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Whom, When, How, and with What Therapy to Treat Acute Hepatitis C?
By
Ronald Baker, PhD  A
cohort study published in 2001 by Jaeckel et al showed that 6 months of treatment
with standard
interferon alfa-2b monotherapy (Intron A) at doses used for treatment
of chronic hepatitis C was enough to eradicate HCV infection in 98% of patients
with acute hepatitis C
[1].
However, the issue of what is the optimal treatment for acute hepatitis
C has been debated since publication of those study results. There is still no
consensus on whom to treat, when to treat, which interferon to use (conventional
or pegylated), and what dosing schedule to implement. The lack of standard guidelines
for treatment of acute HCV infection is reflected in the lack of precise recommendations
in the most recent consensus
statement from the NIH in 2002. Results
of the Jaeckel et al trial using interferon alfa-2b monotherapy for 24 weeks showed
that HCV could be eradicated in 98% of patients independently of HCV genotype
[1]. Because pegylated interferons have replaced conventional interferon
(IFN) in the therapy of chronic hepatitis C, the aim of the current study by
Wiegand et al was to analyze the efficacy of early treatment of acute hepatitis
C with peginterferon
alfa-2b monotherapy (PegIntron). The authors report the final results
of their open, uncontrolled, multicenter trial in the February 2006 issue of Hepatology
[2]. Between February 2001 and February 2004, the researchers evaluated 89
patients with acute hepatitis C collected from 53 different German centers and
coordinated within the network of the HEP-NET Study Group. HCV Infection among these study participants was due to intravenous drug
abuse, sexual transmission,
medical procedures, needlestick injuries and other potential modes (tattooing,
acupuncture). Sixty-six percent of the patients had HCV
genotype 1. All patients in the study received peginterferon alfa-2b at a dose of
1.5 microgram/kg once weekly for 6 months. Treatment was initiated after an average
of 76 days (range 14-150 days) from the presumed exposure. End-of-treatment
response (ETR) and sustained
virological response (SVR) were defined as undetectable
HCV RNA at the end of therapy and after 24 weeks of follow-up,
respectively. Results
- ETR
was 82% at the end of treatment and 71% at the end of follow-up.
- Of
89 individuals, 65 (73%) were adherent
to therapy, receiving 80% of the interferon dosage within 80% of
the scheduled treatment duration.
- ETR
and SVR rates in this subpopulation were 94% and 89%, respectively.
- A
maximum alanine aminotransferase
level of more than 500 U/L prior to therapy was the only factor
associated with successful treatment.
In
conclusion, Wiegand et al write, “In acute HCV infection, early treatment with
peginterferon alpha-2b leads to high virological response rates in individuals
who are adherent to treatment.” “The
high number of dropouts underlines the importance of thorough patient selection
and close monitoring during therapy.” “Thus,
future studies should identify factors predicting spontaneous viral clearance
to avoid unnecessary therapy.” Commentary Surprisingly,
the results obtained in the more recent trial by Wiegand et al that utilized peginterferon
alfa-2b (PegIntron) were worse than those in the earlier 2001 study
of Jaeckel et al that used conventional
interferon alfa-2b (Intron A). In an editorial also published
in the February 2006 of Hepatology [3], Antonio Craxi and Anna Licata
of the GI and Liver Unit at the University of Palermo, Italy note that in the
Jaeckel et al study, patients obtained an ETR of 98% and an SVR of 98% utilizing
conventional interferon alfa-2b versus an ETR of 82% and an SVR of only 71% in
the more recent Wiegand et al study using peginterferon
alfa-2b. Also noteworthy, utilization of an induction dosage in
Jaeckel's study obtained an early viral clearance at 4 weeks of therapy in 72%
of patients. Four week data in the Wiegand et al study were not available. The low SVR rate in the Wiegand study probably is due to a high rate of
non-adherence in
that study, say Craxi and Licata in their editorial. Twenty-one percent of patients
did not take at least 80% of the intended peginterferon dosage for 80% of the
scheduled period. Many of them either dropped out of the study or were lost to follow-up. Craxi and Licata suggest that rather than risk poor adherence and a high
