HIV resistance during antiviral therapy

HIV resistance during antiviral therapy - Production of...

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Production of resistant HIV mutants during antiretroviral therapy Ruy M. Ribeiro* and Sebastian Bonhoeffer ²‡ *Wellcome Trust Centre for the Epidemiology of Infectious Diseases, Department of Zoology, University of Oxford, South Parks Road, OX1 3PS, Oxford, United Kingdom; and ² Friedrich Miescher Institut, P.O. Box 2543, CH-4002 Basel, Switzerland Communicated by Robert M. May, University of Oxford, United Kingdom, April 19, 2000 (received for review December 25, 1999) HIV drug therapy often fails because of the appearance of multi- drug-resistant virus. There are two possible scenarios for the outgrowth of multidrug-resistant virus in response to therapy. Resistant virus may preexist at low frequencies in drug-naı ¨ve patients and is rapidly selected in the presence of drugs. Alterna- tively, resistant virus is absent at the start of therapy but is generated by residual viral replication during therapy. Currently available experimental methods are generally too insensitive to distinguish between these two scenarios. Here we use determin- istic and stochastic models to investigate the origin of multidrug resistance. We quantify the probabilities that resistant mutants preexist, and that resistant mutants are generated during therapy. The models suggest that under a wide range of conditions, treat- ment failure is most likely caused by the preexistence of resistant mutants. I n recent years, management of HIV infection has greatly im- proved because of the development of new treatment protocols, involving the combination of highly potent drugs (1–5). However, combination therapy is not effective in all patients and may fail because of severe side effects, nonadherence to therapy protocol, lack of potency of drugs, or emergence of resistant virus (refs. 2 and 6; See y trtgdlns.html and refs. therein). Generally, there are two main processes leading to resistance- related treatment failure: preexisting resistant strains may be selected by the drugs used, or resistant mutants are generated de novo by residual virus replication during treatment. It is impor- tant to distinguish between these processes, because they require different actions to improve therapy. If treatment fails because of preexisting resistant virus, than increasing the efficacy of the drugs (for example by increasing the dosage) may not suffice to control virus replication. Rather, several drugs with different resistance profiles need to be combined, reducing the likelihood that strains resistant to combination therapy are present in the first place. On the other hand, if resistance arises de novo during treatment, then increasing the dosage of the drug may lead to a more effective treatment. In this case, the objective would be to minimize any residual replication of the sensitive virus during therapy, because this would reduce the probability of producing a resistant mutant.
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HIV resistance during antiviral therapy - Production of...

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