Predictive Factors for Reactivation of Hepatitis B Following Hepatitis B e Antigen Seroconversion in Chronic Hepatitis B
2007; Elsevier BV; Volume: 133; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2007.08.039
ISSN1528-0012
Autores Tópico(s)Liver Disease Diagnosis and Treatment
ResumoBackground & Aims: Predictors of reactivation of hepatitis B following hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B have rarely been reported before and deserve further study. Methods: A total of 133 HBeAg-positive asymptomatic carriers who have undergone HBeAg seroconversion were studied. Reactivation of hepatitis B was defined as elevation of alanine aminotransferase >2 × upper normal limit accompanied by serum hepatitis B virus DNA detectable by hybridization assays. Results: The samples consisted of 75 men and 58 women, and the mean age at entry was 28.2 ± 6.9 years. One hundred eight subjects had genotype B, and 25 had genotype C. The maximal alanine aminotransferase levels during the HBeAg-positive phase were 5 × upper normal limit in 49, 40, and 44 subjects, respectively. HBeAg seroconversion occurred after a mean follow-up of 4.6 ± 3.7 years. During a mean follow-up of 5.8 ± 4.6 years following HBeAg seroconversion, reactivation of hepatitis B occurred in 26 patients at 3.3% per year. Multivariate analyses demonstrated that reactivation of hepatitis B correlated significantly with genotype C (P = .003), male sex (P = .03), alanine aminotransferase levels >5 × upper normal limit during the HBeAg-positive phase (P = .02), and age at HBeAg seroconversion ≥40 years (P = .002). Conclusions: At baseline, genotype C and male sex are independent factors predictive of reactivation of hepatitis B. Additionally, the likelihood of reactivation of hepatitis B is increased if more rigorous immune-mediated hepatocytolysis or more prolonged immune clearance phase is necessary to eliminate the virus. Background & Aims: Predictors of reactivation of hepatitis B following hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B have rarely been reported before and deserve further study. Methods: A total of 133 HBeAg-positive asymptomatic carriers who have undergone HBeAg seroconversion were studied. Reactivation of hepatitis B was defined as elevation of alanine aminotransferase >2 × upper normal limit accompanied by serum hepatitis B virus DNA detectable by hybridization assays. Results: The samples consisted of 75 men and 58 women, and the mean age at entry was 28.2 ± 6.9 years. One hundred eight subjects had genotype B, and 25 had genotype C. The maximal alanine aminotransferase levels during the HBeAg-positive phase were 5 × upper normal limit in 49, 40, and 44 subjects, respectively. HBeAg seroconversion occurred after a mean follow-up of 4.6 ± 3.7 years. During a mean follow-up of 5.8 ± 4.6 years following HBeAg seroconversion, reactivation of hepatitis B occurred in 26 patients at 3.3% per year. Multivariate analyses demonstrated that reactivation of hepatitis B correlated significantly with genotype C (P = .003), male sex (P = .03), alanine aminotransferase levels >5 × upper normal limit during the HBeAg-positive phase (P = .02), and age at HBeAg seroconversion ≥40 years (P = .002). Conclusions: At baseline, genotype C and male sex are independent factors predictive of reactivation of hepatitis B. Additionally, the likelihood of reactivation of hepatitis B is increased if more rigorous immune-mediated hepatocytolysis or more prolonged immune clearance phase is necessary to eliminate the virus. See editorial on page 1718. See editorial on page 1718. The epidemiologic and clinical features of hepatitis B virus (HBV) infection vary between high and low HBV endemic areas.1Chu C.M. Liaw Y.F. Natural history differences in perinatally versus adult-acquired disease.Curr Hepat Rep. 2004; 3: 123-131Crossref Google Scholar In high endemic areas such as Taiwan, HBV infection occurs predominantly during the perinatal period or early childhood, and there is a high rate of persistent infection.1Chu C.M. Liaw Y.F. Natural history differences in perinatally versus adult-acquired disease.Curr Hepat Rep. 2004; 3: 123-131Crossref Google Scholar The natural history of chronic HBV infection comprises 3 chronologic phases: an initial immune tolerant phase during which the patients are positive for hepatitis B e antigen (HBeAg) and have normal alanine aminotransferase (ALT) levels, followed by an immune clearance phase when the HBeAg-positive patients have raised ALT levels, and, finally, the low replication phase when HBeAg seroconverts to its antibody (anti-HBe) and ALT normalizes.2Chu C.M. Karayiannis P. Fowler M.J. et al.Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum.Hepatology. 1985; 5: 431-434Crossref PubMed Scopus (312) Google Scholar, 3Chu C.M. Natural history of chronic hepatitis B virus infection in adults with emphasis on the occurrence of cirrhosis and hepatocellular carcinoma.J Gastroenterol Hepatol. 2000; 15: E25-E30Crossref PubMed Scopus (169) Google Scholar Patients in the third phase usually have serum HBV DNA undetectable by hybridization assays and are termed "inactive HBsAg carriers." The ultimate outcome of chronic HBV infection appears to depend on the duration of the immune clearance phase and on the severity of liver damage during this phase.4Liaw Y.F. Tai D.I. Chu C.M. et al.The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.Hepatology. 1988; 8: 493-496Crossref PubMed Scopus (573) Google Scholar, 5Fattovich G. Brollo L. Giustina G. et al.Natural history and prognostic factors for chronic hepatitis type B.Gut. 1991; 32: 294-298Crossref PubMed Scopus (379) Google Scholar Additionally, reactivation of hepatitis B may occur following HBeAg seroconversion, also significantly contributing to the development of cirrhosis.6Hsu Y.S. Chien R.N. Yeh C.T. et al.Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.Hepatology. 2002; 35: 1522-1527Crossref PubMed Scopus (622) Google Scholar, 7Chu C.M. Hung S.J. Lin J. et al.Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.Am J Med. 2004; 116: 829-834Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 8Chu C.M. Liaw Y.F. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up.Hepatology. 2007; 45: 1187-1192Crossref PubMed Scopus (294) Google Scholar Two published studies from Taiwan prospectively followed-up the natural course following spontaneous HBeAg seroconversion.6Hsu Y.S. Chien R.N. Yeh C.T. et al.Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.Hepatology. 2002; 35: 1522-1527Crossref PubMed Scopus (622) Google Scholar, 7Chu C.M. Hung S.J. Lin J. et al.Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.Am J Med. 2004; 116: 829-834Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar The annual rates of reactivation of hepatitis B (ALT >twice the upper limit of normal [ULN] and detectable serum HBV DNA by hybridization assays) were 3.3% in a study involving patients with chronic hepatitis B6Hsu Y.S. Chien R.N. Yeh C.T. et al.Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.Hepatology. 2002; 35: 1522-1527Crossref PubMed Scopus (622) Google Scholar and 2.2% in a study involving asymptomatic patients.7Chu C.M. Hung S.J. Lin J. et al.Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.Am J Med. 2004; 116: 829-834Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar Other studies recently reported from Taiwan showed that the annual rate of reactivation of hepatitis B in anti-HBe-positive asymptomatic carriers was 1.5%.8Chu C.M. Liaw Y.F. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up.Hepatology. 2007; 45: 1187-1192Crossref PubMed Scopus (294) Google Scholar, 9Chu C.M. Liaw Y.F. Spontaneous relapse of hepatitis in inactive HBsAg carriers from Taiwan.Hepatol Int. 2007; 1: 311-315Crossref PubMed Google Scholar Very few studies have addressed predictors of reactivation of hepatitis B following HBeAg seroconversion. In a previous study from Taiwan, reactivation of hepatitis B was considerably more frequent in males than females.7Chu C.M. Hung S.J. Lin J. et al.Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.Am J Med. 2004; 116: 829-834Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar However, the sex-related difference was not correlated with HBV genotype. In other studies from Hong Kong and Taiwan, reactivation of hepatitis B was considerably more frequent in genotype C infection than genotype B infection.10Chu C.M. Liaw Y.F. