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Fwd: [NATAP] Age & Ribavirin Dose Affect PegIFN/RBV Therapy

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  • claudine intexas
    hcv@natap.org wrote: NATAP - http://www.natap.org Age & Ribavirin Dose Reductions Reduce SVR to Peginterferon+Ribavirin Reported by Jules Levin EASL April
    Message 1 of 1 , Apr 15, 2005
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      hcv@... wrote:

      NATAP - http://www.natap.org

      Age & Ribavirin Dose Reductions Reduce SVR to Peginterferon+Ribavirin

      Reported by Jules Levin
      EASL
      April 13-17, 2005
      Paris, France

      Reductions in ribavirin dosing decreases liklihood of achieving a sustained viral response. Missing doses of ribavirin particularly during the first 12 weeks after starting therapy is worse in reducing likelihood of achieving SVR. Reductions in RBV dosing is more likely to compromise achieving SVR than reducing of peginterferon dosing.

      Age affects response to HCV therapy with peginterferon plus ribavirin. This has been observed in many studies over the years. The study presented at EASL & discussed below found 67% SVR for patients <40 yrs vs 44% for patients >40 yrs. Read the results below because the older patients also had some negative predictive factors.

      Taken together these studies suggest: don't miss nor reduce ribavirin doses, or you will compromise your ability to achieve SVR, and when you delay therapy by years you may compromise your ability to achieve SVR.

      Roche released a Press Announcement today containing a brief summary of these 2 studies plus a third study. But I took the opportunity to add much more information from the studies to the summaries below.

      Press Release
      ���New Data on Most Prescribed Hepatitis C Therapy Pegasys(R) Presented at European Association for the Study of the Liver (EASL) Conference���

      PARIS, April 15 /PRNewswire/ -- New Pegasys(R) (peginterferon alfa-2a) data, including exploration of factors associated with treatment response in hepatitis C patients, were revealed in 33 oral and poster presentations at the 40th Annual Meeting of The European Association for the Study of the Liver, April 13 - 17, in Paris, France.

      Pegasys and Copegus(R) (ribavirin, USP), are approved by the U.S. Food and Drug Administration for the treatment of chronic hepatitis C and are the only combination regimen FDA-approved for the treatment of chronic hepatitis C in patients coinfected with hepatitis C and HIV.

      Hepatitis C is a blood-borne virus that chronically infects an estimated 2.7 million Americans. The virus is a leading cause of cirrhosis and liver cancer and is the number-one reason for liver transplants in the U.S.

      According to the Centers for Disease Control, approximately 1.25 million Americans are chronically infected with hepatitis B, a virus that can be transmitted through sexual contact and contact with infected blood.

      Data from several Pegasys studies will be presented and discussed at the meeting, including:

      1. The Influence of Cumulative Peginterferon Alfa-2a (40 KD) and Ribavirin (RBV) Exposure on Sustained Virological Response (SVR) Rates in Patients with Genotype 1 Chronic Hepatitis C (Viral Hepatitis: Hepatitis C Clinical Poster Session; 4/15/05)

      This analysis of pooled data from two phase III trials looked at the relationship between cumulative ribavirin exposure (total drug administered) and the desired outcome (sustained virological response, or SVR) in 569 chronic hepatitis C patients treated with Pegasys and ribavirin.

      Patients infected with genotype 1 were more likely to maintain the prescribed dose of Pegasys than the prescribed dose of ribavirin during 48 weeks of treatment. Indeed, almost 75% of all patients maintained full exposure to Pegasys. Reductions in the dose of ribavirin were more likely to compromise the liklihood of achieving an SVR than reductions in the dose of Pegasys. Avoiding RBV dose reductions & discontinuations within the first 12 weeks particularly, but as well between weeks 12 and 48, will likely improve overall SVR rates in patients infected with genotype 1. These findings have been observed in studies previously. It is important to consider taking EPO if anemia (reduced hemoglobin occurs). Studies show that taking EPO improves hemoglobin, and improves fatigue & quality of life.

      The analysis found that as the cumulative dose of ribavirin decreased, SVR rates also decreased. Sixty-six percent of patients who took greater than 97 percent of the recommended ribavirin dose achieved an SVR compared to only 33 percent in patients who took less than 60 percent of the recommended ribavirin dose.

      Note on this poster from Jules Levin: here is additional key information reported on the poster. There was also a positive correlation between cumulative ribavirin exposure during weeks 1-12 & SVR. However, lower SVR rates in patients with reduced exposure during weeks 1-12 cannot be attributed solely to early dose reductions because most of these patients (>75%) continued to have reduced exposure to ribavirin throughout the 48-week treatment period.

      For every 10% reductionb in total cumulative RBV dose between weeks 1 & 48 the odds of an SVR decreased by a factor of 0.82. for every 10% reduction in the total cumulative ribavirin dose after week 12 the odds of an SVR decreased by a factor of 0.79.

      SVR RATE ACCORDING TO CUMULATIVE EXPOSURE TO RIBAVIRIN IN WEEKS 1 to 48 IN PATIENTS COMPLETING 48 WEEKS OF TREATMENT WITH PEGASYS.

      e97% (n=245): 66% SVR
      80 to <97% (n=81): 62% SVR
      60 to <80% (n=68): 57% SVR
      <60% (n=33): 33% SVR
      Total (n=427): 62% SVR
      p-value=0.0056 across all cumulative exposure levels.

