Peginterferon Alfa-2a/ribavirin Treatment in Patients with Chronic HCV Genotype 1: Efficacy Is Improved in Patients with Early Stages of Fibrosis

Treatment with peginterferon and ribavirin (PEGIFN/RBV) is the standard of care for patients with hepatitis C virus (HCV) infection. Patients with chronic HCV and advanced fibrosis or cirrhosis (CX) are at risk for developing disease progression and hepatic decompensation and are therefore candidates for treatment.

In contrast, the risk:benefit ratio of PEGIFN/RBV therapy is controversial for patients with mild or no fibrosis (NoF), particularly patients with HCV genotype 1 who have a lower overall rate of sustained virologic response (SVR).

Researchers therefore examined the relationship between liver histology, SVR and the incidence of Laboratory abnormalities (LA) during treatment with PEGIFN alfa-2a/RBV [Pegasys/Copegus] in patients with HCV genotype 1.

Data were reviewed from 328 patients with chronic HCV genotype 1 treated with PEGIFN alfa-2a (180 mg/week) [Pegasys] plus RBV (1000/1200 mg/day) for 48 weeks in two registration trials.

All patients had a baseline liver biopsy. A subset of the biopsies were assessed for fibrosis by a local pathologist and staged as either NoF, portal (PF), incomplete septa (IS) or CX.

HCV RNA titer was determined by Roche Amplicor.

SVR and LAs were examined as a function of baseline fibrosis score.

Results

The number of patients and SVR for each fibrosis group are listed in the TABLE below.

· Patients with NoF/PF had an SVR of 56% (135/241) whereas 42% (37/87) of patients with IS/CX achieved SVR (p<0.03).

· No significant differences in gender (73% male), race (84% Caucasian), or baseline HCV RNA titer >800,000 IU/ml (67%) were present between the 2 groups.

· In contrast, patients with IS or CX were older (p<0.001).

· Only grade 3 thrombocytopenia was more frequent in patients with IS/CX than noF/PF (10 % vs 2%; p<0.001).

· No grade 4 thrombocytopenia was observed.

Conclusions

The authors conclude, “Patients with NoF/PF have a superior SVR to patients with IS/CX. These patients should not defer therapy and wait for evidence of fibrosis progression as this only reduces their chance for SVR.

Baseline Fibrosis score, N=328	N (%)	SVR	Age, Mean ± SD	ALT, Mean ± SD
NoF	65	34 (52%)	38 ± 10	84 ± 50
PF	176	101 (57%)	43 ± 10	114 ± 113
IS	51	25 (49%)	48 ± 10	133 ± 99
CX	36	12 (33%)	50 ± 8	151 ± 134

05/16/05

Reference
M L Shiffman and others. Peginterferon Alfa-2a/ribavirin Treatment in Patients with Chronic HCV Genotype 1: Efficacy Is Improved in Patients with Early Stages of Fibrosis. Abstract S1568. Digestive Disease Week 2005. May 14-19, 2005. Chicago, IL

http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_051605d.html

Peginterferon Alfa-2b (PegIntron) Therapy for 8 Weeks in Acute Hepatitis C Genotypes 1 and 4: A Pilot Study

The efficacy and duration of peginterferon treatment in acute hepatitis C have not been adequately evaluated. This study was designed to determine the efficacy, safety, long term outcome and cost-effectiveness of 8 weeks peginterferon alfa (PEG IFN) [PegIntron] monotherapy in patients with acute hepatitis C virus (HCV) genotypes 1 or 4.

This intent to treat, controlled multicenter trial was designed to treat patients with acute hepatitis C with detectable HCV-RNA at 8 weeks after the first positive PCR.

Sixty-two patients with proven acute HCV genotypes 1 (n= 23) and 4 (n=39) were enrolled and prospectively followed.

Ten subjects refused treatment but were followed through the study.

Fifty-two patients without spontaneous recovery at week 8 were assigned to receive 1.5 mg/kg peginterferon alfa-2b S.C.once weekly for 8 weeks while patients who still have detectable HCV-RNA after 8 weeks of treatment continued therapy until 12 weeks.

The primary end point was sustained virological response (SVR), defined as undetectable HCV RNA 48 weeks after end of treatment.

All patients were followed for 3 years after therapy.

Results

· Four untreated subjects (40%) had spontaneous recovery.

· Among the 52 treated patients, 41 (79%) patients (genotype 4: 32 patients, genotype 1: 9 patients) had undetectable HCV-RNA after 8 weeks therapy and treatment was stopped while 11 patients (genotype 1) had persistent viremia so treatment was continued until 12 weeks.

