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Discussion
The decision to initiate treatment in patients with genotype 1 HCV infection who are eligible to receive pegylated interferon is complex and must balance, among other factors, quality of life, patient preferences, available regimens and risks of disease progression. Using decision-analytic modelling, we found that the benefits of waiting for all oral therapy in patients who wished to avoid pegylated interferon as well as retreatment were time-limited. In an era of interferon-free therapy with restrictions to access, waiting for interferon-free therapy is beneficial so far as this delay did not exceed 3–3.2 years. These findings were more pronounced with increasing age at the time of decision.
For patients who have no absolute contraindication to interferon-containing therapy, but wish to avoid the medication given its poor tolerability, this analysis may inform in several ways the process of shared decision-making with providers regarding the common question, 'How long can I wait before I need to be treated?' Firstly, assuming that retreatment is not an option, the decision around the timing of HCV therapy is driven to the greatest extent by treatment efficacy. Although the use of health utilities and QALYs remain somewhat controversial as a measure of health benefit, it is interesting to note that results remained stable even when the quality of life on either treatment was equivalent to zero, or death. This may provide information on how the discussion regarding preferences of treatment acceptability may be framed for those patients who are fearful of the side effects of treatment and believe that their quality of life during this time would be very low. Secondly, we see that patients, even those who are not currently cirrhotic, cannot wait for therapy forever. The health benefits conferred by interferon-free therapy over interferon-containing therapy, including superior efficacy and tolerability, are lost after approximately 3 years as they are outweighed by increasing HCV-related morbidity and mortality.
While this analysis explores the trade-off between waiting for interferon-free therapy from a pure health benefit perspective, the high costs and variable cost-effectiveness of new DAAs, including sofosbuvir, have been previously discussed. Deuffic-Burban and colleagues have reported that in genotype 1 HCV-infected patients, interferon-free therapy was cost-effective compared to telaprevir- or boceprevir-based triple therapy in patients with greater than stage F2 fibrosis. Based on current costs of sofosbuvir and simeprevir, an analysis by Hagan et al. found that interferon-free therapy could be considered cost-effective based on a range of frequently reported willingness to pay thresholds of $80 000/QALY to $100 000/QALY. We explored the additional strategy of offering retreatment with interferon-free therapy for individuals who have failed immediate therapy with an interferon-containing regimen. While this strategy results in the greatest QALY gain for patients, it is unlikely to meet societal cost-effectiveness thresholds given the high cost of repeated therapy. In the United States, the heterogeneity of coverage for DAAs by state Medicaid programmes and commercial insurers, including increased cost sharing to patient, limiting treatment courses and/or limiting coverage of treatment to only patients with cirrhosis, may increase out-of-pocket costs and impact some patients' decisions regarding treatment initiation. In developing countries, price negotiations and prioritization of regimens that allow for simplified models of care may define therapeutic options. This analysis provides projections for the clinical consequences of preferences regarding treatment options, retreatment and timing for a population facing highly variable healthcare financing.
This analysis has several limitations. The phase 3 trials on which treatment efficacy and probability of adverse effects were based had limited enrolment of patients with cirrhosis. We examined the impact on this uncertainty through probabilistic sensitivity analysis and found our results to be stable. Similarly, data on quality of life while on treatment were obtained from a single study on patient-reported outcomes. Deterministic sensitivity analysis broadly varying these values did not alter results. Risks of loss to follow-up during the wait for interferon-free therapy may increase with longer wait times; however, this was not modelled. It is important to note that results are based on population-based estimates of disease progression. This was evaluated through probability distributions to account for uncertainty in the primary data. In our analysis, we used a multiplicative method to combine the utilities for outcomes that comprised of multiple health states, a technique that is widely used but criticized for lack of empirical support. Our results remained robust with sensitivity analyses using additive and minimum health state models for calculating joint utilities. Finally, a treatment strategy in which noncirrhotic patients are made to wait until they are cirrhotic prior to receiving treatment, while reflective of some insurer practices, was beyond the scope of this analysis.
In conclusion, the selection of optimal treatment for chronic hepatitis C and timing thereof is complex, and patient choices may be impacted by preferences surrounding interferon, desire for immediate treatment and access to interferon-free therapy. We used decision-analytic modelling to evaluate the clinical consequences of immediate, interferon-containing therapy versus delayed, interferon-free therapy for chronic hepatitis infection in patients with and without cirrhosis. We found that while waiting 1 year for interferon-free therapy resulted in superior health benefits compared to one-time immediate therapy with interferon over a broad range of sensitivity analyses, these benefits were time-limited. Such data can improve shared decision-making by informing the communication of the risks and benefits of various treatment options.
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