I was just reading the post from HectorSF from the AASLD and I have also read similar information at the Clinical Options site. The new guidelines recommend Riba dose reduction with the new PI's when anemia occurs as it has not been shown to reduce SVR chance. I know this topic of reduced riba has been debated many times on this forum. But as it pertains to triple therapy.. I get the feeling that researchers are comfortable based on the data that reducing riba is as effective without impacting SVR as using procrit.
My question though is nowhere can I find the guidelines on reducing riba in triple tx. Reduce by 200 mg as a first step, but for how long? If you reduce riba after UND is it safe to stay on reduced riba for 11, 12 weeks? The research doesn't seem to be clear on exactly what level of reduced riba is safe without impacting SVR chance.
Glad to hear the new guidelines state that the Riba can be reduced, hopefully it will put an end to some of the debating that goes on. Tx is not a one size fits all t-shirt. As far as triple therapy goes, personally I don't know but this will bump you up.
That's a good question sandy....Shiffman ,when presenting to docs on the CCO sirt certainly promotes Riba reduction ,as it seemed to have very little effect on lessening SVR rates in trials for both P.I"s(as long as already UND.),however it seems not at all clear on how long this reduction should continue.
My take on it is this...and obviously only my non-professional opinion.
The P.I:s seem to work extremely fast....it looks like in a week or two at most and from some of the reports here ..even in a matter of a couple of days,and altho INF and Riba is still a big part of the mix, it may be they feel Riba is somewhat less a part as it certainly was with SOC..
A Couple of reasons I say that 1) Vertex ,as we know is doing a triple therapy trial that will end everything at 12 weeks(if Und at Wk.4),therefore it stands to reason they must feel this has a good chance of success...in other words they are banking on not needing Riba at all after you have been clear for 8 weeks 2) some of the all oral trials are without Riba completely, and seem to be having very good early results.
So .. again...my take on this is they just are coming to the co conclusion with the P.I. on board ,. Riba is not going to be as important (at least in the doses we had to take) as it once was.
I know there are some folks here who may want to show up at my place with lighted torches for saying that,,,,however I feel this is what the future possibly holds and hence knowlegable guys like Shiffman and some others are going about it this way.
as always in this game..I guess the future will tell the story...
"I know there are some folks here who may want to show up at my place with lighted torches for saying that" you made be burst out laughing when I read this.. you are right, things can get a little testy here at times. :)
I agree with you Will, I think the playing field as we know it is rapidly changing and we may find out through some of these new trials that riba is not as critical with the addition of the new drugs as previously thought.
My doc seems to think I should stay on 800 mg for my remaining 9 weeks, that will mean of 30 weeks tx, I will be reduced from 1000 to 800 for 14 of those weeks. Hmm.. I do feel sooo much better with just that 200 mg difference.
I will be very curious to see how the Vertex 12 week trial progresses.
Interesting information. It seems that people that need to dose reduce riba with triple still fair well, but as stated earlier how much is too little? It seemed clear from previous trials that no or low dose riba arms rather then response guided riba reductions were not successful.
Aren't the all oral studies still using ribavirin? It seems to still be an important part of the mix. Hopefully in the next few years right combo of DAAs will be available so we won't need either interferon or riba but if I was treating right now I would be cautious about riba reductions especially considering the possibility of resistance with these new drugs. My personal take is that the jury is still out.
"The SVR rate in the 12-week telaprevir plus Peg-IFN without ribavirin arm in PROVE2 was 29%."
12/12 arm: 60%
12/24 arm: 69%
12/12/no RBV arm: 36%
Control arm: 48%
The early viral response rates at week 4 and week 12 were extremely high, with up to 80% undetectable in the telaprevir/IFN/RBV arms and about 70% at the end of therapy. This compared with about 50% undetectable at the end of therapy in the control arms and 60% in the no-ribavirin arm in PROVE 2.
However the relapse rates, where relapse was defined as viral reappearance after the end of therapy, were higher in the control arms (about 22%) and the 12/12 arms (about 30%) than in the longer arms (2-6% in the 12/24 and 12/48 arms in PROVE 1 and 14% in the 12/24 arm in PROVE 2, though only 7% in patients who had been undetectable by week 4.) There was a particularly high relapse rate of 48% in patients in PROVE 2 who did not take ribavirin.
Our results show the necessity of administer- ing ribavirin in combination with peginterferon alfa and telaprevir. Ribavirin will most likely be required in combination with the use of other spe- cific HCV inhibitors and peginterferon alfa to achieve the high rates of sustained virologic re- sponse seen in our study. Among patients receiv- ing telaprevir-based regimens, the addition of riba- virin increased the sustained virologic response
rates by preventing relapse and the emergence of both low-level and high-level telaprevir resistance. In spite of its moderate, transient antiviral effect on HCV replication when administered as mono- therapy,13 ribavirin has been shown to prevent viral breakthrough during, and relapse after, the treat- ment period by significantly accelerating the sec- ond slope of viral-RNA decrease in patients who have a response to the antiviral effect of peginter- feron alfa.14 The modes of action of ribavirin re- main under debate.15-19 Our study results are con- sistent with the notion that ribavirin does not act by directly inhibiting HCV replication, since it can- not be replaced by a potent HCV inhibitor in com- bination with peginterferon alfa-2a.
