Treatment with Interferon Alfa and Ribavirin Among Hemodialysis patients with Genotypes 1 and 4 Hepatitis C

Retreatment of Interferon Nonresponders with a Reinforced Regimen Should Be Focused on Genotype 2/3 Patients and Younger Genotype 1/4 Patients
 

Retreatment of chronic hepatitis C patients nonresponders to interferon (IFN) alone with the standard dose of IFN [3 million units (MU) thrice weekly (TIW)] plus ribavirin for 24 weeks has yielded low sustained virological response (SVR), averaging 8%.

The aim of the present, open-labelled, randomized study was to evaluate the efficacy of IFN induction therapy followed by prolonged high dose of IFN plus ribavirin in nonresponders.

One hundred and fifty-one patients were randomized to receive 5 MU daily of IFN alfa-2b (group 1, n = 73) or 5 MU TIW of IFN alfa 2b (group 2, n = 78) for 4 weeks followed by IFN (5 MU TIW) plus ribavirin (1000/1200 mg/daily) for 48 weeks in both groups.

In an intention-to-treat analysis, the sustained virological response (SVR) at 24-week follow-up was 33 and 23% for group 1 and 2, respectively (P = 0.17).

The overall SVR was 52 and 18% in patients with genotype 2/3 and 1/4, respectively.

Among genotype 1/4 patients the SVR was 29 and 11% for age younger or older than 40 years.

Compared with genotype 2/3 patients, the risk (95% confidence interval) of nonresponse to retreatment was 3.0-fold (1.17-8.0) in younger genotype 1/4 patients and 8.4-fold (3.0-23.29) in older genotype 1/4 patients.

“In conclusion,” write the authors, “ these results suggest that retreatment with a reinforced regimen should be focused in nonresponder genotype 2/3 patients and younger genotype 1/4 patients, who are most likely to benefit.”

“Induction therapy does not improve SVR.”

10/22/04

Reference
G Fattovich and others. A randomized trial of prolonged high dose of interferon plus ribavirin for hepatitis C patients nonresponders to interferon alone. Journal of Viral Hepatitis 11(6): 543-551. November 2004.

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Effects of Ribavirin Combined with Interferon Alfa on Viral Kinetics in Patients with HCV Genotype 1 and High Baseline Viral Load
 

This study aimed to find how ribavirin increases viral disappearance in patients with hepatitis C virus (HCV) of genotype 1 and high baseline viral loads (>5.0 x10⁵ copies/mL) when given with interferon (IFN).

Using the real-time quantitative polymerase chain reaction, the investigators measured serum HCV in 20 patients during the first 12 weeks of therapy with IFN alfa-2b (Intron A) and ribavirin (Rebetol).

Controls were 10 similar patients given IFN alfa-2b (Intron A) alone.

IFN alfa-2b was given at 6 MU daily for 2 weeks, and then three times weekly. Ribavirin was given at 600 or 800 mg daily.

Serum HCV RNA decreased rapidly in the first phase, during the first 24 h of therapy (day 0), and more slowly in the early second phase (days 1-14).

The median decrease was by 1.41 and 0.078 log 10/day in these two phases in the combination therapy group, and 0.90 and 0.081 log 10/day in the monotherapy group.

The difference between groups in the first phase was not significant (P = 0.24), nor was that in the next phase (P = 0.68).

Later in the second phase, between days 14 and 84, the median decrease was larger in the combination therapy group (0.030 log 10/day) than in the monotherapy group (0.015 log 10/day, P = 0.035).

The authors conclude, “In patients with HCV genotype 1 and high viral loads, the effects of ribavirin with IFN alfa appeared slowly, after the earliest days of treatment. A long-term favorable outcome of combination therapy may be associated with a rapid viral decline in this later phase of therapy.”

10/25/04

Reference
M Enomoto and others. Effects of ribavirin combined with interferon- 2b on viral kinetics during first 12 weeks of treatment in patients with hepatitis C virus genotype 1 and high baseline viral loads. Journal of Viral Hepatitis 11(5): 448-454. September 2004.

