Swimming in cloudy waters: Efforts to prevent HCV-related HCC

Abstract

Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N, Arakawa Y, Hashimoto E, Hirota K, Yoshida H, Ohashi Y, Omata M (University of Tokyo, Japanese Red Cross Medical Center, Nippon University School of Medicine, and Tokyo Women’s Medical College, Tokyo; Chiba University School of Medicine, Chiba; and Mito Saiseikai Hospital, Ibaraki, Japan). Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005;142:105–114. The most dreaded complications of hepatitis virus C (HCV) infection are cirrhosis and, in particular, hepatocellular carcinoma (HCC). Intense research over the last decade has resulted in an improved understanding of the biology of HCC, a wider armamentarium of palliative options and liver transplantation of highly selected patients in an attempt to achieve cure. However, the overall prognosis for patients developing HCC remains poor. Considering the burgeoning population at risk for HCC from chronic HCV infection, there has been tremendous interest in the ability of interferon (IFN) therapy to prevent the occurrence of HCC. The present study explores the ability of IFN therapy to reduce the development of HCC in patients with established cirrhosis secondary to HCV infection. The Tokyo-Chiba hepatitis research group has previously reported the efficacy of IFN alfa-2a and natural IFN in treating HCV infection in cirrhotic patients (Hepatology 1999;29:1573–1580, Liver 2000;20:271–280). In these studies, a total of 271 patients received non-pegylated IFN therapy (treated group). Seventy-four patients with HCV who fulfilled the inclusion criteria declined to receive IFN therapy (untreated group). The differing incidence of HCC in the 2 groups during a median follow-up of 6.8 years is reported in this study. The treated and untreated groups were similar except for differences in age (57 vs 61 years, P < .001) and serum ALT levels (97 IU/L vs 75 IU/L, P = .008). The end-of-treatment response rate and sustained response rate for HCV genotype 1 were 35% (70 of 199 patients) and 15% (30 of 199 patients), respectively. For non-1 genotypes, the rates were 64% (46 of 72 patients) and 47% (34 of 72 patients), respectively. HCC was detected in 119 patients during follow-up: 31% (84 of 271 patients) of the treated group and 47.3% (35 of 74 patients) of the untreated group. Eleven of 64 (17.2%) of the sustained virologic responders developed HCC compared with 73 of 207 (35.3%) of the nonresponders. When analyzed by the Kaplan-Meier method, the cumulative incidence of HCC was lower in the IFN-treated patients. Seventeen percent (45 patients) from the treated group and 32% (24 patients) from the untreated group died during the follow-up period. Deaths from liver disease (HCC, hepatic failure, or varix rupture) occurred in none of the 64 sustained responders, 15% (32 of 207 patients) of the nonresponders, and 26% (19 of 74 patients) of the untreated patients (P < .001 and P = .08, respectively). IFN-treated patients were also found to have a better chance of survival than the untreated patients. Furthermore, sustained virologic response was associated with a better chance of survival (P = .003 compared to the untreated group) than was nonsustained virologic response (P = .19 compared with the untreated group). Despite concerted attempts to diagnose HCC early and the wide array of therapeutic modalities including surgical resection, liver transplantation, local ablation, and chemo-embolization, the overall prognosis for a patient with HCC is poor. The available surveillance methodology is suboptimal, tumors are frequently inoperable at diagnosis, advanced liver disease precludes surgical resection, and even in the MELD-era, liver transplantation is limited to highly select patients. Local therapies such as chemo-embolization, percutaneous ethanol injection, and radiofrequency ablation are palliative. An estimated 3.9 million persons are infected with HCV in the United States (N Engl J Med 1999;341:556–562) and the risk of HCC in patients with HCV infection increases dramatically once cirrhosis occurs. Cirrhosis typically occurs 2–3 decades following infection with HCV. Mathematical modeling suggests that unless we find an effective therapeutic strategy for these patients, we will see a steady increase in the number of patients with cirrhosis and its consequences. There is dire need to prevent the occurrence of hepatitis C, but in the absence of a vaccine, we have to concentrate our efforts to prevent the progression of chronic hepatitis C. IFN alfa has been used to treat HCV for over 2 decades. The recent introduction of pegylated IFN and combination therapy with ribavirin has significantly improved sustained virologic response rate and may modify the natural history of the