Newswise — BOSTON – Data from a new study presented this week at The Liver Meeting® – held by the American Association for the Study of Liver Diseases – found that hepatitis C virus-related hepatocellular carcinoma (HCC) patients who achieved sustained virologic response (SVR) – denoting an undetectable level of HCV virus - with any oral direct-acting antiviral (DAA) had over 60-70 percent improvement in five-year survival. This improvement was found in both all-cause and liver-related cancers and was compared to patients with untreated hepatitis C virus (HCV). The study’s findings suggest that anyone with HCV-related HCC who is a candidate for HCC therapy should also be considered for DAA therapy.

There is limited data on survival outcomes for patients with HCV-related HCC following an HCV cure with DAAs. To address this lack of data, a multinational study was conducted by researchers in the U.S., Korea, Japan and Taiwan in order to compare survival rates in patients who achieved SVR with patients whose HCV was untreated.

“Patients with HCC have such dismal prognosis, especially those who are not candidates for curative treatment, and unfortunately, these are the majority of the HCC population. Systemic palliative therapies for HCC generally have increased median survival of treated patients by a few months, and many of these treatments are poorly tolerated,” says Mindie H. Nguyen, MD, MAS, professor of medicine at Stanford University in California. “I have observed significant improvement in survival for hepatitis B-related HCC patients who received antiviral treatment for hepatitis B, even in patients with advanced tumor and/or liver disease stages. So, I wanted to see if antiviral treatment with DAA for HCV-related HCC patients can yield similar or even better results, since DAA therapies are very well tolerated even in patients with very advanced liver disease and HCC. Prior studies have also shown that cure rates with DAAs for HCV-related HCC are similar to rates in patients without HCC (about 95 percent). Patients with untreated or only partially treated HCC have a lower cure rate at 85 percent, though this is still fairly high and should not exclude these patients from HCV treatment.”

The study’s participants included 1,676 mono-infected HCV-related HCC patients: 614 were seen at two U.S. medical centers, and 1,062 at six medical centers in Korea, Japan and Taiwan from 2005-2017. Patients were put into two groups: those untreated for HCV and those treated for HCV with DAAs who achieved SVR. There were 1,239 patients in the untreated group and 437 in the SVR group. The researchers matched and balanced the two groups based on a number of demographics, liver function and HCC characteristics, and they evaluated survival rates taking into consideration when patients began treatment. 

After patient matching, the researchers ended up with 321 pairs of patients (321 untreated and 321 SVR, all treated for HCC). After time-varying adjustment for the HCV treatment start time, SVR patients had significantly higher five-year overall survival rates compared to those untreated for HCV (87.78 percent compared to 66.05 percent). The SVR group also had higher liver-related survival compared to untreated patients (90.90 percent compared to 68.76 percent). SVR was independently associated with a 63 percent lower risk of all-cause mortality and a 76 percent lower risk of liver-related mortality, according to multivariate regression analysis. Further analysis at 90, 180 and 360 days also showed that achieving SVR with DAAs was independently associated with a lower risk of death compared to no HCV treatment.  

“SVR patients following treatment with very safe and well-tolerated DAAs could increase their survival rates by a median of 18 months, [which is] considerable progress compared to other currently available systemic therapies for HCC. I believe the next important step is to study the current DAA utilization among HCC patients and how to optimize its use,” says Dr. Nguyen.

 “Our results clearly showed that SVR by DAA therapy is associated with improved overall survival, which is the most important endpoint for patients with a cancer,” says co-author of the study, Hidenori Toyoda, MD, PhD, director of hepatology in the Department of Gastroenterology at Ogaki Municipal Hospital in Japan. “Next, we should elucidate how SVR by DAA contributes to improved survival of patients with HCC, whether through the improvement of liver function which, in turn, provides patients with more hepatic reserve more opportunities to get HCC treatment, through both initial and repeat treatment, or through more direct effects that suppress the recurrence and/or progression of HCC.”

