This Web Site is committed to the memory of Janis Morrow.
54th Annual Meeting of
The American Association for
the Study of Liver Diseases
October 24, 28- 2003
Boston, Massachusetts
Page Eight
Ribavirin Issues
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Ribavirin Dosage Significantly Affects Virological
Response Rates in HCV Patients Treated with Interferon/Ribavirin http://www.hivandhepatitis.com/2003icr/03_assld/main.html
The influence of absolute dose and dose in mg per kg body weight of
ribavirin on sustained virologic response (SVR) in interferon-based
combination treatment of chronic hepatitis C as well as the influence of
dose reduction is still controversial. In this study, investigators address this problem by reanalyzing data of 343 previously untreated patients with chronic hepatitis C from a multicenter trial who were treated with Pegasys (interferon alfa-2a) plus ribavirin and amantadine or interferon alfa-2a plus ribavirin (Berg et al, Hepatology 2003, 37, 1359-1367) and completed therapy.
The researchers used a multivariate approach to account for correlations of
the dose of ribavirin with body weight and body mass index (BMI) and known
predictor variables from this data set which are low baseline HCV RNA, high
platelet counts, high pretreatment ALT, and low γ glutamyl transpeptidase (GGT)
as well as HCV genotype non-1. Because per protocol, dosage of ribavirin was weight-adjusted (1000 mg for body weight below 75 kg and 1200 mg for body weight 75 kg or more) and body weight was positively correlated with GGT and negatively correlated with platelet counts, respectively, the investigators used a stratification with respect to genotype (GT 1 vs. non-1), GGT, and platelet counts in the analysis of ribavirin dose.
When comparing body weight, BMI, the absolute intention to treat (ITT)
ribavirin dose as well as the ITT dose of ribavirin measured in mg per kg
body weight and the respective ribavirin doses at the end of treatment (EOT),
a significant association with SVR was found for the EOT ribavirin dosage
(mg per kg body weight) and BMI (p=1.8% and p=3.0%, respectively).
For predicting SVR, a weight-based ribavirin dosage threshold of 13.75 mg/kg
was calculated using receiver operating characteristics (ROC) curves. The
SVR rate was 66% (112/169) in patients with a ribarivin dose of more than
13.75 mg/kg as compared with 46% (79/172) in patients receiving equal or
less than 13.75 mg/kg ribavirin at EOT. In conclusion, the analysis of ribavirin dosage motivates new considerations of weight-adjustments of the ribavirin dosage to further increase SVR in HCV-infected patients treated with combination therapy. 10/27/03
Reference
Peginterferon Commonly Causes Clinically Significant
Depressive Symptoms, but Not Major Depression, and Ribavirin May Contribute
to Depression in a Dose-dependent Manner Interferon (IFN)-alfa plus ribavirin is the only FDA-approved treatment for hepatitis C (HCV) infection. Unfortunately, IFN-alfa/ribavirin therapy is associated with depression in a high percentage of patients.
To further examine the
development of depression during treatment for HCV and the risk factors
involved, researchers conducted a 24-week prospective cohort study of
patients receiving PEG-Intron (pegylated IFN-alfa-2b/PEG IFN) and ribavirin
for the treatment of HCV. The study sample was derived from a larger multi-center, randomized clinical trial designed to compare the efficacy of standard versus weight based dosing of ribavirin plus PEG IFN. 150 patients from this trial volunteered to participate in the study, completed 24 weeks of treatment with PEG IFN/ribavirin and were included in data analysis. Subjects were evaluated at baseline (prior to start of PEG IFN/ribavirin) and following 4, 8, 12 and 24 weeks of therapy. At baseline, subjects were screened for past or current major depression and substance abuse by telephone. Subjects also completed the Zung Self Rating Depression Scale (SDS), a 20-item self-report instrument widely used to evaluate depressive symptoms in the medically ill.
