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Is Antiviral Drug-Induced Hepatitis B Surface Antigen Loss Durable?
All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Gastroenterology 2014;-:1–2
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
SELECTED SUMMARIES Philip S. Schoenfeld, Section Editor John Y. Kao, Section Editor STAFF OF CONTRIBUTORS Joseph Anderson, White River Junction, VT Darren M. Brenner, Chicago, IL Andrew T. Chan, Boston, MA Francis K. L. Chan, Hong Kong, China Massimo Colombo, Milan, Italy Gregory A. Cote, Indianapolis, IN B. Joseph Elmunzer, Ann Arbor, MI Alex Ford, Leeds, United Kingdom Timothy B. Gardner, Lebanon, NH Lauren B. Gerson, San Francisco, CA
Michelle Kang Kim, New York, NY W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Edward V. Loftus, Rochester, MN Uma Mahadevan, San Francisco, CA Laurent Peyrin-Biroulet, Vandoeuvre-lès-Nancy, France Mark Pimentel, Los Angeles, CA Jesus Rivera-Nieves, San Diego, CA Joel H. Rubenstein, Ann Arbor, MI
IS ANTIVIRAL DRUG-INDUCED HEPATITIS B SURFACE ANTIGEN LOSS DURABLE? Kim GA, Lim YS, An J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability? Gut 2014;63: 1325–1332. In patients with chronic hepatitis B, seroclearance of hepatitis B surface antigen (HBsAg) is an important milestone. Patients with spontaneous HBsAg seroclearance seldom experience virologic relapse and have a low risk of disease progression and hepatocellular carcinoma. Similarly, after a course of immunomodulatory treatment with interferon or peginterferon, >10% of patients may eventually develop HBsAg seroclearance, and the response is highly durable (J Hepatol 2009;50:1084–1092; Gastroenterology 2009;136:2169–2179; Hepatology 2010;51:1945–1953). The situation with oral nucleoside analogs (NUCs) is less certain. NUCs have potent antiviral activity but do not have a direct immunomodulatory effect. Because of their ease of use and favorable safety profile, NUCs have been the preferred treatment in the majority of patients. However, in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, NUC-induced HBeAg seroconversion is not as durable as spontaneous HBeAg seroconversion (Hepatology 2000;32:803–806; J Antimicrob Chemother 2013;68:2332– 2338). This leads to the important question of whether NUC-induced HBsAg seroclearance is durable and translates to good clinical outcomes. In a recent paper, Kim et al reported a large, retrospective cohort of 5,409 patients with chronic hepatitis B who were initially treated with lamivudine or entecavir (Gut 2014;63:1325–1332). During a median follow-up of 6 years, 110 patients (2.0%) achieved HBsAg seroclearance (0.33% per year). The overall prognosis of patients with NUCinduced HBsAg seroclearance was good. Only 1 patient developed hepatocellular carcinoma and another required liver transplantation, but died after an unrelated surgery. None of the other patients with HBsAg seroclearance died, underwent liver transplantation, or developed hepatocellular carcinoma. Using propensity score matching, patients
Sameer Saini, Ann Arbor, MI Ekihiro Seki, La Jolla, CA Shamita B. Shah, Stanford, CA Pratima Sharma, Ann Arbor, MI Amit Singal, Dallas, TX Jan Tack, Leuven, Belgium Akbar Waljee, Ann Arbor, MI Alastair J. M. Watson, Norwich, United Kingdom
with HBsAg seroclearance had 90% reduction in the risk of death or liver transplantation (hazard ratio, 0.10; P ¼ .02) and hepatocellular carcinoma (hazard ratio, 0.06; P < .01). The next question is the durability of HBsAg seroclearance. Among 111 patients with HBsAg seroclearance, 8 had HBsAg reversion within 3 years. The cumulative rates of HBsAg reversion were 7.6% at 12 months and 11.7% at 36 months. However, the HBsAg level remained low (0.05-1.0 IU/mL), and 7 patients lost HBsAg again later. In addition, 17 patients had detectable hepatitis B virus (HBV) DNA despite HBsAg seroclearance. The cumulative rates of virologic reversion were 13.8% at 1 year, 18.7% at 2 years, and 