HCV GENOTYPE 2 AND 3 CAN BE CURED BY PEG-IFN-ALFA-2B AND RBV FOR 12 WKS: A RANDOMIZED CONTROLLED STUDY

A. Mangia¹, N. Minerva³, G.L. Ricci¹⁰, M. Romano⁸, V. Carretta⁴, M. Persico⁹, D. Bacca⁶, F. Spirito¹, F. Vinelli², M. Annese⁵, A. Giangaspero⁷, G. Scotto², A. Andriulli¹

¹IRCCS - CSS San Giovanni Rotondo (FG), San Giovanni Rotondo, Italy, ²Ospedali Riuniti - Foggia, Università Di Foggia, Foggia, Italy, ³Medicina - Ospedali Di Canosa, Canosa, Italy, ⁴Medicina - Ospedali Di Venosa, Venosa, Italy, ⁵Medicina - Ospedali Di Policoro, Policoro, Italy, ⁶Medicina - Ospedali Di Casarano, Casarano, Italy,⁷Medicina - Ospedali Di Bari, Bari, Italy, ⁸Ospedale 'S. Pertini', Roma, Italy, ⁹Università Di Napoli, Napoli, Italy,¹⁰Università 'La Sapienza', Roma, Italy.

Objective: to prospectively compare efficacy of PEG-INTRON (PEG-IFN) alfa-2b and ribavirin (RBV) when given for 12 or 24 weeks in naive pts with chronic HCV genotype 2 or 3. Methods: A total of 280 pts, treated with PEG-IFN alfa-2b 1.0 mcg/Kg sc QW plus RBV 1-1.2 g D, were randomized at a 3:1 ratio to 12 wks (N=210, Group A) or 48 wks (n=70, Group B) course of treatment. Efficacy assessment consisted of serum quantitative HCV-RNA at wks 4, 12, and 24 during therapy, and at wk 24 off therapy. In group A, HCV-RNA negative pts at wk 4 had to stop therapy at wk 12, whereas viremic pts had to stay on therapy until wk 24. Results: Data are summarized in the table. In 130 pts in group A who experienced HCV clearance within 4 wks, EVR was 99.2%, SVR 89.2%, whereas 10% of pts relapsed off therapy. The remaining 80 pts from group A, viremic at wk 4, experienced EVR of 81.2% after 6 months of tx, SVR of 78.7% at 6 months off tx, whereas 2.5% of them relapsed at follow-up. In the 70 pts from group B, EVR and SVR were both 81.4% with no relapse. No correlation between baseline viremia and relapse was found. Conclusions: The majority of pts with genotypes 2 or 3 and early viral clearance can be cured by only12 wks of treatment with PEG-IFN alfa-2b and RBV. Longer treatment with combination therapy may be needed only in pts still viremic at wk 4.

A RANDOMIZED TRIAL OF PEGINTERFERON ALFA-2B AND LAMIVUDINE COMBINATION TREATMENT VERSUS LAMIVUDINE MONOTHERAPY IN CHINESE PATIENTS WITH HBEAG-POSITIVE CHRONIC HEPATITIS B

H.L.Y. Chan¹, N.W.Y. Leung², A.Y. Hui1, C.T. Liew³, A.M.L. Chim¹, F.K.L. Chan¹, L.C.T. Hung¹, J.J.Y. Sung¹

¹Department Of Medicine And Therapeutics, Chinese University Of Hong Kong, Hong Kong ²Department Of Medicine, Alice Ho Nethersole Hospital, Hong Kong ³Department Of Pathology, Chinese University Of Hong Kong, Hong Kong

Background:

The benefit of conventional interferon and lamivudine combination treatment over lamivudine monotherapy was controversial in chronic hepatitis B. We conducted a randomized trial to evaluate the efficacy of peginterferon α-2b and lamivudine combination for chronic hepatitis B in Chinese patients.

Methods:

We randomly assigned treatment naive HBeAg-positive chronic hepatitis B patients to receive either 32-week peginterferon α-2b (1.5 mcg/kg/week, maximum 100 mcg) and 52-week lamivudine (100 mg daily) combination treatment or 52-week lamivudine (100 mg) monotherapy at 1:1 ratio. The primary endpoint was sustained virological response (HBeAg seroconversion with HBV DNA <500,000 copies/ml) at 24 weeks after cessation of treatment.

