FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2000363077> ?p ?o ?g. }

• W2000363077 endingPage "S309" @default.
• W2000363077 startingPage "S303" @default.
• W2000363077 abstract "The most effective means of preventing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is to prevent HBV infection via global vaccination of infants. Universal vaccination of newborns has been shown to significantly reduce the incidence of HCC among Taiwanese children. Among HBV carriers, the incidence of HCC was significantly higher in those who were hepatitis B e antigen positive, suggesting that antiviral therapy that results in viral clearance or sustained suppression of HBV replication should reduce the incidence of HCC. Review of data from >1000 chronic hepatitis B patients who received interferon treatment found that interferon has no or minimal overall effect on preventing HCC, but a beneficial effect may be attained in responders. The negative results are in part related to the small number of patients, short duration of follow-up, and low response rate to interferon therapy. Only 1 prospective randomized controlled trial of antiviral therapy with incidence of HCC as an endpoint has been reported. In this trial, 651 Asian patients with compensated HBV-related cirrhosis were randomized to receive lamivudine or placebo. After a median follow-up of 32 months, HCC was diagnosed in 3.9% lamivudine-treated patients and in 7.4% placebo controls (P = 0.047). Further studies using antiviral agents with lower risk of drug-resistance are needed to confirm these results. In addition, questions on who to treat and how long treatment should be administered must be addressed before recommendations on the use of antiviral therapy to prevent HBV-related HCC can be made. The most effective means of preventing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is to prevent HBV infection via global vaccination of infants. Universal vaccination of newborns has been shown to significantly reduce the incidence of HCC among Taiwanese children. Among HBV carriers, the incidence of HCC was significantly higher in those who were hepatitis B e antigen positive, suggesting that antiviral therapy that results in viral clearance or sustained suppression of HBV replication should reduce the incidence of HCC. Review of data from >1000 chronic hepatitis B patients who received interferon treatment found that interferon has no or minimal overall effect on preventing HCC, but a beneficial effect may be attained in responders. The negative results are in part related to the small number of patients, short duration of follow-up, and low response rate to interferon therapy. Only 1 prospective randomized controlled trial of antiviral therapy with incidence of HCC as an endpoint has been reported. In this trial, 651 Asian patients with compensated HBV-related cirrhosis were randomized to receive lamivudine or placebo. After a median follow-up of 32 months, HCC was diagnosed in 3.9% lamivudine-treated patients and in 7.4% placebo controls (P = 0.047). Further studies using antiviral agents with lower risk of drug-resistance are needed to confirm these results. In addition, questions on who to treat and how long treatment should be administered must be addressed before recommendations on the use of antiviral therapy to prevent HBV-related HCC can be made. There is strong evidence for an etiological association between chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) (Table 1).1Kew M. Hepatitis B virus and hepatocellular carcinoma. In: Lai CL, Locarnini S, eds. Hepatitis B virus. London: International Medical Press (chapter 13).Google Scholar HBV along with cigarette smoking are considered the most potent environmental carcinogens. In a landmark study by Beasley et al.,2Beasley R.P. Hwang L.Y. Lin C.C. Chien C.S. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22,707 men in Taiwan.Lancet. 1981; 2: 1129-1133Abstract PubMed Scopus (402) Google Scholar 22,707 Taiwanese men, of whom 3454 tested positive for hepatitis B surface antigen (HBsAg), were followed for a mean of 8.9 years; the relative risk of HCC among HBsAg carriers was found to be 98 (Table 2).3Beasley R.P. Hepatitis B virus. The major etiology of hepatocellular carcinoma.Cancer. 