Understanding drug resistance for monotherapy treatment of HIV infection.
The purpose of this study was to investigate strategies in the monotherapy treatment of HIV infection in the presence of drug-resistant (mutant) strains. A mathematical system is developed to model resistance in HIV chemotherapy. It includes the key players in the immune response to HIV infection: virus and both uninfected CD4+ and infected CD4+ T-cell populations. We model the latent and progressive stages of the disease, and then introduce monotherapy treatment. The model is a system of differential equations describing the interaction of two distinct classes of HIV--drug-sensitive (wild type) and drug-resistant (mutant)--with lymphocytes in the peripheral blood. We then introduce chemotherapy effects. In the absence of treatment, the model produces the three types of qualitative clinical behavior--an uninfected steady state, an infected steady state (latency), and progression to AIDS. Simulation of treatment is provided for monotherapy, during the progression to AIDS state, in the consideration of resistance effects. Treatment benefit is based on an increase or retention in CD4+ T-cell counts together with a low viral titer. We explore the following treatment approaches: an antiviral drug which reduces viral infectivity that is administered early--when the CD4+ T-cell count is > or = 300/mm3, and the late--when the CD4+ T-cell count is less than 300/mm3. We compare all results with data. When treatment is initiated during the progression to AIDS state, treatment prevents T-cell collapse, but gradually loses effectiveness due to drug resistance. We hypothesize that it is the careful balance of mutant and wild-type HIV strains which provides the greatest prolonged benefit from treatment. This is best achieved when treatment is initiated when the CD4+ T-cell counts are greater than 250/mm3, but less than 400/mm3 in this model (i.e. not too early, not too late). These results are supported by clinical data. The work is novel in that it is the first model to accurately simulate data before, during and after monotherapy treatment. Our model also provides insight into recent clinical results, as well as suggests plausible guidelines for clinical testing in the monotherapy of HIV infection.
Kirschner
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Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor 48109-0620, USA. kirschne@malthus.micro.med.umich.edu
Webb
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D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004352:Drug Resistance, Microbial; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D006801:Humans; D008433:Mathematics; D008954:Models, Biological
D019380:Anti-HIV Agents