Triple combination treatment for chronic hepatitis C with Protease Inhibitors, pegylated interferon and ribavirin: ‘Lead-in or no lead-in’?

Protease inhibitors are direct acting antiviral agents (DAA) that target the protease of the hepatitis C virus (HCV) 1. In combination with pegylated interferon (PEG-IFN) and ribavirin (RBV), they increase the effectiveness of antiviral therapy in naïve patients infected with genotype 1 resulting in an increase in sustained virological response (SVR) from around 40% to nearly 70% or more 2, 3. The major disadvantages of protease inhibitors are the possible development of viral resistance (which may be long lasting and reduce future treatment options) and a range of side effects. Furthermore, protease inhibitors are expensive and substantially increase the overall cost of therapy.

Early phase 2 studies with the protease inhibitor boceprevir compared the benefits of a 4-week lead-in with PEG-IFN/RBV in treatment naive patients 4 and showed a small, statistically insignificant benefit of the lead-in phase for a reduction in relapse rate and breakthrough leading to a modest increase in SVR. However, the study was not designed to detect a significant difference with the lead-in phase. Based on these data, the authors suggest that the lead-in phase may improve response rates by reducing the development of viral resistance and subsequent phase three trials with boceprevir have all used a ‘lead-in’ phase. The drug has been licensed with a 4-week PEG-IFN/RBV lead-in 3-5. As the treatment duration was based on response-guided therapy in the phase 3 studies evaluating boceprevir, the lead-in phase may increase the percentage of patients with shorter treatment 3. Indeed, the phase 2 study SPRINT-1 has shown that the lead-in phase was associated with almost twice as many patients with undetectable HCV RNA at week 4 [rapid virological response (RVR)] with triple therapy (62 vs 38%, P < 0.001), which is one of the major rules for a shorter treatment duration 4. In contrast, a phase 3 trial with the protease inhibitor telaprevir in patients who had not responded to therapy with PEG-IFN/RBV showed no significant difference in RVR, relapse, breakthrough or overall SVR between patients who did or did not receive a 4-week PEGIFN/RBV lead-in phase 6. These data (combined with those of the phase 3 clinical trial with telaprevir that did not include a lead-in, showing SVR rates of 75%) resulted in licensing of telaprevir without a lead-in phase. Thus we now have access to two potent DAA agents – one (boceprevir), licensed for use with a lead-in phase and the other (telaprevir), licensed for use without a lead-in, although there is high quality data showing that a lead-in phase does not enhance or reduce the efficacy of therapy. The only potential benefit of a lead-in phase could be to shorten the treatment duration with the boceprevir-based regimen, although no such benefit was seen with a telaprevir-based regimen. It is therefore reasonable to assume that the benefits of a lead-in phase on overall treatment efficacy are relatively small. Clearly future clinical trials examining the benefits of the lead-in phase in different patient cohorts may modify this view.

The two currently licensed protease inhibitors (boceprevir and telaprevir) differ in their duration of therapy – telaprevir is given for the initial 12 weeks of therapy (in combination with PEG-IFN/RBV) while boceprevir is given for the entire duration of treatment (usually 24 or 48 weeks, with a 4-week boceprevir free lead-in phase). It could be argued that avoiding a lead-in phase and rapidly reducing the viral load with ab initio combination therapy allows a shorter duration of therapy. If this is proven it would provide a very powerful argument to exclude the lead-in phase of therapy. However, although there is an attractive theoretical argument for initiating therapy with three potent drugs and then reducing to maintenance therapy with two agents (a strategy widely used in other infections such as tuberculosis and currently under evaluation in HIV), there is no evidence in chronic HCV that an induction-maintenance regimen allows shorter therapy. Clearly if future trials demonstrate that triple therapy ab initio allows a shorter duration of combination therapy then this will again be a very powerful argument in favour of avoiding a lead-in phase. However, as studies using a shorter duration of boceprevir in patients with a lead-in phase have not been confirmed, the hypothesis that high dose induction therapy allows a shorter duration of overall protease inhibitor therapy remains unproven. Once again, future clinical trials will demonstrate whether or not avoiding a lead-in phase allows a reduction in the overall duration of therapy.

Because studies to-date have failed to demonstrate a clear virological and efficacy advantage of the lead-in phase, the arguments for and against the use of a lead-in phase must focus upon side effects, patient choice and ease of administration. The chief disadvantage of the lead-in phase is the inconvenience to the patient. Four weeks of PEG-IFN/RBV therapy followed by the introduction of a new agent is inconvenient to the patient and requires additional visits to the clinic. In general, patients require considerable support during the first 4 weeks of antiviral therapy (we currently see patients every week for the first 4 weeks and then reduce the frequency of visits to fortnightly). The introduction of new agents with additional complications and side effects will necessitate an increase in the frequency of visits after 4 weeks to ensure compliance and monitor any new side effects. Given the constraints on healthcare resources and the pressure on patients to minimize time off-work, additional visits to the clinic represent a significant disadvantage to complex regimens. Concern has already been expressed that the infrastructure in the USA (one of the most well funded and supported healthcare system in the world) is insufficient to treat all of the patients currently wishing to receive protease inhibitors and any increase in the complexity of treatment and increase in clinic visits will, inevitably, reduce the number of patients who can be effectively treated.

