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CROI 2014 & EASL 2014: Treating Hepatitis B and C in HIV+ People Reduces Liver Disease

Effective antiviral treatment that suppresses hepatitis B virus (HBV) repliaction or eradicates hepatitis C virus (HCV) can lower the risk of developing advanced liver disease including cirrhosis, hepatocellular carcinoma, and decompensation in people with HIV and viral hepatitis coinfection, according to studies presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI) and EASL International Liver Congress.

Tenofovir for HIV/HBV Coinfection

At the EASL meeting, Gilles Wandeler from Bern University Hospital presented findings from a study of HIV positive people with hepatitis B in the Swiss HIV Cohort Study. HIV/HBV coinfected patients make up 6% of the cohort and account for a majority of cases of hepatocellular carcinoma (HCC), a type of liver cancer typically seen in people with cirrhosis. European guidelines recommend HCC screening every 6 months for HIV/HBV coinfected people.

The analysis included all 789 HIV/HBV coinfected patients in the cohort. Most were men, about three-quarters were Caucasian, and the median nadir (lowest-ever) CD4 T-cell count was approximately 240 cells/mm³. About one-quarter were triple-infected with HCV and about 5% had hepatitis delta (HDV), a defective virus that only occurs with HBV. About half reported using alcohol, another risk factor for liver cirrhosis and HCC.

About two-thirds had used tenofovir (Viread), usually in combination with emtricitabine (both components of the Truvada, Atripla, Complera, and Stribild coformulations) or lamivudine (3TC, Epivir), while 20% had used either emtricitabine or lamivudine without tenofovir. All 3 drugs are dually active against both HIV and HBV. The remaining 11% had not used drugs active against HBV.

Over more than 8000 patient-years of follow-up, a total of 22 people (3%) developed hepatocellular carcinoma and 18 died of HCC. Risk factors for HCC included HCV, HDV, cirrhosis, non-Caucasian race/ethnicity, and taking tenofovir for less than half the total follow-up period.

The overall incidence of liver cancer was 0.27 per 100 person-years. Among people who used tenofovir the incidence was 0.16 per 100 person-years, compared with 0.31 among those who used no drugs active against HBV and 0.33 among those who used lamivudine or emtricitabine alone.

Only 1 person (5%) with HCC took tenofovir for more than half the follow-up period, compared with 30% of patients who did not develop HCC. Relative to people taking no HBV-active drugs, the risk of developing HCC was 50% lower among people who took tenofovir (incidence rate ratio 0.50).

"HCC incidence was lowest in those on [tenofovir]," the researchers concluded. Among individuals without risk factors -- including taking tenofovir less that half of follow-up time -- "there were no HCC cases during over 800 years of follow-up."

Fibrosis in HIV/HCV Coinfected People 

As reported at CROI, Marc Arthur Loko from INSERM in Bordeaux, France, and colleagues looked at liver fibrosis progression among HIV/HCV coinfected people and the effect of successful hepatitis C treatment.

The ANRS CO13 HEPAVIH Cohort included HIV/HCV coinfected patients who received hepatitis C treatment using pegylated interferon and ribavirin and had available FibroScan transient elastometry liver stiffness measurements from before and after treatment. The researchers also look at the FIB-4 and APRI biomarker indices of liver fibrosis.

Among 160 patients included in the analysis, 69 (43%) achieved sustained virological response (SVR), or continued undetectable HCV viral load after completion of treatment. After a median 3 years of follow-up, a significant decrease in liver stiffness was observed among people who achieved SVR: -19% after 1-2 years, -31% after 2-3 years, and -25% after 3-4 years. Similar patterns were observed using APRI and FIB-4. Successful treatment was associated with reduced liver stiffness in both patients with and without cirrhosis.

Non-responders experienced a transient improvement in liver stiffness during the first year after completing treatment, but this was not sustained. In a multivariate analysis, SVR was the only factor associated with long-term improvement in liver stiffness.

"In HIV/HCV coinfected patients, liver stiffness is significantly reduced after treatment, and this improvement continues off treatment in patients who achieve a SVR," the researchers concluded.

Liver Decompensation

Three other presentations at CROI focused on liver decompensation among HIV/HCV coinfected people. Decompensation occurs when the liver can no longer carry out its vital functions, leading to symptoms such as bleeding veins (varices) in the esophagus or stomach, ascites (abdominal fluid build-up), bacterial peritonitis (abdominal infection), and hepatic encephalopathy (brain impairment).

Temitope Olufade from Merck and colleagues evaluated the effects of sustained response to hepatitis C treatment on risk of liver decompensation in HIV/HCV coinfected and HCV monoinfected individuals.

The analysis included 467 HIV/HCV coinfected patients and 11,395 HCV monoinfected patients treated with interferon-based therapy through the U.S. Veterans Health Administration between October 2005 and December 2012. Most were men, the mean age was 55 years, and about 11% had cirrhosis.