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.J Hepatol. 2005; 43: 411-417Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 11Chu C.J. Hussain M. Lok A.S. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C.Gastroenterology. 2002; 122: 1756-1762Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar Similarly, this difference was not corrected by the confounding factor of sex. Furthermore, these studies did not use survival analysis to assess the time elapsed from study entry to reactivation of hepatitis B. Recently, an interesting observation revealed that the risk of reactivation of hepatitis B in anti-HBe-positive asymptomatic carriers was extremely low for patients aged below 30 years on study entry but increased significantly with increasing age of study entry.9Chu C.M. Liaw Y.F. Spontaneous relapse of hepatitis in inactive HBsAg carriers from Taiwan.Hepatol Int. 2007; 1: 311-315Crossref PubMed Google Scholar Although the age of HBeAg seroconversion in this cohort remains largely unknown, patients aged below 30 years on study entry can be considered to have early HBeAg seroconversion. These observations suggest that early HBeAg seroconversion may be associated with low risk of reactivation of hepatitis B. However, both age of HBeAg seroconversion and risk of reactivation of hepatitis B correlate with HBV genotype: genotype B infection is associated with earlier HBeAg seroconversion,10Chu C.M. Liaw Y.F. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.J Hepatol. 2005; 43: 411-417Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 11Chu C.J. Hussain M. Lok A.S. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C.Gastroenterology. 2002; 122: 1756-1762Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar, 12Kao J.H. Chen P.J. Lai M.Y. et al.Hepatitis B virus genotypes and spontaneous hepatitis B e antigen seroconversion in Taiwanese hepatitis B carriers.J Med Virol. 2004; 72: 363-369Crossref PubMed Scopus (151) Google Scholar in addition to lower frequency of reactivation of hepatitis B, than genotype C infection.10Chu C.M. Liaw Y.F. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.J Hepatol. 2005; 43: 411-417Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 11Chu C.J. Hussain M. Lok A.S. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C.Gastroenterology. 2002; 122: 1756-1762Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar Thus, it can be argued that the risk of reactivation of hepatitis B in relation to the age of HBeAg seroconversion should be correlated with HBV genotypes. We therefore conducted this analysis to correlate the risk of reactivation of hepatitis B following spontaneous HBeAg seroconversion with baseline and follow-up clinical and laboratory variables using Cox proportional hazards regression models. From 1982 to 2000, 206 asymptomatic adults incidentally identified as hepatitis B surface antigen (HBsAg) carriers during blood donation or health checkup were prospectively followed-up provided they fulfilled the following criteria: (1) HBeAg positive, anti-HBe negative, normal ALT level (0–36 U/L), no evidence of cirrhosis based on clinical grounds and liver ultrasonography13Lin D.Y. Sheen I.S. Chiu C.T. et al.Ultrasonographic changes of early liver cirrhosis in chronic hepatitis B: a longitudinal study.J Clin Ultrasound. 1993; 21: 303-308Crossref PubMed Scopus (165) Google Scholar and no concomitant infection with hepatitis C virus or hepatitis D virus at baseline; (2) no antiviral or immunomodulatory therapy before entry or during follow-up, as reported earlier.10Chu C.M. Liaw Y.F. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.J Hepatol. 