Results:

Fifty patients were randomized to each of the combination treatment and monotherapy groups. The rate of sustained response was higher among patients who received combination treatment than those who received lamivudine monotherapy (36% versus 14%, p=0.03). At the end of treatment, combination treatment recipients, as compared to lamivudine monotherapy recipients, were more likely have virological response (60% versus 28%, p=0.003), had more substantial reduction of logHBV DNA (3.91 versus 2.83, p<0.001) and were less likely have lamivudine resistant mutants (21% versus 40%, p=0.045). There was no difference in the percent of patients with normalization of alanine aminotranferase and histological improvement between the two studied groups at the end of treatment.

Conclusions:

In Chinese patients with HBeAg-positive chronic hepatitis B, combination treatment of peginterferon α-2b and lamivudine was associated with a significantly higher virological response than lamivudine monotherapy.

VIRAL DYNAMICS DURING PEG-INTERFERON ALONE AND IN COMBINATION WITH LAMIVUDINE

M. van Zonneveld¹, B.E. Hansen², H.G.M. Niesters³, R.A. de Man¹, S.W. Schalm¹, H.L.A. Janssen¹

¹Gastroenterology And Hepatology, Erasmus Mc, Rotterdam, The Netherlands ²Epidemiology And Biostatistics, Erasmus Mc, Rotterdam, The Netherlands ³Virology, Erasmus Mc, Rotterdam, The Netherlands

To evaluate viral dynamics during therapy with pegylated interferon alpha-2b (PEG-IFN) and establish if combination therapy with lamivudine has an additive effect, we analyzed viral decline in 36 HBeAg positive chronic hepatitis B patients who completed 24 weeks of PEG-IFN monotherapy or combination therapy. Serum HBV-DNA levels were measured frequently (days 0-4, 7, 14, 21, 28, and monthly thereafter) to assess HBV dynamics. Response (serum HBeAg loss) was achieved in 7 (39%) of the combination therapy group and 8 (44%) of the monotherapy group. Throughout the study period, we found a significantly faster HBV-DNA decline in the combination therapy group, compared to the monotherapy group. In the combination therapy group we found a biphasic decline of HBV-DNA. The efficacy of combination therapy was 94.9%. In this group, HBV-DNA decline during the first week was associated with response. In the monotherapy group, a more complex HBV-DNA decay pattern was found, not fitting a biphasic model. In this group, a typical staircase pattern with minimal decline in the first weeks, but a sudden HBV-DNA decrease after 12 to 20 weeks, was found in 6 of the 8 responders (75%). In conclusion, combination therapy with PEG-IFN and lamivudine is more effective in suppressing HBV replication than PEG-IFN. This did not result in enhanced sustained response rates. Only for patients treated with combination therapy initial was decline of HBV-DNA indicative of response. For patients treated with PEG-IFN alone response was associated with HBV-DNA decline after 12 weeks, probably due to enhanced immune reactivity.

LIVER HISTOLOGY IN CHRONIC HEPATITIS B PATIENTS AFTER 1 YEAR OF TREATMENT WITH PEGYLATED INTERFERON ALPHA-2B IN COMBINATION WITH LAMIVUDINE OR PLACEBO

M. van Zonneveld¹, P. Zondervan², R.A. de Man¹, S.W. Schalm¹, H.L.A. Janssen¹

¹Gastroenterology And Hepatology, Erasmus Mc, Rotterdam, The Netherlands ²Pathology, Erasmus Mc, Rotterdam, The Netherlands

