Prevention of hepatocellular carcinoma: a concise review of contemporary issues

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1 284 Wi-Sun Wong V, et l., 2012; 11 (3): CONCISE REVIEW My-June, Vol. 11 No.3, 2012: Prevention of heptocellulr crcinom: concise review of contemporry issues Vincent Wi-Sun Wong,*, ** Henry Lik-Yuen Chn*, ** * Deprtment of Medicine nd Therpeutics, The Chinese University of Hong Kong. ** Institute of Digestive Disese, The Chinese University of Hong Kong. ABSTRACT Heptocellulr crcinom (HCC) is the fifth most common cncer nd the second leding cuse of cncer deths in men. Due to differences in the prevlence of virl heptitis, the incidence of HCC in low nd middle income countries is much higher thn tht of high income countries. Strtegies to limit the impct of HCC include primry prevention ginst new cses of virl heptitis, secondry prevention of HCC in susceptible individuls, nd erly HCC detection. Universl heptitis B vccintion hs resulted in drmtic reduction in incident cses of chronic heptitis B nd HCC in children nd dolescents, nd the full effect is expected in the next 20 yers. The key hurdle for universl vccintion is the cost nd the ccessibility in low nd middle income countries. Rndomized controlled trils nd met-nlyses showed tht successful tretment of chronic heptitis B nd C cn reduce the risk of HCC nd cirrhotic complictions. HCC surveillnce by regulr ultrsound exmintion nd lph fetoprotein testing leds to erly cncer detection nd offers the opportunity for curtive tretment. Since ll these mesures re costly nd require mnpower nd infrstructure support, the implementtion should rely on the liison mong helthcre providers nd policymkers. The cost-effectiveness of vrious strtegies should lso be studied bsed on locl situtions. Key words. Heptitis B. Heptitis C. Liver neoplsms. Antivirl gents. Heptitis B vccines. INTRODUCTION Heptocellulr crcinom (HCC) is the fifth most common cncer nd the second leding cuse of cncer deths in men worldwide. 1 Due to geogrphicl differences in the underlying etiologies such s virl heptitis nd lcoholism, the globl distribution of HCC is uneven. The incidence nd mortlity of HCC in low nd middle income countries re much higher thn those of high income countries. Since lte stge HCC is lmost uniformly lethl, the key to the control of the disese includes prevention nd erly cncer detection. This review focuses on the impct of vccintion progrms nd ntivirl therpy in the Correspondence nd reprint request: Henry Lik-Yuen Chn, M.D. Deprtment of Medicine nd Therpeutics, 9/F Prince of Wles Hospitl Ngn Shing Street, Shtin, Hong Kong Tel.: Fx: E mil: hlychn@cuhk.edu.hk Mnuscript received: November 17, Mnuscript ccepted: December 05, prevention of HCC, s well s the efficcy of HCC surveillnce progrms. The prcticl nd finncil implictions of such progrms in developing countries re discussed. EPIDEMIOLOGY OF HCC According to GLOBOCAN, there were pproximtely 748,300 new cses of primry liver cncers in ,900 people were estimted to die from primry liver cncers, indicting tht most of the new cses would eventully die from the disese. HCC ccounts for 85 to 90% of ll primry liver cncers. 2 Among 748,300 new cses of primry liver cncers in 2008, 626,700, or 84%, occurred in developing countries. The incidence is highest in Estern Asi (ge-stndrdized incidence rtes 35.5/100,000 in men, 12.7/100,000 in women). Other high-rte res include: Southest Asi (21.4/100,000 in men, 9.0/100,000 in women), Middle Afric (18.9/100,000 in men, 9.6/100,000 in women),

