Does antiviral therapy reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis C?

Infection with the Hepatitis C virus (HCV) affects nearly 200 million people in the world. It is a leading cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC). It is estimated that 25% of HCC worldwide is related to HCV, being the main cause in Western Europe, North America and Japan. HCV can be implicated in the development of HCC in an indirect way through induction of chronic inflammation, or directly by means of viral proteins activating several signaling pathways. For patients with clinically significant hepatic fibrosis there is widespread agreement that antiviral therapy is indicated in order to eliminate the virus. It is generally accepted that sustained virologic response (SVR), i.e. undetectable HCV RNA at 24 weeks after treatment withdrawal, is associated with resolution of liver disease in patients without cirrhosis. In the last decades, results of treatment for chronic hepatitis C have improved substantially. The current standard of care is a combination of pegylated interferon and ribavirin for 24 to 48 weeks, depending on the genotype. In the near future, this standard of care will include addition of directly-acting antivirals. In 2011 two protease inhibitors (boceprevir and telaprevir) have been registered for use in adults with genotype 1 chronic hepatitis C, increasing the SVR rates from less than 50% to about 70% in patients treated with a triple combination. There is limited evidence for the role of interferon-based therapy in primary, secondary and tertiary prophylaxis of HCC in patients with chronic Hepatitis C, as most studies were primarily designed to assess the antiviral effect of treatment and not the long-term impact on the natural history of the disease. Further prospective studies using the more successful emerging treatments of chronic hepatitis C are to be conducted to evaluate the risk of HCC.     

Does antiviral therapy for hepatitis B and C prevent hepatocellular carcinoma?

Approximately 75% to 80% of hepatocellular carcinomas (HCC) worldwide are attributed to chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infection. Thus, effective prevention of HBV and HCV infection and progression from acute HBV and HCV infection to chronic hepatitis, cirrhosis and HCC might prevent as many as 450,000 deaths from HCC each year. The most effective approach to preventing HCC is to prevent HBV and HCV infection through vaccination. Indeed HBV vaccine is the first vaccine demonstrated to prevent cancers. However, a vaccine for HCV is not available and for persons who are chronically infected with HBV or HCV, antiviral therapy is the only option for preventing HCC. Direct evidence supporting a benefit of antiviral therapy on the prevention of HCC has been shown in a few randomized controlled trials. There is abundant evidence that antiviral therapy, in patients with long-term virological response, can improve liver histology, providing indirect support that antiviral therapy may prevent HCC by slowing progression of liver disease and possibly even reversing liver damage. Nevertheless, the risk of HCC remains in patients with chronic HBV or chronic HCV infection if treatment is initiated after cirrhosis is established. These data indicate that treatment might be of greater benefit if instituted earlier in the course of chronic hepatitis B or C. Safer, more effective, and more affordable antiviral therapies are needed for both hepatitis B and hepatitis C so more patients can benefit from treatment and more HCCs can be prevented.     

The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus–related hepatocellular carcinoma

Background/aimsWhether entecavir (ETV) or tenofovir disoproxil fumarate (TDF) affords the better prognosis after curative treatment of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. We compared recurrence and death rates between patients taking ETV and those taking TDF.MethodsBetween 2013 and 2017, patients with HBV-related HCC who had undergone hepatic resection (n=421) or radiofrequency ablation (n=305) as first-line anti-HCC treatment in three institutes were consecutively enrolled. All patients received ETV or TDF as a first-line antiviral. The cumulative probabilities of recurrence and death were assessed. We adjusted for viral factors, including the HBV-DNA load, and tumor and demographic factors.ResultsDuring the study period (median 46.6 [interquartile range 25.3–58.9] months), 227 patients experienced recurrence and 53 died. In the ETV (n=405) and TDF (n=321) groups, the annual incidences of recurrence (10.61 and 11.21 per 100 person-years, respectively; P=727) and death (2.28 and 1.79 per 100 person-years, respectively; P=277) were similar, with adjusted hazard ratios (aHRs) of 0.932 (P=0.622) and 0.667 (P=0.193), respectively. When stratified by treatment modality and the timing of antiviral therapy commencement, the values were similar (all P>0.05). Inverse probability of treatment weighting (IPTW) analyses yielded results that were similar in the two groups in terms of recurrence (aHR=1.038, P=0.963) and death (aHR=0.799, P=0.431). Furthermore, the early (<2 years) and late (≥2 years) recurrence risks were not statistically different in the two groups (both P=0.400), as confirmed by IPTW analysis (P=0.502 and P=0.377, respectively).ConclusionsThe prognoses in terms of recurrence and death after curative treatment of HBV-related HCC were not statistically different between the ETV and TDF groups. Further validation studies are needed.     