1988; 61: 1942-1956Crossref PubMed Scopus (1151) Google Scholar Worldwide, chronic HBV infection is the most common cause of HCC. Therefore, the most effective means of preventing HCC is to prevent HBV infection via vaccination.Table 1Evidence for an Etiological Association Between Chronic HBV Infection and HCCGeographical correlation between prevalence of chronic HBV infection and incidence of HCCHigh prevalence of HBsAg among patients with HCCRelative risk of HCC among HBsAg carriers: 100HBV infection precedes development of HCCDetection of integrated HBV DNA in HCCHBV vaccination significantly reduces incidence of childhood HCCAnimal models show association between chronic hepadnavirus infection and HCC Open table in a new tab Table 2Incidence of HCC in Relation to Status of HBV Serological MarkersHBV markers at enrollmentPopulation at riskNo. with HCCIncidence of HCC per 100,000/yrHBsAg+3454152495 Known cirrhosis4082247 No cirrhosis3414144474HBsAg−19,25395 Anti-HBc+, anti-HBs+15,57075 Anti-HBc+, anti-HBs−2248210 Anti-HBc−127200 Unknown16300Adapted from Beasley.3Beasley R.P. Hepatitis B virus. The major etiology of hepatocellular carcinoma.Cancer. 1988; 61: 1942-1956Crossref PubMed Scopus (1151) Google Scholar Open table in a new tab Adapted from Beasley.3Beasley R.P. Hepatitis B virus. The major etiology of hepatocellular carcinoma.Cancer. 1988; 61: 1942-1956Crossref PubMed Scopus (1151) Google Scholar The exact mechanisms by which HBV infection causes HCC are unclear. Two pathways have been proposed (Figure 1).4Chisari F.V. Klopchin K. Moriyama T. Pasquinelli C. Dunsford H.A. Sell S. Pinkert C.A. Brinster R.L. Palmiter R.D. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice.Cell. 1989; 59: 1145-1156Abstract Full Text PDF PubMed Scopus (588) Google Scholar, 5Brechot C. Gozuacik D. Murakami Y. Paterlini-Brechot P. Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).Semin Cancer Biol. 2000; 10: 211-231Crossref PubMed Scopus (252) Google Scholar One involves chronic necroinflammation of hepatocytes, cellular injury, mitosis, and hepatocyte regeneration. The other pathway evokes direct oncogenic potential of HBV through chromosomal integration (cis-activation) or transactivation of cellular genes. It is likely that both pathways contribute to HBV-related hepatic carcinogenesis. Thus, treatment that is effective in eradicating HBV or in sustained suppression of HBV replication and the accompanying necroinflammation may reduce the risk of HCC among persons who are infected with HBV. HBV vaccine is the first vaccine that has been shown to prevent cancer. A study of Taiwanese children found that the average annual incidence of liver cancer in children 6–14 years of age declined from 0.70 per 100,000 between 1981 and 1986 to 0.57 between 1986 and 1990 and to 0.36 between 1990 and 1994 (P < 0.01).6Chang M.H. Chen C.J. Lai M.S. Hsu H.M. Wu T.C. Kong M.S. Liang D.C. Shau W.Y. Chen D.S. Taiwan Childhood Hepatoma Study GroupUniversal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children.N Engl J Med. 1997; 336: 1855-1859Crossref PubMed Scopus (1561) Google Scholar The decrease in incidence of HCC coincided with the implementation of a nationwide hepatitis B vaccination program for newborns and children in July 1984 and an ensuing decline in HBsAg carrier rate from 9.8% in 1984 to 1.3% in 1994 and 0.7% in 1999 among persons younger than 15 years of age7Ni Y.H. Chang M.H. Huang L.M. Chen H.L. Hsu H.Y. Chiu T.Y. Tsai K.S. Chen D.S. Hepatitis B virus infection in children and adolescents in a hyperendemic area 15 years after mass hepatitis B vaccination.Ann Intern Med. 2001; 135: 796-800Crossref PubMed Scopus (308) Google Scholar (Figure 2). It is anticipated that the implementation of global vaccination of all newborns will ultimately lead to a worldwide reduction in incidence of HBV-related HCC, although it may take a few decades for the impact to be observed among adults and in countries with low or intermediate carrier rates. Using sensitive amplification assays, many studies have shown that HBV DNA persists at very low levels among persons who have serological recovery from transient HBV infection.8Michalak T.I. Pardoe I.U. Coffin C.S. Churchill N.D. Freake D.S. Smith P. Trelegan C.L. Occult lifelong persistence of infectious hepadnavirus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis.Hepatology. 1999; 29: 928-938Crossref PubMed Scopus (112) Google Scholar In most instances, these low levels of HBV are not associated with liver injury, but mild hepatitis and fibrosis have been reported in some subjects more than 10 years after recovery from an acute HBV infection,9Yuki N. Nagaoka T. Yamashiro M. Mochizuki K. Kaneko A. Yamamoto K. Omura M. Hikiji K. Kato M. Long-term histologic and virologic outcomes of acute self-limited hepatitis B.Hepatology. 2003; 37: 1172-1179Crossref PubMed Scopus (132) Google Scholar and HCC has been reported in persons with serological markers of recovered HBV infection. In the latter situation, it is not clear if HCC developed in individuals who recovered from acute HBV infection or in carriers who spontaneously cleared HBsAg after many decades of chronic HBV infection. Whatever the situation may be, the risk of HCC is substantially lower in persons who are immune to HBV. Thus, in the study by Beasley et al.,3Beasley R.P. Hepatitis B virus. The major etiology of hepatocellular carcinoma.Cancer. 