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AASLD 2016: Is Improved Treatment Reducing Liver Cancer Among People with Hepatitis B?


The incidence of hepatocellular carcinoma (HCC) appears to be decreasing and mortality improving among chronic hepatitis B patients treated with suppressive antiviral therapy, according to studies presented at the recent 2016 AASLD Liver Meeting in Boston. However, liver cancer remains a major indication for liver transplants and has a negative effect on survival of people with hepatitis B.

The incidence of hepatocellular carcinoma (HCC) appears to be decreasing and mortality improving among chronic hepatitis B patients treated with suppressive antiviral therapy, according to studies presented at the recent 2016 AASLD Liver Meeting in Boston. However, liver cancer remains a major indication for liver transplants and has a negative effect on survival of people with hepatitis B.

Over years or decades chronic hepatitis B virus (HBV) infection can lead to advanced liver disease including cirrhosis and HCC, and it is a leading cause of liver cancer worldwide. Antiviral therapy using nucleoside/nucleotide analogs such as entecavir (Baraclude) or tenofovir disoproxil fumarate (Viread) is the mainstay of treatment for chronic hepatitis B. While these drugs can suppress HBV replication during therapy -- and can thereby reduce the risk of liver disease progression -- they usually do not lead to a cure and long-term treatment is generally required.

Yao-Chun Hsu from E-Da Hospital and colleagues looked at changes in the risk of HCC over time among chronic hepatitis B patients in Taiwan who received optimal antiviral therapy.

This retrospective cohort study looked at more than 65,000 Taiwanese residents who received entecavir or tenofovir DF between 2008 and 2013, identified in Taiwan’s national healthcare database. People treated for less than 3 months, those previously exposed to other nucleoside/nucleotide analogs such as lamivudine (Epivir), those with pre-existing malignancies, and those who developed HCC within 3 months of starting therapy were excluded. The final analysis included 27,820 eligible patients. Nearly three-quarters were men, the median age was 48 years, a third had cirrhosis, and 7% were coinfected with hepatitis C.

A total of 802 patients developed HCC over a median follow-up period of 29 months. Cumulative incidence rates during the first, second, and third years were 1.82%, 3.05%, and 4.06%, respectively.

HCC incidence declined significantly with more time on treatment (adjusted incidence rate ratio [IRR] 0.73, or about a 27% reduction per year). Cirrhosis was the strongest predictor of developing HCC in a multivariate analysis (adjusted hazard ratio [HR] 4.91), followed by male sex (adjusted HR 1.73), older age (adjusted HR 1.65 per decade), diabetes (adjusted HR 1.25), and hepatitis C coinfection (adjusted HR 1.23).

"The incidence rate of HCC decreased year by year in chronic hepatitis B patients on entecavir or tenofovir," the researchers concluded. They suggested their study could inform a surveillance strategy to more intensively monitor those at greatest risk, as well as identify modifiable factors to reduce liver cancer risk.

In a related study, George Papatheodoridis from the University of Athens Medical School and colleagues assessed HCC incidence beyond the first 5 years on entecavir or tenofovir DF. The researchers had previous shown that HCC could still develop within the first 5 years of treatment despite viral suppression.

This analysis included more than 1900 Caucasian adults with chronic hepatitis B at 10 centers in Europe. About 70% were men, the mean age was 53 years, 18% were HBeAg-positive, most reported little alcohol use, and just over a quarter had compensated cirrhosis. People with pre-existing HCC, decompensated cirrhosis, or hepatitis C or HIV coinfection were excluded. Participants were treated with entecavir or tenofovir DF for at least a year; about 40% had previously used other antivirals and about 20% had used pegylated interferon. Of these, 1205 patients who did not develop HCC within the first 5 years on therapy were followed for at least an additional 5 years.

HCC was diagnosed in 5% of participants within the first 5 years of therapy, and in 17 of the 1205 patients (1.4%) still at risk beyond the first 5 years. 9 patients with cirrhosis (2.8%) and 8 without cirrhosis (0.9%) developed liver cancer after 5 years on treatment. The annual HCC incidence rate was 1.22% within the first 5 years and 0.73% after 5 years.

There was no difference in pre- and post-5 year HCC incidence among non-cirrhotic patients, but the risk dropped significantly after 5 years for people with cirrhosis (from 3.21% to 1.57%). All HCC cases diagnosed after 5 years occurred in people who were older than 50 when they started treatment, and being over 50 was a significant predictor of late HCC.

"The difference in the HCC incidence rates between initially cirrhotic and non-cirrhotic patients becomes less pronounced after year 5, when older age, especially age >50 years, represents the main risk factor for HCC development," the researchers concluded.

Mortality and Liver Transplants


Papatheodoridis and his team also looked at survival of people with and without cirrhosis in this cohort of 1951 patients on long-term entecavir or tenofovir DF. All were treated for at least 1 year (median 6 years). Follow-up continued through April 2016.

Over a median follow-up period of 6 years, 37 non-cirrhotic patients (2.7%) and 44 patients with cirrhosis (8.4%) died from any cause; 10 (0.7%) and 23 (4.4%) of these deaths were due to liver-related causes. 37 non-cirrhotic patients (2.7%) and 80 cirrhotic patients (15.2%) developed HCC, and 8 (0.6%) and 9 (1.7%), respectively, received liver transplants.

Cumulative survival probability for the whole patient population at 1, 3, 5, 8, and 10 years was high: 99.7%, 97.8%, 95.9%, 94.1, and 94.1%, respectively. However, survival rates were significantly higher for non-cirrhotic patients (100%, 98.5%, 97.3%, 96.2%, and 96.2%) compared to those with cirrhosis (99.1%, 95.9%, 92.8%, 89.3%, and 89.3%).