Patients in all four boceprevir groups had higher rates of SVR than did the control group (58/107 [54%, 95% CI 44-64], p=0.013 for PRB28; 58/103 [56%, 44-66], p=0.005 for PR4/PRB24; 69/103 [67%, 57-76], p<0.0001 for PRB48; and 77/103 [75%, 65-83], p<0.0001 for PR4/PRB44; vs 39/104 [38%, 28-48] for PR48 control). Low-dose ribavirin was associated with a high rate of viral breakthrough (16/59 [27%]), and a rate of relapse (six of 27 [22%]) similar to control (12/51 [24%]). Boceprevir-based groups had higher rates of anaemia (227/416 [55%] vs 35/104 [34%]) and dysgeusia (111/416 [27%] vs nine of 104 [9%]) than did the control group.
Here’s a (rather recent) link to non-IFN/non-riba treatment:
Reported by Jules Levin
EASL 2011 April 2 Berlin Germany
Presented by Anna Lok
“...from Jules: this is the biggest story & news to come out of this meeting, needless to say, and the biggest advancement in medicine in 50 years. In this study 4/11 null-responders receiving BMS-790052 (NS5A inhibitor) + BMS-650032 (protease inhibitor) alone for 24 weeks achieved SVR12 & SVR24. The presentation says "HCV infection can be cured without interferon & ribavirin". BMS-790052 & BMS-650032 with peg/RBV for 24 weeks: 10/10 patients achieved SVR12 & 9/10 achieved SVR24: "QUAD therapy can result in a high rate of cure in this difficult to treat population" (1 patient < LLOQ at week 24 post treatment undetectable on retesting 35 days later). This is the proof of concept we have been waiting for that at least some patients can be cured without peg/rbv, now these are the hardest to treat patients null-responders...”
If I’m reading this correctly, the data is for previous non-responders using BMS-790052 + BMS-650032 without other adjuncts. Looks like these guys were *really* riba reduced :o).
I read about that study, but 4 out of 11 isn't good enough for me to join that band wagon yet. Still as they said, proof of concept.
Here is a study they will be doing with triple therapy and no riba/interferon
Official Title: Open-Label, Multiple-Dose, Dose Escalation Study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Coadministration of BMS-650032, BMS-790052, and BMS-791325 When Administered for 24 or 12 Weeks in Treatment-Naïve Subjects Infected With Hepatitis C Virus Genotype 1
I did have my riba reduced during a telaprevir trial. I still SVR'd. The new PI's make up for any negative impact that reducing riba would have had in the past. It is a whole new ball game with the PI's involved.
I would rather have my riba reduced then subject my body to a forth harsh drug. Procrit, etc is some nasty stuff.
I thought this was interesting although it's about a year and a half old:
"from Jules: in 2011 the first 2 protease inhibitors are expected to become available as they are in phase 3 studies now and will be used in combination with peg/rbv. Over the following several years numerous additional oral HCV drugs in a number of different classes are expected to become available as now there are about 25 oral drugs in development. It remains to be seen if peg/rbv can be eliminated from therapy. Drug classes include protease inhibitors, several types polymerase inhibitors that may be able to be combined in 1 regimen, NS5A inhibitors, and there are 2 new interferons in early clinical development, lambda interferon and locteron, that appear to have less side effects than the peginterferon used now. I expect eventually therapy will be reduced to perhaps 12 weeks for some patients but even in 2011 duration of therapy with 1 oral +peg/rbv will be 24 weeks. Combination therapy in the future will consist of several oral drugs - 2, 3 or even 4 - with or without peg/rbv. Oral drugs are expected to be equally effective in all ethnicities so there should not be major barriers to curing African-Americans and Latinos if testing/screening, linkages to care and patient services are adequately providing and if we can prevent too much drug resistance."
Wow; all four study arms and none of them involve either IFN or riba. Treatment is certainly changing, Dave. I suppose it’s only a matter of time now before the nasties are morphed out of the equation. There’s likely to be a substantial pay day for the companies involved, hmm?
suppose it’s only a matter of time now before the nasties are morphed out of the equation.
Kinda my thoughts Bill...but will take some time huh. .... but that Inci ,is quite a nasty...from what folks have been reporting.... :)
Here is the data the source documents referred to in the new AASLD Guidelines for telaprevir that you asked about in your questions. (Others can read the data on boceprevir).
24. Sulkowski MS, Reddy R, Afdhal NH, Di Bisceglie AM, Zeuzem S,
Poordad F, et al. Anemia had no effect on efficacy outcomes in treatment naive patients who received telaprevir-based regimen in the
ADVANCE and ILLUMINATE phase 3 studies. J Hepatol 2011;
41% (361/885) of patients in the T12PR developed anemia (hemoglobin < 10 g/dL) during treatment. Seventy four percent (267/361) of T12PR patients with anemia achieved SVR.