1988; 61: 1942-1956Crossref PubMed Scopus (1151) Google Scholar the incidence of HCC was significantly lower in immune persons compared with carriers, 5 versus 495 per 100,000 per year (Table 2).3Beasley R.P. Hepatitis B virus. The major etiology of hepatocellular carcinoma.Cancer. 1988; 61: 1942-1956Crossref PubMed Scopus (1151) Google Scholar Similarly, studies in woodchucks found that HCC developed in 100% of woodchucks with chronic woodchuck hepatitis virus infection but in only 17% of woodchucks with recovered woodchuck hepatitis virus infection and none of the noninfected woodchucks.10Gerin J.L. Experimental WHV infection of woodchucks an animal model of hepadnavirus-induced liver cancer.Gastroenterol Jpn. 1990; 25: 38-42PubMed Google Scholar These data indicate that robust immune response that prevents progression from acute to chronic HBV infection is associated with significantly lower risk of HCC. Because the risk of progression from acute to chronic HBV infection is highest among infants, universal immunization of infants is the most effective way of preventing chronic HBV infection and HCC. For the 350 million persons with chronic HBV infection worldwide, HBV vaccination would not be effective in preventing HCC. Several factors have been reported to be associated with increased risk of HCC among HBsAg carriers: male gender, older age (or longer duration of infection), Asian or African race, cirrhosis, family history of HCC, exposure to aflatoxin, alcohol and tobacco, coinfection with hepatitis C and D virus, and more recently viral factors including HBV genotype, core promoter variants, and presence of hepatitis B e antigen (HBeAg) (Table 3).11Lok A.S. McMahon B.J. AASLD Practice Guidelines Chronic hepatitis B.Hepatology. 2001; 34: 1225-1241Crossref PubMed Scopus (806) Google Scholar, 12Fattovich G. Natural history of hepatitis B.J Hepatol. 2003; 39: S50-S58Abstract Full Text Full Text PDF PubMed Google Scholar, 13Benvegnu L. Fattovich G. Noventa F. Tremolada F. Chemello L. Cecchetto A. Alberti A. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study.Cancer. 1994; 74: 2442-2448Crossref PubMed Scopus (291) Google Scholar, 14Kao J.H. Chen P.J. Lai M.Y. Chen D.S. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers.Gastroenterology. 2003; 124: 327-334Abstract Full Text PDF PubMed Scopus (471) Google Scholar Apart from environmental agents, most of these risk factors are not reversible. Thus, prevention of HCC in persons with chronic HBV infection is a major challenge.Table 3Factors Associated With Increased Risk of HCC Among HBsAg CarriersMale genderOlder age (longer duration of infection)Alcohol, cigarettes, aflatoxinCoinfection with HCV or HDVViral factors: HBV genotype C > B Core promoter/X gene mutation HBV replication statusRace: Asians, AfricansFamily history of HCC Open table in a new tab Based on the postulated mechanisms of HBV-related hepatic carcinogenesis, it would seem logical that the risk of HCC is lower in carriers with earlier HBeAg seroconversion, sustained suppression of HBV replication, and associated necroinflammatory liver injury. However, many studies found that most HBsAg positive patients with HCC were HBeAg negative with undetectable serum HBV DNA using hybridization assays. In these studies, HBeAg and HBV DNA were tested at the time of diagnosis of HCC, and may not reflect HBV replication levels during the precancerous stage. Retrospective analysis of patients with chronic HBV infection, who had been longitudinally followed, showed that patients who had spontaneous HBeAg seroconversion had reduced risk of cirrhosis and liver-related mortality, but these studies failed to show a significant reduction in incidence of HCC.12Fattovich G. Natural history of hepatitis B.J Hepatol. 2003; 39: S50-S58Abstract Full Text Full Text PDF PubMed Google Scholar, 15de Jongh F.E. Janssen H.L. de Man R.A. Hop W.C. Schalm S.W. van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver.Gastroenterology. 1992; 103: 1630-1635Abstract PubMed Google Scholar, 16Fattovich G. Giustina G. Schalm S.W. Hadziyannis S. Sanchez-Tapias J. Almasio P. Christensen E. Krogsgaard K. Degos F. de Moura M. Carneiro Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis.Hepatology. 1995; 21: 77-82PubMed Google Scholar In 1 study, 161 European patients with HBV-related compensated cirrhosis were followed for a median of 6 years, the 5-year cumulative HCC incidence among patients who were HBeAg positive, HBeAg negative/HBV DNA positive, or HBeAg negative/HBV DNA negative at entry was 9%, 14%, and 8%, respectively (P = 0.4).17Fattovich G. Pantalena M. Zagni I. Realdi G. Schalm S.W. Christensen E. