Genotype Research 2004

Genotype Research 2004

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2006 Research

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2003 Articles 2002-2001 Articles


	Infection with Hepatitis C Virus Genotype 4 in the United States
	Cross-Genotype Immunity to Hepatitis C Virus.
	HCV Genotype 4
	Treatment for Chronic Hepatitis C: Updated Swedish Consensus Guidelines
	HCV Patients with Genotype 1b May Show a Sustained Response and ALT Improvement After Prolonged Re-treatment with Interferon Alfa
	Efficacy of Early Retreatment with Interferon Beta for Relapse in Patients with Chronic Hepatitis C Genotype Ib
	Is a 48-week Course of Treatment with Peginterferon Plus Ribavirin Too Short to Maximize a Sustained Viral Response Among Patients with Hepatitis C virus Genotype 1?
	Pegasys plus Copegus: Newly Published Data Reports Highest Overall Sustained Virological Response Ever - 63%- All Genotypes Listed

Infection with Hepatitis C Virus Genotype 4 in the United States

	Journal of Clinical Gastroenterology 2004; 38(1):68-71 Andre C. Lyra, MD; Sunil Ramrakhiani, MD; Bruce R. Bacon, MD; Adrian M. Di Bisceglie, MD From the Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University, St. Louis, MO. Background: Hepatitis C virus genotype differences seem to be of considerable clinical significance because they affect responses to antiviral therapy. HCV genotype 4 is rare in the United Sates and there are few published data regarding response to therapy in patients with HCV genotype 4 infection. Objectives: To assess epidemiologic factors associated with HCV genotype 4 infection in United States and to describe the response rate to therapy with the combination of alpha interferon and ribavirin. Methods: All hepatologists in our Division were asked for information about patients they had treated with HCV genotype 4. In addition, we searched the computer database from Saint Louis University Hospital in the last 40 months (1999 to 2002). Twenty HCV genotype 4 patients were identified. A retrospective chart review was performed to collect information about their demographics, risk factors for acquisition of infection, baseline laboratory studies and response to antiviral therapy. Results: A risk factor for exposure to HCV was noted in 14 cases (70%); 12 patients had a history of illicit drug use, whereas a history of blood transfusion was detected in three cases; 1 patient had both risk factors. Only 4 of 20 individuals had fibrosis stage 3 or 4 on liver biopsy. Seventeen patients were treated, 14 of whom completed therapy; 10 patients were sustained responders. Conclusions: As with other HCV genotypes, most patients with HCV genotype 4 in the United States acquire the infection through intravenous drug use, liver disease is often mild to moderate in severity and 59% of our patients had a sustained virologic response after combination therapy with interferon and ribavirin. PATIENTS and METHODS Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States, with the prevalence of anti-HCV in the general population of the United States being 1.8%. 1 This corresponds to an estimated 3.9 million individuals having been infected with HCV. The striking genetic heterogeneity of the RNA genome of HCV is well recognized. This genetic diversity extends to include 6 major genotypes, over 80 subtypes and minor variants referred to as "quasispecies". 2 The occurrence of HCV genotypes tends to vary with geographic region. Thus, HCV genotype 1 accounts for approximately two-thirds of HCV-infected individuals in the United States. The next most common is genotype 2 (14%), followed by genotype 3 (6-8%). 3, 4 In one study the prevalence of HCV genotype 4 infection among 438 patients from 10 tertiary referral centers across the United States was 1.1%. 3 HCV genotype differences seem to be of considerable clinical significance because they affect responses to antiviral therapy. In particular, it is well known that patients infected with HCV genotypes 2 and 3 respond much better to antiviral therapy than those infected with genotype 1. 5 HCV genotype 4 appears to be prevalent in the Middle East and Central Africa, where it has been reported to be frequently associated with cirrhosis and a poor response to interferon. 6, 7 There are few published data from the United States regarding response to therapy in patients with HCV genotype 4 infection. The aim of the present study is to assess epidemiologic factors associated with HCV genotype 4 infection in the United States and to determine the response to therapy with the combination of alpha interferon and ribavirin.PATIENTS AND METHODS We retrospectively studied patients with HCV genotype 4 infection who were referred to Saint Louis University. All hepatologists in our Division were asked for information about patients they had treated with HCV genotype 4. In addition, we searched the computer database from Saint Louis University Hospital in the last 40 months (1999 to 2002). There were 1250 tests for HCV genotyping that were performed during this period; 8 patients (0.6%) were found to have genotype 4. In total, we were able to identify 20 patients who were infected with HCV genotype 4. All had anti-HCV and HCV RNA detectable in serum. A retrospective chart review was performed to collect information about their