Switching to raltegravir from efavirenz is associated with
significant improvements in liver steatosis for HIV-positive people with
non-alcoholic fatty liver disease, Spanish investigators report in the
online edition of Clinical Infectious Diseases. The benefits of
changing therapy were observed in people with and without active
hepatitis C virus (HCV) co-infection. “It is highly likely that the
results reported…can be generalized to HIV-infected patients without HCV
co-infection,” comment the authors.
Non-alcoholic fatty liver disease (NAFLD) is common among people with
HIV. The condition can increase the risk of liver fibrosis progression.
Causes of NAFLD include metabolic disorders and therapy with
antiretrovirals that cause mitochondrial toxicity. Efavirenz has been
associated with this side-effect and the progression of liver steatosis
(accumulation of fat in the liver). In contrast, raltegravir does not
cause mitochondrial toxicity. However, the effect of therapy with this
drug on fatty liver disease in unclear.
Liver disease is now a leading cause of serious illness and death
among people with HIV, especially if they have co-infection with HCV.
Identification of antiretrovirals that do not cause liver-related
side-effects is therefore a priority.
A non-invasive test, used instead of a biopsy, to measure the stiffness
or elasticity of the liver using an ultrasound probe.
- mitochondrial toxicity
are structures in human cells responsible for energy production. When damaged by
anti- HIV drugs, this can cause a wide range of side-effects, including
possibly fat loss.
Improvement in a tumour. Also, a mathematical model that allows us to measure the degree to which one of more factors influence an outcome.
Abnormal fat deposits in the liver.
With this in mind, investigators in Spain designed an open-label,
multicentre, randomised study to assess the impact on liver steatosis
over 48 weeks of switching from efavirenz to raltegravir while
maintaining a stable nucleoside reverse transcriptase inhibitor (NRTI)
backbone (emtricitabine/tenofovir or lamivudine/abacavir).
The study population consisted of 39 individuals with hepatic
steatosis, all with a suppressed viral load and evidence of significant
liver steatosis. A total of 19 were randomised to switch to raltegravir,
the other 20 remaining on efavirenz. Approximately three-quarters of
the participants taking raltegravir and two-thirds of those treated with
efavirenz had detectable HCV viral load. People with active
drug/alcohol abuse were excluded from participation.
Changes in liver steatosis were assessed by transient elastography (Fibroscan), which measures liver stiffness and fat accumulation in the liver.
Liver fat is calculated by measuring the controlled attenuation
parameter (CAP). At baseline, all the participants had hepatic
steatosis defined as CAP values above 238 dB/m.
At the start of the study, the median CAP values were 273 dB/m for
people taking raltegravir and 263 dB/m for those remaining on efavirenz,
a non-significant difference.
After 48 weeks of therapy, median CAP values had fallen to 250 dB/m
in the raltegravir group but increased to 286 dB/m for individuals on
efavirenz (p = 0.035). The median difference in CAP values between
baseline and week 48 was a fall of 20 dB/m for people on raltegravir
compared to an increase of 30 dB/m for those on efavirenz (p = 0.011).
At the end of follow-up, CAP measurements below 238 dB/m – indicative
of the absence of significant liver steatosis – were observed in 47% of
individuals on raltegravir but just 15% of the efavirenz group (p =
Results remained unchanged when the investigators restricted their
analysis to individuals on the emtricitabine/tenofovir NRTI backbone.
Analysis of the 26 people with active HCV disease at baseline showed
median baseline CAP values 277 dB/m and 262 dB/m for the raltegravir and
efavirenz groups, respectively.
At week 48, median CAP values had fallen to 266 dB/m for the people
taking raltegravir but increased to 285 db/m for those remaining on
efavirenz. The median difference in CAP measurements between baseline
and week 48 was a fall of 7 dB/m for people on raltegravir and an
increase of 30 dB/m for those on efavirenz (p = 0.019). At the end of
follow-up, 36% of people on raltegravir had CAP values indicating no
significant liver steatosis compared to 8% of people on efavirenz.
“After 48 weeks, HIV-infected individuals with NAFLD switched from an
EFV [efavirenz]- to a RAL [raltegravir]-based combination showed a
decrease in the degree of hepatic steatosis, as measured by CAP,
compared to patients with an EFV-based regimen,” write the authors. “In
addition, the proportion of patients showing regression in significant
hepatic steatosis after 48 weeks was greater in those who switched from
EFV to RAL.”
The researchers suggest that the improvements seen in the raltegravir
group may be related to the discontinuation of a drug associated with
“Replacement of EFV by RAL among patients with significant hepatic
steatosis led to reductions in the grade of hepatic steatosis, even
reversal of fatty liver in some cases,” they conclude. “These results
need confirmation in a larger study.”