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis a cohort study of 297 patients.Am J Gastroenterol. 2002; 97: 2886-2895Crossref PubMed Google Scholar The lack of correlation between HBV replication and HCC in these retrospective studies may in part be related to small sample size and short duration of follow-up as well as the low overall incidence of HCC. The only study that prospectively evaluated the effect of HBV replication on the risk of HCC included 11,893 Taiwanese men followed for a mean of 8.5 years. The incidence rate of HCC per 100,000 person years was 1169 among men who were HBsAg positive and HBeAg positive at enrollment, 324 for those who were HBsAg positive only, and 39 for those who were HBsAg negative.18Yang H.I. Lu S.N. Liaw Y.F. You S.L. Sun C.A. Wang L.Y. Hsiao C.K. Chen P.J. Chen D.S. Chen C.J. Taiwan community-based cancer screening projectHepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med. 2002; 347: 168-174Crossref PubMed Scopus (1043) Google Scholar After adjusting for age, hepatitis C status, and use of cigarettes and alcohol, the relative risk for HCC was 9.6 (95% CI, 6.0–15.2) among men who were positive for HBsAg alone and 60.2 (95% CI, 35.5–102.1) for those who were positive for both HBsAg and HBeAg (Table 4). A nested case-control study of 44 men with HCC and 86 matched controls, who were HBsAg positive and HBeAg negative at enrollment, found that the adjusted odds ratio for HCC was 6.0 (95% CI 1.7–21.4) for subjects with serum HBV DNA >13.0 pg/mL compared with those who had undetectable HBV DNA (<2.5 pg/mL) at enrollment. This study confirmed that among persons with chronic HBV infection, the risk of subsequent HCC development was increased in those who had higher levels of HBV replication, but this study did not provide data comparing the incidence rate of HCC among carriers who had HBeAg seroconversion during follow-up versus those who remained HBeAg positive. In a 12-year follow-up study of 1536 Alaskan natives chronically infected with HBV, 72.5% of those who were initially HBeAg positive cleared HBeAg during the first 10 years of follow-up. A higher rate of HCC was observed among carriers who reverted back to HBeAg positive after initial HBeAg seroconversion compared with those who had sustained HBeAg seroconversion.19McMahon B.J. Holck P. Bulkow L. Snowball M.M. Serologic and clinical outcomes 1536 Alaska natives chronically infected with hepatitis B virus.Ann Intern Med. 2001; 135: 759-768Crossref PubMed Scopus (347) Google Scholar These 2 studies support the notion that carriers with persistently high levels of HBV replication have higher risk of HCC.Table 4Incidence of HCC During Follow-upHBV antigen status at enrollmentPerson-year of follow-upNo. of menNo. of cases of HCCIncidence rate (95% CI) cases/100,000 person yearRelative risk*Cox proportional hazards model after adjustment for other risk factors. (95% CI)HBsAg−, HBeAg−74,20595322939 (26–56)1HBsAg+, HBeAg−15,418199150324 (241–428)9.6 (6–15)HBsAg+, HBeAg+2736370321169 (800–1651)60.2 (36–102)Adapted from data.18Yang H.I. Lu S.N. Liaw Y.F. You S.L. Sun C.A. Wang L.Y. Hsiao C.K. Chen P.J. Chen D.S. Chen C.J. Taiwan community-based cancer screening projectHepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med. 2002; 347: 168-174Crossref PubMed Scopus (1043) Google Scholar* Cox proportional hazards model after adjustment for other risk factors. Open table in a new tab Adapted from data.18Yang H.I. Lu S.N. Liaw Y.F. You S.L. Sun C.A. Wang L.Y. Hsiao C.K. Chen P.J. Chen D.S. Chen C.J. Taiwan community-based cancer screening projectHepatitis B e antigen and the risk of hepatocellular carcinoma.N Engl J Med. 2002; 347: 168-174Crossref PubMed Scopus (1043) Google Scholar Spontaneous clearance of HBsAg occurs rarely among patients with chronic HBV infection. Several reports found that chronic hepatitis B patients who had spontaneous HBsAg clearance remained at risk of developing HCC, although the risks of hepatic decompensation and liver-related mortality were reduced.20Fattovich G. Giustina G. Sanchez-Tapias J. Quero C. Mas A. Olivotto P.G. Solinas A. Almasio P. Hadziyannis S. Degos F. de Moura M.C. Krogsgaard K. Pantalena M. Realdi G. Corrocher R. Schalm S.W. European Concerted Action on Viral Hepatitis (EUROHEP)Delayed clearance of serum HBsAg in compensated cirrhosis B relation to interferon alpha therapy and disease prognosis.Am J Gastroenterol. 1998; 93: 896-900Crossref PubMed Scopus (164) Google Scholar, 21Huo T.I. Wu J.C. Lee P.C. Chau G.Y. Lui W.Y. Tsay S.H. Ting L.T. Chang F.Y. Lee S.D. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis.Hepatology. 