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Early discontinuation of 'ineffective' anti-viral therapy may prove less popular with patients than with health care providers
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"Discontinuation of pegylated interferon plus ribavirin in patients who are not responding to therapy - patients' views of early cessation of therapy"
Alimentary Pharmacology & Therapeutics
Volume 21 Issue 1 Page 43 - January 2005
Authors-R. D'Souza*, J. Main + , M. Crossey + , W. Rosenberg , I. M. Murray-Lyon§, C. Hayward¶ & G. R. Foster*
*Department of Gastroenterology, Hepatobiliary Group, Queen Mary's School of Medicine and Dentistry, Barts and The Royal London, London, UK; +Imperial College School of Medicine at St Mary's Hospital, London, UK; University of Southampton School of Medicine, Southampton, UK; §Chelsea and Westminster Hospital, London, UK; ¶Roche Products Ltd, Welwyn Garden, London, UK
SUMMARY
Background: Current therapy for chronic hepatitis C infection involves a course of pegylated interferon and ribavirin. Patients who do not show a virological response after 12 weeks of therapy have a low probability of sustained virological response and it is therefore recommended that such patients stop treatment.
Aim: To assess patients' views of early treatment cessation.
Methods: We conducted a open-labelled study in three UK centres, in which patients with biopsy-proven chronic hepatitis C requiring therapy were offered the choice of a full course of therapy with 40 kDa pegylated interferon- alpha 2a plus ribavirin (24 or 48 weeks depending on viral genotype) or early cessation if therapy had failed after 12 weeks.
Results: Ninety-five participants were enrolled and the majority (69%) did not wish to discontinue therapy even if it had low probability of success. In this unselected UK population, very few patients (4%) did not achieve an early virological response with the 40-kDa pegylated interferon- alpha 2a plus ribavirin and two of the four early virological non-responders decided to continue therapy.
The majority of the patients enrolled in the study (98%) were Caucasians (and from all social classes), and and our results may not be applicable to all patient populations. All the patients in this study had liver biopsy-proven moderate/severe disease.
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Conclusion: Early discontinuation of 'ineffective' anti-viral therapy may prove less popular with patients than with health care providers, and further patient-directed education regarding the cost-effectiveness of therapy will be needed if early discontinuation of unsuccessful therapy is to be accepted by patients.
Fig 1
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Introduction
Chronic infection with the hepatitis C virus (HCV) affects over 170 million individuals worldwide. 1 Therapy is currently recommended for patients with progressive chronic hepatitis C and involves a 24-48-week course of treatment with a pegylated interferon (PEG-IFN) and ribavirin. 2 Therapy is effective in over 50% of patients but is associated with side-effects and is expensive. 3, 4
As sustained virological response (SVR) ('viral eradication') is the primary aim of therapy for patients with chronic HCV infection. The ability to predict outcome and to identify non-responders during the first few weeks of therapy has the potential to avoid the inconvenience, costs and side-effects of unsuccessful therapy. Combination therapy with PEG-IFN for hepatitis C is accompanied by complex viral dynamic changes 5 that have the potential to identify treatment failure at an early stage. A number of studies have shown that patients who do not achieve an early virological response (EVR) (defined as a fall in serum HCV RNA concentration to < 50 IU/mL or a decrease of at least 2 log units after 12 weeks 6, 7 ) have a very low probability (< 3%) of achieving a SVR and most treatment algorithms recommend that patients not responding after 12 weeks of treatment should discontinue the medication. 6, 7 Patients' views of this cost-effective strategy have not yet been determined. Early testing is not recommended for genotype 2 or 3 patients in current treatment algorithms, nonetheless EVR is the best early end point for all patients regardless of genotype with negative predictive values of 99% for genotype 1 and 91% for genotype 2 or 3. 6 We included patients of all genotypes in this study as genotyping was not available for the majority of patients until the third month after starting treatment.
The purpose of this study was to try and ascertain patients' views of early discontinuation of 'unsuccessful therapy' in a 'real-life' clinical setting. Here, we show that patients prefer to continue medication even when they know that the chance of a successful response is low.
