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CROI 2012: ART Liver Toxicity is Lower with Modern Regimens, but Still a Risk for HIV/HCV Coinfected

Liver toxicity related to antiretroviral therapy (ART) has become less common in recent years thanks to development of better tolerated drugs and improved understanding of how to use them. But HIV positive people coinfected with hepatitis C remain at higher risk, researchers reported at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) this month in Seattle.

Hepatotoxicity is a known side effect of certain antiretroviral drugs. The NRTIs didanosine (ddI; Videx) and stavudine (d4T; Zerit) can cause liver steatosis and enlargement related to mitochondrial toxicity, the NNRTI nevirapine (Viramune) can cause hypersensitivity reactions that involve the liver, and protease inhibitors (especially ritonavir, or Norvir) can lead to liver injury signaled by elevated alanine aminotransferase  (ALT) enzyme levels. People with pre-existing liver disease -- including viral hepatitis -- are more prone to drug-related liver toxicity.

As HIV treatment has evolved over the past 2 decades, drugs have become more effective, easier to tolerate, and more convenient. Mark Hull from the British Columbia Centre for Excellence in HIV/AIDS in Vancouver and colleagues

Looked at the association between time of ART initiation and hepatotoxicity, and its relation to hepatitis C virus (HCV) status.

This analysis included 748 treatment-naive patients enrolled in the British Columbia Drug Treatment Program who started combination ART between 1997 and 2009. Most (91%) were men, the median age was 42 years, 24% were injection drug users, and 26% were HIV/HCV coinfected. All had normal ALT at baseline and at least 12 months of follow-up laboratory results.

The researchers divided participants into 3 groups based on when they started HIV treatment:

• Period 1: January 1, 1997 through December 31, 1999, the beginning of the combination ART era;
• Period 2: January 1, 2000 through December 31, 2003;
• Period 3: January 1, 2004 through December 31, 2009.

Hepatotoxicity was defined as ALT rising to more than 5 times the baseline level. Incidence rates of liver toxicity were determined for each time period, according to HCV status.

Results

• A total of 107 people (14%) started treatment during Period 1, 208 people (28%) did so during Period 2, and 433 people (58%) did so during Period 3.
• The average time to development of hepatotoxicity was about 10 months.
• The overall incidence of hepatotoxicity decreased substantially over time:
  • Period 1: 17 cases per 100 person-years;
  • Period 2: 10 cases per 100 person-years;
  • Period 3: 7 cases per 100 person-years.
• However, the risk of hepatotoxicity remained significantly higher for HIV/HCV coinfected compared with HIV monoinfected people:
  • Period 1: 38 vs 2 cases per 100 person-years, respectively;
  • Period 2: 30 cases vs 1 case per 100 person-years, respectively;
  • Period 3: 25 vs 2 case per 100 person-years, respectively.
• In a multivariate analysis, the following factors were significant predictors of hepatotoxicity:
  • Baseline HCV status: adjusted relative risk (RR) 12.01, or 12-fold higher risk;
  • Period of ART initiation: adjusted RR 2.56 for Period 1 vs Period 3 and 0.73 for Period 2 vs Period 3;
  • Injection drug use: adjusted RR 1.63;
  • ART regimen: adjusted RR 1.64 for NNRTI vs protease inhibitor.
• Alcohol use and switching regimens within the first year of therapy were not significant risk factors for hepatotoxicity.
• In a sub-analysis of specific drugs, incidence of hepatotoxicity was as follows:
  • Protease inhibitor regimens: 7 cases per 100 person-years;
  • NNRTI nevirapine: 16 cases per 100 person-years;
  • NNRTI efavirenz (Sustiva): 9 cases per 100 person-years.

Based on these findings, Hall's team concluded, "Incidence of hepatotoxicity has diminished in the modern combination ART era, but remains significantly higher in those with HCV coinfection."

"Early HCV therapy may serve to decrease the risk of hepatotoxicity following combination ART initiation," they suggested.

Studies have shown that coinfected people who achieve sustained virological response to hepatitis C treatment -- generally regarded as a cure -- are less likely to experience ART-related hepatotoxicity than non-responders with persistent HCV infection.

Although the researchers recommended that coinfected patients "should be assessed for consideration of HCV therapy prior to combination ART initiation as a means of decreasing subsequent combination ART-related hepatotoxicity," many experts favor treating HIV first or simultaneously, since people with well-controlled HIV and higher CD4 cell counts respond better to hepatitis C treatment.

4/3/12

Reference

M Hull, W Zhang, B Yip, J Montaner, et al. Initiation of ART in the Modern Era Is Associated with Decreased Risk of Hepatotoxicity in HIV/HCV Co-infected Patients. 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012). Seattle, WA. March 5-8, 2012. Abstract 778.