· The overall SVR in all treated patients was 92.3% [39/41 (90%) in the 8-week treatment group and 10/11 (91%) 27 in the 12-week treatment group].

· SVR after 8 weeks peginterferon alpha-2b therapy was achieved more frequently among genotype 4 patients irrespective of viral load while in genotype 1 patients SVR after 8 weeks was more likely in patients with low viral load compared with those with high viral load.

· Peginterferon alfa-2b therapy was well tolerated in both groups and was associated with significant improvement in the quality of life.

· None of patients with SVR had detectable HCV-RNA 3 years after completing treatment.

Conclusions

In conclusion, the authors write, “Peginterferon alfa-2b monotherapy for 8 weeks induces high sustained virologic response rates in patients with acute hepatitis C virus with genotype 1 and 4.”

“HCV genotype 1 with high viral load may require longer treatment duration. Peginterferon alfa therapy in acute hepatitis C seems cost effective as it reduces the incidence of chronicity and improves thequality of life.^”

05/16/05

Reference
S Kamal and others. Peginterferon Alfa-2b (PegIntron) Therapy for 8 Weeks in Acute Hepatitis C Genotypes 1 and 4: A Pilot Study. Abstract 84 (oral). Digestive Disease Week 2005. May 14-19, 2005. Chicago, IL. http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_051605c.html

Efficacy of Daily Consensus Interferon (Infergen) and Ribavirin Compared to Peg-Interferon Alfa2b (PegIntron) and Ribavirin in Treatment-Naive Patients with HCV Genotype 2 or 3

Consensus interferon (CIFN; Infergen) is a synthetic type 1 interferon with enhanced in vitro activity compared to conventional IFN-alfa (IFNa). In the prospective, randomized multicenter PegIntron-Against-Consensus-Trial (PACT), the efficacy and safety of daily CIFN-treatment and ribavirin is compared to peg-IFNa2b [PegIntron] plus ribavirin.

400 patients with chronic HCV infection and serotype-2 or -3 will randomly be assigned to treatment with 9 mcg qd CIFN sc. (group A) or peg-IFNa2b (1,5 mcg/kg body weight once weekly, group B), each in combination with ribavirin (>10,6 mg/kg body weight) for 24 weeks.

Treatment is interrupted for primary non-response, if viral load drops by less than 2 log until week 12 or drops by more than 2 log but remains positive at week 16.

Follow up includes further 24 weeks. Viral response rates are analyzed by the Roche COBAS Amplicor HCV Monitor v2.0 test.

129 patients out of 199 patients enrolled before November 2004 reached at least the end of treatment at week 24 and represent the base of this interim analysis.

Results

· There were no significant differences in patient baseline characteristics between both treatment groups concerning age, gender, genotype and viral load.

· The virological response rates analyzed as intent-to-treat are shown in the Table:

Group A

Group B

wk 12

(n=67)

wk 24

(n=68)

wk 48

(n=43)

wk 12

(n=60)

wk 24

(n=61)

wk 48

(n=38)

PCR neg

99%

93%

95%

92%

94%

95%

· Thus, end-of treatment response (ETR) rates as well as sustained virological response (SVR) rates were very high and identical in both treatment groups.

· This was also true for all subgroup analyses, including analysis according to baseline viral load (< vs. ≥ 800.000 IU/ml) gender, body weight (< vs. ≥ 75 kg) and age (< vs. ≥ 60 yrs).

· Treatment was rather well tolerated in both treatment groups, as there were no significant differences in the numbers of serious adverse events or preterm treatment discontinuations.

Conclusions

In conclusion, the authors write, “In treatment-naive patients with chronic hepatitis C and serotype-2 or -3 infection, daily treatment with CIFN combined with ribavirin has the same antiviral efficacy and safety profile as weight adjusted peg-IFNa2b. Further analyses will show whether some subgroups might preferentially benefit from one or the other interferon.”

05/18/05

Reference
W Bocher and others. Interim Results From the PACT-Trial: High Antiviral Efficacy Of Daily Consensus Interferon/ribavirin Compared To Peg-Interferon Alfa2b/ribavirin in Treatment-Naive Patients With Chronic Hepatitis C and Serotype-2 or -3. SABstract S1531. Digestive Disease Week 2005. May 14-18, 2005. Chicago, IL.
http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_051805e.html

No Correlation Found Between Steatosis and Liver Fibrosis in HCV Genotype 1 Infection

Liver steatosis is generally regarded as a risk factor for chronic liver disease. Moreover, steatosis is considered in HCV-related chronic active hepatitis (CAH) as an adjunctive factor of progression and evolution of liver disease. In particular, steatosis is thought to be specifically related to the course of the disease in genotype 3a patients with CAH.

