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Hepatitis C virus (HCV) infection affects up to 200 million individuals worldwide and is an important cause of both morbidity and mortality. Indeed up to 30% will develop cirrhosis with the attendant risks of liver failure and the development of hepatocellular cancer (HCC).[2, 3] Antiviral treatment has improved during the last two decades, but sustained virological response (SVR) rates remained below 50% for individuals infected with genotype 1 HCV who were treated with pegylated interferon and ribavirin. Since these were until recently the only available treatments many patients have been treated and not cured. Many of these individuals have cirrhosis, are at significant risk from liver related mortality and are prime candidates for more efficacious treatments that will reduce this mortality risk. To estimate this risk reduction it is crucial to understand the impact of the surrogate outcome of SVR on liver-related morbidity and mortality. This understanding permits well-informed discussion with patients who are considering retreatment.
In the last year, the first generation of directly acting antiviral (DAA) agents has been licensed for treatment of patients with genotype 1 HCV infection. These are NS3 serine protease inhibitors that, when used with pegylated interferon and ribavirin, substantially improve response rates and have the potential to cure many individuals who would not have been cured with the previous standard of care.[5, 6] This increased cure rate comes at the expense of increased adverse events and an increased pill burden. Furthermore, DAAs have the potential to cause drug resistance, analogous to that seen with antiviral treatment for human immunodeficiency virus and hepatitis B virus (reviewed in). Resistant species are associated with antiviral treatment failure, but the long-term ramifications of resistance are not known. It is possible that resistance to these agents will compromise the chance of treatment success with regimens that contain similar agents in the future. To limit the development of resistance, all of the phase II and III studies employed strict stopping rules to prevent futile drug exposure. Despite this up to 50% of those treated and who were not cured still developed drug resistant variants although these were frequently short-lived in the plasma.
In the boceprevir development programme and in the phase III study of previously treated subjects with telaprevir, a 4-week lead-in phase with pegylated interferon and ribavirin was employed.[8-10] This strategy confirmed that interferon responsiveness was a key determinant of successful treatment. It has been suggested that the lead-in could be used to identify individuals with poor interferon response where treatment with first-generation protease inhibitors should be avoided, thus eliminating the risk of drug resistance and reducing the frequency and severity of treatment-associated adverse events.[11-13] Indeed, some experts would use the 4-week lead-in with both telaprevir and boceprevir where poor interferon response might be expected to aid decision making. This approach is the subject of intense debate as some patients with poor response during the lead-in phase are subsequently cured with DAA containing treatment.
The aims of this study were therefore twofold: first to quantify the benefit associated with protease inhibitor treatment in previously treated subjects to aid patient selection for treatment, and second to evaluate the benefits and risks of using a lead-in phase with interferon and ribavirin dual therapy to identify patients who will benefit from addition of a protease inhibitor. The comparative effectiveness of treatment strategies was assessed using hypothetical patient cohorts over a clinically relevant 5-year follow-up period.
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The development of novel DAA agents targeting HCV has the potential to significantly improve outcomes for subjects with HCV infection.[5, 6] There are however a number of questions regarding how, and in whom, these agents should be used.[13, 14, 31] This analysis provides a clear rationale for prioritising subjects with advanced fibrosis who are at significant risk of liver-related morbidity and mortality for treatment. This group represents at least 25% of infected subjects at current estimates and targeted treatment offers the potential to reduce liver-related mortality in a relevant timeframe. Our modelling cautions against the use of the 4-week lead-in phase as a universal decision point in subjects with advanced fibrosis as this strategy will disadvantage as many as 37% of subjects who would otherwise ultimately have derived benefit from continued treatment.
Recent licensing of DAA agents has brought further complexity to the management of genotype 1 HCV infection. In addition, the rapid development of new agents has led to uncertainty regarding which subjects to treat now, and which patients might be deferred from treatment. Using the analyses presented here we have illuminated this difficult topic, particularly highlighting the benefits of treating subjects with advanced fibrosis. This population is in need of effective treatment and the benefit of this analysis is that it clarifies the clinical outcome that results as a consequence of treatment vs. no treatment in a clinically relevant timeframe. There is clinical heterogeneity in a group containing all subjects with advanced fibrosis (METAVIR F3/F4), however, the data included in the model are supported by clinical data drawn directly from this population. For instance, treatment responses are from randomised controlled data, and long-term follow-up data are from a meta-analysis of more than 1400 subjects.[9, 21] Using these analyses to support clinical decision making and the prioritisation of subjects for treatment should allow clinicians to maximise treatment benefit through mortality reduction in the next 5 years despite relatively low SVR rates and whilst further developments in therapy occur. Furthermore, the analyses provide critical information in the explanation of the potential benefits (and risks) of treatment for clinicians to share with subjects with advanced fibrosis who are considering treatment.