Effects of a 24-week course of interferon-α therapy after curative treatment of hepatitis C virus-associated hepatocellular carcinoma

AIM： To assess whether a 24-wk course of interferon （IFN） could prevent hepatocellular carcinoma （HCC） recurrence and worsening of liver function in patients with hepatitis C virus （HCV）-infected patients after receiving curative treatment for primary HCC.
METHODS： Outcomes in 42 patients with HCV infection treated with IFN-α, after curative treatment for primary HCC （IFN group）, were compared with 42 matched curatively treated historical controls not given IFN （non- IFN group）.
RESULTS： Although the rate of initial recurrence did not differ significantly between ]FN group and non-IFN group （0%, 44%, 61~, and 67% ys 4.8%, 53~, 81%, and 87% at 1, 3, 5, and 7 years, P = 0.153, respectively）, ]FN group showed a lower rate than the non-IFN group for second recurrence （0%, 10.4%, 28%, and 350/0 ys 0%, 30~ , 59%, and 66% at 1, 3, 5 and 7 years, P = 0.022, respectively）. Among the ]FN group, patients with sustained virologic response （SVR） were less likely to have a second HCC recurrence than ]FN patients without an SVR, or non-IFN patients. Multivariate analysis identified the lack of SVR as the only independent risk factor for a second recurrence, while SVR and Child-Pugh class A independently favored overall survival.
CONCLUSION： Most intrahepatic recurrences of HCV-related HCC occurred during persistent viral infection. Eradication of HCV is essential for the prevention of HCC recurrence and improvement of survival.     

Does interferon therapy prevent hepatocellular carcinoma in patients with chronic viral hepatitis?

Chronic hepatitis C and B are well-recognized and potentially preventable risk factors for hepatocellular carcinoma (HCC) development. Clinical and epidemiological studies suggest that therapy with interferon-α may reduce the overall risk of HCC development in patients with chronic hepatitis C, who achieve sustained virological response, but even in those who fail to eradicate the infection. In chronic hepatitis B, interferon therapy reduces the risk of HCC development in HBeAg-positive and cirrhotic patients who achieve persistent suppression of viral replication, while in HBeAg-negative patients the beneficial effect of interferon-α is not definitively confirmed. The preventive role of interferon-α after potentially curative treatment for HCC in both chronic hepatitis B and C is uncertain due to methodological flaws of the existing studies and prospective randomized controlled trials with pegylated interferon-α are needed to clarify this issue.     

Postoperative interferon α treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial

Background/Aims: Recurrence after resection of hepatocellular carcinoma (HCC) is a frequent event. This study evaluated the effect of postoperative interferon α (IFN α) treatment on recurrence and survival in patients with hepatitis B virus (HBV)-related HCC. Method: Two hundred and thirty six patients were randomized after resection into IFN α treatment (5 mu i.m. tiw for 18 months) and control groups. Treatment was terminated if recurrence was diagnosed, and recurrence was managed the same way in both groups. Statistical analysis was based on the method of intent-to-treat. Results: The two groups were comparable in all clinicopathological parameters. The median overall survival was 63.8 months in the treatment group and 38.8 months in the control group (P=0.0003); the median disease-free survival period was 31.2 versus 17.7 months (P=0.142). Fever, leucocytopenia, and thrombocytopenia were adverse effects in the treatment group, but were mostly manageable. Conclusions: IFN α treatment improved the overall survival of patients with HBV-related HCC after curative resection, probably by postponing recurrence.     

Does the choice of treatment influence survival of patients with small hepatocellular carcinoma in compensated cirrhosis?

