Saturday, August 13, 2011

Realize the advance in Hepatitis C treatment, but remain cautious.

J Hepatol. 2011 Aug 8. [Epub ahead of print]

Realize the advance in HCV treatment, but remain cautious.

Asselah T.
Service d'hépatologie, Hôpital Beaujon, Clichy, France and INSERM, U773, Centre de Recherche Bichat-Beaujon CRB3, and University Paris Diderot.

Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin.

In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response.

A total of 663 patients were assigned to one of three groups:
the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug.

Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%).

Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase.

(Funded by Tibotec and Vertex Pharmaceuticals; REALIZE number, NCT00703118.).

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From Podium to Practice: Clinical Impact of New Data From EASL 2011
Source: CCO Independent Conference Coverage of the 2011 Annual Meeting of the European Association for the Study of the Liver*
By: Graham R. Foster, FRCP, PhD, Paul Y. Kwo, MD, Stefan Zeuzem, MD

BL is a patient infected with genotype 1 hepatitis C virus (HCV) who previously relapsed following peginterferon/ribavirin therapy. You are planning to begin a course of telaprevir-based therapy in this patient.

Would you counsel this patient that a peginterferon/ribavirin lead-in phase would be a useful tool in guiding the course of her therapy? To maximize the value of your assessment, this response is required.

REALIZE: Telaprevir Plus Peginterferon alfa-2a/Ribavirin in Patients With Genotype 1 HCV Who Failed Previous Peginterferon/Ribavirin

Expert Analysis

Stefan Zeuzem, MD: At the 2011 Annual Meeting of the European Association for the Study of the Liver (EASL), investigators presented extensive new data from studies evaluating the efficacy and safety of direct-acting antiviral (DAA) agents for the treatment of HCV infection. Two key discussion points that emerged from these studies included how can these agents be combined to optimize patient outcomes and what are the most important predictors of response? In addition, several notable reports focused on emerging data related to the treatment of hepatitis B virus (HBV) infection, hepatocellular carcinoma, and nonalcoholic steatohepatitis. We will begin this Expert Analysis with an in-depth review of the HCV highlights from the meeting.

The randomized, placebo-controlled phase III REALIZE trial evaluated telaprevir plus peginterferon alfa-2a/ribavirin in patients infected with genotype 1 HCV who previously failed peginterferon/ribavirin therapy (Capsule Summary).[1] In total, 662 patients were randomized to the following treatment arms: telaprevir plus peginterferon alfa-2a/ribavirin for 12 weeks followed by peginterferon alfa-2a/ribavirin alone for 36 weeks (n = 266); peginterferon alfa-2a/ribavirin lead-in for 4 weeks then telaprevir plus peginterferon alfa-2a/ribavirin for 12 weeks followed by peginterferon alfa-2a/ribavirin alone for 32 weeks (n = 264); or peginterferon alfa-2a/ribavirin alone for 48 weeks (n = 132). The study included patients with previous null response, partial response, or relapse following at least 1 previous course of peginterferon/ribavirin therapy; patients with previous viral breakthrough were excluded.
The sustained virologic response (SVR) rates were significantly higher in the telaprevir-containing arms relative to the peginterferon/ribavirin control arm in each previous treatment failure subgroup (P < .001 for each comparison); however, SVR rates to telaprevir-based treatment were notably higher among previous relapsers vs previous partial or null responders (83% to 88% vs 29% to 59%, respectively), with previous null responders exhibiting the lowest SVR rates of 29% to 33%.

Among previous relapsers, SVR rates to telaprevir-based therapy were similar regardless of fibrosis stage. These data suggest that the lower response rates among previous partial and null responders are not related to fibrosis stage but rather to their poor responsiveness to peginterferon/ribavirin. In addition, SVR rates to telaprevir-based therapy were higher with subtype 1b HCV compared with subtype 1a HCV (in particular for previous partial and null responders).

Graham R. Foster, FRCP, PhD: To investigate the predictors of response to telaprevir-based therapy among treatment-experienced patients, my colleagues and I[2] conducted a retrospective subanalysis of the REALIZE study comparing the use of previous response categories (null, partial, or relapse) vs HCV RNA response to a 4-week peginterferon/ribavirin lead-in phase as predictors of SVR (Capsule Summary).

The current subanalysis was restricted to patients treated in the control arm (n = 121) and in the telaprevir arm that included a 4-week peginterferon/ribavirin lead-in phase: peginterferon/ribavirin for 4 weeks followed by telaprevir plus peginterferon/ribavirin for 12 weeks followed by peginterferon/ribavirin for 32 weeks (n = 240). The importance of the REALIZE study was that it included true null responders whose HCV RNA decreased by < 2 log10 at Week 12 of peginterferon/ribavirin, as well as patients who experienced some degree of viral suppression (partial responders whose HCV RNA decreased by ≥ 2 log10 at Week 12 but remained detectable during treatment) and relapse patients (HCV RNA undetectable at the end of treatment but detectable after stopping treatment). Enormous efforts were taken to establish a previous treatment history before patients were enrolled. The question posed by the retrospective analysis was, “Is it better to examine the patients’ previous treatment response or to give the patients a quick 4-week lead-in of peginterferon and ribavirin to characterize them as responders vs nonresponders?”

This analysis concluded that if there is a very clear history showing how the patient previously responded to peginterferon/ribavirin, one can obtain a good prediction of how the patient will respond to retreatment with telaprevir-based therapy. Specifically, previous relapsers experienced a 90% SVR rate with telaprevir-based therapy. By contrast, the SVR rate was 58% among previous partial responders and 30% among previous null responders.

