S121
a-Interferon treatment in Chinese patients with chronic hepatitis B
A.S.F. Lok’, CL. Lai’, P.C. Wu’, J.Y.N. Lad, E.K.Y. Leuog’,L.S.K. Wang’ andY.L. Fun& ‘fi,nunnena ofM&ineand *Pmhafo&y,UnivmL’y ofHongKong,Queen Mat-yHqikd, if- Kong
a-Interferon has heen shown tobe themost promisingantiviralagentin thetreatmentof chronichcpatis B vins infection in Caucasianpatients.The experiencewithrecombinant interferonalfa-2aandaIfa-2bin fourrandom&3amtxolM hiak in Chineseadultsandcbikbeois revIewedhere.a-Interferoaalonehaslittlebag-m bcoefitin tbetrcatmentoftxllese patientswithcbnmichepatitisB virusinfection,qeciatly in patientswho havenormalorncar -al . feraseIevels.The x?qaQsein patientswith ekvated amblo_ferase level.3appearsto be better.The poor antiviratresponsein patientswithnormalaminotrarwferase levelsis probablydue to v toteto HBVinducedby exposurcto thevirusin earlytife. pred&om pretreatment does WI seem to have any addidonal benefit to using intclferoll alone in these patients, while the effect in patientswith elevated aminotramfeme
There am appror. 3Ol million hepatitis B surfaceantigen (HBsAg) #%uzfen worldwide(1); of these, go% are C&esesubjec&.Thellfetime&x.fdeatbfromliverdiseaseforChincsecarrknhaskcntltimatedtobc50% for males and 14%for fem8les (2). Thus, a safe and efb the treatment for chmdc hepatitis B virus(HBV) infcc-
tionisWgeOtlyMded. In Caucasianpatients,a-interfcnwrhas been shown to be a promisingantiviralagentfor the treatmentofchronic HBV infection(3-7). However, there are major differ, age ofacquisitionand cncesinthemodeof~ cIInicaI courseof HBV infectionbetweenAsian and Caucasianpcpltlations. Estimatesbavesbowntbatabout40% of ulincsc HBsAg calTiersacquiretbefr infectioepelinataIIyor duringearIy childhood(8). Iofcctiondtig early life may InduceimmunobJgfcal tokrance to I-IBV, resultingin prristent virw3replkation.
kvels remains to be proven.
Tnbk in Chitrue adults In a raudomized cootxolledtrialof reum&iuantinter-
feron alfa-2ain Chineseadults(9). 72 +mk (58 men and 14women),aged lF46yeam (mediao29 years),who had been HBsAg and HE&g positivefor more than 6 mant~andhaddtabkserumHBVDNAkvctr,~rrrandon&d to receiveeitheroo bvatmentor interfemn al& 24 (Roferon,Bn la Rot&e)at doses of 2.5,s or 10 mtllion units (MU)& given totramuscularly (i.m.) 3 timesweekly(1.i.w.)for 12-24 weeks. SerumHBV DNA levelsfeIIin aUpatientsduring inttrfemn (@FN)treatmentand bacamcundctcctablein 38 (70%)at theend of the treatHtcnt pE.liod. oncL?ssatioll of therapy,there was a reboundiacreascblSerUmI+BV DNA
level
in same
of th.5 aeared
pptienk.
Fineen
treatedpatientsandone controlclearedHBeAgwitbtm12
ASP.