2 Prevention of heptocellulr crcinom., 2012; 11 (3): Western Afric (16.6/100,000 in men, 8.0/100,000 in women), nd Southern Afric (13.9/100,000 in men, 5.1/ 100,000 in women). In contrst, the incidence is less thn 10.0/ 100,000 in men nd 5.0/100,000 in women in most prts of Europe nd North Americ. Corresponding figures re 6.3/100,000 in men nd 4.4/100,000 in women in Cribben countries, nd 5.3/100,000 in men nd 3.9/100,000 in women in South Americ. Mle prepondernce is consistently observed mong different countries, with mle-to-femle rtio between 2:1 nd 4:1. The trend of HCC lso differs much cross vrious countries (Figure 1). In some prts of Americ, the incidence hs incresed by more thn 2-fold from 1970s to lte 1990s. 3,4 In Asi, the incidence is sttic or decresing in some res like Kore, Singpore nd Hong Kong. 5 The phenomenon is not completely understood. In some Western countries, the increse cn be prtly explined by immigrtion from countries with high prevlence of liver diseses. An lterntive explntion is tht countries with rising incidence in HCC tend to hve higher prevlence of heptitis C virus (HCV) infection. Besides, the incresing incidence of obesity nd dibetes my hve contributed to HCC risk in some countries. HEPATITIS B VIRUS AND HCC It is estimted tht over 350 million people re chroniclly infected with heptitis B virus (HBV) worldwide. 6 Up to 25% of these ptients would eventully die from liver disese. Globlly, HBV ccounts for 30 nd 53% of ll cses of cirrhosis nd HCC, respectively. 7 Among different liver diseses, chronic heptitis B is unique in tht HCC my develop in liver with little or no fibrosis. This is becuse HBV is directly crcinogenic, prtly explined by the integrtion of HBV DNA into the humn chromosomes nd the ction of HBx regultory protein. 8,9 Vccintion The first HBV vccine ws developed from humn serum nd licensed by the Food nd Drug Administrtion of the United Sttes in This ws subsequently replced by the development of recombinnt yest (Scchromyces cerevisie) vccine tht expresses HBsAg in The vccintion is given in 3 doses s intrmusculr injections. The first nd second doses re given 1 to 2 months prt. The third booster dose is given 6 to 12 months lter. The response to vccine declines with ge. As the prevlence of HBV infection in most middle nd low income countries is high, childhood immuniztion, preferbly since birth, should be recommended. After completion of 3 doses of vccine, 90% of helthy dults nd over 95% of children would develop protective ntibodies. Infnts of mothers with chronic heptitis B derive further protection with the ddition of heptitis B immune globulin. Positive HBsAg is found in only 6% of infnts who receive both heptitis B immune globulin nd vccine, compred to 29% of those receiving immune globulin lone, 25% of those receiving vccintion lone, nd 88% of those without prophylxis Chin Hong Kong Kore Singpore Tiwn USA UK Cost Ric Columbi Figure 1. Incidence of HCC in Asi, USA nd UK in (A) men nd (B) women, (per 100,000 popultion). 4,5

3 286 Wi-Sun Wong V, et l., 2012; 11 (3): HBV vccine Free HBV vccine Free vccintion introduced US$1 service fee service Western Chin (Urbn) Centrl Chin (Urbn) Estern Chin (Urbn) Western Chin (Rurl) Centrl Chin (Rurl) Estern Chin (Rurl) Figure 2. Coverge rte of HBV vccine in infnts in minlnd Chin. Although the ntibody level ginst HBsAg tends to wne with time, this does not pper to be importnt cliniclly. In 12-yer follow-up study of Seneglese infnts, HBsAg crrier rte remined low mong vccinted children. 