**Part 2**

**Developing New Antivirals** 

68 Antiviral Drugs – Aspects of Clinical Use and Recent Advances

Pearson, C. R.; Simoni, J. M.; Hoff, P.; et al. (2007). Assessing antiretroviral adherence via

Perelson, A. S.; Neumann, A. U.; Markowitz, M.; et al. (1996). HIV-1 dynamics in vivo:

Perelson, A. S.; Essunger, P.; Cao, Y.; et al. (1997). Decay characteristics of HIV-1-infected compartments during combination therapy. *Nature*, Vol.387, pp.188–191 Perelson, A. S. & Nelson, P. W. (1999). Mathematical analysis of HIV-1 dynamics in vivo.

Pfister, M.; Labbé, L.; Hammer, S. M.; et al. (2003). Population Pharmacokinetics and

Vrijens, B. & Goetghebeur, E. (1997). Comparing compliance patterns between randomized

Vrijens, B.; Goetghebeur, E.; de Klerk, E.; et al. (2005). Modelling the association between

Wakefield, J. C. (1996). The Bayesian approach to population Pharmacokinetic models.

Wu, H. & Ding, A. A. (1999). Population HIV-1 dynamics in vivo: applicable models and

Wu, H.; Kuritzkes, D. R.; McClernon, D. R.; et al. (1999). Characterization of viral dynamics

and virological endpoints. *Journal of Infectious Diseases*, Vol.179, pp.799–807 Wu, H.; Huang, Y.; Acosta E. P.; et al. (2005). Modeling long-term HIV dynamics and

drug resistance. *J Acquir Immune Defic Syndr*., Vol.39, pp.272-283

Trial Group Study 398. *Antimicrob Agents Chemoter*., Vol.47, pp130-137 Sheiner, L. B. (1985). Modeling pharmacodynamics: parametric and nonparametric

*Estimation, and Control*. pp.139-152, Raven Press, New York.

*Journal of the American Statistical Association*, Vol.91, pp.61–76

treatments. *Control Clin Trials*. , Vol.18, pp.187-203

issues. *AIDS and Behavior*, Vol.11, pp.161-173

Vol.271, pp.1582–1586

pp.2719-2731

pp.410-418

*SIAM Review*, Vol.41, pp.3-44

electronic drug monitoring and self-report: an examination of key methodological

virion clearance rate, infected cell life-span, and viral generation time. *Science*,

Pharmacodynamics of Efavirenz, Nelfinavir, and Indinavir: Adult AIDS Clinical

approaches. In: Rowland M, et al, eds*. Variability in Drug Therapy: Description,* 

adherence and viral load in HIV-infected patients. *Statistics in Medicine*, Vol.24,

inferential tools for virological data from AIDS clinical trials. *Biometrics*, Vol.55,

in Human Immunodeficiency Virus Type 1-infected patients treated with combination antiretroviral therapy: relationships to host factors, cellular restoration

antiretroviral response: effects of drug potency, pharmacokinetics, adherence and

**5** 

*USA* 

**Use of Animal Models** 

Zandrea Ambrose *University of Pittsburgh,* 

**for Anti-HIV Drug Development** 

Animal models serve as important tools for preclinical testing of therapeutic regimens against human immunodeficiency virus (HIV-1), the primary etiologic agent that causes acquired immunodeficiency syndrome (AIDS). Infection and treatment of patients often cannot be controlled in clinical studies. In addition, performing certain procedures and sampling cannot be routinely performed in humans with ease and may be unethical. There are many different primate and murine models of HIV/AIDS, each with their advantages and disadvantages. Some models are appropriate in certain contexts but not others. Knowing how the different models work and their limitations will help guide the researcher to select the appropriate model to answer a specific question. Information gained from the use of preclinical testing of antiretroviral therapies will help identify and improve

preventive, therapeutic, and eradication strategies against HIV/AIDS in humans.

**2. HIV-1 infection of nonhuman primates or humanized mice: Which is the** 

An animal model for human disease should mimic the infection of humans as closely as possible. The disease course in the model should be similar to or more accelerated than in humans. In the case of HIV-1, an animal model that progresses to AIDS over the period of many years will cost time and money in preclinical studies. The use of animals instead of humans usually means certain procedures can be performed more easily and/or ethically. For example, removing vital organs to study pathogenesis, drug penetration, immunity, or virology cannot be performed in humans but can be done after necropsy of an animal. Moreover, unlike in humans, the exact virus, timing of infection, and timing of treatment

HIV-1 does not efficiently replicate in most animals, including nonhuman primates. This is due to differences in host cell factors present in different species that are required for infection or due to innate immunity that appears to have evolved in mammals to ward off infections. Thus, either modification to HIV-1 or to the animal must be made for significant viral replication to occur. This is important for assessing the efficacy of experimental interventions for inhibiting the virus rather than spontaneous control by the host immune

**1. Introduction** 

**better model to use?** 

can be controlled in a model.

system.