The two established therapies for chronic hepatitis B (CHB), interferon and lamivudine, have shown to improve liver histology. We studied the effect of pegylated interferon alpha-2b (PEG-IFN) therapy alone and in combination with lamivudine on liver histology. A total of 266 HBeAg-positive CHB patients were treated for 52 weeks with PEG-IFN 100 mg/week in combination with either lamivudine 100 mg/day or placebo in a double-blinded, randomized, multi-center study. PEG-IFN dose was halved after 32 weeks of treatment. Liver biopsies were requested before treatment and at the end of treatment (optional). All biopsies were blinded and scored according to the Ishak system, which includes a necroinflammatory score (0-18) and a fibrosis score (0-6). Paired and evaluable biopsies were available for 110 patients. The mean baseline scores of the two treatment groups were comparable. Overall, inflammation score improved (mean score 5.5 pretreatment vs 3.9 post treatment, p<0.001) and there was a slight progression in fibrosis (mean score 2.4 pretreatment vs 2.7 post treatment, p=0.03). Necroinflammatory score improved in 25 patients (48%) in the combination group and in 31 patients (53%) in the PEG-IFN monotherapy group. Fibrosis score improved more often in the combination group (17 patients (33%) versus 13 patients (22%) respectively (p=0.23)). In responders (n=48), defined as HBeAg negative at the end of follow-up, inflammation score improved in 65%, compared to 38% of non-responders (n=0.06). In conclusion, PEG-IFN therapy improves liver histology in CHB patients. We found an improvement in necroinflammatory scores, but no significant reduction of fibrosis in both treatment groups.

RETREATMENT WITH PEGYLATED INTERFERON ALPHA-2B AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C NON RESPONDERS TO INTERFERON MONOTHERAPY OR INTERFERON AND RIBAVIRIN COMBINATION

C. Bapin¹, P. Fabbro-Peray², S. Hachemane¹, F. Blanc¹, D. Diaz⁴, P. Pueyo³, D. Larrey¹

¹CHU Montpellier, Montpellier, France ²CHU Nimes, Nimes, France ³CH Carcassone, Carcassone, France ⁴Agrel, Languedoc-Roussillon, France

AIM:

To assess the efficacy and safety of a treatment with pegylated interferon alpha-2b (PegIFN) and ribavirin (RBV) in patients with prior non virological response to IFN or to IFN-RBV therapy and to compare two dose regimens. METHODS: 88 patients received: 1) PegIFN 1.5 microg/kg/week and RBV 1000-12000 mg/day for 48 weeks or 2) PegIFN 2 microg/kg/week for 12 weeks, then 1.5 microg/kg/week for 36 weeks and RBV 1000-12000 mg/day for 48 weeks.

RESULTS:

83 patients were analysed. Baseline characteristics were comparable in the two groups: mean age: 51 vs 50 years, male: 55% vs 70%, Genotype 1: 83.7% vs 74.2%, HCV RNA titer > 800 000 UI/ml 63% vs 61%, F3-F4 fibrosis : 32.5% vs 46.15%, prior monotherapy 34.9% vs 40%. The sustained response rate ( SR) across the two groups was 24%. Patients with genotype 1 had lower SR than genotype non 1 patients: 19.6% vs 57.1% (p=0.01). SR was higher in patients non-responders to IFN than patients non-responders to IFN-RBV combination: 34.5% vs 19.6%. The SR was slightly higher for patients in group 27.5% than 20.9% in group 2 (p=0.7). Safety: of the 17 patients who had discontinued the treatment (20.5%): 9 in group 1 and 8 in group 2, intolerance to treatment was the cause in 9 patients (10.8%).

CONCLUSION:

a 48 week PegIFN-RBV therapy was associated with a SR in 24% of non-responders to IFN or IFN-RBV combination. Induction dosing did not provide a significantly higher response.

HCV CORE AG AS A PREDICTOR OF NON-RESPONSE IN GENOTYPE 1 CHRONIC HEPATITIS C PATIENTS TREATED WITH PEGINTERFERON ALFA-2B PLUS RIBAVIRIN

M. Buti¹, A. Valdes¹, C. Mendez¹, M. Schaper², S. Sauleda³, F. Rodriguez-Frias², R. Jardi², R. Esteban¹, J. Guardia¹

¹Servicio de Hepatologia, Barcelona, Spain ²Laboratorio De Bioquimica, Barcelona, Spain ³Banco De Sangre Y Centro De Transfusiones Y Tejidos, Spain

Background/Aims:

Chronic Hepatitis C Patients infected by genotype 1 are the least responsive to combination therapy and therefore monitoring response is important in identifying non-responders quickly, permitting therapy discontinuation and avoiding side effects and costs. We examined the usefulness of measuring total HCV Core Ag in early treatment with peginterferon alfa 2b and ribavirin in genotype 1 patients in the prediction of response and compared the results with those from HCV RNA quantification.

