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Cause of resistance
Sep 7, 2004

Dr. Sherer-

We always hear that the main cause of resistance is missing doses. My question is does resistance eventually occur anyway? Could someone take their meds 100% of the time and still become resistant to their meds?

If so, is it some meds more than others that this happens to?

thanks!

Response from Dr. Sherer

This is an excellent and important question.

Clinical studies suggest that problems with adherence, e.g. missed doses, is the most common cause of regimen failure and drug resistance. One reason that we HIV physicians are so quick to point this out is to motivate our patients to be vigilant with the best possible adherence, since it is entirely within their (your) control...and nearly entirely out of ours.

We suspect it, but we don't know whether drug resistance is inevitable, i.e. whether it will occur in everybody even in the presence of perfect adherence. There is actually credible evidence on both sides of this argument.

On the pessimistic side, there is evidence that viral evolution and ongoing replication of HIV virions occurs in people even with excellent adherence and repeated viral loads below 50 copies/ml. Using 'ultra-fine' techniques to measure viral load in the blood, this is true even with people who have less than THREE copies/ml in their blood. Furthermore, there is evidence that viral evolution occurs in several distinct pathways in distinctly sequested sites in a single person, i.e. one pathway in the central nervous system, another in the blood, and still another in the gonads. At a minimum, we have to understand from this evidence that there are innumerable opportunities for the development of drug resistance, and several that we are unable to detect by our current standard measures. Finally, on that theme, there are well documented cases of patients with excellent adherence experiencing virologic failure and developing new resistance mutations. (However, with our current regimens, excellent adherence is far more commonly rewarded with good outcomes, a rising CD4 cell count, and an undetectable viral load.)

The above sounds pretty discouraging. On the other hand, in answer to your second question, the frquency of drug resistance to the PI class appears to be significantly lower when boosted PIs are used early in the regimen, i.e. when a patient is drug-naive, or PI-naive. In that setting, for example with lopinavir/r (Kaletra), and to a lesser extent fos-amprenavir (Lexiva), no resistance to the protease class has been observed with standard resistance testing when patients on these regimens have virologic failure, even after 5 years in one study of LPV/r. (This provides one of the strong arguments for using boosted PIs early in the course of treatment.)

In the meantime, people living with HIV need to keep it simple with their medicines. Take them as prescribed, take all doses, and you have done everything you can do to allow for the best outcome.


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