demographics, risk factors for acquisition of infection, baseline laboratory studies including liver biopsy results, and response to antiviral therapy. Serum HCV RNA levels and HCV genotyping assays were performed by 2 commercial clinical laboratories. HCV RNA levels were determined in most cases using the Amplicor HCV version 1.0 kit from Roche (Branchburg, NJ), however the results are not comparable between the 2 laboratories. In 12 cases, the HCV was genotyped by sequencing and phylogenetic analysis of PCR products from the NS5B region; and in 8 cases HCV genotyping was performed by restriction fragment length polymorphisms (RFLP) analysis of 5` untranslated region (5`UTR). Sixteen patients were treated with interferon and ribavirin in combination at standard doses (alpha interferon 3 million units 3 times a week and ribavirin 1,000 to 1,200 mg per day based on body weight). One of these 16 patients was a previous non-responder to interferon mono-therapy. Two patients were treated with pegylated interferon and ribavirin. The other 2 patients were not treated. HCV RNA was assessed at baseline and at 3, 6, 12, and 18 months after starting treatment. Patients who still had detectable HCV RNA by PCR at 6 months were defined as non-responders and their therapy was stopped. Patients who had undetectable HCV RNA by PCR at 6 months were treated for an additional 6 months. Sustained biochemical and virologic response was defined as normal ALT and negative HCV RNA 6 months after therapy was stopped. RESULTS The baseline demographics, liver biopsy, and laboratory data from these patients are summarized: risk factors—55% IDU (n=11), cocaine snorting 10% (n=2), 30% (n=6) >1 million copies/ml; mean ALT 95 U/L (range 15-202); stage of fibrosis—11 stage 2, 5 stage 1, 2 stage 3, 2 stage 4. Fourteen patients were white, most of them born in the United States. Four patients were African American, 1 was an Egyptian who had immigrated to the US approximately 30 years ago, and 1 was a black woman from Zaire who had just immigrated to the United States. They were all adults and half were men. A risk factor for exposure to HCV was noted in 14 cases (70%); a history of illicit drug abuse including intravenous drug use and snorting cocaine was obtained from 12 patients, whereas a history of blood transfusion was detected in 3 cases; 1 patient had both illicit drug use and blood transfusion as risk factors. In the patient of Egyptian nationality, the patient from Zaire, and in 4 other patients, no source of HCV infection could be identified. HCV RNA was detectable in serum of all cases, but because 2 different laboratories performed the assays mean values could not be calculated. The baseline HCV RNA was above 1 million copies per ml in 6 patients. Most of the patients had mild to moderate liver disease on biopsy and only 4 individuals had bridging fibrosis or cirrhosis present. Interestingly, one of these patients with cirrhosis was the subject of Egyptian nationality. He has since developed hepatocellular carcinoma. Thirteen patients have completed 6 to 12 months of therapy. An additional patient completed 8 months of treatment and then discontinued therapy because of side effects. Two patients discontinued therapy a few weeks after starting due to adverse reactions, whereas 1 patient was lost to follow-up. Two patients were not treated and another is still on the second month of treatment with pegylated interferon and ribavirin. Seven of the 14 individuals who completed treatment (50%) had undetectable HCV RNA at 3 months of therapy. Ten of the 14 patients (71%) are sustained responders whereas 4 were non-responders (29%). When excluding from analysis the patient who is still on the second month of therapy, overall 10 of 17 treated patients (59%) had a sustained virologic response. Interestingly, the patient who was treated for only 8 months was a sustained responder, and 1 patient with cirrhosis at liver biopsy who was an African American also had a sustained response after using the combination of pegylated interferon and ribavirin. The subject who was re-treated with combination therapy was a sustained responder also. Sustained responders frequently had baseline serum HCV RNA levels below 1 million copies/ml and negative HCV RNA by qualitative PCR at 3 months of therapy. In addition, 8 out of 10 sustained responders had hepatic stage of fibrosis 1 or 2. On the other hand, 3 out of 4 non-responders had baseline serum HCV RNA levels higher than 1 million copies/ml and all 4 had detectable HCV RNA at 3 months of therapy. Of note, the patient of Egyptian nationality was a non-responder. DISCUSSION We describe patients infected with HCV genotype 4 who seem to be different from those in countries from the Middle East where this genotype is prevalent. Thus, most of our patients were white, born in the United States and 12 of 20 (60%) appeared to have acquired HCV through illicit drug abuse, including intravenous drug use and snorting cocaine. Reports from Western European countries have also encountered a high rate of HCV transmission through intravenous drug use in subjects with HCV genotype 4. Therefore, in a study from Spain 10 of 11 individuals found to be infected with this HCV genotype were intravenous drug users. 8 In French populations, 36% to 65% of HCV genotype 4 infections have occurred through intravenous drug abuse. 