13 Further boosters t school did not ffect the protection rte. The strongest evidence comes from epidemiologicl studies tht show no increse in HBsAg crrier rte in dolescents who hve received vccintion yers go. 14,15 This indictes tht new HBV infection is exceedingly rre in vccinted persons. Alongside with reduction in HBsAg crrier stte, the incidence of HCC in vccinted persons hs lso declined. Bsed on experience in Tiwn, the nnul incidence of HCC in children 6 to 14 yers of ge declined from 0.70 per 100,000 children between 1981 nd 1986 to 0.57 between 1986 nd 1990, nd to 0.36 between 1990 nd A follow-up study confirmed tht the protection ginst HCC hd extended to dolescents up to the ge of 19 yers. 17 Becuse of this cohort effect, the true impct on the popultion incidence of HCC would only be cler t lest 20 yers fter the introduction of mss vccintion. When the vccintion cohort reches dulthood, the popultion incidence of HBV infection nd HCC is expected to decrese drmticlly. According to recent Asi-Pcific working prty consensus sttement, universl vccintion to HBV is the most importnt preventive strtegy ginst HBV-relted HCC. 18 However, this progrm is only effective if infnts re relly receiving the vccine (Figure 2). The experience from minlnd Chin illustrtes how public helth policy influences the effectiveness of the vccintion progrm. When HBV immuniztion ws introduced in 1992, the fmilies hd to py for the vccine. The vccine coverge t tht time ws only 30%, nd prticulrly worse in poor nd rurl res. 19 In 2002, the government decided to support free HBV vccine, but the fmilies still need to py round US$1 s service chrge. It ws not until June 2005, when the government wived ll vccintion-ssocited chrges, the vccintion coverge in children incresed drmticlly to 90%. As result, the popultion prevlence of HBsAg hs declined from 9.8% in 1992 to 7.2% in In children below the ge of 5, the prevlence hs decresed from 9.7% in 1992 to 1.0% in Another chllenge is the ccessibility of vccine in rurl re. For exmple, the vccine coverge in the poorer Western prt of Chin is lwys lower thn the Estern prt, even when the vccintion is completely free of chrge. 19 Another exmple is Vietnm, where only 70% of the provinces hve implemented vccintion into the expnded immuniztion progrm in Antivirl therpy High serum lnine minotrnsferse nd HBV DNA levels, persistently positive heptitis B e ntigen (HBeAg) nd liver cirrhosis re ssocited with disese progression nd HCC development Antivirl therpy effectively controls these risk fctors nd is expected to improve clinicl outcomes. The best evidence on the efficcy of orl ntivirl drug cme from n Asin multicenter tril. 25 Six hundred nd fifty-one ptients with histology-proven dvnced fibrosis or erly cirrhosis were rndomized to receive lmivudine (n = 436) or plcebo (n = 215). At medin follow-up of 32 months, disese progression, defined by heptic decompenstion, HCC, spontneous bcteril peritonitis, bleeding vrices, or liver-relted deth, occurred in 7.8% in the lmivudine group nd 17.7% in the plcebo group (p = 0.001). HCC occurred in 3.9% in the lmivudine group nd 7.4% in the plcebo group (p = 0.047). Unfortuntely, the study ws originlly plnned for 5 yers but ws premturely terminted t round 3 yers becuse of significnt difference in the primry end point. This resulted in indequte power to ssess individul outcomes. For exmple, lthough the difference in HCC reched borderline sttisticl significnce, the result ws no longer significnt if cses of HCC occurring during the first yer of study were excluded. Controversies lso exist mong ptients who hve dvnced liver cirrhosis. In two rndomized, controlled trils (entecvir vs. defovir nd telbivudine vs. lmivudine, respectively), more

4 Prevention of heptocellulr crcinom., 2012; 11 (3): potent virl suppression mong ptients suffering from dvnced liver cirrhosis (Child s grde B or C) ws not trnslted to reduction of HCC or improvement in survivl. 26,27 A met-nlysis of 12 studies (n = 2,742) showed tht interferon reduced the risk of HCC by 34% compred to no tretment or plcebo. 