Interferon-based therapy induces changes in viral dynamics in chronic hepatitis C (CHC) patients. The aim of this study was to assess early hepatitis C virus (HCV)-RNA changes and evaluate its predictive value to achieve sustained viral response (SVR) in patients with CHC treated with peginterferon alfa-2b (Peg-Intron) weekly plus ribavirin daily for 48 weeks.
HCV-RNA was measured at baseline, 48 h, 4, 12, 24 and 48 weeks of treatment and 24 weeks after treatment.
Results
Eighteen HCV genotype 1 patients were included (13 male, five female) with a mean age of 44.4+/-11.9 years.
Nine patients achieved SVR (50%).
Viral decline occurred as early as 48 h; the magnitude of decline was statistically different between both groups (P<0.01).
Responders had a >/=1 log(10) drop in HCV-RNA at 48 h (positive predictive value (PPV) of 89% to achieve SVR) that persisted at week 4.
By week 12, serum HCV-RNA was undetectable (PPV 100%).
Conclusions
The authors conclude, “Our data indicate that peginterferon alpha-2b plus ribavirin treatment produces significant changes in HCV dynamics that can be detected as early as 48 h after the first dose of peginterferon alfa-2b and that these changes are useful in predicting response to therapy in CHC patients.”
Departments of Gastroenterology and Infectology, Instituto Nacional de Ciencias Medicas y Nutricion 'Salvador Zubiran', Mexico City, Mexico.
02/16/05
Reference
J F
Gallegos-Orozco and others. Early hepatitis C virus changes and
sustained response in patients with chronic hepatitis C treated with
peginterferon alpha-2b and ribavirin. Liver International 25(1):
91-95. February 2005
HCV Patients Whose ALT Levels Are Less Than Twice the Upper
Limit of Normal After Interferon Therapy Have Decreased Risk of Liver Cancer
In this study, the incidence of hepatocellular carcinoma/HCC (liver cancer) in C-viral chronic hepatitis (CH) and liver cirrhosis (LC) patients after interferon (IFN) therapy was evaluated according to alanine aminotransferase (ALT) levels.
Two hundred sixty-nine patients with C-viral CH and LC were treated with natural IFN-alpha. The efficacy of IFN therapy was evaluated based on virologic response and ALT levels in the following groups: virologic-sustained responders (VSR); biochemical-sustained responders (BSR); partial responders (PR), which consisted of BSR patients whose serum ALT levels later relapsed; non-responders (NR)1, which included patients with serum ALT levels that were usually less than 80 IU/l; and NR2, NR with ALT levels persistently more than 80 IU/l.
Results
Of the 269 patients, 22 (8.2%) developed HCC after IFN therapy. The incidence of HCC (%/patient/year) was 0.78%, 0%, 0%, 0.17%, 4.68% in VSR, BR, PR, NR1, NR2, respectively.
Multivariate analysis revealed that an increase in ALT levels to more than 80 IU/l is an important risk factor for the occurrence of HCC. [emphasis added—Ed].
Conclusions
The authors write, “We concluded that the patients with ALT levels less than twice the upper limit of normal after IFN therapy have a reduced risk of progression to HCC from C-viral chronic liver disease.”
Division of
Gastroenterology and Hepatology, Department of Medicine, Nihon University
School of Medicine, Itabashi-ku, Tokyo, Japan.
02/16/05
Reference
M Moriyama and
others. Decreased risk of hepatocellular carcinoma in patients with chronic
hepatitis C whose serum alanine aminotransferase levels became less than
twice the upper limit of normal following interferon therapy.
Liver International
2005 25(1): 85-90. February 2005
http://www.hivandhepatitis.com/hep_c/news/2005/021605_b.html
Peginterferon Alfa-2a (Pegasys) for Hepatitis C Recurrence
After Liver Transplantation
There is currently no effective treatment for recurrent hepatitis C after orthotopic liver transplantation (OLT). Researchers in the Pegasys Transplant Study Group performed two randomized, controlled trials - a prophylaxis trial and a treatment trial - to evaluate the safety and efficacy of peginterferon alfa-2a (Pegasys) in patients who had undergone OLT.
The prophylaxis trial enrolled 54 patients within 3 weeks after OLT, and the treatment trial enrolled 67 patients 6 to 60 months after OLT.
In each trial, patients were randomized to treatment with once weekly injections of 180 microgram peginterferon alfa-2a or no antiviral treatment for 48 weeks and were followed up for 24 weeks thereafter.
Results
Peginterferon alfa-2a treated patients had significantly lower hepatitis C virus RNA levels and more favorable changes in hepatic histological features compared with untreated controls.
However, only 2 treated patients in the prophylaxis trial (8%) and 3 in the treatment trial (12%) achieved a sustained virological response (SVR).
