1990; 11:s1294132
HEPAT 00733
Problems in the management of chronic hepatitis B with interferun: experience in a randomized, muPticentre study
5129
G. REALDI
s130
etal.
conventionalhistolugicaldiagnosis (chronic persistent Many variables affect the response to IFN therapy in chronic HBV infection, and several features in particular have been shown to be strongly associated with a puw reqnse (1-S). These include: neonatal infection (which may account for poor response usuallyseemin Chinese patients (6,7}); IFN resistance due to geneticor acquired factors, such as the development of antibodiesto IFN; and immunedefects as observed in human immunodefi-
the
ciency virus (HIV) antibody
positive patients
hepatitis, chronic active hepatitis and cirrhosis)am2the histological activity index described by KnodeU et al.
ww Statistical analysis included Fisher’s exact test, Student’s t-test and Wilcoxon’s test. Prdictive variables for a bighcr response were evaluated by multiple regression analysis in a fclrward stepwise manner.
(5). Coin-
fection with other viruses, such as the hepatitis delta virus may also affect response to IFN treatment(9). randomized, controlIed trial was designed to investigate the long-term efficacy of B low due uf recombinant htetiemn a&-Za io the treatment of HBeAg and HBV DNA @tive patientswith chronichepatitis and to assess factors significantly asso-
RWlltS
(HDV),
Our prospective,muiticentre,
ciated with a favourable
patimts were
79 subjects. IF&treated and con~ro1 simiIar with respect to initial clinical and seralogical features (Table 1). Table 2 shows the serological events of all patients at 4 months (end of therapy)
response to therapy.
PadentsrmdMe&&s The minimum number of patients to be enr0iled was calculated to be 80, assuming a spontaneous anti-HBe sereconversion rate of lo%, an expectedresponserateof at least40%in treatedpatients,andtype I andII errors of 5 and 20%, respectively. Eighty-two It&n patients entered this trial on the basis of the following criteria: (i) hepatitis 3 surface antigen (HBsAg), HBeAg and HBY DNA positive for at least 12
months;(ii) abnormallevels of serum aminotransferase activity;(iii)HDV andanti-HIVnegative;and(iv)chronic hepatitison biopsy taken within 6 months of entry. Patients were randomized to receive either 4.5 (MU) of recombinant interferon alfa-2a Hoffmann La Roche) intramuscularly thrice months or no treatment. All patients were
Three of the 82 patients withdrew from the study. Thercfoxe,a finalevaluation of efficacywas performedin
million units (Roferan-A, weekly for 4 followed at
intervalsfor 16 monthsafter randomizationand liverbiopsywas repeatedat the end of thisfollowup.
and at 16 months after
randomization. Ciearance of serum HBV DNA and normalization of serum ALT levels were signi&antly more frequent in treated patients &au in controls at the end of therapy. After 16 months’ foilow up, treated patients showed a statisticslily s&n&ant difference compared to controls with regard to H&Ag ckaranclc and ALT normalization; the rate of HBV DNA ckarancc did not differ tignifrcantly, although it was higher in patients receiving IFN (41 vs. 25%). Several patints in both groups experienceda transjeatHBV DNA negativity during follow up and the rate of HBV reactivation wig very similar in tieatedpatientsand in controls. As shown in Table 3, histolo@cal analysis of the ktitiai
TABLE 1
Pretmtment patient dwacteristics Features
regular
HBsAg, HBeAg, anti-HBe, anti-HDV and anti-HIV were determined by use of solid-phase radioimmunoassay or enzyme-linked immunosorbent assays (Abbott Laboratories, Chicago, IL), Serum WBV DNA was measured by moIecuIar hybridization using a 32P-laMI& HBV DNA probe and scored semi-quantitatively from grade O4, Hepatitis ddta antigen (HDAg) in the liver was examined by direct immunofluorescence. Liver biopsies were available from all 82 patients before randomization, and from 64 at the end of follow up. Histological features were interpreted by two independent observers, from coded tissue specimens. The biopsy specimens
were evaluated
using two different
methods:
Sex (Z mait) Age (yearn)* Familyh&toryof HBV infcctioa (%) Knowndurationof HI&antigenaemia (UlOMhS)
ALT
(times upperrangeof normal)
64 33 31 40
4.8
35
4
Serum HBV DNA
1+ 2+ 3+ 4+ Histdogy CPH CAH Active cirrlmis * Mean value. CPH = chronic p&tent hepatitis. CAH Q chronicactivehepatitis.
