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Alan Franciscus
Editor-in-Chief
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In This Issue:
Diagnostics:
Comparison of Three Commercially
Available Assays for HCV RNA Using the International Unit
Standard: Implications for Management of Patients with Chronic
Hepatitis C Virus Infection in Clinical Practice
Clinical Relevance of Total HCV Core Antigen
Testing for Hepatitis C Monitoring and for Predicting Patients’
Response to Therapy
Biochemical Surrogate Markers of Liver Fibrosis and Activity
in a Randomized Trial of Peginterferon Alfa-2b and Ribavirin
Hepatitis C Therapy
A Multicenter Study
of Recombinant Human Interleukin 12 for the Treatment of Chronic
Hepatitis C Virus Infection in Patients Non-Responsive to
Previous Therapy
High Sustained Virological Response in Chronic Hepatitis C
by Combining Induction and Prolonged Maintenance Therapy
Effects of Alpha Interferon Induction plus Ribavirin
With or Without Amantadine in the Treatment of Interferon
Non-Responsive Chronic Hepatitis C: A Randomised Trial
Reinforced Interferon Alpha-2b and Ribavirin
is More Effective than Standard Combination Therapy in the
Retreatment of Chronic Hepatitis C Previously Nonresponsive
to Interferon: A Randomized Trial
Twelve Weeks of Follow-up is Sufficient for the
Determination of Sustained Virologic Response in Patients
Treated with Interferon-a for Chronic Hepatitis C
Regression of Fibrosis in Chronic Hepatitis C
after Therapy with Interferon and Ribavirin
Dynamics of Alanine Aminotransferase During
Hepatitis C Virus Treatment
Effect of Treatment with Peginterferon or Interferon
AIfa-2b and Ribavirin on Steatosis in Patients Infected with
Hepatitis C
Hepatitis C: Natural History and Pathogenesis
Predicting Progression to Cirrhosis in Chronic Hepatitis C
Virus Infection
Cost-Effectiveness of Treatment for Chronic
Hepatitis C Infection in an Evolving Patient Population
Comparison
of Three Commercially Available Assays for HCV RNA Using the
International Unit Standard: Implications for Management of
Patients with Chronic Hepatitis C Virus Infection in Clinical
Practice
Mitchell L. Shiffman, M.D., Andrea Ferreira-Gonzalez,
Ph.D., K. Rajender Reddy, M.D., Richard K. Sterling, M.D.,
Velimir A. Luketic, M.D., R. Todd Stravitz, M.D., Arun J.
Sanyal, M.D., Carleton T. Garrett, M.D., Ph.D., Maria De Medina,
M.S.P.H., and Eugene R. Schiff, M.D.—Hepatology Section,
USA and Division of Molecular Diagnostics, Virginia Commonwealth
University Health System—Medical College of Virginia,
Richmond, Virginia; Division of Gastroenterology and Hepatology,
University of Pennsylvania, Philadelphia, Pennsylvania; and
Center for Liver Diseases, University of Miami, Miami, Florida
Source: The American Journal of Gastroenterology
Vol. 98, No 5, 2003
Introduction
HCV RNA (viral load) testing is used to confirm active infection
in patients who test positive for HCV antibodies (anti-HCV)
and during treatment to confirm that the viral load is decreasing
or is undetectable during and after HCV therapy. Viral load
testing during treatment can identify patients who are unlikely
to achieve an sustained virological response allowing the
physician and the patient to decide if treatment should be
discontinued.
Objective
The aim of this study was to evaluate the impact of the international
unit standard for measuring HCV RNA (viral load) in the management
of patients with chronic hepatitis C (HCV) infection.
Patients
This small prospective study of 106 patients (mean age -44
yo), male (62%), African American (24%), bridging fibrosis
or cirrhosis (38%), genotype 1 (75%) received interferon and
ribavirin for 6 to 12 months, depending on genotype.
Methods
Three assays were used—Amplicor Monitor PCR, the National
Genetics Institute PCR assay, and branched chain DNA. Viral
load was measured at four points (baseline, 3 months after
the start of therapy, at the end of treatment, and 6 months
after discontinuation of therapy). Four hundred and twenty
four samples were analyzed.
Results
Of the sample analyzed, 82-89% of values were within 1 log
unit and 85-92% were within 2 log units by the various assays.
This variability was not dependent upon HCV genotype. HCV
RNA (viral load) was undetectable in 1.4-6.8% of samples when
virus was detected by another assay. The mean viral load in
these discordant samples was 1.47-6.33 log IU/ml (30-2,100,000
IU/ml).