Methods:

Two-hundred and sixty-eight serum samples from 46 genotype 1 patients receiving combination therapy were examined for HCV Core Ag and quantitative HCV RNA.

Results:

At baseline, mean HCV RNA and HCV Core Ag concentrations were significantly lower in sustained virologic responders than in non-responders. The negative predictive value of HCV Core Ag testing in predicting non-response at week 12 is 100%, and for a 2 log drop in HCV RNA, using two quantitative tests, it is 88%.

Conclusions:

HCV Core Ag determination allows the identification of non-responders with only one test at week 12 and permits stopping therapy in these patients. HCV Core Antigen testing is cheaper and easier to perform than HCV RNA quantification.

SHORT COURSE OF PEGYLATED ALFA INTERFERON IN ACUTE HCV HEPATITIS

G. Calleri¹, F. Gaiottino¹, G. Leo¹, S. Belloro¹, P. Romano², G. Dalmasso², A. Traverso³, R. Carbone⁴, P. Orsi⁴, G. Tinelli⁵, P. Caramello¹, G. Di Perri¹

¹Departmento Fo Infectious Diseases - 'Amedeo Di Savoia ' Hospital, Torino, Italy ²Departmento Fo Infectious Diseases - 'S.Croce Hospital', Cuneo, Italy ³Departmento Fo Infectious Diseases - 'Ospedale Regionale', Aosta, Italy ⁴Departmento Fo Infectious Diseases - 'SS.Antonio E Biagio' Hospital, Alessandria, Italy ⁵Departmento Fo Infectious Diseases - 'Ospedale Civile', S.Angelo Lodigiano, Italy

Background:

Acute hepatitis C is seldom symptomatic and proceeds to chronicity in 70-85% cases. A 6 months early treatment with alfa-interferon reduces the chronicity rate.

Aim:

To investigate if a shorter course of Peg-interferon is equally effective.

Methods:

Multicenter open-label study. Acute hepatitis C defined as: elevated ALT, positive HCV-RNA and anti-HCV seroconversion in the previous 6 months. Treatment: pegylated interferon alfa-2b 1,5 mcg/Kg weekly for 3 months.

Results:

Nineteen patients were enrolled so far, in 6 centers. Preliminary results refer to 15 patients who completed therapy (7/15 male, mean age 31, risk factor: 10 IVDU, 1 health-care worker, 4 unknown). Genotype: 1a/b=6 cases, 2a/c=5, 3a=2, 4=2. Median ALT level in the acute phase: 955 (range: 401-1893). Eight/15 were symptomatic. Treatment was started within 4-90 days. Treatment was well tolerated: no severe adverse events, no ALT flares. There was 1 drop-out for logistic reasons. HCV-RNA dropped to negative (PCR) in 13/14 patients at month 1 and in 14/14 at month 3 during treatment. Eight/14 patients (57%) remained negative during follow up (median 3 months, range 1-12), while 6/14 (43%) relapsed at month 1. Relapse was more frequent in genotype 1 (4/6 cases=66%) than 2-3-4 (2/8=25%) (non significant) and in female sex (5/7=75%, vs. 1/7=14%; Fisher exact test p=0,04).

Conclusions:

Pegylated interferon is well tolerated in acute hepatitis C. After a prompt clearance of HCV, a relapse is frequent in genotype 1 patients. A more aggressive treatment, possibly including ribavirin, or a prolonged course, is probably desirable at least in genotype 1.