Those who advocate an introductory lead-in phase of therapy often cite the possibility of modifying therapy based on the results of the lead-in phase. Theoretically, there are three circumstances in which the results of a lead-in phase could influence the therapeutic decision: (i) patients with a RVR could be treated with PEG-IFN/RBV, (ii) triple therapy should be discussed in poor interferon responders, i.e. viral load drop < 1 log₁₀, (iii) in patients with poor tolerance, the PEG-IFN/RBV dosage could be tailored during the lead-in phase. However, the costs and benefits of this approach have never been assessed in a prospective clinical trial. It seems reasonable to consider 24 weeks of therapy with PEG-IFN/RBV in patients with a low viral load at baseline and who achieve an RVR as small-scale studies suggest that this regime will lead to an SVR in around 90% of treated patients 7. In genotype 1 patients treated with PEG-IFN/RBV, the IL28B polymorphism has been associated with SVR 8, 9. As one-third of CC patients achieve an RVR after PEG-IFN/RBV treatment, IL28B genotype determination could be one way to select patients who do not need triple therapy. 10. The difficulty with this approach is that most RVR patients have a high viral load at baseline and therefore need a 48-week course of PEG-IFN/RBV 7. Otherwise a proportion of these patients (perhaps as many as 20%) will relapse when PEG-IFN/RBV is withdrawn. Thus, these patients will require therapy for 48 weeks including a protease inhibitor. This approach is likely to be very costly to patients who do not achieve an SVR with PEG-IFN/RBV alone and in the absence of a formal study to demonstrate equivalence and to show the cost-effectiveness of this strategy it would be inappropriate to recommend it. Simple calculations suggest that if one in five patients receiving PEG-IFN/RBV relapses and requires 48 weeks of therapy with a protease inhibitor, then the financial benefits of the lead-in phase will be minimal and, for patients who take time off from work to complete a course of treatment the costs will be substantially higher. Those advocating the value of a lead-in phase need to present clear modelling data based on reasonable assumptions of relapse demonstrating unequivocal cost effectiveness before such an approach can be widely introduced. Moreover, the negative predictive value of the lead-in phase must to be assessed in the clinical setting and the cost effectiveness and value of this cumbersome approach need to be demonstrated. For patients who have a less than one log₁₀ drop in viral load during the lead-in phase (poor interferon responders) the benefits of therapy are likely to be significantly reduced with a marked reduction in SVR rates and a high risk of viral resistance, hampering future therapeutic options. For instance, the rate of SVR with a telaprevir-based regimen is only 15% in prior non-responders who have a less than one log₁₀ drop in viral load during the lead-in phase. However, whether the reduction in SVR is sufficient to justify withdrawing therapy remains to be determined. Patients who respond poorly to PEG-IFN/RBV tend to have adverse factors (such as cirrhosis) that increase their risk of developing complications of the disease and the advantages of withdrawing therapy and waiting for more effective compounds in this population of patients at the greatest risk of complications remains to be seen. On the other hand, the risk of viral resistance in poor interferon responders should be taken into account in case of mild liver disease.

Patient choice is increasingly important as patients become viewed as ‘active’ rather than ‘passive’ consumers. There is no doubt that patients would much prefer to initiate therapy with the most potent drugs. Initiating treatment with the ‘old fashioned,’ less effective agents is not likely to find favour among knowledgeable consumers.

In summary, a lead-in phase with PEG-IFN/RBV offers no virological or clinical benefits except a shorter duration of treatment with the boceprevir-based regimen. Although the value of this approach in selecting patients who are most likely to benefit from the addition of a protease inhibitor has not yet been proven, the lead-in phase could be reasonably considered in two sub-groups: (i) patients who could benefit from a 24-week course of PEG-IFN/RBV, i.e. low viral load at baseline with CC IL28B genotype and mild liver disease (ii) patients at high risk of viral resistance occurrence, i.e. non-responders to prior treatment. However, the use of a lead-in selector will potentially increase the overall costs of therapy (by failing to identify patients who are likely to relapse) and may prevent those most at risk of progressive disease from accessing effective therapies. In an era of evidence-based medicine, it is important that patients be managed using the best available evidence and those advocating a change in management based upon the results of a lead-in should conduct appropriate clinical trials to assess the value of these regimes before they are recommended as the standard of care.