29.6% at 4 years. Again, the HBV DNA remained low, at <2,000 IU/mL. It is reassuring that none of those patients required retreatment with NUCs. Negative HBeAg, lower HBV DNA, and high alanine aminotransferase level (>5 times the upper limit of normal at baseline) were associated with HBsAg seroclearance. In contrast, patients with cirrhosis were less likely to achieve HBsAg seroclearance. For some reasons, the use of entecavir as opposed to lamivudine was associated with lower rate of HBsAg seroclearance (hazard ratio, 0.30; P ¼ .05). This may be partly explained by the longer treatment and follow-up duration of patients taking lamivudine. Moreover, patients with HBsAg seroclearance had lower HBsAg levels 2 years before seroclearance and had steeper slope of decline in HBsAg. Comment. The study by Kim et al answers the 2 most important questions on NUC-induced HBsAg seroclearance (Gut 2014;63:1325–1332). First, NUC-induced HBsAg seroclearance is associated with good prognosis. Second, although around 10% of patients may experience HBsAg reversion after initial seroclearance, it is mostly transient and rarely associated with significant viral activities. In other words, NUC-induced HBsAg seroclearance can be considered durable. Several Asian groups have studied the natural history of spontaneous HBsAg seroclearance. This is associated with improvement in histologic necroinflammation and fibrosis (J Hepatol 2005;42:188–194). Overall, hepatocellular carcinoma develops in 1.1%–10.2% of patients after seroclearance (Gastroenterology 2002;123:1084–1089; J Hepatol 2005;42: 188–194; Hepatology 2007;45:1187–1192; Gastroenterology 2008;135:1192–1199). Importantly, complications
DIS 5.2.0 DTD YGAST59394_proof 23 October 2014 3:22 pm ce
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
2
121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180
Selected Summaries
Gastroenterology Vol.
rarely occur unless the patient has delayed seroclearance (after the age of 50 in the Hong Kong study), cirrhosis before seroclearance or coinfection with hepatitis C virus or the delta virus. HBV DNA and covalently closed circular DNA remain detectable in the liver in the majority of patients. This explains the risk of reactivation during immunosuppression or cancer chemotherapy (Hepatology 2006;43:209–220; J Clin Oncol 2009;27:605–611). Although HBsAg seroclearance was durable in the study by Kim et al (Gut 2014;63:1325–1332), the HBsAg reversion and HBV DNA detectability rates were higher than what was reported in cohorts of spontaneous or interferon-induced HBsAg seroclearance. This in itself is not surprising. After all, NUCs do not have direct immunomodulatory effects. However, it is unclear whether consolidation therapy after HBsAg seroclearance is needed. In the paper by Kim et al, the total duration of treatment was not associated with HBsAg reversion. The authors may also wish to explore the effect of the duration of consolidation therapy after HBsAg seroclearance. On the other hand, it is interesting to note that prior drug-resistant HBV mutants (mainly lamivudine resistance) did not affect the rate of HBsAg seroclearance or reversion. In previous studies using less robust stopping rules (eg, HBeAg seroconversion or persistent HBV DNA undetectability), history of drug resistance increases the risk of virologic relapse (Aliment Pharmacol Ther 2011;34: 344–352). Based on these new data, it is safe to stop NUCs after HBsAg seroclearance even in patients with prior drugresistant mutants. In recent years, there has been rekindled interest in HBsAg quantification. Because quantitative HBsAg basically measures the same viral antigen, it is conceivable that lower HBsAg levels are associated with future seroclearance (J Infect Dis 2011;204:408–414; Hepatology 2012;55: 68–76; Hepatology 2013;58:923–931). However, because HBsAg seroclearance is rare during NUC treatment, it is unclear if low HBsAg level alone may be a sufficient
-,
No.
