Controversy Triple therapy with first generation HCV protease inhibitors: lead-in or no lead-in phase ?
Alina Pascale1, Lawrence Serfaty 1,2 1 Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France 2 INSERM, UMR_S938, UPMC Paris 6, France
Received 27 July 2012; accepted 27 September 2012. published online 10 October 2012.
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Journal of Hepatology (2012), doi: http://dx.doi.org/10.1016/j.jhep.2012.09.023
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The standard therapeutic approach currently recommended for patients infected with genotype 1 hepatitis C virus (HCV) is the triple therapy combining pegylated interferon (PEG-IFN), ribavirin (RBV) and NS3/NS4 protease inhibitors, boceprevir or telaprevir [1].
Protease inhibitors (PIs) are direct acting antiviral drugs (DAA) which, when added to PEG-IFN and RBV, are able to achieve a significant gain in terms of sustained virological response (SVR), both in naïve and treatment-experienced patients [2-5]. The use of these new molecules, despite its incontestable benefits, reveals on the other hand new challenges: the emergence of variants with reduced sensitivity to PIs, the development of new or higher rate of side effects, drug to drug interactions, and significant increase in the overall cost of antiviral therapy.
Among the two DAAs commonly used in combination with PEG-IFN and RBV (PEG-IFN/RBV) for the treatment of genotype 1 HCV patients, boceprevir has been licensed with a lead-in phase, while telaprevir has been licensed without. EMA approved regimen of both drugs are reported on figures 1 and 2.
Lead-in phase and triple therapy effectiveness
The impact of lead-in phase on triple therapy effectiveness has been investigated in two therapeutic trials, one in treatment-naïve, one in treatment-experienced patients. In treatment-naïve patients, the effect of a lead-in phase of PEGIFN/RBV therapy is based on the phase II trial SPRINT-1 evaluating boceprevir-based triple therapy [6]. Though not the primary end-point, the comparison between arms with or without lead-in phase showed no statistically significant difference in terms of SVR rates (66% vs. 60%, p>0.05).
In terms of virological breakthrough, there was a tendency of lower rate in patients treated with lead-in (4 vs 9%, p=0.06). In contrast, the rate of rapid virological response at week 4 of triple therapy was significantly higher in patients treated with lead-in vs no lead-in phase (62% vs. 38%, p <0.001).
According to response-guided therapy (RGT) regimen (figure), this result suggests that lead-in phase might increase the number of patients eligible for a short treatment duration with boceprevir based triple therapy (28 weeks) [2]. There are no available data regarding lead-in phase in naïve patients receiving telaprevir-based triple therapy.
In treatment-experienced patients, the impact of lead-in phase on triple therapy effectiveness is based on phase III REALIZE study evaluating telaprevir [4]. There was no difference in terms of SVR
rates between patients treated with or without a lead-in phase, either for previous relapsers (88% vs. 83%), partial responders (54% vs. 59%) or null responders (33% vs. 29%). Neither virological breakthrough rate was significantly influenced by lead-in phase (1 vs 1% in previous relapser and 17 vs 19% in previous non-responders).
In prior relapsers, however, the rates of rapid virological response at week 4 of triple therapy was significantly higher with lead-in vs no lead-in phase (89 vs 70%, p<0.05). Because telaprevir was licensed with RGT in non-cirrhotic relapser patients (figure 2), this result suggests that lead-in may increase the percentage of patients eligible for shorter duration treatment.
In summary, there is no clear advantage of lead-in in terms of SVR rates in patients treated with boceprevir or telaprevir-based triple therapy. However, in patients eligible for RGT, lead-in may shorten the duration of treatment in a significant number of cases by increasing the RVR rate on triple therapy (Table-see below). Opposite, in patients eligible for fixed duration of treatment, lead-in could be avoided, including in patients receiving boceprevir-based triple therapy (Table-see below).
Lead-in phase as predictor: impact on therapeutic decision
In the setting of new challenges raised by the use of PIs - such as development of viral resistance associated with treatment failure, side effects or treatment cost -, predictors of response to triple therapy are highly needed.
