HTA. technology overview. Overview of Granulocyte-Colony Stimulating Factor for Antiviral- Associated Neutropenia. Supporting Informed Decisions

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1 Canadian Agency for Drugs and Technologies in Health Agence canadienne des médicaments et des technologies de la santé technology overview HTA Issue 48 December 2008 Overview of Granulocyte-Colony Stimulating Factor for Antiviral- Associated Neutropenia Supporting Informed Decisions

2 Until April 2006, the Canadian Agency for Drugs and Technologies in Health (CADTH) was known as the Canadian Coordinating Office for Health Technology Assessment (CCOHTA). Publications can be requested from: CADTH Carling Avenue Ottawa ON Canada K1S 5S8 Tel Fax or downloaded from CADTH s website: Cite as: Dryden DM, Fassbender K, Doucette K, Tandon P, Milne A, Vandermeer B, Durec T. Overview of Granulocyte-colony stimulating factor for antiviral-associated neutropenia [Technology Overview number 48]. Ottawa: Canadian Agency for Drugs and Technologies in Health; Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Ontario, Prince Edward Island, Saskatchewan, and Yukon. The Canadian Agency for Drugs and Technologies in Health takes sole responsibility for the final form and content of this report. The views expressed herein do not necessarily represent the views of Health Canada or any provincial or territorial government. Reproduction of this document for non-commercial purposes is permitted provided appropriate credit is given to CADTH. CADTH is funded by Canadian federal, provincial, and territorial governments. Legal Deposit 2008 National Library of Canada ISSN: (print) ISSN: (online) O0473 December 2008 PUBLICATIONS MAIL AGREEMENT NO RETURN UNDELIVERABLE CANADIAN ADDRESSES TO CANADIAN AGENCY FOR DRUGS AND TECHNOLOGIES IN HEALTH CARLING AVENUE OTTAWA ON K1S 5S8

3 Canadian Agency for Drugs and Technologies in Health Overview of Granulocyte-Colony Stimulating Factor for Antiviral-Associated Neutropenia December 2008 We thank Julie Lavender for her assistance in creating this overview from a longer report authored by Dryden DM, Fassbender K, Doucette K, Tandon P, Milne A, Vandermeer B, Durec T. Granulocytecolony stimulating factor for antiviral-associated neutropenia: Systematic review and economic evaluation [Technology Report 115]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2008.

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5 1 Introduction Granulocyte-colony stimulating factor (G-CSF) is a hematopoetic growth factor that acts on granulocytes. It increases neutrophil production and enhances the functions of neutrophils. In Canada, there are two hematopoetic growth factors: filgrastim and pegfilgrastim. The standard antiviral treatment of hepatitis C in Canada (pegylated interferon with ribavirin) has led to neutropenia, which is a blood disorder that is characterized by an abnormally low number of neutrophils. It has been proposed that G-CSF can be used to control antiviralassociated neutropenia. There is uncertainty about the cost-effectiveness of G-CSF in comparison with that of dose reduction of pegylated interferon. The prevalence of hepatitis C in Canada is estimated to be 0.8%. Approximately 5,000 persons are newly infected each year. 1 There are six genotypes of hepatitis C virus. Genotype 1 accounts for more than 60% of cases in Canada, followed by genotype 2 (11% to 16%), genotype 3 (6% to 14%), and genotypes 4, 5, and 6 (less than 5%). 2,3 One week of G-CSF (filgrastim) therapy costs between C$206 and C$296. In Canada, pegylated interferon and ribavirin are packaged together. There are two formulations of pegylated interferon. The weekly cost of pegylated interferon alpha-2a and ribavirin is C$396. The weekly cost of pegylated interferon alpha-2b and ribavirin is between C$375 and C$416 depending on the patient s weight. 2 Objectives The purpose was to evaluate the clinical efficacy, safety, and cost-effectiveness of filgrastim or pegfilgrastim monotherapy for antiviral-associated neutropenia in adults with chronic hepatitis C infection who have not been previously treated with antiviral therapy (treatment-naïve). The objectives were met by addressing seven research questions: What is the clinical efficacy of G-CSF in improving clinical markers (for example, neutrophil count) compared with interferon dose reduction or treatment discontinuation? What is the clinical-effectiveness of G-CSF in improving patient outcomes (for example, sustained virological response, infection, survival) compared with interferon dose reduction or treatment discontinuation? What is the clinical-effectiveness of G-CSF in improving health-related quality of life compared with interferon dose reduction or treatment discontinuation? What, if any, differences in harm are there between G-CSF monotherapy and G-CSF plus epoetin (or darbepoetin) combination therapy? What is the cost-effectiveness of adding G-CSF compared with interferon dose reduction or treatment discontinuation? What is the impact on health resources (including publicly funded drug plan budgets) of funding filgrastim or pegfilgrastim compared with interferon dose reduction or treatment discontinuation? 1