SK?2 montbs of entry into the trial. but this improvement was not always sustained. At 1 year. only eight (15%) treated patients and one (5.5%) control were still HBeAg negedve. None of the patients or controls became negative for HBsAg (Table 1). Patients who received the highest dose (10 MU/mz) of IFN had a higher rate of sustained antiviral response. However, this dose was associated with more frequent and serious side effects. Sex, age. previous history of acute hepatitis, ration of the presence of HBsAg, pretreatment
known duserum ala-
nine aminotransferase (ALT) and HBV DNA levels, and histological stage of liver disease did not correlate significantly with a sustained response, although the patients who had a sustained clearance of HReAg tended to have higher ALT and lower HBV DNA levels in serum than those who bad transient or no HBeAg clearance. In the eight treated patients who had sustained
the high frequency (47%) of reactivation. the underlying cause of which is unclear. None of the patients received immunosuppressive therapy, admitted to homosexual practice or was positive for antibody to human immunodeficiency virus (anti-HIV). Reactivation after spontanenus HBeAg clearance had been reported in apparently immunocompetent Chinese patients (10). In the IFNtreated
patients,
reactivation
to the development became detectable IFN therapy
could in part be attributed
of IFN antibodies (IFB-Ab). IFN-Ab 2-6 months after commencement of
in 21 (39%) of 54 treated
patients.
The de-
velopment of EN-AL reversed the initial antiviral response with reappearance of HBV DNA in serum in 12 and HBeAg in three patients. Sustained clearance of HBeAg was achieved in one (5%) patient with and seven (21%) patients without IFN-AL.
clear-
ance of HBeAg within 12 months of entry, there was a striking decrease in serum ALT, the median ALT levels et entry and I2 months being 98 and 22 WI, re~pd~ely @ c 0.05). However, the histological features in the biop sies obtained 12-24 momhs after initiation of treatment were similar to those obtained before treatment. The major side effects were an ‘influenza-like’ illness initially, followed by anorexia, fatigue, hair loss and weight loss. Two patients developed neuropsychiatric syr.$oms which necessitated withdrawal af therapy in one patient. A possible explanation for the low response rate in Chinese adults is the long delay between the onset of infection and initiation of treatnmn, since most patients were probably infected perinatally or during early childhood. IO these patients, it is likely that HBV DNA had already become integrated into the host pnome, thus making eradication of the virus difficult. Against this hypothesis are findings from Southern blot hybridization analysis of the pre-treatment liver biopsies which failed to demonstrate integration of HBV DNA [unpublished observatiOilS).
Certainly, one of the factors which contributed to the pwr long-term response rate among Chinese patients was TABLE l
LOK et al.
Trialin Chinese children Studies in Caucasian patients have shovm that patients with a shorter duration of infection are more likely to respond to a-interfemn therapy and some eventually clear HBsAg (3.4). Tbesc studies suggested that a better atttiviral response in Chinese patients might be achieved by initiating treatment at an earlier hge. In a randomized contmlkd trial of remmbinant interferon alf&?a fill. 24 Chinese cbildrea. aced 1.5 to 5 veers. who bad HBsAg. HBeAg and HBV DNA in their serum were randomized to receive interferon alla-Zp 10 MUhnz t.i.w. for 12 weeks or placebo (oral vitamin B syrup). All
,.
I
_
,
children were asymptomatic and appeared to have mild disease. Only two bad ekvated sertmt ALT levek at entry. Serum HBV DNA levelsfell in all 12 children during IFN treatment but the fall was sustained in only two. At 12 months, all 24 children remained HBeAg positive (Table 2). lltus, the antiviral response to a-lM alone was poor in Chinese patients even when treatment was initiated within 5 years of HBV infection. This pwr response could WI be attributed to an inadequate dcsagc or duration of treatment. since a similar regimen has been sltowtt to pmdua a high rate of response in Caucasian adults (3,4). A more
Sl23 likely explanation for the pow response in Chinese children was the presence of profound immonobgical tokrante to HBV. induced by exporurc to the virus early in life. Despite a high virus toad. most carrier children were asymptomatic with normal serum ALT kvelr (12). Studies in Caucasian patients showed that those with active liver disease and high ALT levels are more likely to respond to antiviral therapy (5.7.13). Only two of the 24 children in this study had elevated serum ALT levels at entry; both cleared HBeAg spontaneously
18 months af-
ter entering the trial. Apart from the initial ‘influenza-like’ symptoms, all the children toicrated the treatment very well. Pyxxia during the fint 2 weeks of therapy was rcduad hy gradually cscaMing the dose tiom an initial 3~ of 2.5 up to 10 MIJlmz.
