June 2, 2011
Table of Contents
We'll likely look back on May 2011 as a landmark month in the history of hep C treatment: It brought the approval in the U.S. of two new hep C drugs, Incivek (telaprevir) and Victrelis (boceprevir). They are the first two drugs approved for the treatment of hep C in almost a decade.
Although Incivek and Victrelis have only been approved to fight a specific strain of hep C, known as genotype 1, they have the potential to virtually double the chances of treatment success for many people living with that strain. Which is a good thing, since genotype 1 is the most common strain of hep C in the U.S. -- and the hardest to treat.
To help explain why these new hep C drugs are such a big deal, we spoke with Barbara McGovern, M.D., an associate professor of medicine at the Tufts University School of Medicine, and a member of the Antiviral Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA), which unanimously recommended both drugs for approval in April (a recommendation the FDA clearly took to heart). Below is a transcript of the interview.
(To learn the basics about each drug, read AIDS InfoNet's fact sheets on Incivek and Victrelis. If you have specific questions about these new drugs, or about treatment of HIV/hepatitis C coinfection in general, you can ask Dr. McGovern directly in our "Ask the Experts" forum on coinfection.)
Myles Helfand: Let's start with the basics on boceprevir and telaprevir. What makes them different from the drugs that we have long had for hep C treatment?
Barbara McGovern, M.D.
Barbara McGovern: There are vast differences. Pegylated interferon is a nonspecific antiviral medication that pretty much regulates a person's immune system. So it makes it more efficient at fighting the hep C virus. Whereas both boceprevir and telaprevir are targeted drugs, specifically for hepatitis C. And because of that, they are very effective, and they're very potent, because they act at one part of the viral lifecycle. That is why we are seeing dramatic falls of viremia in a very short period of time.
Myles Helfand: Why is it that these drugs have to be used in concert in peginterferon and ribavirin?
Barbara McGovern: The bottom line is that when they tried to use these medications alone, there was the development of rapid resistance. So it's very akin, in that way, to HIV -- where, if you think back to certain drugs that were used, any short period of exposure to monotherapy leads to rapid development of resistance. For example, with lamividine (Epivir, 3TC). The same thing would happen with hepatitis C -- that we see the development of resistance very quickly.
Myles Helfand: So there are no treatment situations, then, in which we're talking about a mix-and-match type situation? This is always one of the two peginterferon drugs; ribavirin; and one of the two new protease inhibitors?
Barbara McGovern: You know, what was really interesting: A lot of people were just hoping we could get rid of ribavirin because of the anemia issues. So when telaprevir was studied without ribavirin, and just in combination with peg[interferon]; what was interesting about that was, when you looked at the on-treatment responses, they weren't so far off.
But where you really saw the problems was in relapse. Once you stopped the treatment with peg and telaprevir, you saw that a lot of the patients had rebound viremia off the two drugs -- which shouldn't be surprising to anyone, knowing that what we learned about ribavirin eons ago, back in 1998, was that ribavirin had a very important role in the prevention of relapse.
Ribavirin has never been thought of as a very potent antiviral. But it does have this very special property, and no one's quite sure [what it is]. There are a lot of mechanisms that have been proposed for ribavirin.
Myles Helfand: So, when you take the two drugs we've long used for hep C treatment and you add either boceprevir or telaprevir into the mix, how are cure rates impacted?
Barbara McGovern: When telaprevir was studied with peg and ribavirin, and then there was another arm of telaprevir and just peg alone, it was the same phenomenon: The on-treatment response looked OK. But then when you stopped all treatment, there were a lot of relapses in the dual-therapy arm of peg and telaprevir. So it was very obvious that even though you had these potent protease inhibitors on board, ribavirin is a special drug in preventing relapse. And we still need it; there's no question.
Myles Helfand: What are we actually talking about in terms of percentage differences in SVR with adding one of these protease inhibitors to a hep C regimen? [SVR is short for "sustained virologic response," which means that there's no sign of hep C in a person's blood six months after stopping hep C treatment. It's the gold standard measurement for treatment success.]
Barbara McGovern: It's a really dramatic difference. For genotype 1 infections, the big Phase 4 studies that have been done [in which people took peginterferon and ribavirin] showed response rates of 42 to 46 percent. A few studies sometimes eked out about 50 percent. But that was pretty much where you could get.
Whereas with the addition of a protease inhibitor, you're seeing response rates of 75 to 80 percent.
Myles Helfand: And this is for type 1, right? Which is the least treatable of the hepatitis C types.
Barbara McGovern: That's exactly right. So it's very exciting.
