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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