Conclusion
The authors concluded that their data demonstrated approximately
90% of serum values for HCV RNA (viral load) were within 1
log unit by the international unit standard regardless of
which viral load test was used. However, false positive and
false negative results as well as variations in viral load
level of more than 1 to 2 logs units can occur with any of
the assays, and these results may have an impact upon the
management of patients receiving HCV medications. It is therefore
unwise to base important treatment decisions based on a single
viral load determination.
Back to top
Clinical
Relevance of Total HCV Core Antigen Testing for Hepatitis
C Monitoring and for Predicting Patients’ Response to
Therapy
M. Maynard, P. Pradat, P. Berthillon, G. Picchio, N. Voirin,
M. Martinot, P. Marcellin and C. Trepo - Hdtel-Dieu, Lyon,
France; Clinical Diagnostics, Raritan, NJ, USA; U271, Lyon,
Prance; and U 483, Hopital Beau Jon, Paris, France
Source: Journal of Viral Hepatitis, 2003,
10, 318-32
Introduction
Diagnosing HCV infection is accomplished by a combination
of the detection of the HCV antibody test and the HCV-RNA
(viral load) test. Monitoring treatment is usually assessed
by measuring HCV-RNA (viral load) and to a lesser extent alanine
aminotransferase levels (ALT, biochemical response). The recently
developed ELISA method for detection of HCV Core protein has
been shown to be useful in the quantitative evaluation of
HCV viral load. This method appears to show sensitivity and
specificity comparable to that of commercially available viral
load test, correlates well with these assays regardless of
genotype, appears to be suitable for large-scale screening
of blood donations, and for monitoring the response of interferon
treatment.
Objective
To study the correlation between total Hepatitis C virus (HCV)
Core antigen (Ag) and HCV-RNA, and to assess the proficiency
of HCV Core Ag testing in monitoring and predicting virologic
response during and after pegylated interferon (PEG-IFN) and
ribavirin combination therapy.
Patients/ Methods
This is a single-center, prospective study. A total of 307
samples from treated and untreated patients were used to assess
the correlation between the total HCV Core Ag test and quantitive
HCV-RNA assays (Superquant, and Quatiplex branched DNA 2.0
assay).
Twenty-four patients received combination
therapy for 48 weeks. Blood samples were collected at day
0, and week 2, 4, 12, 24, 48 and 72 for virologic evaluation.
Results
A linear relation exists between total HCV Core Ag and HCV-RNA
levels. At 3 months the positive predictive value (PPV) of
response to therapy was 100% with either HCV Core Ag or HCV-RNA.
For HCV Core Ag the negative predictive value (NPV) was 100%
whereas for HCV-RNA the NPV was 80% (P> 0.05).
At month 1, the PPV was 95% and 100% when
determined by HCV Core Ag and HCV RNA, respectively. The NPV
value was 100% for HCV Core Ag and 33% for HCV-RNA (P = 0.005).
HCV Core Ag quantification could be useful
in clinical practice to predict a sustained virological response
early during therapy (4 weeks), reaching an optimal performance
at month 3.
Conclusion
The determination of total HCV Core Ag levels in serum constitutes
an accurate and reliable alternative to HCV-RNA for monitoring
and predicting treatment outcome in patients receiving PEG-IFN/ribavirin
combination therapy.
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Biochemical
Surrogate Markers of Liver Fibrosis and Activity in a Randomized
Trial of Peginterferon Alfa-2b and Ribavirin
Thierry Poynard, John McHutchison, Michael Manns, Rob
P. Myers, and Janice Albrecht
Source: Hepatology, Vol. 38, No. 2, 2003
Introduction
In patients infected with hepatitis C virus (HCV), some recent
studies have shown the predictive value of combinations of
simple serum biochemical markers: Fibrotest (FT) for the diagnosis
of significant fibrosis (ranging from few septa to cirrhosis)
and Actitest (AT) for the assessment of necroinflammatory
activity fibrosis and activity.
The liver biopsy is the standard of care
in evaluating the health of the liver. The liver biopsy is
also important because it can aid the physician and patient
in making appropriate HCV management and treatment decisions.
In addition repeated biopsies can be used to determine disease
progression over a period of time.
Objective
The primary aim of this multicenter, respective study was
to assess the diagnostic value of FT-AT in patients at baseline
and at end of follow-up. In contrast to previous reports,
the METAVIR and Knodell scoring systems, including the components
of the histologic index. The secondary aims were to assess
the variation of FT-AT according to virologic response; to
assess the concordance between FT-AT and histologic variations;
to compare a decision algorithm without liver biopsy; and
lastly to compare FT-AT and liver biopsy as trial end points
for evaluating histologic impact.