28 Similrly, nlysis of 5 studies (n = 2289) showed tht lmivudine reduced the risk of HCC by 78%. Another metnlysis of 11 studies showed tht interferon ws effective in reducing the risk of other cirrhotic complictions s well. 29 Overll, ptients with histologicl nd biochemicl improvements with ntivirl therpy re less likely to develop cirrhotic complictions nd HCC. 30 The costs nd reimbursement policy of ntivirl drugs strongly shpe prescription behvior. At present, mny low nd middle income countries (e.g. Indonesi, Philippines, Vietnm) hve low reimbursement coverge. The chepest drug lmivudine is often prescribed. This results in lrge popultion of ptients with ntivirl drug resistnce. In Chin, most ptients re on lmivudine or defovir due to the low drug cost. A lrge-scled surveillnce of drug resistnce hs shown tht 43% of ptients on lmivudine nd 8% of ptients on defovir hve genotypic resistnce to these drugs. 31 Furthermore, significnt number of ptients re put on sequentil ntivirl therpy nd multi-drug resistnt HBV mutnts hve emerged. Hong Kong, Tiwn nd Kore dopt prtil reimbursement policy. Ptients my hve free ntivirl drugs if they fulfill certin criteri. Owing to the finncil sitution of the helth uthority, these criteri re usully more stringent thn the regionl tretment guidelines. In report from Hong Kong in 2008, 40% of ptients who were indicted for tretment did not receive nti-virl therpy for finncil reson, nd 83% of the treted ptients were purchsing their own mediction. 32 In Tiwn, reimbursement is provided for limited period of 1 yer before 2009 nd 3 yers t present by the Ntionl Helth Insurnce Policy. After tht, the ptients hve to py for further tretment or stop tretment premturely. This hs led to high rte of disese relpse nd clinicl deteriortion due to premture cesstion of ntivirl tretment. 33 Therefore, cost-effectiveness nlysis on the use of ntivirl therpy is very importnt in the implementtion of reimbursement policy. Entecvir nd tenofovir re generlly recommended s the first-line tretment in Americ nd Europe due to their high ntivirl potency nd low risk of drug resistnce, 34,35 nd the benefit of tenofovir is lso confirmed by cost-effectiveness nlysis in Europe. 36 However, the cost of drugs differs gretly in different geogrphicl regions. For exmple, entecvir nd tenofovir re much more expensive thn lmivudine nd telbivudine in most middle nd low income countries. A cost-effectiveness nlysis cross the Asi-Pcific region hs demonstrted tht the use of telbivudine s the first line gent nd tenofovir for suboptiml ontretment responders nd drug resistnce might be the most cost-effective pproch in terms of 2-yer HBV DNA suppression. 37 HEPATITIS C VIRUS AND HCC Chronic infection with HCV ffects more thn 170 million people worldwide. 38 In Western world, HCV is the leding cuse of cirrhosis nd HCC. Although the picture is overwhelmed by HBV in most developing countries, HCV infection is not uncommon in some res (Figure 3). 39 At present, HCV vccine is still under development. Among ptients with chronic heptitis C, the stndrd tretment is peginterferon-lph nd ribvirin. After course of tretment, sustined virologicl response (SVR), i.e. undetectble HCV RNA 6 months post-tretment, is chieved in 50 to 60% of cses. 40 In met-nlysis of 20 studies including 9 rndomized controlled trils nd 4,700 ptients, ntivirl therpy with interferon nd/or ribvirin significntly reduces the risk of HCC development (risk rtio 0.43; 95% confidence intervl 0.33, 0.56). 41 The reduction in HCC, liver decompenstion nd cirrhotic complictions is primrily observed in ptients chieving SVR. 42 HCV genotype is one of the most importnt fctors ffecting the tretment response. In ptients Prevlence (%) Egypt Pkistn Chin Indonesi Brzil Indi Jpn Itly USA Frnce Figure 3. Seroprevlence of HCV infection in developing nd developed countries. 39 Austrli Cnd Germny

