Jmmalof EhVk
He~loiqy,
s133
1990, 11: s133-SI36
HEPAT MI732
Interferon
alfa-2b treatment of HBeAg negative/serum positive chronic active hepatitis type R
HBV DNA
S. Hadziyannis, T. Bramou, A. Makris, G. MoussuuIis, L. Zignego and C. Papaioannou Nalionol Cmterfur Commicuble
Liver Diwmes, Acodmic
ikpartmenr of Medicine, ffippokrutiun Central Hospitul,Athens, Greece
A randomized mntroiled trial of recombit who were IE@Y~ for serum
interferon alfa-2b has ken initiated in patients ti chronic tive hepatitk hepatitis Beantigen but positive for SXUUIhepatitis B virus DNA and hepatitis B me antigen exprmion in the liver. Twenty-hve patients received interferon aIfa-2b3 million units thrice weeklyfor 14-16 weeks and 25 served as untreated controls. Seventeen patients in the treament and 18 in the umtrol group have &e,ady cornp&d a l&month period of observation. Interferon alfa-2bwas weUtoleratedby aUpatieMs.At the end of therapy, m pkte reqon~, d&ued as disappearanceof hepatitis B virus DNA from serum and return of azanineamiaotransferaseto normal, were obscrvtd in 10 (59%) of W 17 treated patients compared ?Onone in the COIIIICII group @ ( 0.01). Twelv? mti after Ibe bullet of interferon alfa-2b therapy, 11(65%) of the 17 txeated ~aticnt~were mnpkte responderscornpared to 2 (11%) of 18 in the control group @ x 0.01). FII per cent (4/B)of unnpkte respwdtrs to interferon alfa-2b &crapy, f&wed for 16-24 months, experie~ reactivatirms of hepatitis B vinrs replication with ream of =m hepatitis B vints DNA and Breturn of serum alanine a~~&~transferase activity. The respnse 10 interferon 4&-2b thempy appeared tu be ir&~nck~t of pre-treatment serum aianine aminotrmfera~ and hepatitisI virus DNA kvels.
In the Mediterranean area and Asia, 3540% of patients with hepatitis B surface antigen (HBsAg) positive chronic active hepatitis (CAH) are negative for serum hepatitis B e antigen {HBeAg) and possess antibodies to HBeAg (anti-HBe positive) (1-3). However, despite the absenceof HBeAg, 2040% of these patients are positive for hepatitis B virus DNA (HBV DNA) in the serum, and hepatitis B core antigen (HBcAg) exprmim in the liver (S-6). Persistence of HBV replication in patients with HBeAg negative CAH is usually associated with severe liver d&as and poor prognosis (3,7,8). Results from studies ia northern Italy and Greece have shown camadictq results with a-interferou treatment (3,9- 11).
The aim of this randomizedcontrolled trial was to evaluate the efficacy of interferon alfa-Zb (IFN) therapy in HBeAg negative/HBV DNA positive CAH on the basis of liver biochemistries, HBV replication, liver histology and sunrival. The results reported in this paper deai with the safety and &cacy of TFNtherapy on serum biocbemist&s and EIBV replication in 17 EN-treated patients and X8 untreated cunuols foIlowed up for at least 12 months.
Fifty patients (47 male and
rive CM,
who
3 female) with HBsAg pwihad been HBeAg negativelsgrum HBV
ComspmdcRcc: Professw Stephmos Hadziyannk, Professor of Medicine, Academic tkpar~menr of Medicine, Hippokrath Athens 11527,Greece. 01~%7#!WSJWOQ
1990Elscvier Science Publishers l3.V. (Biomedical Division)
Getwal Hospital,
3134 DNA positive for more than 1 year, were enrolled. Their characteristics are shown in Table 1. The patients allocated to the two groups were well matched in terms of age, sex, duration of disease, serum HBV DNA levels, SC+ rum alanine aminotransferase (ALT) values and liver his-
Serum HBV DNA was assayed by a spot molecular hy bridization technique (12) and was subsequently quantitated by a commercially available solution hybridization
toIugjr+ AI1 patients were negative for antibodies to the hepatitis delta virus (anti-HDV) and to the human immu-
fur HBsAg, HBcAg, HBeAg and HDAg by immunofluorescence methods which have been described elsewhere
nodeficiency virus (anti-HIV). Patients with decompensated cirrhosis and those who had received therapy with
(4,141.