13 7 10 8
11 IS 11 3
16 16 7
16 I8 6
931 fibrosis in the initial biopsy predicted HBV DNA clearance independmtly (p c 0.05) in bated subjects. Low serum HBV DNA levels and presence of severe b,ftemmation and necrotic ectivity on liver biopsy were predictive factors of HBV DNA c,eereece in both treated end control patients.
1nttiemn gr@JP (n = 39)
During therapy Neguivizatie” af HBVDNA Redwtianof HB”DNAtitre “BV DNA rextivatiee At tk ce4ottberapy HBVDNAncSativc “BeASnepativs AfTDommI Still “B” DNA pDai!k
lW39#6%)
lrMq25%)
6.04
31!39(79%) VlS(z7%)
,7140(42%) 5mpo%)
0.w 0.22
13ny33sp [email protected]%) m39(31%) 26,X$67%)
_wqIZ.S%)~ 4/@J(lO%) mO(12.5%) 3514w7.590)
O.cQ5 0.,6 O.c4 -
During feuew“p FeItheracgadviza~ &HBy DNA TotafnumbRofpaf*als fiBVDNAcq$i\2 RCWOftlBV DNAtim “BVDNArwctivatioa
13WW)
15ci5(43%)
0.38
X09(67%)
2W43@0%)
0.10
7W2783 12t26+46%)c
lrn5(.M%) l@=W%)
6.37 0.51
and .xcond biopsy specimens showed a statistically signi& cam impmvement in portal in&mtnatioo and in piecemeal and bridging necrmis in treated subject& The histak&al improvement we5 most amspiceous in patients gltwittg a reSpoosc to therapy. On stepwise multiple-regression analysis, bigb serum AL.T levels at presentation, female sex end a low YUIC for
Treated (n = 33) E
The side effects of IFN therapy were mild (41%) or moderate (51%) in nature. No patient in the treated group required witbdrawel of therapy or dose reduction for unexpected o* sewre adverse effects of the drug.
Cbmeic HBV infection is a worldwide health problem end treatment remains unsaisfactary. This t&l was undettakeo to evaluate whether a 4-month coutse of recom. binattt interfemn aIfS-a tkraov cmdd induce termi-
in a signscant pe;ce.otage of patients
with cbmnic bepatitis B. The remits of this study, conducted in three Italian ceattres, demonam telhataIow&seoflFNiseffecfive in mmmlling disase aaivity in HBeAg-. HBV DNApc&ive chronic bqatitis. faked, we were &de to induce a penistettt biochemical remkiott and a aignifcant imprmement in bistofqica, in&me&m and ,,ecmsis. A high rate of viral reactivation ~a9 obaetved during folkw UD in several ca?es who initiallv had cleared HBV DNA.
complete Of virus repkatiotl WaS not lKecBarily assxziated with a Ielapse of liver disease. In abOut half of the treated patients, w effect of Ji=N wee observed. It is conceivable that a different tberapeutic schedule should be explored, eqecielly for cases with bigber levels of HBV nplieatioo and tower diseese activity. In particular, a nmre prdooged regimen cd thempy
3.6 5.4
,a 1.5
0.5 1.2
0.7 1.1
1.3 1.5
p value’
0.02
0.0:
0.03
N.S.
N.S.
(” - 31) BefOre After p valea’
4.5 4.4 N.S.
1.4 1.4 N.S.
0.7 1.4 N.S.
Cl.7 1.0 N.S.
1.5 1.1 N.S.
coetmtl
8 wikcaee’?.tea(. N.S. = mtsiqi6cam.