1998; 28: 231-236Crossref PubMed Scopus (206) Google Scholar Most of the studies involved very small numbers of patients, and information on other concomitant causes of liver disease was not provided. A recent study from Taiwan reported that HCC was not detected in any of 163 patients with chronic HBV (but no hepatitis C virus or hepatitis D virus) infection who had spontaneous HBsAg clearance after a mean follow-up of 5 years.22Chen Y.C. Sheen I.S. Chu C.M. Liaw Y.F. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection.Gastroenterology. 2002; 123: 1084-1089Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar These data indicate that the risk of HCC is substantially reduced in patients with chronic HBV infection who managed to clear HBsAg. Unfortunately, only a very small percentage of carriers, less than 1% per year, spontaneously clear HBsAg.23Liaw Y.F. Sheen I.S. Chen T.J. Chu C.M. Pao C.C. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection a prospective study.Hepatology. 1991; 13: 627-631Crossref PubMed Scopus (241) Google Scholar Based on the foregoing discussions, antiviral therapy that results in viral clearance or sustained suppression of HBV replication and associated hepatic necroinflammation should reduce the incidence of HCC. Data in support of this hypothesis may be obtained through long-term follow-up of previously treated patients or prospective study with incidence of HCC as the endpoint. Reports based on the former approach have focused on the effects of interferon therapy because the other approved treatments, lamivudine and adefovir dipivoxil, have only been available in recent years. Individual studies have in general failed to show an effect of interferon on reducing the incidence of HCC. However, the negative results may be related to the small number of patients in each study, the low rate of antiviral response, the short duration of follow-up, the ethical and logistical difficulties in withholding treatment from controls during the course of follow-up, and the slow rate of HCC development even in untreated patients. The ultimate proof that antiviral therapy can prevent HCC in patients with chronic HBV infection relies on data from prospective randomized controlled clinical trials. Such trials will need to enroll a large number of patients with high risk of HCC followed for an adequate duration. To date, only 1 randomized controlled trial reported a decrease in incidence of HCC among hepatitis B patients who received interferon therapy compared to untreated controls. In this study, 67 interferon-treated and 34 untreated HBeAg-positive Taiwanese men, who participated in a randomized trial of interferon, were followed for 1–12 years. HCC was detected in 1 (1.5%) of the 67 treated patients and in 4 (12%) untreated patients (P = 0.04) (Table 5).24Lin S.M. Sheen I.S. Chien R.N. Chu C.M. Liaw Y.F. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.Hepatology. 1999; 29: 971-975Crossref PubMed Scopus (417) Google Scholar The only treated patient who developed HCC had HBeAg seroconversion initially but became HBeAg positive again 14 months after the end of therapy and remained HBeAg positive with elevated aminotransferases until death. All 4 untreated patients who developed HCC remained persistently HBeAg positive during the course of follow-up.Table 5Effect of Interferon Therapy on Incidence of HCC Among Patients With Chronic Hepatitis BAuthor, yearFollow-up, (yr) mean (range)Mean age (yr)No. (%) of patients with cirrhosisNo. (%) With HCCInterferonControlRespondersNonrespondersLin, 1999aRandomized controlled trial, HBeAg+ patients.247 (1–12)322 (12%)1/28 (3.8%)0/39 (0)4/34 (11.8%)Papatheodoridis, 2001bNonrandomized trial, HBeAg− patients, 1 or more courses of interferon.256 (1–13)48125 (31%)1/57 (1.8%)16/152 (10.5%)15/195 (7.7%)Lampertico, 2003cCase series, HBeAg− patients.265.5 (0.5–13)4635 (35%)2/30 (7%)5/71 (7%)NAvan Zonneveld, 2004dCase series, HBeAg+ patients, 1 or more courses of antiviral therapy.279 (0.3–24)3430 (19%)2/54 (3.7%)6/111 (5.4%)NAa Randomized controlled trial, HBeAg+ patients.24Lin S.M. Sheen I.S. Chien R.N. Chu C.M. Liaw Y.F. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.Hepatology. 1999; 29: 971-975Crossref PubMed Scopus (417) Google Scholarb Nonrandomized trial, HBeAg− patients, 1 or more courses of interferon.25Papatheodoridis G.V. Manesis E. Hadziyannis S.J. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B.J Hepatol. 2001; 34: 306-313Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholarc Case series, HBeAg− patients.26Lampertico P. Del Ninno E. Vigano M. Romeo R. Donato M.F. Sablon E. Morabito A. Colombo M. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholard Case series, HBeAg+ patients, 1 or more courses of antiviral therapy.27Van Zonneveld M. Honkoop P. Hansen B.E. Niesters H.G. Murad S.D. De Man R.A. Schalm S.W. Janssen H.L. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.Hepatology. 