assay(Germstics, Abbott Laboratories) (13). Liver biopsies were examined immunohistochemically
corticosteroids, immunosuppressive drugs or antiviral agents during the last &month period were excluded from the trial. Patients were randomly assigned to receive 3 million units (MU) IFN thrice weekly (t.;.w.) for 14-16 weeks (ti = 2s) or no treatment (31= 25). Clinical, biochemicaland
IFN therapy was well tolerated by all patients. Il~e adverse reactions commonly asstiated with IFN, of fever, fatigue and headache, were observed in the majority of
virological parameters were assessed weekly during the treatment period and monthly during the Z-yearfollow-up period after randomimtion. A second Iiver biopsy was
treated casesbut no serious treatment-related side effects were observed. Two patients squired a temporary dose reduction to 2 MU because of the appearanceof transient
performed 6-12 months after the end of therapy, A FCCond cyde of treatment with 5 MU IFN t.i.w. was given to persistently HBV DNA positive patients who had raised ALT levels for more than 6 months after the end of the first course of treatment. Responses to treatment were classified as: complete, if HBV DNA disappeared from the serum and ALT returned to normal; partial, if serum HBV DNA and ALT values were reduced to more than 50% of pre-treatment values; and no response, if ALT and serum HRV DNA
neutropenia and thrombocytopenia. Eighteen control patients and 17 IFMreated patbats have so far completed the study. Complete and partial rcsponses to IFN therapy at the end of treatment and at 6 and 12 months after entry are shown in Table 2. ‘LOSSof HBV DNA from the serum and normalization of ALT Ievels occurred in 10 (59%) of the 17 treated patients at the end of treatment but was not Seen in the 18 untreated controls. A partial response was &served in the Stven IXmaining treated patients. This pattern of response pr-
levels were unchanged or decreased by less than 50% of pre-treatment levels. The evaluation of the response to treatment at the end of therapy and after 6 and 12 months follow up was based on three consecutive examinations.
sisted at 6 and i2 mnoatiis’ Wow up, with a sign&ant tiference ip < 0.01) maintained between the tw0 groups (Table 21, A typical complete response to EN therapy in an HBeAg negative/anti-HBe positive patient with CAH,
TABLE I Patientcharacteristics Characteristic
Untreated contr& (n=25)
Male/female Mean age (years)
(range) Known duration of HBV infection (yea@ Ami-HBe positive Mean serum HBV DNA (p&d) WB~~ Meanpre-treatment serum
AL-i’(KM) (range) Histological diagnosis: CAH CAH with cirrhosis
2x!
49 (26-66) l-13 24’ 26 (4-103) E-683) 15 10
RWNJltS
maintained for 1 year after the start of therapy, is shown inFig. 1. Three partial responders at 6 months achieved complete loss of HEW DNA from the serum and ALT normaiization after 12 months. Thus, 11(65%) of 17 EN-treated patients compared with two (11%) of 18 untreated controls showed a complete response after 1 year (p K 0.01). TABLE 2
l-15 25
24 (d-871 175 (80-390) 13
12
i One patient was persistently HkAg negative/anti-HBe negative. ALT = Manine aminotransfcrast. CAH = Chronic active hepatitis.
._ End of treatment 10 (S9) C months 8 (47.5) 12months 11 1W
0 1
(01 (6) 2 (11)
IFN = Recombinant interferon alfa-2b.
’ n = 17, ‘rr=18.
7
(411
6 (35) 3
(t7.S)
4 (zz) 5 (28) 6
(331
Response to IFN treatment was found to be independent of age, sex, serum HBV DNA levels, ALTlevek and the presence of cirrhosis. Eight of the 11 treated patients and two untreated controls who had a complete response at 12 months have since completed a 2.year period of observation. In four of the eight treated complete responders and both untreated mmplete responders, relapses were observed during the second year, with reappearance of serum HBV DNA and inerased ALT activity (Fig. 2).