-
stopping rule. In a small study of 53 HBeAg-negative pa- 181 tients treated with lamivudine, all patients with HBsAg 182 100 IU/mL at the end of treatment and >1-log decline in 183 HBsAg during treatment had sustained off treatment 184 response at 12 months (HBV DNA <200 IU/mL; Antivir 185 Ther 2011;16:1249–1257). This notion was not confirmed 186 by a larger entecavir-treated cohort of 184 HBeAg-negative 187 patients (Gut http://dx.doi.org/10.1136/gutjnl-2014- 188 307237 [Epub ahead of print]). However, 91.4% of the Q1189 patients relapsed after stopping entecavir, rendering all 190 predicting factors meaningless. 191 Finally, it is noteworthy that the NUC-induced HBsAg 192 seroclearance rate was only 0.33% per year, which is not 193 higher than the reported annual incidence of spontaneous 194 HBsAg seroclearance of 0.5%–2.0% (Gastroenterology 195 2002;123:1084–1089; J Hepatol 2005;42:188–194; Hep- 196 atology 2007;45:1187–1192; Gastroenterology 2008;135: 197 1192-1199). The decline in HBsAg level during NUC therapy 198 is very slow and tends to level off over time (J Hepatol 199 2011;54:449–454; J Hepatol 2013;59:709–716). Thus, 200 although NUC-induced HBsAg seroclearance is durable and 201 associated with favorable clinical outcomes, new treatments 202 are needed to increase the likelihood of this important 203 endpoint. At present, peginterferon treatment in patients 204 well controlled with NUCs appears a possible solution 205 (J Hepatol http://dx.doi.org/10.1016/j.hep.2014.05.044 206 [Epub ahead of print]). Novel treatment targets are also Q2207 being explored (Gastroenterology 2013;144:1508–1517; 208 J Hepatol 2013;58:861–867). 209 210
VINCENT WAI-SUN WONG GRACE LAI-HUNG WONG FRANCIS KA-LEUNG CHAN Department of Medicine and Therapeutics and Institute of Digestive Disease and State Key Laboratory of Digestive Disease The Chinese University of Hong Kong Hong Kong
DIS 5.2.0 DTD YGAST59394_proof 23 October 2014 3:22 pm ce
Q3211
212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240
Gastroenterology 2014;-:1–2
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
SELECTED SUMMARIES Philip S. Schoenfeld, Section Editor John Y. Kao, Section Editor STAFF OF CONTRIBUTORS Joseph Anderson, White River Junction, VT Darren M. Brenner, Chicago, IL Andrew T. Chan, Boston, MA Francis K. L. Chan, Hong Kong, China Massimo Colombo, Milan, Italy Gregory A. Cote, Indianapolis, IN B. Joseph Elmunzer, Ann Arbor, MI Alex Ford, Leeds, United Kingdom Timothy B. Gardner, Lebanon, NH Lauren B. Gerson, San Francisco, CA
Michelle Kang Kim, New York, NY W. Ray Kim, Rochester, MN Paul Y. Kwo, Indianapolis, IN Edward V. Loftus, Rochester, MN Uma Mahadevan, San Francisco, CA Laurent Peyrin-Biroulet, Vandoeuvre-lès-Nancy, France Mark Pimentel, Los Angeles, CA Jesus Rivera-Nieves, San Diego, CA Joel H. Rubenstein, Ann Arbor, MI
IS ANTIVIRAL DRUG-INDUCED HEPATITIS B SURFACE ANTIGEN LOSS DURABLE? Kim GA, Lim YS, An J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability? Gut 2014;63: 1325–1332. In patients with chronic hepatitis B, seroclearance of hepatitis B surface antigen (HBsAg) is an important milestone. Patients with spontaneous HBsAg seroclearance seldom experience virologic relapse and have a low risk of disease progression and hepatocellular carcinoma. Similarly, after a course of immunomodulatory treatment with interferon or peginterferon, >10% of patients may eventually develop HBsAg seroclearance, and the response is highly durable (J Hepatol 2009;50:1084–1092; Gastroenterology 2009;136:2169–2179; Hepatology 2010;51:1945–1953). The situation with oral nucleoside analogs (NUCs) is less certain. NUCs have potent antiviral activity but do not have a direct immunomodulatory effect. Because of their ease of use and favorable safety profile, NUCs have been the preferred treatment in the majority of