5 288 Wi-Sun Wong V, et l., 2012; 11 (3): with genotypes 2 nd 3 HCV infection, SVR cn be chieved in 80 to 90% of treted ptients. On the other hnd, genotype 1 HCV infection is difficult to tret, with only 40 to 50% of ptients responding to tretment. In Asi, the predominnt genotype is genotype Genotype 2 HCV is lso commonly found in Tiwn nd Jpn, while genotype 6 HCV is common in Hong Kong nd Vietnm. Egypt is unique in hving very high popultion prevlence of HCV infection nd tht genotype 4 is the predominnt genotype. Although current tretment guidelines recommend similr tretment for genotypes 1, 4, 5 nd 6, smll studies from Asi suggest tht the tretment response for genotype 6 HCV is better thn tht for genotype 1, with SVR in 70 to 80%. 44,45 The response rte for genotype 4 is 50 to 60%. 46 For yers, it hs been known tht Africns with chronic heptitis C respond less well to tretment thn Cucsins, while studies from Asi consistently report the best results. 47,48 There re number of hypotheses to explin the observtion. For exmples, Asins were believed to hve better drug dherence, smller body size nd less insulin resistnce. Recent genomic studies, however, reveled tht genetic fctor is ctully the min reson underlying the difference. Three independent genome wide ssocition studies showed tht gene polymorphism ner the IL2B gene, which encodes interferon-λ-3, is strong predictor of tretment response in ptients with chronic heptitis C Interestingly, the fvorble llele ssocited with high rte of SVR is found in over 90% of the Chinese popultion but less thn hlf in Africns. 52,53 One min chllenge to the current stndrd of cre using peginterferon nd ribvirin includes suboptiml response rte mong genotype 1 HCV infected ptients. The sitution is expected to be revolutionized by the introduction of direct cting ntivirls. Phse 3 studies confirmed tht the ddition of HCV protese inhibitors boceprevir or telprevir significntly increses the rte of SVR nd reduces virologicl relpse in both tretment-nïve nd previously treted ptients with genotype 1 HCV infection Furthermore, interferon-free regimens using combintion of different directly cting ntivirls re under ctive development. 58 This will open new tretment opportunities for ptients not tolerting or with contrindictions to interferon. 59 However, these direct cting ntivirl gents will be very expensive nd impose hevy finncil burden to low nd middle economic countries. More studies re required before recommendtion cn be mde on the use of direct ntivirl gents in these regions, prticulrly mong ptients who hs fvorble IL28B genotype nd erly virologicl response to the stndrd peginterferon nd ribvirin combintion therpy. In recent cost-effectiveness nlysis in Americ, telprevir inclusive regime is not cost-effective s initil therpy s compred to stndrd of cre mong ptients with genotype 1 HCV infection nd the CC IL28B genotype. 60 Three lrge rndomized controlled trils (HALT-C, COPILOT nd EPIC3) ddressed the question of whether low dose mintennce peginterferon tretment my reduce the risk of HCC in chronic heptitis C ptients with dvnced liver fibrosis or cirrhosis who did not chieve SVR with stndrd therpy None of the trils showed ny difference in the incidence of HCC in treted nd untreted ptients up to 4 yers of follow-up. On long-term follow-up up to medin of 6.1 yers in the HALT-C tril, ptients with bseline liver cirrhosis treted with peginterferon hd delyed reduced incidence of HCC by pproximtely 50% s compred to the untreted controls. 64 In view of the side effects nd costs of extended peginterferon tretment, more dt on the efficcy nd cost-effectiveness on will be needed before long-term mintennce peginterferon tretment cn be recommended for non-responders nd relpsers. AFLATOXIN Afltoxin is nother risk fctor of HCC in humid countries fvoring the growth of Aspergillus flvus nd Aspergillus prsiticus. In those res, elevted urinry fltoxin B1 metbolites doubles the risk of HCC. 65 Afltoxin induces the trnsversion G T in codon 249 of the p53 tumor suppressor gene in humn heptocytes. 