drop out rate, it may be more productive not to offer all patients immediate therapy
for acute HCV infection and to “wait and see and to identify subjects with spontaneous
viral clearance.” In particular, they emphasize the high number of drop outs and
lack of adherence among injection drug users (IDU)
who enrolled in the Wiegand trial: “The rationale to treat IVDUs in
the acute phase must hence be very carefully weighed against the likelihood of
spontaneous resolution.” The Italian researchers suggest further that peginterferon given once
weekly may not be as effective as conventional interferon given 3 times weekly
in the setting of acute HCV infection: “The real issue, in the age of PEG IFNs,”
write Craxi and Licata, “is whether results can be reproduced by once-weekly regimens.” Comparability
of dosages between standard and peginterferon is also a matter of concern. Higher
amounts of interferon during the first weeks of therapy seem to be the most effective
approach, according to Craxi and Licata. In the trial by Jaeckel et al a regimen
of 5 MU of IFN once a day for 4 weeks followed by 5 MU of IFN twice weekly for
20 weeks achieved SVR in almost all patients. Similar results were obtained by Delwaide et al, [4] who used the
same high induction dose. A meta-analysis study by Craxi and Licata [5]
provides further evidence that treatment with a daily dose of standard interferon
is the best option for obtaining an SVR. All these studies used standard interferon
alfa and tried to optimize pharmacodynamics
by giving it daily. Would
use of combination
therapy with ribavirin improve the SVR rate? Craxi and Licata think
not: “Data from a small study with standard IFN with or without ribavirin
do not suggest any improvement in efficacy.” [6] Summary In summary, there are still more questions than answers about the best
approach to acute HCV infection. In general, the evidence seems to support the
use of standard
interferon alfa monotherapy, although it may be advisable to carefully
screen patients to identify those who might have a spontaneous resolution of infection,
thus avoiding the need for treatment altogether. Clearly, there is no “one size fits all” approach to treatment of patients
with acute hepatitis C. When, in whom, how, and with which therapy
to start (conventional interferon alfa monotherapy or peginterferon alfa monotherapy)
are core issues [7]. So far, no study has shown a benefit for combination
therapy with interferon plus ribavirin. If a patient appears likely not to have spontaneous resolution of infection,
then a decision to treat needs to be highly individualized, and based on a variety
of factors that could influence outcome: baseline clinical condition, likelihood
of adherence, ability to tolerate a high frequency and intensity of psychiatric
side effects, genotype,
age,
and injection drug use history. 02/03/06 Sources 1. J Wiegand and others (for the German HEP-NET Acute HCV Study
Group). Early monotherapy with pegylated interferon alpha-2b for acute hepatitis
C infection: The HEP-NET acute-HCV-II study. Hepatology 43: 250-256. February
2006. 2. A Craxi
and A Licata. Acute hepatitis C: In search of the optimal
approach to cure (Editorial). Hepatology 43(2): 221-224. February 2006.
References 1.
E Jaeckel and others. Treatment of acute hepatitis C with
interferon alfa-2b. N Engl J Med 2001; 345: 1452-1457. 2.
J Wiegand and others (for the German HEP-NET Acute HCV Study Group). Early monotherapy
with pegylated interferon alpha-2b for acute hepatitis C infection: The HEP-NET
acute-HCV-II study. Hepatology 43(2): 250-256. February 2006. 3.
A Craxi and A Licata. Acute hepatitis C: In search of
the optimal approach to cure (Editorial). Hepatology 43(2): 221-224. February
2006. 4. Delwaide
J, Bourgeois N, Gerard C, De Maeght S, Mokaddem F, Wain E, et al. Treatment
of acute hepatitis C with interferon alpha-2b: early initiation of treatment is
the most effective predictive factor of sustained viral response. Aliment Pharmacol
Ther 2004; 20: 15-22. 5.
A Licata, A Craxi and others. When and how to treat
acute hepatitis C? J Hepatol 2003; 39: 1056-1062.
6.
P Rocca and others. Early treatment of acute hepatitis C with interferon alpha-2b
or interferon alpha-2b plus ribavirin: study of sixteen patients Gastroenterol
Clin Biol 2003; 27: 294-299. 7.
H Wedemeyer, E Jackel and others.
Whom? When? How? Another piece of evidence for early treatment of acute hepatitis
C. Hepatology; 39: 1201-1203. | 