Drs. Nguyen and Toyoda will present these findings at AASLD’s press conference in Room 210 at the Hynes Convention Center in Boston on Saturday, Nov. 9 from 4 – 5:30 PM. The study entitled “HCV Cure by All Oral DAA Improves 5-Year Overall and Liver-Related Survival in HCV-Related HCC Patients: A Real-World, Propensity Score-Matched Study From Both East and West” will be presented on Sunday, Nov. 10 at 8:30 AM in Room 304/306. The corresponding abstract (number 0040) can be found in the journal, HEPATOLOGY.

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Authors: Hansen Dang1,2, Dr. Yee Hui Yeo1, Dr. Satoshi Yasuda3, Dr. Chung-Feng Huang4, Dr. Etsuko Iio5, Dr. Charles S Landis6, Dae Won Jun7, Dr. Masaru Enomoto8, Dr. Eiichi Ogawa9, Dr. Pei-Chien Tsai4, An Le1, Matthew Liu6, Dr. Mayumi Maeda1, Brian Nguyen1, Nathan Ramrakhiani1, Dr. Linda Henry1, Dr. Ramsey Cheung1,10, Prof. Akihiro Tamori8, Dr. Takashi Kumada11, Yasuhito Tanaka5, Dr. Ming-Lung Yu4, Dr. Hidenori Toyoda3 and Mindie H. Nguyen, MD, MAS, AGAF, FAASLD1, (1)Division of Gastroenterology and Hepatology, Stanford University Medical Center, (2)University of California, Davis, (3)Department of Gastroenterology, Ogaki Municipal Hospital, (4)Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, (5)Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, (6)University of Washington, (7)Department of Gastroenterology, Hanyang University, (8)Department of Hepatology, Osaka City University Graduate School of Medicine, (9)Department of General Internal Medicine, Kyushu University Hospital, (10)Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care, (11)Department of Nursing, Gifu Kyoritsu University

Abstract Text

Background: Data on survival outcomes of HCV-related HCC patients following HCV cure with DAAs are limited. We aimed to compare survival rates in this population vs. those who did not receive treatment for HCV.

Methods: Our study consisted of 1676 mono-infected HCV-related HCC patients seen at two U.S. medical centers (n=614) and six Asia medical centers (n=1062; Korea, Japan, and Taiwan) from 2005-2017 and categorized into two groups: patients untreated for HCV (untreated group) and DAA-treated patients with SVR (SVR group). We used propensity score matching (PSM: PSM: age, sex, country, cirrhosis, ALBI, Milan criteria, HCC treatment, and AFP) to balance the two groups, used Kaplan-Meier analysis with episode splitting to adjust for HCV treatment start time to calculate survival rates, treated HCV treatment status as a time-varying exposure on multivariate Cox proportional hazards regression modeling, and used landmark analysis to avoid immortal time bias via synchronizing the follow-up of the untreated and SVR groups.

Results: There were 1239 patients in the untreated group and 437 in the SVR group. Initial analysis revealed significant differences between the two groups in several demographic and liver function or HCC characteristics. After PSM, background risks of the 321 pairs of matched patients (321 untreated for HCV, 321 SVR, all received treatment for HCC) were balanced (all p>0.05, Table 1). After

time-varying adjustment for HCV treatment start time, compared to untreated patients, SVR patients had significantly higher 5-year overall survival (87.78% vs. 66.05%, p<0.001, Fig 1A) as well as liver-related survival (90.90% vs. 68.76%, p<0.001, Fig 1B). Multivariable regression analysis showed that SVR was independently associated with 63% lower risk of all-cause mortality (HR=0.37; 95% CI: 0.16 – 0.83, p=0.016) and 76% lower risk of liver-related mortality (HR=0.34; 95% CI: 0.13 – 0.88, p=0.026).

Landmark analysis at 90, 180, and 360 days also consistently showed that SVR with DAAs was independently associated with lower risk of death when compared to no HCV treatment (HRs ranged 0.22 to 0.44, all p<0.05).

Conclusion: In our multinational real-world PSM study, HCV-related HCC patients who achieved SVR with DAAs had over 60-70% improvement in 5-year survival (both all-cause and liver-related) compared to patients untreated for HCV. Thus, HCV-related HCC patients who are candidates for HCC therapy should also be considered for DAA therapy.

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