EFFICACY OF PEG-INTERFERON ALPHA-2B MONOTHERAPY IN ACUTE HEPATITIS C: A PRELIMINARY ANALYSIS

T. Santantonio¹, E. Sinisi¹, F. Signorile¹, A. Guastadisegni¹, C. Casalino¹, M. Mazzola², R. Francavilla², G. Pastore¹

¹Clinic Of Infectious Diseases, University Of Bari, Bary, Itali ²Division Of Infectious Diseases, Bisceglie Hospital, Itali

IFN monotherapy is effective in reducing the high rate of chronic evolution of acute hepatitis C (AHC), yielding a sustained virological response in 98% of patients treated with daily IFN induction. However, optimal regimen and timing of treatment remain undefined. Our aim was to evaluate the efficacy of pegylated-interferon (Peg-IFN) for 6-months in AHC patients and to verify if treatment response rate is reduced by delaying therapy for 12 weeks, the interval required to exclude patients with spontaneous resolution. Sixteen consecutive patients (diagnosis based on documented anti-HCV seroconversion) viremic after 12 weeks from disease onset, were treated with Peg-IFN-alpha-2b at 1.5 mcg/kg QW for 6 months. Patients (11 males, 5 females, mean age: 36.2 yrs) were HBsAg and anti-HIV negative. Seven patients had genotype 2a/2c, 6 patients gen-1b, and 3 patients gen-3a. Mean HCV RNA and ALT levels at baseline were 316,396+/-421,476 IU/ml and 256+/-188 U/l (normal value<40), respectively. At end of treatment, 15/16 (94%) showed virological response, while 14/16 (87%) had normal ALT levels; one of these with slightly increased ALT levels showed normal values after therapy discontinuation. All patients completed 3 months follow-up with virological and biochemical response observed in 15/16 (94%). Ten patients completed 6-months follow-up with a sustained virological and biochemical response in 9/10 (90%). Treatment was well-tolerated and no Peg-IFN dose reduction was necessary. These preliminary results show that Peg-IFN-alpha-2b is safe and effective in inducing resolution of acute hepatitis C in almost all treated patients after failure to spontaneously clear HCV infection.

WEIGHT-ADJUSTED HIGHER DOSES OF RIBAVIRIN ARE ASSOCIATED WITH EARLY VIROLOGIC RESPONSES TO HEPATITIS C VIRUS (HCV) THERAPY

C.B. Hare¹, J.J. Loveland², A.H. Chu², V.P. Gotz², J.A. Morris²

¹Postive Health Program, UCSF/SFGH, San Francisco Ca, USA ²ProSanos Corporation, La Jolla, USA

The purpose of this study was to characterize interferon alfa 2-b plus ribavirin (REB) and peginterferon alfa 2-b (PEG-I) + ribavirin (RBV) treatment strategies and early virologic (EVR) and biochemical responses (EBR). Patient information was collected from a retrospective medical record review of 998 patients with HCV in an intent-to-treat fashion. Package insert (PI) doses were compared with actual doses prescribed to REB- or PEG-I + RBV-treated patients. Univariate analysis and logistic regression were used to explore the effects of treatment, dose and patient characteristics on EVR and EBR. Two hundred PEG-I + RBV- and 312 REB-treated patients reached the analysis target of 24±6 weeks. Interferon alfa 2-b was prescribed to 99% of REB-treated patients according to the PI whereas PEG-I doses differed from the PI in 52% of patients. RBV was prescribed per PI recommendations to 71% of patients receiving REB therapy. Contrary to the PI, weight-adjusted dosing of RBV was noted in 70% of PEG-I + RBV-treated patients. A greater rate of EVR occurred with PEG-I + RBV therapy than REB (29% vs. 18%, p=0.018). Higher doses of RBV plus PI-doses of PEG-I was associated with higher rates of EVR (OR=2.37, 95% CI=1.05-5.66). Off-label doses of PEG-I plus higher doses of RBV were not associated with EVR. Doses of PEG-I + RBV associated with an EVR had no significant effect on EBR. Weight-adjusted doses of RBV greater than 800 mg/day were associated with higher rates of EVR when used with 1.5 mcg/wk of PEG-I in the treatment of HCV.

