatitis C or hepatitis B.

At each follow-up time point of six months, 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.

However, efavirenz-based regimens showed a greater improvement in ALT compared with nevirapine-based regimens. The increased risk of liver damage in nevirapine-based regimens compared with those containing efavirenz is well documented.

At baseline, elevated creatinine and blood urea nitrogen, indicative of kidney dysfunction, were present in 24 (3.4%) and 84 (12.1%) children, respectively. Globular filtration rate was used as a substitute for creatinine clearance as creatinine value is affected by age and body weight. A low globular filtration rate suggests kidney dysfunction.

At each follow-up time point of six months, median blood urea nitrogen increased by 1.6 (95% CI: 0.4-2.7) mg/dL, p = 0.01 and the globular filtration rate decreased by 35.6 (95%CI: 17.7-53.4) mL/min/1.73m2.

These findings, the authors note, highlight an important aspect of optimising treatment for HIV-positive children, namely the safety of ART. Understanding safety profiles is critical as adverse events can affect not only adherence (resulting in more infections and treatment failure), but also organ failure, increased death and disease, and lower quality of life.  

Tenofovir–based regimens have previously been linked to kidney function abnormalities and disease. In this study, children on a tenofovir-based regimen had lower globular filtration rates compared to other regimens but the difference was not statistically significant.

The authors note while decreases in AST and ALT following the start of ART could mean stabilisation of liver damage, they could also mean a deterioration leading to end-stage liver disease. Further tests, they add, including ultrasound would help rule out the latter.

The high prevalence of children with signs of liver damage at enrolment is consistent with other studies. While the decrease in liver enzyme abnormalities over time is possibly encouraging, the deterioration in kidney function is concerning. These findings, the authors note, stress the need for regular monitoring of kidney function and liver damage and merit further study.

References

Tadesse BT et al. Hepatic and renal toxicity and associated factors among HIV-infected children on antiretroviral therapy: a prospective cohort study. HIV Medicine, doi: 10.1111/hiv.12693, 2018.