6 Are there reimbursement criteria (for example, disease severity, hepatitis C virus genotype, type of interferon used) that would allow the optimal use of G-CSF in this population? 3 Clinical Review Methods A systematic review was conducted to identify controlled trials and observational studies that assessed the effect of G-CSF or dose reduction strategies to control neutropenia in treatmentnaïve adults with hepatitis C who were being treated with combination interferon and ribavirin. Using a literature search strategy designed by an information specialist, we conducted electronic searches. Updates were done in March There were no language restrictions. We identified grey literature by searching other specialized databases and the Internet, by handsearching the reference lists of included studies and abstracts of scientific meetings, and by contacting experts and authors. One of four reviewers screened studies by titles, abstracts, and keywords. Next, two of five reviewers independently examined the full text of the articles that were potentially relevant. Studies were included if they were reports of primary research and if the study design was a clinical trial, controlled before-and-after study, or prospective or retrospective observational study (cohort, interrupted time series, case series, and case control). The study population included adult patients who were treatment-naïve for antiviral therapy, who were receiving combination antiviral therapy (pegylated or non-pegylated interferon with ribavirin), and who had antiviral-induced neutropenia. The intervention in the study had to be administration of G- CSF, dose reduction of antiviral therapy due to neutropenia, or discontinuation of antiviral therapy due to neutropenia. The outcomes varied by intervention and included at least one outcome of interest (for example, neutrophil count, virological response, health- related quality of life, and adverse events or effects). Two of five reviewers worked independently to extract or verify relevant data from the included studies. Disagreements were resolved by consensus or with the help of a neutral third person. The quality of randomized controlled trials was assessed using the Jadad scale and the Schulz criteria for allocation concealment. The quality of controlled clinical trials was assessed using a modified Jadad scale. The quality of cohort studies was assessed using the Newcastle-Ottawa Scale. For the case series, we developed a 14-item tool that focused on the risk of selection bias, attrition bias, detection bias, and assessment bias. Descriptive statistics were used to summarize data. As appropriate, we calculated the risk ratio, weighted mean difference, standardized mean difference, and adverse events risks. We calculated 95% confidence intervals for each measure. Although we planned to use metaanalysis to derive pooled estimates, this was not possible because the definition of neutropenia was inconsistent across studies. 4 As a result, we synthesized data qualitatively. Fisher s exact test was used to compare dichotomous summaries between groups. 5 2

