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Clinical & Cost Implications of Early Viral Response Treatment Management Algorithms & Adherence During PegInterferon and Ribavirin Therapy
 
 
  CLINICAL IMPLICATIONS OF TESTING VIRAL RESPONSE DURING RIBAVIRIN AND PEGINTERFERON ALFA-2B TREATMENT FOR CHRONIC HEPATITIS C
 
AASLD, Nov 2002
 
Testing viral response during antiviral therapy can predict the likelihood of sustained viral response and could enable treatment discontinuation in those unlikely to respond with further therapy. Criteria for defining early viral response during treatment could vary by timing and degree of viral response. The ideal criteria would not miss any sustained viral responses.
 
The aim of this study is to determine optimal viral response criteria for monitoring response to ribavirin+peginterferon alfa-2b. We examined qualitative (viral negative) and quantitative (in 1/2 log viral load decrements) responses at weeks 4, 12 and 24 to 800 mg of ribavirin daily and 1.5 mcg/kg peginterferon alfa-2b weekly (PegR8) for 48 weeks (Manns Lancet 2001) and the subset receiving >10.6 mg/kg of ribavirin (PegRW). We determined the likelihood of sustained viral response and the clinical impact on missed sustained viral responses and discontinuations for each early viral response criteria.
 
Patients achieving 4 week viral negative responses had an 89-91% likelihood of sustained viral response, but applying such stringent criteria would have led to prematurely discontinuing therapy and missing 51-57% of sustained viral responses. Delaying assessment until week 24 would have missed none of the sustained viral responses (negative predictive value=100%) but would have prolonged therapy unnecessarily in 18-21% of patients. The optimal early viral response criteria consisted of a viral negative or a 2 log decrease in viral load after 12 weeks of therapy. Using this early viral response definition, the table shows sustained viral response results for patients with a positive early viral response (positive predictive value). Among these early viral responders, adherence for 80% of the duration and 80% of the dose of both drugs (80/80/80+) increased the sustained viral response by another absolute 3-5%. For either PegR8 or PegRW, applying this early viral response criteria would result in missing none of the sustained responders (negative predictive value=100%). Overall, 21% of patients receiving PegR8 and 18% of those receiving PegRW did not achieve an early viral response and could have therapy stopped after 12 weeks. For genotype 1, 29% for PegR8 and 25% for PegRW could have stopped therapy after 12 weeks. Rechecking a qualitative PCR at week 24 would have allowed discontinuation of therapy in 40-48% of patients with 2 log decrease at week 12. For genotype 2/3, 1% for PegR8 and none for PegRW could have stopped therapy after 12 weeks.
 
Our results suggest that viral response at 12 weeks can accurately distinguish subgroups with a high likelihood of sustained viral response. Such testing for genotype 2/3 may be unnecessary because of the high likelihood of early viral response and sustained viral response. Clinical decisions to continue ribavirin and peginterferon alfa-2b should also consider variability in the accuracy of quantitative viral assays, potential stabilization of fibrosis progression in patients with advanced histology, and patient tolerance to treatment.
 
John B Wong, Tufts-New England Medical Center, Boston, MA; Gary L Davis, Baylor University Medical Center, Dallas, TX; John G McHutchison, Scripps Clinic, La Jolla, CA; Michael P Manns, Medizinische Hochschule Hannover, Hannover, Germany; Janice K Albrecht, Schering-Plough Research Institute, Kenilworth, NJ
 
EFFECT OF TREATMENT MANAGEMENT ALGORITHMS ON RIBAVIRIN AND PEGINTERFERON ALFA-2B COSTS FOR CHRONIC HEPATITIS C
 
AASLD, Nov 2002
 
Peginterferon alfa-2b and ribavirin have the highest sustained response rates for chronic hepatitis C but published drug cost estimates usually assume full dosing for 48 weeks. These estimates neglect dose reductions and discontinuations that occur during treatment as well as clinical management algorithms that lead to drug stoppage in those unlikely to benefit from further therapy.
 
The aim of this study is to estimate the antiviral drug costs associated with peginterferon alfa-2b+ribavirin. We analyzed actual drug dosing for 511 patients who were intended to receive 800 mg of ribavirin daily and 1.5 mcg/kg peginterferon alfa-2b weekly (PegR8) for 48 weeks and for the subset receiving >10.6 mg/kg of ribavirin (PegRW) (Manns Lancet). Based on ribavirin capsules and peginterferon vials used in this trial, we determined the drug costs for 1) full dosing (Full), 2) intent to treat with reductions and discontinuations as occurred in the trial (ITT), 3) discontinuing therapy in those who were HCV RNA-positive after 24 weeks (Stop24), 4) criteria in Stop24 and also limiting therapy in those with genotype 2/3 to 24 weeks (Stop2/3), and 5) criteria in Stop2/3 and also discontinuing therapy in those viral positive or with <2 log drop in viral load in non-genotype 2/3 patients after 12 weeks (Stop12). Any missing PCR values were assumed to be positive.
 
