On the role of resonance in drug failure under HIV treatment interruption

BACKGROUND: The application of highly active antiretroviral therapy (HAART) against HIV can reduce and maintain viral load below detection limit in many patients. Continuous HAART, however, can have severe side effects. In this context, structured treatment interruptions (STI) were considered to be a promising strategy. However, using CD4 cell count to guide intermittent therapy starting and stopping points, the SMART study (strategies for management of antiretroviral therapy), revealed that STI were associated with increased risk of AIDS and other complications. Additionally, short-term periodic (e.g. one week on / one week off) interruption therapies have shown virus rebound exceeding a given “failure threshold”, without any evidence for the evolution of drug resistance. Currently, the only hypothesis explaining the failure of STI is the “resonance hypothesis”, which posits that treatment failure is due to a resonance effect between the drug treatment and the viral population. In the present study we used a mathematical model to analyse the parameters affecting the output of drug treatment interruption and the premises of the resonance hypothesis. METHODS: We used a population dynamic model of HIV infection. Simulations and analytical approximations of deterministic and stochastic versions of the model were studied. RESULTS AND CONCLUSION: The present study examines the roles of the most important parameters affecting the viral rebound, responsible for drug failure. We related these findings to the resonance hypothesis, and showed that the degree of sustainability of damping oscillations present in the model after the acute phase is strongly linked to their amplitude, which determines the resonance level. Stochastic simulations of the same model even revealed sustained oscillations in virus population for small virus population sizes. Given that pronounced viral load oscillations have not been observed in HIV-1 patients, the link between oscillations and resonance level suggests that treatment failure due to a resonance effect is not plausible. Moreover, the failure threshold is attained before the virus population crosses the set point while growing. As the maximum virus population is reached even after the set point is crossed, the role of resonance effects in the context of treatment interruptions cannot explain drug failure.