Telaprevir for Previously Treated Chronic HCV Infection

Telaprevir for Previously Treated Chronic HCV Infection

NEJM April 7 2010

John G. McHutchison, M.D., Michael P. Manns, M.D., Andrew J. Muir, M.D., Norah A. Terrault, M.D., Ira M. Jacobson, M.D., Nezam H. Afdhal, M.D., E. Jenny Heathcote, M.D., Stefan Zeuzem, M.D., Hendrik W. Reesink, M.D., Jyotsna Garg, M.S., Mohammad Bsharat, Ph.D., Shelley George, M.D., Robert S. Kauffman, M.D., Ph.D., Nathalie Adda, M.D., Adrian M. Di Bisceglie M.D., for the PROVE3 Study Team



ABSTRACT


Background - Patients with genotype 1 hepatitis C virus (HCV) who do not have a sustained response to therapy with peginterferon alfa and ribavirin have a low likelihood of success with retreatment.


Methods - We randomly assigned patients with HCV genotype 1 who had not had a sustained virologic response after peginterferon alfa–ribavirin therapy to one of four treatment groups: 115 patients to the T12PR24 group, receiving telaprevir (1125-mg loading dose, then 750 mg every 8 hours) for 12 weeks and peginterferon alfa-2a (180 µg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 24 weeks; 113 patients to the T24PR48 group, receiving telaprevir for 24 weeks and peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group); 111 patients to the T24P24 group, receiving telaprevir and peginterferon alfa-2a for 24 weeks (at the same doses as in the T12PR24 group); and 114 patients to the PR48 (or control) group, receiving peginterferon alfa-2a and ribavirin for 48 weeks (at the same doses as in the T12PR24 group). The primary end point was sustained virologic response (undetectable HCV RNA levels 24 weeks after the last dose of study drugs).


Results - The rates of sustained virologic response in the three telaprevir groups — 51% in the T12PR24 group, 53% in the T24PR48 group, and 24% in the T24P24 group — were significantly higher than the rate in the control group (14%; P<0.001, P<0.001, and P=0.02, respectively). Response rates were higher among patients who had previously had relapses than among nonresponders. One of the most common adverse events in the telaprevir groups was rash (overall, occurring in 51% of patients, with severe rash in 5%). Discontinuation of study drugs because of adverse events was more frequent in the telaprevir groups than in the control group (15% vs. 4%).


Conclusions - In HCV-infected patients in whom initial peginterferon alfa and ribavirin treatment failed, retreatment with telaprevir in combination with peginterferon alfa-2a and ribavirin was more effective than retreatment with peginterferon alfa-2a and ribavirin alone.


Worldwide, an estimated 170 million people have chronic hepatitis C virus (HCV) infection, and in many of these people, cirrhosis and complications of end-stage liver disease will develop.1,2 Chronic HCV infection is the leading cause of liver disease and is the leading indication for liver transplantation in the United States and Europe.3 Currently available treatment for HCV infection necessitates peginterferon alfa injections combined with oral ribavirin for 24 or 48 weeks (depending on the HCV genotype).4 Overall, in 40 to 50% of patients infected with HCV genotype 1 who have not previously been treated, the currently available treatment results in short- and longer-term benefits associated with sustained virologic response.5,6,7,8,9,10,11 For patients in whom a sustained virologic response is not achieved, retreatment options are limited to reexposure to the same medications, with potential modification of the dose or duration of the regimen. These retreatment strategies are associated with clinically significant morbidity and generally have a very limited chance of resulting in a successful outcome.11,12 Therefore, the development of effective regimens to retreat patients with chronic HCV infection who did not have a sustained response to previous therapy is an urgent priority.


Telaprevir, an orally bioavailable inhibitor of the nonstructural 3/4A (NS3/4A) HCV protease,13 is one of several investigational agents that specifically targets HCV with the goal of improving the chance of a sustained virologic response. In two recent phase 2, multicenter studies of telaprevir in combination with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not previously been treated, the addition of telaprevir for 12 weeks, as part of a combination regimen with a total duration of 24 weeks in most patients, significantly increased the rates of sustained virologic response, albeit with more patients in the telaprevir group than in the control group discontinuing therapy because of adverse events.14,15 In the current study, we aimed to assess the safety and efficacy of telaprevir-based therapy in patients with HCV infection who had not had a sustained response to an initial full course of treatment with peginterferon alfa and ribavirin.