Phase 3 trials have suggested that lead-in phase, by assessing the sensitivity to interferon, was able to predict triple therapy effectiveness [2,4,5,7]. Post-hoc analysis of boceprevir phase III trials showed that viral load decline > 1.0 log (interferon sensitive response) or < 1.0 log (poor interferon response) at the end of lead-in was the strongest independent predictor of SVR, both in naïve and treatment experienced patients [8]. Viral load decline was also predictive of resistant variants emergence (41% in patients with < 1.0 log decline vs. 6% in patients with > 1.0 log of decrease) [2,5]. However, the main issue to address is whether viral load decline during lead-in phase is enough accurate for the prediction of SVR and to impact the therapeutic decision. In naïve patients, the relationship between viral load decline during lead-in phase and response to triple tharapy has been investigated in SPRINT-2 study evaluating boceprevir [2].
Viral load decline at the end of lead-in phase was related with the SVR rate, since a less than 1.0 log viral load decline (poor interferon response) was associated with a 28% SVR rate in RGT arm and 40% in fixed-duration arm, while a more than 2.0 log viral load decline was associated with a SVR rate > 80%. However, given its low negative predictive value, lead-in may have no major impact for the decision of initiating or not triple therapy in poor interferon responders.
The only decision impact could be the choice of fixed duration treatment that achieves a higher rate of SVR compared to RGT in this subgroup of patients [2]. On the other hand, lead-in phase may avoid disavantages of triple therapy in highly interferon sensitive patients with rapid virological response (RVR), ie HCV RNA undetectable at week 4 of lead-in. Indeed, in this subgroup of patients, PEG-IFN/RBV was able to achieve a SVR rate higher than 90%, similar to SVR rates achieved with boceprevir or telaprevir-based triple therapy [2,3]. Therefore, despite the lack of randomized study, PEG-IFN/RBV could be a therapeutic alternative to triple therapy in genotype 1 RVR patients.
Concern is about the duration of treatment that is 48 weeks compared to 24 weeks with triple therapy. Only the subgroup of RVR patients with low baseline viral load may benefit of a 24 weeks course of PEG-IFN/RBV [9]. Another concern is the rather small proportion of patients with RVR, less than 10%, requiring a large number of patients to be screened. Interleukin-28-B (IL28B) genotyping could be one way to select patients for PEG-IFN/RBV, as more than 30% of patients with CC genotype may achieve a RVR [10]. Accordingly, French guidelines have proposed a 4 weeks course of PEG-IFN/RBV prior to triple therapy (boceprevir or telaprevir-based) in naïve patients with IL-28B CC genotype and fibrosis score ≤ F2 [11] (Table-see below).
In a recent published study, this strategy was considered as cost-effective, atleast in the setting of boceprevir-based triple therapy [12]. On the other hand, a retrospective study from the phase II telaprevir trials has suggested that CC patients may benefit from shortening triple therapy to 12 weeks instead of the usual 24 weeks [13]. This should be confirmed by larger prospective studies. In treatment-experienced patients, the accuracy of lead-in for the prediction of SVR to triple therapy has been investigated in RESPOND-2 and PROVIDE studies evaluating boceprevir, and in REALIZE study evaluating telaprevir [4,5,7]. In prior relapsers or partial responders, SVR rates according to viral load decline < 1.0 log vs. > 1.0 log at the end of lead-in were respectively 37% vs. 81% and 37% vs. 61% in boceprevir RESPOND-2 study and, 62% vs. 88% and 56% vs. 59% in telaprevir REALIZE study [4,5].
Therefore, SVR rates were rather high, even in poor interferon responders, suggesting that lead-in may have no major impact on treatment decision, ie initiating or not triple therapy, in prior relapsers or partial responders. In prior null responders, SVR rates according to viral load decline < 1.0 log vs > 1.0 log at the end of lead-in were respectively 36 vs 55% in boceprevir PROVIDE study and 15 vs 54% in telaprevir REALIZE study [4,7].
In REALIZE study, the relatively low SVR rate in poor interferon responders, i.e. 15%, may question the use of telaprevir in this very difficult-to-treat population. It should be noted that about half of patients had severe fibrosis, a baseline parameter also highly predictive of SVR in prior null responders. Indeed, the SVR rate was lower that 10% in case of extensive fibrosis associated with poor interferon response.