The aim of this study was to test the role of steatosis in liver damage (fibrosis) in a consecutive case-study of genotype 1b patients who have undergone liver biopsy because of an increase of serum ALT.

180 patients ( sex: M98/F82; median age: 51 range 17 - 68) underwent ultrasound examination and liver biopsy. Based on liver histology patients were divided according to steatosis into four classes: 1 (no steatosis), 2 (steatosis < 30%), 3 (steatosis 30 – 50 %), 4 (steatosis > 50 %).

Results:

· Histological Activity Index (HAI) was evaluated according to ISHAK’ s score.

· Median fibrosis value was S 2 (ranging 0 – 6; 23 patients showed liver cirrhosis) in all the 4 classes and no statistical significance was found between groups.

· Virological and epidemiologic characteristics, biochemical data, BMI, Apparent Duration of Disease (ADD) of all patients were recorded and statistical correlation checked.

· A univariate and multivariate analysis vs fibrosis were performed in all the patients and tested statistically significant only for age, ADD, diabetes and ALT (p< 0.00), but not for steatosis.

Conclusion

The authors conclude, “Steatosis does not seem to be an independent adjunctive risk factor of liver disease progression in CAH/genotype 1b HCV-infected patients….Age, ADD, diabetes and increase of ALT seem to be the only independent factors associated with liver fibrosis progression.”

05/02/05

Reference
M Persico and others. NO CORRELATION BETWEEN FAT LIVER ACCUMULATION AND LIVER FIBROSIS IN GENOTYPE 1B HCV RELATED CHRONIC LIVER DISEASE. Abstract 593. 40^th EASL. April 13-17, 2005. Paris, France.

HCV genotype 5 has a similar response to peginterferon plus ribavirin as genotype 1

By Jillian L. Lokere, MS

April 16, 2005 — Patients infected with HCV genotype 5 have responses to peginterferon plus ribavirin similar to those with genotype 1 infection, according to a poster presented by Francois D'heygere and colleagues from the Algemeen Ziekenhuis Groeninge, Kortrijk, Belgium at the 40th Annual Meeting of the European Association for the Study of the Liver.

There are at least 6 different HCV genotypes throughout the world. Genotype 1 is the most prevalent, accounting for 40% to 80% of all infections. Genotype 5 is generally confined to South Africa, but small pockets of genotype 5 infection have been reported in Western Europe.

Sustained virologic response (SVR) rates to peginterferon plus ribavirin treatment differ by genotype, with clinical studies reporting a response rate of about 50% for genotype 1. Because so few patients who are infected with genotype 5 receive such treatment, there are few data about SVR rates in this population. Preliminary evidence has suggested that genotype 5 may respond better than genotype 1.

To clarify, D'heygere and colleagues compared SVR rates between genotype 1 and genotype 5 HCV-infected patients in Belgium. A total of 21 patients with genotype 5 infection were selected from a database of 443 patients who were enrolled in the Belgian Randomised Trial for Naive and Relapsers (BERNAR-1). This trial used either standard interferon alfa-2a 6 MIU 3 times weekly for 8 weeks, followed by 3 MIU 3 times weekly for 40 weeks, or peginterferon alfa-2a 180 µg weekly for 48 weeks. All patients also received ribavirin 1000 to 1200 mg daily. The 21 selected patients were about evenly divided between the interferon group and the peginterferon group, and 81% of them were treatment-naive. An additional 21 patients with genotype 1 infection were then selected to match those with genotype 5 infection on the basis of age, gender, baseline viral load, cirrhosis status, pretreatment status, and treatment group.

At 24 weeks after the end of treatment, 48% of patients in the genotype 5 group and 38% of patients in the genotype 1 group had an SVR, a difference which was not quite statistically significant. Among those who received peginterferon rather than standard interferon, the SVR rate was 55% in both groups.

The investigators concluded that patients with genotype 5 infection respond to peginterferon plus ribavirin treatment similarly to those with genotype 1 infection, although genotype 5 patients appeared to respond less well to standard interferon treatment.

