Mark S. Sulkowski, MD - 12/12/2012 More from this author
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Anemia in Patients Treated With PIs
Clinicians have now been using boceprevir and telaprevir in combination with peginterferon/ribavirin for approximately 1.5 years since their approval, and the biggest obstacle faced by clinicians is the increase in anemia with both of the HCV protease inhibitors (PIs). Although we all have previous experience with anemia management from when peginterferon/ribavirin was the standard of care, the addition of PIs has compounded this issue.
The prescribing information for the PIs recommends reducing ribavirin for anemia management; however, many clinicians have been reluctant to take this approach for fear of compromising a patient’s ability to achieve an SVR—an idea left over from the days of the 80-80-80 rule that was coined more than a decade ago to describe response to therapy with standard interferon 3 times weekly plus ribavirin.
The Need to Dose Reduce
The point I’d like to make is that our understanding of anemia with ribavirin has evolved and we need to move beyond this entrenched concept. Here’s the new thinking for the management of anemia with triple therapy including telaprevir or boceprevir: We need to dose reduce ribavirin in patients with anemia, and we need to do it relatively aggressively. The foundation of this statement are data showing that ribavirin dose reduction does not impair a patient’s likelihood of achieving SVR; on the contrary, it is often key to successful therapy by keeping patients on therapy rather than discontinuing due to anemia complications.
How low can you go and how soon can you dose reduce? One of the most critical findings from recent analyses is that ribavirin dose reduction even during the first 4 weeks of PI administration did not affect the likelihood of response; furthermore, ribavirin dose reduction for anemia while HCV RNA is still detectable also was not associated with worse outcomes. These data give us comfort that we can reduce ribavirin for anemia early in the course of therapy if necessitated by significant anemia.
Many clinicians cling to the idea that more ribavirin is always better, but this idea ignores one of the realities of ribavirin pharmacokinetics—there is wide variability in exposure between individuals. In other words, 2 patients ingesting that same dose of ribavirin can have markedly different plasma exposures. Renal clearance of ribavirin is one of the major drivers of this variability. Several published studies as well as the US Food and Drug Administration analysis of anemia in the telaprevir and boceprevir registration trials clearly demonstrate that the degree of anemia is related to the plasma ribavirin concentrations. In other words, the development of anemia is a marker of higher ribavirin exposure. In the large IDEAL trial of peginterferon/ribavirin, anemic patients actually had a higher SVR rate than nonanemic patients, including those who reduced their ribavirin dose from 1000 or 1200 mg/day to 600 mg/day. The same pattern was observed in the SPRINT-2 trial of boceprevir-based therapy, where SVR rates were higher for individuals who developed anemia when compared with individuals who did not develop anemia. This concept of anemia indicating adequate ribavirin plasma concentration is key in approaching ribavirin dose reductions with confidence. When ribavirin is reduced, we can think of this as an adjustment of the ribavirin dose for that unique patient to a more tolerable level.
My Approach to Anemia Management
In my practice, we monitor our patients taking PI-based therapy pretty closely. I generally recommend complete blood count monitoring every 2 weeks while a patient receives triple therapy. If the patient has a large decline in hemoglobin from baseline or if hemoglobin levels are < 10 g/dL, I drop the ribavirin dose to 600 mg/day. Some clinicians prefer to drop by 200 mg/day increments but, in my experience, that is not aggressive enough and I would rather drop the ribavirin dose to 600 mg/day and then attempt to increase the dose once the patient’s hemoglobin level stabilizes. In my view, it’s better to be safe than sorry; in the case of anemia, a less aggressive approach may lead to the need for epoetin alfa or blood transfusions or, in the worst case scenario, treatment discontinuation. I do use some erythropoietin in my practice but generally reserve that approach for patients who fail the initial strategy of ribavirin dose reduction. I don’t think that there is any rationale to use epoetin alfa as a primary means of preventing ribavirin dose reduction.
If these strategies are followed, I believe you can limit the number of patients who take epoetin alfa, avoid blood transfusions, and most importantly, prevent treatment discontinuation due to anemia. Keep in mind that the most important part of the old 80-80-80 rule was staying on therapy for at least 80% of the treatment duration. Staying on treatment is the key to success with triple therapy.
Your Thoughts?
How do you manage anemia during PI-based therapy? Have recent clinical trial analyses changed your management strategy?
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