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HAART Choices - Tough Decisions
Jun 10, 2001

I have been on a "drug holiday" since February (when I was found to have lactic acidosis). At the time I was on a successful combination of ddI, hydroxyurea, 3TC, Sustiva which kept me undetectable for well over two years.

Based on my previous history (but no resistance testing), it is very likely that I have some resistance to AZT, 3TC, Crixivan and Nelfinivir.

My doctors propose that I start on Abacavir, 3TC, Sustiva. I have a few concerns that I'd appreciate your thoughts on:

1. Abacavir: Would AZT mutations = cross-resistance to Abacavir?

2. 3TC: Any concern that I've kept 3TC through several regimens, including a couple which have "failed"? Did good results in my last combination indicate that 3TC is still effective for me?

3. Sustiva: Has a long half and develops resistance quickly on it's own. We stopped HAART all at once due to lactic acidosis. Did not have an opportunity to continue other meds for several days after stopping Sustiva. Any concern that this could have caused some resistance to Sustiva (and entire class of NNRTIs)?

My ID specialist has suggested the possibility of adding Kaletra as booster for the first few months until my viral load becomes undetectable. We would then remove Kaletra (and keep it as a future option). This might lessen the chance of developing resistance while my viral load is high, and would also allow me to stay off PI's some more (after those initial few months). Do you have any thoughts on this potential strategy?


Response from Dr. Cohen

Tough issues but here are some guesses.

1. Yes, there is some cross resistance from AZT mutations and the impact of abacavir. In fact, AZT mutations appear to have an impact on several of the other nucleoside antivirals, including ddI. So, another way to look at your question is whether there is any way to know if abacavir is any less potent than ddI plus hydroxyurea was, given your history. And it is hard to be certain since cross resistance to ddI and abacavir do not track in parallel lines. But it is likely that abacavir still has quite decent if not maximal potency to offer here. Whether you want to rely on it to get your viral load back down is the key to your query #3.

2. As for continued 3TC - it is clear from the initial studies that even after 3TC resistance, this medication can contribute about a half log in viral suppression. That is because there is a price that HIV must play to create 3TC resistance - and this price is about a half log. So it is likely, although not definitive, that 3TC is still an important component of your regimen. Could your regimen have been equally successful with just ddI, hydroxyurea, and Sustiva? Well, we have no data since no one has been that "creative" or even motivated enough to try it. So given your success using it, and our assumptions, yes, most of us would assume 3TC still has something to contribute.

3. Sustiva - The odds of your developing resistance during the stop are quite low. While we have few data, based on the case series we have, the risk is clearly less than 5% that resistance would happen. That your viral load was suppressed for two years helps increase the comfort level - and it might be even more comforting if you had no "blips" (transient readings over 50) in your viral load over that time period. But the prevailing wisdom is to go with what is likely - you would usually not get resistance to Sustiva while stopping all meds with a viral load below 50. Nonetheless, the NNRTI mutations can sometimes be found even in someone not on them - so if this is sufficiently a concern, you can certainly get a genotype just to check. It most likely won't be there - and a negative test does have caveats - but it is just another way to increase the odds. This may also apply to the cross resistance in the nukes - while they may be missed off meds, what does show up may be helpful to you.

So - as for the proposed approach of starting a fourth med - and if successful, stopping it down the line - it is again an option only now being evaluated. And it is a reasonable one to evaluate, and even to try. We don't yet know for sure if doing this helps - in other words, it may be that if the three meds you will be on can keep your viral load <50 once there, they would also be enough to get you there. Said the other way, if the four meds you use to get to <50 are all needed, then stopping one may not work as a strategy to making three less-than-adequate meds work. But - it may be true that it can work - we just lack any examples of this from the trials that have tried this. But this type of research continues - since there is still a reason that this strategy could be true.

You don't mention your off treatment viral load/Cd4 count. This may be another way to help predict what to do - since if you had a viral load over 100,000 for example, it may be a bit more important to have the Kaletra for longer term, there to balance against any partial resistance in the abacavir.

But, if your an optimist, and/or have reasonable viral load/cd4 numbers, it is quite likely that it should work fine.

Good luck.

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