ofHepatology, ElHSilX

Joumui

19po;11: s137-s140

s137

Treatment of chronic hepatitis B with interferon alfa-Zb

LX.Miillerl, R. Baumgarten2, R. Markus2, M.Schulz’, H. Wittenberg’, B. Hintsche-Kiige#, J.-D. Fengleg, P. Van Wuwd, H. M&l”, H. Klein’, K. M&IN& and F-W. Schmidt1 ‘Aheilung fsir Gamunterobgk undHepaw~o@e,zcrtmvrPfirinrwreMedizinundDemnah& MedizinbcheHochschukffamwm, Hannuver, Federal Republic of Germany, 2hfekthsklinik dcr SMtiden Ilrankenkawm lkdin-Rmrlatotr Berg, Geman Democratic Republic, 3Abteiiungjiiir Kknipche immundogic Zentmm Innme Medizin und Dermatolqiz &r W&M&&n Hochrchlrk Hmtnovm, Hanmver, Republic of Gmrrcmy and %ainu fir Medizinkhe Virdogit dcs &r&ha Me&in (U~W) &Y HumboIdt-UnivekMt, Berlin, Gem Dmwcmric Rpb&

Fedml

A totztl of 58 patients with histologically cot&rued chronic viral hepatitis B and presence of hepat& B surfantigen and hepatitis B virus DNA (HBV DNA) in the serum were randomized in a prospe&e~y umtmUed trial, ThirlypaGcnts were treated with 3 megaunits of recombinant interferon alfa-2b (SNTRON A, R S&ring-Pkugh, Essex Corporatjon) s&utaneuu~ly thrice weekly for 4 months. Twenty-eight c0n&uIs rmivd no treatment. The post-treatmat fduw=up @cd am&t4 of 6 months. Twenty-eight treated patients and 27 mtrols completed female pat&t of the group showed a compkte response, and eight other treated patients (32%) &owed a pcutial response to thempy, Three patients in the control group (11%) lost hepatitis B e antigen and HBV DNA qmtantmusiy. Thisfhcbgis statistically sign&act @ < 0.05). The elimination of hepatitis B virus markers from tbc serumwas associated witi a nomalization of aminotramferase activities in the serum. Reactivation of hepatitis was not obsemed after seroconversion.

treatment

interfcrons are endogenous glywproteins that exhibit antiviral, immunomodulatory and antiproliferative prop e&s. They can now be produced by biotechnoiogical methads and have been used ia mmerous clinical trials for the treatment of chronic viral hepatitis, ia these studies, most of which involved smail numbers of patients, response rates of M% have been reported (l-5). A raudomized, controlled Ctid trial in a c.au&an patient population has been pcr&ned in order to evaluate the effect of low doses of the well-towted mrnbinant interferon alfadb (INTRON A, R Schering-mgh, E. _I’? Pharma GmbH, Munich, P.R.G.) on hepatitis B virus (HEV) replication and its ability to promote hepatitis rel&iiOIl.

the~T&wA. One

A total of 58 p&cuts (46 male, 12 female; aged 18-65 years) entered the w between 1987 and SS & were raudomized to receive either interferon (IFN) (n = 30) or no treatment (n = 28). These patientsshowed h&@U evidence uf chronic hepatitis and were seropo&ive for hepatitis I3 surface antigen (mg) and HBV DNA for more than 6 months. Patients with hepatitis delta virus and human immunudc~ciency virus infeaio~, douxupensated &rho&, chronic ronal insufiiciency, or those requiring haen&.ialy& or immanosuppressive therapy, as well as patients with previw organ transplantationsor considered to bu of poor general condition, were exeluded. The pre=m of anti-s to hepatiti B e anti-

SI38 gen (anti-HBe) in the semm was not considered en exclusion miterion. Ftiy informed written consent for patticipetion in the trial wes obtained from all of the patients. Histological examioation revealed chronic penistent hepatitis (CPH) in 27 patients, chronic active hepatitis (CAH) in 28 end the early onset of cirrhosis in three pa tients. There were no significant group dtierences

in sex

Partiel response: Elimination of HBeAg and HBV DNA, while HBsAg persisted, and normalization of ALT activity at least until completion of the follow-up period (6 months). No responre: No change or transient end decrease in HBeAg titre.

loss of HBV DNA

and age of the patients, duration of disease, aminotmttsferese activity, scum eoncetttration of HBV DNA and histological findings. Twenty-eight

treated

patients

(hep

atitis B e antigen (HBeAg) present in 27) and 21 e0ntt01s (HBeAg present io 26) completed the protocol. One patient in the treatment group and one patient in the control group were withdrawn from the study due to lack of cornpliance. One female patient developed a psychosis while being mated with IFN, which necessitated discontimtation of treatment.