At 12 weeks post-treatment, 24% of HIV/HCV coinfected patients and 31% of HCV monoinfected patients achieved SVR. People who were cured had a lower incidence of liver decompensation than non-responders in both the coinfected group (4.2 vs 13.3 events per 1000 person-years) and the monoinfected group (3.4 vs 16.7 events per 1000 person-years). The adjusted hazard ratio (HR) of decompensation for coinfected non-responders was 1.74, rising to 5.13 for monoinfected non-responders. However, among people who were cured, the risk of decompensation was not significantly higher for coinfected compared with monoinfected patients (adjusted HR 1.67).

"Achieving SVR following interferon-based treatment decreased rates of hepatic decompensation among HIV/HCV coinfected and HCV monoinfected patients," the researchers concluded. "HIV/HCV coinfected patients who achieved SVR did not have a higher rate of hepatic decompensation than HCV monoinfected patients with SVR."

These findings, they added, "suggest that successful HCV therapy is associated with reduced liver complications in both HIV/HCV coinfected and HCV monoinfected patients."

The same research team also compared rates of liver decompensation between HIV/HCV coinfected people and those with HIV/HBV/HCV triple infection, and looked at the effect of drugs dually active against HIV and HBV.

This analysis included 149 patients with HIV/HBV/HCV and 4902 with HIV/HCV receiving care through the Veterans Health Administration between October 2005 and February 2012; again, most were middle-aged men.

The incidence of decompensation was significantly higher among triple-infected compared with dual-infected patients (24.1 vs 10.8 events per 1000 person-years; adjusted HR 2.40). When classified by type of treatment, however, decompensation risk was substantially higher for those triple-infected patients who did not use antiretrovirals active against HBV (adjusted HR 2.48), but not for those who used dually active agents such as tenofovir (adjusted HR 1.09).

"Controlling HBV viremia with HBV therapy is important to reduce rates of hepatic decompensation in HIV/HBV/HCV triply infected persons," the researchers concluded.

Finally, Juan Macías from Hospital Universitario de Valme in Seville, Spain, and colleagues looked at short-term risk of decompensation among HIV/HCV coinfected patients with moderate versus advanced liver fibrosis.

Given the difficult side effects and suboptimal cure rates of interferon-based therapy, and the pending availability of better direct-acting antiviral agents, many people with hepatitis C have deferred treatment if they do not have advanced liver disease and are thought to be at low risk for liver failure. But HIV/HCV coinfected people experience more rapid liver disease progression, on average, than those with HCV alone, which could make waiting unwise for this population.

This prospective analysis included 540 coinfected people with available liver biopsies who either had not been treated for hepatitis C or were non-responders to interferon-based therapy. Most were men, the mean age was 47 years, the median CD4 count was approximately 460 cells/mm³, and a majority had undetectable HIV viral load. At baseline, about 7% had absent fibrosis (stage F0), 22% had mild fibrosis (F1), 22% had moderate fibrosis (F2), 24% had advanced fibrosis (F3), and 25% had cirrhosis (F4).

During a median follow-up period of 5.6 years, decompensation occurred in none of the patients with stage F0 fibrosis, 5 people (4%) with stage F1, 7 people (6%) with stage F2, 12 people (9%) with stage F3, and 29 people (21%) with stage F4.

The likelihood of not experiencing decompensation over 1 year was 98% for people with stage F1, F2, or F3 fibrosis, falling to 85% for those with cirrhosis. At 3 years the corresponding probability were 98% for F1 and F2, 94% for F3, and 79% for F4. At 5 years, the probability dropped to 91% for F1, 86% for F2, 78% for F3, and 66% for F4. Over time, the probability of remaining free of decompensation was not significantly lower for coinfected people with stage F2 versus those with F3.

"HIV/HCV coinfected patients with F2 are at a risk of [decompensation] not significantly different from individuals with F3," the researchers concluded. "Consequently, a similar degree of priority for [hepatitis C] therapy should be given to them."

5/13/14

References

G Wandeler, D Kraus, M Egger, et al (Swiss HIV Cohort Study). Reduced incidence of hepatocellular carcinoma in HIV/HBV-coinfected patients receiving tenofovir. 49th European Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O120.

MA Loko, C Gilbert, K Lacombe, et al. Significant Decrease of Liver Fibrosis in HIV-HCV Coinfected Patients Treated for HCV Infection. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 653.

TO Olufade, Li Wang, S Devine, et al. Sustained Virologic Response and the Risk
of Liver Decompensation in HCV and HIV/HCV Patients. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 641.

TO Olufade, Li Wang, Scott Devine, et al. Hepatic Decompensation in HIV/HBV/HCV Patients and the Impact of HBV Therapy. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 645.

J Macías, M Márquez, D Merino, et al. Short-Term Risk of Decompensation Among HIV/HCV-Coinfected Patients With Significant Fibrosis. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 646.