Patients/ Methods
A total of 1,530 patients from a randomized trial comparing
three interferon plus ribavirin combination treatments were
considered for this retrospective study. Patients were previously
untreated for their hepatitis C, had HCV RNA detectable in
the serum, and had elevated alanine aminotransferase (ALT)
levels.
Treatment consisted of either interferon
3 MU three times a week and ribavirin (1,000 mg if weight
below 75kg, 1,200 mg greater than 75 kg) or the new combination
of 1.5 µg/kg peginterferon and ribavirin (800 mg) for
48 weeks.
Three hundred fifty-two patients who had
had 2 interpretable liver biopsies (at baseline and at 24
week follow-up) and stored blood samples before and after
treatment were selected.
One hundred forty-four patients received
the standard interferon and ribavirin therapy and 208 received
the peginterferon plus ribavirin treatment.
FT markers include a2-macroglobulin, haptoglobin,
y-glutamyl transpeptidase (GGT), total bilirubin and apolipoprotein
A1. The AT combines the 5 markers for FT plus ALT.
Results
The analysis of the data showed that FT-AT gave similar results
to liver histology. The biochemical markers were found to
be highly predictive of the health of the liver with a higher
power for the biochemical markers.
The biochemical markers have significant
predictive values both for the diagnosis of fibrosis and for
activity. FT-AT increases parallel the increase in fibrosis
stage and activity grade. Comparing the different treatment
regimes found that patients who achieved an SVR for both therapies
showed 3 significant differences between FT values before
and after treatment.
Conclusion
The authors concluded that biochemical markers have improved
and should now be considered both for the initial evaluation
and for follow-up. The authors believe that a biopsy should
not be mandatory due to the limits and risk of biopsy. It
was also recommended conducting a prospective randomized trial
of 2 strategies comparing a strategy without and with biopsy
to confirm the results of this trial. However, they noted
that it would require a large number of patients to estimate
the severe adverse events. Finally, the authors concluded
that a simplification of liver damage assessment should accelerate
the management of chronic hepatitis C.
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A
Multicenter Study of Recombinant Human Interleukin 12 for
the Treatment of Chronic Hepatitis C Virus Infection in Patients
Non-Responsive to Previous Therapy
Paul J. Pockros, Keyvr Patel, Christopher O’Brien,
Myron Tong, Coleman Smith, Vinod Rustgi, Robert L. Carrithers,
John G. McHutchison, Elizabeth Olek, and Michael F. DeBruin
Source: Hepatology, Vol.37, No. 6, 2003
Introduction
Recombinant human interleukin 12 (IL-12) is an immunomodulatory
cytokine that is active against several viruses. Treatment
options are limited in patients with chronic hepatitis C with
nonresponse to previous interferon (IFN)-based therapy. Prior
dose-ranging studies have indicated drug tolerability and
transient suppression of hepatitis C virus (HCV) RNA by IL-12.
Objective
The aim of this study was to determine the safety and efficacy
of prolonged IL-12 therapy in patients who have failed treatment
with IFN-a with or without ribavirin.
Patients/ Methods
A total of 225 patients at 21 U.S. sites who had a history
of nonresponse to IFN-a or combination IFN-a plus ribavirin
for treatment of HCV were randomized to 500 ng/kg IL-12 or
placebo subcutaneously twice weekly for 12 weeks.
The groups were then unblended. The patients
receiving IL-12 continued for another 36 weeks, and the placebo
group received 48 weeks of treatment with IL-12 in an open-label
fashion.
HCV RNA, serum alanine aminotransferase
(ALT) level, and a repeat liver biopsy were assessed at 24
weeks following therapy.
Results
Approximately 1% (2 of 160) of nonresponsive patients enrolled
for treatment had a sustained virologic response to IL-12
therapy, but 3% (7 of 225) developed severe adverse events
probably related to treatment, resulting in early termination
of the trial.
Common adverse effects reported by most
patients included chills, fever, fatigue, headache, and arthralgia
(joint pain).
At termination of the study, 160 patients
had received at least 8 weeks of treatment with 1L-12. Paired
liver biopsy specimens were avail able for evaluation in 54
patients, but there were no significant changes in Knodell
fibrosis or histologic activity index (HAl) scores.
Conclusion
The authors concluded that IL-12 as monotherapy at the doses
used in this trial for chronic hepatitis C reported low efficacy,
was poorly tolerated, and is unlikely to provide an alternative
to conventional interferon based therapy.
Back to top
High Sustained
Virological Response in Chronic Hepatitis C by Combining Induction
and Prolonged Maintenance Therapy
J.M. Vrolijk, F.C. Bekkering, J.T. Brouwer, Hansen B,
and Schalm S.