(
a-Interferon treatment in Chinese patients with chronic hepatitis B
A.S.F. Lok’, CL. Lai’, P.C. Wu’, J.Y.N. Lad, E.K.Y. Leuog’,L.S.K. Wang’ andY.L. Fun& ‘fi,nunnena ofM&ineand *Pmhafo&y,UnivmL’y ofHongKong,Queen Mat-yHqikd, if- Kong
a-Interferon has heen shown tobe themost promisingantiviralagentin thetreatmentof chronichcpatis B vins infection in Caucasianpatients.The experiencewithrecombinant interferonalfa-2aandaIfa-2bin fourrandom&3amtxolM hiak in Chineseadultsandcbikbeois revIewedhere.a-Interferoaalonehaslittlebag-m bcoefitin tbetrcatmentoftxllese patientswithcbnmichepatitisB virusinfection,qeciatly in patientswho havenormalorncar -al . feraseIevels.The x?qaQsein patientswith ekvated amblo_ferase level.3appearsto be better.The poor antiviratresponsein patientswithnormalaminotrarwferase levelsis probablydue to v toteto HBVinducedby exposurcto thevirusin earlytife. pred&om pretreatment does WI seem to have any addidonal benefit to using intclferoll alone in these patients, while the effect in patientswith elevated aminotramfeme
There am appror. 3Ol million hepatitis B surfaceantigen (HBsAg) #%uzfen worldwide(1); of these, go% are C&esesubjec&.Thellfetime&x.fdeatbfromliverdiseaseforChincsecarrknhaskcntltimatedtobc50% for males and 14%for fem8les (2). Thus, a safe and efb the treatment for chmdc hepatitis B virus(HBV) infcc-
tionisWgeOtlyMded. In Caucasianpatients,a-interfcnwrhas been shown to be a promisingantiviralagentfor the treatmentofchronic HBV infection(3-7). However, there are major differ, age ofacquisitionand cncesinthemodeof~ cIInicaI courseof HBV infectionbetweenAsian and Caucasianpcpltlations. Estimatesbavesbowntbatabout40% of ulincsc HBsAg calTiersacquiretbefr infectioepelinataIIyor duringearIy childhood(8). Iofcctiondtig early life may InduceimmunobJgfcal tokrance to I-IBV, resultingin prristent virw3replkation.
kvels remains to be proven.
Tnbk in Chitrue adults In a raudomized cootxolledtrialof reum&iuantinter-
feron alfa-2ain Chineseadults(9). 72 +mk (58 men and 14women),aged lF46yeam (mediao29 years),who had been HBsAg and HE&g positivefor more than 6 mant~andhaddtabkserumHBVDNAkvctr,~rrrandon&d to receiveeitheroo bvatmentor interfemn al& 24 (Roferon,Bn la Rot&e)at doses of 2.5,s or 10 mtllion units (MU)& given totramuscularly (i.m.) 3 timesweekly(1.i.w.)for 12-24 weeks. SerumHBV DNA levelsfeIIin aUpatientsduring inttrfemn (@FN)treatmentand bacamcundctcctablein 38 (70%)at theend of the treatHtcnt pE.liod. oncL?ssatioll of therapy,there was a reboundiacreascblSerUmI+BV DNA
level
in same
of th.5 aeared
pptienk.
Fineen
treatedpatientsandone controlclearedHBeAgwitbtm12
ASP.
