Coinfection

EACS 2015: Successful Hepatitis C Treatment Lowers Risk of Death for HIV/HCV Coinfected People

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Hepatitis C treatment that leads to sustained virological response (SVR) -- generally regarded as a cure -- was associated with a reduced risk of liver-related death and improved overall survival in an analysis of 3500 HIV and hepatitis C virus (HCV) coinfected patients, according to a presentation at the 15th European AIDS Conference last week in Barcelona. A related study found that while some liver-related events are declining over time, liver cancer remains a risk for coinfected people.

Over years or decades chronic HCV infection can lead to serious liver disease including cirrhosis, hepatocellular carcinoma (HCC, a type of liver cancer), and end-stage liver failure necessitating a liver transplant. Research has shown that HIV-positive people coinfected with HCV experience more rapid liver disease progression, on average, than those with hepatitis C alone.

Lars Peters from Rigshospitalet in Copenhagen and fellow investigators withthe COHERE Hepatitis Subgroup looked at the long-term risk of all-cause, liver-related, and non-liver-related death among HIV/HCV coinfected individuals, and its relation to hepatitis C treatment response, in a large multi-cohort study.

Prior research has shown that sustained response to hepatitis C treatment is associated with reduced mortality among HIV-negative people with HCV, Peters noted as background. The survival benefit of treatment for coinfected patients could be greater due to their accelerated fibrosis progression, or less because they are more likely to die of other "competing" causes.

COHERE (Collaboration of Observational HIV Epidemiological Research in Europe), part of the EuroCoord network of HIV cohort studies, is comprised of 33 prospective cohorts from across Europe; this analysis included data from 18 of these cohorts.

The analysis included all HIV/HCV coinfected COHERE participants who had ever started interferon-based hepatitis C therapy and were followed for at least 96 weeks. (Interferon-free therapy using direct-acting antiviral agents is too recent to have played a role in this study.)

Overall, nearly 80% were men, the median age at hepatitis C treatment initiation was 42 years, and 60% had a history of injecting drug use. Most were on antiretroviral therapy (ART) and the median CD4 T-cell count was 426 cells/mm3. Just 4% were triply infected with hepatitis B virus (HBV). Over half (56%) had HCV genotype 1.

Among the 3500 coinfected patients who started hepatitis C treatment, 28.5% were responders, 45.3% were non-responders, and 26.2% had unknown response.

Compared to non-responders, the responders started interferon-based therapy later (2007 vs 2005), were less likely to inject drugs (47% vs 65%), and were more likely to have hepatitis B (5.1% vs 3.6%). Responders had a higher median CD4 count (461 vs 405 cells/mm3) and were less likely to have been diagnosed with AIDS.

Responders were also less likely than non-responders to have HCV genotype 1 (50% vs 62%), which does not respond as well to interferon. Median APRI scores -- a biomarker index used to estimate liver fibrosis -- were 0.8 for non-responders and 0.9 for responders at the start of treatment, suggesting moderate to advanced fibrosis; a score over 1.5 suggests cirrhosis.

The researchers assessed survival times starting from week 96 after treatment initiation until death or last follow-up visit.

Results

"HIV/HCV co-infected patients with a favorable virological response to HCV treatment had reduced incidence of liver-related death and improved overall survival," the researchers concluded.

A limitation of this study is the lack of follow-up HCV RNA measurements for all participants, but Peters said this would tend to underestimate rather than exaggerate the survival benefit of successful treatment.

Trends in HCC and Liver-related Events

Lars Iversen Gjaerde from the University of Copenhagen and colleagues looked at shifts in hepatocellular carcinoma and other liver-related events among HIV/HCV coinfected participants in four prospective cohort studies.

As background, Gjaerde said prior research shows that while liver-related mortality among coinfected people seems to have declined during the past decade, HCC may have increased.

This analysis included 7229 HIV/HCV coinfected people followed from 2001 through 2014 in the EuroSIDA Study, the Swiss HIV Cohort Study, the Canadian Co-infection Cohort, and the South Alberta Clinic Cohort. A majority (68%) were men, most were white, and the median age was 38 years. About 60% had a history of injection drug use and 5% also tested positive for HBV. Hepatitis C status was determined by HCV antibodies, not HCV RNA, so it is possible some presumed co-infected participants had actually cleared HCV.

A total of 72 cases of HCC and 375 other liver events occurred during approximately 45,000 person-years of follow-up, giving crude incidence rates of 1.6 and 8.6 cases per 1000 person-years, respectively.

People diagnosed with HCC were slightly older than those diagnosed with other liver events (median 50 vs 44 years, respectively), were more likely to be HBV-positive (8% vs 6%), and had a lower APRI score (1.8 vs 2.5). They were also more likely to be on ART and had a higher CD4 cell count.

The incidence of HCC rose during the study period, from 0.4 to 2.3 cases per 1,000 person-years, an average 11% increase per calendar year. In contrast, other liver events declined by 4% per year, after peaking in 2003-2004.

Cirrhosis was the strongest predictor of HCC, Gjaerde said, conferring a 13-fold higher risk. Older age and hepatitis B were also significant risk factors, while a higher CD4 count was protective. Peters suggested that the increase in HCC could be explained by more cirrhotics in the population over time. Cirrhosis, older age, and low CD4 count -- but not hepatitis B -- were also significant risk factors for other liver events.

In conclusion, this study showed "opposing trend in crude incidence rates," which are increasing for HCC and decreasing for other liver events, according to the researchers.

Implications

Though assigned to debate whether HCV clearance "solves everything," Juan Berenguer from Hospital Gregorio Marañón in Madrid and Stefan Mauss from the Centre for HIV and Hepatogastroenterology in Düsseldorf started out in agreement, and instead focused on liver-related outcomes and extra-hepatic (outside the liver) manifestations of HCV infection.

Studies are in accord that successful treatment reduces liver-related complications including advanced fibrosis, cirrhosis, and elevated portal pressure -- the best predictor of liver decompensation -- Berenguer summarized. Nevertheless, people who achieve SVR still have a small remaining risk of decompensation and HCC, so they should continue to undergo regular liver cancer screening.

Mauss explained that there is less evidence for the effects of successful treatment on extra-hepatic manifestations, which may include cryoglobinemia, type 2 diabetes, and increased cardiovascular risk. Hepatitis C treatment improves survival for people with advanced liver disease, but this is mainly due to a decrease in liver-related deaths. But treatment appears to also reduce non-liver-related events and death in people with less advanced fibrosis.

Taken together, this research shows that treating hepatitis C can have numerous benefits including reduction of liver cancer and liver-related deaths. If interferon-based therapy demonstrated these improved outcomes -- despite its poor tolerability and suboptimal efficacy -- the highly effective new interferon-free DAA treatments are likely to be even more advantageous.

10/28/15

References

L Peters and COHERE Hepatitis Subgroup in EuroCoord. Is Response to Anti-HCV Treatment Predictive of Mortality in HCV/HIV Co-infected Patients? 15th European AIDS Conference. Barcelona, October 21-24, 2015. AbstractPS7/4.

LI Gjaerde, L Shepherd, A Mocroft, et al. Trends in Incidence and Risk Factors for Hepatocellular Carcinoma and Other Liver Events in HIV and Hepatitis C Virus Co-infected Individuals from 2001 to 2014: A Multi-cohort Study. 15th European AIDS Conference. Barcelona, October 21-24, 2015. AbstractPS7/2.

J Berenguer and S Mauss. HCV Eradication -- Everything Solved? 15th European AIDS Conference. Barcelona, October 21-24, 2015.