patients. However, in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, NUC-induced HBeAg seroconversion is not as durable as spontaneous HBeAg seroconversion (Hepatology 2000;32:803–806; J Antimicrob Chemother 2013;68:2332– 2338). This leads to the important question of whether NUC-induced HBsAg seroclearance is durable and translates to good clinical outcomes. In a recent paper, Kim et al reported a large, retrospective cohort of 5,409 patients with chronic hepatitis B who were initially treated with lamivudine or entecavir (Gut 2014;63:1325–1332). During a median follow-up of 6 years, 110 patients (2.0%) achieved HBsAg seroclearance (0.33% per year). The overall prognosis of patients with NUCinduced HBsAg seroclearance was good. Only 1 patient developed hepatocellular carcinoma and another required liver transplantation, but died after an unrelated surgery. None of the other patients with HBsAg seroclearance died, underwent liver transplantation, or developed hepatocellular carcinoma. Using propensity score matching, patients
Sameer Saini, Ann Arbor, MI Ekihiro Seki, La Jolla, CA Shamita B. Shah, Stanford, CA Pratima Sharma, Ann Arbor, MI Amit Singal, Dallas, TX Jan Tack, Leuven, Belgium Akbar Waljee, Ann Arbor, MI Alastair J. M. Watson, Norwich, United Kingdom
with HBsAg seroclearance had 90% reduction in the risk of death or liver transplantation (hazard ratio, 0.10; P ¼ .02) and hepatocellular carcinoma (hazard ratio, 0.06; P < .01). The next question is the durability of HBsAg seroclearance. Among 111 patients with HBsAg seroclearance, 8 had HBsAg reversion within 3 years. The cumulative rates of HBsAg reversion were 7.6% at 12 months and 11.7% at 36 months. However, the HBsAg level remained low (0.05-1.0 IU/mL), and 7 patients lost HBsAg again later. In addition, 17 patients had detectable hepatitis B virus (HBV) DNA despite HBsAg seroclearance. The cumulative rates of virologic reversion were 13.8% at 1 year, 18.7% at 2 years, and 29.6% at 4 years. Again, the HBV DNA remained low, at <2,000 IU/mL. It is reassuring that none of those patients required retreatment with NUCs. Negative HBeAg, lower HBV DNA, and high alanine aminotransferase level (>5 times the upper limit of normal at baseline) were associated with HBsAg seroclearance. In contrast, patients with cirrhosis were less likely to achieve HBsAg seroclearance. For some reasons, the use of entecavir as opposed to lamivudine was associated with lower rate of HBsAg seroclearance (hazard ratio, 0.30; P ¼ .05). This may be partly explained by the longer treatment and follow-up duration of patients taking lamivudine. Moreover, patients with HBsAg seroclearance had lower HBsAg levels 2 years before seroclearance and had steeper slope of decline in HBsAg. Comment. The study by Kim et al answers the 2 most important questions on NUC-induced HBsAg seroclearance (Gut 2014;63:1325–1332). First, NUC-induced HBsAg seroclearance is associated with good prognosis. Second, although around 10% of patients may experience HBsAg reversion after initial seroclearance, it is mostly transient and rarely associated with significant viral activities. In other words, NUC-induced HBsAg seroclearance can be considered durable. Several Asian groups have studied the natural history of spontaneous HBsAg seroclearance. This is associated with improvement in histologic necroinflammation and fibrosis (J Hepatol 2005;42:188–194). Overall, hepatocellular carcinoma develops in 1.1%–10.2% of patients after seroclearance (Gastroenterology 2002;123:1084–1089; J Hepatol 2005;42: 188–194; Hepatology 2007;45:1187–1192; Gastroenterology 2008;135:1192–1199). Importantly, complications
DIS 5.2.0 DTD YGAST59394_proof 23 October 2014 3:22 pm ce
61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120
2
121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180
Selected Summaries
Gastroenterology Vol.
