SUMMARY: 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.

By Liz Highleyman

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.

Briefly, the SMART 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 kidney disease.

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.

At baseline, 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 follow-up period.

Results

	A total of 50 deaths occurred during follow-up, 30 in the treatment interruption arm and 20 in the continuous therapy arm.
	The 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.
	Patients with elevated hyaluronic acid at baseline also had significantly higher levels of IL-6 and D-dimer, but not CRP.
	During 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.
	Participants 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.
	People 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%.
	Risk 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.

"Levels 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 concluded.

3/12/10

Reference
L 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 660).