The development of
clinically relevant depressive symptoms was considered to have occurred if
patients developed an SDS score equal to or greater than 60 (consistent with
the presence of moderate to severe depression) at any point during the 24
week treatment period. Study Results Mean SDS score at baseline for the study sample as a whole was 41.8 (SD 10.0). During 24 weeks of IFN-alfa/ribavirin treatment, mean maximum SDS score for the group as a whole increased to a maximum of 55.6 (SD 10.2), with the majority of the increase from baseline occurring in the first 4 weeks of treatment. Thirty eight percent of patients developed SDS scores equal to or greater than 60 during treatment, while 11% of patients met criteria for major depression. In a univariate analysis, factors that correlated with the development of clinically significant depressive symptoms included weight-based dosing of ribavirin and past history of major. Weight-based ribavirin dosing continued to predict the development of depressive symptoms after adjustment for age, gender, past history of depression, antidepressant use at baseline or during treatment, history of substance abuse and baseline SDS score. Past history of major depression did not predict the development of depressive symptoms after adjustment for these factors, suggesting that the effect of past major depression may be mediated in part by an increased likelihood of patients with a history of depression having elevated SDS scores at baseline. Consistent with this, patients with a past history of major depression had significantly higher baseline SDS scores. Baseline SDS score predicted the development of significant depressive symptoms. Conclusions Results from this study suggest that the development of clinically significant depressive symptoms, but not major depression, is common in patients receiving pegylated PEG IFN plus ribavirin for HCV infection. Moreover, while PEG IFN has traditionally been viewed as the causative agent for depression during combined therapy, these data indicate that ribavirin may also contribute to the development of depressive symptoms, and that the effect may be dose related. Finally, the association between past depression and the development of depressive symptoms during treatment appears to be mediated by the increased likelihood for patients with a past history of depression to demonstrate increased depressive symptoms just prior to commencing IFN-alfa/ribavirin therapy. This finding highlights the importance of evaluating a patient’s mood status prior to commencing treatment for HCV. 10/27/03
Reference
At 24 Weeks, a Ribavirin Dose of 1000mg/day Appears to
Offer No Advantages Over a Dose of 800mg/day in HIV-HCV Coinfected Patients
The purpose of this trial
was to evaluate the efficacy and safety of Pegasys (peginterferon
alfa-2a/40KD) in combination with two different doses of Copegus (ribavirin)
in patients with HIV-HCV coinfection. Patients aged ≥18 years with HIV/HCV coinfection, HCV RNA levels >600 IU/mL, elevated ALT levels, liver biopsy findings consistent with a diagnosis of chronic hepatitis C, and a CD4+ cell count ≥200 cells/mm3 were eligible for this randomized multicenter, open-label, pilot study. Patients had not received previous treatment with interferon or ribavirin, and had either been receiving stable highly active antiretroviral therapy (HAART) for ≥6 weeks or were willing to delay inititation of HAART for ≥6 weeks.
Patients were excluded if
they had an absolute neutrophil count <1500 cells/mm3, hemoglobin levels <11
g/dL (women) or 12 g/dL (men), platelet count <90,000 cells/mm3, liver
fibrosis with a severity of ≥4 on the METAVIR scale, an active HIV-related
opportunistic infection or other serious systemic disease.
All patients received
Pegasys 180 μg once weekly and were randomized to treatment with ribavirin
at a dosage of 800 or 1000 mg/day for 48 weeks. Virological response was
defined as undetectable HCV RNA (<50 IU/mL by COBAS AMPLICOR® HCV Test,
v2.0). Virological results at week 24 are presented here.
Study Results
One hundred forty-nine
patients were randomized, and 144 started treatment and received at least
one dose of peginterferon alfa-2a (40KD) and ribavirin 800 mg/day (n = 70)
or 1000 mg/day (n = 74). To date, virological response data after 24 weeks
are available for 108 patients. The two treatment groups were comparable
with regard to baseline characteristics.
The overall virological
response (HCV RNA <50 IU/mL) at week 24 was 59.3% (64 of 108 patients) (see
Table below). In patients with HCV genotypes 1, 2/3 and 4, virological
responses were obtained in 47.5% (28/59), 84.4% (27/32) and 52.9% (9/17),
respectively. Virological response rates were generally similar in those
receiving Pegasys and either ribavirin 800 mg/day (55.1%) or 1000 mg/day
(59%).
None of the following
baseline factors significantly affected the probability of achieving a
virological response at 24 weeks: sex, body weight, age, HCV genotype, HCV
RNA levels, HIV RNA levels, CD4+ cell count, receipt of HAART,
aminotransferase levels, extent of liver fibrosis.
Adverse event data are
available for 118 patients. Adverse events were similar to those reported in
trials with this combination in HCV monoinfected patients. The most common
adverse events were neutropenia (n = 33), fever (21), influenza-like
symptoms (21), asthenia (18), and gastrointestinal events (14). Anemia was
reported in 6 patients. The majority of adverse events were mild (57.6%) or
moderate (36.4%) in severity. Seven patients withdrew from the study because
of adverse events.
Conclusion
11/10/03
Reference
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