Hepatitis C Treatment Reduces HIV Progression and Death in HIV/HCV Coinfected

HIV positive people who achieve sustained virological response (SVR) to interferon-based therapy for chronic hepatitis C not only lower their risk of liver-related complications and death, but also have lower rates of HIV disease progression and all-cause mortality, according to a study published in the May 18, 2012, advance online edition of Clinical Infectious Diseases.

It is well established that sustained response to hepatitis C treatment reduces development of advanced liver disease including cirrhosis and hepatocellular carcinoma -- and consequently the risk of liver-related death -- but its effect on overall mortality in HIV/HCV coinfected people is not clear.

Juan Berenguer and fellow investigators with the GESIDA HIV/HCV Cohort Study Group assessed the effect of sustained treatment response on HIV progression and mortality not related to liver disease.

This observational cohort study included about 1600 consecutive HIV/HCV coinfected patients at 19 centers in Spain who were treated with interferon plus ribavirin between 2000 and 2008 -- before the advent of HCV direct-acting antiviral agents.

Three-quarters of study participants were men and the median age was 40 years. The median baseline CD4 T-cell count was relatively high, at 527 cells/mm³, and 70% had undetectable HIV RNA, but 23% had prior AIDS-defining conditions. Patients had been infected with HCV for a median of 18 years; 61% had difficult-to-treat HCV genotypes 1 or 4, the same proportion had high baseline HCV viral load, and 39% had advanced fibrosis or cirrhosis (stage F3-F4) at baseline.

About half were treated with pegylated interferon alfa-2a (Pegasys), 38% received pegylated interferon alfa-2b (PegIntron), and 13% received conventional thrice-weekly interferon alfa, all in combination with ribavirin. During hepatitis C treatment 79% were also on combination antiretroviral therapy (ART).

Results

• 626 out of 1599 patients (39%) achieved SVR, or continued undetectable viral load after completion of treatment -- 26% for genotypes 1/4 and 63% for genotypes 2/3.
• Factors independently associated with SVR were HCV genotype 2/3, baseline HCV viral load < 500,000 IU/mL, and absence of advanced fibrosis.
• Non-responders were also more likely than sustained responders to have detectable HIV viral load.
• Non-responders were also more likely to have CD4 T-cell counts < 200 cells/mm³ after stopping interferon/ribavirin, which could not be explained by differences in HIV suppression.
• After a median follow-up period of nearly 5 years, patients without sustained response had an increased risk of liver-related events and liver-related deaths compared with sustained responders (about 14% vs 2%, respectively).
• Non-responders were more likely than sustained responders to die from any cause (about 9% vs 1%, respectively).
• Interferon non-responders were also significantly more likely than sustained responders to experience:
  • AIDS-defining conditions: 0.84 vs 0.29 per 100 person-years, respectively (P = 0.003);
  • Non-liver-related deaths: 0.65 vs 0.16 per 100 person-years (P = 0.002);
  • Deaths that were neither liver-related nor AIDS-related: 0.55 vs 0.16 per 100 person-years (P = 0.002).
• After adjusting for other factors including demographics, CD4 count, and ART use, adjusted hazard ratios for non-responders compared with sustained responders were:
  • 1.90 -- nearly double the risk -- for new AIDS-defining conditions;
  • 3.19 -- more than triple the risk -- for non-liver-related deaths;
  • 2.85 -- nearly triple the risk -- for non-liver-related/non-AIDS-related deaths.

"Our findings suggest that eradication of HCV after therapy with [interferon-ribavirin] in HIV/HCV coinfected patients is associated not only with a reduction in liver-related events, but also with a reduction in HIV progression and mortality not related to liver disease," the study authors concluded.

"We found that failure to achieve an SVR was associated with increased risk of liver decompensation, hepatocellular carcinoma, liver transplantation, and liver-related death," they elaborated in their discussion. "Most non-liver-related deaths were due to non-AIDS-defining cancers, cardiovascular events, and bacterial infections."

"The increased risk of non-liver-related death and non-liver-related/non-AIDS-related death among non-responders [compared with] responders found in our study may be explained by several factors, including immune activation, defective immunity, systemic inflammation, and liver disease itself," the researchers wrote. "Just as combination ART causes a decline in the high levels of inflammation and hypercoagulation that are characteristically associated with untreated HIV infection, eradication of HCV may have similar effects."

"These findings support an increasingly strong rationale for earlier evaluation of new direct-acting antivirals against HCV in coinfected patients, a subgroup with a hugely unmet need for treatment," they recommended.

6/1/12

Reference

J Berenguer, E Rodríguez, P Miralles, et al (GESIDA HIV/HCV Cohort Study Group). Sustained Virological Response to Interferon Plus Ribavirin Reduces Non-Liver-Related Mortality in Patients Coinfected With Human Immunodeficiency Virus and Hepatitis C Virus. Clinical Infectious Diseases. May 18, 2012 (Epub ahead of print).