Reference

D'heygere F,George C, Nevens F, et al. Patients infected with HCV-5 present the same response rate as patients infected with HCV-1: results from the Belgian Randomised Trial for Naive and Relapsers (BERNAR-1). Program and Abstracts of the 40th Annual Meeting of the European Association for the Study of the Liver. Abstract 558.

http://clinicaloptions.com/hep/news/news_EASL2005_558.asp

The Effectiveness of Standard and Pegylated Interferon Plus Ribavirin in Treatment-naïve Patients with Chronic Hepatitis C Virus Genotype 5 in France

The prevalence of HCV genotype 5 in France is 2%. Little is known about virological response in this population. Individuals with HCV genotype 5 have poor responses to interferon/ribavirin therapy and are usually treated for 48 weeks The aim of the present study was to assess the antiviral response in naïve patients treated woth standard Interferon or Pegylated Interferon plus Ribavirin for 48 weeks.

French researchers performed a retrospective study in order to estimate the virological response after a treatment of 48 weeks in treatment-naïve HCV genotype 5 patients. A total of 82 patients were included. Twenty eight patients received standard Interferon (3 MU*3/week) (G1) and 54 were treated with Peg-Interferon 1.5 mcg/kg/week (PegIntron) or 180 mcg/week [Pegasys] (G2) plus Ribavirin (800-1200 mg/day).

Sustained virological response (SVR) was defined as an undetectable HCV RNA at week 72. Patients were considered as adherent if they received ≥ 80% of both their total Interferon and Ribavirin doses for ≥ 80% of the expected duration of therapy (AASLD 2004).

Results

Baseline characteristics were: mean age 58 years, sex ratio 1.4 (M/W), fibrosis score (Metavir): 63% ≥ F2, 22% F4 and pre-therapeutic viral load > 800000 UI/mL: 52%. Transmission routes were: transfusions (54%), intravenous drug use (2%), others (18%) and unknown (39%).

· SVR rate in intent-to-treat analysis was achieved in 61% (64% in G1 and 60% in G2, p: NS).

· In univariate analysis, the rate of SVR did not depend on age (<vs.≥ 45 years), sex, fibrosis score (<vs.≥ F2) or viral load (<vs.≥ 800000 UI/mL).

· SVR was 84% (16/19) in adherent and 54% (32/59) in non adherent patients (p<0.05).

· I35 patients received a Ribavirin dose ≤ 800 mg/day. SVR rate was significantly associated with Ribavirin adherence alone. SVR rate was statistically superior (p<0.01) in Ribavirin adherent patients 86% (18/21) versus non adherent patients 53% (30/57).

The authors conclude

· Combination therapy (standard or Peg-Interferon plus Ribavirin) is efficient in 61% of HCV genotype 5 infected patients.

· Adherence to Ribavirin strongly improves SVR (86%).

· This is the first study conducted in a large cohort of HCV genotype 5 patients showing that these patients can have a good response to combination therapy.

05/13/05

Reference
C Bonny and others. EFFICACY OF INTERFERON (STANDARD OR PEGYLATED) PLUS RIBAVIRIN IN NAÏVE PATIENTS WITH HEPATITIS C VIRUS GENOTYPE 5. A FRENCH NATIONAL STUDY. Abstract 549. 40^th EASL. April 13-17, 2005. Paris, France.

In Genotype 1 Patients with Low Viral Load Who Become HCV RNA Negative at Week 4, Treatment with Peginterferon Alfa-2b (PegIntron) for 24 Weeks Has Similar High Efficacy with Superior Safety Compared to 48-week Therapy

The results of prior studies suggest that patients with genotype 1 patients and low HCV viral load (G1LVL) have high sustained virologic response rates (SVR) similar to genotype 2/3 patients. Recent data also have demonstrated that genotype 2/3 patients respond similarly with 24 weeks of therapy as historical 48-week treated controls.

No similar data exist for G1LVL patients. The objective of the current study was to compare the efficacy of 24 weeks of peginterferon alfa-2b/ribavirin (PegIntron/ribavirin/ P/R) with a historical control treated for 48 weeks with PegIntron plus a similar ribavirin dose (>10.6 mg/kg) (Manns, Lancet 2002).

Treatment-naïve G1LVL patients (≤2 million copies/mL) were treated for 24 weeks with PEG-Intron 1.5 µg/kg/week subcutaneously plus oral ribavirin 800-1400 mg/day based on body weight. Plasma HCV RNA was determined at treatment weeks 4, 12, 24 and follow-up weeks 12 and 24 using quantitative PCR assay (Taq-Man/sensitivity 29 IU/ml). Genotype was determined by sequencing the PCR product.

Results

· A total of 235 G1LVL patients were treated (237 enrolled).

· End of treatment (EOT) virologic response was 81% and SVR was 50% with 24 weeks treatment.