Seventy three percent (384/524) of T12PR without anemia achieved SVR.
Seventy-two percent (260/361) of T12PR patients with anemia had ribavirin dose reduction due to adverse events compared to 11% (60/524) of T12PR without anemia, respectively.
SVR was achieved by 76% (243/320) of patients with ribavirin dose reduction in the T12PR compared with 72% (408/565) of patients without ribavirin dose reduction in the T12PR.
In patients treated with telaprevir-based therapy, anemia as well as ribavirin dose reduction had no apparent effect on SVR rates. These data suggest that management of treatment-related anemia with ribavirin dose reduction appeared not to impact SVR with telaprevir-based therapy.
"Reduce by 200 mg as a first step, but for how long? "
"If you reduce riba after UND is it safe to stay on reduced riba for 11, 12 weeks? "
Hemoglobin <10 g/dl is considered anemia.
The dosage of riba was reduced to 600 mg/per day according to “package insert directions”.
Time of first Ribavirin dose modification appeared not to affect SRV rates.
7 days was considered “dose interruption”
76% (24 weeks) and 73% (48 weeks) with “dose interruptions” achieved SVR.
Great information Hector. I am confused by the statement below. I assume all of the people were not reduced to 600mg per day although perhaps they were. It would be good to know what HGB levels were vs what level of ribavirin reduction was used.
"The dosage of riba was reduced to 600 mg/per day according to “package insert directions.”
Thanks Hector! I was actually looking for Boceprevir data since I am on Vic.. but this is great information and likely applies. I am digging around on natap site now to see if I can find the same data for BOC.
Sandy -- Wow. My mind is reeling. Thanks very much for posting this question, as the info here helps me too. Trying to see what is best, without 'doctoring myself', is a bit of a balancing act today.
Spectda, Hector, Bill, Can-do-man......thank you for doing your homework and shedding some insight on this debate. I really do think it is a different ball game with the P.I.'s, not quite as cookiecutter as they (the great and powerful Oz of Merck and Vertex) anticipated. Maybe that is why we are seeing so many different moves from doctors, from patient to patient. Either way, I am taking everything your have said here very seriously. Thank you.
I think, that one of the reasons, I fell to achieve SVR in my last treatment, is that I had to reduce Riba dose, since my low platelets and wbc! After I read in some articles, that Riba dosage is very important!
I'm in a PI study and was told going into it that if necessary, my riba dosage would be reduced by 200 mg a day (incremenets, increasing if necessary) FIRST. And the dosage would remain lowered as long as necessary.
Copyman: That's not much of a dosage reduction to be basing an opinion on that dosage reduction of ribavirin isn't harmful because you did and you got SVR. One week dosage reduction of riba on SOC after Week 12 is considered acceptable and you had two and then none again at all. That's a drop in the bucket for dosage reduction comparatively.
As for the rest of it, the devil is in the details, seems to me, as Spectda points out. How many were dose reduced, by how much and what do other studies say? I've seen a solid study posted by someone else that clearly indicated the impact of dosage reduction of SOC during triple therapy. Slight drop in SVR rates across the board. I personally don't think there's enough data out on this yet to make me comfortable with reducing Riba as a first choice when HGB drops and I'd like to see more data coming out of "Phase IV" first.
It's long been known that riba does its 'heavy lifting' (even for SOC) during the early part of tx. The 'scarfle-riba-till-your-ears-bleed' torch people never had reason on their side, other than it was a cheap, easy way to tweak your tx.
who (at 100 kg) dose reduced from 1200 to 800 and wasn't anywhere close to anemic)
No matter what the studies say, I am glad I don't have to fight the battle. Procrit should be on my doorstep when I get home tonight and boy, am I looking forward to that burn!
Even if you add all those studies together, how many people are we talking about? Low thousands, maybe? Seems I read that 17,000 people have started INC since May. Anybody heard how many Victrelis patients there are? What I would like to see is surveys done by the two drug companies filled out by the doctors on HGB levels, treatment (riba reduction, procrit, transfusion, other) and, of course, outcome.
Thanks for all the comments.. the real answer I suppose with the new drugs is that we just don't know yet. There is just not enough data and we are all guniea pigs of sorts with this new PI's right now.
We shall see... but I am with copyman, I would rather have my riba reduced than put yet another drug in the mix.
My point about the reduction was that only reducing by 400mg can have an impact on a persons HGB increasing. Much better then rescue drugs in my opinion. Reducing riba should at least be tried before procrit.
I would be leery lowering riba before 12 weeks. I would consider rescue drugs if is was before at least 8 weeks. Usually HGB drops after 8 weeks which is plenty of time for riba to have built up in a persons system.
And I only say the riba reduction is better if on triple therapy. If on SOC only then NO reduction of peg or riba.
No Sueze, I was not on triple therapy, only on SOC , which is Pegasys and Ribavirin, for 48 weeks. I was UND , at week 12, but again detectable, at the week 48., I was all the time at dose of 800 mg of Ribavirin. I think it was not enough, for achieving SVR.
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