Abstract
Since the introduction of antiretroviral therapy (ART), the lifespan and quality of life of patients infected with HIV have been significantly improved. But treatment efficacy was compromised eventually by the development of resistance to antiretroviral drugs, and more new anti-HIV drugs with lower toxicity and higher activity were needed. Based on the experience and lessons learned from the treatment in the developed countries, US FDA suggested that more pharmacodynamical researches should be considered ahead of the clinical trials. To facilitate the anti-HIV drug research and development, we reviewed a few specialized issues that should be focused on drug evaluations in vitro, including: 1) Mechanism of action studies, demonstrating the candidate drug’s efficacy to specifically inhibit viral replication or a virus-specific function and confirm the drug target. 2) Drug resistance studies, selecting the drug-resistant variants in vitro and determining the activities inhibiting HIV isolates resistant to approved antiretroviral drugs of the same class. 3) Antiviral activity in vitro in the presence of serum proteins, ascertaining whether an investigational product is significantly bound by serum proteins. 4) Combination activity analysis, evaluating in vitro antiviral activity of an investigational product in two-drug combinations with other drugs approved.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Berenbaum M C. 1989. What is synergy? Pharmaco Rev, 41(2): 93–141.
Bilello J A, Bilello P A, Stellrecht K, et al. 1996. Human serum α1 acid glycoprotein reduces uptake, intracellular concentration, and antiviral activity of A-80987, an inhibitor of the human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother, 40(6): 1491–1497.
Bulgheroni E, Citterio P, Croce F, et al. 2004. Analysis of protease inhibitor combinations in vitro: activity of lopinavir, amprenavir and tipranavir against HIV type 1 wild-type and drug-resistant isolates. J Antimicrob Chemother, 53(3): 464–468.
Chou T C, Motzer R J, Tong Y, et al. 1994. Computerized quantitation of synergism and antagonism of taxol, topotecan, cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst, 86(20): 1517–1524.
Deminie C A, Bechtold C M, Stock D, et al. 1996. Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication. Antimicrob Agents Chemother, 40(6): 1346–1351.
Dorr P, Westby M, Dobbs S, et al. 2005. Maraviroc (UK427,857), a potent, orally bioavailable and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother, 49(11): 4721–4732.
Dressler V, Müeller G, Sühnel J. 1999. CombiTool — a new computer program for analyzing combination experiments with biologically active agents. Comput Biomed Res, 32: 146–160.
FDA. 2005. Guidance for Industry: Antiviral Drug Development-Conducting Virology Studies and Submitting the Data to the Agency (DRAFT GUIDANCE). No. 5
FDA. 2004. Guidance for Industry: Role of HIV Drug Resistance Testing in Antiretroviral Drug Development (DRAFT GUIDANCE). No. 12
Fleury H J, Toni T, Lan N T, et al. 2006. Susceptibility to antiretroviral drugs of CRF01_AE, CRF02_AG, and subtype C viruses from untreated patients of Africa and Asia: comparative genotypic and phenotypic data. AIDS Res Hum Retroviruses, 22(4): 357–366.
Flexner C W, 2003. Advances in HIV pharmacology: protein binding, pharmacogenomics, and therapeutic drug monitoring. Top HIV Med, 11(2): 40–44.
Greco W R, Bravo G, Parsons J C. 1995. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev, 47(2): 331–385.
Lin J H, Lu A Y, 1997. Role of pharmacokinetics and metabolism in drug discovery and development. Pharmaco. Rev, 49(4): 403–449.
Parkin N T, Schapiro J M. 2004. Antiretroviral drug resistance in non-subtype B HIV-1, HIV-2 and SIV. Antivir Ther, 9(1): 3–12.
Prichard M N, Shipman C Jr. 1990. A three-dimensional model to analyze drug-drug interactions. Antiviral Res. 14: 181–206.
Shipman C Jr. 1995. Analysis of drug-drug interactions: an overview. Antiviral Res, 29: 41–43.
Straetemans R, O’Brien T, Wouters L, et al. 2005. Design and analysis of drug combination experiments. Biometrical J, 47(3): 299–308.
Vergne L, Stuyver L, Van Houtte M, et al. 2006. Natural polymorphism in protease and reverse transcriptase genes and in vitro antiretroviral drug susceptibility of non-B HIV-1 strains from treatment-naïve patients. J Clin Virol, 36: 43–49
White R L, Burgess D S, Manduru M, et al. 1996. Comparison of three different in vitro methods of detecting synergy: time-kill, checkerboard, and E test. Antimicrob. Agents Chemother, 40(8): 1914–1918.
Witvrouw M, Pannecouque C, Switzer W M, et al. 2004. Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis. Antivir Ther, 9(1): 57–65.
Author information
Authors and Affiliations
Corresponding author
Additional information
Foundation item: This work was supported by Major Science and Technology Special Projects (2009 ZX09301).
Rights and permissions
About this article
Cite this article
Zhuang, Dm., Li, Jy. A few specialized issues that should be focused on anti-HIV drug evaluation in vitro. Virol. Sin. 25, 301–306 (2010). https://doi.org/10.1007/s12250-010-3139-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12250-010-3139-8