9, 10 On the other hand, in a study from Kuwait where there was a high proportion of subjects of Egyptian nationality, none of the patients was an intravenous drug user. 11 In addition, most patients in this small cohort had mild to moderate liver disease and only 4 had bridging fibrosis or cirrhosis present. This is also in contrast to studies from the Middle East and Africa where HCV genotype 4 is frequently associated with cirrhosis. Interestingly, the only patient of Egyptian nationality from our study had no identifiable source of the HCV infection and had cirrhosis at liver biopsy. Our patients had a remarkably high rate of response to antiviral therapy with the combination of interferon and ribavirin. Thus, 10 of 14 (71%) individuals who completed approximately 12 months of therapy had a sustained virologic response. Interestingly, 4 of these 9 responders had normal ALT levels before treatment, however, these are baseline levels and we are not aware of other ALT measurements in the 6 months preceding the start of therapy. On the other hand, in the study from Kuwait, the sustained virologic response rate of individuals with HCV genotype 4 who completed combination therapy was 42%, whereas in a study from Egypt it was 21%. 11, 12 Other previous studies of antiviral treatment have also shown a poor response rate with interferon therapy alone. 6, 13 The reasons for the better response to therapy in our patients are unclear but might be related to the differences in populations mentioned previously. Therefore, our patients are from a different ethnic background and appear to have had a different source of HCV infection in comparison to patients from the Middle East. Differences in ethnicity have been described to interfere with response to therapy for hepatitis C viral infection. Thus, African Americans seem to have a worse overall response to interferon treatment than whites. 14 Moreover, most of our patients had mild to moderate histologic liver disease, low HCV viral load before treatment, and one of the sustained responders was treated with pegylated interferon, which has been reported to improve the response rate to combination therapy. Possibly, the association of all these factors favored the response to treatment. It is also important to consider the possibility of patient selection bias secondary to the small number of subjects. Nevertheless, it should be noted that HCV genotype 4 is rare in the United States with the prevalence being reported to be as low as 1.1% among subjects who are referred to tertiary centers. In our center, the incidence rate seemed to be around 0.6% in a 3-year period. Therefore, the few cases that are described here probably reflect reasonably well the patients infected with HCV genotype 4 who are referred to our center. In conclusion, we report 20 patients who were infected with HCV genotype 4 and were evaluated in Saint Louis University. Most of these individuals acquired the infection through intravenous drug use, had mild to moderate histologic liver disease, and had a sustained virologic response after combination therapy with interferon and ribavirin. REFERENCES Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999; 341:556-562. Farci P, Purcell RH. Clinical significance of hepatitis C virus genotypes and quasispecies. Semin Liver Dis. 2000; 20:103-126. Lau JY, Davis GL, Prescott LE, et al. Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Ann Intern Med. 1996; 124:868-876. Blatt LM, Mutchnick MG, Tong MJ, et al. Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States. J Viral Hepat. 2000; 7:196-202. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998; 19:1485-1492. el-Zayadi A, Simmonds P, Dabbous H, et al. Response to interferon-alpha of Egyptian patients infected with hepatitis C virus genotype 4. J Viral Hepat. 1996; 3:261-264. Xu LZ, Larzul D, Delaporte E, et al. Hepatitis C virus genotype 4 is highly prevalent in central Africa (Gabon). J Gen Virol. 1994; 75:2393-2398. Sanchez-Quijano A, Abad MA, Torronteras R, et al. Unexpected high prevalence of hepatitis C virus genotype 4 in Southern Spain. J Hepatol. 1997; 27:25-29. Zylberberg H, Chaix ML, Brechot C. Infection with hepatitis C virus genotype 4 is associated with a poor response to interferon-alpha. Ann Intern Med. 2000; 16:845-846. Remy AJ, Verdier E, Perney P, et al. Route of infection, liver histology and response to interferon in patients with chronic hepatitis caused by genotype 4 HCV infection in a Western country. J Hepatol. 1998; 29:169. Koshy A, Marcellin P, Martinot M, et al. Improved response to ribavirin interferon combination compared with interferon alone in patients with type 4 chronic hepatitis C without cirrhosis. Liver. 2000; 20:335-339. el-Zayadi A, Selim O, Haddad S, et al. Combination treatment of interferon alpha-2b and ribavirin in comparison to interferon monotherapy in treatment of chronic hepatitis C genotype 4 patients. Ital J Gastroenterol Hepatol. 1999; 31:472-475. al-Faleh FZ, Sbeih F, al-Karawi M, et al. Treatment of chronic hepatitis C genotype 4 with alpha-interferon in Saudi Arabia: a multicenter study. Hepatogastroenterology. 1998; 45:488-491. Howell C, Jeffers L, Hoofnagle JH. Hepatitis C in African Americans: summary of a workshop. Gastroenterology. 2000; 119:1385-1396.

