Early antiretroviral therapy (ART) reduces the risk of liver
fibrosis progression in people living with HIV, including in people who do not
have co-infection with viral hepatitis, according to the results of the SMART
study published in Hepatology.

People with a high CD4 cell count (500 cells/mm3)
who started immediate ART were about a third less likely to experience fibrosis
progression compared to people who started ART when their CD4 cell count fell
to 350 cells/mm3. Baseline fibrosis was also more likely to resolve
in people who initiated ART at the higher CD4 threshold.

“In this largest study of its kind in predominantly
HIV-monoinfected individuals, we show firstly that significant fibrosis was
rare and both fibrosis and other liver related events continued to be uncommon
over 14,379 person year of follow-up,” comment the authors. “We also found a
potential benefit of reducing markers of liver fibrosis among persons
immediately treated with ART and confirmed lack of hepatotoxicity of the ART
regimens used in this study.”

Liver disease is a leading cause of serious illness and
death among people with HIV. The risk is increased by co-infection with
hepatitis B or hepatitis C, as well as by alcohol or drug dependence. The risk
of non-alcoholic
fatty liver disease (NAFLD)
is increased in individuals who are overweight
or obese, have high cholesterol and triglyceride levels, have high blood
pressure and insulin resistance or have type 2 diabetes.

The role of ART in reducing or causing liver fibrosis
progression is unclear. The START (Strategic Timing of Antiretroviral
Treatment) study provided an opportunity to address this gap in research.

The randomised controlled trial involved ART-naïve
HIV-positive patients with a CD4 cell count above 500 cells/mm3.
Participants were randomised to start immediate ART or to defer treatment until
their CD4 cell count fell to 350 cells/mm3. The study was designed
to inform decisions about when to initiate ART, its
results showing the benefits of early treatment
especially in relation to
avoiding cancers and other serious illnesses. 

Individuals were enrolled between 2009 and 2013 at 222
treatment centres in 35 countries. The investigators analysed the prevalence
and risk factors of significant fibrosis at enrolment and during follow-up, and
the effect of early ART compared to delayed therapy on progression of liver
fibrosis over time.

Liver function was assessed using two validated
non-invasive scoring systems (APRI and FIB-4). The first takes into account aspartate
aminotransferase (AST) and platelet counts, with the second also considering
age and alanine aminotransferase (ALT).

A total of 4580 people were included in the analysis, with
2273 randomised to immediate ART and 2307 to deferred ART. The median age was
36 years, 27% were female and 30% were black. Almost half the participants
(45%) currently smoked or had quit, 3% had diagnosed alcohol or substance
dependence, 4% had co-infection with hepatitis C and 3% with hepatitis B. The prevalence
of chronic liver disease (0.3%), hepatic steatosis (0.2%) and diabetes (3%) was
low. Approximately 2% were taking statins and just over 1% were on tuberculosis
therapy.

The median CD4 cell count was 651 cells/mm3 and
5% had a viral load below 200 copies/ml before starting ART. Abnormal
laboratory values were present in 26% for ALT, 6% for AST, 2% for platelets,
0.6% for albumin and 7% for bilirubin.

At baseline, rates of liver fibrosis were low. Overall, 84%
of people had no significant fibrosis at baseline by either APRI or FIB-4 and
94% had no significant fibrosis by both APRI and FIB-4. A low proportion of
people had intermediate significant fibrosis scores by either APRI or FIB-4
(15%) or both (5%). Confirmed significant fibrosis was present in just 1% by
either APRI and FIB-4 and in 0.3% using both measures.

For people without fibrosis at baseline, immediate ART was
associated with a significant reduction in the risk of developing fibrosis (HR
= 0.66; 95% CI, 0.57-0.78, p 0.001).

Factors associated with an increased fibrosis score during
follow-up using both APRI and FIB-4 included deferred ART, male gender and
hepatitis co-infection. Additionally, a history of alcoholism or substance
abuse and higher ALT were risk factors by APRI only, whereas lower albumin,
higher total cholesterol and higher triglycerides were associated with
increased risk by FIB-4 only.

The risk of developing fibrosis during follow-up did not
differ according to baseline viral load (above vs below 100,000 copies/ml).
Changes in fibrosis score did not differ according to type of ART
(non-nucleoside reverse transcriptase inhibitor vs protease inhibitor).

Incidence of hepatic flare was low in both the immediate and
deferred treatment groups. However, people taking immediate ART were
significantly more likely to experience normalisation of elevated baseline
fibrosis scores than those in the deferred ART group (HR = 1.6; 95% CI, 1.13-1.9,
p 0.001).

There was a very low incidence of viral hepatitis infection
in both study groups. Very few liver events were reported during follow-up and
there were no liver-related deaths.

“Our results support current guidance to initiate ART in all
patients with HIV regardless of CD4 count, particularly considering that modern
ART regimens have lower rates of hepatotoxicity than older regimens,” conclude
the authors. “Patients with hepatitis B and C co-infection, as well as those
with NAFLD and existing steatosis, should be particularly prioritized for
treatment to possibly reduce progression of liver fibrosis in such patients
with elevated risk and to preserve overall liver health.”