Infection with HIV is
associated with an increased risk of hepatic dysfunction, and death related to
liver dysfunction, according to the results of a large US study published in
the online edition of the Journal of
Acquired Immune Deficiency Syndromes.
A lower CD4 cell count
and higher viral load were associated with liver disease and liver-related
was no evidence that antiretroviral therapy increased the risk of adverse
liver-related outcomes. Indeed, HIV treatment reduced the risk of death caused
by hepatic dysfunction.
“Our study results
clearly did not point to ART [antiretroviral therapy] as contributing to risk;
in fact risk was reduced with longer duration,” emphasise the investigators.
The advent of
effective antiretroviral treatment has transformed the prognosis of many
However, liver disease
is an increasingly important cause of serious illness and even death in
individuals with HIV.
A number of possible
reasons have been identified. There include co-infection with hepatitis B
and/or hepatitis C and drug and alcohol misuse. Some anti-HIV drugs can also
cause liver-related side-effects.
California wanted to establish if HIV-positive patients were more likely to
develop hepatic dysfunction or die of liver-related causes than age and
sex-matched HIV-negative individuals. The researchers also wished to see if any
specific causes were related to liver disease and death caused by hepatic
dysfunction in HIV-infected patients.
designed a study involving 20,755 HIV-positive patients who received care between
1996 and 2008, each of whom was matched with ten HIV-negative controls of the
same sex and age who received care over the same period.
was defined as:
Diagnosis with liver failure.
Diagnosis with hepatic encephalopathy.
Oesophageal varices (if bleeding).
ALT/AST levels five-times the upper limit of
normal if accompanied by elevated ammonia and/or elevated international
normalised ratio greater than the upper normal limit.
Deaths were considered
as related to hepatic dysfunction if:
patients were predominantly men (91%), over half were white (51%) and the mean
age at start of follow-up was 41 years.
A total of 437
HIV-positive patients were diagnosed with hepatic dysfunction. The incidence
was 491 events per 100,000 person years of follow-up. This compared to 755
events in the HIV-negative controls, an incidence of 67 per 100,000 person
calculated that the incidence of liver dysfunction was 6.5 times higher in the
HIV-positive patients compared to the controls (p < 0.001).
There were 170 liver
dysfunction-related deaths among the HIV-positive patients. This provided an
incidence of 188 per 100,000 person years. In contrast, 192 deaths due to the
same cause were recorded in the HIV-negative controls, an incidence of 17 per
100,000 person years.
of hepatic dysfunction-related death was six times higher (risk ratio 5.9) in the HIV-positive
patients than the controls (p < 0.001).
Among the patients
with HIV, the most common primary causes noted when hepatic dysfunction was
listed as a cause of death included HIV/AIDS (69%) and other liver-related
Immune dysfunction at
all levels increased the risk of hepatic dysfunction or death. However,
compared to HIV-uninfected individuals it was lowest for those with a CD4 cell
count above 500 cells/mm3 and highest for patients with a CD4 cell
count below 200 cells/mm3 not taking antiretroviral therapy
(adjusted risk ratio, 59.4; 95% CI, 39.3-89.7, p < 0.001).
There was also a
consistent relationship between a higher viral load (above 100,000 copies) and an increased risk of
hepatic dysfunction and death from such problems.
Analysis was then
restricted to the patients with HIV.
The strongest risk
factor for hepatic dysfunction was co-infection with hepatitis B and/or C (aRR
= 5.3; 95% CI, 4.3-6.4, p < 0.001). Other risk factors included a CD4 cell
count below 200 cells/mm3, viral load above 500 copies/ml, alcohol
or drug use and diabetes.
investigators examined whether cumulative antiretroviral use was associated
with adverse liver outcomes.
There was no evidence
that the use of antiretroviral therapy was associated with hepatic dysfunction.
This was the case for regimens based on protease inhibitors and those based on
a non-nucleoside reverse transcriptase inhibitor (NNRTI).
For death related to
hepatic dysfunction, the investigators found a protective effective of
antiretroviral therapy, each year of therapy reducing the risk by 17% (aRR =
0.83; 95% CI, 0.72-0.94, p = 0.004).
cumulative use of ART did not increase risk of either hepatic dysfunction or
hepatic dysfunction-related death,” write the authors. They believe this
finding is “reassuring, and clinically of great importance in light of calls…to
increase the number of HIV-infected individuals on ART.”
The investigators conclude
that their findings “suggest that early diagnosis of HIV and subsequent
initiation of ART prior to significant CD4 cell count decline may partially
mitigate the risk of hepatic dysfunction or hepatic dysfunction-related death.”