Source: Journal of Viral Hepatitis, 10, 205-209
(2003)
Introduction
The most difficult to treat HCV patients are those with genotype
1 infection, high viral load, cirrhosis or those that have
not previously responded to prior treatment of HCV with interferon
and ribavirin.
Objectives
The authors studied the treatment regime that combines high
dose induction interferon (IFN) followed by prolonged daily
interferon and ribavirin treatment in these difficult to treat
patients.
Patients
This was a small prospective study of 24 patients (male=17),
mean age 47 YO, with genotype 1 (11 pts), cirrhosis (11 pts),
previous non-responders to interferon (15), high viral load
(17) or a combination of these characteristics in a single
center study. These patients were estimated to have less than
a 30% chance of achieving a sustained virological response
rate.
Methods
Patients were treated with 10 million units (MU) daily for
four weeks followed by 5 MU/day until week 4, 3 MU/day until
week 52 and 3 MU three times a week until week 76 in combination
with 1-1.2 grams ribavirin daily.
Note: This is the first
study in which patients were treated with daily high-dose
induction for longer than 12 weeks.
HCV viral load levels were taken weekly
until week 4 and at least once every 3 months for the remainder
of the treatment period using a viral load test with a detection
limit below 500 copies/mL.
Results
Intention to Treat Analysis (SVR):
| |
Number of Patients |
SVR |
| All |
24 |
16 (67%) |
Genotype
•Non-1
•1
|
13
11
|
10 (77%)
6 (55%) |
Cirrhosis
•Absent
•Present
|
13
11
|
12 (92%)
4 (36%) |
Response to previous treatment:
•Nonresponder
•Relapser /naive
|
14
10
|
10 (71%)
6 (60%)
|
Per Protocol Analysis (SVR):
| |
Number of Patients |
SVR |
| All |
20 |
16 (80%) |
Genotype
•Non-1
•1 |
11
9
|
10 (91%)
6 (67%) |
Cirrhosis
•Absent
•Present
|
12
8
|
12(100%)
4 (50%) |
Response to previous treatment:
•Nonresponder
•Relapser /naive |
13
7
|
10 (77%)
6 (60%)
|
Note: SVR was achieved
in almost all of patients without cirrhosis
Summary/ Conclusion
The authors found that the virological response occurred rapidly
(< 8 weeks of treatment) in all patients with a sustained
virological response rate. The relapse rate after stopping
therapy was only 5%. Side effects were seen frequently—six
patients had to be hospitalized (5 out of 6 had cirrhosis).
The authors concluded that this new treatment
of induction and prolonged daily interferon plus ribavirin
therapy produced a high SVR in patients who are less likely
to respond to HCV medications (genotype 1, cirrhosis, high
viral load or previous non-response to therapy or combination
of these characteristics). In addition the authors recommended
that further research is needed to evaluate this regime in
larger controlled studies that include pegylated interferon
and ribavirin in this patient population.
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Effects
of Alpha Interferon Induction plus Ribavirin With or Without
Amantadine in the Treatment of Interferon Non-Responsive Chronic
Hepatitis C: A Randomised Trial
I E Adinolfi, R Utili, A Tonziello, G Ruggiero
Source: Gut 2003;52:701—705
Introduction
Fifty per cent of chronic hepatitis C patients are non-responders
to interferon based therapy. At present, there are no recommended
therapeutic options for non-responders.
Objectives
The aim of this single center, prospective, open label study
was to evaluate the safety and long term effect of alpha interferon
induction therapy plus ribavirin with or without amantadine
in the treatment of interferon non-responsive chronic hepatitis
C.
Patients/Methods
A total of 114 consecutive patients were randomly divided
into three groups with a final 2:2:1 ratio:
•Group A (44 patients – Genotype 1 –
70%) received interferon alfa 2b, 3 million units (MU), three
times a week, and oral ribavirin (1000 mg/day);
•Group B (46 patients – Genotype 1 –
72%) received interferon 3 MU daily for the first four weeks
and subsequently 3 MU three times a week, and ribavirin as
in regimen A;
•Group C (24 patients – Genotype 1 –
71%) received interferon and ribavirin as in regimen B, plus
oral amantadine hydrochloride (200 mg/day). The duration of
treatment was 12 months.
Results
The end of treatment response for groups A and B was 25% and
29%, respectively, and for group C, 68% (p.<0.05) at the
end of one year of follow up, a sustained response was observed
for six (25% SVR - genotype 1 – 13%) patients in group
C, one (2% SVR- genotype 1 – 3%) patient in group A,
and two (4% SVR - genotype 1 – 0%) patients in group
B (p<0.002).
The triple regimen was well tolerated and
did not increase the frequency or severity of side effects.