www.natap.org

Virol. 2004 Feb 1; 78(3): 1575-1581.

Cross-Genotype Immunity to Hepatitis C Virus.

Lanford RE, Guerra B, Chavez D, Bigger C, Brasky KM, Wang XH, Ray SC, Thomas
DL.

Departments of Virology and Immunology. Comparative Medicine, Southwest
National Primate Research Center, Southwest Foundation for Biomedical
Research, San Antonio, Texas 78227. Department of Medicine, Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205.

Recent studies in humans and chimpanzees suggest that immunity can be
induced to diminish the incidence of chronic hepatitis C virus (HCV)
infection. However, the immunity that promotes viral recovery is poorly
understood, and whether the breadth of this adaptive immunity is sufficient
to overcome the substantial intergenotype antigenic diversity represents a
final obstacle to demonstrating the feasibility of vaccine development. Here
we demonstrate that recovery from a genotype 1 HCV infection protects
chimpanzees against infection with representatives of other genotypes that
exhibit up to 30% divergence at the amino acid level, including challenges
with genotype 4, a mixture of genotypes 2 and 3, and a complex inoculum
containing genotypes 1, 2, 3, and 4. In each instance, the level and
duration of viremia were markedly reduced in comparison to the primary
infection in the same animal. The data indicate that epitopes conserved
between genotypes must play an essential role in immunity. The inocula used
in the rechallenge studies induced typical primary infection profiles in
naive chimpanzees. Rechallenge infections were associated with rapid
increases in the intrahepatic transcripts of interferon-stimulated genes,
even in animals exhibiting apparent sterilizing immunity. Protective
immunity was often associated with an early increase in gamma interferon
transcripts in the liver and increases in intrahepatic transcripts of Mig, a
T-cell chemokine that is a gamma interferon response gene. These studies are
the first to show that cross-genotype immunity can be induced to HCV,
demonstrating the feasibility of developing a vaccine protective against all
HCV strains.

PMID: 14722311 [PubMed - as supplied by publisher

HCV Genotype 4

http://www.hcvadvocate.org/news/newsRev/2004/HJR-1.2.html#1

HCV genotype is an important consideration because it affects how well individuals respond to therapy. Genotype 1 is most common in the U.S.—accounting for about two-thirds of cases—and is most difficult to treat. The next two most common genotypes, 2 and 3, respond more rapidly to treatment. Relatively little research has been done on genotype 4, which accounts for the majority of cases in the Middle East and parts of Africa, but is rare in North America.

In the January 2004 issue of the Journal of Clinical Gastroenterology, André Lyra, MD, and colleagues reported on the epidemiology of genotype 4 HCV in the U.S. The researchers asked hepatologists for information about genotype 4 patients they had treated and searched the St. Louis University Hospital database for cases seen between 1999 and 2002. Medical charts were reviewed for patient demographics, HCV risk factors, and response to therapy. In this sample, 20 individuals with genotype 4 were identified; most had a history of injection drug use. Of the 17 patients treated with interferon plus ribavirin (14 of whom completed therapy), 10 (59%) achieved a sustained virological response (SVR).