Liver disease in HBeAg negative/anti-HBe positive patients with replicating HBV k twally severe. needing therapeutic intervention. All patients in the prewnt study had hktological cbaogcs of seven CAH, wbicb in 44% (z/SO) bad already pmgrewd to cirrbosk. Tile results obtained with 3 months’ treatment with 3 MU lE+J t.i.w. in patknts titb sucb Evcrc dkeasc WelE quite impressi”e, with all treated patients showing either a mmpl.:te (59%) or a partial (41%) response compared to 0% complete and 22% partial responses in the untreated controls @ < 0.01). A similar effect has &a been obserwd in a small group of Italian cases treated with larger doses of fecotttbiiant IFN for3 months (9) and in an ongoing study using 5 MU lymphoblastoid IFN for 6monlhs (11).
In the pre~enl study. lwc-thirdr of the EN-treated patients remained serum HBV DNA negatiw with normat ALT levels for that 6 mm&s, ccqwd to only. 11% of the untreated amtmk. These 6miittgs. tbougb differrnt~mthoaerecniooneoftheltalipns~(9), suggest that IFN treatmat of .wi-l-me positiveJwBv DNApositivepadentswithCAHmaysi~~ tbe wtfawwabk of the disease. on tbc other band, the large number of rebqses (4/s) during the ycand year of tba follow-up p&d clearly indicates that a longer duration of therapy or repeated onuses of the same regbnen are rteaaytoachicvehmg-lastb.long-lastingrcn6r siOn.Inth~p~~UtSnrdy,~JeeoadcourSeofIFN~~ iOI&pEdcas*iWiSfOUUdtOk~ulUy&ZtiVC~tbZ first cycle of treatment. Frequent relapses have also been observedin the studybyBnmetmetal. (9). bat notintbe second oqoing Ralian trial (11). Wbetber relapses are linked to the development of a prescore mutatiott in the HRV gettome (lS) or to some other mechanism of HBV resistance or escape is impwihk to say. Finally, since liver rebiopsy has been scheduled 6-9 ntontbs after ioductiott of complete remission, the effect of IFN therapy on liver histology cannot as yet be evaluated.
He~loiqy,
s133
1990, 11: s133-SI36
HEPAT MI732
Interferon
alfa-2b treatment of HBeAg negative/serum positive chronic active hepatitis type R
HBV DNA
S. Hadziyannis, T. Bramou, A. Makris, G. MoussuuIis, L. Zignego and C. Papaioannou Nalionol Cmterfur Commicuble
Liver Diwmes, Acodmic
ikpartmenr of Medicine, ffippokrutiun Central Hospitul,Athens, Greece
A randomized mntroiled trial of recombit who were IE@Y~ for serum
interferon alfa-2b has ken initiated in patients ti chronic tive hepatitk hepatitis Beantigen but positive for SXUUIhepatitis B virus DNA and hepatitis B me antigen exprmion in the liver. Twenty-hve patients received interferon aIfa-2b3 million units thrice weeklyfor 14-16 weeks and 25 served as untreated controls. Seventeen patients in the treament and 18 in the umtrol group have &e,ady cornp&d a l&month period of observation. Interferon alfa-2bwas weUtoleratedby aUpatieMs.At the end of therapy, m pkte reqon~, d&ued as disappearanceof hepatitis B virus DNA from serum and return of azanineamiaotransferaseto normal, were obscrvtd in 10 (59%) of W 17 treated patients compared ?Onone in the COIIIICII group @ ( 0.01). Twelv? mti after Ibe bullet of interferon alfa-2b therapy, 11(65%) of the 17 txeated ~aticnt~were mnpkte responderscornpared to 2 (11%) of 18 in the control group @ x 0.01). FII per cent (4/B)of unnpkte respwdtrs to interferon alfa-2b &crapy, f&wed for 16-24 months, experie~ reactivatirms of hepatitis B vinrs replication with ream of =m hepatitis B vints DNA and Breturn of serum alanine a~~&~transferase activity. The respnse 10 interferon 4&-2b thempy appeared tu be ir&~nck~t of pre-treatment serum aianine aminotrmfera~ and hepatitisI virus DNA kvels.
