Pharmacy Division Ramathibodi Hospital


News 19/01/2545


Abstracts in Hepatitis
Recent Findings in the Journals

Steven K. Herrine, MD, Series Editor, Jefferson Medical College, Philadelphia

[Infect Med 18(11):490-496, 2001. © 2001 Cliggott Publishing Co., Division of SCP/Cliggott Communications, Inc.]

Clearance Kinetics of Hepatitis C Virus Under Different Antiviral Therapies

Optimal Hepatitis C Regimen Would Include Interferon Plus Amantadine And Ribavirin

Torre F, Giusto R, Grasso A, et al. J Med Virol. 2001;64:490-496.

Interferon (IFN) alfa has been the standard treatment for hepatitis C virus (HCV) infection. Using the kinetic curves of viral clearance, this study compared 3 treatment regimens based on IFN alone or in combination with amantadine or ribavirin to determine the mechanisms of action and the most suitable way to use these drugs. The early clearance kinetics of HCV were studied in 22 patients with chronic hepatitis C under different antiviral treatments: IFN, 3 MU daily (7 patients); IFN, 3 MU daily, plus amantadine, 200 mg (7 patients); and IFN, 3 MU daily, plus ribavirin, 1 to 1.2 g (8 patients), for 6 months. HCV RNA was assessed qualitatively and quantitatively on serial samples. The HCV RNA decay curves suggested a different behavior of viral clearance induced by the 3 treatments. While no significant differences were present in the first 6 hours, at between 6 and 12 hours ribavirin induced a rapid decline in the viral load. Amantadine seemed to accelerate it in the third phase (12 to 30 hours) and to provoke a more pronounced viral decline when compared with IFN alone (P < .05) or with IFN plus ribavirin (P < .025) (baseline to 30 hours). Thus, while IFN remains the principal antiviral drug, amantadine upholds the viral decline. Ribavirin, although synergistic with IFN, does not seem to improve the IFN effect during the earliest phase of treatment but probably supports the effects of IFN later on. A new dynamic approach to hepatitis C treatment can therefore be developed.

Editorial Comment

As the toll from hepatitis C mounts in the United States and Europe, continued efforts are under way to improve response rates using IFN-based therapies. During the past several years, increasing attention has been paid to the kinetics of HCV during antiviral therapy. It is now well established that viral decline after a single dose of any type 1 IFN consists of 2 distinct phases. The first phase, that of free virion clearance, is characterized by a rapid diminution of circulating HCV RNA. The second phase, that of infected cell death and clearance, is characterized by a much slower reduction in viremia. The rates of the 2 phases are determined by viral, host, and pharmacologic factors. This article applies the tools of viral kinetics to the study of amantadine, an antiviral that enjoyed a brief period of enthusiasm in hepatitis C therapy in the late 1990s. Although the efficacy of amantadine has been a matter of some controversy, recent Italian data describing its use in combination with both IFN and ribavirin have encouraged new investigations. Twenty-two patients were studied: 7 received IFN (type not specified), 7 received IFN plus amantadine, and 8 received IFN plus ribavirin. Ribavirin was shown to increase the effectiveness of the latter part of the first phase, while amantadine had a dramatic effect on the third phase of viral kinetics. IFN seemed to be the only drug of the 3 that had an effect during the very earliest part of the first phase. Based on their analysis of the above data, the authors conclude that an optimal regimen would involve early induction with IFN, followed by relatively early introduction of ribavirin to "maintain" the effect of IFN. Amantadine should be included in the mix, they further speculate, given the dramatic improvement in the second phase of kinetics offered by the drug. While the number of patients in this trial is far too small to draw a conclusion regarding antiviral efficacy, the approach offers insight into the direction of hepatitis C therapy: Patients may best be stratified according to risk of progression, host factors, and viral factors, with the optimal "mix" and duration of therapy designed to suit the individual.

A Randomized, Double-Blind Trial Comparing Pegylated Interferon Alfa-2b to Interferon alfa-2b as Initial Treatment for Chronic Hepatitis C

Pegylated Interferon May Have Place As Monotherapy

Lindsay KL, Trepo C, Heintges T, et al. Hepatology. 2001;34:395-403.