7 Results From 9,372 citations that were identified from the original searches, 9,194 were excluded, resulting in 178 potentially relevant studies, Fifty-six studies from the grey literature and 26 studies from the search update were added for a total of 260. Of these, 15 unique studies were included in the clinical review to address effectiveness 6-12 and safety There was one randomized controlled trial, 9 one controlled clinical trial, 7 two retrospective cohort studies, 6,16 and 11 case series with no controls. 8,10-15,17-20 All studies were published between 1999 and Most were conducted in the United States, with the others being conducted in France, Georgia, Germany, Greece, Italy, and Mexico (one study each). There were between eight and 255 study participants in each study. Overall, the quality of included studies was low. The randomized controlled trial had unclear allocation concealment and low methodological quality. The controlled clinical trial received a point for one component of the Jadad scale. The methodological quality of the observational studies was generally good. Because of the design of observational studies, however, there is a higher risk of bias, which means that the conclusions of this systematic review must be interpreted taking into account the quality of the primary literature. One study reported the source of funding, which was industry funding. 20 a) Clinical-effectiveness analysis G-CSF versus interferon dose reduction (neutrophil count less than /L): One randomized controlled trial 9 that included a total of 41 participants with neutropenia and genotype 1 infection compared the effect of G-CSF with that of pegylated interferon dose reduction on sustained virological response. Twenty-two people received 300 µg of filgrastim by subcutaneous injection once per week, and 19 received a dose reduction or temporary discontinuation of pegylated interferon. None of those receiving G-CSF had to reduce their dose or discontinue pegylated interferon. Those who received G-CSF had a higher rate of sustained virological response than those who had a dose reduction. Ten of 50 individuals in a case series 8 developed neutropenia and required a dose reduction of pegylated interferon after receiving a standard course of antiviral therapy. Nine of the 10 individuals were also given G-CSF (300 µg twice per week). Of the nine, eight were later able to continue with a full dose of pegylated interferon. The sustained virological response rate for those who resumed their pegylated interferon was higher than for those who did not resume interferon treatment. The difference was not statistically significant. The sustained virological response rate was the highest for the 27 individuals who did not require any dose reduction of antiviral therapy. Genotype data were not reported. G-CSF versus interferon dose reduction (neutrophil count less than /L): In Koskinas et al. s 7 controlled clinical trial, 20 patients with neutropenia received G-CSF (150 µg to 300 µg by subcutaneous injection twice per week), and 19 patients had a pegylated interferon dose reduction (for two weeks) or temporary discontinuation (for one to two weeks). All patients were genotype 1. Sustained and early virological response rates were higher for those who received G-CSF than for those who had a dose reduction. These differences were not statistically significant. 3

8 In Koirala et al. s 6 cohort study involving 60 patients, comparisons were made between 30 patients who developed neutropenia and received G-CSF (300 µg subcutaneously each week) and 30 patients who did not develop neutropenia and completed the full course of pegylated interferon and ribavirin. Most patients (70%) had genotype 1. At the end of antiviral therapy, an early virological response was achieved in more of the non-g-csf group than in the G-CSF group. The difference between groups was not statistically significant. Six months after completing antiviral therapy, a sustained virological response was achieved in 13/17 individuals in the non-g-csf group compared with 13/21 in the G-CSF factor group. The difference between groups was not statistically significant. Other outcomes: Information about health-related quality of life and long-term survival (beyond 24 weeks after completing antiviral treatment) was not reported in any of the included studies. The deaths that were reported in the studies were not attributed to neutropenia, infections, or G- CSF. Liver transplant recipients: Patients with recurrent hepatitis C after liver transplantation were examined in three case series studies A dose reduction of pegylated interferon or a dose reduction of pegylated interferon plus G-CSF were treatments for antiviral-associated neutropenia. Of the 24 patients who received G-CSF in these studies, nine achieved a sustained virological response. b) Safety analysis Five studies provided safety data on G-CSF. One study was a randomized controlled trial, 9 one was a controlled clinical trial, 7 and three were observational studies. 13,18,20 The most common adverse effects were bone pain, rash, body aches, headache, and splenomegaly. Consistent with previous research, the studies showed that adverse effects were clinically insignificant, transient, required only supportive interventions, and caused no long-term consequences. 21,22 With regard to the possible harm of taking G-CSF with epoetin (or darbepoetin), one observational study 20 found that the adverse effects were clinically insignificant, transient, and required only supportive interventions. The risk of infection that is associated with neutropenia in people who are receiving antiviral therapy is low, as shown through observational and clinical trial evidence. The infections that occurred were minor, did not require hospitalization, were managed with antibiotic or antifungal agents, and were resolved without lasting consequences. 4 Economic Review Methods Using a literature search strategy designed by an information specialist, we conducted electronic searches. We also searched for studies of adverse effects. No language restrictions were applied. Updates were done in March We identified grey literature by searching other specialized 4