PEGYLATED INTERFERON PLUS RIBAVIRIN FOR THE TREATMENT OF RECURRENT HCV INFECTION AFTER LIVER TRANSPLANTATION

S. Lorenzini¹, M. Biselli¹, A. Gramenzi¹, F. Bollino¹, C. Cursaro¹, M. Bernardi¹, P. Andreone¹

¹Dipartimento Di Medicina Interna, Cardioangiologia, Epatologia Dell'Università Di Bologna, Servizio Di Semeiotica Medica / Policlinico S. Orsola-Malpighi, Bologna, Italy

Background:

Hepatitis C virus (HCV) re-infection is almost universal after liver transplantation (OLT) leading to chronic hepatitis and cirrhosis, and the role of antiviral treatment remains unknown.

Methods:

Between November 2001 and October 2003, 18 HCV recurrent OLT patients were treated with pegylated interferon alfa-2b (80 mg/weekly) and ribavirin (600 mg/daily). Fourteen patients had HCV genotype 1, two 2a/2c and one genotype 4. At start-up, median HCV-RNA levels were 5 MEq/ml (range 0,07-22,8 MEq/ml). Three out 18 patients had compensated cirrhosis, and 15 patients histologically proven chronic hepatitis. After 6 months, only patients with negative serum HCV-RNA continued therapy for an additional 6 month period.

Results:

All cirrhotic patients dropped out after 3 months of therapy because of disease decompensation. After 6 month of treatment, HCV-RNA loss was observed in 8/18 (44%) patients. At the end of treatment, 7/18 (39%) patients were HCV-RNA negative because one patient experienced a virological breakthrough at the 9th month. After 6 months of follow-up, the sustained virological response was 6/18 (33%). Sixteen patients experienced anemia and 12 neutropenia. Neutropenic patients were treated with granulocyte colony-stimulating factor without modification of pegylated interferon dose. Among the anemic patients, ribavirin was reduced in 6 and discontinued in 2. In the remaining 8 patients, erythropoietin was administered, but, among them, 4 patients further required ribavirin dose reduction.

Conclusions:

in OLT patients with recurrent chronic hepatitis C, pegylated interferon plus ribavirin is effective in among 1/3 of patients. However, numerous severe adverse events occurred, including decompensation in cirrhotic patients.Poster 490: Topic – Prediction of Response

KINETIC OF VIROLOGICAL RESPONSE DURING PEG-IFNS IN CHRONIC HEPATITIS C

S. Luise¹, E. Bernardinello¹, L. Cavalletto¹, L. Chemello¹, S. De Carlo¹, K. Mattiello¹, A. Gottardo¹, I. Mezzocolli¹, A. Gatta¹

¹Department Of Clinical And Experimental Medicine, Clinica Medica ⁵, Azienda Ospedaliera Di Padova, Padova, Italy

AIMS:

To compare the kinetic of viral response (VR) in patients with chronic hepatitis C treated with two different PEG-IFNs (alfa-2a or 2b).

PATIENTS/METHODS:

75 patients (age:43±9,5years; M/F:57/18) received 180 mcg/weekly of PEG-IFN-alfa-2a (n=23) or 1,5 mcg/kg/weekly of PEG-IFN-alfa-2b (n=52), all in combination with ribavirin (15mg/kg/daily). Baseline characteristics between the groups were comparable. HCV-RNA levels were tested by PCR and quantitative-bDNA in all patients at week 4, 12, 24 during therapy. 74 patients had a liver biopsy pre-therapy.

RESULTS:

are shown in the table at each time point. At week 24, 19/23 (83%) patients treated with PEG-IFN-alfa-2a and 45/52 (87%) with PEG-IFNalfa-2b reached a VR.

CONCLUSIONS:

At week 4 the kinetic of VR with PEG-IFN-alfa-2b was earlier than with PEG-IFN-alfa-2a therapy (48% vs 35%), while the decrease of HCV-RNA <2log was similar. Liver fibrosis >F3 wasn’t a negative prognostic factor for early VR in the 2 groups (40% vs 41%), in particular during PEG-IFN-alfa-2a therapy. At week 12, HCV-genotype 2 or 3 showed a better VR than HCV 1or 4 in each group (100% with PEG-IFN-alfa-2a and 96% with PEG-IFN-alfa-2b vs 36% and 61%, respectively).