Results
One hundred and one patients were asked to participate in the study and ninety-five were willing to enter the trial. Table 1 shows the demographics of the study population. The majority of the patients enrolled in the study (98%) were Caucasians and from all social classes.
Figure 1 shows the views of the patients when asked if they wished to receive a full course of therapy or to discontinue unsuccessful therapy after 12 weeks. Prior to therapy, the majority of patients (69%) did not wish to discontinue therapy after 12 weeks even if there was no virological response. They were prepared to suffer the inconvenience and side-effects of therapy even if the chance of viral eradication was low. In our cohort of patients, only a small minority (4%) did not respond to therapy with the 40-kDa PEG-IFN alpha 2a after 12 weeks. The patients who did not respond were asked again if they wished to stop therapy and two (of 4) agreed to do so. The other two patients completed their course of therapy, but neither achieved an SVR. The EVR and SVR rates are shown in Table 2.
Discussion
Combination therapy for chronic HCV infection with a PEG-IFN and ribavirin is successful in majority of the treated patients but a significant proportion of those treated still fail to achieve a sustained response. 3,4 Considerable ingenuity has been used to analyse early virological events during combination therapy and these studies have led to robust management algorithms that allow the early identification of patients who are very unlikely to achieve an SVR. These predictive tests have been used to develop treatment recommendations that are widely followed. 5-7 However, while these algorithms have proved popular with clinicians and health care providers, patients' opinions have not, to date, been sought. In this UK-based study, we sought to determine whether patients wish to discontinue seemingly 'futile' treatment for chronic HCV.
In this observational study, the majority of patients (69%) did not wish to discontinue therapy even if it had low probability of success. All the patients in this study had liver biopsy-proven moderate/severe disease and compliance to therapy may vary depending on the severity of liver disease, thus, influencing willingness to discontinue treatment in the case of early non-response. Further studies are needed to assess this and to determine whether a pre-treatment liver biopsy modifies patient motivation. Our study involved three UK tertiary referral centres and it is possible that patients attending these centres were particularly well motivated. The majority of patients (86%) had not had their genotype analysed until after the third month and, therefore, this would not have biased our patients in favour of receiving a full course of therapy. In addition, the presence of nurse specialists within the UK may have led to the higher responses than are seen in global studies. As patients in the UK are usually treated at their local centre, it is unlikely that our patients are a self-selected group and as patients with the unfavourable genotype 1 also wished to receive a full course of therapy, it seems unlikely that the high proportion of patients with genotypes other than 1 affected our conclusions.
We questioned patients before therapy and after 3 months of treatment. Not surprisingly, all patients who were responding to therapy wished to continue. Forty-five per cent of patients had difficult-to-treat genotypes (1 and 4); however, only a handful of patients (n = 4) did not respond to therapy after 12 weeks, which was unexpected. As a result, too few early non-responders were available for validating patients' views on discontinuation. Nevertheless, the observation that half of the patients who were not responding to treatment after 12 weeks did wish to complete the course, suggests that early discontinuation of therapy in early virological non-responders may not be popular with patients and further studies are clearly indicated. Secondly, there is tentative evidence from our data that performing an EVR in genotype 2 and 3 patients was not beneficial as all of them had an EVR and went on to complete treatment. This is in concordance with current treatment algorithms for HCV. 6, 7
In the UK, anti-viral therapy for chronic HCV is free of charge to the patient. Clearly, the responses of our patients may have been very different if they were required to fund their therapy from their own resources and it is unclear whether our findings can be extrapolated to other health care systems, where the burden of medication costs falls more heavily on the individual. Moreover, the patients enrolled in our study were predominantly Caucasians and and our results may not be applicable to all patient populations. Nevertheless, our study shows, for the first time, that the assumptions of managers, clinicians and health care providers that patients will want to discontinue poorly effective therapy may not be correct. If cost-effective health care measures are to be introduced, it is clear that considerable patient education will be needed to persuade patients to stop anti-viral therapy prematurely.
Methods
This was a open-label study, in which patients with chronic hepatitis C requiring therapy were offered the choice of a full course of therapy with 40 kDa PEG-IFN alpha 2a plus ribavirin (24 or 48 weeks depending on viral genotype) or early cessation if therapy had failed after 12 weeks.