2005; 43: 411-417Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Of these, 133 who had documented seroconversion from HBeAg to anti-HBe during follow-up and had regular follow-up for a minimum of 1 year following HBeAg seroconversion were enrolled into the present study. Patients who had alcohol or drug usage that might be possible etiologic agents of hepatitis were excluded. No patient in this cohort admitted intravenous drug abuse or homosexuality. On entry, the patients were tested for liver biochemical tests, virologic markers (HBsAg, HBeAg, anti-HBe, antibody against hepatitis C virus [anti-HCV], and antibody against hepatitis D virus [anti-HDV]), α-fetoprotein, and liver ultrasonography. Liver biochemical tests were assayed every 6 months if ALT levels were normal and every 1–3 months or more often if ALT levels were raised. HBsAg, HBeAg, anti-HBe, and α-fetoprotein were assayed every 6 months or more often if clinically indicated. Assays for anti-HCV and anti-HDV were repeated if ALT levels increased to more than twice the ULN. Serum HBV DNA was not routinely assayed but was measured when ALT levels increased to more than twice the ULN following HBeAg seroconversion. HBsAg, HBeAg, anti-HBe, and anti-HDV were assayed by radioimmunoassay (Abbott Diagnostics, North Chicago, IL). Anti-HCV was tested by second- or third-generation enzyme immunoassay (Abbott Diagnostics). HBV DNA was tested by sandwich molecular hybridization assays using a Digene Hybrid Capture System (Digene Diagnostics, Inc, Beltsville, MD). The detection sensitivity was 0.5 pg/mL (1.4 × 105 copies/mL). HBV genotypes were determined using the polymerase chain reaction (PCR) restriction fragment length polymorphism of the surface gene of HBV, as previously described.10Chu C.M. Liaw Y.F. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.J Hepatol. 2005; 43: 411-417Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Reactivation of hepatitis B was diagnosed when ALT levels raised to more than twice the ULN, accompanied by positive serum HBV DNA by hybridization assays.6Hsu Y.S. Chien R.N. Yeh C.T. et al.Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.Hepatology. 2002; 35: 1522-1527Crossref PubMed Scopus (622) Google Scholar, 7Chu C.M. Hung S.J. Lin J. et al.Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.Am J Med. 2004; 116: 829-834Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 8Chu C.M. Liaw Y.F. HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up.Hepatology. 2007; 45: 1187-1192Crossref PubMed Scopus (294) Google Scholar, 9Chu C.M. Liaw Y.F. Spontaneous relapse of hepatitis in inactive HBsAg carriers from Taiwan.Hepatol Int. 2007; 1: 311-315Crossref PubMed Google Scholar, 10Chu C.M. Liaw Y.F. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.J Hepatol. 2005; 43: 411-417Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar To compare characteristics between groups, either the χ2 test or the Fisher exact test was used to analyze categorical variables, and the Student t test or Wilcoxon nonparametric test was used to analyze continuous variables. The incidence rate of reactivation of hepatitis B per 100 person-years was calculated as number of incident cases divided by total person-years of follow-up multiplied by 100. The 95% confidence interval for the incidence rate was calculated by using a Poisson distribution for the observed number of incident cases.14Daly L.E. Bourke G.L. Interpretation and uses of medical statistics. Blackwell Science, London2000Crossref Scopus (37) Google Scholar Estimates of the rate of reactivation of hepatitis B were calculated by the actuarial analysis method, and the difference was determined using the long-rank test. Univariate and multivariate analyses were conducted to identify factors associated with reactivation of hepatitis B. Variables with P values ≤ .1 in the univariate models were tested in a multivariate setting using the Cox proportional hazards regression models. Statistical procedures were performed using SPSS statistical software (version 13.0; SPSS Inc, Chicago, IL). P values < .05 were considered significant. Table 1 lists the clinical and laboratory data at baseline and during follow-up of the total study patients and their comparison between the male and female patients. The male patients were significantly less likely to have ALT levels 5 × ULN during the HBeAg-positive phase than the female patients.Table 1Baseline and Follow-Up Data of 133 HBeAg Positive Asymptomatic CarriersDataTotal (n = 133)Men (n = 75)Women (n = 58)Age on entry (y)28.2 ± 6.928.3 ± 6.428.2 ± 7.529 (23–33)29 (24–33)28 (22–33) <3074 (56)43 (57)31 (53) ≥30 years59 (44)32 (43)27 (47)Genotype B108 (81)64 (85)44 (76) C25 (19)11 (15)14 (24)Maximal ALT during HBeAg-positive phase 5 × ULN44 (33)32 (43)bP = .008.12 (21)bP = .008.Interval from entry to HBeAg seroconversion (y)4.6 ± 3.74.6 ± 4.04.5 ± 3.33.5 (1.5–6.5)3.5 (1.1–6.4)4.3 (2.0–6.5)Age at HBeAg seroconversion (y)32.8 ± 7.332.8 ± 7.232.8 ± 7.533 (28–37)33 (29–37)34 (26–38) .1 unless otherwise noted.ALT, alanine aminotransferase; ULN, upper limit of normal.a P = .04.b P = .008.c P = .005. Open table in a new tab NOTE. Data are given as mean ± SD, number (%), or median (interquartile range). P (men vs women) > .1 unless otherwise noted. ALT, alanine aminotransferase; ULN, upper limit of normal. ALT levels normalized in all patients following HBeAg seroconversion. During a mean follow-up of 5.8 ± 4.2 years following HBeAg seroconversion, 28 patients had raised ALT levels >2 × ULN. Of these, none had serologic evidence of superinfection with hepatitis C or hepatitis D virus. Twenty-six patients (93%) were positive for HBV DNA, including 3 with reversion of HBeAg and 23 with persistent anti-HBe, and were diagnosed as having reactivation of hepatitis B. The remaining 2 patients (7%) were negative for HBeAg and HBV DNA in all available serum specimens. The annual rate of reactivation of hepatitis B was estimated to be 3.3%. The cumulative probabilities of reactivation of hepatitis B were 15.1%, 29.8%, and 32.8%, respectively, after 5, 10, and 15 years of follow-up (Figure 1). Table 2 lists the person-years of follow-up and the event of reactivation of hepatitis B, stratified according to HBV genotype, sex, maximal ALT levels during the HBeAg-positive phase, and age at HBeAg seroconversion, of the total study patients and the comparison between the male and female patients. The incidence rate of reactivation of hepatitis B tended to be higher in males than females in each subgroup.Table 2Calculated Rates of Reactivation of Hepatitis B Following HBeAg SeroconversionVariablesTotalMenWomenNo. at riskPerson-years of follow-upReactivation of hepatitis BNo. at riskPerson-years of follow-upReactivation of hepatitis BNo. at riskPerson-years of follow-upReactivation of hepatitis BNRate (95% CI)/100 person-yearsNRate (95% CI)/100 person-yearsNRate (95% CI)/100 person-yearsGenotype B108671172.53 (1.48–4.06)64401143.49 (1.91–5.86)4427031.11 (0.23–3.25) C2510598.57 (3.92–16.27)1142716.67 (6.70–34.34)146323.17 (0.38–11.47)Maximal ALT during HBeAg positive phase 5 × ULN44219125.48 (2.83–9.57)32161106.21 (2.98–11.42)125823.45 (0.42–12.46)Age at HBeAg seroconversion 5 × ULN during the HBeAg positive phase, and age at HBeAg seroconversion ≥40 years.Table 3Variables Predictive for Reactivation of Hepatitis B Following HBeAg SeroconversionFactorsUnivariate analysisMultivariate analysisHazard ratio (95% CI)P valueHazard ratio (95% CI)P valueAge on entry— <30 y1 ≥30 y1.05 (0.49–2.27).88Sex Female11 Male3.22 (1.22–8.55).0192.99 (1.08–8.22).034Genotype B11 C3.18 (1.39–7.30).0063.75 (1.56–9.01).0031Maximal ALT during HBeAg-positive phase 5 × ULN3.01 (1.12–8.08).0293.57 (1.22–10.46).02Interval from entry to HBeAg seroconversion (y)1.06 (0.94–1.18).36—Age at HBeAg seroconversion <40 y11 ≥40 y3.93 (1.62–9.92).00254.40 (1.69–11.36).0024CI, confidence interval; ALT, alanine aminotransferase; ULN, upper limit of normal. Open table in a new tab CI, confidence interval; ALT, alanine aminotransferase; ULN, upper limit of normal. The cumulative probabilities of reactivation of hepatitis B stratified according to HBV genotype, gender, age at HBeAg seroconversion 5 × ULN during the HBeAg-positive phase and those who were older than 40 years at the time of HBeAg seroconversion had higher risk of reactivation of hepatitis B. The cumulative probabilities of reactivation of hepatitis B stratified according to sex and HBV genotype, sex and age at HBeAg seroconversion, and HBV genotype and age at HBeAg seroconversion are shown in Figure 3A, B, and C, respectively. The cumulative probabilities of reactivation of hepatitis B after 7 years of follow-up were greater than 