Index to Hepatitis C News Articles by Topic [ A -- Z ]

 

Different mechanisms of steatosis in hepatitis C virus genotypes 1 and 3 infections
	Journal of Viral Hepatitis Volume 11 Issue 5, September 2004   C. HÈzode1,2, F. Roudot-Thoraval2,3, E.-S. Zafrani4, D. Dhumeaux1,2 and J.-M. Pawlotsky2   Departments of 1Hepatology and Gastroenterology, 2Virology (EA 3489) , 3Public Health, and 4Pathology, HÙpital Henri Mondor, UniversitÈ Paris XII, CrÈteil, France   Summary   This study reports evidence that hepatocellular steatosis, a frequent histological feature of chronic hepatitis C, is principally metabolic in hepatitis C virus (HCV) genotype 1-infected patients, whereas it is principally virus-induced in HCV genotype 3-infected patients.   Multivariate analysis of data on 176 patients with chronic hepatitis C revealed that the severity of steatosis was independently related to HCV RNA load alone in patients infected by HCV genotype 3, whereas it was independently related to the body mass index, daily alcohol intake and histological activity grade (but not viral load) in patients infected by HCV genotype 1.   These findings suggest that steatosis is a cytopathic lesion induced by HCV genotype 3, whereas HCV genotype 1 is not steatogenic per se or at the usual in vivo expression levels.

http://www.natap.org/

 

 

RBV Kinetics--Improves Early Response
	"Effects of ribavirin combined with interferon-alpha2b on viral kinetics during first 12 weeks of treatment in patients with hepatitis C virus genotype 1 and high baseline viral loads"   Journal of Viral Hepatitis Volume 11 Issue 5, September 2004   M. Enomoto1, S. Nishiguchi1, M. Kohmoto1, A. Tamori1, D. Habu1, T. Takeda1, S. Seki1 and S. Shiomi2   1Department of Hepatology, Graduate School of Medicine, Osaka City University Medical School, Osaka; and 2Department of Nuclear Medicine, Graduate School of Medicine, Osaka City University Medical School, Osaka, Japan   Summary   This study aimed to find how ribavirin increases viral disappearance in patients with hepatitis C virus (HCV) of genotype 1 and high baseline viral loads (>5.0 x105 copies/mL) when given with interferon (IFN).   Using the real-time quantitative polymerase chain reaction, we measured serum HCV in 20 patients during the first 12 weeks of therapy with IFN-alpha2b and ribavirin. Controls were 10 similar patients given IFN-alpha2b alone. IFN-alpha2b was given at 6 MU daily for 2 weeks, and then three times weekly. Ribavirin was given at 600 or 800 mg daily.   Serum HCV RNA decreased rapidly in the first phase, during the first 24 h of therapy (day 0), and more slowly in the early second phase (days 1-14). The median decrease was by 1.41 and 0.078 log 10/day in these two phases in the combination therapy group, and 0.90 and 0.081 log 10/day in the monotherapy group.   The difference between groups in the first phase was not significant (P = 0.24), nor was that in the next phase (P = 0.68). Later in the second phase, between days 14 and 84, the median decrease was larger in the combination therapy group (0.030 log 10/day) than in the monotherapy group (0.015 log 10/day, P = 0.035).   In patients with HCV genotype 1 and high viral loads, the effects of ribavirin with IFN-alpha appeared slowly, after the earliest days of treatment. A long-term favourable outcome of combination therapy may be associated with a rapid viral decline in this later phase of therapy.

http://www.natap.org/

ALSO:

Effects of Ribavirin Combined with Interferon Alfa-2b on Viral Kinetics During First 12 Weeks of Treatment in Patients with HCV Genotype 1 and High Baseline Viral Loads

This study aimed to find how ribavirin increases viral eradication in patients with hepatitis C virus (HCV) genotype 1 and high baseline viral loads (>5.0 x10⁵ copies/mL) when given with interferon (IFN).

Using the real-time quantitative polymerase chain reaction, we measured serum HCV in 20 patients during the first 12 weeks of therapy with IFN-2b (Intron A) and ribavirin. Controls were 10 similar patients given IFN-2b alone.

IFN-2b was given at 6 MU daily for 2 weeks, and then three times weekly. Ribavirin was given at 600 or 800 mg daily.