G. l?JXI,DI
S132
with the same tell-t&rated
dosage might be beneficial to
achieve a permanent suppression tivirat replication. Retrospective analysis has suggested that patients nmr
likely to respond to IFN therapy are women and those with higher initial levelsof serumaminotransferases(3,ll). The results of our study have cunfirmedthe importance of both these parameters by comparing, for the first time, data obtained in treated and untreated patients. In addition, a low grade of fibrosis in the initial liver biopsy, probably reflecting a short duration of liver disease, was another factor significantly associated with a favourable
1 Alexander GJM, Brahm J, Fagm EA, et al. W
of HBsAg with intcrfcroa ticrapy in chronic hepatitis B virus infectioa. Law& 1987;ii: 66-9.
2 SaraG, Malla G, R&a F, et al. A oontrokd trial of human lympIwblast&d interlcron in cbmnic hepatitis B in Italy. Hcpat&g)l1989;3: 33&U. 3 Scullard GH, Poktd RB, Smith JL, et al. Antivkal treatment of chronic hepatitis I3 vim infection. I. Changes in VW marktff
with interferon wmbined with adetie arabiwside. J Infect Dis 1981;143:772-83. 4 Novick DM, l_ok ASF, Thomas HC. Diminished responsi~e~ of homosexual men to antiviral therapy for HBsAgqwsitive chronicLiverdisease. J Hepatol1984; 1:29-35. 5 McDonald JA, Caruso L, Kzmyiannls P, et al. Diminislxd rcsponsivcacss of male homosexual cbrwic hepatitis B virus carriers with HTLV-tl1 antibodies u1 recombinant a-intcrZcron. 1Iepatotogy1987; 7: 719-u. 6 Lai CL, Lok ASF, Lin HJ, tt al. PIx&o-controlfed trial of re-
et al.
response to IFN treatment. As a corollary to this, a low pretreatment serum HBV DNA level,and severe inkmation and necrusis on liver biopsy were predictive fattars of HBV suppression both in treated and in control
subjects, In our study, we were not able to show a signWant change in liverhistologybetweentreatedand controlpatients in terms of prevention of progression to cirrIxAs. Ia this sense, the therapeutic efficacyof IFN with respect to its ultimate effect on the natural history of the disease remains to be determined,
HEPAT 00733
Problems in the management of chronic hepatitis B with interferun: experience in a randomized, muPticentre study
5129
G. REALDI
s130
etal.
conventionalhistolugicaldiagnosis (chronic persistent Many variables affect the response to IFN therapy in chronic HBV infection, and several features in particular have been shown to be strongly associated with a puw reqnse (1-S). These include: neonatal infection (which may account for poor response usuallyseemin Chinese patients (6,7}); IFN resistance due to geneticor acquired factors, such as the development of antibodiesto IFN; and immunedefects as observed in human immunodefi-
the
ciency virus (HIV) antibody
positive patients
hepatitis, chronic active hepatitis and cirrhosis)am2the histological activity index described by KnodeU et al.
ww Statistical analysis included Fisher’s exact test, Student’s t-test and Wilcoxon’s test. Prdictive variables for a bighcr response were evaluated by multiple regression analysis in a fclrward stepwise manner.
(5). Coin-
fection with other viruses, such as the hepatitis delta virus may also affect response to IFN treatment(9). randomized, controlIed trial was designed to investigate the long-term efficacy of B low due uf recombinant htetiemn a&-Za io the treatment of HBeAg and HBV DNA @tive patientswith chronichepatitis and to assess factors significantly asso-
RWlltS
(HDV),
Our prospective,muiticentre,
ciated with a favourable
patimts were
79 subjects. IF&treated and con~ro1 simiIar with respect to initial clinical and seralogical features (Table 1). Table 2 shows the serological events of all patients at 4 months (end of therapy)
response to therapy.
