Interferon response reduces liver disease and death in HIV/HCV co-infected people

Effective interferon-based therapy that produces sustained virological response led to significant reductions in liver decompensation, HIV disease progression and both overall and liver-related mortality among people with HIV and hepatitis C co-infection, according to a presentation at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last week in Denver.

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to severe liver disease including cirrhosis and hepatocellular carcinoma, a type of liver cancer. People co-infected with both HIV and HCV tend to experience more rapid liver disease progression and respond less well to interferon-based therapy than those with hepatitis C alone. HIV-negative people with hepatitis C are generally not treated if they have mild to moderate liver disease, but people with co-infection may benefit from earlier therapy due to their risk of more aggressive disease.

Juan Berenguer from Hospital Gregorio Marañón and fellow investigators with the GESIDA 3603 HIV/HCV Cohort Study looked at the effects of successful interferon-based therapy on liver disease progression and death amongst people with HIV/HCV co-infection who didn't have advanced liver fibrosis at baseline.

While the clinical benefits of sustained virological response (SVR), or continued undetectable viral load 12 or 24 weeks after completing treatment have been well characterised for people with co-infection who have advanced liver disease, outcomes for people with co-infection who have milder liver damage are less well understood, the researchers noted as background.

This analysis included 695 participants in the GESIDA 3603 cohort, a group of co-infected patients at 19 clinical centres in Spain who started treatment with conventional or pegylated interferon plus ribavirin between January 2000 and January 2008.

About three-quarters of participants were men, most were white, the median age was 40 years and more than 80% had a history of injection drug use. The median CD4 T-cell count was high, at 546 cells/mm³, but 20% had a history of AIDS (CDC Category C disease).

Two-thirds of participants had difficult-to-treat HCV genotypes 1 or 4, the rest genotypes 2 or 3. Pre-treatment liver biopsies showed that 11% did not have fibrosis (Metavir stage F0), 42% had mild fibrosis (F1) and 47% had moderate fibrosis (F2). People with bridging fibrosis (F3) or cirrhosis (F4) were not included in this analysis.

The researchers looked at various liver-related outcomes including liver decompensation (inability to perform critical functions), hepatocellular carcinoma, liver transplantation, liver-related death and all-cause mortality. Assessments of liver damage were made using biopsies and transient elastometry (FibroScan), a non-invasive method that uses sound waves to measure liver stiffness.

Overall, 35% of study participants achieved sustained response. Factors significantly associated with greater likelihood of SVR included HCV genotype 2 or 3 vs 1 or 4 (odds ratio [OR] 4.24), pre-treatment HCV viral load <500,000 IU/ml (OR 1.88) and no heavy alcohol use (<50 g/day; OR 4.04). Liver stiffness scores decreased significantly more following treatment amongst people who achieved SVR.

Over a median follow-up period of 59 months, event rates for people with and without SVR were as follows:

• Liver decompensation: 0.26 vs 0.84 per 100 person-years
• Hepatocellular carcinoma: 0.13 vs 0 per 100 person-years
• Liver-related mortality: 0 vs 0.09 per 100 person-years
• All-cause mortality: 0.39 vs 0.63 per 100 person-years
• Progression to AIDS: 0.13 vs 0.55 per 100 person-years.

Participants who achieved SVR were significantly less likely than non-responders to experience liver decompensation (1.1 vs 6.2%; p =.010) and all liver-related events (p<0.001). Successfully treated patients were also less likely to experience HIV disease progression to AIDS (0.7 vs 3.3%; p<0.05).

People with sustained response were found to have significantly lower liver-related mortality (0.4 vs 2.6%; p = 0.024) and overall mortality (1.5 vs 5.2%; p = 0.010).

However, when results were broken down by pre-treatment liver disease stage, differences in outcomes (except for AIDS) remained significant only for people with moderate fibrosis (F2), not for those with absent or mild fibrosis (F0-F1).

"Eradication of HCV in HIV/HCV co-infected patients with non-advanced liver fibrosis (F0 to F2), and, more specifically, with moderate stages of liver fibrosis (F2), is associated with a reduction in the risk of mortality and liver-related events," the researchers concluded.

"These findings constitute a strong rationale for considering anti-HCV treatment in this population group, particularly treatment based on the newer and more effective direct antiviral agents," they added.

Following the presentation Joseph Eron noted that numbers of people with specific fibrosis stages were small, so we cannot assume treatment conferred no benefit for people with less advanced liver disease. Dr Berenguer agreed, stating, "I think if we follow them longer, even patients with mild fibrosis would get benefits."

Berenguer and Jose Miro from the University of Barcelona, who discussed liver transplantation at the same session, both acknowledged that their presentations were largely history due to the advent of effective new direct-acting anti-HCV drugs.

Interferon/ribavirin dual therapy cures only about half of people with HCV genotype 1 – even less among those with HIV – with a year of difficult-to-tolerate therapy. This is currently being replaced by triple therapy with add-on HCV protease inhibitors, bringing cure rates up to around 75% even for people with co-infection. Next-generation antivirals now under study, which will first be used as interferon add-ons and eventually in all-oral regimens, promise to bring SVR rates into the 80 to 100% range with shorter, better-tolerated courses of treatment.

Without the disadvantages of year-long therapy, potentially severe side-effects and suboptimal response rates, people with HIV/HCV co-infection will have more incentive to undergo treatment that reduces their long-term risk of liver failure and death.