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Treatment Failure/Choices Choices update
Dec 18, 2000

Hi Doctor Cohen:

You asked me to let you know what happened with my possible treatment failure. To refresh I'm on Combivir/Ziagen and the viral load has risen. I have 215 (AZT) 184 (3TC) 63 (naturally occuring) and 77 (Viracept). I've had a previous treatment failure on Combivir and Viracept a few years ago and followed that regimen with Combivir/Norvir/Fortavase(400 each) When I wrote you last my VL had gone up to 500 but I've just gotten off the phone with my doctor and it has dropped to 263. Such a shawnda!! The bottom line is that it's hanging around and is not undetectable. I think the danger here is that if I don't go ahead and make a change I'll end up with more mutations and cross resistance. So I'm going in tomorrow for a geno-type and a pro-viral DNA geno-type. While I don't expect an accurate geno-type because the VL is below 1000, I think the pro-viral will be accurate. After I give that blood tomorrow I'm going off meds for a week or so to get results and figure out how to go from here. You mentioned a few alternatives for me and I hope you can help me a little more. I have a bad history of side effects with Norvir/Fortavase (lipids and liver) which is why I changed to the current regimen so I need a combo that will give me minimal long term side effects and long term supression. Can you give me some specific alternatives with or without the possible 74 mutation that can occur with Ziagen failure? And if possible something that will leave me something else to go to if I experience another failure. I appreciate your help. My doc and I will of course talk all of this over but he knows you and thinks you are brilliant so he's receptive to suggestions. It also appears to me that with my history and currently available drugs this may be my last bite of the apple until new classes of drugs come out. Too many "look-alike" drugs in the pipeline. Different classes and resistance profiles, T-20, PMPA, DAPD, PRO 542 and others are still a way off. Thanks again for sharing your hard earned knowledge. If I don't mail you again before, have a Happy Hanukkah or Merry Christmas.

Atlanta

Response from Dr. Cohen

Hey Atlanta.

Thanks for the seasonal greetings with a multiple choice in the religious section... and I think you get the award for the first attempted use of Yiddish in a query. Although I think you added a southern accent in the spelling of it...

Here are some more specific thoughts. First, it is not so clear that the 77 mutation you mention has anything to do with the Viracept - it appears to be one of these common mutations that may not reflect use of a specific drug - so it may be that you still have no mutations in the PI class. Recall that viracept tends to have either the 30 or the 90 mutation as its primary mutations - the 77 may be a secondary, or even what is called a polymorphism, meaning normal variation in HIV. If that is right, and the DNA genotype is both accurate and similar in outcome - you may have all of the PIs available to you in addition to the nonnukes. In addition, the 74 rarely shows up on regimens containing Combivir/Ziagen - so ddI would remain an option most likely.

What are the options? Since your viral load is so close to suppressed, one approach has been called "intensification" also known as adding a single drug to a not fully suppressive combo... and getting away with it. It is tricky business - but your viral load is low enough that adding one drug would be a reasonable option here. We tend to not use any medication that is "one mutation away" from higher level resistance since we are adding just one drug to control the HIV that is at least partially resistant to your current meds. Which excludes the use of the nonnukes and perhaps nelfinavir (your prior use would be another reason to not rely on it here). And most would not use four nucleosides antivirals excluding ddI as the choice. Which leaves some PI - including the more recent approach of low dose ritonavir, e.g. 100 mg twice a day, in combination with one of the other PIs, like amprenavir, saquinavir, or indinavir. Nelfinavir has less data supporting its use with this ritonavir booster approach, so another reason we might not choose it here. Note than 100mg. twice a day ritonavir would less frequently cause problems with the lipids and liver function changes you saw previously. And if I recall, you were also on Zocor/simvastatin to treat the lipids - we have since learned that this is not the best choice with ritonavir as it too is boosted - and perhaps was the cause of some of your liver function abnormalities??

We have some pretty solid data that Kaletra (formerly known as Cal-etra but that's a separate issue...) can be successful "salvage" for the other PIs - this comes from studies when the PIs were used without ritonavir - it is not yet as well defined how the addition of the low dose ritonavir might change this story. Nonetheless, it is reasonable to consider these options. It is also reasonable to at least consider Kaletra since it is potent and potentially can be followed by boosted amprenavir, although this is based on predictions by tests, rather than actual experience yet.

If you wanted to make more than one med change at a time - you then have many more options to consider. For example, if I am right about the lack of significant PI resistance, then you can consider any of the PIs, especially with boosting from the ritonavir. The PIs with the least impact on lipids are saquinavir and amprenavir - it is less clear how they will rank if adding the low dose ritonavir. The PIs might be used either with the other classes, or even in a dual PI combination -for example, some have studied 4 caps twice a day of both amprenavir and saquinavir boosted by 100 twice a day of ritonavir. There is info to support that two PIs are more active than one - although again this comes largely from the era before we boosted the levels - it is less known if this would still hold. The dual PI option might be one way to avoid using the nonnuke for this combination, adding them to the nucleosides. If instead you did just one PI here - you can add the nonnuke and at least some of the nucleosides you are now on. (If you only add the PI without the nonnuke, then we're back to intensification above.) And as mentioned, we do have some successful PI sequences based on current studies. Saving the nonnuke is desirable from the perspective of another hit at the bat, but is also a key way to make sure this next round works. Finally, to be complete, it is an option to just do a nonnuke with a boosted PI(s) combo - saving the nukes for some future go round. It is pretty clear they are still very active given your viral load - you can either build on this, or put it in the bank.

There is always a balance. One final thought that may help - The best way to ensure successful sequences is to use a combo potent enough so that resistance won't even develop on this next combo. Then all of the new meds will stay fully active while on the combo. This won't lead to any more cross resistance either, allowing you to make substitutions in case of toxicity, rather than having to account for resistance while making these substitutions. It is hard enough to find the right med combo that doesn't lead to side effects for you - it is much harder if you are also battling resistance.

Hope that helps. By the way, I appreciate you and your clinicians vote of confidence, although it might be time for a recount... hope this discussion of options doesn't change either of your minds.

CC

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



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