      SVR RATE ACCORDING TO CUMULATIVE EXPOSURE TO RBV IN WEEKS 1 to 12 IN PATIENTS COMPLETING 48 WEEKS of TREATMENT WITH PEGASYS.

      e97% (n=325): 66% SVR
      80 to <97% (n=56): 57% SVR
      60 to <80% (n=44): 45% SVR
      <60% (n=2): 0%
      total n=427: 62% SVR

      REASONS FOR RBV DOSE REDUCTIONS
      SVR rates were lower in patients who required RBV dose reductions during the first 12 weeks (49%) than after week 12 (61%) of therapy for adverse events or lab abnormalities.

      A total of 76 of 427 patients (18%) required RBV dose reductions for anemia or adverse reactions/lab abnormalities during the first 12 weeks of therapy and 102 (24%) required RBV dose reductions after week 12. A further 190 (44%) patients had the dose of RBV reduced for other reasons, and 59 patients (14%) did not require dose reductions.

      SVR RATE According to the reason for & timing of RBV dose reductions in patients completing 48 weeks of treatment with Pegasys.

      ADVERSE EVENT or LAB ABNORMALITY
      <12 weeks
      all: 49%
      anemia: 54%
      other: 40%

      >12 weeks
      all: 61%
      anemia: 64%
      other: 58%

      non-safety reasons: 65%
      no dose reduction: 68%


      2. Age and Sustained Virological Response in Patients With Persistently 'Normal' ALT and Chronic Hepatitis C Treated With Peginterferon Alfa-2a (40KD) Plus Ribavirin (Viral Hepatitis

      A retrospective analysis of 422 chronic hepatitis C patients (in a randomized multinational phase III trial) with persistently 'normal' ALT levels showed that younger patients had higher response rates to Pegasys and Copegus treatment compared to older patients. Patients received Pegasys 180 ug/week plus RBV 800 mg/day for either 24 weeks or 48 weeks plus 24 weks of treatment-free followup. The study was designed before the optimal treatment regimen for genotype 1 was established as 48 weeks with 1000/1200 RBV mg/day. There has been previously observed to be a negative relationship between increasing age & the probability of achieving an SVR in patients with chronic HCV & elevated ALT activity; thus younger patients have a higher probability of achieving an SVR with peginterferon plus RBV than older patients.

      The older patient group in this study had a higher mean viral load and a greater proportion of Black patients than the younger group. Black patients do not respond as well to therapy as Caucasians and lower viral loads have a better response rate than higher viral loads.

      In the study, patients were divided into two groups based on age (<40 or >40), and were treated for 24 or 48 weeks. The study found that overall 67% of patients in the younger group (n=75) achieved an SVR compared to 44% of those in the older group (n=135) (p=0.002; Odds Ratio: 2.58). Among patients with genotype 1, 54% of patients in the younger group (n=46) had an SVR compared to 34% in the older group (n=95) (p=0.020; Odds Ratio: 2.34).

      Among patients with genotype 2 or 3, an SVR was achieved by a lower percentage of patients aged >40 yrs than <40 after either 24 weeks (69% vs 79%, respectively; p=0.44 NS, OR: 1.67) or 48 weeks of treatment (71% vs 88%, respectively; p=0.15 NS, OR= 2.80).


      3. Clustering of Poor Prognostic Factors in Patients with Chronic Hepatitis C

      An analysis of 2,404 patients from two multinational, randomized, controlled phase III studies showed that a cluster of poor prognostic characteristics, and not weight alone, may explain why lower response rates to therapy are observed in heavier patients, irrespective of the pegylated interferon therapy used.

      Patients were divided into three weight categories: <65 kg, <65-<85 kg, >85 kg. As previous studies with both pegylated interferons have shown, the patients in the highest weight category experienced lower SVR rates than lighter weight patients. The heaviest patients were also more likely to be male, black, cirrhotic, and infected through intravenous drug use, which are characteristics that are typically associated with lower treatment response rates.

      About Pegasys

      Pegasys, a pegylated alpha interferon, and Copegus, an oral antiviral medication, were approved by the FDA in December 2002 for use in combination for the treatment of adults with chronic hepatitis C who have compensated liver disease and have not previously been treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis. In addition, Pegasys is the only pegylated interferon approved by the FDA for use alone and in combination with Copegus for the treatment of chronic hepatitis C in patients coinfected with hepatitis C and HIV who are clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy).

      Roche filed a submission with the U.S. Food and Drug Administration in 2004 to market Pegasys for the treatment of hepatitis B. Action on the submission is expected in 2005.


      Facts About Pegasys (Peginterferon alfa-2a) in Combination with Copegus

      PEGASYS, alone or in combination with COPEGUS(R), is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that is clinically stable (eg, antiretroviral therapy not required or receiving stable antiretroviral therapy).

      Alpha interferons, including PEGASYS(R) (Peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).

      Use with Ribavirin. Ribavirin, including COPEGUS(R), may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).

      PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment. Pegasys is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).

      COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.

      Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. During treatment, patients' clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score greater than or equal to 6) is observed.

      The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed in clinical trials (N=451) were fatigue/asthenia (65%), headache (43%), pyrexia (41%), myalgia (40%), irritability/anxiety/nervousness (33%), insomnia (30%), alopecia (28%), neutropenia (27%), nausea/vomiting (25%), rigors (25%), anorexia (24%), injection site reaction (23%), arthralgia (22%), depression (20%), pruritus (19%) and dermatitis (16%). The adverse event profile of coinfected patients treated with PEGASYS and COPEGUS was generally similar to that shown for monoinfected patients. Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%) weight decrease (16%) and mood alteration (9%).

      Serious adverse events included neuropsychiatric disorders (suicidal ideation and suicide attempt), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including psoriasis and lupus), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).

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