Serum HCV RNA decreased rapidly in the first phase, during the first 24 h of therapy (day 0), and more slowly in the early second phase (days 1-14). The median decrease was by 1.41 and 0.078 log 10/day in these two phases in the combination therapy group, and 0.90 and 0.081 log 10/day in the monotherapy group.

The difference between groups in the first phase was not significant (P = 0.24), nor was that in the next phase (P = 0.68).

Later in the second phase, between days 14 and 84, the median decrease was larger in the combination therapy group (0.030 log 10/day) than in the monotherapy group (0.015 log 10/day, P = 0.035).

Conclusion

In patients with HCV genotype 1 and high viral loads, the effects of ribavirin with IFN- appeared slowly, after the earliest days of treatment. A long-term favorable outcome of combination therapy may be associated with a rapid viral decline in this later phase of therapy.

FDA-approved Therapies for Hepatitis C

Ribavirin

HCV genotypes

09/20/04

Reference
M Enomoto  and others. Effects of ribavirin combined with interferon- 2b on viral kinetics during first 12 weeks of treatment in patients with hepatitis C virus genotype 1 and high baseline viral loads. Journal of Viral Hepatitis 11(5): 448-455. September 2004.

http://www.hivandhepatitis.com/hep_c/news/2004/092004_b.html

 

 

