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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
RibavirinTorre 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 (Hepatitis C Virus) 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 Hepatitis C Virus 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.
Hepatitis C Virus RNA was assessed qualitatively and quantitatively on serial samples.
The Hepatitis C Virus 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 CommentAs 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 Hepatitis C Virus 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 Hepatitis C Virus
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 MonotherapyLindsay 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 [Hepatitis C Virus] 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 CommentType 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 Hepatitis C Virus 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
CareManns 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 [Hepatitis C Virus] 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 Hepatitis C Virus 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 Hepatitis C Virus genotype 1
infections.Editorial CommentIn spite of the known morbidity associated
with chronic Hepatitis C Virus 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 Hepatitis C Virus RNA 6 months after the completion of
treatment. Many current controversies surrounding Hepatitis C Virus 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 Hepatitis C Virus genotype 1
infection, the SVR was 42%, a substantial improvement of the current
standard of care. In those with Hepatitis C Virus 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 pa- tients with chronic Hepatitis C Virus 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 VaccineYoung 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 ± 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 CommentHepatitis 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.
http://gastroenterology.medscape.com/SCP/IIM/2001/v18.n11/m1811.05.herr/m1811.05.herr-01.html
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