PadentsrmdMe&&s The minimum number of patients to be enr0iled was calculated to be 80, assuming a spontaneous anti-HBe sereconversion rate of lo%, an expectedresponserateof at least40%in treatedpatients,andtype I andII errors of 5 and 20%, respectively. Eighty-two It&n patients entered this trial on the basis of the following criteria: (i) hepatitis 3 surface antigen (HBsAg), HBeAg and HBY DNA positive for at least 12
months;(ii) abnormallevels of serum aminotransferase activity;(iii)HDV andanti-HIVnegative;and(iv)chronic hepatitison biopsy taken within 6 months of entry. Patients were randomized to receive either 4.5 (MU) of recombinant interferon alfa-2a Hoffmann La Roche) intramuscularly thrice months or no treatment. All patients were
Three of the 82 patients withdrew from the study. Thercfoxe,a finalevaluation of efficacywas performedin
million units (Roferan-A, weekly for 4 followed at
intervalsfor 16 monthsafter randomizationand liverbiopsywas repeatedat the end of thisfollowup.
and at 16 months after
randomization. Ciearance of serum HBV DNA and normalization of serum ALT levels were signi&antly more frequent in treated patients &au in controls at the end of therapy. After 16 months’ foilow up, treated patients showed a statisticslily s&n&ant difference compared to controls with regard to H&Ag ckaranclc and ALT normalization; the rate of HBV DNA ckarancc did not differ tignifrcantly, although it was higher in patients receiving IFN (41 vs. 25%). Several patints in both groups experienceda transjeatHBV DNA negativity during follow up and the rate of HBV reactivation wig very similar in tieatedpatientsand in controls. As shown in Table 3, histolo@cal analysis of the ktitiai
TABLE 1
Pretmtment patient dwacteristics Features
regular
HBsAg, HBeAg, anti-HBe, anti-HDV and anti-HIV were determined by use of solid-phase radioimmunoassay or enzyme-linked immunosorbent assays (Abbott Laboratories, Chicago, IL), Serum WBV DNA was measured by moIecuIar hybridization using a 32P-laMI& HBV DNA probe and scored semi-quantitatively from grade O4, Hepatitis ddta antigen (HDAg) in the liver was examined by direct immunofluorescence. Liver biopsies were available from all 82 patients before randomization, and from 64 at the end of follow up. Histological features were interpreted by two independent observers, from coded tissue specimens. The biopsy specimens
were evaluated
using two different
methods:
Sex (Z mait) Age (yearn)* Familyh&toryof HBV infcctioa (%) Knowndurationof HI&antigenaemia (UlOMhS)
ALT
(times upperrangeof normal)
64 33 31 40
4.8
35
4
Serum HBV DNA
1+ 2+ 3+ 4+ Histdogy CPH CAH Active cirrlmis * Mean value. CPH = chronic p&tent hepatitis. CAH Q chronicactivehepatitis.
13 7 10 8
11 IS 11 3
16 16 7
16 I8 6
931 fibrosis in the initial biopsy predicted HBV DNA clearance independmtly (p c 0.05) in bated subjects. Low serum HBV DNA levels and presence of severe b,ftemmation and necrotic ectivity on liver biopsy were predictive factors of HBV DNA c,eereece in both treated end control patients.
1nttiemn gr@JP (n = 39)
During therapy Neguivizatie” af HBVDNA Redwtianof HB”DNAtitre “BV DNA rextivatiee At tk ce4ottberapy HBVDNAncSativc “BeASnepativs AfTDommI Still “B” DNA pDai!k
lW39#6%)
lrMq25%)
6.04
31!39(79%) VlS(z7%)
,7140(42%) 5mpo%)
0.w 0.22
13ny33sp [email protected]%) m39(31%) 26,X$67%)
_wqIZ.S%)~ 4/@J(lO%) mO(12.5%) 3514w7.590)
O.cQ5 0.,6 O.c4 -
During feuew“p FeItheracgadviza~ &HBy DNA TotafnumbRofpaf*als fiBVDNAcq$i\2 RCWOftlBV DNAtim “BVDNArwctivatioa
13WW)
15ci5(43%)
0.38
X09(67%)
2W43@0%)
0.10
7W2783 12t26+46%)c
lrn5(.M%) l@=W%)
6.37 0.51
and .xcond biopsy specimens showed a statistically signi& cam impmvement in portal in&mtnatioo and in piecemeal and bridging necrmis in treated subject& The histak&al improvement we5 most amspiceous in patients gltwittg a reSpoosc to therapy. On stepwise multiple-regression analysis, bigb serum AL.T levels at presentation, female sex end a low YUIC for
Treated (n = 33) E
The side effects of IFN therapy were mild (41%) or moderate (51%) in nature. No patient in the treated group required witbdrawel of therapy or dose reduction for unexpected o* sewre adverse effects of the drug.
