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HIV resistance despite perfect HAART adherence: complete viral suppression needed. (Infectious Diseases).

SAN FRANCISCO -- Even perfect adherence to highly active antiretroviral therapy will not prevent the appearance of resistant viral strains in HIV infection, Dr. David Bangsberg said at a meeting on HIV management sponsored by the University of California, San Francisco.

A substantial proportion of patients with HIV continue to have viremia despite flawless adherence to antiretroviral regimens. This ongoing viremia sets the stage for the evolution of drug resistance.

Only with complete or nearly complete viral suppression will perfect adherence prevent the development of drug resistance, said Dr. Bangsberg of the university. The evidence for this iconoclastic conclusion comes from both experimental studies and mathematical modeling.

In one study of 42 individuals with HIV by Dr. Bangsberg and his colleagues, increasing adherence (as assessed by unannounced pill counts) was related to a decreased viral load, as expected. But individuals with resistant viral strains, as opposed to wild-type virus, all had between 65% and 100% adherence. In fact, many of those with resistant virus had between 90% and 100% adherence.

A separate study included 148 treatment-experienced HIV-positive patients undergoing highly active antiretroviral therapy (HAART). Of those, 57 patients with detectable viremia were followed for primary or secondary drug-resistant mutations after 6 months of HAART. Dividing that group into quintiles based on adherence, the highest quintile--those with 92%-100% adherence--developed the largest number of drug-resistance mutations. The lowest quintile--those with 0%-41% adherence--developed the smallest number of mutations.

Dr. Bangsberg cited another study showing that when patients stop HAART, they quickly revert from drug-resistant strains to the wild-type strain, implying that drug-resistant mutations are less fit than the wild-type virus. "This suggests that you need a high level of drug pressure, meaning a high level of adherence, to select for and maintain drug-resistant virus."

"Even if we had an intervention that led to everybody being fully adherent, we would still see the evolution of drug resistance," he said. That's because 40% of the patients who have ongoing viremia have 100% adherence.

The prevailing view of the relationship between adherence and the probability of developing resistance is that it forms a symmetrical bell-shaped curve, with little resistance at very low levels of adherence (because of inadequate drug pressure to select resistant virus) and very high levels of adherence (because of complete viral suppression). High amounts of resistance, according to this view, would develop only with intermediate levels of resistance.

But Dr. Bangsberg's mathematical model of drug resistance shows the curve skewed far to the right. The model estimated development of drug-resistance mutations at 10,000 randomly selected levels using empirically derived relationships and used a Poisson regression to estimate mutations for viremic and nonviremic patients.

The resulting curve suggests that the greatest amount of resistance develops at about 70% adherence; resistance declines only modestly as one moves to 100% adherence. The curve skews further to the right when one factor in that more drug-resistance mutations develop with increasing treatment durations; that analysis indicates that the greatest amount of resistance develops with 80% adherence.

In another manipulation of his model, Dr. Bangsberg assumed that a fully suppressive drug regimen could be developed. In that case, the adherence-resistance curve would shift back to the left and regain its bell-shaped character. Resistance would peak at about 40% adherence; 100% adherence would result in practically no resistance because 95% of the patients would have their viral loads suppressed to Less than 50 copies/mL.

Despite the evidence that current HAART regimens can lead to resistance even with perfect adherence, "I'm not suggesting that good adherence is a bad thing," he said. "While the relationship between adherence and drug resistance may be complex, I believe that the relationship between adherence and clinical outcome is more straightforward."

In other words, greater adherence to drug regimens may indeed lead to an increased number of drug-resistance mutations, but greater adherence also clearly leads to better clinical outcomes.

Clinically, one should strive for a state of perfect adherence, full viral suppression, and drug-sensitive virus, he said. That state is better than excellent (or perfect) adherence, partial viral suppression, and resistant virus. And even that state is clearly much better than nonadherence, no viral suppression, and wild-type virus.
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Author:Finn, Robert
Publication:Internal Medicine News
Date:Apr 1, 2003
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