66 In humn HCC tissues, the presence of fltoxin DNA dducts correlte with p53 muttions nd p16 methyltion. 67 It is possible to reduce fltoxin in food products by dry storge conditions. 68 HCC SURVEILLANCE The mesures described in previous sections im t preventing new HBV nd HCV infection (primry prevention) nd preventing HCC development in t risk individuls (secondry prevention). The im of HCC surveillnce progrms is to identify erly cncers so tht the ptients my still undergo curtive tretment nd chieve complete remission. The lrgest rndomized controlled tril testing the efficcy of HCC screening ws conducted in urbn Shnghi, Chin. 69 The study cluster rndo-

6 Prevention of heptocellulr crcinom., 2012; 11 (3): Tble 1. Scoring systems to predict HCC risk in chronic heptitis B ptients. Author/Yer Popultion Follow-up Score Performnce Yuen, et l. 820 chronic heptitis B 77 months 16 * sex (mle =1, femle = 0) + ge + AUROC: 0.88 t 5 yers, ptients t hospitl clinic. 3 * HBV DNA (log copies/ml) t 10 yers. At cutoff 19 * core promoter muttions of 101 points, the sensitivity (mutnt = 1, wild type = 0) + 30 * cirrhosis nd specificity for HCC ws (presence = 1; bsence = 0). 84 nd 76% t 5 yers, nd 88 nd 79% t 10 yers, respectively. Wong, et l. 1,005 chronic heptitis B 10 yers Age (> 50 yers = 3 points; 50 yers = 0) + AUROC 0.76 t 5 yers ptients in n HCC lbumin ( 35 g/l = 20 points; > 35 g/l = 0) + nd 0.78 t 10 yers. surveillnce project bilirubin (> 18 µmol/l = 1.5 points; At cutoff of 5 points, the (trining cohort); 424 ptients 18 µmol/l = 0) + HBV DNA (> 6 log copies/ml sensitivity nd specificity in hospitl clinic = 4 points; 4-6 log = 1 point; 4 log = 0) were 78 nd 73% t 5 yers, (vlidtion cohort). + cirrhosis (yes = 15 points; no = 0) nd 81 nd 76% t 10 yers, respectively. Yng, et l. Chronic heptitis B ptients 11.4 yers Sex (mle = 2 points; femle = 0) + ge (1 point AUROC 83% t 5 yers from 7 Tiwn townships for every 5 yers) + fmily history of HCC nd 82% t 10 yers. rndomly ssigned to the (yes = 2 points; no = 0) + lcohol consumption derivtion cohort (n = 2,435) (yes = 1 point; no = 0) +ALT (< 15 U/L = 0; nd vlidtion cohort = 1 point; 45 = 3 points) + HBeAg (n = 1,218). (positive = 3 points; negtive = 0). (Alterntive models incorporting HBV DNA nd genotypes vilble). Yng, et l. 3,584 non-cirrhotic ptients 12.0 yers A 17-point score comprising of 5 vribles: AUROC 78% t 5 yers from Tiwn (development (development sex, ge, ALT, HBeAg nd HBV DNA. nd 81% t 10 yers. cohort) nd 1,505 ptients in 2 cohort); 6.3, 9.4 Hong Kong nd 1 South nd 7.0 yers Kore centers (3 vlidtion (vlidtion cohort). cohorts). ALT: lnine minotrnsferse. AUROC: re under the receiver operting chrcteristics curve. HBV: heptitis B virus.

7 290 Wi-Sun Wong V, et l., 2012; 11 (3): mized ptients with chronic heptitis to HCC screening (n = 9,373) or no screening (n = 9,443). Ptients in the screening group hd lph fetoprotein testing nd ultrsound exmintion every 6 months. More resectble HCC were identified in the screening group. Besides, mong ptients with HCC, 5- yer survivl rte ws 46% in the screening group nd 0% in the control group. In rel life clinicl prctice, the mjority of HCC ptients cnnot undergo curtive tretment becuse of dvnced tumor stging nd poor liver function. 70 However, HCC identified by regulr surveillnce re typiclly smller nd fewer in number As result, more ptients cn undergo surgery or locl bltive therpy, nd chieve better survivl. Ultrsound exmintion nd lph fetoprotein testing re lbor-intensive nd costly. 74 Most developing countries cnnot fford indiscriminte surveillnce of ll ptients with chronic liver diseses. Studies hve showed tht HCC surveillnce would be more cost-effective if the screening tests re sensitive in detecting smll HCCs, the incidence of HCC is high, nd curtive tretments re vilble. 