This international, randomized, active-controlled, parallel-group, double-blind, dose-finding study compared peginterferon alfa-2b with interferon alfa-2b for the initial treatment of compensated chronic hepatitis C. We randomly assigned 1219 subjects to receive either the standard 3-times-weekly interferon alfa-2b dosage (3 MIU) or the once-weekly peginterferon alfa-2b (0.5, 1, or 1.5 µg/kg). Subjects were treated for 48 weeks and then followed for an additional 24 weeks. All 3 peginterferon alfa-2b doses significantly (P =< .042) improved virologic response rates (loss of detectable serum hepatitis C virus [HCV] RNA) after treatment and after follow-up, compared with interferon alfa-2b. Unlike the end-of-treatment virologic response, the sustained virologic response rate was not dose-related above 1 µg/kg of peginterferon alfa-2b, because of a higher relapse rate among patients treated with 1.5 µg/kg of peginterferon alfa-2b, particularly among patients infected with genotype 1. All 3 peginterferon alfa-2b dosages decreased liver inflammation to a greater extent than did interferon alfa-2b, particularly in patients with sustained responses. No new adverse events were reported, and the majority of adverse events and changes in laboratory values were mild or moderate. In conclusion, peginterferon alfa-2b maintained (0.5 µg/kg) or surpassed (1 or 1.5 µg/kg) the clinical efficacy of interferon alfa-2b while preserving its safety profile. The higher rate of virologic response during treatment with 1.5 µg/kg of peginterferon alfa-2b in patients infected with genotype 1 and high viral levels warrants further evaluation.

Editorial Comment

Type 1 interferon, especially interferon alfa, has been the mainstay of hepatitis C therapy for a decade. This drug is limited by its mode of administration, short half-life, side-effect profile, and limited efficacy. The addition of ribavirin to the standard regimen has dramatically improved efficacy, but post-treatment relapses and viremic breakthroughs during therapy have remained commonplace. Viral kinetic studies have demonstrated a 2-phase pattern in the reduction of hepatitis C viremia during interferon therapy. The nature of these curves has prompted the use of daily interferon (induction therapy) and higher-dose regimens, with little improvement in efficacy. The technique of protein pegylation, with its resultant increase in the half-life of bioactive proteins, has been brought to bear on interferon therapy. Pilot studies showed great promise, leading to this pivotal trial of pegylated interferon alfa-2b versus standard interferon monotherapy. Comparison with the current standard of care, interferon plus ribavirin, was not performed, because the trial predated the approval of that combination. This dose-finding trial compared the efficacy of 3 doses of pegylated interferon alfa-2b: 0.5, 1, and 1.5 µg/kg/wk, all administered subcutaneously for 48 weeks. Sustained virologic response was highest in the 1 and 1.5 µg/kg groups, at 25% and 23%, respectively. End-of-treatment response was highest in the 1.5 µg/kg group, but higher relapse rates, perhaps related to the higher proportion of patients infected with HCV genotype 1, accounted for the comparatively lower sustained response rate. The therapy was well tolerated, with only the incidence of injection site reactions increased in the pegylated interferon groups. This trial will stand as a landmark in the treatment of hepatitis C, but more recent work using the combination of pegylated interferon plus ribavirin will soon overshadow these results. Pegylated interferon monotherapy may still have a place as treatment of those unable to receive ribavirin, especially those with renal insufficiency, but more data must be generated in these groups.

Peginterferon Alfa-2b Plus Ribavirin Compared with Interferon Alfa-2b Plus Ribavirin for Initial Treatment of Chronic Hepatitis C: a Randomised Trial

Pegylated Interferon-Ribavirin Signals New Phase In Hepatitis C Care

Manns PM, McHutchison JG, Gordon SC, et al. Lancet. 2001;358:958-965.

A sustained virologic response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy for chronic hepatitis C. In this randomized trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin. The investigators assigned 1530 patients with chronic hepatitis C to interferon alfa-2b, 3 MU subcutaneously 3 times a week, plus ribavirin, 1000 to 1200 mg/d orally; peginterferon alfa-2b, 1.5 µg/kg/wk, plus 800 mg/d of ribavirin; or peginterferon alfa-2b, 1.5 µg/kg/wk for 4 weeks, then 0.5 µg/kg/wk plus ribavirin, 1000 to 1200 mg/d for 48 weeks. The primary end point was the SVR rate (hepatitis C virus [HCV] RNA undetectable in serum at 24-week follow-up). Analyses were based on patients who received at least 1 dose of study medication. The SVR rate was significantly higher (P = .01 for both comparisons) in the higher-dose peginterferon group (274 [54%] of 511) than in the lower-dose peginterferon (244 [47%] of 514) or interferon (235 [47%] of 505) group. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 145 (42%) of 348, 118 (34%) of 349, and 114 (33%) of 343. The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified body weight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for body weight (mg/kg). Side- effect profiles were similar among the treatment groups. In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b, 1.5 µg/kg/wk, plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.