40% for genotype C males, males with age at HBeAg seroconversion ≥40 years, or genotype C carriers with age at HBeAg seroconversion ≥40 years and less than 10% for genotype B females, females with age at HBeAg seroconversion <40 years, or genotype B carriers with age at HBeAg seroconversion 1 × 105 copies/mL, 104–105 copies/mL, and <104 copies/mL in 34, 3, and 3 patients, respectively (Chu, unpublished observations, 2007). These data suggested that, if we adopted HBV DNA level of 104 copies/mL as a cut-off value to diagnose reactivation of hepatitis B, reactivation of hepatitis B may be missed in approximately half of patients with relapse of hepatitis who were negative for HBV DNA by hybridization assays. Nevertheless, the number of these patients was relatively small in the current study, so it seems that the major conclusion of this study might not change substantially without inclusion of these patients. This investigation had several unique features. The patients in this study cohort were followed-up from the immune tolerant phase, and, thus, the ALT activities during immune clearance phase could be clearly defined with minimal selection bias. Additionally, all patients had documented age of HBeAg seroconversion. Both variables were among the 4 factors identified in this study as being independently associated with reactivation of hepatitis B following HBeAg seroconversion (Table 3). It should be pointed out that 37% of patients had minimally raised ALT levels ( 5 × ULN during immune clearance phase had higher risk for reactivation of hepatitis B following HBeAg seroconversion than those with ALT levels 5 × ULN usually reflects vigorous host immune reaction to HBV20Liaw Y.F. Hepatitis flares and hepatitis B e antigen seroconversion: implication in anti-hepatitis B virus therapy.J Gastroenterol Hepatol. 2003; 18: 246-252Crossref PubMed Scopus (143) Google Scholar and correlates with HBeAg seroconversion in patients with genotype C infection who are slower in HBeAg seroconversion but more inclined to suffer reactivation of hepatitis B than those with genotype B infection, as shown in the previous study.10Chu C.M. Liaw Y.F. Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline.J Hepatol. 2005; 43: 411-417Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar These findings suggest that HBV is more likely to reactivate if more rigorous immune-mediated hepatocytolysis is necessary to achieve HBeAg seroconversion. The present results also demonstrated that reactivation of hepatitis B correlated significantly with patient age at the time of HBeAg seroconversion. Previous studies in Taiwan have demonstrated that the prevalence of serum HBeAg in asymptomatic HBsAg carriers reduced with increasing age and that less than 10% of HBsAg carriers over 40 years of age were HBeAg positive.19Chu C.M. Sheen I.S. Lin S.M. et al.Sex difference in chronic hepatitis B virus infection: studies of serum HBeAg and alanine aminotransferase levels in 10,431 asymptomatic Chinese HBsAg carriers.Clin Infect Dis. 1993; 16: 709-713Crossref PubMed Scopus (63) Google Scholar These data suggest that most HBsAg carriers in Taiwan undergo HBeAg seroconversion before 40 years of age. In keeping with this postulation, only 16% (21/133) of HBsAg carriers in this cohort underwent HBeAg seroconversion after 40 years of age (Table 1). Notably, it has been shown that patients with HBeAg seroconversion after 40 years of age had much higher risk of progression to cirrhosis than those with earlier HBeAg seroconversion.21Chu C.M. Liaw Y.F. Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion.J Viral Hepat. 2007; 14: 147-152Crossref PubMed Scopus (130) Google Scholar HBeAg seroconversion after 40 years of age thus can be considered as "delayed" HBeAg seroconversion with unfavorable outcome.21Chu C.M. Liaw Y.F. Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion.J Viral Hepat. 