A Question on Dosage
Oct 5, 2001
Brian, after reveiwing many of your responses in this fourm(by the way excellent job!)I have come to notice that most of the treatment regimens being utilized are 2x daily dosage regemins. Does it appear that the 2x dosage will work as well long term as the 3x dosage that were oginionally used when the cocktails came out 5-6yrs ago? I have been looking at lots of research on the subject of adhearance, treatment failure, and HIV mutation, what I have found is that most of the mutation and subsequent treatment failures are directly related to the lack of adhearance to medication and the proper taking of them with/without food(dietary restrictions). True many of the adhearance problems can be blamed on the fact that the patient may not be ready for treatment(ie. on going drug addictions and other mental problems may play a role in proper adhearance) but the truth is that taking a drug 2x or god forbid 3x with 100 adhearance is a daunting task to put it mildly! People forget, people are put in ackward postions re: they dont want to take the med in front of others, the dietary restrictions also can get in the way. While I am saying it is of the UTMOST importance that everyone make the effort to adhear 100 of the time, I can sympatize with those who find this very very difficult. All of the research I have found directly connects adhearance to recovery(reduction of VL and increase in CD numbers and percentages) But equally important I now have found that it is directly related to greatly reduced likelyhood of transmission. I belive that where it is VL1500 we see virtually no transmission. That means adhearance can also slow or perhaps come really really close to stoping the spread of the virus. So what to do? Well I have two questions. First when(how long) do you think it will be before we can see a 1x regemin? What about a 4 drug 1x combo with low pill burdons? Dr Ho recently used a 4 drug combo in his findings he found that drug combo to be far more potent than the traditional 3x combo. So what I think everyone should look to perhaps next is a 4 drug combo that is 1x and has a low pill burdon(perferably 4-5pils take only once a day) I think that if this were achived(hopefully with drugs that also that act on mutation virus would be awsome! My second question is what about BMS232632, when do you think this potential once a day PI will be available? I understand it is currently in phase III testing, What is its resistance profile? Will it be more potent than the current PI's available and do you think it will work well on resistant virus? What about a 4 drug, dual PI regemin with BMS232632? Sorry to ask so many question but I am sure others would like to know this as well. Hope you are doing well...Take care
Response from Dr. Boyle
A long question deserves a long answer! I agree with your statements regarding adherence. It is a signficant reason for patients failing antiretroviral therapy and developing resistance. Several studies have shown that adherence can be improved by simplifying antiretroviral regimens, for example, by decreasing pill burden, dosing schedules, and eliminating dietary restrictions. Studies have also shown potent twice daily regimens using drugs with long half-lives (the time it takes for 1/2 of the drug to be eliminated), for example ritonavir-boosted protease inhibitors or NNRTIs such as efavirenz (Sustiva/Stocrin), outperform regimens that are given three times a day both in the short and long term. This may in part be due to the "forgiveness" built into these regimens as a result of their long half-lives which limit the very tight and strict timing requirements of some of the non-ritonavir boosted protease inhibitor regimens, for example regimens that involve indinavir thrice daily or nelfinavir twice daily, but also may be due to their low pill burden and better tolerance. So, the bottom line is twice daily regimens that we are using have been shown to be superior in many respects to the older regimens, including long-term success rates. As far as once daily regimens, several have already been shown to be highly successful including ddI, 3TC and efavirenz once daily and ddI, FTC and efavirenz. Nevirapine (Viramune) has also been used in some regimens but I have less confidence in its potency and have some concerns regarding rash and liver toxicity. Some protease inhibitors, for example fortovase/ritonavir, are also being studied as once daily therapies, but in general these involve a lot of pills and do not have the forgiving pharmacokinetics of th NNRTI based regimens. When tenofovir is approved, which should happen in the next month or so (the FDA panel just recommended limited approval), that will be another once daily drug. d4T ER (Zerit ER), which will be dosed once daily, is also entering studies and there is some evidence that abacavir (Ziagen) can also be dosed once daily. Atazanavir (BMS 232632) appears to be a good drug as well and will be the first once daily PI. At this point, it's resistance profile is not well defined and hyperbilirubinemia (which can cause people to be jaundiced/yellow) may be a problem in some patients. It does not, however, elevate lipids (triglycerides/cholesterol) like the other PIs. So, we have a lot of drugs for putting together once daily regimens, and more are on the way. You should discuss once daily regimens with your doctor before making any changes in your regimen and you should note that of the drugs mentioned only efavirenz and ddI have actually been FDA approved for once daily dosing. As far as 4 drug regimens, the data has yet to clearly establish that these are superior to potent 3 drug regimens and tolerance/adherence remain significant issues with some of these regimens. As pill burden decreases, however, and tolerability improves, I suspect that we will use more and more 4 drug regimens, especially in patients with some degree of underlying resistance.
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