Prevention of Hepatocellular Carcinoma

Antiviral therapy for hepatitis B-related liver cancer prevention is more cost-effective than cancer screening - (03/30/09)
Articles in Press
Prevention of hepatocellular carcinoma: The holy grail of hepatitis B treatment☆
Morris Sherman
published online 09 March 2009.
Corrected Proof
Associate Editor: J.M. Llovet
In this issue of the Journal, Robotin et al. [1] 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 <20,000iu/ml>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], 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]. 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 [4], [5]. 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 [6], [7]. 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]. Others have shown that even patients with ALT below the laboratory ULN are at risk for HCC [8], and that a relative risk of 60 for HCC remains in patients who have normal ALT compared to the risk in the uninfected) [9]. This decision analysis treated patients with ALT >1.5×ULN differently from those with lower ALT. If the ALT <1.5×uln>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]. Presumably similar considerations will apply to tenofovir, an equally potent agent with low resistance rates [11]. 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]. 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 [3], [12], [13]. 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 [14], [15]. 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 [16], [17], 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] 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] 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]. 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.
References
[1].. [1]Robotin MC, Kansil M, Howard K, George J, Tipper S, Dore GJ, et al. Antiviral therapy for hepatitis B-related liver cancer prevention is more cost-effective than cancer screening. J Hepatol. 2009;.
[2].. [2]Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–1236. MEDLINE CrossRef
[3].. [3]Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73. CrossRef
[4].. [4]European Association for Study of the Liver. EASL clinical practice guidleines: management of chronic hepatitis B. J Hepatol 2009;50:227–42.
[5].. [5]Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–539. MEDLINE CrossRef
[6].. [6]Prati 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;137:1–10.
[7].. [7]Kim HC, Nam CM, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328:983.
[8].. [8]Yuen MF, Yuan HJ, Wong DK, Yuen JC, Wong WM, Chan AO, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut. 2005;54:1610–1614. MEDLINE CrossRef
[9].. [9]Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347:168–174. CrossRef
[10]. [10]Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007;133:1437–1444. Abstract Full Text Full-Text PDF (303 KB) CrossRef
[11]. [11]Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442–2455. CrossRef
[12]. [12]Chen G, Lin W, Shen F, Iloeje UH, London WT, Evans AA. Chronic hepatitis B virus infection and mortality from non-liver causes: results from the Haimen City cohort study. Int J Epidemiol. 2005;34:132–137. MEDLINE CrossRef
[13]. [13]Yu MW, Yeh SH, Chen PJ, Liaw YF, Lin CL, Liu CJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265–272.
[14]. [14]Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–1531. CrossRef
[15]. [15]Yuen MF, Seto WK, Chow DH, Tsui K, Wong DK, Ngai VW, 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;12:1295–1303.
[16]. [16]Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology. 2007;45:307–313. MEDLINE CrossRef
[17]. [17]Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, 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;40:883–891. MEDLINE CrossRef
[18]. [18]Tong MJ, Hsien C, Hsu L, Sun HE, Blatt LM. Treatment recommendations for chronic hepatitis B: an evaluation of current guidelines based on a natural history study in the United States. Hepatology. 2008;48:1070–1078. CrossRef
[19]. [19]Stravitz RT, Heuman DM, Chand N, Sterling RK, Shiffman ML, Luketic VA, et al. Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome. Am J Med. 2008;121:119–126. Abstract Full Text Full-Text PDF (380 KB) CrossRef
Department of Medicine, University of Toronto and University Health Network, Toronto, Canada
Toronto General Hospital, NCSB 11C 1252, 585 University Avenue, Toronto, Ont., Canada M5G 2N2. Tel.: +1 416 340 4756; fax: +1 416 591 2107.
☆ The author declared that he does not have anything to disclose regarding funding with respect to this manuscript. He has however declared a relationship with the manufacturers of the drugs involved