This study confirms that HCV genotype 4 is uncommon in the U.S., but—in contrast to some previous research—indicates that this genotype causes mild to moderate liver disease and responds well to therapy. At the American Association for the Study of Liver Diseases (AASLD) conference this past October, two research teams reported genotype 4 SVRs of 61% (using Peg-Intron plus ribavirin) and 50% (using Pegasys plus ribavirin). Together, these results suggest that genotype 4 HCV may be easier to treat than previously believed.

Treatment for Chronic Hepatitis C: Updated Swedish Consensus Guidelines

In 1999 a Swedish national expert panel published recommendations for the treatment of chronic hepatitis C (HCV) infection. Recently, pegylated interferon (peg-IFN) products have been introduced, and an increased knowledge concerning treatment of acute HCV and HCV-human immunodeficiency virus (HIV) coinfection has been gained.

As a result of this, an update of the Swedish recommendations was developed following an expert meeting in October 2002. The panel now recommends the use of peg-IFN together with ribavirin as the standard treatment.

Following are the primary recommendations for various patient groups:

Owing to the excellent response rates in HCV genotype 2 and 3 infections, these patients can be treated for 24 weeks without preceding liver biopsy;

For patients with genotype 1 infection (with a slightly below 50% sustained response rate after 48 weeks treatment) and only mild histological disease, treatment can be postponed until future better treatment options become available;

In patients who fail to achieve a 99% reduction (2 log drop) in viral titre after 12 weeks of treatment, discontinuation of therapy is recommended;

Patients previously treated with IFN monotherapy and not having achieved a sustained virological response are recommended the same combination treatment as treatment-naive patients;

IFN monotherapy is recommended in patients with acute hepatitis C;

For children with chronic HCV infection, combination treatment is mainly recommended in clinical trials;

For HCV-HIV coinfected patients, combination treatment is recommended and preferably given when blood CD4 counts are above 350/ml and before antiretroviral treatment (ART) is needed;

Concurrent ART or prominent liver fibrosis requires frequent monitoring because of the increased risk for mitochondrial toxicity and liver failure.

Department of Infectious Diseases, Sahlgrenska University Hospital/Ostra, Goteborg, Sweden.

01/12/04

Reference
R Wejstal and others. Chronic hepatitis C: updated Swedish consensus. Scandanavian Journal of Infectious Diseases 35(8): 445-51. December 2003.

HCV Patients with Genotype 1b May Show a Sustained Response and ALT Improvement After Prolonged Re-treatment with Interferon Alfa

The aim of the current pilot study was to investigate the efficacy of prolonged interferon alfa (IFN) retreatment for 3 years in chronic hepatitis C patients with high viral load and IFN treatment-resistant genotype 1b.

The study was conducted in 12 patients, not HCV RNA-negative after completion of initial treatment. Retreatment consisted of administration of 6 million international units (MIU) of natural interferon-alfa two or three times a week for 3 years.

Results

One patient withdrew for personal reasons. All other 11 patients completed treatment without any serious adverse reactions and were followed for 3 years.

Of the patients, 4 (36%) showed a sustained virological response, 5 (45%) showed a biochemical response, and 2 (18%) relapsed after retreatment. All patients with a sustained response had a transient response to initial therapy. Patients showing a sustained response tested negative for HCV RNA within the first 6 months of retreatment.

The authors conclude, “After prolonged IFN retreatment, a significant number of patients showed a sustained response for the first time and long-term improvement in ALT level.”

Department of Internal Medicine, Shin-Kokura Hospital, Kitakyushu, Japan

02/06/04

Reference
H Nomura and others. Pilot study of prolonged interferon-alpha retreatment in chronic hepatitis C patients with genotype 1b. Hepatology Research 27(4): 266-271. December 2003.

Efficacy of Early Retreatment with Interferon Beta for Relapse in Patients with Chronic Hepatitis C Genotype Ib

Interferon (IFN) retreatment for hepatitis C virus (HCV) relapsers has been effective under some conditions. Japanese researchers conducted a randomized, controlled trial of IFN beta retreatment for HCV relapsers after failure of IFN alfa.

The investigators gave IFN beta 6MIU therapy to 43 patients who had relapse of HCV after 24 weeks of IFN alfa monotherapy.

The 43 patients were randomly assigned to two groups: Group A started retreatment within 4 weeks after relapse; and Group B started retreatment 24 weeks or more after relapse.