Can You Have Multiple Genotypes?
"Changes in the Prevalence of Hepatitis C Virus Genotype among Injection Drug Users: A Highly Dynamic Process"   The Journal of Infectious Diseases 2004;190:1199-1200   Matthias Schröter, Bernhard Zöllner, Rainer Laufs, and Heinz-Hubert Feucht   Zentrum für Klinisch-Theoretische Medizin I, Institut für Infektionsmedizin, Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany   To the Editor—With great interest we have read the article by van Asten et al. in The Journal of Infectious Diseases [1]. An important aspect of their study is its detailing of the introduction and spread of "new" hepatitis C virus (HCV) genotypes among injection drug users (IDUs).   Changes of subtype distributions in a given population were shown, for the first time, by our group several years ago [2]. In that study, it was demonstrated that subtype 1b was the prevailing subtype in the German population until subtype 1a started spreading in the early 1980s [2]. This led to a substantial change of the most prevalent HCV subtype, especially in younger people. To highlight the question of whether this change was a single effect, a multicenter study was performed 2 years ago [3]. In that study, we demonstrated that the epidemiology of HCV genotypes in IDUs is subjected to highly dynamic changes. Profound changes in the prevalence of different HCV genotypes were noted between 1994--1995 and 2000--2001, when large populations of IDUs (n = 144 and n = 172, respectively) were compared. These changes are summarized in figure 1. The introduction of genotypes that were formerly unknown in this risk population (4 and 2a/b) and the ability of these genotypes to establish significant prevalence within a period of only 6 years are remarkable.   The theory of 2 independently developing HCV epidemics had been proposed elsewhere [4], because the epidemiology of HCV subtype 3a and other subtypes seemed to be very different between IDUs and non-IDUs. However, there are indications that the dynamics observed among IDUs also influence the genotypic distribution among the entire population of patients. Although subtype 3a was detected nearly exclusively among IDUs in 1994--1995, 〜45% of patients infected with subtype 3a had never been IDUs. In the majority of these people, high-risk sexual behavior (HRSB) was the most probable risk factor for acquiring HCV infection [3]. It can be assumed from these data that the higher the prevalence of a certain genotype among the population of IDUs, the higher is the risk of this genotype spreading beyond the boundaries of the IDU scene. This is most probably due to HRSB, which, today, is one of the major risk factors for acquiring HCV [3, 5]. On the other hand, new genotypes can be introduced in the population of IDUs. This has been demonstrated very convincingly for genotype 4, which was introduced by immigrants from northern Africa and the Arabian peninsula [1, 3], and for genotype 2 [3]. In our population of patients, these genotypes established a prevalence of 7% and 8%, respectively, within only 6 years (figure 1). In analogy to the findings for subtype 3a, these genotypes may also spread over the boundaries of the IDU scene with increasing prevalence.   However, knowledge of these dynamic changes of the distribution of HCV genotypes provides information regarding not only the epidemiology, but also the treatment, of HCV. In a population with a high risk of repeated HCV infections, the probability of infection with different HCV genotypes is associated with the speed of changes of the genotype distribution. We have shown that, in at least 18% of IDUs with long-term follow-up (up to 7 years), multiple HCV infections detected by intraindividual changes of the predominant HCV genotype occurred [6].   It is well known that, in patients infected with multiple HCV genotypes, one of the infecting virus strains establishes predominance, and, by use of polymerase chain reaction--based methods, usually only the actual prevailing strain can be detected in these patients [7]. However, minor strains do not become eliminated, and we have demonstrated in various patients that these minor strains can reappear [6, 8]. These findings are of importance, especially in the context of therapy with pegylated interferon and ribavirin. It has been shown that reemergence of minor strains is a possible cause for failure of therapy [6, 8]. Therefore, the recommendation was made to repeat genotyping in patients who do not respond to therapy as expected. This enables adjustment of the regimen to the actual predominant HCV genotype.   These findings underline the importance of the described dynamic changes of the epidemiological distribution of HCV genotypes among IDUs They are important for better understanding (1) the epidemiology of HCV and (2) possible factors influencing outcome of therapy.   References 1. van Asten L, Verhaest I, Hernandez-Aguado I, et al. Spread of hepatitis C virus among European injection drug users infected with HIV: a phylogenetic analysis. J Infect Dis 2004; 189:292--302. 2. Feucht HH, Schröter M, Zöllner B, Polywka S, Nolte H, Laufs R. The influence of age on the prevalence of hepatitis C virus subtypes 1a and 1b. J Infect Dis 1997; 175:685--8. 3. Schröter M, Zöllner B, Schäfer P, et al. Epidemiological dynamics of hepatitis C virus among 747 German individuals: new subtypes on the advance. J Clin Microbiol 2002; 40:1866--8. 4. Pawlotsky JM, Tsakiris L, Roudot-Thorval F, et al. Relationship between hepatitis C virus genotypes and sources of infection in patients with chronic hepatitis C. J Infect Dis 1995; 171:1607--10. 5. Alter MJ, Kruszon-Moran D, Nainan OV, et al. Prevalence of hepatitis C virus infection in the United States. N Engl J Med 1999; 341:556--62. 6. Schröter M, Zöllner B, Schäfer P, Laufs R, Feucht HH. The rapidly changing epidemiology of HCV genotypes: consequences for the individual therapeutic regimen [session WD4]. In: Program and abstracts of the 11th International Symposium on Viral Hepatitis and Liver Disease (Sydney). Adelaide: Australian Centre for Hepatitis Virology, 2003:95. 7. Widell A, Mansson S, Persson NH, Thysell H, Hermodsson S, Blohme I. Hepatitis C superinfection in hepatitis C virus (HCV)--infected patients transplanted with an HCV-infected kidney. Transplantation 1995; 60:642--7. 8. Schröter M, Feucht HH, Zöllner B, Schäfer P, Laufs R. Multiple infections with different HCV genotypes: prevalence and clinical impact. J Clin Virol 2003; 27:200--4.   J Clin Virol. 2003 Jul;27(2):200-4. Multiple infections with different HCV genotypes: prevalence and clinical impact.   Schroter M, Feucht HH, Zollner B, Schafer P, Laufs R.   Institut fur Medizinische Mikrobiologie und Immunologie, Universitatsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. mschroet@uke.uni-hamburg.de   BACKGROUND: In a HCV genotype 3a-infected patient, viremia with a different genotype (1b) was detected after 16 weeks of ineffective therapy. Serological typing revealed that this genotype had already been present prior to therapy.   OBJECTIVES: To investigate the epidemiology of multiple HCV infections and the therapeutical consequences for patients superinfected with a new HCV strain.   METHODS: Sera of 600 patients were screened for infection with multiple genotypes by using sequencing and a serological assay in parallel.   RESULTS: Infection with two different HCV types was detected in 13 patients. The prevailing strain was genotyped by sequencing. From two of these patients additional sera were available which had been drawn up to 24 and 28 months prior to the current sample, respectively. Those early samples showed viremia with a HCV subtype that could not be detected by PCR afterwards. Only antibodies to the initial strain were detectable in the later samples.   CONCLUSION: In patients serially infected by different HCV strains, one strain will prevail as the viremic virus. Under antiviral therapy, the displaced strain may become viremic again and may influence the outcome of therapy. Detection of inferior strains by serological assays before antiviral therapy may be important for choosing the adequate regimen.   http://www.natap.org/   HCV Therapy Should Depend on Genotype, Doc Says
by John C. Martin	Article Date: 08-04-04