The table shows the drug costs for both regimens and shows that these management algorithms result in substantial reductions in likely drug costs. Checking a qualitative PCR at week 24 would allow discontinuation in the 31-36% of patients who are unlikely to respond with further therapy. If the duration of therapy is also limited to 24 weeks for those with genotype 2/3, in all, 60-61% may stop therapy after 24 weeks. Checking a qualitative and a quantitative PCR at week 12 and discontinuing therapy for those PCR positive with <2 log decrease in viral load would allow stopping therapy for 23-24% of patients at week12. Because most genotype 2/3 patients respond by 12 weeks, also applying the same Stop12 rule for those with genotype 2/3 would only increase drug stoppage at week 12 to 24-26% of all patients. Although the goal was 48 weeks of treatment, the overall observed ITT mean duration of therapy was 42 weeks. Alternative management algorithms would decrease the overall mean duration of therapy for all patients to 37 weeks with Stop24, 31 weeks with Stop2/3 and 29 weeks with Stop12. For the 61-62% of patients affected by these treatment management algorithms, the observed mean 40 week therapy duration with ITT would be reduced to 31-32 weeks with Stop24, 21 weeks with Stop2/3 and 18-19 weeks with Stop12.
 
Our results suggest that treatment management algorithms substantially reduce antiviral drug costs and the duration of therapy. Drug costs should be weighed against the cost and likelihood of complications from hepatitis C and should consider therapeutic effectiveness. Individual decisions to continue ribavirin and peginterferon alfa-2b should also consider the potential clinical benefits for specific patient characteristics, such as advanced fibrosis.
 
John B Wong, Tufts-New England Medical Center, Boston, MA; Gary L Davis, Baylor University Medical Center, Dallas, TX; John G McHutchison, Scripps Clinic, La Jolla, CA; Michael P Manns, Medizinische Hochschule Hannover, Hannover, Germany; Janice K Albrecht, Schering-Plough Research Institute, Kenilworth, NJ
 
This study abstract was submitted for presentation at AASLD but was not accepted for presentation by the review committee.
 
Economic and Clinical Implications of the Loss of Adherence to Weight-Based Dosing of Ribavirin and PegInterferon alfa-2b for Chronic Hepatitis C
 
AASLD November 2002
 
Editorial note from Jules Levin: from a patient point of view these study results suggest that better adherence improves chances of developing cirrhosis, improves life expectancy, quality-adjusted life expectancy, and also reduces costs to the healthcare system. Therefore, adherence programs are just as important in HCV as they are in HIV and financial support to implement them should come from the US Federal, state and local governments.
 
Adherence to the intended drug dosage for the intended therapeutic duration with ribavirin and peginterferon alfa-2b for chronic hepatitis C virus leads to the highest sustained viral response rate.
 
The aim of this study is to estimate the clinical and economic cost of the loss of adherence to ribavirin plus pegylated interferon alfa-2b. We divided 188 patients who received >10.6 mg/kg of ribavirin daily and 1.5 mcg/kg pegylated inteferon alfa-2b weekly for 48 weeks (Manns Lancet 2001) into 3 groups: 1) <80, with 31 patients receiving drug for <80% of the 48 weeks; 2) >80/<80 with 51 patients receiving <80% of the dose of either drug but treated for >80% of the 48 weeks; and 3) >80/80/80, with 106 patients receiving >80% of the dose of both drugs for >80% of the 48 weeks.
 
We examined sustained response rates and drug use, and applied these data to a computer cohort simulation (Wong JAMA 1998) to project lifelong clinical and economic outcomes.
 
The table shows the results. The relatively high cirrhosis incidence reflects that only 15% of trial participants had mild hepatitis. Just attempting combination therapy (even without completing 80% of the 48 weeks) would decrease the relative incidence of cirrhosis by 37% and extend life by 1.9-2.6 years at a $6,000 savings. If adherence could be improved so that treatment occurs for >80% of the 48 weeks (even with <80% of the drug dosage), the gains are even larger: a doubling of the sustained response rate, a 58% reduction in cirrhosis, a 3-4 year increase in life expectancy and over $10,000 in savings. Finally, increasing adherence to >80/80/80 would increase sustained viral response by a further 15%, reduce cirrhosis by 74%, increase life expectancy by 4-6 years and reduce costs by >$15,000. When including antiviral costs, moving from no therapy to <80 had a marginal cost-effectiveness ration of $2,700 per quality-adjusted life year gained; and lastly moving from >80/<80 to >80/80/80 had a cost-effectiveness ratio of $1,000 per quality-adjusted life year gained. Even with discounting, these ratios were all <$11,000 per quality-adjusted life year gained.
 
We conclude that these results suggest that the loss of adherence leads to decreases in sustained viral responses, higher future liver complication rates and costs, and decreased survival. Clinical studies to improve adherence should be performed. Increased adherence would prevent the loss of potential benefit from combination therapy resulting from premature discontinuation or dose reduction.
 
 
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