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.

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

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

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

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.