The following had to be divided into several pieces to meet Yahoo requirement of <4000 characters. But all came from the same source as the previous post and the entirety is not edited.
Nezam H. Afdhal, MD, FRCPI:
Boceprevir is a second protease inhibitor currently under study in phase II trials and entering phase III analysis. At the 2008 EASL meeting, Kwo and colleagues presented data from the Serine Protease Inhibitor Therapy (SPRINT-1) trial—a worldwide, multicenter trial of patients with HCV genotype 1 randomized to multiple different combinations of peginterferon alfa-2b, ribavirin, and boceprevir (Capsule Summary). The purpose of this fairly large trial (approximately 100 patients per arm) was to determine the safety, efficacy, and optimal treatment strategy for use of boceprevir in treatment-naive patients. One strategy included a lead-in phase in which patients were pretreated with peginterferon alfa-2b and ribavirin before the addition of boceprevir; the second was a noninduction triple-therapy strategy; and the third strategy combined boceprevir with low-dose ribavirin. The focus of the presentation at the 2008 EASL meeting was on 3 of the 6 arms: 1) triple therapy with peginterferon alfa-2b 1.5 µg/kg/week, ribavirin 800-1400 mg/day, and boceprevir 800 mg 3 times daily for 24 weeks, 2) a 4-week pretreatment phase with peginterferon/ribavirin followed by 24 weeks of triple therapy, and 3) a peginterferon/ribavirin control arm in which patients were treated for 48 weeks. The rationale for the 4-week pretreatment period was to allow peginterferon/ribavirin to reach steady state before the addition of boceprevir, thereby potentially decreasing the risk of virologic breakthrough and resistance development.
Data are currently available through Week 40 only, representing 12 weeks after the end of treatment in the boceprevir-containing arms. The investigators found that 39% and 60% of patients in the noninduction and the lead-in arms, respectively, achieved RVR vs only 8% of patients in the control arm. Similarly, 73% and 78% of patients achieved EVR in the noninduction arm and lead-in arm, respectively, vs only 34% of controls. Most importantly, 55% of patients in the noninduction arm and 57% of patients in the lead-in arm had sustained undetectable HCV RNA levels at 12 weeks posttreatment (SVR12)—a highly respectable SVR12 rate for a short duration of therapy (SVR12 for the control group is not yet available).
Of interest, the very high RVR rates of 85% to 90% seen with telaprevir were not achieved in this trial with boceprevir, yet SVR rates were still relatively high. This finding may suggest that continuing boceprevir for 24-48 weeks—instead of stopping after 12 weeks as in the telaprevir trials—is beneficial.
I do not know about someone "reliable" but here is my 2 cents worth.
One important piece of info that one can hung his teeth on is the fact that TVR showed a proof of concept data for previous nnresponders. The fact that 70% or more of the patients in each of the previous nonresponder groups has an RVR at week 4 of the treatment is something that no other compound has achieved so far. As you may know RVR is an indication that the therapy will usually succeed for those who complete the treatment.
As it was posted by someone, the mid stage results of Prove 3 for nonresponders so far has shown that 52% of the previously nonresponders were virus free after 3 months. That is a very good news.
My hope is that eventually most of the remaining nonresponders will also become virus free. For thost who unfortunately may still not be cured I think eventually a combination theray of several protease inhibitators an also some polymerese compounds such as IDIX is developing may do the trick.
These are very interesting articles, chock full of information.
Can someone (reliable) on the messageboard possibly summarize the findings of the two articles?
em? third? glad? paul? Who wants to give it a shot?
Happy trading to all!
Overall, RVR was the best predictor of response, whereas lack of RVR predicted relapse. In addition, although many patients did not achieve undetectable HCV RNA at Week 4, relatively low rates of breakthrough were observed in the trial. These data show that, even if the patient is not HCV RNA negative by Week 4, SVR rates continue to increase and breakthrough is rare. Although detailed virologic data on these patients were not presented, I think these results heighten interest in this drug and suggest that continuing it for longer durations than telaprevir is likely beneficial for these patients.
Ira M. Jacobson, MD:
One of the potentially confusing aspects of this trial is that the patients in the lead-in group received an extra 4 weeks of treatment vs the noninduction group before RVR was assessed—in other words, RVR in the lead-in arm was measured after 4 weeks of triple therapy, which had been preceded by 4 weeks of lead-in, whereas RVR in the noninduction arm was measured after 4 weeks of total therapy with all 3 drugs. Therefore, the RVR rate of 60% in the lead-in group is really a result of 8 weeks of therapy and the RVR rate of 39% in the noninduction arm is a result of 4 weeks of triple therapy. When analyzed in that context, virologic breakthrough levels of 7% in the noninduction group do not seem significantly higher than the 4% seen in the lead-in group. Another important observation in this study is that the interim response rate in the low-dose ribavirin group, for whom we have no SVR data yet, is lower than the standard ribavirin dosing group, signifying once again the importance of ribavirin as an adjunct to therapy.
Stefan Zeuzem, MD:
The use of a lead-in phase is a potentially very useful treatment strategy because it helps to characterize the patients in terms of response. For example, some genotype 1 patients with low viremia do achieve RVR on standard therapy and therefore would not need to add a protease inhibitor, whereas others not responding as well during this lead-in phase might benefit from the addition of a protease inhibitor. In addition, the lead-in phase may allow the identification of true peginterferon/ribavirin null responders. For those patients, one would be more concerned that the triple-therapy strategy would be equivalent to administering monotherapy with the protease inhibitor. Through the analysis of the lead-in phase in this study, it may be possible to identify the minimum level of susceptibility to peginterferon/ribavirin that is required for successful triple therapy. By doing so, we could avoid exposing patients to therapy that would result in the emergence of resistant strains.
Although it is tempting to compare SVR rates from different trials of different protease inhibitors, it is more appropriate to evaluate the difference in SVR rates obtained with the protease inhibitor vs the control in each individual study. The SVR at Week 12 posttreatment for the control patients was not available, but given that the EVR rate in this group was only 34%, it can be predicted that there will be a substantial difference in response rates between control patients and treated patients. It seems unlikely that a 34% rate of HCV RNA negativity at Week 12 could produce a more than 50% rate of SVR12, as seen in the boceprevir-treated patients, at least from my experience with peginterferon/ribavirin combination therapy.
Nezam H. Afdhal, MD, FRCPI:
I was fascinated to see that in the noninduction group, response rates increased from an RVR of 39% to an SVR12 of 55%. Those data call into question the paradigm of using RVR as a predictor for SVR12 in the setting of STAT-C therapies.