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is resistance inevitable?
Jul 16, 2006

i've been on sustiva/truvada for 16 months, and haven't yet missed a dose. my question: have there been studies on 100% (or practically 100%) regimen-compliant patients to determine whether resistance to certain hiv meds. is inevitable, even without ever missing a dose? i'm specifically interested in the meds i'm taking, but any data on hiv drugs would be helpful. i'm certainly going to aim for a 100% track record, but i also want to be prepared in case drug resistance is simply not avoidable. thanks in advance. this site has been a tremendous resource for me. sometimes the info is a bit scary, but ultimately, ignorance is even more so.

Response from Dr. Sherer

Thanks for the comment that while knowledge may be scary, ignorance is worse. I agree - and I would also say that understanding HIV takes time and a positive dialogue with your doctor. There is always pressure on you and your doctor to accomplish many tasks at each visit - so a patient can and should be forceful in asking questions, as well as respectful of the time available. If possible, write down the questions as they come up - many physicians have fax numbers or email addresses, and could answer them between visits, or be better prepared for your visit.

This is a common question, and one that we don't have the complete answer for. We know that two thirds of patients with excellent adherence maintained complete virologic control for three years in one extended clinical trial; some of those patients may now be in their fifth year without breakthrough.

In the longest clinical trial on record, after seven years, 60% of patients retained complete virologic control on their original regimen of Kaletra (a protease inhibitor) and two nucleosides.

So far so good, but this doesn't exactly answer your question, which is, is it inevitable that each of these patients and you eventually develop resistance to your current regimen? The honest answer is that we don't know. There are reasons to be concerned that it may be inevitable - and reasons, like the above trials, to be hopeful that it may not be inevitable.

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.

I urge you to take these questions and these responses to your next visit with your doctor.


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