infection with hepatitis C genotype 3 often clears spontaneously, which can spare the patient unnecessary treatment, according to German doctors.¹

Scientists at Hannover Medical School in Hannover, Germany and their colleagues who initiated a study on this topic say 15 to 50 percent of untreated patients may experience this type of spontaneous clearance. "Therefore, factors are needed to identify patients prior to therapy who have a higher or lower risk for developing a chronic course to avoid unnecessary treatment," wrote the researchers, headed by Heiner Wedemeyer, M.D., in Hannover Medical School's department of Gastroenterology, Hepatology and Endocrinology.

A Mounting Infection
According to experts, hepatitis C infection has reached epidemic proportions around the world, accounting for more than 1 million new cases each year. Four million people in the U.S. alone are infected, and 30,000 new infections are estimated to occur each year. The hepatitis C virus is classified into various groups, or strains, known as genotypes and subtypes. Genotype 1, subtype b (genotype 1b) is thought to be more closely associated with severe liver disease, and a more aggressive course than the other HCV genotypes.²

It is also well known that treatment in patients with HCV genotype 1 is more often unsuccessful compared to patients with genotypes 2 and 3.³ That's why genotype testing is part of a standard protocol when designing an individual treatment regimen for hepatitis patients, said Wedemeyer, in an e-mail interview with Priority Healthcare.

This study led to "important new data for the management of acute HCV," he said.

Homing in on Genotype 3
To further understand the course of hepatitis infection based on genotype, Wedemeyer and his team evaluated 1,176 inmates at a German prison, screening them for anti-HCV antibodies. Ninety-two of them tested positive, the scientists reported. Of those, nearly all reported using IV drugs for an average of 3 years prior to imprisonment.

Those inmates who tested positive were then genotyped, and Wedemeyer and his colleagues found that genotype 3 prevalence was "significantly higher" among inmates who had cleared HCV spontaneously compared to those who were diagnosed with chronic infection. Specifically, 86 percent of the prisoners with that genotype spontaneously cleared the virus, compared to 36 percent of those who had chronic infection.

Further, 93 percent of the inmates exposed to HCV genotype 1 went on to develop chronic infection, compared to just under two-thirds of those exposed to genotype 3, the researchers noted.

Researchers: Avoid Unnecessary Treatment
"Thus, acute infection in young Caucasian men with HCV genotype 3 leads more often to spontaneous clearance than infection with HCV genotype 1," the scientists wrote.

Individual treatment strategies for patients with different genotypes is probably appropriate, based on these findings, said Wedemeyer.  While chronic infection emerges in the "vast majority" of genotype 1 cases, unnecessary treatment might be avoided in those with genotype 3, he said.

"Considering also the high chance of successful treatment of chronic HCV genotype 3 infection with pegylated interferon in combination with ribavirin, we suggest not to treat acute hepatitis C genotype 3 infection early, but rather to wait at least 3 months after the onset of symptoms when chronicity becomes likely," wrote Wedemeyer and his team.

It's not exactly known why genotype 3 patients tend to spontaneously clear the virus compared to other genotypes, Wedemeyer explained. "It is mostly likely due to the higher sensitivity to type 1 interferons, as we know already for chronic hepatitis C," he said.

1. Lehman M, Meyer MF, Monazahian M, Tillmann HL, Manns MP, Wedemeyer H. High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infection. J Med Virol 2004 Jul;73(3):387-91.
2. Zein NN. Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev 2000 Apr;13(2):223-35.
3. Viral Hepatitis C. National Center for Infectious Diseases. Centers for Disease Control and Prevention (CDC).

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.