Early liver enzyme elevations wane with prolonged HAART treatment in women with HCV

Antiretroviral therapy for HIV is safe for women coinfected with hepatitis C virus (HCV), according to an American study published in the August 1st edition of Clinical Infectious Diseases. The US investigators also found that many women’s liver enzyme levels actually fell after the initiation of HAART, and that when HAART did lead to an increase in liver enzymes, these increases tended to be mild and to decrease with time.

A number of antiretroviral drugs have been associated with liver toxicity, which is often first signaled by increased levels of two liver enzymes, alanine and aspartate aminotransferase (ALT and AST, respectively). Several short-term studies have shown that certain protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are linked to elevated liver enzymes, especially in individuals with liver disease such as viral hepatitis. Nevirapine (Viramune) in particular has been associated with both acute and delayed hepatotoxicity. Other research, however, has failed to confirm a link between antiretroviral drugs and liver toxicity.

To examine the prevalence of long-term hepatotoxicity in women, Audrey French and colleagues conducted a longitudinal analysis of ALT and AST levels in HIV-infected women with and without HCV from the time they started highly active antiretroviral therapy (HAART). The subjects were participants in the Women’s Interagency HIV Study (WIHS), a longitudinal observational study of HIV-infected and at-risk women. Participants had clinic visits every 6-12 months, which included physical examinations and blood sample collection.

The present study included 456 HIV/HCV-coinfected women and 650 HIV positive women without HCV who initiated HAART between 1 April 1995 and 31 March 2002. A majority of the subjects were African American (59% coinfected, 51% HCV negative). At the time of HAART initiation, the coinfected women were older (42 vs 37 years), but the two groups had similar CD4 cell counts (about 300 cells/mm³) and HIV viral loads (about 3.95 log₁₀ copies/ml). Most women (73%) initiated HAART with a PI, while 19% started with a NNRTI -- usually nevirapine (78%).

The authors’ longitudinal analysis included 312 HIV/HCV-coinfected and 446 HCV negative women, who were on HAART for a mean of 1.8 years. The researchers calculated the number of subjects with ALT and AST levels greater than the upper limit of normal (ULN). ULN differs somewhat from laboratory to laboratory; for this study, ULN was defined as 40-65 IU/L for ALT and 35-50 IU/L for AST.

Not surprisingly, coinfected women had higher ALT and AST levels both before and after HAART initiation compared with HCV negative women. When HAART was started, about one-third of the coinfected women had at least mildly elevated ALT and about one-half had at least mildly elevated AST. However, fewer than 7% had moderately elevated ALT and less than 12% had moderately elevated AST (greater than 3 times the ULN), and fewer than 4% had severely elevated ALT or AST (greater than 5 times the ULN). Among the 63 coinfected subjects with moderate to severe aminotransferase elevations, 36 (57%) continued their HAART regimen, 18 (29%) discontinued HAART, and 9 (14%) switched to a different class of drugs. Overall, the proportion of coinfected women with elevated ALT or AST declined during the period they were on HAART.

The researchers also conducted a subanalysis of 667 women categorized by HCV status and type of antiretroviral therapy; 212 coinfected and 327 HCV negative women initiated HAART with a PI but no NNRTI, while 54 coinfected and 74 HCV negative women started with a NNRTI but no PI. At all time points, coinfected women had significantly higher ALT and AST levels than HCV negative women. Among the 539 women taking PIs, aminotransferase levels declined by about 4-5% of the ULN per year (p = 0.007 for AST for coinfected and HCV negative women, and for ALT for HCV negative women; p = 0.06 for ALT for coinfected women). Among the 128 women taking NNRTIs, however, aminostransferase levels increased slightly, though the change was not statistically significant (p = 0.19-0.71).

The authors found that women who had lower ALT and AST (less than 1.5 times the ULN) when starting HAART tended to maintain stable levels, while those with higher pre-HAART aminotransferase levels (greater than 1.5 times the ULN) experienced significant decreases over time. In fact, the women with the highest pre-HAART liver enzyme levels saw the greatest declines after initiating combination antiretroviral.

“We found that the proportion of women who had moderately or severely elevated aminotransferase levels while receiving HAART, even among those with hepatitis C coinfection, was low and decreased over time,” the authors concluded. “Our findings lend support to assertions that antiretroviral therapy is safe for women with HCV infection.”