Cbmeic HBV infection is a worldwide health problem end treatment remains unsaisfactary. This t&l was undettakeo to evaluate whether a 4-month coutse of recom. binattt interfemn aIfS-a tkraov cmdd induce termi-
in a signscant pe;ce.otage of patients
with cbmnic bepatitis B. The remits of this study, conducted in three Italian ceattres, demonam telhataIow&seoflFNiseffecfive in mmmlling disase aaivity in HBeAg-. HBV DNApc&ive chronic bqatitis. faked, we were &de to induce a penistettt biochemical remkiott and a aignifcant imprmement in bistofqica, in&me&m and ,,ecmsis. A high rate of viral reactivation ~a9 obaetved during folkw UD in several ca?es who initiallv had cleared HBV DNA.
complete Of virus repkatiotl WaS not lKecBarily assxziated with a Ielapse of liver disease. In abOut half of the treated patients, w effect of Ji=N wee observed. It is conceivable that a different tberapeutic schedule should be explored, eqecielly for cases with bigber levels of HBV nplieatioo and tower diseese activity. In particular, a nmre prdooged regimen cd thempy
3.6 5.4
,a 1.5
0.5 1.2
0.7 1.1
1.3 1.5
p value’
0.02
0.0:
0.03
N.S.
N.S.
(” - 31) BefOre After p valea’
4.5 4.4 N.S.
1.4 1.4 N.S.
0.7 1.4 N.S.
Cl.7 1.0 N.S.
1.5 1.1 N.S.
coetmtl
8 wikcaee’?.tea(. N.S. = mtsiqi6cam.
G. l?JXI,DI
S132
with the same tell-t&rated
dosage might be beneficial to
achieve a permanent suppression tivirat replication. Retrospective analysis has suggested that patients nmr
likely to respond to IFN therapy are women and those with higher initial levelsof serumaminotransferases(3,ll). The results of our study have cunfirmedthe importance of both these parameters by comparing, for the first time, data obtained in treated and untreated patients. In addition, a low grade of fibrosis in the initial liver biopsy, probably reflecting a short duration of liver disease, was another factor significantly associated with a favourable
1 Alexander GJM, Brahm J, Fagm EA, et al. W
of HBsAg with intcrfcroa ticrapy in chronic hepatitis B virus infectioa. Law& 1987;ii: 66-9.
2 SaraG, Malla G, R&a F, et al. A oontrokd trial of human lympIwblast&d interlcron in cbmnic hepatitis B in Italy. Hcpat&g)l1989;3: 33&U. 3 Scullard GH, Poktd RB, Smith JL, et al. Antivkal treatment of chronic hepatitis I3 vim infection. I. Changes in VW marktff
with interferon wmbined with adetie arabiwside. J Infect Dis 1981;143:772-83. 4 Novick DM, l_ok ASF, Thomas HC. Diminished responsi~e~ of homosexual men to antiviral therapy for HBsAgqwsitive chronicLiverdisease. J Hepatol1984; 1:29-35. 5 McDonald JA, Caruso L, Kzmyiannls P, et al. Diminislxd rcsponsivcacss of male homosexual cbrwic hepatitis B virus carriers with HTLV-tl1 antibodies u1 recombinant a-intcrZcron. 1Iepatotogy1987; 7: 719-u. 6 Lai CL, Lok ASF, Lin HJ, tt al. PIx&o-controlfed trial of re-
et al.
response to IFN treatment. As a corollary to this, a low pretreatment serum HBV DNA level,and severe inkmation and necrusis on liver biopsy were predictive fattars of HBV suppression both in treated and in control
subjects, In our study, we were not able to show a signWant change in liverhistologybetweentreatedand controlpatients in terms of prevention of progression to cirrIxAs. Ia this sense, the therapeutic efficacyof IFN with respect to its ultimate effect on the natural history of the disease remains to be determined,