· The 48 week historical control had similar EOT of 74% but higher SVR of 71%. This difference was due to high virologic relapse rate after 24 weeks of therapy (37%) compared to historical control (4%).

· A subset of patients treated for 24 weeks, those who became HCV RNA negative at treatment week 4, had a similarly high SVR (89%) compared to the historical control (85%).

· In contrast, SVR was low (25%) and relapse high (75%) in those patients who first had an undetectable HCV RNA at week 12.

· Discontinuation (3%) and dose reductions (25%) for adverse events were lower than in the historical control (14%, 49%, respectively).

Conclusion

Overall, 24 week treatment with P/R in G1LVL patients achieves similar EOT response, but lower SVR compared to a 48-week treated historical control. However, for patients who become HCV RNA negative at week 4, treatment for 24 weeks has similar high efficacy with superior safety compared to 48 week therapy.

Saarland University Hospital, Homburg/Saar, Germany, Hospital Vall D'Hebron, Barcelona, Spain,
University Clinic of Vienna, Vienna, Austria , Ikem, Prague, Czech Republic, Hopital Saint LUC - UCL, Bruxelles, Belgium, Warsaw Medical University, Warsaw, Poland, St. Laszlo Hospital, Budapest, Hungary, Huddinge University Hospital, Stockholm, Sweden, Schering-Plough Research Institute, Kenilworth NJ, USA .

04/18/05

Reference
S Zeuzem and others. EFFICACY OF 6 MONTHS TREATMENT WITH PEG-INTERFERON ALFA-2B PLUS RIBAVIRIN (P/R) IN PATIENTS INFECTED WITH HEPATITIS C WITH GENOTYPE 1 OF LOW VIRAL LOAD (G1LVL). Abstract 625. 40^th EASL. April 13-17, 2005. Paris, France.

http://www.hivandhepatitis.com/2005icr/easl/docs/041805_f.html

2005

DOES THE CLINICAL OUTCOME OF HEPATITIS C INFECTION VARY WITH THE INFECTING HEPATITIS C VIRUS TYPE?

H.E. Harris¹, K.P. Eldridge¹, C-G. Teo², S. Harbour², M.E.B. Ramsay¹

¹Immunisation Department, Centre for Infections, Health Protection Agency, London, UK
²Sexually Transmitted And Blood-Borne Virus Laboratory, Centre for Infections, Health Protection Agency, London, UK

Introduction

It is not known whether differences in the natural history of hepatitis C virus (HCV) can be explained by differences in the infecting genotype.

Aim

The aim of this study was to describe the prevalent genotypes in a national cohort of patients who acquired HCV infection at a known date and to investigate whether there was any evidence to suggest that the natural history of their infections might vary with the infecting type.

Methods

Data on clinical outcomes were extracted from the HCV National Register and mortality data were taken from death certification. Sera were available for 749 cases who had been enrolled in the UK HCV National Register. HCV RNA-positive specimens were genotyped and HCV RNA-negative specimens were serotyped. Logistic regression analysis was used to investigate the effect of HCV type on viral clearance and histological stage of liver disease. 444 of the sera were found to carry HCV RNA. The most prevalent HCV types were 1 (52%), 3 (29%) and 2 (16%). Of the 305 specimens found to be HCV RNA-negative, it was possible to serotype 160 of them; serotypes 1 (58%), 3 (24%) and 2 (13%) were the most common. There was no evidence of any association between viral type and: mortality, signs and symptoms of liver disease or histological grade of liver disease. A significant association was observed between viral type and response to treatment, with type 1 infections being associated with poor response to treatment when compared to types 2 or 3 (P=0.003). Viral type was independently associated with spontaneous viral clearance, with type 1 being more likely to clear spontaneously than non-1 types (OR 0.50, 95% CI 0.30–0.84, P= 0.009). Viral type was also independently associated with histological stage of liver disease, with type 1 being associated with stage scores above the median when compared to non-1 types (OR 2.03; 95% CI 1.07-3.83; P=0.03).

Results

The results of this study suggest that HCV type 1 infection is more likely to be associated with spontaneous clearance but is clinically more aggressive than type non-1 infection when it persists.

http://www.hcvadvocate.org/news/reports/EASL_2005/April%2015.htm#April15_3

Nine of 10 Chronic Hepatitis C Patients Achieve a Cure 24 Weeks Post-treatment with High Dose Ribavirin Plus Standard Dose Peginterferon Alfa-2a (Pegasys)

By Ronald Baker, PhD

Ninety percent of genotype 1 patients with a high viral load enrolled in a pilot study in Sweden achieved undetectable HCV RNA 24 weeks post-treatment with a regimen of high dose ribavirin plus standard dose peginterferon alfa-2a (Pegasys). By standard definitions, this means they were cured. Results of the small pilot study appear in the current issue of Hepatology (February 2005).

