In my experience it is quite common to attend medical conference in which, at the end, there are some session called “taking home message” or wrapping up: some key opinion leaders take care to summarize the hot topics of the conference. During the Liver Meeting in San Francisco something of different was made by Gregory T. Everson, Professor of Medicine, University of Colorado School of Medicine, Denver. Prof. Everson was able to provide in about 30 minutes state of the art, what we have learned by the use of the two new PI and what kind of drugs issues and decision we have to face in the next 12-18 months, considering the use of multiple drugs with the goal of obtaining viral clearance and interferon free regimes:
During this Conference we had a lot of presentations regarding new future drugs candidate for hepatitis C, but this year 2011 we had the first two protease inhibitors in the market. In your wrap-up at the end of the Conference, you started explaining what we have learned from the use of these new two drugs…
Boceprevir and telaprevir are the two drugs you are referring to. They are protease inhibitors and they both work at exactly the same site for the hepatitis C virus. What we found is that those two drugs, when added to peginterferon and ribavirin, each individually of course, increases the chance to clear HEP C from about 40% up to 75%. So, there has been about an overall 30% improvement in the chance to clear hepatitis C with the two new protease inhibitors. The most important thing for doctors and patients, though, is to understand that these drugs have to be given with peginterferon and ribavirin, they can never ever be given alone. If you take the drugs alone, you’ll become resistant and it won’t work, you have to take those drugs with peginterferon and ribavirin, that’s why we use the term “triple therapy”: peginterferon, ribavirin with either telaprevir or boceprevir.
But we have also learned is that the backbone, the answer to interferon is relevant in terms of the final sustained biological response.
Yes, that’s correct. Studies at this meeting actually addressed that particular point, which is: it’s the background of interferon responsiveness that predicts who best will be able to respond to treatment with the triple therapy. In addition, another big factor predicting response is how much scar tissue build-up there is in the liver, how much fibrosis, and the patients who have extensive fibrosis or cirrhosis seem to have a lower ability to respond to triple therapy and clear hepatitis C and, if you combine those two factors together, a poor response to interferon and a lot of fibrosis in the liver, cirrhosis, those two factors together really knock down the ability clear hepatitis C with triple therapy. In fact, in that particular subgroup, even though the numbers are relatively small, it isn’t that much better than just peginterferon and ribavirin alone, both running around 10 to 15% chance to achieve SVR. The point is that the populations with the poorest response to interferon are: prior treatment failures, people when given interferon who don’t run their hepatitis C RNA down, underlying cirrhosis, perhaps African-American or black race and, we haven’t much data, but perhaps even in Latinos there is a factor, but so far most of the data with telaprevir- and boceprevir-based triple therapy suggest that Latinos respond just about as well as Caucasians.
Many studies at this meeting are related to the costs about these drugs…
Yes, cost is definitely a factor. I mean, obviously access to the treatment is going to be dictated by ability to pay or coverage of being insured or having some third-party payer mechanism. So, there have been many studies at this meeting about cost effectiveness.
The usual parameter or threshold that is used for cost effectiveness is somewhere around 50.000 dollars – you know? – for improved outcomes and, with both telaprevir and boceprevir they seem to exceed those thresholds, I mean stay under those thresholds, so that the quality of life gained by clearing HEP C, the reduction in risk for liver-related complications, is so great that it offsets the cost factor in terms of the cost effectiveness of the treatment. Nonetheless, it would be awfully nice if we could run down the cost of these protease inhibitors to the point where it becomes more widely available, more universally available and hopefully with new drug development there will be more competition and more price adjustment and hopefully that will come and reduce the cost down, hopefully.
We have a lot of new protease inhibitors in the pipeline. Can you list the most common problems or issues related to this class of drugs?
The common problem with protease inhibitors is the risk of resistance, so if you are resistant to one you may become resistant to others. The good news on that is that the more potent the protease inhibitor, the less likely these resistant variants will emerge. Also, the good news about most of the resistant variants is that they are sensitive to interferon and ribavirin, so the triple therapy with the protease inhibitors seems to keep most of the resistance issues in abeyance. And then, if we add other drugs such as polymerase inhibitors, NS5A inhibitors, there is no cross-over in the resistance, so that using double drug therapies, triple drug therapies may over time actually eliminate the resistance issue. The other thing with protease inhibitors, there are, you know there is always some side effects with these drugs. The side effects are generally relatively mild, occasionally they can be severe, with telaprevir rash can be an issue, with both drugs anemia can be an issue and with boceprevir some of the patients complain of a pretty significant foul taste in the mouth. The new drugs, also some of them have some rash issues, some of them have some problems with gastrointestinal upset and some of them have some issues with even liver blood test elevations. Most of it seems to be relatively benign because the treatment courses are getting shorter and shorter, so the exposure to a patient may be less and less and hopefully that will translate into less toxicity.
And also there will be a possible reduced pill burden…
Yes. You know, right now the number of pills required with the current triple therapy regimens is pretty high. I mean, the ribavirin pill use per day is about, depending on the preparation, up to 6 pills a day and then with telaprevir it’s another 6 pills a day and boceprevir is another 12 pills a day, so, depending on what regimen you are on, you got a fair number of pills to take every day and it’s very difficult for a lot of people to do that. The other part of it is that it’s recommended that you have meals with each of the doses and I had some patients who complain that they are gaining weight on the treatment because of the amount of meals they are eating and they are not used to eating as much and that’s in direct contradistinction to when, in the peginterferon and ribavirin days when the main complaint was some weight loss and loss of appetite and now we are forcing them to eat and the good news is that they are keeping their weight up, that bad news in America they are getting a little too heavy.
In your talk you mentioned the results of “quad” therapy, that were presented during this Conference..
“Quad” therapy is peginterferon and ribavirin with two direct-acting antivirals and it’s a promising strategy in the fact that it seems to shorten the duration, it may also improve the chance to be cured of HEP C, but all the studies presented at this year’s Liver Meeting are what we call phase II studies, and so you have to be very cautious about projecting from phase II studies to what’s going to happen in the bigger trials and in the future, but it’s promising, there is no question about it.
There also new drug classes arriving just behind the corner, I am referring to the drugs that address host factors…
Exactly. In addition to these drugs that are specifically targeting the virus, there is a number of new ideas about how to ramp up the host antiviral activity, and so cyclophilin inhibitors, inhibitors of the uptake process of the virus into the liver and even microRNA strategies are evolving and there were several abstracts at this meeting presented on these evolving new strategies.
Is it possible to speculate when the future will happen?
Well, I don’t claim to see the future, the projections are perhaps that we may start to see some of these drugs emerge out of the Phase III trials, as early as 2014, possibly even in the last quarter of 2013, but there is rarely a smooth road to full approval of therapy, so I think somewhere around by the year 2015 we should be seeing additional drugs in the armamentarium of medications to treat patients with hepatitis C.
Last question: in 1991 we started with the monotherapy of interferon and now we are in a new condition to decide how many drugs combine and when these drugs must be use. Should we think about possible future as a time during which therapy will be without interferon?
I think everyone will be happy, including the doctors and especially the patients. I think the future of this is going to be where physicians will sit with their patient and they will work together to devise the best treatment plan. Hopefully, we are going to have many, many drugs to pick from that all of which are highly effective and each with their own specific characteristics that make then desirable for a given patient. So, I think we are going to see patient-centered care and patient-centered approaches to the treatment of HEP C in the future.
Articolo presente in – HAART and correlated pathologies n. 13 –