Results

Nine patients showed sustained virological response (SR) to the retreatment. All of these patients were in a low viral load subgroup. The SR rate in Group A (8/22, 36%) was significantly higher than in Group B (1/21, 5%) (P=0.0128).

Among patients with lower viral load, the SR rate in Group A (8/10, 80%) was also significantly higher than in Group B (1/8, 13%) (P=0.0076).

The authors conclude, “The retreatment with IFN beta is effective for patients with HCV low viral load, and the sooner after the relapse the retreatment is started, the better the clinical results will be.”

Department of Internal Medicine, Shin-Kokura Hospital, 1-3-1 Kanada, Kokurakitaku, 803-8505, Kita-Kyushu, Japan.

02/04/04

Reference
H Nomura and others. Efficacy of early retreatment with interferon beta for relapse in patients with genotype Ib chronic hepatitis C. Hepatology Research 28(1): 36-40. January 2004.

Is a 48-week Course of Treatment with Peginterferon Plus Ribavirin Too Short to Maximize a Sustained Viral Response Among Patients with Hepatitis C virus Genotype 1?

Hepatitis C virus (HCV) is a major cause of mortality and morbidity and has infected 2.7 million individuals in the United States alone. Although there have been major advances in therapy for infection with HCV, patients infected with genotype 1 strains have a much poorer prognosis for clearing the virus than do patients infected with genotype non-1 strains, even if they receive treatment with high-dose pegylated interferon (IFN) plus ribavirin.

Therapy with pegylated IFN plus ribavirin is associated with a response rate of ~ 50% among patients infected with HCV genotype 1; also, the regimen is expensive and is associated with a number of predictable toxicities. Flu-like syndrome, depression, and alterations in hemoglobin levels and white blood cell (WBC) counts are common adverse events that occur with prolonged therapy with this regimen.

Consequently, it is not trivial to suggest the use of longer durations of therapy with this regimen, because of both the cost of therapy and the attendant toxicities. The response rate among patients infected with HCV of genotype non-1 is ~ 80%. It is important to attempt to improve the response rates among patients infected with genotype 1, so as to obtain approximately the same response rate as that observed among patients not infected with genotype 1, given the severe long-term sequelae attendant to continued rounds of replication of HCV.

In the current study, researchers present an analysis of a large trial of pegylated IFN plus ribavirin. The results of this trial have been presented elsewhere [Manns and others. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358: 958-965].

The objective of the study was to develop models and to examine the effect of duration of therapeutic response on outcome. The central idea of these analyses is that the major benefit of antiviral therapy can be seen through its effect on the virus load.

The investigators wanted to determine whether the current state-of-the-art 48-week duration of pegylated IFN plus ribavirin therapy is optimal for patients infected with HCV of genotype 1.

It was thought that there may be an association between the duration of therapeutic response during drug therapy (i.e., having an undetectable HCV load in serum for a specific number of weeks continuously) and the probability of attaining a long-term response after discontinuation of therapy.

A model predicting SVR was generated; it included the following covariates: duration of continuous non-detectability of an HCV load in serum, estimated creatinine clearance, and whether the isolate was of genotype 1.

The validation model demonstrated positive and negative predictive values as well as sensitivity and specificity exceeding 90%.

The model predicted that patients infected with HCV genotype 1 require continuous non-detectability of virus load in serum for 36 and 32 weeks, to attain 90% and 80% probabilities, respectively, of a SVR.

The average time to clear serum of genotype-1 virus was 30.4 weeks, which indicates that the 48-week duration of therapy provided a suboptimal probability of a SVR.

Conclusions

For some patients, suboptimal therapy with pegylated IFN plus ribavirin may need to be of longer duration than the currently recommended 48 weeks. If the hypothesis can be proved to be true, it has the possibility of adding 14% more patients to the long-term response group.

This hypothesis requires prospective validation.

Ordway Research Institute, Albany, New York.

03/17/04

Reference
G L Drusano and S L Preston. A 48-Week Duration of Therapy with Pegylated Interferon2b plus Ribavirin May Be Too Short to Maximize Long-Term Response among Patients Infected with Genotype-1 Hepatitis C Virus. The Journal of Infectious Diseases 189(6): 964-970. March 15, 2004.

www.hivandhepatitis.com

Pegasys plus Copegus: Newly Published Data Reports Highest Overall Sustained Virological Response Ever - 63%
Alan Franciscus, Editor-in-Chief

The Annals of Internal Medicine recently published an article on the clinical trial data results from a large international multcenter phase III clinical trial in order to assess the safety and efficacy of 24 or 48 weeks of treatment with Pegasys plus Copegus at low or standard ribavirin dose.