	7 men, 3 women, with mean age of 51 participated (no African Americans, no cirrhotics);
	All 10 participants were genotype 1, high viral load;
	Patients coinfected with HIV or other diseases were excluded;
	After dose adjustments, mean daily ribavirin dose was 2,540 mg/day (1,600-4,000) at week 2 (the recommended ribavirin dose is rarely above 1,200 mg/day);
	Pegasys (peginterferon alfa-2a) dosing was standard: 180 microgram weekly;
	Side effects were severe, particularly anemia and hemolysis; all patients required erythropoietin, and two patients required 2 separate blood transfusions;
	Treatment duration was 48 weeks;
	At the 24-week post-treatment follow-up, 9 of 10 patients had undetectable HCV RNA.

Background

Ribavirin is an antiviral drug that is approved in the US and Europe for use in combination with interferon alfa for the treatment of chronic hepatitis C. The current standard of care in both the US and Europe is combination treatment with peginterferon alfa-2a (Pegasys) or 2b (Peg-Intron) plus ribavirin.

Although the mechanism of action of ribavirn with interferon is not yet completely understood, it is believed to act in synergy with interferon to contribute to significantly increasing (perhaps doubling) the sustained viral response (SVR) rate by preventing virological relapse.

While the effectiveness of antiviral therapy for chronic hepatitis C has improved, individuals with HCV genotype 1, especially those with a high viral load, still do not generally experience an SVR. The SVR rate for these individuals using the current standard of care (peginterferon alfa plus ribavirin) is about 40%.

Ribavirin Dosing

One of the most controversial issues in the management of chronic hepatitis C is the question of what is the optimal dose of ribavirin and whether higher doses of ribavirin produce more effective results than standard doses?

The current recommendation for HCV genotype 1 patients is combination treatment with once weekly peginterferon alfa plus two daily doses of ribavirin for 48 weeks. The current recommended daily dose of ribavirn depends on which brand of interferon alfa is used. In the US, in combination with Pegasys, the FDA-approved dose for ribavirin is 1,000 or 2,000 mg daily, when total body weight is less than 75 kilograms or more than 75 kilograms, respectively; when used with Peg-Intron, the FDA-approved daily dose for ribavirin is a fixed dose of 800 mg. To confuse things even further, the approved daily ribavirin dose in Europe is weight-based, with 800 mg recommended for individuals weighing less than 65 kilograms, 1000 mg for individuals weighing 65-85 kilograms, and 1200 mg for those weighing more than 85 kilograms.

The Swedish Pilot Study

In the current pilot study, the objective was to evaluate the standard dose of peginterferon alfa-2a plus a daily dose of ribavirin that was individualized and calculated from a pharmacokinetic formula based mainly on renal function. In order to reach the targeted concentration of ribavirin in the blood serum, the study participants needed a mean ribavirin dose of 2,540 mg/day (range (1,600-4,000 mg/day). This equals more than double the currently recommended daily ribavirin dose.

Inclusion/Exclusion Criteria

The inclusion criteria for the pilot study were: age >18 years, elevated alanine aminotransferase, positive anti-HCV antibody test, detectable serum HCV RNA, and a liver biopsy consistent with chronic HCV but without cirrhosis.

Patients with other forms of liver disease, active hepatitis A or hepatitis B infection, hepatocellular carcinoma, human immunodeficiency virus infection, anemia, a previous diagnosis of severe depression or other psychiatric disease, significant cardiac disease, renal disease, seizure disorders, severe retinopathy, or pregnancy were excluded from the study.

Adverse Effects

The main side effect was anemia, which was controlled with erythropoietin. Two patients required blood transfusions. However, only minor treatment interruptions occurred among the ten patients who were treated with doses of ribavirin substantially exceeding standard doses. One patient was withdrawn at week 24 because of a lack of viral response, and one patient at week 39 because of side effects, primarily interferon associated.

Conclusions

At follow-up (24 weeks post treatment), nine of ten patients had undetectable HCV RNA. The primary goal of this small pilot study was to determine feasibility and safety of the treatment, and not virological outcome. However, in this difficult-to-treat patient population with genotype 1 and a high viral load, nine of ten patients were cured by standard definitions, which seems to be a better response than that found in studies using standard ribavirin doses.