SK?2 montbs of entry into the trial. but this improvement was not always sustained. At 1 year. only eight (15%) treated patients and one (5.5%) control were still HBeAg negedve. None of the patients or controls became negative for HBsAg (Table 1). Patients who received the highest dose (10 MU/mz) of IFN had a higher rate of sustained antiviral response. However, this dose was associated with more frequent and serious side effects. Sex, age. previous history of acute hepatitis, ration of the presence of HBsAg, pretreatment
known duserum ala-
nine aminotransferase (ALT) and HBV DNA levels, and histological stage of liver disease did not correlate significantly with a sustained response, although the patients who had a sustained clearance of HReAg tended to have higher ALT and lower HBV DNA levels in serum than those who bad transient or no HBeAg clearance. In the eight treated patients who had sustained
the high frequency (47%) of reactivation. the underlying cause of which is unclear. None of the patients received immunosuppressive therapy, admitted to homosexual practice or was positive for antibody to human immunodeficiency virus (anti-HIV). Reactivation after spontanenus HBeAg clearance had been reported in apparently immunocompetent Chinese patients (10). In the IFNtreated
patients,
reactivation
to the development became detectable IFN therapy
could in part be attributed
of IFN antibodies (IFB-Ab). IFN-Ab 2-6 months after commencement of
in 21 (39%) of 54 treated
patients.
The de-
velopment of EN-AL reversed the initial antiviral response with reappearance of HBV DNA in serum in 12 and HBeAg in three patients. Sustained clearance of HBeAg was achieved in one (5%) patient with and seven (21%) patients without IFN-AL.
clear-
ance of HBeAg within 12 months of entry, there was a striking decrease in serum ALT, the median ALT levels et entry and I2 months being 98 and 22 WI, re~pd~ely @ c 0.05). However, the histological features in the biop sies obtained 12-24 momhs after initiation of treatment were similar to those obtained before treatment. The major side effects were an ‘influenza-like’ illness initially, followed by anorexia, fatigue, hair loss and weight loss. Two patients developed neuropsychiatric syr.$oms which necessitated withdrawal af therapy in one patient. A possible explanation for the low response rate in Chinese adults is the long delay between the onset of infection and initiation of treatnmn, since most patients were probably infected perinatally or during early childhood. IO these patients, it is likely that HBV DNA had already become integrated into the host pnome, thus making eradication of the virus difficult. Against this hypothesis are findings from Southern blot hybridization analysis of the pre-treatment liver biopsies which failed to demonstrate integration of HBV DNA [unpublished observatiOilS).
Certainly, one of the factors which contributed to the pwr long-term response rate among Chinese patients was TABLE l
LOK et al.
Trialin Chinese children Studies in Caucasian patients have shovm that patients with a shorter duration of infection are more likely to respond to a-interfemn therapy and some eventually clear HBsAg (3.4). Tbesc studies suggested that a better atttiviral response in Chinese patients might be achieved by initiating treatment at an earlier hge. In a randomized contmlkd trial of remmbinant interferon alf&?a fill. 24 Chinese cbildrea. aced 1.5 to 5 veers. who bad HBsAg. HBeAg and HBV DNA in their serum were randomized to receive interferon alla-Zp 10 MUhnz t.i.w. for 12 weeks or placebo (oral vitamin B syrup). All
,.
I
_
,
children were asymptomatic and appeared to have mild disease. Only two bad ekvated sertmt ALT levek at entry. Serum HBV DNA levelsfell in all 12 children during IFN treatment but the fall was sustained in only two. At 12 months, all 24 children remained HBeAg positive (Table 2). lltus, the antiviral response to a-lM alone was poor in Chinese patients even when treatment was initiated within 5 years of HBV infection. This pwr response could WI be attributed to an inadequate dcsagc or duration of treatment. since a similar regimen has been sltowtt to pmdua a high rate of response in Caucasian adults (3,4). A more
Sl23 likely explanation for the pow response in Chinese children was the presence of profound immonobgical tokrante to HBV. induced by exporurc to the virus early in life. Despite a high virus toad. most carrier children were asymptomatic with normal serum ALT kvelr (12). Studies in Caucasian patients showed that those with active liver disease and high ALT levels are more likely to respond to antiviral therapy (5.7.13). Only two of the 24 children in this study had elevated serum ALT levels at entry; both cleared HBeAg spontaneously
18 months af-
ter entering the trial. Apart from the initial ‘influenza-like’ symptoms, all the children toicrated the treatment very well. Pyxxia during the fint 2 weeks of therapy was rcduad hy gradually cscaMing the dose tiom an initial 3~ of 2.5 up to 10 MIJlmz.
(