2004; 39: 804-810Crossref PubMed Scopus (298) Google Scholar Open table in a new tab Other reports on the effect of interferon therapy on the incidence of HCC were based on nonrandomized studies or case series with treated patients only. Three studies enrolled patients with chronic hepatitis with or without cirrhosis suggest that the risk of HCC may be reduced in the responders but a beneficial effect of interferon could not be shown because of the lack of randomized controls (Table 5). In 1 nonrandomized study, 209 interferon-treated and 195 untreated HBeAg-negative Greek patients were followed for 1–13 years; the incidence of HCC was similar in the 2 groups, but treated patients with sustained biochemical response had lower incidence of HCC.25Papatheodoridis G.V. Manesis E. Hadziyannis S.J. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B.J Hepatol. 2001; 34: 306-313Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar However, a case series of 101 HBeAg-negative Italian patients followed for 0.5–11 years after a 24-month course of interferon therapy found that HCC was detected in an equal proportion of responders and nonresponders.26Lampertico P. Del Ninno E. Vigano M. Romeo R. Donato M.F. Sablon E. Morabito A. Colombo M. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy.Hepatology. 2003; 37: 756-763Crossref PubMed Scopus (204) Google Scholar Another case series of 165 HBeAg-positive Dutch patients followed for a median of 0.3–24 years after receiving interferon therapy found that treatment did not reduce the overall incidence of HCC, but responders had significantly reduced risk of HCC.27Van Zonneveld M. Honkoop P. Hansen B.E. Niesters H.G. Murad S.D. De Man R.A. Schalm S.W. Janssen H.L. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.Hepatology. 2004; 39: 804-810Crossref PubMed Scopus (298) Google Scholar A meta-analysis identified 7 studies that compared the incidence of HCC between 853 interferon-treated patients and 652 untreated controls with compensated HBV-related cirrhosis.28Camma C. Giunta M. Andreone P. Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis An evidence-based approach.J Hepatol. 2001; 34: 593-602Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar The pooled estimate was significantly in favor of a protective effect of interferon, with a 6.4% difference in risk (95% CI −2.8% to −10%) (Table 6). However, there was marked heterogeneity among the studies.Table 6Effect of Interferon Therapy on Incidence of HCC Among HBsAg+ Cirrhotic PatientsAuthor,aAll were nonrandomized trials. yearFollow-up, months mean (range)No. (%) with HCCInterferonControlOon, 199212 (12–60)0/600 (0)10/180 (6%)Mazzella, 199649 (12–119)2/34 (6%)4/28 (14%)Fattovich, 199786 (80–92)3/40 (8%)4/50 (8%)IIHSCSG, 1998NA8/49 (16%)18/97 (19%)DiMarco, 199893 (6–180)2/26 (8%)6/60 (10%)Ikeda, 199884 (6–168)10/94 (11%)51/219 (23%)Benvegnu, 199872 (NA)0/10 (0)4/18 (22%)NA, not available. Adapted with permission.28Camma C. Giunta M. Andreone P. Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis An evidence-based approach.J Hepatol. 2001; 34: 593-602Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholara All were nonrandomized trials. Open table in a new tab NA, not available. Adapted with permission.28Camma C. Giunta M. Andreone P. Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis An evidence-based approach.J Hepatol. 2001; 34: 593-602Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar Based on available data, interferon treatment of chronic hepatitis B has no or minimal effect on preventing HCC, but a beneficial effect may be attained in responders, particularly those who otherwise had high risk of HCC. The negative results are likely related to the small sample size, short duration of follow-up, low response rate to interferon therapy, and low incidence of HCC even in untreated patients. Prospective randomized controlled trials with incidence of HCC as an endpoint are needed to provide the ultimate proof that antiviral therapy can prevent HCC. To date, only one such trial has been conducted. Preliminary results of this trial were recently presented. In this trial, 651 HBsAg-positive Asian patients with compensated liver disease, who were positive for HBeAg and/or serum HBV DNA (using branched DNA assay with detection limit of 700,000 copies/mL), with Ishak fibrosis score ≥4 (bridging fibrosis and cirrhosis) were randomized to receive lamivudine 100 mg daily or placebo in a 2:1 ratio.29Liaw Y.F. Sung J.Y.J. Chow C.H. Shue K. Keene O. Farrell G. Effects of lamivudine on disease progression and development of liver cancer in advanced chronic hepatitis B a prospective double-blind placebo-controlled clinical trial.Hepatology. 