OBJECTIVE: Untreated patients with small, single hepatocellular carcinoma (HCC) in compensated cirrhosis are characterized by a relatively good prognosis. METHODS: We report the findings generated in a retrospective study on a cohort of 186 consecutive patients with small (< 5 cm) HCC in Child A or B cirrhosis, who were transplanted (four), underwent surgery (15), or were treated with percutaneous ethanol injection (117), lipiodol chemoembolization (44) or best supportive care (six), depending on their clinical features. RESULTS: Overall survival was 26% at 5 years (31% Child A, 20% Child B), with a mean and median survival of 44 and 38 months, respectively. The longest survival was obtained with transplantation and surgery, and the worst with best supportive care. When untreated patients were not considered, no significant differences were observed between the different types of treatment, however, even when patients in the Child A group were considered alone. Almost all the patients who underwent surgery relapsed. No significant difference was observed in relation to the stage of the disease, while alpha-fetoprotein levels were singled out as the only relevant prognostic factor in a multivariate Cox's regression model. Costs per year of life saved were extremely high for transplantation and lowest for ethanol injection, with surgery being less expensive than chemoembolization. CONCLUSIONS: This study confirms that patients with single, small HCC nodules in well compensated cirrhosis should be treated. The choice of type of treatment should be based on the availability of local resources and expertise, and on the patients' preference, after they have been properly informed on the survival, morbidity and mortality related to each treatment option. The relative cost of the procedures should also be considered.     

Effects of interferon-α therapy on serum and liver HBV DNA in patients with chronic hepatitis B

The aim of this study was to evaluate the effect of interferon- therapy on serum and liver HBV DNA in 20 patients with chronic hepatitis B and to correlate the presence or absence of HBV DNA with the clinical response. There were 11 responders and all lost HBV DNA from the serum. Ten of the 11 were followed for 36 months following IFN treatment and remained well with absence of HB_eAg and HBV DNA from the serum and with normal ALT. Five also lost HB_sAg. HBV DNA became undetectable in the liver of nine of 10 of these patients in whom liver tissue was available for study. HBV DNA persisted in the liver of seven of nine nonresponders and was not detected in two in spite of the presence of HBV DNA and HB_eAg in the serum of these two patients. We conclude that IFN may induce long remissions in patients with chronic hepatitis B with loss of HBV DNA from the serum and that occasionally HBV DNA may persist in the liver of such patients.This work was supported in part by Health and Welfare Canada Grant 6606-2435-52.     

Could anti-HCV treatment prevent recurrence of hepatocellular carcinoma in HIV-infected patients? Two case reports

Highly active antiretroviral therapy (HAART) has proven long-term efficacy in human immunodeficiency virus (HIV) infection. Combination therapy with pegylated interferon and ribavirin has become the standard of care in patients with both hepatitis C virus (HCV) chronic hepatitis and HIV/HCV co-infection. Data on the safety and efficacy of combination therapy in chronic hepatitis C patients with hepatocellular carcinoma (HCC) is scarce and even more so in HIV/HCV co-infected subjects. We report the successful administration of both HAART and anti-HCV therapies in two HIV/HCV co-infected patients after HCC eradication. These encouraging results might argue for the feasibility of an aggressive approach in the management of co-infected patients with HCC.     

Is serum level of methylated RASSF1A valuable in diagnosing hepatocellular carcinoma in patients with chronic viral hepatitis C?

Background and study aimsThe detection of the promoter hypermethylation of RASSF1A in serum DNA could be a valuable biomarker for early detection of preneoplastic lesions and early cancer development among high-risk populations who are at a high risk of hepatocellular carcinoma (HCC). Therefore, we aimed determining the serum level of methylated RASSF1A sequence in patients with chronic hepatitis C viral infection and to evaluate the predictive value of it as a diagnostic marker for HCC in patients with chronic hepatitis C viral infection.Patients and methodsSerum levels of methylated RASSF1A were detected and measured using real-time PCR after digestion with a methylation-sensitive restriction enzyme in 40 patients with chronic HCV infection, 40 patients with HCC (on top of HCV) and 20 controls.ResultsMethylated RASSF1A was detected in 10% of the controls, 62.5% of HCV group and in 90% of HCC group. Chronic HCV patients had insignificantly higher levels than the controls. The levels were significantly higher in patients with HCC compared to the controls (p = 0.0001) and chronic HCV patients (p = 0.001). By logistic regression analysis, the serum methylated RASSF1A was found to differentiate HCC patients from healthy controls with an AUROC of 0.83 nmol/L, and an overall predictive accuracy of 77.5%. It was able to differentiate patients with HCC from those with chronic HCV infection alone with an AUROC of 0.733 and an overall predictive accuracy of 72.5%.ConclusionThe mean serum levels of methylated RASSF1A could be of value for early diagnosis of HCC especially in high risk patients with HCV infection.