The study was a randomized, double-blind trial that enrolled 1,311 hepatitis C positive patients from 99 international centers. The lead author of the study was S.J. Hadziyannis, MD, for the Pegasys International Study Group.
All patients were treated with Pegasys 180 µg /week and were randomized into four treatment arms:

• 24 weeks - Pegasys plus ribavirin 800 mg/daily.
• 24 weeks - Pegasys plus ribavirin 1000 or 1200 mg/daily.
• 48 weeks - Pegasys plus ribavirin 800 mg/daily.
• 48 weeks - Pegasys plus ribavirin 1000 or 1200 mg/daily.

The primary endpoint of this study was end of treatment response and sustained virological response at the end of treatment and during the 12 to 24 weeks of follow-up.

It is well known that certain co-factors can influence treatment outcome: low viral load, minimal liver disease progression and infection with HCV genotypes 2 or 3 are all factors that predict a more favorable treatment outcome. This report will focus on the overall sustained virological response rate ((SVR) - undetectable HCV RNA or viral load achieved 24 weeks post treatment) - as well as on the SVR based on genotype, viral load and degree of HCV disease stage or progression. This is important since the majority of people in the United States are infected with genotype 1 with a high viral load, and these patients are considered the most difficult to treat with current HCV medications.

High viral load is defined as over 2,000,000 copies; low viral load is defined as under 2,000,000 copies.

Results: Genotype 1 - The Most Difficult to Treat
The authors reported an overall 52% SVR for all genotype 1 patients, and the study confirmed that the optimal dose of ribavirin is 1000-12000 mg/daily with treatment duration of 48 weeks.

The study also analyzed the treatment outcome by low viral load (65% SVR) and high viral load (47% SVR).

The authors further analyzed the SVR rates of patients according to the extent of fibrosis at baseline and found that patients without cirrhosis attained a 57% SVR versus 41% SVR for patients with cirrhosis or bridging fibrosis.

Results: Genotypes 2 and 3
As expected the SVR rates for people infected with HCV genotypes 2 and 3 were much higher than those attained by genotype 1 patients. The study also confirmed the results of previous Pegasys/Copegus studies that showed that a 24 week treatment duration and a ribavirin dose of 800 mg/daily produced the optimal sustained virological response rate for people with genotypes 2 and 3. The overall SVR for genotypes 2 and 3 was 84%. Results based on viral load were: 88% SVR for patients with genotypes 2 and 3, low viral load; and 82% SVR for patients with a high viral load.

The analysis by histology found that 87% of those patients without cirrhosis or bridging fibrosis achieved an SVR, as opposed to 75% for those patients with bridging fibrosis or cirrhosis.

Safety
The reported adverse events (side effects) were mild to moderate in severity and were typical of those reported in previous clinical trials of Pegasys plus Copegus.

Conclusion
The authors of this study concluded that the study demonstrated that treatment with Pegasys plus Copegus may be individualized by genotype.

Key Points

Sustained virological response (SVR) rates:
• Overall SVR was 63%, which is the highest response rate ever re-ported in a hepatitis C treatment clinical trial.
• Genotype 1 = 52% SVR.
• Genotype 1, high viral load = 47% SVR.
• Genotype 1, low viral load = 65% SVR.
• Genotypes 2 and 3 = 84% SVR.
• Genotypes 2 and 3, high viral load = 82% SVR.
• Genotypes 2 and 3, low viral load = 88% SVR.

Treatment Duration and ribavirin dosage:
• Genotype 1 - 48 weeks with ribavirin dose of 1000-1200 mg/day.
• Genotype 2 & 3 - 24 weeks with ribavirin dose of 800 mg/day.

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Results

Results

Reference H Nomura and others. Efficacy of early retreatment with interferon beta for relapse in patients with genotype Ib chronic hepatitis C. Hepatology Research 28(1): 36-40. January 2004.

03/17/04

Reference
H Nomura and others. Efficacy of early retreatment with interferon beta for relapse in patients with genotype Ib chronic hepatitis C. Hepatology Research 28(1): 36-40. January 2004.