and HIV/HCV Coinfected People with Impaired Liver Function and Inflammation
Have Higher Risk of Non-AIDS Death
HIV positive study participants
with hepatitis B virus (HBV)
or hepatitis C virus (HCV) coinfection
who had higher blood levels of biomarkers associated with
impaired liver function and inflammation were more likely
to die of non-AIDS-related causes, researchers with the SMART
treatment interruption trial reported last month at the 17th
Conference on Retroviruses and Opportunistic Infections (CROI
2010) in San Francisco.
Lars Peters from the Copenhagen HIV Program in Denmark and fellow investigators
with the INSIGHT SMART Study Group aimed to learn more about risk factors
for disease progression and death in coinfected individuals.
trial enrolled more than 5000 HIV positive adults starting in 2000.
Participants entered the study with a CD4 count above 350 cells/mm3,
and were randomly assigned either to stay on continuous antiretroviral
therapy (ART) or to suspend treatment when their CD4 cell count was
above this level, resuming when it fell below 250 cells/mm3.
The treatment interruption arm was discontinued ahead of schedule in
January 2006 after a preliminary analysis showed that participants in
that group had higher rates of death and both AIDS-defining opportunistic
illness and non-AIDS conditions including cardiovascular, liver, and
SMART researchers later
reported that HIV/HBV or HIV/HCV coinfected participants were more
likely to die than those with HIV alone. While coinfected participants
made up 17% of the study population, they account for nearly half of
non-AIDS deaths. In the treatment interruption arm, coinfected patients
were at increased risk of non-AIDS death if they had an elevated baseline
plasma level of hyaluronic acid, an extracellular matrix component used
as a marker for liver fibrosis.
In the current study, presented in a poster at CROI, the researchers
hypothesized that people with existing liver impairment (defined as
hyaluronic acid > 75 ng/mL) would have higher levels of the inflammation
biomarkers interleukin 6 (IL-6) and high-sensitivity C-reactive protein
(CRP) and the coagulation biomarker D-dimer than people with normal
liver function, and that the ability of biomarkers to predict non-AIDS
death would differ according to hyaluronic acid level.
This analysis included 655 coinfected participants (about one-quarter
women) who had baseline hyaluronic acid measurements and samples available
for checking the other biomarkers. Within this group, 82% had HIV/HCV,
16% had HIV/HBV, and 2% had HIV/HBV/HCV triple infection. The median
age was about 46 years, about 65% had suppressed viral load (< 400
copies/mL), and the median CD4 count was high, at nearly 600 cells/mm3.
the median hyaluronic acid level was 30 ng/mL, but 17% started with
an elevated level. Levels were measured again at the end of a 6-months
total of 50 deaths occurred during follow-up, 30 in the treatment
interruption arm and 20 in the continuous therapy arm.
most frequent causes of death were infections (14%), non-AIDS cancers
(12%), causes related to substance use (12%), liver complications
(8%), cardiovascular disease (8%), kidney disease (8%), and violent
death; 26%, however, died from unknown causes.
with elevated hyaluronic acid at baseline also had significantly
higher levels of IL-6 and D-dimer, but not CRP.
follow-up, the average D-dimer level increased more in the treatment
interruption arm than in the continuous therapy arm, but the difference
was not significant for CRP or IL-6.
with elevated baseline hyaluronic acid were significantly more likely
to die than those with lower levels, both before and after adjusting
for other biomarkers and risk factors.
with higher levels of hyaluronic acid plus 1 other biomarker accounted
for 48% of non-AIDS deaths, while those with lower levels of both
accounted for 8%.
of non-AIDS death range from about a 4-fold increase with elevated
hyaluronic acid + D-dimer to about a 6-fold increase for elevated
hyaluronic acid + either IL-6 or CRP.
of IL-6 and D-dimer were elevated in HIV/hepatitis coinfected patients
with impaired liver function (HA >75 ng/mL)," the investigators
summarized. "Interruption of ART led to further activation of coagulation
but not inflammatory processes."
"Patients with impaired liver function and already activated coagulation
processes are at particularly high risk of non-AIDS death," they
Peters and others (INSIGHT SMART Study Group). Biomarkers of Inflammation
and Coagulation and Risk of Non-AIDS Death (NAD) in HIV/Hepatitis Co-infected
Patients in the SMART Study. 17th Conference on Retroviruses & Opportunistic
Infections (CROI 2010). San Francisco. February 16-19, 2010. (Abstract