The authors conclude, “A high dose of ribavirin according to an individualized schedule is feasible but associated with more frequent and serious side effects such as anemia. The viral response merits further evaluation.”

Although the promising results of this small pilot study were striking, and seem to open up a new direction in experimentation with ribavirin dosing and its relationship to improved SVR rates, it’s hard to ignore the potentially deleterious safety issues that might be encountered by many patients using such high ribavirin doses.

As well, cost issues must be considered, not just for the peginterferon and for the high ribavirin dosing, but also for the erythropoietin and possibly blood transfusions. Still, a 90% SVR for genotype 1 patients with high viral loads! It’s a thrilling thought to contemplate!

02/11/05

Departments of Infectious Diseases, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden; Clinical Pharmacology, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden; Renal Medicine, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden.

Reference
K Lindahl, L Stahle, A Bruchfeld and R Schvarcz. High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology 41(2): 275-279. February 2005.

Budget Impact Analysis of 2 Different Methods of Evaluating Early Viral Response to Peginterferon Alfa-2b (Peg-Intron) Plus Ribavirin Therapy in Genotype 1 Patients

Genotype 1 patients with chronic hepatitis C are the least responsive to peginterferon and ribavirin therapy and therefore monitoring early virologic response (EVR) is an important tool for identifying non-responders quickly, permitting therapy discontinuation and avoiding side effects and costs.

The objective of the current study was to analyze the financial impact of two different measurement techniques for evaluating the EVR during peginterferon alfa-2b (Peg-Intron) plus ribavirin therapy and to compare the results with the full 48 week course of therapy in genotype 1 naive patients with chronic hepatitis C.

A financial impact model was developed to compare two different strategies of determining EVR and the resultant impact on treatment costs compared with standard 48 weeks course of therapy.

Strategy 1: peginterferon alfa-2b plus ribavirin for 12 weeks. Patients with a decline in HCV-RNA >2 logs continue therapy to complete 48 weeks.

Strategy 2: peginterferon alfa-2b plus ribavirin for 12 weeks. Patients with HCV Core Ag negative continue therapy to complete 48 weeks.

	EVR	PPV (EVR and SVR)
Strategy 1	74%	86%
Strategy 2	82%	84%

EVR was defined at week 12 as either a decline of >2 logs in HCV RNA levels tested with a quantitative HCV RNA assay (total 2 tests: baseline / week12) or undetectable HCV Core Ag at week 12 (1 HCV Core Ag test).

Clinical data was taken from multi-center trials [JP1] , while costs were taken from published literature based on the perspective of the Spanish Health Care System. The base-case scenario assumed that a potential study population of 85,000 people with genotype 1 would be eligible for treatment in Spain.

Results

For genotype 1 patients with chronic hepatitis C, testing EVR by HCV Core Ag was the most effective strategy resulting in 58,548 patients reaching SVR and an overall budget of US $1,338 million (US $22,858 per successfully treated patients).

Conversely, evaluating EVR by means of quantitative HCV-RNA resulted in 54,094 patients and an investment of US $1,276 million (US $23,589 per successfully treated patient). The incremental cost per successfully treated patient with strategy 2 versus strategy 1 therefore represents US $13,988.

Conclusion

The authors conclude, “Assessment of EVR, specifically by HCV Core Ag test, in genotype 1 chronic hepatitis C patients treated with peginterferon alfa-2b and ribavirin provides an accurate tool for identifying patients with SVR resulting in a lower overall cost. This strategy should be recommended in current clinical practice.”

12/03/04

Reference
M Buti and others. BUDGET IMPACT ANALYSIS OF TWO DIFFERENT METHODS OF EVALUATING EVR TO PEGINTERFERON ALFA-2B (PEGINTRON®) PLUS RIBAVIRIN (REBETOL) THERAPY IN GENOTYPE 1 NAIVE PATIENTS WITH CHRONIC HEPATITIS C. Abstract 427 (poster). October 29-November 2, 2004. Boston, MA.

http://www.hivandhepatitis.com/2004icr/aasld/docs/hcv/120304_a.html

Comparison of 2 Doses of Peginterferon Alfa-2b Plus Weight-based Ribavirin for Treatment-naïve Patients with Genotype 1 HCV

Patients who receive > 10.6 mg/kg of ribavirin plus 1.5 mg/kg of peginterferon alfa-2b (PEG Intron) have sustained virological response rates > 60% (Manns et al. Lancet, 2001). However, patients with HCV genotype 1 infection have not fared as well.

Even with optimum doses of PEG Intron and ribavirin, fewer than 50% of patients achieve a sustained response to treatment. This is a problem of increasing importance since 70% of U.S. patients with chronic hepatitis C have genotype 1 infection.

