Reversibility of HIV drug resistance.

Using a mathematical model, Blower et al. (1) predicted the impact of antiretroviral therapy (ART) on future trends in the sexual spread of human immunodeficiency virus (HIV). The model employed Latin hypercube sampling to allow for the high degree of uncertainty in the estimation of many model parameters. The authors incorporated into their model the assumption that patients with drug-resistant virus who cease treatment (YR U in the model) will revert to being drug sensitive (YS ) within a short period (2 weeks to 6 months). Existing data do support the notion of a conversion from a predominantly resistant to sensitive virus detectable in the blood following cessation of treatment (2), and the subsequent transmission of drug-sensitive virus (3). Blower et al. included in their model a probability ( pS ) that patients with drug resistance may transmit drug-sensitive virus. However, although studies suggest that drug-sensitive virus may reemerge in patients’ blood following cessation of therapy, there is no evidence that the patients become “sensitive” to further treatment with the same ART regimen. Clinical practice with such patients affirms that reinstitution of drug therapy rapidly selects again for resistant virus, and the patient once again becomes unresponsive to the ART regimen. The model of Blower et al. assumed that drug-resistant patients are able to revert to drug sensitivity and complete another round of identical therapy, as if they were drug naı̈ve. Indeed, it was assumed that they do so at a high rate. As a result, in the model, very few patients remained drug resistant and untreated. Because this group is expected both to have a high death rate (relative to all treated groups) and to exert an influence on the spread of resistant virus, their absence is significant. In addition, because this group kept cycling back into the drug-sensitive group, they then benefited from the long survival time and low transmission rates of drug-sensitive, treated patients. The transmission of drug-resistant HIV is a major public health issue. As Blower et al. illustrate, increases in risk behavior related to optimism over the benefits of drug therapy may increase in the overall burden of HIV. The model offered by Blower et al. provides an important framework for future analysis of the HIV epidemic, and it is essential that such models accurately reflect our current understanding of the infection. In the case of both individual patients and the community as a whole, once antiretroviral-drug resistance is present, there is no turning back the clock.