Well, pretty impressive, to hear Dr. Calvin Cohen, Research Director of Community Research Initiative of New England, Consultant to Pilgrim Health Care, and Clinical Instructor at Harvard Pilgrim Health Care say that:
VIRACEPT HAS THE ADVANTAGE OVERALL , compared to the other protease inhibitors, in patients using single protease inhibitors. Cohen favors Viracept because it is dosed twice a day, the BID data are very attractive, it seems to be a well tolerated drug, with a lower incidence of lipodystrophy and more tolerable than the others and less side effects.
Cohen says: "RIGHT NOW WE HAVE IT (HIV TREATMENT) DOWN TO A HANDFUL OF PILLS, TWICE A DAY, AND YOU'RE DONE.
THAT IS SOMETHING THAT IS ATTRACTIVE AND I 'M NOT SURE IT HAS GOTTEN OUT TO EVERYONE WHO NEEDS TO HEAR IT. THERE ARE EFFORTS TO MAKE IT CLEAR THAT TREATMENT HAS GOTTEN BETTER AND IS WORTH KNOWING ABOUT."
"IN SOME WAYS, SUSTIVA AND VIRACEPT WAS THE GOLD STANDARD AND OTHER NUKES COULD BE ADDED" -As far as treating nucleoside experienced patients, which are the majority of patients.
There are efforts to educate the community so that patients will be tested and receive treatment. There is no doubt that we have new options now that we didn't have 2 or 3 years ago. Some of the newspaper headlines about pill burden and the charts about Crixivan, having to take it every 8 hours and don't eat here and don't eat there and drink lots of water convinced people not to seek treatment. All those horror stories were enough to convince people it was not worth it, despite the progress.
He said that initially Crixivan showed some of the most impressive data, but attempts to dose it twice a day failed. And now that patients have other options, they don't have to take it. So in the past year, the choice has been between three.
Fortovase (Saquinavir) is 8 pills, twice a day, in contrast to Viracept, which is 5 pills, twice a day. He sees no reason to take more pills, as there is no advantage of Fortovase over Viracept, that he knows, and no reason to take this, although it is nice to have an extra option if patients can't take Viracept.
With patients who start off with a very high viral load, there is the belief that the Ritonavir/Saquinavir combination is more potent. However, anything with
Ritonavir now is problematic, because of Abbot's production problems in producing Ritonavir capsules. Having tasted Ritonavir liquid, he says it is among the most bitter substances ever created. The problem looks like it will not be fixed this year, and it will be a problem for any patients who are sensitive to taste. It will be a problem for half of his patients.
Amprenavir- is 8 very large gel caps- twice a day, some can't handle it, it is swallowable, but unless there is some advantage….the pill burden will be an issue. Dr. Cohen says that it seems to be as potent as the others at 16 weeks* with 80% undetectable. So far Glaxo is suggesting that it does not have that lypodystrophy profile, and Cohen says he doesn't know if we should trust that, but that is what a drug has to show: that is safe and effective.
(*Aside Vertex reported 16 week data for Agenerase+3TC+ZDV:
86% were <400 copies at 16 weeks using On Treatment Analysis,
59% were <400 copies at 16 weeks, using Intent to Treat Analysis,
which is what the FDA requires now. These were treatment naïve patients.
Also Vertex or Glaxo reported on a combination of Agenerase and Abacavir-where lipid levels rose initially- triglycerides and cholesterol -but returned to baseline with continuation of therapy. Interesting that lipid levels returned to normal without treatment. This was also the study where they claimed superior immune reconstitution.)
medscape.com
Dr. Cohen said that "We still have a limited repertoire of drugs, with only 3 classes of medication, and no proof of a second generation product, that is effective against resistant virus, so there is a sense of awareness of trying to get the most out of these medicines, which means hitting as hard as possible to minimize resistance. But with the increasing reports of side effects, there is a reluctance on the part of some to use these, more so in Europe. Our field is in somewhat of a confused state now. One of the areas of controversy is whether to hit hard early to avoid resistance or whether to hit as hard as we need to, but to plan for a second hit. Resistance does happen even with very potent regimens, so we need to save drugs for a second chance. Resistance will be a major issue and drugs will have to proceed forwards towards view to how well they overcome resistance.
He was asked about Sustiva (and he never even used the words "potease sparing regimen.") He says Sustiva will be popular for 2 different reasons -ease of dosing- three pills once a day, no food preferences, and he says that patients are doing well, 90% have their virus suppressed at 7-8 months, in combination with other drugs.
I am surprised Cohen gave those numbers: those are "On Treatment" analysis figures, and even Dupont reported lower numbers at ICAAC. At ICAAC Dupont reported that 72% were <400 copies, and 64% were <50 copies, at 36 weeks, using Intent to Treat, where NC=F.