Conclusion
The authors concluded that their study demonstrates that for
the treatment of interferon non-responder hepatitis C patients,
the association of interferon plus ribavirin has a negligible
long term effect whereas a triple regimen including interferon,
ribavirin, and amantadine can be an effective and safe treatment.
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Reinforced
Interferon Alpha-2b and Ribavirin is More Effective than Standard
Combination Therapy in the Retreatment of Chronic Hepatitis
C Previously Nonresponsive to Interferon: A Randomized Trial
T. Poynard, P. Marcellin, A. Bissery, R. P. Myers, J.
Moussallj, F. Degos, D. Dhumeaux, G. Riachi, J. P. Bronowicki,
P. Brissot, c. Buffet, L. Serfaty, S. Naveau, P. Sogni, M.
Beaugrand, S. Gayno, D. Larrey,D. Samuel, C. Eugene, S. Pol,
P. Bedossa,V. Daurat and P. Chaumet-Riffaud for the multicenter
GER-CYT-RIBANON group
Hepatogastroenterology, Groupe Hospitalier
Pitié-Salpétrière, Université
Paris 6, CNRS ESA 8067 Paris, Prance; Beaujon, Clichy; Groupe
Hospitalier Pitié-Salpétriére; Henri
Mondor, Crétoil; Hopital Charles Nicolle, Rouen; Brabois,
Nancy; 7 Pontchaillou, Rennes; Bicétre, Kremlin Bicétre;
9 St Antoine, Paris; Hopital Antoine Bécléré,
Clamart; Cochin, Paris; Jean Verdier, Bondy; René Dubos,
Pontoise; St Eloi Montpellier; Paul Brousse Villejuif; Leon
Touh Poissy; Necker, Paris; Bicétre, Kremlin Bicétre;
and Delegation a la Recherche Clinique, Hopital Saint Louis,
Paris
Source: Journal of Viral Hepatitis 2003;
10: 197-204
Introduction
Interferon-alpha (IFN) monotherapy results in sustained virological
clearance in a minority of patients (15% SVR) with chronic
hepatitis C. Recent studies suggest that higher doses of interferon
in combination with ribavirin may increase the rate of response.
However, the role of this therapy has yet to be definitively
established.
Objectives
The aim of this study was to assess the effect of a reinforced
regimen combining ribavirin and high-dose interferon for 48
weeks compared with a nonreinforced regimen combining a standard
interferon regimen and ribavirin for 24 weeks in nonresponders
with chronic hepatitis C.
Patients/Methods
A total of 231 patients with chronic hepatitis C and previous
non-response to interferon monotherapy were randomized. The
reininforced group (n = 14) received IFN-2b, 6 million units
(MU) thrice weekly (TIW) and ribavirin for 48 weeks, and the
nonreinforced group (n = 117) received IFN-2b, 3 MU TIW and
ribavirin for 24 weeks.
The main outcome measure was a sustained
virological response, defined as negative serum hepatitis
C virus (HCV)-RNA 24 weeks following the end of treatment.
This endpoint was determined in 98 patients of the reinforced
group and 105 patients of the nonreinforced group.
Results
At the end of follow-up, a sustained virological response
was observed in 29 of the 98 patients (29.6%) in the reinforced
group vs 6 of the 105 patients (15.2%) in the nonreinforced
group (P = 0.014). In multivariate analysis, factors associated
with a sustained virological response were treated with a
reinforced regimen [odds ratio (OR) 2.9; P = 0.06] and genotype
2 or 3 (OR 8.8; P C 0.0002).
A total of 160 patients had paired biopsies
before and after treatment. Histological activity improvement
was observed in 32 of 80 patients (40%) and fibrosis worsening
in 26 of 80 patients (33%) in the reinforced group vs 13 of
80 (16 %) and 19 of 80 (24%) in the nonreinforced group (P
= 0.30 and 0.20, respectively).
Although significantly more effective,
tolerance of the high-dose, prolonged duration regimen was
poor. In comparison to standard treatment, more patients receiving
the reinforced regimen were hospitalized for serious adverse
events and nearly three times as many discontinued treatment
prematurely (30% vs. 11%). The authors noted that this increase
in adverse events was not observed in a recent trial comparing
peginterferon plus ribavirin vs. standard interferon plus
ribavirin therapy and could be explained by the action of
pegylated interferon in minimization of fluctuations of interferon
levels.
Conclusion
The authors concluded that in nonresponders, a high-dose 48-week
regimen of IFN and ribavirin combination was more effective
than a regimen with interferon at lower dose and ribavirin
for 24 weeks only.
