HCV or HBV Coinfection Are Risk Factors for Liver-Related Death in the D:A:D Study

By Liz Highleyman

Liver-related deaths are a major contributor to mortality in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, and are often related to hepatitis B or C virus (HBV, HCV) coinfection, according to a study reported in the August 14/28, 2006 Archives of Internal Medicine.

D:A:D is an ongoing study of adverse events associated with antiretroviral therapy in the U.S., Europe, and Australia. There is concern that antiretroviral drugs can cause serious and potentially fatal liver toxicity, especially in patients with co-existing hepatitis B or C. The D:A:D cohort includes 23,441 HIV positive participants followed for 3.5 years to date, for a total of 76,893 person-years (PY).

Results

During the follow-up period, there were a total of 1246 deaths due to all causes (5.3%, or 1.62 per 100 PY).

Of these, 14.5% were liver-related.

Among the patients who died of liver-related causes, 66.1% had HCV coinfection, 16.1% had HBV coinfection, and 7.1% had both viruses.

Patients whose latest CD4 cell count was below 50 cells/mm3 were 16 times more likely to die due to liver-related causes than patients with CD4 counts above 500 cells/mm3 (adjusted relative risk [RR] = 16.1).

A 2-fold lower CD4 cell count was associated with a 23% increased risk of liver-related death (RR = 1.23).

Each additional log higher HIV viral load level was associated with an increased risk of 27% (RR = 1.27)

Other risk factors that predicted liver-related death were:

- HCV infection (RR = 6.7);
- active HBV infection (RR = 3.7);
- injection drug use (RR = 2.0);
- older age (RR = 1.3 per additional 5 years).

By univariate analyses, there was no relationship between cumulative years on HAART and liver-related death (RR = 1.00).

After adjusting for the most recent CD4 cell count and other patient characteristics, however, there was an increased risk of liver-related mortality per year of suboptimal monotherapy or dual antiretroviral therapy before HAART (RR = 1.09), and per year of HAART (RR = 1.11; P = .02).

Conclusion

"Liver-related death was the most frequent cause of non-AIDS-related death," the authors concluded. "We found a strong association between immunodeficiency and risk of liver-related death. Longer follow-up is required to investigate whether clinically significant treatment-associated liver-related mortality will develop."

In their discussion, the researchers noted that while liver disease was the most common non-AIDS-related cause of death (14.5%), AIDS-related disease still accounted for the largest proportion of deaths (31.1%).

More than 76% of the liver-related deaths in this study, they said, were associated with either HBV or HCV coinfection (or both). "Antiretroviral therapy has been reported to reduce liver-related mortality in HCV coinfected persons, but we found no such effect," they wrote.

In contrast, just 2.7% of all liver-related deaths were reportedly directly related to hepatotoxicity due to antiretroviral medications. "The link with acute hepatotoxicities for some antiretroviral drugs is an undisputed but infrequent cause of mortality," they wrote. "In contrast, the possible long-term adverse effects of [HAART] on hepatic function are controversial…The present results do not allow us to reach firm conclusions about any relationship between prolonged [HAART] and liver-related death."

"[T]here may be negative effects of [HAART] on the liver in addition to the positive effects acting via CD4 cell count increases," they added. "However, the residual relationship was relatively modest and of borderline statistical significance, so it is difficult to rule out confounding." Further, the association between pre-HAART use of mono- or dual antiretroviral therapy may suggest that the prolonged use of nucleoside reverse transcriptase inhibitors (NRTIs) -- which have been around longer than any other anti-HIV drugs -- might be a risk factor for hepatotoxicity.

The authors said they were surprised to find such a strong relationship between liver-related deaths and cellular immunodeficiency. While higher viral load was also linked with higher mortality, more than half of those who died of liver-related causes had undetectable HIV viral load at the time of death. This finding "underlines the importance of HIV treatment strategies that prevent immunodeficiency," they wrote.

"These findings suggest that the effect of immunodeficiency on the risk of these types of death remains present even in patients with CD4 cell counts of 200 to 500 [cells/mm3]," the continued. Therefore, "Future studies should explore the possible benefits and risks of starting antiretroviral therapy at CD4 cell counts higher than currently recommended in patients with a known risk of liver-related death."

10/17/06

Reference
R Weber, C A Sabin, N Friis-Moller, and others (the Data Collection on Adverse Events of Anti- Adverse Events of Anti-HIV Drugs Study Group). Liver-Related Deaths in Persons Infected With the Human Immunodeficiency Virus: The D:A:D Study. Archives of Internal Medicine 166(15): 1632-1641. August 14/28, 2006.

Additional D:A:D Study Articles

Protease Inhibitor Therapy Increases Risk of Myocardial Infarction: D:A:D Study

Limited Impact of Antiretroviral Therapy on Risk of Liver-related Death: The D:A:D Study

Metabolic and Adverse Events Report from the 13th CROI