In the boceprevir PROVIDE study, the higher SVR rate in poor interferon responders, i.e. 36%, could be explained by the small proportion of patients with severe fibrosis. Moreover, small sample size population could hamper interpretation of results.
In summary, lead-in phase is a good predictor of SVR to triple therapy in treatment experienced patients but may have no major impact on therapeutic decision, excepted in prior null responders (Table). In this subgroup of patients, lead-in seems to have some advantage, at least for the decision of initiating telaprevir-based triple therapy, and benefit-risk ratio should be reevaluated in case of poor interferon response. In patients with undetermined previous response profile, lead-in phase might be informative for reclassification but finally without any significant impact on therapeutic decision.
Lead-in phase and tolerance with triple therapy
By testing the tolerance with PEG-IFN/RBV prior to initiating triple therapy, lead-in phase could be helpfull for the management of patients, especially in cirrhotics. The French CUPIC study reported a high risk of serious adverse events, including death, in this population when exposed to triple therapy [14]. The lead-in phase may permit dosage adjustment of PEG-IFN and RBV according to clinical tolerance, especially hematological toxicity, as well as the initiation, if needed, of growth factors, prior to introducing triple therapy. In a randomized trial evaluating management of anemia in boceprevir treated patients, RBV dosage adjustments as first line during lead-in phase had no major impact on SVR rate, compared to EPO use [15].
These results should be tempered by the fact that less than 10% of patients had cirrhosis and by the notable decrease of SVR rate in patients with severe fibrosis randomized in the RBV arm. Specific studies are needed in cirrhotic patients prior drawing definitive conclusion. Moreover, we don’t know whether PEG-IFN/RBV dosage adjustment during lead-in phase has different impact on SVR compared to dosage adjustment during triple therapy
Lead-in phase, practical issues and cost-effectiveness
There are important practical issues that argue against the use of the lead-in phase, as the increase in the total duration of treatment (minimal duration of 28 weeks in naïve patients), the inconvenience to the patient, who is subjected to an initial period of 4 weeks of PEG-IFN/RBV therapy requiring additional visit and blood sample at the end of lead-in. Thus, the lead-in phase may complicate the therapeutic schema, both for the patient and for the physician. Another important practical issue is the short delay required for HCV RNA result at the end of lead-in phase, in case of treatment decision. Along with practical issues of therapy also comes an increased overall treatment cost, which, when added to the cost of antiviral therapy using PIs, may result in a cost/benefit profile less favorable.
Until now, the lead-in strategy was validated as cost-effective regarding the selection for dual therapy of naïve genotype 1 patients with fibrosis score F2 in the setting of boceprevir-based triple therapy [12]. Indeed, selective treatment strategy guided by RVR in naïve patients was cost effective compared to universal boceprevir-response guided therapy. In the setting of telaprevir-based triple therapy, selective treatment strategy guided by IL-28B genotype was also cost-effective but leadin strategy was not evaluated. The authors recommend using PI-free strategies as firstline therapy in patients with IL28B CC genotype or in those who achieve RVR.
Cost effectiveness analysis of selective treatment strategies in prior null responders needs further consideration.
In conclusion, lead-in phase with PEG-IFN/RBV offers no clearly proven virological benefit, excepted a shorter duration of treatment in non-cirrhotic naïve patients receivingboceprevir-based regimen or in relapsers receiving telaprevir-based regimen. In view of its value for the prediction of the triple therapy effectiveness, lead-in phase should be considered in 2 sub-groups of patients: 1) those who could benefit from a 24-week course of PEG-IFN/RBV, i.e low viral load at baseline, with CC IL-28B genotype and mild liver disease ≤ F2, 2) those who are poor interferon responders, especially prior null responders in whom initiation of triple therapy should be reevaluated. An additional benefit would be the possibility of tailoring PEG-IFN/RBV dosage during the lead-in phase in patients with poor tolerance, but this strategy needs addtional investigations, especially in cirrhotics. For all other categories of patients, there is no clear evidence to justify the use of lead-in phase. In the approaching era of far more efficient therapeutic regimen in chronic hepatitis C, it is probable that the terms of this controversy will be no longer relevant.
Table : Usefulness of lead-in phase in boceprevir- or telaprevir-based regimen according to patients status, naïve or treatment-experienced
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