The telaprevir trial that is in progress right now: We don't have SVR data from it, but we do have 12-week data in HIV/hepatitis C-coinfected people, and that 12-week data looks fabulous. It looks like about 70 percent of patients obtain virologic suppression by week 12. Now, that doesn't tell us what the SVR rate will eventually be. But it's pretty darn exciting because that is a tremendous number, a tremendous proportion of patients who are attaining virologic suppression at an early time point. In fact, even the week 4 data look really strong.
A very important point is that these drugs haven't been studied for any other genotype except for genotype 1. For telaprevir, there is some data that it might be effective against genotype 2. For boceprevir, I'd have to double check this, but I'm pretty certain it doesn't have other suspected activity against other genotypes.
So for genotype 3 patients, the protease inhibitors don't really add anything. In the U.S., we're dealing with genotypes 1, 2, and 3 -- mainly genotype 1. So it's really great news for the vast majority of patients. But we can't generalize it to all hep C patients.
Myles Helfand: Let's talk about people with HIV, specifically. Is there anything that either clinicians or their patients need to know about potential interactions with these new hep C protease inhibitors?
Barbara McGovern: Yeah, this is a biggie. Telaprevir is hopefully going to be a very important drug for our patients. Now, what's important to point out is that there are drug interactions with efavirenz (Sustiva, Stocrin). That calls for increased dosing of telaprevir. And in terms of some drug interaction studies that they did with protease inhibitors, it looked like atazanavir (Reyataz) was the least affected.
The way they structured the trial was to enroll patients who were on either an atazanavir- or an efavirenz-containing treatment regimen. And the background nukes that were used were tenofovir (Viread) and emtricitabine (Emtriva, FTC) [which are available together in a single-dose combo pill, Truvada]. I would certainly not use telaprevir in someone who is not on either one of those regimens.
It's a little bit limiting, but to play it safe, I certainly wouldn't want to give telaprevir to someone where we might compromise either their HIV care or risk the hep C drug getting eaten up by the background [HIV] protease inhibitor.
We don't know enough about this yet. But it looks like the main interactions are that telaprevir makes the area under the curve [i.e., the lowest concentration of the drug in a person's blood] for the protease inhibitors go down significantly. But the effect on atazanavir is less than the other protease inhibitors. It's quite dramatic with darunavir and fosamprenavir; those are two drugs I would certainly not want to be giving in combination with telaprevir. As I mentioned, with the efavirenz, you must increase the dose of telaprevir.
Myles Helfand: That can get a little bit spooky for second line treatment, then. You're saying essentially it's OK for Atripla, as long as you adjust the telaprevir dose. But then when it comes to second-line therapies, when you start pulling in more protease inhibitors, like Kaletra (lopinavir/ritonavir) -- it sounds like you're saying it's maybe best to just go back to the peg plus ribavirin.
Barbara McGovern: Well, I think it's a discussion you have to have with the patient. If they're not on the background [HIV] drugs that were studied, then you have the conversation. You will need to change your background therapy to these drugs, either efavirenz or an atazanavir-based regimen if it's appropriate. Obviously, if you have a patient who has a history of drug resistance to either one of those HIV regiments, that's not going to be an option.
So you have to do it cognizant of the HIV resistance history. If there are issues where the patient is concerned about atazanavir, for example, because of cosmetic jaundice or things like that, at least you could have the conversation that says, "You know, you're only going to be on telaprevir for 12 weeks. So let's switch your regimen. I could give you the telaprevir; add it on to this new regimen. And then, once the telaprevir is over with, we can consider switching you back to the regimen that you like the best, if that's an issue."
I think those are the conversations you have to have. But keep in mind, telaprevir's only for 12 weeks. So I think as long as drug resistance isn't a major issue, I think you can get by.
Myles Helfand: Are there any other special indications that either of these drugs have when it comes to specific populations -- particularly African-Americans, who we know, as it is, are disproportionately impacted by hep C?
Barbara McGovern: I think that this is going to be such an important advance for that patient population. What we have known for a very, very long time is that African Americans do not respond to treatment the same way as Caucasians do. For a long time it was believed that the reason for that was because the proportion of patients who are African American who have genotype 1 is greater than 90 percent, whereas that's not the case in Caucasians.
But then when they did studies that took African-Americans and Caucasians with genotype 1 infection and compared them head-to-head, it was clear that the African Americans had almost half the treatment response rates of Caucasians. There are two very important studies that showed the same results. The response rates in African-Americans were like 22, 25 percent -- really discouraging.
But the data with the protease inhibitors seems to suggest response rates greater than 60 percent. So although it's not as high as Caucasians, it's still remarkably better. So it's a big advance for that patient population, as well.