rarely occur unless the patient has delayed seroclearance (after the age of 50 in the Hong Kong study), cirrhosis before seroclearance or coinfection with hepatitis C virus or the delta virus. HBV DNA and covalently closed circular DNA remain detectable in the liver in the majority of patients. This explains the risk of reactivation during immunosuppression or cancer chemotherapy (Hepatology 2006;43:209–220; J Clin Oncol 2009;27:605–611). Although HBsAg seroclearance was durable in the study by Kim et al (Gut 2014;63:1325–1332), the HBsAg reversion and HBV DNA detectability rates were higher than what was reported in cohorts of spontaneous or interferon-induced HBsAg seroclearance. This in itself is not surprising. After all, NUCs do not have direct immunomodulatory effects. However, it is unclear whether consolidation therapy after HBsAg seroclearance is needed. In the paper by Kim et al, the total duration of treatment was not associated with HBsAg reversion. The authors may also wish to explore the effect of the duration of consolidation therapy after HBsAg seroclearance. On the other hand, it is interesting to note that prior drug-resistant HBV mutants (mainly lamivudine resistance) did not affect the rate of HBsAg seroclearance or reversion. In previous studies using less robust stopping rules (eg, HBeAg seroconversion or persistent HBV DNA undetectability), history of drug resistance increases the risk of virologic relapse (Aliment Pharmacol Ther 2011;34: 344–352). Based on these new data, it is safe to stop NUCs after HBsAg seroclearance even in patients with prior drugresistant mutants. In recent years, there has been rekindled interest in HBsAg quantification. Because quantitative HBsAg basically measures the same viral antigen, it is conceivable that lower HBsAg levels are associated with future seroclearance (J Infect Dis 2011;204:408–414; Hepatology 2012;55: 68–76; Hepatology 2013;58:923–931). However, because HBsAg seroclearance is rare during NUC treatment, it is unclear if low HBsAg level alone may be a sufficient
-,
No.
-
stopping rule. In a small study of 53 HBeAg-negative pa- 181 tients treated with lamivudine, all patients with HBsAg 182 100 IU/mL at the end of treatment and >1-log decline in 183 HBsAg during treatment had sustained off treatment 184 response at 12 months (HBV DNA <200 IU/mL; Antivir 185 Ther 2011;16:1249–1257). This notion was not confirmed 186 by a larger entecavir-treated cohort of 184 HBeAg-negative 187 patients (Gut http://dx.doi.org/10.1136/gutjnl-2014- 188 307237 [Epub ahead of print]). However, 91.4% of the Q1189 patients relapsed after stopping entecavir, rendering all 190 predicting factors meaningless. 191 Finally, it is noteworthy that the NUC-induced HBsAg 192 seroclearance rate was only 0.33% per year, which is not 193 higher than the reported annual incidence of spontaneous 194 HBsAg seroclearance of 0.5%–2.0% (Gastroenterology 195 2002;123:1084–1089; J Hepatol 2005;42:188–194; Hep- 196 atology 2007;45:1187–1192; Gastroenterology 2008;135: 197 1192-1199). The decline in HBsAg level during NUC therapy 198 is very slow and tends to level off over time (J Hepatol 199 2011;54:449–454; J Hepatol 2013;59:709–716). Thus, 200 although NUC-induced HBsAg seroclearance is durable and 201 associated with favorable clinical outcomes, new treatments 202 are needed to increase the likelihood of this important 203 endpoint. At present, peginterferon treatment in patients 204 well controlled with NUCs appears a possible solution 205 (J Hepatol http://dx.doi.org/10.1016/j.hep.2014.05.044 206 [Epub ahead of print]). Novel treatment targets are also Q2207 being explored (Gastroenterology 2013;144:1508–1517; 208 J Hepatol 2013;58:861–867). 209 210
VINCENT WAI-SUN WONG GRACE LAI-HUNG WONG FRANCIS KA-LEUNG CHAN Department of Medicine and Therapeutics and Institute of Digestive Disease and State Key Laboratory of Digestive Disease The Chinese University of Hong Kong Hong Kong
DIS 5.2.0 DTD YGAST59394_proof 23 October 2014 3:22 pm ce
Q3211
212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240