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Question about Resistance
Oct 8, 2006

Hi Dr. Young, I have a quick question about resistance (I know, not another one of those). I'd really appreciate your thoughts on something Dr. Sherer (who btw I think is also an amazing doc) said about the issue...here is part of one of his responses to someone who was concerned about resistance:

"The bad news is that even in the presence of excellent control with a measured viral load consistently below the threshold of detection, e.g. 50 copies/ml in the blood, there is still evidence of ongoing viral replication, though at a lower rate, both in blood cells and in tissue cells (such as the gonads or the nervous system). Research done with 'ultrasensitive' viral load assays, which can measure down to less than 3 copies/ml, show that replication continues even with suppression in the blood stream at this level, and that ongoing mutations do continue to occur.

This might suggest that eventually, enough mutant clones will be created that any regimen will be overcome. But, the good news is that we don't see the evidence of this inevitability for prolonged periods of time, as described by the clinical trials above, eg 3 or more years with Sustiva and Truvada, and longer for Kaletra containing regimens.

The most important thing that you can do, as you say, is to hold up your end of the work, and be as close to 100% adherence as possible. Unfortunately, this leads to the other piece of bad news in this discussion. All HIV clinicians have experience with patients who, like yourself, give credible histories of being near-100% compliant with their medications, including your current regimen, and yet develop drug resistance within one or two years of starting the meds. Sometimes we can't explain why this has happened, eg there are no lapses in adherence, no apparent drug interactions, no causes of poor drug absorption, and even adequate drug levels in the blood when these measurements are taken.

My summary of these contradictory observations is a positive one. First, there is strong evidence that what YOU and your doctor do makes a huge difference in your risk of drug resistance, so remain vigilant and try to create an air-tight system to prevent any missed doses. Secondly, I believe the evidence that suggests that resistance is NOT inevitable. At the cellular level, what this means is that the small number of escape mutants that are continuing to evolve, even in the presence of full viral suppression, are being controlled by one or more of the three drugs in your regimen. So that even if a K103N mutant clone arises with resistance to Sustiva, its rapid growth is suppressed by the other members of the regimen, i.e. by the tenofovir and emtricitabine in your Truvada."

Well, I'm just curious to know if, in your professional opinion, you agree with Dr. Scherer's findings/opinions. Lol, I'm certainly not trying to pit docs against eachother. I'm just curious if his assessment of the situation mirrors your own. I was a little disheartened upon hearing about the ongoing (albeit small) replication of HIV that is going on despite using HAART...that scares me a lot. Also, the unexplained viral breakthrough in patients that are very adherent to their meds also scares me...has this happened a lot in your clinic? Still, I am happy to hear that he thinks resistance is NOT inevitable despite all the conflicting evidence. What do you think? I look forward to hearing from you. Thanks so much.

Response from Dr. Young

Thanks for your post.

Dr. Sherer's comments quite accurately sum up the data on resistance; though the very good news is that despite the observation of very low level viral replication, there is scant evidence that this results in treatment failure in the vast majority of adherent patients.

It could be that such minority variants explain the occasional adherent patient who has virologic failure with no detectable drug resistance mutations.

So, overall, I don't see reason for being disheartened. Rather I'd redirect your thoughts to the idea of being informed of the reason why continued vigilance and monitoring of adherence, laboratory testing and when needed, resistance testing are important.

I hope this is helpful BY



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