2007; 14: 147-152Crossref PubMed Scopus (130) Google Scholar Conceivably, delayed HBeAg seroconversion is associated with prolonged active viral replication and necroinflammation, which may contribute to the progression to cirrhosis. Perhaps the most interesting and original finding of this investigation is that reactivation of hepatitis B was considerably more frequent in patients with delayed HBeAg seroconversion compared with those who underwent HBeAg seroconversion before 40 years of age (Table 3 and Figure 2C). This may further contribute to the progression to cirrhosis in patients with delayed HBeAg seroconversion. This study has several other limitations. First, the number of patients enrolled is relatively small. However, all of these 133 patients were followed-up from the immune tolerant phase through HBeAg seroconversion and afterwards. Second, serum HBV DNA was only tested to confirm reactivation of hepatitis B in patients with raised ALT levels following HBeAg seroconversion, and no adequate serum samples were available for retrospective analysis of HBV DNA at the time of HBeAg seroconversion. Recent studies have demonstrated that viral load is an independent variable for progression to cirrhosis and hepatocellular carcinoma.22Iloeje U.H. Yang H.I. Su J. et al.Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study GroupPredicting cirrhosis risk based on the level of circulating hepatitis B viral load.Gastroenterology. 2006; 130: 678-686Abstract Full Text Full Text PDF PubMed Scopus (1353) Google Scholar, 23Chen C.J. Yang H.I. Su J. et al.REVEAL-HBV Study GroupRisk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.JAMA. 2006; 295: 65-73Crossref PubMed Scopus (2666) Google Scholar Further studies are required to correlate serum levels of HBV DNA at the time of HBeAg seroconversion with subsequent risk of reactivation of hepatitis B. Third, there were no adequate serum samples to test precore or basal core promoter variants in this cohort of patients with reactivation of hepatitis B. The role of these viral mutants in HBsAg carriers with reactivation of hepatitis B may vary with different geographic areas.24Funk M.L. Rosenberg D.M. Lok A.S. World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants.J Viral Hepat. 2002; 9: 52-61Crossref PubMed Scopus (313) Google Scholar In our previous study, 87% of these patients had precore stop mutant, whereas the frequency of basal core promoter mutant was not studied.6Hsu Y.S. Chien R.N. Yeh C.T. et al.Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.Hepatology. 2002; 35: 1522-1527Crossref PubMed Scopus (622) Google Scholar Of the 37 patients with reactivation of hepatitis B (HBV DNA ≥104 copies/mL) mentioned before, 21 (56.8%) had solely precore A1896 mutant, 4 (10.8%) had solely basal core promoter T1762/A1764 mutant, 10 (27.0%) had both mutants, and only 2 (5%) had neither, giving 83.8% and 37.8% overall prevalence rates of precore A1896 mutant and basal core promoter T1762/A1764 mutant, respectively (Chu, unpublished observations, 2007). In conclusion, the annual rate of reactivation of hepatitis B following HBeAg seroconversion is estimated at 3.3% using hybridization assays. HBV genotype C infection and male sex are independent predictors of reactivation of hepatitis B. Additionally, reactivation of hepatitis B correlates significantly with ALT levels >5 × ULN during the immune clearance phase as well as with age at HBeAg seroconversion ≥40 years. The latter findings suggest that the likelihood of HBV reactivation is increased if more rigorous immune-mediated hepatocytolysis or more prolonged immune clearance phase is necessary to eliminate the virus. Hepatitis B: Explosion of New KnowledgeGastroenterologyVol. 133Issue 5PreviewAs regular readers of Gastroenterology and Clinical Gastroenterology and Hepatology appreciate, a steady flow of publications in both journals continues to expand our knowledge of the natural history and management of chronic hepatitis B virus (HBV) infection. This explosion of new knowledge is appropriate and much needed, because chronic hepatitis B is an important public health problem globally and in the United States. It is estimated that worldwide up to 400 million people have chronic HBV infection,1,2 and treatment options to control active viral replication and disease progression continue to expand. Full-Text PDF
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