When assessing SVR rates based on response to the 4-week peginterferon/ribavirin lead-in, it is interesting that some patients who ultimately did very well with telaprevir-based retreatment initially responded rather poorly through 4 weeks of treatment. For example, 10% of previous relapsers experienced a < 1 log10 reduction in HCV RNA after the 4-week lead-in phase; however, 62% of these patients achieved SVR with subsequent telaprevir-based therapy. Likewise, previous partial responders who experienced a < 1 log10 HCV RNA reduction during the 4-week lead-in phase achieved a 56% SVR rate with telaprevir-based retreatment. That finding raises concern that if treatment response predictions were based on the 4-week lead-in response in this population, clinicians may discontinue therapy in a significant minority of patients who would otherwise have achieved SVR. Thus, I would counsel our case patient (a previous relapser) that a 4-week lead-in phase would add very little value and would not be helpful in determining her optimal course of therapy.

By contrast, response to the 4-week lead-in phase had much stronger predictive value among previous null responders. The SVR rate following telaprevir-based therapy among previous null responders who experienced a < 1 log10 HCV RNA decrease during the 4-week lead-in phase was 15% vs 54% in the subgroup who achieved ≥ 1 log10 HCV RNA reduction with the lead-in.
Therefore, in my practice, I plan to treat all patients for whom I have identified a well-characterized previous null response with a 4-week lead-in of peginterferon/ribavirin prior to adding telaprevir; if they do not exhibit an adequate response to the lead-in, I will discuss with them the limited value of continuing treatment. However, if they do respond, I will encourage them to initiate a telaprevir-based regimen. On the other hand, I will not assess the HCV RNA response at Week 4 in previous relapsers and previous partial responders because I do not think the information will alter my management plan. There are also patients for whom I do not have sufficient information to accurately characterize their previous treatment response; in those patients, the 4-week lead-in might provide some additional information, although this approach should be used with caution, bearing in mind that if their previous response was partial or relapse, a poor response to the 4-week lead-in may not portend a low likelihood of SVR.

Paul Y. Kwo, MD: I agree completely that the 4-week lead-in will be very useful in patients who do not have an accurate viral kinetics profile from their previous treatment course, with the important caveat noted by Dr. Foster that if the unknown previous response was relapse or partial response, basing the retreatment decision on the 4-week lead-in response may discourage therapy in a considerable proportion of patients who would have benefited. For example, in the REALIZE study, previous relapsers with a less than 1 log10 IU/mL reduction in HCV RNA after the 4-week lead in went on to a high SVR rates (62%). If one had relied on just the lead-in period to decide whether or not to add telaprevir because you did not have accurate pretreatment viral kinetics—that is, if one chose to stop treatment and not add telaprevir—one might potentially deny a relapse patient a very good opportunity to achieve SVR. In well-characterized null responders, I concur with Dr. Foster’s approach of using a lead-in in this setting as well.

Stefan Zeuzem, MD: In considering the poorer SVR rates among previous null responders, there are 4 key factors that potentially impact their retreatment response: liver histology, HCV subtype, IL28B genotype, and response to a 4-week peginterferon/ribavirin lead-in phase. It is important to distinguish between the relative contributions of each of these factors in order to determine the best individualized treatment approach for previous null responders. A careful dissection of an individual patient’s likelihood of response to retreatment with a protease inhibitor–containing regimen can allow clinicians to better counsel patients on the relative benefit of initiating retreatment at the current time vs waiting until newer, more effective therapies such as quadruple regimens are available.

As noted earlier, fibrosis stage did not appear to be a significant factor in previous relapsers; however, in previous partial and null responders, SVR rates were impaired in patients with cirrhosis. The significance of IL28B genotype is also likely to be limited in this setting because the majority of patients with a null response to previous peginterferon/ribavirin will have the unfavorable CT or TT genotype. However, this analysis of the REALIZE trial showed convincingly that among previous null responders, response to the 4-week lead-in phase of peginterferon/ribavirin alone identified subgroups with a notable difference in SVR rates with telaprevir-based therapy. Based on these data, I agree that previous null responders may represent a population in which response to 4-week peginterferon/ribavirin lead-in could be an important determinant of whether to proceed with treatment using protease inhibitor–based triple therapy or to wait longer for more effective options.

Paul Y. Kwo, MD: For previous null responders, the risks of offering therapy to those who have a poor response to a 4-week lead-in include the adverse effects of peginterferon/ribavirin and the generation of resistance associated variants. Also, preliminary data suggest that more effective regimens with combinations of DAA agents may be available in the future for this group of patients. The most challenging patients continue to be previous null responders with advanced fibrosis. This group exhibits poor response to peginterferon/ribavirin and they often have many negative predictive factors, yet these patients are most at risk for decompensated cirrhosis, hepatocellular cancer, and the need for liver transplantation. In the absence of other available protocols or for this group it may be reasonable to consider retreatment despite the lower likelihood of success.

Graham R. Foster, FRCP, PhD: I agree entirely, particularly when considering that in the United Kingdom 20% of patients are dying on the wait list for liver transplantation. In that context, a 15% chance of response may well be worth taking even among this group with a poor initial response to a peginterferon/ribavirin lead-in phase. Therefore, it is important to counsel the patient on their options, provide them with all of the data, and help them to make the most informed decision possible.

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