2003; 38: 262A-263ACrossref Google Scholar The clinical endpoints of this study included increase in Child-Pugh score by 2 or more points or development of 1 of the following complications: HCC, spontaneous bacterial peritonitis, renal insufficiency, or bleeding varices. The study included 436 patients in the lamivudine group and 215 in the placebo group. Mean age of the patients was 44 years, and 85% were men. This study was terminated early based on recommendations by an independent data and safety monitoring board. At the time of data analysis, the patients had a median follow-up of 32 months (0–42). HCC was diagnosed in 17 (3.9%) lamivudine-treated patients and 16 (7.4%) placebo controls, with a hazard ratio of 0.49 (95% CI 0.25–0.99) (P = 0.047) (Table 7). When the 5 HCC cases in year 1 were excluded, the hazard ratio for the treated group was 0.47 and the difference was no longer significant (P = 0.052). This elegant trial showed that antiviral therapy may reduce the incidence of HCC in patients with chronic HBV infection. Longer follow-up will be needed to determine if a protective effect on HCC can be confirmed and to identify the subset of patients who are most likely to benefit. This is particularly important because other studies on lamivudine therapy in patients with HBV-related decompensated cirrhosis found that, despite biochemical and clinical improvement, HCC can occur. Given the very high rate (49%) of lamivudine resistance, it is obvious that future trials should examine other antiviral agents that are equally efficacious and safe but with lower risk of drug resistance. These trials should also address the questions regarding who should be treated and how long treatment should be administered. Will treatment prevent HCC in patients with lower HBV DNA levels, those with lesser degrees of fibrosis, or those who already have hepatic decompensation? What is the endpoint of treatment? Will the protective effect on HCC be maintained after treatment is stopped?Table 7Randomized Controlled Trial of Lamivudine Treatment in Patients With HBV-CirrhosisLamivudine (n = 436)Placebo (n = 215)Hazard ratio (95% CI)POverall disease progression34 (7.8%)38 (18%)0.45 (0.28–0.73)0.001 Increase in CP score15 (3.4%)19 (8.8%)0.45 (0.22–0.90)0.023 HCC17 (3.9%)16 (7.4%)0.49 (0.25–0.99)0.047aAfter exclusion of 5 HCC cases in year 1, HR = 0.47, p = 0.052 Renal insufficiency2 (0.5%)0—— Bleeding varices2 (0.5%)3 (1.4%)——Adapted from data.29Liaw Y.F. Sung J.Y.J. Chow C.H. Shue K. Keene O. Farrell G. Effects of lamivudine on disease progression and development of liver cancer in advanced chronic hepatitis B a prospective double-blind placebo-controlled clinical trial.Hepatology. 2003; 38: 262A-263ACrossref Google Scholara After exclusion of 5 HCC cases in year 1, HR = 0.47, p = 0.052 Open table in a new tab Adapted from data.29Liaw Y.F. Sung J.Y.J. Chow C.H. Shue K. Keene O. Farrell G. Effects of lamivudine on disease progression and development of liver cancer in advanced chronic hepatitis B a prospective double-blind placebo-controlled clinical trial.Hepatology. 2003; 38: 262A-263ACrossref Google Scholar In summary, prevention of HBV-related HCC is best accomplished by preventing HBV infection via HBV vaccination (Figure 3). Concerted efforts among the scientific community, public health officials, and philanthropists are needed to ensure implementation of global childhood HBV vaccination. For persons who are already chronically infected, development of more effective antiviral therapies that can result in sustained suppression of HBV replication and reduction of necroinflammatory liver damage in a high proportion of patients with chronic hepatitis B will likely lead to reduction in incidence of HCC (Figure 3). These treatments must be safe and affordable with low risk of drug resistance. For patients who fail to achieve sustained response after a course of therapy and for patients who have advanced liver disease, there may be a role for maintenance antiviral therapy in preventing HCC. Such treatment must have established long-term safety, be affordable, and have low risk of drug resistance. In addition, questions on who to treat and how long treatment should be administered must be addressed before recommendations on the use of antiviral therapy to prevent HBV-related HCC can be made." @default.
• W2000363077 created "2016-06-24" @default.
• W2000363077 creator A5010854797 @default.
• W2000363077 date "2004-11-01" @default.
• W2000363077 modified "2023-10-17" @default.
• W2000363077 title "Prevention of hepatitis B virus–related hepatocellular carcinoma" @default.
• W2000363077 cites W126234141 @default.
• W2000363077 cites W1960579853 @default.
• W2000363077 cites W1964039671 @default.
• W2000363077 cites W1984724288 @default.
• W2000363077 cites W1990223022 @default.
• W2000363077 cites W2009554180 @default.
• W2000363077 cites W2033704186 @default.
• W2000363077 cites W2051586219 @default.