75 Therefore, the surveillnce progrm should focus on ptients t high risk of HCC development nd be supported by effective referrl nd provision of tretment. For exmple, ll ptients who hve liver cirrhosis, which is the most importnt risk fctor for HCC, should undergo regulr HCC surveillnce unless the cndidte hs decompensted disese nd is not suitble for liver trnsplnttion. 76 As liver biopsy my not be fesible or cceptble to ll ptients for the dignosis of erly liver cirrhosis, non-invsive mesure of liver fibrosis such s trnsient elstogrphy my be useful in this setting In chronic heptitis B, number of clinicl, biochemicl nd virologicl fctors hve been shown to be ssocited with HCC risk in ddition to liver cirrhosis. Long-term epidemiologicl studies hve estblished the role of positive HBeAg, high HBV DNA nd virl genotypes in HCC development. 24,80 In study of 3,653 chronic heptitis B ptients in Tiwn (REVEAL study), the incidence of HCC ws 108 per 100,000 person-yers for n HBV DNA level of < 300 copies/ml nd 1,152 per 100,000 personyers for n HBV DNA level of 1 million copies/ml or bove t men follow-up of 11.4 yers. 23 Genotype C HBV, prticulrly subgenotype Ce (prevlent in Est Asi such s Kore, Jpn nd Northern prt of Chin), is ssocited with higher risk of HCC thn genotype B HBV. 24,81,82 Incorporting different risk fctors, investigtors hve derived nd vlidted vrious combined prediction scores for HCC development (Tble 1). There is incresing evidence tht the level of HBsAg cn reflect the host immune control of the HBV. 87 In n post-hoc nlysis of the REVEAL study, the level of serum HBsAg cn further strtify the risk of HCC mong ptients who hve HBV DNA < 10,000 copies/ml. 88 CONCLUSIONS The development of HBV vccine nd ntivirl therpy ginst HBV nd HBV hs revolutionized the mngement of chronic virl heptitis nd resulted in drmtic improvements in clinicl outcomes. Together with generl preventive mesures, the number of ptients ffected by virl heptitis nd cirrhotic complictions is expected to decline. HCC surveillnce further llows detection of erly cncers nd provision of curtive therpy. In the ner future, the key is to ensure vilbility nd ffordbility of these mesures to people in low nd middle income countries (Figure 4). HBV vccintion Tretment of cute heptitis C Antivirl therpy for HBV nd HCV Avoid excessive lcohol Regulr HCC surveillnce by ultrsound nd/ or lph fetoprotein Perintl heptitis B immunoglobulin Primry prevention (Prevention of virl heptitis) Secondry prevention (Prevention of HCC in susceptible ptients) Erly HCC detection Sfe sex Prevent needle shring Antivirl therpy for HBV nd HCV Sfe food storge to prevent fltoxin Erly curtive tretment of HCC Figure 4. Model for the control of HCC t the popultion level.

8 Prevention of heptocellulr crcinom., 2012; 11 (3): COMPETING INTERESTS Vincent Wong hs served s n dvisory committee member for Roche, Novrtis, Giled nd Otsuk. He hs lso served s speker for Bristol-Meyers- Squibb, Roche, Novrtis, Abbott Dignostics nd Echosens. Henry Chn is consultnt for Abbott, Bristol Myer Squibb, Giled, Merck, Novrtis nd Roche, nd hs received honorrium for lecture for Abbott, Bristol Myer Squibb, Echosens, Giled, Glxo-Smith-Kline, Merck, Novrtis nd Roche. ABBREVIATIONS HBeAg: heptitis B e ntigen. HbsAg: heptitis B surfce ntigen. HBV: heptitis B virus. HCC: heptocellulr crcinom. HCV: heptitis C virus. SVR: sustined virologicl response. REFERENCES 1. Jeml A, Bry F, Center MM, Ferly J, Wrd E, Formn D. Globl cncer sttistics. CA Cncer J Clin 2011; 61: El-Serg HB, Rudolph KL. Heptocellulr crcinom: epidemiology nd moleculr crcinogenesis. Gstroenterology 2007; 132: El-Serg HB, Dvil JA, Petersen NJ, McGlynn KA. 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