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Twelve
Weeks of Follow-up is Sufficient for the Determination of
Sustained Virologic Response in Patients Treated with Interferon-a
for Chronic Hepatitis C
Stefan Zeuzeml, E. Jenny Heathcote, Mitchell L. Shiffman,
Teresa L. Wright,Vincent G. Bain, Morris Sherman, S. Victor
Feinman, Michael W. Fried, Jens Rasenack,
Christoph Sarrazin, Donald M. Jensen, Amy Lin, Joseph H. Hoffman,
Farhad Sedarati
Homburg/Saar, Germany, Toronto, Toronto,
ON Canada, College of Virginia Commonwealth University, Richmond,
VA, USA, California San Francisco, San Francisco, CA, USA,
University of Alberta, Edmonton, AR Canada, General Hospital,
Toronto, ON Canada, Sinai Hospital, Toronto, ON Canada, University
of North Carolina, Chapel Hill, NC, USA, Clinic of Freiburg,
Freiburg, Germany, Rtesh-Presb Luke’s Medical Center,
Chicago, JL, USA, Hoffinann-La Roche, Nutley, NJ, USA
Source: Journal of Hepatology 39 (2003) 106-111
Introduction
The current standard for the determination of sustained virologic
response in patients treated for hepatitis C is undetectable
hepatitis C virus (HCV) RNA 24 weeks following the completion
of therapy. Sensitive molecular tests may permit earlier determination
of sustained virologic response following the completion of
therapy in end-of-treatment responders.
Methods
This was a retrospective study of previous phase II/III clinical
trials in which 132 of 566 (23%) received standard interferon
for 48 weeks and had end of treatment response, while 492
of 875 (56%) patients received pegylated interferon a-2a for
48 weeks and had end of treatment response. At the end of
follow-up, 80 interferon alpha 2a patients achieved a sustained
virological response (SVR) compared to 262 pegylated interferon
a-2a. HCV RNA (viral load) was determined by polymerase chain
reaction assay (Amplicor HCV Monitor vs. 2.0) at baseline
and monitored at 4-week intervals throughout the treatment
and 24-week post-treatment follow-up periods.
Results
End-of-treatment and sustained response (24 week follow-up)
were achieved in 624 and 342 patients, respectively. For all
treatments, relapse was most frequent at weeks 52 and 56 and
became rare following week 60. Only six patients out of 348
patients (2%) became HCV RNA positive between weeks 60 and
72. An analysis of baseline characteristics was conducted
but failed to identify any specific factors associated with
early or late response.
Conclusion
The authors concluded that this finding suggests that determination
of HCV RNA levels at 12 weeks of follow-up may be sufficient
for making decisions related to the management of most patients
treated with standard or pegylated interferon a.
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Regression
of Fibrosis in Chronic Hepatitis C after Therapy with Interferon
and Ribavirin
Asma Arif, MD, Robert A. Levine, MD, Schuyler 0. Sanderson,
MD, Leslie Bank, MD, Raja P. Velu PHD, Ashok Shah, MD, Thomas
C. Mahl, MD and Daniel H. Gregory, MD.
Source: Digestive Diseases and Sciences,
Vol. 48, No. 7 (July 2003), pp. 1425-1430 (© 2003)
Introduction
Interferon and ribavirin decrease necroinflammation in chronic
hepatitis C with or without virological clearance; however,
reversibility of fibrosis remains to be established.
Objective
In this retrospective study, the authors evaluated the effect
of combination therapy (interferon and ribavirin) on virological
and liver histopathological outcomes in 52 treatment naïve
patients and 79 patients unresponsive to interferon monotherapy.
Methods
One hundred four patients (predominately genotype 1) completed
interferon and ribavirin treatment after 24-48 weeks. Fifty-six
paired liver biopsies (mean biopsy interval 28 months) were
assessed by the Ishak score. Sustained virological response
(SVR) rates were 37% in naïve patients and 22% in re-treated
patients.
Results
In virological responders and nonresponders, fibrosis and
necroinflammation scores decreased by -0.91 (P = 0.04) and
-0.5 (P = 0.02) and by -2.8 (P = 0.001) and -0.66 (P = 0.06),
respectively.
Conclusion
The authors concluded that combination therapy improves fibrosis
in both virological responsders and nonresponders and treatment
strategies in virological non-responders who show fibrosis
regression should include consideration of maintenance therapy,
if such treatment eventually proves to benefit histological
outcomes. In addition they commented that efficacy should
not only judged by “virological cure” 24 weeks
after combination therapy, but by fibrosis regression.