In the Mediterranean area and Asia, 3540% of patients with hepatitis B surface antigen (HBsAg) positive chronic active hepatitis (CAH) are negative for serum hepatitis B e antigen {HBeAg) and possess antibodies to HBeAg (anti-HBe positive) (1-3). However, despite the absenceof HBeAg, 2040% of these patients are positive for hepatitis B virus DNA (HBV DNA) in the serum, and hepatitis B core antigen (HBcAg) exprmim in the liver (S-6). Persistence of HBV replication in patients with HBeAg negative CAH is usually associated with severe liver d&as and poor prognosis (3,7,8). Results from studies ia northern Italy and Greece have shown camadictq results with a-interferou treatment (3,9- 11).
The aim of this randomizedcontrolled trial was to evaluate the efficacy of interferon alfa-Zb (IFN) therapy in HBeAg negative/HBV DNA positive CAH on the basis of liver biochemistries, HBV replication, liver histology and sunrival. The results reported in this paper deai with the safety and &cacy of TFNtherapy on serum biocbemist&s and EIBV replication in 17 EN-treated patients and X8 untreated cunuols foIlowed up for at least 12 months.
Fifty patients (47 male and
rive CM,
who
3 female) with HBsAg pwihad been HBeAg negativelsgrum HBV
ComspmdcRcc: Professw Stephmos Hadziyannk, Professor of Medicine, Academic tkpar~menr of Medicine, Hippokrath Athens 11527,Greece. 01~%7#!WSJWOQ
1990Elscvier Science Publishers l3.V. (Biomedical Division)
Getwal Hospital,
3134 DNA positive for more than 1 year, were enrolled. Their characteristics are shown in Table 1. The patients allocated to the two groups were well matched in terms of age, sex, duration of disease, serum HBV DNA levels, SC+ rum alanine aminotransferase (ALT) values and liver his-
Serum HBV DNA was assayed by a spot molecular hy bridization technique (12) and was subsequently quantitated by a commercially available solution hybridization
toIugjr+ AI1 patients were negative for antibodies to the hepatitis delta virus (anti-HDV) and to the human immu-
fur HBsAg, HBcAg, HBeAg and HDAg by immunofluorescence methods which have been described elsewhere
nodeficiency virus (anti-HIV). Patients with decompensated cirrhosis and those who had received therapy with
(4,141.
assay(Germstics, Abbott Laboratories) (13). Liver biopsies were examined immunohistochemically
corticosteroids, immunosuppressive drugs or antiviral agents during the last &month period were excluded from the trial. Patients were randomly assigned to receive 3 million units (MU) IFN thrice weekly (t.;.w.) for 14-16 weeks (ti = 2s) or no treatment (31= 25). Clinical, biochemicaland
IFN therapy was well tolerated by all patients. Il~e adverse reactions commonly asstiated with IFN, of fever, fatigue and headache, were observed in the majority of
virological parameters were assessed weekly during the treatment period and monthly during the Z-yearfollow-up period after randomimtion. A second Iiver biopsy was
treated casesbut no serious treatment-related side effects were observed. Two patients squired a temporary dose reduction to 2 MU because of the appearanceof transient
performed 6-12 months after the end of therapy, A FCCond cyde of treatment with 5 MU IFN t.i.w. was given to persistently HBV DNA positive patients who had raised ALT levels for more than 6 months after the end of the first course of treatment. Responses to treatment were classified as: complete, if HBV DNA disappeared from the serum and ALT returned to normal; partial, if serum HBV DNA and ALT values were reduced to more than 50% of pre-treatment values; and no response, if ALT and serum HRV DNA
neutropenia and thrombocytopenia. Eighteen control patients and 17 IFMreated patbats have so far completed the study. Complete and partial rcsponses to IFN therapy at the end of treatment and at 6 and 12 months after entry are shown in Table 2. ‘LOSSof HBV DNA from the serum and normalization of ALT Ievels occurred in 10 (59%) of the 17 treated patients at the end of treatment but was not Seen in the 18 untreated controls. A partial response was &served in the Stven IXmaining treated patients. This pattern of response pr-
levels were unchanged or decreased by less than 50% of pre-treatment levels. The evaluation of the response to treatment at the end of therapy and after 6 and 12 months follow up was based on three consecutive examinations.
