Prevention of hepatocellular carcinoma: The holy grail of hepatitis B treatment
Authors: Morris Sherman
Journal: Journal of Hepatology (2009)

Antiviral therapy for hepatitis B-related liver cancer prevention is more cost-effective than cancer screeningJournal of HepatologyVol. 50Issue 5PreviewIn Australia, Asian-born populations are 6–12 times more likely to develop hepatocellular cancer (HCC) than Australian-born individuals. We therefore, modelled the consequences of different management strategies for chronic hepatitis B (CHB) in Asian-born adults aged ⩾35 years. Full-Text PDF In this issue of the Journal, Robotin et al. [[1]Robotin M.C. Kansil M. Howard K. George J. Tipper S. Dore G.J. et al.Antiviral therapy for hepatitis B-related liver cancer prevention is more cost-effective than cancer screening.J Hepatol. 2009; 50: 990-998Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] describe a decision analysis looking at the cost efficacy of treating patients with hepatitis B to prevent the development of hepatocellular carcinoma (HCC). They conclude that treating patients with active hepatitis B is a cost-effective way of preventing HCC. As with all decision analysis models, the devil is in the details and before accepting that the model reflects real life, it is important to examine the design of the model and the assumptions required to run the model. First, the population that was chosen was the Asian population with chronic hepatitis B infection because in Australia (and probably in North America), chronic hepatitis B disproportionately affects immigrants from Asia. Second, they compared three strategies. The “control” strategy or “low uptake” strategy was applied to patients with low viral loads <20,000 IU/mL for those under age 50, and <2000 IU/mL for those over age 50, who were managed only by blood testing with no HCC surveillance. The alternate therapy group patients had higher viral loads. If the ALT was less than 1.5× the upper limit of normal no treatment was offered, but patients underwent HCC surveillance. Finally, if the ALT was >1.5× the upper limit of normal, patients were all treated with entecavir and underwent HCC surveillance. Are these reasonable strategies to include in a cost efficacy analysis? The “low uptake” strategy unfortunately, still represents the state of affairs for many patients with hepatitis B in the Western world, where hepatitis B awareness among family physicians can be abysmal. Therefore it is appropriate as a control strategy. The lack of HCC surveillance in these groups is not consistent with guidelines, which indicate that surveillance should be offered to all Asian males over age 40 and Asian women over age 50 regardless of viral load or ALT [[2]Bruix J. Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5149) Google Scholar], but this does not reflect reality. The current HCC screening guidelines are too broad, and will probably be refined in future as more information about HCC risk becomes available. It may well be that patients whose disease has been inactive for years (as in the low uptake group) do not need surveillance. The REVEAL study data suggested that if the viral load was low the risk of HCC was very low [[3]Chen C.J. Yang H.I. Su J. Jen C.L. You S.L. Lu S.N. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Crossref PubMed Scopus (2598) Google Scholar]. Therefore this may be a reasonable strategy. For those with higher viral loads the treatment strategies are slightly different than those described in practice management guidelines. Most practice guidelines do not discuss age as a consideration in deciding on treatment, whereas in this analysis, treatment was limited to patients over age 35, and criteria for starting therapy changed at age 50. All guidelines agree that patients with high viral loads and elevated ALT should be treated [4European Association for Study of the Liver. EASL clinical practice guidleines: management of chronic hepatitis B. J Hepatol 2009;50:227–42.Google Scholar, 5Lok A.S. McMahon B.J. Chronic hepatitis B.Hepatology. 2007; 45: 507-539Crossref PubMed Scopus (2173) Google Scholar]. There is less unanimity for patients with lower ALT concentration. Given that the laboratory ALT upper limit of normal (ULN) is too high, laboratory normal ALT becomes an unreliable marker of inactive disease [6Prati D. Taioli E. Zanella A. Della Torre E. Butelli S. Del Vecchio E. et al.Updated definitions of healthy ranges for serum alanine aminotransferase levels.Ann Intern Med. 2002; 137: 1-10Crossref PubMed Scopus (1160) Google Scholar, 7Kim H.C. Nam C.M. Jee S.H. Han K.H. Oh D.K. Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study.BMJ. 2004; 328: 983Crossref PubMed Google Scholar]. The REVEAL study showed that patients who were anti-HBe-positive with normal transaminases had a risk of HCC that was not much different from those with elevated ALT, and that the major determinant of the development of HCC was the viral load, not the ALT [[2]Bruix J. Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5149) Google Scholar]. Others have shown that even patients with ALT below the laboratory ULN are at risk for HCC [[8]Yuen M.F. Yuan H.J. Wong D.K. Yuen J.C. Wong W.M. Chan A.O. et al.Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications.Gut. 2005; 54: 1610-1614Crossref PubMed Scopus (325) Google Scholar], and that a relative risk of 60 for HCC remains in patients who have normal ALT compared to the risk in the uninfected) [[9]Yang H.I. Lu S.N. Liaw Y.F. You S.L. Sun C.A. Wang L.Y. et al.Hepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med. 2002; 347: 168-174Crossref PubMed Scopus (1072) Google Scholar]. This decision analysis treated patients with ALT >1.5 × ULN differently from those with lower ALT. If the ALT <1.5 × ULN cohort were to have been treated, the reduction in HCC incidence might have been greater. In real life, liver biopsy would distinguish those with high viral loads who needed treatment from those who did not, but this analysis did not consider biopsy. If anything, excluding the ALT <1.5 × ULN cohort from treatment under-estimated the potential treatment effect, so this is a conservative approach, and therefore acceptable. All subjects in the high viral load/ALT >1.5 × ULN cohort received treatment. This may be overkill, because it is not certain that all such patients are at significant risk of HCC. Patients with late reactivation of disease after many years of inactive infection are probably not at as high HCC risk as those who have had persistently active disease during an equivalent period. However, this is also a conservative strategy because treating patients not at risk for HCC will increase costs without an increase in benefit. Those members of the cohort who required treatment were treated with entecavir. Using entecavir simplifies the model because antiviral resistance is not an issue. Resistance to entecavir at 2 years is about 1% [[10]Gish R.G. Lok A.S. Chang T.T. de Man R.A. Gadano A. Sollano J. et al.Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B.Gastroenterology. 2007; 133: 1437-1444Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar]. Presumably similar considerations will apply to tenofovir, an equally potent agent with low resistance rates [[11]Marcellin P. Heathcote E.J. Buti M. Gane E. de Man R.A. Krastev Z. et al.Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.N Engl J Med. 2008; 359: 2442-2455Crossref PubMed Scopus (1012) Google Scholar]. There are a number of other assumptions used in the model that may not be accurate, for instance, that HBeAg seroconversion after interferon or antiviral therapy provides durable protection against active hepatitis in all. However, the major assumption underlying this analysis that is open to question is whether treatment of hepatitis B indeed reduces the risk of HCC. There is so far no direct evidence that this is true. Indirect evidence does suggest that effective treatment will indeed reduce the HCC incidence. Indeed, the new EASL guidelines specifically state that the goal of preventing cirrhosis and HCC can be achieved [[4]European Association for Study of the Liver. EASL clinical practice guidleines: management of chronic hepatitis B. J Hepatol 2009;50:227–42.Google Scholar]. The risk of HCC is proportional to the elevation of HBV DNA measured years before the onset of HCC. This has been demonstrated in several separate large-scale prospective cohort studies [3Chen C.J. Yang H.I. Su J. Jen C.L. You S.L. Lu S.N. et al.Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Crossref PubMed Scopus (2598) Google Scholar, 12Chen G. Lin W. Shen F. Iloeje U.H. London W.T. Evans A.A. Chronic hepatitis B virus infection and mortality from non-liver causes: results from the Haimen City cohort study.Int J Epidemiol. 2005; 34: 132-137Crossref PubMed Scopus (40) Google Scholar, 13Yu M.W. Yeh S.H. Chen P.J. Liaw Y.F. Lin C.L. Liu C.J. et al.Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men.J Natl Cancer Inst. 2005; 97: 265-272Crossref PubMed Scopus (484) Google Scholar]. Since the relationship between viral load and HCC incidence forms a “biological gradient” suggesting a causal relationship, it is reasonable to assume that if the viral load can be reduced with treatment the risk of HCC will also fall. Although the relationship between treatment and HCC risk reduction has not been studied there is clear evidence that treatment of hepatitis B will reduce the overall risk of progression of disease, both in patients with cirrhosis and in non-cirrhotics [14Liaw Y.F. Sung J.J. Chow W.C. Farrell G. Lee C.Z. Yuen H. et al.Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531Crossref PubMed Scopus (2024) Google Scholar, 15Yuen M.F. Seto W.K. Chow D.H. Tsui K. Wong D.K. Ngai V.W. et al.Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease.Antivir Ther. 2007; 12: 1295-1303PubMed Google Scholar]. Since the risk of HCC increases with more advanced disease, presumably the reduction in the risk of progression of disease also results in a reduction of risk of developing HCC. Other indirect evidence includes that in patients who develop antiviral resistance there is an increase in viral load, with exacerbation of disease activity and with an increased risk of disease progression [16Rapti I. Dimou E. Mitsoula P. Hadziyannis S.J. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B.Hepatology. 2007; 45: 307-313Crossref PubMed Scopus (296) Google Scholar, 17Di Marco V. Marzano A. Lampertico P. Andreone P. Santantonio T. Almasio P.L. et al.Italian Association for the Study of the Liver (AISF) Lamivudine Study Group, Italy. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine.Hepatology. 2004; 40: 883-891Crossref PubMed Scopus (250) Google Scholar], whereas patients who do not develop antiviral resistance and who continue to have adequate viral suppression have a much lower incidence of deterioration. Finally, the concept is biologically plausible. In other viral diseases (HIV, hepatitis C) the lower the viral load the less the disease. Why should this be any different in hepatitis B? Do we still need data from a randomized controlled trial (RCT) to convince us that the proposition espoused by Robotin et al. [[1]Robotin M.C. Kansil M. Howard K. George J. Tipper S. Dore G.J. et al.Antiviral therapy for hepatitis B-related liver cancer prevention is more cost-effective than cancer screening.J Hepatol. 2009; 50: 990-998Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] is true, namely that treatment of hepatitis B reduces HCC risk? In my humble opinion, there is sufficient indirect evidence that this is true, that we do not need to wait for data from a RCT, which in any case might never become available. When data from RCTs are not available, or RCTs are not feasible, decision analysis is the next best step. In many countries (my own being a prominent example) publicly funded access to effective hepatitis B antivirals is restricted, using the excuse that no survival benefit has yet been shown and there is a lack of cost efficacy data. This analysis will hopefully positively influence acceptance of the use of potent antivirals for hepatitis B. Tong et al. [[18]Tong M.J. Hsien C. Hsu L. Sun H.E. Blatt L.M. Treatment recommendations for chronic hepatitis B: an evaluation of current guidelines based on a natural history study in the United States.Hepatology. 2008; 48: 1070-1078Crossref PubMed Scopus (76) Google Scholar] have recently demonstrated that if AALSD guidelines for the treatment of hepatitis B had been applied to a cohort of patients who eventually developed HCC only 20–60% would have been candidates for treatment, suggesting that the guidelines issued by most professional societies are too restrictive. Second, even these restrictive guidelines are probably not being applied often enough by primary care physicians, given that only 2% of potential candidates in Australia are being treated (and anecdotally, elsewhere). In addition, data from the USA indicate that only a minority of patients with cirrhosis undergo surveillance before developing HCC [[19]Stravitz R.T. Heuman D.M. Chand N. Sterling R.K. Shiffman M.L. Luketic V.A. et al.Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome.Am J Med. 2008; 121: 119-126Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar]. HCC is increasing in incidence in Western countries as a consequence of the hepatitis C epidemic from the 1950s and 1960s, but also as a result of immigration from Asian countries increasing the prevalence of hepatitis B. Treatment of viral hepatitis B should dramatically reduce the incidence of HCC, but this will only happen if more patients with hepatitis B are treated. In turn, this will require a better understanding of hepatitis among primary care physicians. Educating primary care physicians about hepatitis B remains a challenge.