The Questions On Telaprevir and Boceprevir

Paul Sax • April 28th, 2011

http://blogs.jwatch.org/hiv-id-observations/index.php/hepatitis-c-week-is-upon-us/2011/04/28

After many — and I mean many — years of telling patients that new hepatitis C drugs were “coming soon,” that time has finally come.

An FDA Advisory Panel yesterday favorably reviewed the HCV protease inhibitor boceprevir; today telaprevir got the same unanimous report. The FDA will  certainly follow with approval for both drugs, and hence they will be available for actual use soon.

While these are undoubtedly huge advances for patients with HCV genotype 1 — who faced a 30-40% chance of cure with IF/ribavirin now, compared with up to 80% by adding one of the new drugs — many questions remain about how they will be used, and in whom.
In no particular order, and without even trying to be comprehensive, here are some of the “known unknowns“:
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• How will clinicians choose between them?
• Is a 4-week lead in with IF/RBV (as was done with the boceprevir studies) necessary?  Additionally, is it useful, by identifying “null” responders who will have a higher rate of developing treatment failure and PI resistance?  Could starting all three drugs simultaneously improve outcome?
• How long should treatment be?  Will this vary depending on HCV RNA kinetics from person-to-person?  Seems like this is a situation ripe for sophisticated modeling, and that  more frequent HCV RNA monitoring (especially early) will inform this decision.
• How will patients in the chaotic real world tolerate these drugs?  Interferon/ribavirin is already no picnic, and adding these additional meds will mean additional side effects.
• Related:  Besides the signature toxicities (telaprevir — rash and anemia, boceprevir — anemia and dysgeusia), what other side effects will appear with more widespread use?  Note that it’s not a question of if these side effects will occur, it’s when will occur, and what they will be.
• How will resistance be assayed?  Will genotype testing become commercially available?  If so, what new combination of letters and numbers (i.e. mutations) will need to be memorized?
• How do these advances influence treatment decisions about the patients who don’t have HCV genotype 1, especially those with genotype 4?  I suspect not at all, at least for now.
• How will compliance be with these three-times a day regimens?  Will it improve over the course of therapy, or will patients get “pill fatigue.”  We know they will get regular fatigue — I have yet to see a patient receiving interferon who didn’t mention this as a side effect.
• View from 20,000 feet:  If someone is currently very stable — with low risk of HCV disease progression — should they “act now” or wait for even better, less toxic options?  Given the huge effort in HCV drug development, how long before we have treatments for HCV that are comparably simple to HIV therapy?  Is a single-pill combination tablet too much to ask?  Remember, for HIV, such a treatment would have been unimaginable in 1996; less than 10 years later it was the mostly widely-used HIV combination in the country, and remains so today.
• Who will be the HCV Providers?  Will the legacy of gastroenterologists’ leading the way in hepatitis therapy continue, or will this Infectious Disease finally be embraced by Infectious Disease Doctors?  (Italics represent my view.)
• How much will the new drugs cost?  Will they be covered for all patients?  How about for those who have a favorable IL-28B genotype — and would be likely responders to IF/RBV alone?
• How will our HIV co-infected patients respond?  Data are extremely limited — and the drug-drug interactions promise to be unbelievably complex.  As of April 28 2011, we only have data on use of telaprevir with either EFV or ATV/r.
• How do you design an HCV clinical trial once these drugs are approved?  Will all “control” arms now need to be IF/RBV + something-previr?

Answers to some of these questions will come with formal FDA approval, which will necessarily include some “package insert” indications for therapy.
But stay on your toes, because it seems highly likely that this is one therapeutic area in ID that truly lends itself to the cliche, “moving target.”