disease. However, the role of IFN-based therapies (IFN monotherapy, pegylated IFN monotherapy, and combinations with ribavirin) in preventing or reducing incidence of HCC is controversial. There are fundamental issues and questions regarding the pathogenesis and epidemiology of HCV-related HCC that have yet to be resolved. HCV causes chronic liver injury that may result in continual regeneration and proliferation of hepatocytes. Cumulative genetic mutations and instability could eventually result in malignant transformation and the development of HCC. The timing of these mutations and the genetic triggers that lead to HCC have been extensively studied but are still not well understood. Rather than being the end result of a continuum of molecular events, are HCC and cirrhosis separate complications of chronic inflammation, necrosis, and regeneration, with HCC only taking longer to develop? Whereas hepatitis B incorporates its genome into the host to trigger directly malignant transformation even in the absence of cirrhosis, HCV is an RNA virus that does not incorporate its genome into the host, and cirrhosis precedes HCC in most patients. From an epidemiologic standpoint, the reported differences in the incidence of HCV-related HCC in western and Japanese studies are striking. While the annual rate of HCC development in Europe averaged 3.7% (Gastroenterology 2004;127:S294–S302), in Japan the reported annual incidence varies from 5% to 7% (Ann Intern Med 2005;142:105–114). In the west, HCV-related HCC is almost always associated with cirrhosis, however, about 1.7% of HCV-related HCC in Japan occurs in the absence of cirrhosis (Gastroenterology 2004;127:S35–S50). The efficacy of IFN therapy in preventing HCV-related HCC is also very contentious. There are marked differences in efficacy depending on the geographic location of the study population, the study design (prospective, retrospective), degree of fibrosis, and presence of cirrhosis. Equally problematic has been the analysis of prevention of HCC depending on treatment success subgroups (sustained virologic responders, partial responders, nonresponders, or untreated). All of the published studies have used IFN alfa monotherapy rather than pegylated IFN in combination with ribavirin. The current study attempts to address some of these questions regarding HCV-related cirrhosis in a prospective, but nonrandomized fashion. The patients included in the study were divided into an IFN monotherapy group and an untreated group based on the willingness of the patient to receive antiviral therapy. It has not been shown that IFN therapy in HCV infection with minimal fibrosis (F0 or F1) or no fibrosis alters the risk for subsequent development of HCC. In part, this is because the incidence of HCV-related HCC is extremely low in patients with little or no fibrosis. A very large cohort of patients randomized to therapy or control, followed for an extended period to prove efficacy, seems impractical and is probably unethical. Retrospective series from Japan (Ann Intern Med 1999;131:174–181, J Hepatol 1999;30:653–659, Ann Intern Med 1998;129:94–99) have shown a decrease in incidence of HCV-related HCC after IFN therapy in patients with significant fibrosis (F2 or F3), predominantly in patients who experience sustained virologic response. Interestingly, none of these studies demonstrate a similar benefit in patients with cirrhosis. This is at odds with the findings of Nishigushi et al (Lancet 1995;346:1051–1055) and the present study by Shiratori et al that emphasize the advantage of IFN therapy in patients with cirrhosis. Moreover, Shiratori et al demonstrated a benefit in treated versus untreated patients and in sustained responders versus nonsustained responders over a 7-year follow-up. On the other hand, western studies focusing on patients with cirrhosis, although not as definitive as the Asian literature, have demonstrated a beneficial effect, but only in patients experiencing a virologic response. Much more needs to be learned regarding the pathogenesis and natural history of HCC in patients with HCV. Furthermore, the role of the current standard of care therapy for HCV infection in preventing HCC has to be defined. However, the percentage of patients that achieve a sustained virologic response compared with the astronomical numbers of those infected with HCV (known and unknown infection) is miniscule. Potentially, a reduction in the incidence of HCC will only be achieved if an increasing number of patients are diagnosed and treated early in the course of infection with more effective therapies. Surveillance strategies for the earlier diagnosis of HCC need to be developed. In the meantime, the possibility of preventing the development of HCC will remain a potential gift of treating HCV infection.