9 databases and the Internet and by hand-searching the reference lists of included studies and abstracts of scientific meetings. For the economic review, literature searches produced the same results as the clinical review. One of four reviewers screened studies by titles, abstracts, and keywords; then the full text was retrieved for all potentially relevant articles and those that were deemed to be unclear. Next, two of five reviewers independently examined the full text of the articles retrieved. The inclusion and exclusion criteria for the economic studies were the same as those for the clinical review. Results We included a health economic evaluation 23 and studies that provided information on resource use and the rates of sustained virological response that were associated with using G- CSF and pegylated interferon dose reduction strategies. Chapko and Dominitz 23 evaluated the cost-effectiveness of G-CSF as an alternative to standard pegylated interferon dose reduction strategies in patients with neutropenia. In the base-case analysis, the cost per additional sustained virological response using G-CSF instead of dose reduction was $115,870 for patients with genotype 1 and $134,628 for patients with genotype 2 or 3. The cost per quality-adjusted life year (QALY) gained was $16,247 for patients with genotype 1 and $18,877 for patients with genotype 2 or 3. 5 Economic Evaluation Methods Cost-effectiveness and cost-utility analyses were conducted to compare G-CSF and pegylated interferon dose reduction strategies in treatment-naïve adult patients with antiviral-associated neutropenia (neutrophil counts less than /L). The outcome that was used to measure clinical-effectiveness was a sustained virological response. The resource use was based on standard practices, which refers to optimal or recommended practices in Canada. Information about medication dose, timing, and duration was obtained from the literature, particularly from the Canadian consensus guidelines on the treatment of chronic hepatitis C The clinical probability that neutropenia was controlled and the clinical probability that a sustained virological response was achieved were obtained from the clinical review. A costing model was developed to account for differences that were attributable to G- CSF and pegylated interferon dose reduction strategies. The costs include those for medication during treatment and incremental lifetime costs after treatment failure. Antiviral and G-CSF medication costs are dominant during treatment. All other costs are assumed to be equivalent between the two treatment arms. The modelling assumptions are described in the Technology Report. 29 The costing perspective was that of the ministry of health. The valuation of resources is reported in 2008 Canadian dollars. One-way sensitivity and extremes analyses were conducted to test the underlying assumptions in the model. 5

10 Results In the base case, when using G-CSF rather than pegylated interferon dose reduction, the cost for an additional sustained virological response is $42,737 for people with genotype 1 and $17,151 for people with genotype 2 or 3. When using G-CSF rather than pegylated interferon dose reduction, the cost per QALY gained is $7,785 for people with genotype 1 and $3,124 for people with genotype 2 or 3. The probabilities were examined through sensitivity analyses over a range of clinical scenarios. The base-case estimates were robust for people with genotype 1. In the extremes analysis, there were two worst-case scenarios in which the upper 95% limit of G-CSF and sustained virological response and the lower 5% limit of pegylated interferon dose reduction and sustained virological response were examined. In these cases, an incremental cost-utility ratio threshold for the use of G-CSF falls below what might be considered to be cost-effective. The probability that either scenario will occur is less than 5%. An economic analysis of subgroups of the hepatitis C population was not possible, because the clinical review did not provide the necessary data. As a result, we were unable to examine the cost-effectiveness of using G-CSF for people with cirrhosis, recurrent hepatitis C after liver transplantation, baseline neutropenia, or comorbidities such as HIV. 6 Limitations As with all systematic reviews, our results are limited by the available evidence. Few comparative trials were found, so the evidence on which we based our conclusions is sparse. The definition of neutropenia or the point at which treatment of neutropenia was started varied across studies. We calculated the probabilities of controlling neutropenia and achieving a sustained virological response using data from studies in which treatment was started when the neutrophil count was less than /L. Starting treatment at this point is in line with the current standard of care in Canada. It further reduced, however, the amount of available evidence. There was variability among the studies in the actual dosage and duration of G-CSF that was used. This may result in a bias in drug costs if standard dosages are assumed. Furthermore, prices were not observable, and waste could not be quantified. The potential for bias is limited because the savings due to drug costs were comparatively small. There may be a potential for improvement in the incremental cost-effectiveness ratios when a combination strategy of stepwise G-CSF administration or interferon dose reduction is adopted. It is likely that these savings would be modest. Many variations for pegylated interferon dose reduction could have been used in our model. These may affect the costs of antiviral therapy. Because our model was not sensitive to the cost of pegylated interferon, however, this would not affect our conclusions. 7 Health System Implications The estimated prevalence of hepatitis C in Canada for 2008 is between 264,000 and 330,000 people. Approximately 5,000 new people are infected each year. We assume that 65% of them will be identified as being infected and will be referred to hepatitis C virus clinics. Of these, approximately a third will be eligible for antiviral therapy. 6

