HIV Quasispecies Dynamics during Pro-Active Treatment Switching: Impact on Multi-Drug Resistance and Resistance Archiving in Latent Reservoirs
نویسندگان
چکیده
The human immunodeficiency virus (HIV) can be suppressed by highly active anti-retroviral therapy (HAART) in the majority of infected patients. Nevertheless, treatment interruptions inevitably result in viral rebounds from persistent, latently infected cells, necessitating lifelong treatment. Virological failure due to resistance development is a frequent event and the major threat to treatment success. Currently, it is recommended to change treatment after the confirmation of virological failure. However, at the moment virological failure is detected, drug resistant mutants already replicate in great numbers. They infect numerous cells, many of which will turn into latently infected cells. This pool of cells represents an archive of resistance, which has the potential of limiting future treatment options. The objective of this study was to design a treatment strategy for treatment-naive patients that decreases the likelihood of early treatment failure and preserves future treatment options. We propose to apply a single, pro-active treatment switch, following a period of treatment with an induction regimen. The main goal of the induction regimen is to decrease the abundance of randomly generated mutants that confer resistance to the maintenance regimen, thereby increasing subsequent treatment success. Treatment is switched before the overgrowth and archiving of mutant strains that carry resistance against the induction regimen and would limit its future re-use. In silico modelling shows that an optimal trade-off is achieved by switching treatment at days after the initiation of antiviral therapy. Evaluation of the proposed treatment strategy demonstrated significant improvements in terms of resistance archiving and virological response, as compared to conventional HAART. While continuous pro-active treatment alternation improved the clinical outcome in a randomized trial, our results indicate that a similar improvement might also be reached after a single pro-active treatment switch. The clinical validity of this finding, however, remains to be shown by a corresponding trial.
منابع مشابه
Dynamics of HIV-1 Quasispecies during Antiviral Treatment Dissected Using Ultra-Deep Pyrosequencing
BACKGROUND Ultra-deep pyrosequencing (UDPS) allows identification of rare HIV-1 variants and minority drug resistance mutations, which are not detectable by standard sequencing. PRINCIPAL FINDINGS Here, UDPS was used to analyze the dynamics of HIV-1 genetic variation in reverse transcriptase (RT) (amino acids 180-220) in six individuals consecutively sampled before, during and after failing 3...
متن کاملResistance Risk Management in HIV Therapy Switching with Explicit Quiescent T-Cell Modeling
Highly Active Antiretroviral Therapy (HAART) has proven remarkably effective in controlling the development of HIV. However, drug resistance may compromise these benefits. During the use of HAART, drug-resistant strains can develop and become the dominant species. Because the number of independent treatment regimens is limited, once resistance to all available drug classes arises, the patient w...
متن کاملCharacterization of HIV-1 Near Full-Length Proviral Genome Quasispecies from Patients with Undetectable Viral Load Undergoing First-Line HAART Therapy
Increased access to highly active antiretroviral therapy (HAART) by human immunodeficiency virus postive (HIV⁺) individuals has become a reality worldwide. In Brazil, HAART currently reaches over half of HIV-infected subjects. In the context of a remarkable HIV-1 genetic variability, highly related variants, called quasispecies, are generated. HIV quasispecies generated during infection can inf...
متن کاملResistance mechanism of human immunodeficiency virus type-1 protease to inhibitors: A molecular dynamic approach
Human immunodeficiency virus type 1 (HIV-1) protease inhibitors comprise an important class of drugs used in HIV treatments. However, mutations of protease genes accelerated by low fidelity of reverse transcriptase yield drug resistant mutants of reduced affinities for the inhibitors. This problem is considered to be a serious barrier against HIV treatment for the foreseeable future. In this st...
متن کاملNanotechnology for the Treatment of NeuroAIDS
Submit Manuscript | http://medcraveonline.com ultimately progressing to neuroAIDS [1-3]. This is mainly attributed to the integration of the HIV-1 genome into the host genome causing viral latency. The cells that harbor latent HIV typically stay in specific anatomic sites e.g. secondary lymphoid tissue, testes, liver, gut and the CNS [4,5]. The situation is more complicated because in addition ...
متن کامل