The two major toxicity's of Sustiva are: rash in 1/4 of patients, not that significant, but the big one is that over 1/2 will have some central nervous symptoms such as mood disturbance; dreams or nightmares, anxiety, insomnia, disorientation, which may only last a few weeks, but we're not sure.
Cohen says that the issue of biggest concern with Sustiva is the finding of severe birth defects in two monkeys. He was surprised the FDA approved it as a class 3 category drug, similar to others in the class, but maybe it is because the other companies did not test it in monkeys, only in dogs or cats. It has raised some concerns as more and more women are beginning to take therapy, as the therapy improves, and some women have also been discussing pregnancy as an option, so it will be an issue.
Also cross resistance among NNRTI's is complete; resistance to one will cause failure to the other two. This is on the basis of in vitro testing. NNRTI's are fragile drugs, and only one mutation is required. So you have one chance at this class and that is why there has been such aggressive competition between the three drugs.
At this point it appears that Sustiva has the edge.
Elise Wang asked Dr. Cohen how he thought it will be used in terms of naïve and experienced patients. Basically, he said it works best when it is used as the first treatment in a potent regime as NNRTIs are fragile drugs, and resistance occurs quickly in the absence of complete viral suppression. In that way, protease inhibitors have the advantage, as resistance does not develop as quickly. A lot of Sustiva's success is dependant on the company it keeps. If someone is nucleoside experienced, and even if they are switched to two new nukes, combination therapy with Sustiva and two new nukes is not so successful. So in experienced patients, Sustiva is more likely be used with a protease inhibitor, as a powerful drug regimen is needed. The majority of patients have had nucleoside experience, and the data showed convincingly that a combination of Sustiva plus Viracept was very successful in itself.
DR. COHEN SAID: IN SOME WAYS, SUSTIVA AND VIRACEPT WAS THE GOLD STANDARD AND OTHER NUKES COULD BE ADDED.
The antiretroviral naive patient population is small and is shrinking, as we develop more attractive drugs for this population. It is estimated to be less than 20,000. Most of the patients in treatment are drug experienced, there are very few antiretroviral patients. It is also estimated that there are 20,000 to 100,000 persons unaware or untested for HIV. If PI's fail, some use a NNRTI but there is controversy, some want to preserve the NNRTI, as it is fragile.
He commented that Indinavir needs to be increased 20% when used with Sustiva. Viracept is easier, as the dosage doesn't have to be changed. In one study presented at Geneva, the curve with nucleoside experienced patients on Sustiva plus Viracept did not look as good. It was later found out that patients in that particular treatment arm at that site were not adherent, and apart from this, the combination of Sustiva and Viracept was very successful.
Preveon-Gilead: Cohen says that Preveon has considerable disadvantages.
It is once a day but has only modest activity and 1/2 of patients develop kidney problem at 6 months, which can be reversed, but it s very worrisome. Preveon enhances the activity of those with 3TC resistance. He is not sure if it will get licensed because of the toxicity issue, it will require monitoring. It may have a niche as salvage, but will not be used widely.
Abacavir: Cohen says it is as potent as protease inhibitors, and convenient, it may be once a day. He says it is effective in nucleotide experienced patients (??-I didn't think so, I think it is the opposite) and will probably have more use in nucleoside experienced patients.
However 10% of patients have GI problems such as upset stomach, nausea, feel weak and have malaise.)
About 3% of patients have an adverse allergic reactions, which can be fatal if the patient is rechallenged, once the drug has been stopped. Sometimes patients don't know they have had the reaction or they move and their records don't follow, and there have been cases where patients took just one pill after the hypersensitivity and died. So Abacavir will have to be used cautiously only by clinicians who know how to administer and recognize symptoms. The concern is that clinicians will not know how to monitor for toxicity, and there will be serious problems.
Bristol Myers protease inhibitor in preclinical trials or Phase I (?). The data looked good. Cohen says they are always cautious with early data, but so far it has shown minimal toxicity and is potent. However they only have had 12 patients on it, and it's almost too good to be true. Two years ago we felt the same about ABT378 and that is still in early trials.
As far as lipodystrophy, there is only agreement that there is disagreement, over the incidence, the causes, the symptoms. The Australian group has reported an incidence as high as 80%, but they had questions on their survey like: "Have you noticed a change in your body shape this year?" Cohen thinks the incidence may be closer to 20%, and there is no consensus it is caused by protease inhibitors. It may occur in those who are doing the best, with the most reductions in viral loads. Agouron has reported a 2% incidence of lipodystrophy.
The Australian group also found the highest incidence in the Ritonavir/Fortovase combo therapy, but Cohen says they have not found a higher incidence at all in their patients on Rit/Fortovase.
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