Blood samples were taken et monthly intervals 3 months prior to initiation of therapy, during treabnettt and 6 months efter study completion. Serum anelysis included blood cell wonts, liver function tests. bilitubin. activities of alanine aminotrensferase (ALT), aspettate amino. transferase (AST), v_glutamyltmnsfer (GGT), glutamate dehydrogenase (GLDH), cholinesterase (WE), alkaline phosphatase (ALP), elenrophoresis and prothrombin time. ‘Ihe measttretnent~ were performed according to standardid methods. The HBV serum markers HBsAglanti-HBs end HBeAg/attti-HBe were determined by radioimmunoassay (RIA) test kits (AUSRIA IIn, AUSABR, Abbott-HBeR, Abbott Laboratories, Chicago, iL, U.S.A.). HBV DNA was measured by Hep ProbeTM (GIBCOIBRL, Life Technologies, EggensteinLeopoldshafen, F.R.G.). In order to detect the appearance of IFN antibodies during treatment, eo IFN binding test (ELISA) and IFN neutralization reM (bioassay) were used (6). Treatment consisted of 3 megaunits (MU) of IFN administered subcutaneously (s.c.) three times a week (t.i.w.) over a period of 4 months. llto initial treatment and observation was in hospital followed by continued treatment on tot outpatient basis. Therapeutic response to IFN was assessed according to tlte following criteria: Complete response: Elimination of HBsAg, HBeAg and HBV DNA from the serum and nomtalization of ALT activity, at least until completion of the follow-up ps riod (6 months).

The therapeutic response. was evaluated by the E square-test @ < 0.03). The biochemical and virologjcal results were analysed by the WiIcoxon’s tank sum test.

Resultp Of the 28 patients treated, otte patient showed a ~tttplete response, i.e., induding loss of HBsAg, and eight patients a pattial response. Within the same follow-up PC_ riod, three patients of the contro1 group spotttancously lost HBeAg and HBV DNA and semwnvetted to antiHBe. However, the decrease Itt HRV DNA activity to below detection limits in controls dii ttot correlate with nomxdizatiott of sentm ALT activity. w was the case for treated patients. The difference was sigoificant at tbep < 0.05 level (Fig. 1). WhiIe ottly five of 23 treated male patients elimhtated the HBeAg, four of five treated female patient0 respwded to treatment. The only case of complete scnxottversion from HBsAg to anti-HBs was observed in a %-yearold fe,.iale patient with chronic hepatitis which had persisted over 2 years prior to initiation of therapy. Baseline HBV DNA serttm levels in the group of pa-

a-IWERFERON

IN CHRONIC

HEPATITIS B

5139

tients who

successfully respnded 10 treatment (n = 9) were significandy lower than in non-responders Fable 1). There was no corretation between therapeutic response and following parameters: age, enzyme activities of AST, ALT, GGT, ALP, GLDH, CHE, concentrations of

the

bilirubin and immuno@obufins, electrophoresie, duration of &ease and the patients’ remllection of their acute viral

data months of at least,

in the final analysis. Two ta IFN 2 and In one af t&se of antibodies

4 montiis after the ocnvrence IFN

of 5 months.

t0

hqat&. The &mination of HBV markers in HBeAg positive respenders always mmred ‘m a similar way. In genera!, the decra in HBV DNA to below detection limits occurred rapidly and, ip most cases, within the fust 4 weeks after initiation of treatment. HBeAg was eliminated withim a mean interval of 5.9 f 0.84 months, and serwunversion to anti-Hl3e was okwed at a mean of 6.6 f 0.81 months after initiation of therapy. At day 21 after the onset of

tiealznent ,

The results of 3 MU a pe&d of 4 moati can achieve positive response in of Caucasian B without imm~uppressioo. The response rate comparable with the resnits of hm

HEW DNA was no bnger detectable h the patient who initiaIly showed the presence of anti-H&. The eliariaation of HE&g was foliowed by ~rmalizati~n of ALT a&v@, which was prece&d by B transient increase in ALT activity by 2to 3 times the baseline valuain seven of sine rtsponders. At the time of this report, all patienti had been followed up for 6 to a mkum of 24 months after compkGon of therapy. After seroconverSion to anti-HBe, a0 reactivation has been observed. The IFN was generally well tolerated. At the onset of treatment, all patients showed mild ‘flu-like’ symptoms with increased body temperature to a maximum of

been of iaterferm in different dose regknens and +th Merent treatment durations (l-4.8-16). None of the prcviwsiy d treatment protocols have succeeded in co&derab#y mg the effectiveness of IFN,evtnwithnumerowm&fw&nsandcom~tions

38.5 T. In the majority of paths, these symptoms disappc+ucd&ertbethirdinjectionofIFN. Inonepatient,a pre-cxisting depressive state convertedto overt dqwession, as may occur during iFN treatment (7). This patient discontinued treatment in the 6th week and, 6 weeks later, KBV DNA was M) Ionger de[ectaMe. Following a furtkt 3.5 moat&, she bad also eliminated HBeAg,

fully elucidated. Ia general, HBV DNA concentration can ix affected by M- or pathogen-specific fxtors. The influence of virulence &tom mllst be weighed a@nst the f& that, in our study, HBV DNA -tratiuns we.rz lower in women than in men. Ilx titter ems ?c depend largely on the inu3unorSpnsiWW of the host. It is known, for exampk, that the mark= for viral reph-

siace ti

cation, namely serum levels of DNA @ymerase and HBV DNA, inw&h dru&-idaced imm~nos~ppre~s&n ad that immunoampmmid patients are characprized by @u&&y high HBV DNA Iev& (22-25). These ob%ewti suggest &at &be level!3 of HBV DNA in the mum arc substantially hflutaced by the re-

treatment cycle had not been completed,

1.175 0.w No rt~ponse

p