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Dynamics
of Alanine Aminotransferase During Hepatitis C Virus Treatment
Ruy M. Ribeiro, Jennifer Layden-Alrner, Kimberly A. Powers,
Thomas J. Layden, and Alaii S. Perelson
Source: Hepatology 2003;38:509-517
Introduction
Studies of the kinetics of hepatitis C virus (HCV) decline
during interferon (IFN)-based therapy have led to insights
into treatment efficacy. However, the kinetics of serum alanine
aminotransferase (ALT), an enzyme used as a surrogate of liver
damage, have not been closely monitored, and it is not known
if they correlate with those of HCV RNA.
Objective
The objective of this prospective study was to identify the
association between ALT and HCV RNA (viral load) dynamics.
Methods
The authors analyzed 35 patients treated daily with 10 MIU
IFN-a2b with or without ribavirin for 28 days followed by
standard interferon plus ribavirin therapy.
Results
Patients exhibited 4 patterns of ALT change:
(1) exponential decay of ALT,
(2) transient increase in ALT followed by a decrease to pretreatment
or normal levels,
(3) increase in ALT to a new level, and
(4) no significant change.
By simultaneously modeling HCV and ALT
dynamics, we successfully fit the observed changes. The authors
found ALT decays with t1/2=12.7 hours. The transient increase
in ALT observed in some patients suggested a mild hepatotoxic
effect of interferon.
However, patients with a smaller initial ALT increase achieved
higher rates of viral negativity by week 72 (P = .02). The
week-4 ALT decline correlated with the HCV log drop (P=.006)
and the efficacy of therapy (P=.025).
Conclusion
The authors found that the results suggest the use of ALT
as a surrogate marker for treatment effect in patients with
elevated ALT is consistent with prior studies with standard
interferon.
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Effect
of Treatment with Peginterferon or Interferon AIfa-2b and
Ribavirin on Steatosis in Patients Infected with Hepatitis
C
Thierry Poynard, Viad Ratziu,’ John Mdllutchison,
Michael Manns, Zachary Goodman, Stefan Zeuzem, Zobair Younossi,
and Janice Albrecht
Source: Hepatology 2003; 38: 75-85
Introduction
It has been suggested that hepatitis C virus (HCV) and especially
genotype 3 is associated with steatosis. One strong argument
for a direct effect of the hepatitis C virus is the disappearance
of steatosis with the disappearance of the virus in patients
who were treated with interferon or interferon and ribavirin.
Aim
The aim of this study was to assess the impact of sustained
virologic response on steatosis using a large database of
patients with paired biopsies recently included in a multicenter
randomized trial of pegylated interferon (peginterferon alfa-2b)
and ribavirin combination. This specific aims were:
(1) to assess the prevalence of steatosis
(2) to assess factors associated with steatosis including
infection with genotype 2
(3) to assess the impact of steatosis on treatment response,
and
(4) to assess the impact of treatment on steatosis
Patients/Methods
The authors analyzed 1,428 naïve patients included in
a randomized trial. A single pathologist scored steatosis
at baseline and 24 weeks after the treatment.
Results
At baseline, steatosis was present in 935 of 1,428 patients
(65%), including 175 (83%) of 210 patients with genotype 3
versus 760 (62%) of 1,218 with other genotypes (P < .001).
The variables associated with steatosis in logistic regression
were genotype 3 (P < .00 1), triglycerides greater than
1.7 mmol/L (P < .001), body mass index greater than 27
(P<.04), age greater than 40 years (P < .001), and septal
fibrosis (P = .007).
In genotype 3-infected patients, steatosis
was associated with high viral load and with lower serum cholesterol.
Steatosis was associated with lower sustained response rate,
even after taking into account other factors (P < .001).
Among virologic responders, steatosis was much improved in
genotype 3, improvement of at least 1 grade in 77%, and disappearance
in 46% compared with other genotypes, 46% and 29%, respectively
(P<.001 both comparisons). In genotype 3 responders, the
baseline low serum cholesterol was corrected by treatment
(P < .001). Steatosis was associated with HCV genotype
3, triglycerides, high body mass index, age, fibrosis stage,
and lower virologic response to treatment.
Conclusion
The authors concluded that sustained disappearance of the
hepatitis C virus is associated with reduction of steatosis
in genotype 3 as well as a correction of baseline low serum
cholesterol.
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Predicting
Progression to Cirrhosis in Chronic Hepatitis C Virus Infection
A. J. Freeman, M. G. Law, J. M. Kaldor and C. J. Dore
National Centre in HIV Epidemiology and Clinical Research,
The University of New South Wales, Sydney, Australia
Source: Journal of Viral Hepatitis, 2003,
10, 285-293
Introduction
Predicting progression to cirrhosis is highly variable. Identifying
factors that influence outcome is important in order to counsel
patients regarding their prognosis and to help with disease
management.
Objective
To identify what factors influence HCV liver disease progression
and evaluate the consistency of cofactors across study settings.