In the prophylaxis trial, 8 patients (31%) in the peginterferon alfa-2a group and 9 (32%) in the untreated group were withdrawn prematurely; whereas in the treatment trial, 10 patients (30%) in the peginterferon alfa-2a group and 6 (19%) in the untreated group were withdrawn prematurely.
The incidence of acute rejection was similar in the treated and untreated groups in both the prophylaxis (12% vs. 21%; P = .5) and treatment (12% vs. 0%; P = .1) trials.
In conclusion, the authors write, “Peginterferon alfa-2a treatment for 48 weeks is safe and tolerable and offers some efficacy in the post-OLT setting. Randomized controlled studies are needed to establish the efficacy of pegylated interferon and ribavirin in patients who have undergone OLT.”
Commentary
It seems likely that the SVR rate in these patients would have increased significantly if Pegasys had been offered in combination with ribavirin. There is no explanation of why the standard of care for treatment of HCV monoinfection--peginterferon + ribavirin—was not offered to the patients.
02/14/05
Reference
N Chalasani and others (Pegasys Transplant Study Group).
Peginterferon alfa-2a for hepatitis C after liver transplantation: Two
randomized, controlled trials. Hepatology 41(2): 289-298.
February 2005
http://www.hivandhepatitis.com/hep_c/news/2005/021405_a.html
A 65% SVR Rate Reported in Liver Transplant Patients Treated
with Standard Interferon Alfa-2b or Peginterferon Alfa-2b (Peg-Intron) in
Combination with Ribavirin
HCV infection is the leading indication for liver transplantation worldwide. Although short-term patient and graft survival for HCV patients is similar to other indications, long-term results are inferior. Here Canadian researchers report the results of treatment for recurrent HCV infection at the University of Toronto medical center.
Sixty-one patients with HCV recurrence (75% genotype 1) were treated between August 1999 and December 2003 with standard interferon afa-2b (Intron A) or pegylated interferon alfa-2b (Peg-Intron) in combination with ribavirin (400-1000mg p.o. daily) for 3 to 38 months. Serum aminotransferases, HCV RNA levels and histology were followed.
Results
Three patients discontinued therapy before 3 months and were excluded from analysis. Of the 58 patients treated for at least 6 months, 31/58 (53%) lost HCV RNA. Of these 58 patients, 23 completed treatments, while 35 are still on treatment.
15/23 (65%) remained HCV RNA negative more than six months off treatment (SVR). All patients who became HCV RNA negative normalized their serum aminotransferases. On follow-up biopsy of patients completed treatment, which was available in 15/23, 9/15 (60%) demonstrated histological improvement.
Of the 35 pts continuing on therapy for at least 6 months, 15/35 (43%) have now become HCV RNA negative.
The virologic response rate was 20/28 (71%) in patients on neoral versus 11/30 (37%) in patients on tacrolimus (p= 0.025). More neoral patients achieved an SVR (10/12) than those treated with tacrolimus (5/11) although this did not reach statistical significance (p= 0.09).
Of treated patients; the incidence of biopsy proven rejection was 7%. Growth factors were used in 48% of the patients.
Conclusions
In conclusion, the authors write, “Combination therapy can be used safely and effectively for recurrent HCV, although dose reduction/discontinuation or requirements for growth factors are common. Interestingly the response rate in patients treated with neoral is better than in those patients treated with tacrolimus compatible with a recent report suggesting that neoral inhibits HCV viral replication in vitro.”
“The response rate of 65% is superior to previously reported results, which may reflect longer treatment, use of growth factors and may be [in part due to use of ] neoral as primary immunosuppression.”
University Health Network, University of Toronto., Toronto, ON, Canada.
02/14/05
Reference
A J Al Alwan
and others. SUSTAINED VIROLOGICAL RESPONSE OF 65% IN PATIENTS TREATED WITH
COMBINATION ANTIVIRAL THERAPY FOR RECURRENT HCV FOLLOWING LIVER
TRANSPLANTATION. Abstract 448 (poster). 55th AASLD.
October 29- November 2, 2004. Boston, MA
http://www.hivandhepatitis.com/hep_c/news/2005/021405_b.html
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).
Following are selected highlights of the study and the 72-week findings:
 |
7 men, 3 women, with mean age of 51 participated (no African Americans, no cirrhotics); |
|
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All 10 participants were genotype 1, high viral load; |
|
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Patients coinfected with HIV or other diseases were excluded; |
|
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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); |
|
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Pegasys (peginterferon alfa-2a) dosing was standard: 180 microgram weekly; |
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Side effects were severe, particularly anemia and hemolysis; all patients required erythropoietin, and two patients required 2 separate blood transfusions; |
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Treatment duration was 48 weeks; |
|
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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.
http://www.hivandhepatitis.com/hep_c/news/2005/021105_a.html