• W2000363077 cites W2075365109 @default.
• W2000363077 cites W2076684492 @default.
• W2000363077 cites W2077311317 @default.
• W2000363077 cites W2079462324 @default.
• W2000363077 cites W2079618952 @default.
• W2000363077 cites W2082256923 @default.
• W2000363077 cites W2085523813 @default.
• W2000363077 cites W2096808350 @default.
• W2000363077 cites W2097754581 @default.
• W2000363077 cites W2104475038 @default.
• W2000363077 cites W2148314869 @default.
• W2000363077 cites W2162559479 @default.
• W2000363077 cites W2165605507 @default.
• W2000363077 cites W2314866596 @default.
• W2000363077 cites W2322310797 @default.
• W2000363077 cites W2415371986 @default.
• W2000363077 cites W2616817196 @default.
• W2000363077 cites W4231124841 @default.
• W2000363077 cites W4235965176 @default.
• W2000363077 cites W4237472114 @default.
• W2000363077 cites W4327849090 @default.
• W2000363077 cites W4367435828 @default.
• W2000363077 doi "https://doi.org/10.1053/j.gastro.2004.09.045" @default.
• W2000363077 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/15508098" @default.
• W2000363077 hasPublicationYear "2004" @default.
• W2000363077 type Work @default.
• W2000363077 sameAs 2000363077 @default.
• W2000363077 citedByCount "131" @default.
• W2000363077 countsByYear W20003630772012 @default.
• W2000363077 countsByYear W20003630772013 @default.
• W2000363077 countsByYear W20003630772014 @default.
• W2000363077 countsByYear W20003630772015 @default.
• W2000363077 countsByYear W20003630772016 @default.
• W2000363077 countsByYear W20003630772017 @default.
• W2000363077 countsByYear W20003630772018 @default.
• W2000363077 countsByYear W20003630772019 @default.
• W2000363077 countsByYear W20003630772020 @default.
• W2000363077 countsByYear W20003630772021 @default.
• W2000363077 countsByYear W20003630772022 @default.
• W2000363077 countsByYear W20003630772023 @default.
• W2000363077 crossrefType "journal-article" @default.
• W2000363077 hasAuthorship W2000363077A5010854797 @default.
• W2000363077 hasBestOaLocation W20003630771 @default.
• W2000363077 hasConcept C126322002 @default.
• W2000363077 hasConcept C143998085 @default.
• W2000363077 hasConcept C159047783 @default.
• W2000363077 hasConcept C2522874641 @default.
• W2000363077 hasConcept C2777546739 @default.
• W2000363077 hasConcept C2778019345 @default.
• W2000363077 hasConcept C2780593183 @default.
• W2000363077 hasConcept C3019983190 @default.
• W2000363077 hasConcept C3020804797 @default.
• W2000363077 hasConcept C71924100 @default.
• W2000363077 hasConceptScore W2000363077C126322002 @default.
• W2000363077 hasConceptScore W2000363077C143998085 @default.
• W2000363077 hasConceptScore W2000363077C159047783 @default.
• W2000363077 hasConceptScore W2000363077C2522874641 @default.
• W2000363077 hasConceptScore W2000363077C2777546739 @default.
• W2000363077 hasConceptScore W2000363077C2778019345 @default.
• W2000363077 hasConceptScore W2000363077C2780593183 @default.
• W2000363077 hasConceptScore W2000363077C3019983190 @default.
• W2000363077 hasConceptScore W2000363077C3020804797 @default.
• W2000363077 hasConceptScore W2000363077C71924100 @default.
• W2000363077 hasIssue "5" @default.
• W2000363077 hasLocation W20003630771 @default.
• W2000363077 hasLocation W20003630772 @default.
• W2000363077 hasOpenAccess W2000363077 @default.
• W2000363077 hasPrimaryLocation W20003630771 @default.
• W2000363077 hasRelatedWork W1969621287 @default.
• W2000363077 hasRelatedWork W2369572641 @default.
• W2000363077 hasRelatedWork W2381888253 @default.
• W2000363077 hasRelatedWork W2405130878 @default.
• W2000363077 hasRelatedWork W2474489121 @default.
• W2000363077 hasRelatedWork W2962271213 @default.
• W2000363077 hasRelatedWork W3015095084 @default.
• W2000363077 hasRelatedWork W3163481159 @default.
• W2000363077 hasRelatedWork W3172774620 @default.
• W2000363077 hasRelatedWork W4236089917 @default.
• W2000363077 hasVolume "127" @default.
• W2000363077 isParatext "false" @default.
• W2000363077 isRetracted "false" @default.
• W2000363077 magId "2000363077" @default.
• W2000363077 workType "article" @default.