I think when you're talking to a patient, when you say there's a 1 out of 4 chance of responding, that's pretty discouraging. But when you say 1 out of 2, that sounds a lot better.
Myles Helfand: Let's talk a little about those people for whom hep C treatment hasn't worked in the past. The indication for boceprevir notes that it's not for use by some of these people. Why is that?
Barbara McGovern: I think what you might be referring to is the "null responder." Boceprevir is a very good drug, and in people who relapsed in the past with peg and ribavirin, it has excellent response rates in those patients. It also has excellent response rates in patients who have had a partial response, which basically means that by 12 weeks they had viral load declines of more than 2 logs [99 percent], but did not reach an SVR.
I think you're referring to the "null responders," which means the people who took peg and ribavirin and basically had minimal changes in their viral load responses. They did not study the drug in that population. However, telaprevir was studied in null responders. About a third of those patients do respond when you give them triple therapy -- which is, you know, not as good as the other response categories. But knowing that we're layering a potent agent onto two other agents that the patient barely responded to, it stands to reason that you certainly wouldn't expect as good a response. It's still better than no response.
Myles Helfand: Is there cross-resistance between boceprevir and telaprevir? If a person fails one, could they try another?
Barbara McGovern: Boceprevir and telaprevir have very extensive cross-resistance. That's really important for clinicians to know, and for patients to know.
You yourself referred to HIV a couple of times in this interview, and it keeps harkening back to that. When we first started with HIV medicines, we were so careful to discuss adherence with our patients, and this was such a big part of counseling of patients.
This will have to be a very big part of counseling hep C patients. The good part about this is that it's not for the lifetime of the patient. So the hep C patients have it relatively easy, compared to our HIV patients.
Myles Helfand: Well, except that the side effects are awful.
Barbara McGovern: Yeah. I mean, all these meds -- having a rash and pruritis [itchiness] and all that stuff. I mean, it's going to be tough. But when you think about HIV, taking these meds forever, and having to remember to take pills every single day. However, for the hep C patient, if they are really adherent to these regimens, which is going to be difficult because it's three times a day -- I think taking that midday dose is always going to be hard, especially for people who are working and busy; it's so difficult to remember that midday dose -- I think that's going to be a barrier to adherence. But it's going to be something we have to really emphasize to patients.
If they take it as prescribed, then hopefully they'll get to virologic suppression. And we know that once you get to virologic suppression, then the risk of resistance is very, very low.
If you're taking your medicines in a hit-and-miss fashion, the risk of resistance is extremely high. And then we don't have that second drug to fall back on, in terms of sequencing of therapy. We're not there yet. In fact, it's going to be a while before we get another protease inhibitor that doesn't have this extensive cross-resistance.
Myles Helfand: Why has it been almost a decade since the last hep C drug was approved? And where do we go from here?
Barbara McGovern: Well, now we're just on this incredible pipeline of drugs. It's incredibly exciting, what's coming down the pike.
The discovery of the virus occurred only in 1989. Then you have to start screening compounds [to treat it], trying to find a compound in vitro; the in vitro models were difficult because it took a long time to find a model that actually was something you could work with. So that was a big, big stumbling block. But once that model was found, then that quickened the development of all these different drugs, working at different parts of the lifecycle.
And now, the fruit! All these companies are working simultaneously on it. Now we're seeing the fruition of that. Everyone, kind of in concert, is coming up with all these wonderful drugs. It's just going to be a matter of time, where we're going to have polymerase inhibitors, and more protease inhibitors, and less cross-resistance. We'll have sequencing of therapy, and genotyping and phenotyping [types of resistance tests] will eventually become important in clinical practice. Not now, because we have hardly any drugs. But we're just getting going out of the gate right now. And down the road is just going to be better and better and better, and hopefully, eventually we'll get rid of peg and ribavirin.
But it's just incredibly exciting to look forward. I just can't wait to see, even in just five years, how different things are going to be. The paradigm for treatment is going to be drastically different.
Myles Helfand: It sounds almost like you're painting a picture where, in 5 or 10 years, hep C treatment will be similar to what happened to HIV treatment from 1996 to 2006.
Barbara McGovern: Exactly. That's the exact parallel.
[This transcript has been edited for clarity.]
To learn more about these new additions to the hepatitis C treatment family, read AIDS InfoNet's fact sheets on Incivek and Victrelis. If you have specific questions about these new drugs, or about treatment of HIV/hepatitis C coinfection in general, you can ask Dr. McGovern directly in our "Ask the Experts" forum on coinfection.
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