Note: This study did not
examine co-infection with HIV or HBV but the authors commented
that these coinfections would most likely result in worse
outcomes for patients with chronic HCV infection.
Methods
The authors assessed a systematic evaluation of published
studies to identify factors associated with accelerated fibrosis
progression in patients with chronic hepatitis C virus (HCV)
infection. An ecologic analysis was used to estimate relative
risk (RR) of cirrhosis across four study methodologies:
(1) liver clinic series,
(2) post-transfusion cohorts,
(3) community- based studies and
(4) blood donor series. In each study category.
Results
The following factors were independently associated with disease
progression:
(1) male sex (RR = 1.08);
(2) heavy alcohol consumption (RR = 1.61);
(3) elevated serum ALT levels (RR = 1.23) and
(4) histology demonstrating high-grade necro inflammatory
activity.
Virological factors such as HCV genotype,
viral load and quasispecies diversity were also examined.
A Weibull distribution was used to model disease progression
at a population level. The influence of cofactors on individual
prognosis was examined and an algorithm to predict the risk
of subsequently developing cirrhosis is presented.
The authors found that four factors were
identified as influencing progression in chronic HCV infection:
(1) Gender – Male
(2) Heavy alcohol consumption (>50g alcohol/ day)
(3) Elevated ALT
(4) HAI score
(5) Age at infection
After adjusting for these cofactors, older
age at HCV infection and acquisition of HCV through blood
transfusion were not implicated in influencing disease outcome.
Conclusion
The authors concluded that despite the limitations of ecologic
analyses, the relative risk of fibrosis progression can be
attributed to specific cofactors in their study and can be
used to estimate risk of cirrhosis from the time of infection.
However, it was noted that since the vast majority of people
with chronic HCV infection present with established liver
disease in these studies, further models are needed to predict
both current stage of disease and predict future risk of disease
progression.
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Cost-Effectiveness
of Treatment for Chronic Hepatitis C Infection in an Evolving
Patient Population
Joshua A. Salomon, PhD, Milton C. Weinstein, PhD, James
K. Hammitt, PhD, Sue J. Goldie, MD, MPH
Source: JAMA, July 9, 2003—Vol 290,
No. 2
Introduction
Approximately 2.7 million US individuals are chronically infected
with the hepatitis C virus (HCV). As public health campaigns
are pursued, a growing number of treatment candidates are
likely to have minimal evidence of liver damage.
Objective
The objective of this study was to examine the clinical benefits
and cost-effectiveness of newer treatments for chronic hepatitis
C infection in a population of asymptomatic, HCV seropositive,
but otherwise healthy individuals.
Design and Setting
Cost-effectiveness analysis using a Markov model of the natural
history of HCV infection and impact of treatment. We used
an epidemiologic model to derive a range of natural history
parameters that were empirically calibrated to provide a good
fit to observed data on both prevalence of HCV seropositivity
and time trends in outcomes related to HCV infection.
Patients/Methods
Patients Cohorts of 40-year-old men and women with elevated
levels of alanine aminotransferase (ALT), positive results
on quantitative HCV RNA assays and serologic tests for antibody
to HCV, and no histological evidence of fibrosis on liver
biopsy.
Interventions
Monotherapy with standard or pegylated interferon alfa-2b;
combination therapy with standard or pegylated interferon
plus ribavirin.
Main Outcome
Measures
Lifetime costs, life expectancy, quality-adjusted life-years
(QALYs), and incremental cost-effectiveness ratios.
Results
The probability of patients with chronic HCV developing cirrhosis
over a 30-year period ranged from 13% to 46% for men and from
1% to 29% for women. The incremental cost-effectiveness of
combination therapy with pegylated interferon was as follows:
(1) Men ranged from $26,000 to $64,000 per QALY for
genotype 1 and from $10,000 to $28,000 per QALY for other
genotypes;
(2) Women ranged from $32,000 to $90,000 for genotype
1 and from $12,000 to $42,000 for other genotypes.
Because the benefits of treatment were
realized largely in the form of improvements in health-related
quality of life, rather than prolonged survivorship, cost-effectiveness
ratios expressed as dollars per year of life were substantially
higher. Results were most sensitive to assumptions about the
gains and decrements in health-related quality of life associated
with treatment.
Conclusion
The authors concluded that while newer treatment options for
hepatitis C appear to be reasonably cost-effective on average,
these results vary widely across different patient subgroups
and depend critically on quality-of-life assumptions. They
also noted that as the pool of persons eligible for treatment
for HCV infection expands to the more general asymptomatic
population, it will be imperative for patients and their physicians
to consider these assumptions in making individual-level
treatment decisions.
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