Results


Study Patients


From February through June 2007, a total of 465 patients were randomly assigned to a treatment group, and 453 received at least one dose of study drugs (Figure 1). The baseline characteristics of the study patients were similar across the four treatment groups, except for a significant difference in the median age (Table 1). The majority of patients (306 of 453 [68%]) were men, and the mean age was 51 years. A total of 89% of the study patients (402 of 453) were white. Most patients (418 of 453 [92%]) had HCV RNA levels of 800,000 IU or more per milliliter at baseline. The majority of patients (265 of 453 [58%]) were infected with HCV genotype 1a. In total, 16% of the study population (74 of 453 patients) had cirrhosis. In addition, 57% of patients (260 of 453) were classified as having had a nonresponse to previous HCV therapy, 36% (162 of 453) as having had a relapse, and 7% (31 of 453) as having had a breakthrough.

Efficacy


The rate of the primary efficacy end point, a sustained virologic response, was significantly higher in each of the three telaprevir groups — 51% in the T12PR24 group, 53% in the T24PR48 group, and 24% in the T24P24 group — than in the PR48 group (14%; P<0.001, P<0.001, and P=0.02, respectively) (Table 2).

Responses at the end of the treatment period were higher in the telaprevir groups than in the control group, as were the responses at week 4 and week 12 (Table 2). All patients in the telaprevir groups had a virologic response (a drop of at least 2 log10 units in the HCV RNA level, as compared with the baseline level) at week 12. Nine patients in the PR48 group had an early virologic response (at week 12). Rates of sustained virologic response were higher among patients who had previously had a relapse than among those who had not had a response to previous treatment. The rates of sustained virologic response among patients with no previous response were 39% in the T12PR24 group, 38% in the T24PR48 group, and 11% in the T24P24 group, and the rates among patients with a previous relapse were 69% in the T12PR24 group, 76% in the T24PR48 group, and 42% in the T24P24 group. In the PR48 group, the rates were 9% among patients with previous nonresponse and 20% among patients with a previous relapse.


Overall, relapse rates were 30% in the T12PR24 group, 13% in the T24PR48 group, 53% in the T24P24 group, and 53% in the PR48 group. For the patients in the T12PR24 group who completed treatment, relapse rates were 28% overall, 37% among patients with no previous response, and 18% among patients with a previous relapse. For patients in the T24PR48 group who completed treatment, relapse rates were 4% overall, 4% for patients with no previous response, and 0% for patients with a previous relapse.


Rates of viral breakthrough at week 24 were 13% in the T12PR24 group, 12% in the T24PR48 group, 32% in the T24P24 group, and 3% in the PR48 group. In all three telaprevir groups, the majority of patients with viral breakthrough had not had a previous response (Table 3). Most viral breakthroughs were observed during the first 12 weeks of treatment. In the telaprevir groups, the rates of viral breakthrough were higher among patients infected with HCV genotype 1a (24%) than among patients infected with HCV genotype 1b (11%). Most viral breakthroughs were associated with HCV variants with resistance to telaprevir, as previously observed in studies of patients who had not previously been treated.14,15

Logistic-regression analysis showed that a sustained virologic response was significantly associated with assignment to the T12PR24 or T24PR48 group, an undetectable HCV RNA level during a previous period of treatment with peginterferon alfa and ribavirin, and low baseline viral load (<800,000 IU per milliliter).


With the exception of one patient who was lost to follow-up, in all patients who completed a telaprevir regimen and who had a sustained virologic response 24 weeks after the end of the treatment period, the virologic response was maintained at 48 weeks. Seven of 14 patients in the three telaprevir groups who prematurely discontinued treatment and had a sustained virologic response also underwent a follow-up assessment of the viral level at week 48. In these seven patients, the virologic response was maintained 48 weeks after the end of treatment.
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Safety


Several of the most common adverse events, such as fatigue and influenza-like symptoms, were consistent with typical interferon-related systemic symptoms (Table 4). However, rash and pruritus were more common in the groups that received telaprevir than in the PR48 group; rash and pruritus were also reported in earlier studies of patients who had not previously been treated.14,15 The overall incidence of any rash-related event was 50% in the T12PR24 group and 60% in the T24PR48 group, as compared with 20% in the PR48 group. The severity of the rash was also greater in the T12PR24 and T24PR48 groups than in the PR48 group.

In general, the rashes in patients in the telaprevir groups were described as maculopapular. The median time to the appearance of a rash of any severity in the telaprevir groups was 7 to 28 days. Severe (grade 3) rash was found in 5% of patients in the T12PR24 group, 4% in the T24PR48 group, 3% in the T24P24 group, and 0% in the control group. Eighteen patients in the telaprevir groups (5%), but none of those in the control group, discontinued treatment because of rash. Rash was monitored during the treatment period; medications including topical antiallergic agents and topical and systemic antipruritic agents were allowed, at the investigator's discretion, for all grades of rash. If discontinuation of study medication was indicated, both ribavirin and telaprevir were stopped while patients continued to receive peginterferon alfa-2a. The median time to treatment discontinuation because of rash in the telaprevir groups was 51 to 64 days (range, 4 to 123) after the start of treatment. Severe rashes resolved in 12 of 14 patients within 9 to 104 days after onset; follow-up data were not available for 2 patients; 6 patients had severe rash necessitating corticosteroid treatment; and 1 was hospitalized for severe rash.