Patient Population and Study Design

104 previously untreated patients with genotype 1 infection were randomized to receive either either Group 1: PEG-Intron 1.5 mcg/kg weekly + ribavirin 12-15 mg/kg/day for 48 wk or Group 2: PEG-Intron 3.0 mcg/kg weekly + ribavirin 12-15 mg/kg/day for 24 wks then PEG-Intron 1.5 mcg/kg weekly + ribavirin 12-15 mg/kg/day for 24 wk.

Patients were stratified by the presence or absence of cirrhosis and study region. Treatment was discontinued in patients who had detectable HCV RNA after 24 weeks of therapy. Virological response was defined as absence of detectable HCV RNA by PCR.

Results

To date, 49 and 48 patients have been randomized to groups1 and 2 respectively. 70 patients have completed 12 weeks and 36 patients have completed 48 weeks of treatment.

Virologic response at week 12 was observed in 72% of patients in group 1 and 82% in group 2.

Virological response after 48 weeks of therapy was seen in 65% of patients in group1 and 75% in group 2.

19 patients (13 in group 1 and 6 in group 2) have discontinued therapy due to adverse events or noncompliance.

27% of patients in group 1 and 13% of patients in group 2 have had grade 3 or 4 adverse events. Patient enrollment and follow-up of these patients is ongoing.

Conclusions

The authors conclude, “High dose PEG-Interferon plus weight based ribavirin therapy is tolerated as well as standard doses of PEG-Interferon plus weight based ribavirin. However, there appears to be only a slight increase in efficacy after 12 and 48 weeks of therapy with the higher dose regimen.”

University of Washington, Seattle, WA; Pacific Northwest Hepatology Research Consortium.

12/10/04

Reference
P P Cox and others. COMPARISON OF 2 DOSES OF PEG-INTERFERON ALFA-2B PLUS WEIGHT BASED RIBAVIRIN FOR TREATMENT OF PREVIOUSLY UNTREATED PATIENTS WITH GENOTYPE 1 HCV INFECTION. Abstract 410 (poster). 55^th AASLD. October 29-November 2, 2004. Boston, MA.

http://www.hivandhepatitis.com/2004icr/aasld/docs/hcv/121004_b.html

Response to Treatment in Patients with HCV Genotype 5

By Marina Nunez, MD, PhD

While HCV genotypes 1, 2 and 3 are distributed worldwide, genotypes 4, 5 and 6 are relatively restricted to certain geographical regions. HCV-5 is mainly found in South Africa, but due to migratory movements, a few clusters of patients with this genotype are present in Europe.

Data on the effectiveness of treatment of chronic infection due to HCV-5 are scarce. Two reports were presented this year at EASL addressing this issue.

The first study, performed in France, retrospectively analyzed 82 subjects treated for 48 weeks with either standard interferon (IFN) (N= 28) or pegylated IFN (N= 54), both combined with RBV [1]. The dose of RBV was of 800 mg/day for 35 individuals, and 1,000-1,200 mg/day for the remaining 47.

In an intent-to-treat analysis, early virological response (EVR), end-of-treatment response, and sustained virological response (SVR) were achieved in 83%, 82%, and 61% of patients, respectively.

The second study came from Belgium and evaluated a lower number of patients (N= 21) [2]. They had been treated within a randomized study which compared pegylated IFN versus induction-maintenance treatment with standard IFN, both along with 1,000-1,200 mg/day of RBV for 48 weeks.

In an intent-to-treat analysis, 40% of subjects in the standard IFN group, and 55% in the pegylated IFN group achieved SVR.

A subset of HCV-1-infected patients, matched for several relevant factors, was selected from the database of the study to be compared with those with HCV genotype 5. The SVR in this subjects infected by HCV-1 was of 20% in the standard IFN arm, and of 55% in the pegylated IFN arm.

Therefore, response to pegylated IFN seems comparable in patients with HCV genotype 1 and 5 according to this study.

04/25/05

Reference

1. C Bonny and others. Efficacy of interferon (standard or pegylated) plus ribavirin in naïve patients with hepatitis C virus genotype 5. A French national study. Abstract 549. 40th EASL. April 13-17, 2005. Paris, France.

2. F D’heygere and others. Patients infected with HCV-5 showed no difference in response rates as compared to patients with HCV-1: results from the Belgian randomized trial for naïve and relapsers (BERNAR-1). Abstract 558. 40th EASL. April 13-17, 2005. Paris, France.

Janis