11 If neutropenia is defined as neutrophil counts less than /L, it would cost an extra $11,881 per person to treat individuals with genotype 1 and an extra $4,065 per person to treat patients with genotype 2 or 3. To manage all eligible cases of neutropenia in Canada, it would cost an extra $1,333,584. If neutropenia is defined as neutrophil counts less than /L, an extra $236,451 is required. For the next seven to 10 years, pegylated interferon plus ribavirin is likely to remain the backbone of therapy. Assuming that there are no additional changes to diagnosis and treatment, the impact of adopting G-CSF will be stable in the short to immediate term. 8 Conclusion Within the limitations of existing data, the clinical review was unable to show the superiority of G-CSF versus pegylated interferon dose reduction for achieving a sustained virological response. Although the administration of G-CSF enabled patients to stay on or resume optimal antiviral therapy when compared with patients using pegylated interferon dose reduction strategies, it has not been established that this improves outcomes. The adverse effects of G-CSF treatment are transient and mild and respond to simple treatments that alleviate symptoms. Previous health economic evaluations have been limited in number and scope. This economic evaluation was undertaken from a ministry of health perspective to assess the cost-effectiveness of the use of G-CSF by treatment-naïve hepatitis C patients with antiviral therapy-induced neutropenia compared with that of pegylated interferon dose reduction. G-CSF compared with pegylated interferon dose reduction yields an incremental cost-effectiveness ratio of $42,737 per sustained virological response achieved or $7,785 per QALY gained for patients with genotype 1 infection and $17,151 per sustained virological response achieved or $3,124 per QALY for patients with genotype 2 or 3 infection. Concluding that G-CSF compared with pegylated interferon dose reduction is cost-effective may be premature in light of the weakness of the clinical data. The economic analysis will focus future efforts in gathering additional evidence. In the meantime, techniques such as program-budgeting marginal-analysis are available to decision makers to evaluate this evidence and set priorities. 9 References 1. Remis RS. Ottawa: Health Canada; Wong T, et al. CMAJ 2006;174(5): Zou S, et al. Can Commonwealth Dis Rep 2001;2753: Egger M, et al. Systematic reviews in health care: meta-analysis in context. London: BMJ Publishing Group; Agresti A. Categorical Data Analysis. 2nd Edition. New York: John Wiley and Sons; Koirala J, et al. J Viral Hepatitis 2007;14(11): Koskinas J., et al. J Hepatol 2006;44(Suppl 2):S Senkbeil LE, et al. Hepatology 2003;38(4 Suppl 1):744A. 7

12 9. Sharvadze L, et al. Georgian Med News 2007;(147): Gopal DV, et al. Liver Transpl 2001;7(3): Neumann U, et al. Transplantation 2006;82(1): Sharma S, et al. Liver Transpl 2007;13: Ball LM, et al. Gastroenterology 1999;116(4 Part 2):A Jeffers LJ, et al. Hepatology 2004;39(6): Juarez-Navarro A, et al. Methods Find Exp Clin Pharmacol 2005;27(5): Puoti M, et al. Antiviral Ther 2004;9(4): Renou C, et al. J Hepatol 2002;26(Suppl 1): Sood A, et al. Hepatology 2001;34(4 Pt 2):429A. 19. Soza A, et al. Hepatology 2002;36(5): Younossi ZM, et al. J Viral Hepat 2008;15: Barge AJ. Bone Marrow Transplant 1993;11(Suppl 2): Przepiorka D, et al. Blood 2001;97(11): Chapko MK, et al. Aliment Pharmacol Ther 2006;24(7): Carey E, et al. Hepatology 2002;36(4 Part 2):604A. 25. Fried MW, et al. N Engl J Med 2002;347(13): Gotardo DRM, et al. Liver Transpl 2007;13(Suppl 1):S152-S Maddrey WC. Semin Liver Dis 1999;19(Suppl 1): Manns MP, et al. Lancet 2001;358(9286): Dryden D, et al. Granulocyte-colony stimulating factor for antiviral-associated neutropenia: systematic review and economic evaluation [Technology report]. Ottawa: Canadian Agency for Drugs and Technologies in Health;