Patients who received telaprevir-based therapy were more likely to discontinue treatment because of an adverse event (50 of 339 [15%]) than were controls, who received peginterferon alfa-2a and ribavirin alone (5 of 114 [4%]). Skin disorders were the most frequent cause of discontinuation among the telaprevir groups (accounting for 22 of the 50 patients who discontinued treatment).


Changes in laboratory values during the study were consistent with those reported in association with the use of peginterferon alfa and ribavirin. A decrease in hemoglobin levels was more common in patients receiving telaprevir-based regimens than in controls (Figure 2) and reversed on discontinuation of telaprevir. Treatment with erythropoietin-stimulating agents was prohibited during the course of the study.

Discussion


The results of this study show a benefit of telaprevir in patients who had not had a sustained virologic response to an initial, full course of peginterferon alfa and ribavirin. As in previous studies in untreated patients, a higher breakthrough rate (32%), higher relapse rate (53%), and lower sustained virologic response rate (24%) were observed in the T24P24 group as compared with the T12PR24 group and the T24PR48 group, again demonstrating the necessity for inclusion of ribavirin in combination with telaprevir and peginterferon alfa.14 Patients' previous response to peginterferon alfa and ribavirin also appeared to influence their response to combined treatment with telaprevir. Those who had previously been documented as having clearing of HCV RNA during therapy and who subsequently had a relapse were the most likely to have a response to telaprevir plus peginterferon alfa-2a and ribavirin (69 to 76% of these patients had a sustained virologic response). Those with a previous nonresponse were less likely to have a response after retreatment, but in this subgroup of patients, the observed response rates of 38% in the T24PR48 group and 39% in the T12PR24 group are the highest reported to date and more than four times the response rate in the control group (9%). Results should be interpreted with caution for patients of African, Hispanic, or Asian ancestry, since only a small number of such patients were included in this study.


Viral breakthrough rates were 12 to 13% in patients receiving telaprevir and peginterferon alfa-2a with ribavirin. Viral breakthrough was more common in the absence of ribavirin, occurred early during therapy, was more common in patients who had not had a response to previous therapy than in patients who had had a relapse after previous therapy, and was more frequently observed in patients infected with HCV genotype 1a, as previously reported in patients who had not been treated.14,15 Among patients who had viral breakthrough during the treatment period, sequencing analysis revealed HCV variants with substitutions at the NS3 protease amino acids 36, 54, 155, and 156, findings that are similar to those in patients who had not previously been treated and who had viral breakthrough while receiving telaprevir. The majority of patients who discontinued therapy because of a stopping rule had the V36M/R155K double variant; all but one of the patients had infection with HCV genotype 1a. Relapse rates were substantially lower when telaprevir was added to the retreatment regimen, as in previous studies.14,15 Relapse occurred less frequently with the T24PR48 regimen than with the T12PR24 regimen. As in other studies of telaprevir, rates of discontinuation due to side effects were higher among patients receiving the three-drug combination, and for those patients, discontinuation was most commonly due to rash.


Rates of sustained virologic response were similar in the T12PR24 and T24PR48 groups, and discontinuation of treatment due to adverse events was less common in the T12PR24 group than in the T24PR48 group. Therefore, the overall efficacy and safety results indicate that the T12PR24 regimen appeared to provide a better risk–benefit profile than the T24PR48 regimen. The higher discontinuation rates and the lower relapse rates in the T24PR48 group than in the T12PR24 group suggest that an optimal retreatment regimen may consist of a shorter period of treatment with telaprevir combined with a longer period of treatment with peginterferon alfa and ribavirin. Erythropoietin-stimulating agents were not permitted in this study; however, anemia was more frequently observed in patients who received a telaprevir-based regimen. The study design did not address other possible treatment options, such as 12 weeks of telaprevir plus 48 weeks of peginterferon alfa-2a and ribavirin.


In conclusion, this phase 2 study showed that the addition of telaprevir to current therapy as a retreatment strategy in HCV-infected patients who had not had a sustained response to previous therapy significantly increased the likelihood of eradication of HCV infection.


Supported by Vertex Pharmaceuticals.