Editorial Comment

In spite of the known morbidity associated with chronic HCV infection, the overwhelming majority of infected patients have yet to be identified and offered therapy. This situation is due, at least in part, to the fact that therapy has left much to be desired. Interferon-ribavirin combination therapy, the current standard of care, is associated with an SVR rate of approximately 40%, defined by the absence of circulating HCV RNA 6 months after the completion of treatment. Many current controversies surrounding HCV infection, such as the management of patients with persistently normal transaminase levels, those with mild histologic disease, and those with relative contraindications (eg, depression, ischemic heart disease, decompensated cirrhosis), have taken on importance in the setting of poor therapeutic response rates. Therefore, significantly increasing response rates and tolerability of anti-hepatitis C therapeutic regimens will do much not only to increase the response rates of those who currently present for treatment but also to increase the potential pool of patients willing to be identified and treated. It is in this context that the above landmark article is welcomed to the medical literature. The regimen of pegylated interferon, 1.5 µg/kg/wk in combination with ribavirin, 400 mg orally twice a day, was associated with an SVR rate of 54%. In HCV genotype 1 infection, the SVR was 42%, a substantial improvement of the current standard of care. In those with HCV genotype 2 or 3 infection (about 30% of the infected population in the United States and Europe), the SVR was an astounding 82%. Response was also gratifying in those patients with bridging fibrosis or cirrhosis, a traditionally difficult population to treat. The side-effect profile was comparable to the current standard, with the exception of more frequent injection site inflammation. There can be little doubt that this publication marks the beginning in a new phase in hepatitis C therapy. Pegylated interferon-ribavirin is now the de facto standard of care for patients with chronic HCV infection. The effect of the regimen on previous relapsing or nonresponding patients is under active investigation and remains to be seen.

Adult hepatitis B vaccination using a novel triple antigen recombinant vaccine

Triple Antigen May Improve Effectiveness of Hepatitis B Vaccine

Young MD, Schneider DL, Zuckerman AJ, et al. Hepatology. 2001;34:372-376.

Present hepatitis B vaccines use multidose prolonged regimens, which even health care workers at risk do not always complete. Moreover, when vaccination is completed, there remain some who fail to achieve adequate protection. The protection of adults at risk could be improved if there were a more potent vaccine and/or a shorter vaccination regimen available. Vaccine-naive adults were randomized to vaccination with either Engerix-B (SmithKline Biologicals, Rixensart, Belgium) or a novel triple-antigen (S, pre-S1, and pre-S2) recombinant vaccine (Hepacare; Medeva Pharma Plc, Speke, UK). The primary efficacy parameter was the degree of seroprotection 26 ฑ 2 weeks after beginning vaccination. A total of 304 adults entered the study. Of these, 16 failed to complete the study (9 receiving Hepacare and 7 receiving Engerix-B). With the Engerix-B standard (0, 1, 6 months) regimen, 88% of subjects were protected by month 7, whereas with the triple-antigen vaccine a 2-dose regimen (0, 1 months) provided equivalent protection (91%) within 6 months, and a 3-dose (0, 1, 6 months) regimen was significantly superior (98% seroprotected by 7 months after starting vaccination [P < .001]). With adults at risk for a suboptimal response (older adults, the obese, men, and smokers), the triple-antigen vaccine produced a greater degree of protection. The vaccines had similar safety profiles, and both were well tolerated. In healthy normal adults, a triple-antigen hepatitis B vaccine containing S and pre-S antigens produced an enhanced immunologic response and was as effective as a 2- and 3-dose regimen.

Editorial Comment

Hepatitis B is among the most important diseases in the world. Although most transmission worldwide is vertical and occurs in developing nations, this viral infection remains an important cause of morbidity and mortality in the developed world. It is estimated that there are some 200,000 to 300,000 new cases of hepatitis B virus (HBV) infection in the United States each year. What is more disturbing than this alarming incidence is that the disease is entirely preventable. Hepatitis B vaccines have been available for nearly 2 decades, first as pooled serum products and now as recombinant preparations. The current regimen is safe and effective, but its use has been hampered by the need for 3 inoculations (0, 1, 6 months). Furthermore, the efficacy of the current hepatitis B recombinant vaccines is decreased in men, older patients, smokers, and the obese. This study investigates the safety and efficacy of a triple-antigen recombinant vaccine to be marketed under the name Hepacare. This preparation includes viral envelope proteins in addition to the standard S protein. The inclusion of S, pre-S1, and pre-S2 proteins is the derivation of the term "triple-antigen" vaccine. Adults from around the United States were recruited, with exclusion criteria, including immunosuppression, HIV infection, and pregnancy/lactation. The triple-antigen preparation provided seroprotection (defined as anti-HBs level greater than 10 IU/L) in 91% after the first 2 doses, while the standard preparation provided 88% seroprotection only after the entire 3-dose program. When the triple-antigen vaccine regimen was completed (0, 1, 6 months), a seroconversion rate of 98% was noted. Side-effect profiles were comparable and were limited mostly to injection site pain. Subgroup analysis showed improved efficacy in the traditionally resistant populations of older adults, men, smokers, and the obese. This report provides encouraging evidence of improvement in the already effective hepatitis B vaccine armamentarium. Future work should focus on more effective mass vaccination programs, availability of vaccine to developing nations, and therapeutic approaches to chronic hepatitis B using immune therapy.

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