Patients with liver biopsy-proven chronic hepatitis C who were eligible for anti-viral therapy according to UK guidelines (National Institute of Clinical Excellence 2 ) were considered for inclusion in the study. Inclusion criteria were the following: aged 18-70 years, HCV antibody and HCV RNA positive, no other cause of liver disease and willing to use effective contraception during the trial. Patients were required to have had a recent liver biopsy showing 'moderate/severe' disease according to a local histopathologist. Patients were excluded if they were pregnant, unable to take effective contraception during the trial, had an abnormal electrocardiogram (ECG), decompensated cirrhosis (Childs-Pugh score >A) and any contraindication to any trial medications. The study took place at three sites (St Mary's, Chelsea and Westminster and Southampton Hospitals) and was approved by the ethics committee at all three sites.
Communication difficulties are often seen between hepatitis C patients and subspecialists. 8 We endeavoured to overcome these communication difficulties by providing each patient at all the three sites with a detailed, standardized comprehensive written information sheet before they consented to take part in the study. This ensured conformity between the multiple centres, by detailing the disadvantages and advantages of continuing anti-viral therapy, if there was no evidence of an early virological response. The chance of clearing the virus without an EVR was clearly documented. All the evidence was delivered in an unbiased and unpressurized way so that the decision to continue or stop treatment was left entirely to the patient. Patients who decided to take part gave their consent to the lead investigator at each site.
The duration of therapy was determined by the genotype of the infecting virus. Patients with HCV of genotypes 2 and 3 received 24 weeks of therapy (unless the patient elected to withdraw from therapy after 12 weeks) and patients with HCV of genotype 1 underwent a total of 48 weeks of treatment, unless they chose to withdraw prematurely. Patients were told that if treatment did not work after 12 weeks they had a 3% chance of the treatment working after 24-48 weeks. 4 Each lead investigator informed the patients that although some experts believed that long-term IFN could reduce scar tissue, 9 there was no evidence that this was the case and clinical trials were examining the issue. Patients were asked to decide whether they wished to continue till the end of treatment or stop after 3 months if treatment was ineffective and their views were recorded.
Treatment was then commenced and at the end of 12 weeks, the response to treatment was assessed by performing a quantitative polymerase chain reaction (PCR) assay [Cobas Amplicor TM HCV Monitor (version 2.0); Roche Diagnostics, UK]. After 14 weeks of therapy, patients were informed of the result of the quantitative PCR assay (performed at week 12) and allowed to chose whether or not they wished to continue therapy for a further 12 weeks (patients with HCV of genotypes 2 and 3) or 36 weeks (patients with HCV of genotype 1 or 4).
References
1 WHO. Global surveillance and control of hepatitis C. J Viral Hepat 1999; 6: 35-47.
2 National Institutes of Health Consensus Development Conference Statement. Management of Hepatitis C: June 10-12 2002. http://consensus.nih.gov/cons/116/116cdc_intro.htm .
3 Manns M, McHutchinson J, Gordon S, et al. Peginterferon a2b plus ribavirin compared to interferon a2b plus ribavirin for the treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358: 958-65.
4 Fried M, Schiffman M, Reddy K, et al. Peginterferon a 2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-82.
5 Zeuzum S, Hermann E, Lee J, et al. Viral kinetics in patients with chronic hepatitis treated with standard and peginterferon alfa-2a. Hepatology 2001; 120: 1438-47.
6 Davis GL. Monitoring of viral levels during therapy of hepatitis C. National Institutes of Health Consensus Development Conference Statement Management of Hepatitis C: June 10-12 2002. Hepatology 2002; 36: S145-S151.
7 Ferenci P, Shiffman M, Fried M, et al. Early prediction of response to 40 kDa peginterferon alfa-2a plus ribavirin in patients with chronic hepatitis C. Hepatology 2001; 34: 351A.
8 Zickmund S, Hillis S, Barnett M, et al. Hepatitis C virus-infected patients report communication problems with physicians. Hepatology 2004; 39: 999-1007.
9 Poynard T, Marcellin P, Lee S, et al. Randomised trial of interferon alfa-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group. Lancet 1998; 352: 1426-32.
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