Development of liver cancer was the major factor affecting overall mortality -- and was in fact the only factor affecting liver-related mortality in this cohort, according to the researchers.

Among patients with HCC, 45.9% of non-cirrhotic patients and 32.5% of those with cirrhosis either died from a liver-related cause or got a liver transplant. In contrast, this occurred in just 0.01% of non-cirrhotic and 1.3% of cirrhotic patients without HCC. Having HCC gave a hazard ratio of 5.47 -- more than 5 times higher risk of all-cause death -- but after adjusting for HCC in a multivariate analysis, cirrhosis had a much smaller though still significant effect (HR 1.08).

Finally, Kellie Young from the Santa Clara Valley Medical Center, Robert Wong from the Alameda Health System, and colleagues used data from the United Network for Organ Sharing registry to evaluate trends in liver transplant wait-list registrations, survival while wait-listed, and the likelihood of receiving transplants among adults with chronic hepatitis B in the U.S.

This retrospectively study looked at approximately 6700 patients (about 80% men) wait-listed during 3 time periods:

  • Era 1: 1992-1996, before treatment with nucleoside/nucleotide analogs;
  • Era 2: 1997-2004, lamivudine and adefovir (Hepsera) available;
  • Era 3: 2005-2015, current therapies available (entecavir starting in 2005 and tenofovir DF in 2008).

The number of wait-listed patients more than doubled from Era 1 (about 900) to Era 2 (about 2800), but then stabilized in Era 3 (about 3000). The proportion of white patients fell over time (from nearly two-thirds to a third) while the proportion of Asians rose (from about a quarter to about half); black and Hispanic patients accounted for a small proportion of transplant candidates across time.

Overall, about a quarter of wait-listed patients had HCC. But the number of candidates with liver cancer rose steadily, from just 5% in Era 1 to 15% in Era 2 and 39% in Era 3, although HCC dipped somewhat in the last 2 years. The proportion of Asians with HCC reached two-thirds in Era 3. Wong suggested this might be because HBV genotypes found in Asia (B and C) may be more likely to cause liver cancer.

During Era 1, 0.9% of wait-listed patients died and 46.6% received transplants within a year; the average time to death on the wait-list was 1432 days and the mean time to transplantation was 273 days. During Era 2, 8.4% died and 40.3% got transplants within a year; the mean times to death and transplantation were 569 and 311 days, respectively. And during Era 3, 6.2% died while waiting and 47.5% got transplants; the mean times to death and transplantation were 350 and 178 days.

The likelihood of dying while on the wait-list was significantly higher in Era 1 compared to Era 2 (HR 4.55), but fell from Era 2 to Era 3 (HR 3.63 vs Era 1). Wait-list mortality was affected by both the number of people who died and time to death on the transplant list. Era 1 had both the smallest number of deaths and the longest mean time to death, which the researchers said might be due to selection bias in favor of healthier patients, as transplant outcomes were poor for hepatitis B patients prior to the 1990s.

The researchers noted that studies have shown that MELD scores at the time of transplantation have increased in recent years, suggesting patients on the wait-list are now sicker. But the decline in the likelihood of death on the wait-list from Era 2 to Era 3 may reflect the improvement in hepatitis B treatment. A subgroup analysis of Era 3 showed that survival increased from 2005-2007 to 2008-2011 (HR 0.77) and 2012-2015 (HR 0.61), even after controlling for disease severity.

The likelihood of receiving a transplant also fell from 2005 to 2015. "These results we believe are a testament to the improved HBV therapy as patients on the waitlist may have delayed progression of their liver disease and thus a delayed need for transplant or longer time on the transplant list," the researchers said. They also found that survival after transplantation improved in each successive era, and also within Era 3.

"While current therapies are effective in suppressing HBV and reducing risk of cirrhosis and hepatocellular carcinoma, our current study demonstrates that HBV-related hepatocellular carcinoma is still a major concern," Wong said in an AASLD press release. "[W]ith the many potential HBV therapies on the horizon, it will be interesting to understand what treatment endpoints are most effective at reducing HBV disease progression and hepatocellular carcinoma (e.g. viral suppression, normalization of alanine aminotransferases, and HBV surface antigen loss)."



Y-C Hsu, H-J Ho, HS El-Serag, et al. Risk of Hepatocellular Carcinoma Decreases over Time in Chronic Hepatitis B Patients on Antiviral Therapy with Entecavir or Tenofovir. Abstract 103.

GV Papatheordoridis, C Yurdaydin, GN Dalekos, et al. The risk of hepatocellular carcinoma (HCC) is decreasing after the first 5 years of entecavir (ETV) or tenofovir (TDF) therapy in Caucasian chronic hepatitis B (CHB) patients. Abstract 1867.

GV Papatheodoridis, GN Dalekos, C urdaydin, et al. Hepatocellular carcinoma (HCC) is the only factor affecting the excellent survival of Caucasian chronic hepatitis B (CHB) patients with or without cirrhosis under long-term entecavir (ETV) or tenofovir (TDF) therapy. Abstract 68.

K Young, B Liu, T Bhuket, et al. Despite Plateauing of Chronic Hepatitis B Virus (HBV) Patients Listed for Liver Transplantation, the Proportion of Patients with HBV-Related Hepatocellular Carcinoma Continues to Rise. Abstract 211.

AASLD. Number of Hepatitis B-Related Liver Transplants Drops While Hepatitis B-Related Liver Cancer Continues to Rise. Press release. November 11, 2016.