The rationale for using the 4-week lead-in phase for decision making has been based on concerns regarding increased toxicity in subjects with advanced disease, and also concerns about the evolution and persistence of drug resistant variants.[11-13] The registration studies for both boceprevir and telaprevir included patients with advanced fibrosis, albeit at a relatively low frequency, and these patients had well compensated liver disease. In subjects treated with pegylated interferon and ribavirin dual therapy there is evidence that the treatment emergent adverse effects of hepatic decompensation and death are more common in those with advanced cirrhosis and portal hypertension.[28, 29] Our analysis indicates that allowing for treatment-associated decompensation at a rate of 1 in 50 treated patients and mortality at 1 in 100 (in keeping with reports from early access programs), there remains a benefit in continuing treatment regardless of treatment response at treatment week 4. The development of resistant variants is more difficult to model since the consequences of these frequently short-lived variants are uncertain. Whilst there is the potential for these variants to persist and to impact on future protease inhibitor containing treatment and candidacy for future clinical trials of perhaps more effective therapies, the likelihood is that for many of the subjects included in this analysis this would be the last opportunity for treatment (prior to liver transplantation or death). This is especially apparent as it is interferon sensitivity that governs the poor responses to treatment in this group and that pegylated interferon is likely to remain a component of standard of care therapy for the next 5 years at least.
This analysis is limited by several factors. The data are extracted from several studies, none of which were intended to address this particular question. Furthermore, none of the studies contained large numbers of patients with advanced fibrosis and indeed the boceprevir development programme did not address treatment responses in prior null responders. The treatment responses for boceprevir and telaprevir appear broadly similar and we therefore considered a prototypic protease inhibitor based on the published data that were available. In sensitivity analyses, we varied the proportions of prior null and partial responders, the SVR rates and the rates of treatment emergent adverse effects to address the areas where there were uncertainty in the primary reports. These analyses indicated that there was benefit of continued treatment regardless of virological response at treatment week 4. There were however important exceptions to this, and that is in scenarios where there are high rates of treatment emergent mortality. In these situation there was no benefit to continued treatment following a <1log10 reduction in HCV RNA when considering 5-year follow-up. These scenarios might be represented by subjects with advanced cirrhosis and significant portal hypertension where treatment is already risky and where a failure to respond to the 4-week lead-in could be considered an indication to stop treatment. The analyses presented here therefore provide important evidence to support individualised treatment decision making in this difficult population. Further studies addressing this population should be carefully designed to ensure that stopping rules are implemented both for virological failure and to protect those included from excessive treatment related morbidity and mortality.
This analysis contains a relatively crude assessment of benefit and harm. Whilst this is based on important clinical outcomes of death, hepatic decompensation and the development of HCC rather than the surrogate measure of SVR it is likely that the lasting benefits of SVR are underestimated. Whilst several investigators have studied the effects of SVR on more relevant outcomes, such as serum biochemistry and fibrosis stage,[35, 36] the overall clinical outcomes of SVR are seldom reported. We therefore utilised a meta-analysis of clinical outcomes after SVR. A more recent prospective report suggests that both the annual risk of liver-related mortality, and the ARR in mortality might be greater than we considered suggesting that the mortality reductions in the base case analysis might underestimate the true effect of treatment. Furthermore considering follow-up of only 5 years duration will underestimate the overall benefit of treatment. This parameter was however set at 5 years to permit decisions to be made in this clinically relevant timeframe. Additional data indicating that productivity is decreased and absenteeism is increased in HCV infected subjects suggests significant additional benefit from successful treatment.[37, 38] Although these outcomes are difficult to model the benefit we have highlighted in continuing treatment regardless of response at treatment week 4 is likely increased when all factors are considered. Of course, additional treatment emergent adverse events will also be incurred through continued treatment of this population regardless of virological response at week 4, and some of these will be severe. In those subjects with advanced disease these are likely to be more frequent, and to contribute to treatment emergent decompensation and death. These events, however, do not negate the benefit of treatment. A decision to wait for further treatment developments in this high-risk group therefore has the potential to cause the greatest harm when compared with any of the treatment strategies presented here and the mortality reduction noted with treatment strongly cautions against that approach.
These analyses describe previously treated subjects with prior null and partial responses. As the absolute risk reduction in mortality associated with successful treatment in the untreated population is likely to be similar these findings are generalisable to all subjects with advanced fibrosis undergoing treatment with protease inhibitor containing treatment. The findings are however not applicable to subjects with early fibrosis where the harms of treatment manifest through treatment emergent adverse effects, or the development of resistant variants, may outweigh the benefits of continued treatment in poor interferon responders. Whilst information on the significance of resistance is emerging there are concerns that the harms relating to resistant variants may be significant and individualised decision making is appropriate until such data are available.
In summary, this analysis indicates that subjects with advanced disease should be prioritised on the basis of need. Furthermore, when considering protease inhibitor treatment of previously treated subjects with advanced fibrosis, this should be done without consideration of interferon responsiveness following the 4-week lead-in. This analysis provides critical information regarding both selection and on-treatment decision making for previously treated subjects that should be included in guidance for physicians using protease inhibitors to treat subjects with HCV infection.