Modeling long-term HIV dynamics and antiretroviral response: effects of drug potency, pharmacokinetics, adherence, and drug resistance.
We propose a long-term HIV-1 dynamic model by considering drug potency, drug exposure, and drug susceptibility. Using a Bayesian approach, HIV-1 dynamic parameters were estimated by fitting the model to viral load data from a phase 1/2 randomized clinical study of 2 indinavir (IDV)/ritonavir (RTV)-containing highly active antiretroviral (ARV) therapy regimens in HIV-infected subjects who had previously failed protease inhibitor-containing ARV therapies. A large between-subject variation in estimated viral dynamic parameters was observed, even after accounting for variations in drug exposure and drug susceptibility, suggesting that characteristics of HIV-1 dynamics are host dependent. Significant correlations of baseline factors such as HIV-1 RNA levels and CD4 cell counts with viral dynamic parameters were found. These correlations coincide with biologic interaction mechanisms between HIV and the host immune system and also provide an explanation for the correlations between the baseline viral load and phase 1 viral decay rate, for which inconsistent results have been reported in the literature. The relations between viral dynamic parameters and virologic response were established, and these results suggest that viral dynamic parameters may play an important role in determining treatment success or failure. In particular, we estimated a drug efficacy threshold for each patient that can be used to assess whether an ARV regimen is potent enough to suppress HIV viruses in the individual patient. Our findings indicate that it is necessary to individualize the ARV regimen to treat HIV-1-infected patients. The proposed mathematic models and statistical techniques may provide a framework to simulate and predict antiviral response for individual patients.
Wu
Hulin
H
Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. hwu@bst.rochester.edu
Huang
Yangxin
Y
Acosta
Edward P
EP
Rosenkranz
Susan L
SL
Kuritzkes
Daniel R
DR
Eron
Joseph J
JJ
Perelson
Alan S
AS
Gerber
John G
JG
D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001499:Bayes Theorem; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008433:Mathematics; D008954:Models, Biological; D010349:Patient Compliance; D012367:RNA, Viral / Q000097:blood
D019380:Anti-HIV Agents; D012367:RNA, Viral