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Treatment Failure/Choices, Choices, Choices
Dec 5, 2000

Hi Doctor Cohen. It's been a long time since I've had to pick that wonderful brain of yours but here goes.... I am apparently experiencing treatment failure. I'm just waiting for my labs to come in next week and confirm so I'm condsidering options. I'm currently on Combivir/Ziagen/Remune. My current numbers are VL of 500 and CD-4 of 989 and 30%. I started the Combivir/Ziagen in June of this year because my previous regimen was killing me with side effects (diarrhea and lipodystrophy). My VL was undetectable at the time of the change. My former regimen was Combivir/Norvir400/Fortavase400/Remune from January 98 until June of 2000. This combination worked well at supressing VL to undetectable and CD-4 was same as now but my liver enzymes and lipids were through the roof despite taking Zocor 40 mg. I was diagnosed in May of 97 with a VL of 2.2 million and a CD-4 of 153 and 13%. My initial treatment started in May of 97 with Combivir/Viracept and failed in December of 97 when I made the switch to the double PI listed above. I have also been on Remune for 2 years and while the jury is still out on that one I'm patient enough to wait because I know it's not harming me. My last geno-type shows mutations at 184 (3TC) 215 (AZT) 63 (normally assciated viral mutation) and 77 (Viracept). I've tried to choose wisely with long term in mind to get as many bites of the apple as I could. Now I have to think again. I've enjoyed the last 5 months of not having uncontrollable diarrhea more than anything. My liver enzymes and lipids have returned to noraml. I guess my options are D4T/DDI/and a PI or a NNRTI or Combivir and an NNRTI or a PI or double PI. I don't want to use Viramune with AZT because a Viramune failure would result in a 103 mutation eliminating the second bite of the apple in that group, Sustiva. If I use Viramune with D4T there's at least a 50% chance that a Viramue failure would result in a 181 leaving me Sustiva in that group. The other options of PIs scare me. I've been reading that Agenerase does not have as many side effects but may not be as potent as others and has a heavy pill burden. Kaletra is supposed to be wonderful but if it fails you eliminate all other PIs because of the resistance pattern. I'm open to suggestions. Give me your thoughts if you can. I also know that 184 and 215 together somewhat cripples the virus and that it makes the virus hypersensitive to AZT even though it reduces potency of 3TC. By the way have you seen what happens to a patient who is left on the D4T/3TC/Viramune even though they have 184, 215 & 181. The virus can't grow. It's called a lethal mutant. Check it out. A couple of patients here are doing it and their VL has gone down while there CD-4 has gone up. Help me if you can. I appreciate it very much. Hope you guys are keeping an eye on what's happening with the Australian DNA

Vaccine candidate for infected patients just starting trials. Thanks so much for your ear and your wonderful brain.

Atlanta

Response from Dr. Cohen

Hey Atlanta - welcome back to the forum, albeit with this news of potential rebound. You clearly are doing your reading, although I differ with some of the conclusions you've read. This is of course the nature of HIV treatment - there are a wide variety of conclusions that we have based on the data available. But perhaps there is some news that can update some of what you've read... and so a long question gets a thorough answer.

First. It is predictable that you might experience rebound on this combo. We have seen examples, confirmed in larger studies, that those who have some nucleoside resistance are less likely to stay suppressed when ziagen is used as "the third drug". As you mentioned, you had resistance to the nukes develop while on Combivir/nelfinavir, and this was suppressed on a dual PI combo. That is because the dual PIs are doing much of the work in this combo. However, ziagen/abacavir has some cross resistance with AZT and 3TC -and is weakened when these mutations are present. So a combo of azt, 3tc, and abacavir would not be as likely to maintain full suppression since each of the three drugs is less than fully potent. Even though there is an interesting interaction with the 184 mutation improving the potency from AZT, it might not be enough here - especially with your potential viral load of over a million. those with such very high viral loads are more likely to have rebound on many combinations. Although not all.

Now - first thing to determine is if a viral load rise to 500 is "failure" yet - as we have cases of those with a temporary increase in the viral load, but who either go back down or hover at a low level for a good while. If you go back down to <50 then the next step is pretty straightforward of just holding on for now. If you hover at a low viral load there is more controversy about what to do but with your CD4 count you could hold on as well for a while. The big concern at these low viral loads is the potential for HIV, once growing, to create more resistance to the meds you are on. And in so doing, create more cross resistance to the class you are on. So in time you might in time develop a 74 mutation (which can happen on abacavir) which could decrease the potency of ddI. And we have also learned that d4T and azt share cross resistance more than initially understood- so I would not count on that med to be fully potent here either.

But if this happens - what would be left to go to? Well you have never taken any of the nonnukes so they would all be fully potent. And you have most of the PIs available to use- the question for you is which you could tolerate.

We have heard about the viramune/nevirapine mutation at 181 which does happen more often in case of failure when on d4T. However, the sad news is that despite this, regimens based on Sustiva next have rarely worked - so sequencing in the nonnuke class is not something you can count on. It appears that you get one good chance. And as for "lethal" mutations - so far, it's an idea that just does not always work out that way, if ever. The three mutations you mention are not "lethal" as HIV can still grow, and develop more mutations that allow it to cause more havoc. While you may know some with stalemate in this case, it is not something we can guarantee. If we could then we would all just use those three meds and no longer worry about any of this...

So - within the PIs there are options that can be potent and fewer side effects. The main approach so far has been to use a lower dose of norvir/ritonavir than the 400 mg you used already. A lower dose has fewer side effects. Fewer problems with diarrhea. Probably less impact on lipids. And this can still boost the potency of a second PI. Which PI to choose is an open question as each med has its plusses and minuses as you point out. But the pill burden is less with this approach - so for example amprenavir would be 4 caps (600 mg) plus one norvir twice a day. Fortovase would be 5 caps (1000mg) plus one norvir twice a day. Crixivan would be two caps (800 mg) twice a day plus one norvir. And Kaletra the new kid in town has the norvir in it - so just 3 (or 4) caps twice a day.

There is more known about sequencing options with standard doses of these other PIs than with kaletra - but less known about salvage when boosting these PIs. And there is some early data to suggest that amprenavir when boosted could be back up after Kaletra... so as always there are options with uncertainty. But we have one study that showed the combination of Sustiva plus (dose adjusted) Kaletra (even with NRTIs that were not fully potent) that was very successful in getting viral suppression - like near 90%. There are side effect issues, but most did tolerate this. Not that this is the best combo - just the one for which we have the most data. Other boosted combos could be an option here - and most likely to work when you add a nonnuke as well. And delavirdine can actually act as a PI booster, which is an options particularly if you can't tolerate any dose of norvir.

The only option I'd discourage is using the nonnuke with only other nukes - at this point you have enough nuke resistance to not risk your nonnuke that way.

As for Remune, well as you say, it doesn't hurt, and might help. We still don't know.

Hope that helps. Great news about that t cell rise. Needless to say, given those T cells, some would question whether you should even be on HIV meds at this point. On the other hand with that viral load set point of over a million, it is rational (even if a bit controversial at your t cell count) to want to be on something if we can find something you can tolerate that is also fully active. (While perhaps the meds and remune have altered what your set point would be off meds... this has rarely if even been seen in studies so far.)

Hope that helps. Let us know what happens.

CC

Ps thanks for the compliments... glad this helps.

Cal Cohen, M.D., M.S.



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