sisted at 6 and i2 mnoatiis’ Wow up, with a sign&ant tiference ip < 0.01) maintained between the tw0 groups (Table 21, A typical complete response to EN therapy in an HBeAg negative/anti-HBe positive patient with CAH,
TABLE I Patientcharacteristics Characteristic
Untreated contr& (n=25)
Male/female Mean age (years)
(range) Known duration of HBV infection (yea@ Ami-HBe positive Mean serum HBV DNA (p&d) WB~~ Meanpre-treatment serum
AL-i’(KM) (range) Histological diagnosis: CAH CAH with cirrhosis
2x!
49 (26-66) l-13 24’ 26 (4-103) E-683) 15 10
RWNJltS
maintained for 1 year after the start of therapy, is shown inFig. 1. Three partial responders at 6 months achieved complete loss of HEW DNA from the serum and ALT normaiization after 12 months. Thus, 11(65%) of 17 EN-treated patients compared with two (11%) of 18 untreated controls showed a complete response after 1 year (p K 0.01). TABLE 2
l-15 25
24 (d-871 175 (80-390) 13
12
i One patient was persistently HkAg negative/anti-HBe negative. ALT = Manine aminotransfcrast. CAH = Chronic active hepatitis.
._ End of treatment 10 (S9) C months 8 (47.5) 12months 11 1W
0 1
(01 (6) 2 (11)
IFN = Recombinant interferon alfa-2b.
’ n = 17, ‘rr=18.
7
(411
6 (35) 3
(t7.S)
4 (zz) 5 (28) 6
(331
Response to IFN treatment was found to be independent of age, sex, serum HBV DNA levels, ALTlevek and the presence of cirrhosis. Eight of the 11 treated patients and two untreated controls who had a complete response at 12 months have since completed a 2.year period of observation. In four of the eight treated complete responders and both untreated mmplete responders, relapses were observed during the second year, with reappearance of serum HBV DNA and inerased ALT activity (Fig. 2).
Liver disease in HBeAg negative/anti-HBe positive patients with replicating HBV k twally severe. needing therapeutic intervention. All patients in the prewnt study had hktological cbaogcs of seven CAH, wbicb in 44% (z/SO) bad already pmgrewd to cirrbosk. Tile results obtained with 3 months’ treatment with 3 MU lE+J t.i.w. in patknts titb sucb Evcrc dkeasc WelE quite impressi”e, with all treated patients showing either a mmpl.:te (59%) or a partial (41%) response compared to 0% complete and 22% partial responses in the untreated controls @ < 0.01). A similar effect has &a been obserwd in a small group of Italian cases treated with larger doses of fecotttbiiant IFN for3 months (9) and in an ongoing study using 5 MU lymphoblastoid IFN for 6monlhs (11).
In the pre~enl study. lwc-thirdr of the EN-treated patients remained serum HBV DNA negatiw with normat ALT levels for that 6 mm&s, ccqwd to only. 11% of the untreated amtmk. These 6miittgs. tbougb differrnt~mthoaerecniooneoftheltalipns~(9), suggest that IFN treatmat of .wi-l-me positiveJwBv DNApositivepadentswithCAHmaysi~~ tbe wtfawwabk of the disease. on tbc other band, the large number of rebqses (4/s) during the ycand year of tba follow-up p&d clearly indicates that a longer duration of therapy or repeated onuses of the same regbnen are rteaaytoachicvehmg-lastb.long-lastingrcn6r siOn.Inth~p~~UtSnrdy,~JeeoadcourSeofIFN~~ iOI&pEdcas*iWiSfOUUdtOk~ulUy&ZtiVC~tbZ first cycle of treatment. Frequent relapses have also been observedin the studybyBnmetmetal. (9). bat notintbe second oqoing Ralian trial (11). Wbetber relapses are linked to the development of a prescore mutatiott in the HRV gettome (lS) or to some other mechanism of HBV resistance or escape is impwihk to say. Finally, since liver rebiopsy has been scheduled 6-9 ntontbs after ioductiott of complete remission, the effect of IFN therapy on liver histology cannot as yet be evaluated.
