Human immunodeficiency virus drug development

Future Anti-Human Immunodeficiency Virus Drugs Under Development... 

In this chapter we describe the current insights into the evolution of viruses under pressure of antiviral therapy and the potential impact on viral fimess. As most recent work in this field has been done in the field of human immunodeficiency virus (HIV), we use the evolution of this virus as the basis for the chapter. Subsequently, we describe resistance evolution for Hepatitis B virus (HBV), where large progress has been made in recent years. Furthermore, we describe the resistance development for Hepatitis C virus (HCV), for which a very active drug development program is undertaken by several pharmaceutical companies. Finally, we discuss resistance evolution for Influenza. 

HIV phenotype A type of resistance testing for human immunodeficiency virus (HIV) in which a patient s blood sample is obtained, and the patient s HIV genes that encode for reverse transcriptase and protease are removed and placed in an HIV viral vector. This viral vector is replicated in a cell culture system with varying concentrations of antiretrovirals. A drug concentration-viral inhibition curve is developed and the concentration needed to inhibit 50% of the patient s virus is reported. This is used to predict resistance versus susceptibility. 

Neuropathy in human immunodeficiency virus infection has many causes. Multiple mechanisms cause neuropathy in patients with HIV. An immune-mediated, Guillain-Barre-like syndrome (see below) may occur at the time of HIV seroconversion. Later in the course of infection, patients may present with mononeuropathy multiplex, sometimes as a consequence of vasculitis associated with coinfection with hepatitis C. Distal sensory-autonomic axonal polyneuropathy may develop in patients with more advanced HIV, either as a consequence of high titers of HIV itself or of the neurotoxicity of antiretroviral drugs [18,19],... 

Pharmacological research has also benefited from the development of sophisticated tools because they have made it possible for researchers to determine the exact molecular structure of compounds involved in the disease process. With this information, they can devise molecules that bond with and inactivate those compounds (just as enzymes bond with substrates). Consider just one example of this process the development of a drug to treat human immunodeficiency virus (HIV) infection. 

Human immunodeficiency virus (HIV) is a single-stranded RNA retrovirus that causes acquired immunodeficiency syndrome (AIDS), a condition in which individuals are at increased risk for developing certain infections and malignancies. The virus is found in two major forms HIV-1, the most prevalent worldwide, and HIV-2, the most common in western Africa. More than 22 million people have died of HIV infection, and 40 million are believed to be infected worldwide. AIDS epidemics threaten populations in sub-Saharan Africa, Southeast Asia, Central and South America, and Russia. In the United States about 450,000 deaths have occurred and another 900,000 people are estimated to carry the virus. Although the development of new drugs, complex multidrug regimens, and behavioral modification have done much to combat the spread of HIV in-... 

The human immunodeficiency virus (HIV) is one of only a few retroviruses known to infect humans. It is estimated that approximately twenty-two million people are now infected worldwide [1]. With only a tiny number of exceptions, infection ultimately leads to the development of the lethal condition of acquired immunodeficiency syndrome, or AIDS. To date, only a handful of drugs have been shown to have any effect on the course of the disease. These are, in general, relatively ineffective at significantly prolonging life, and drug resistance develops rapidly. Equally discouraging, vaccines have not yet been developed to prevent infection. 

Research into the chemistry of template-dependent nucleic acid biosynthesis, combined with modern techniques of molecular biology, has elucidated the life cycle and structure of the human immunodeficiency virus, the retrovirus that causes AIDS. A few years after the isolation of HIV, this research resulted in the development of drugs capable of prolonging the lives of people infected by HIV. 

Efavirenz (DMP 266) (1) is an effective non-nucleoside inhibitor of reverse transcriptase of the human immunodeficiency virus (HIV) recently registered by the US Food Drug Administration (FDA) for treatment of the acquired immunodeficiency syndrome (AIDS).1 2 3 Inhibition of HIV reverse transcriptase by nucleosides like azidothymidine (AZT) (2) is a proven therapy for delaying the progression to AIDS. However, the rapid viral mutation to resistant strains requires the development of new therapeutic agents. The recent development of both protease inhibitors and non-nucleoside reverse transcriptase inhibitors offers hope of effective treatment especially when coadministered. 

Enfuvirtide (Fuzeon , T-20, Ro 29-9800, Hoffmann-La Roche) is a 36-amino acid synthetic peptide with a molecular weight of 4492 Da. It selectively inhibits human immunodeficiency virus (HIV) fusion to the host cell membranes [73]. The N-terminus of the molecule is acetylated and the C-terminus is amidated. A metabolite, M-20, is deamidated at the C-terminus. An ELISA method was initially used during drug development of this compound, but the decision was made to develop and validate an LC-ESI-MS/MS method for the simultaneous determination of enfuvirtide and M-20 for PK studies to support the NDA submission of this product [53]. Some of the issues of LC-ESI-MS/MS application for peptide bioanalysis are highlighted in the following. 

Cys202 [208]. Human immunodeficiency virus (HIV) is the primary cause of acquired immunodeficiency syndrome (AIDS). In an effort to find new drugs preventing the growth of HIV, Masao et al developed an in vitro assay method of RNase H activity associated with reverse transcriptase (RT) from HIV-1. Some 1,4-naphthoquinones moderately inhibited RNase H activity [209]. Several natural occurring naphtoquinones have showed antiretroviral activity [210-211],... 

Treatment of human immunodeficiency virus (HIV) infections has been radically modified during the past two years by the introduction of powerful antiretroviral drugs, and by the development of methods to determine the viral burden in plasma. The introduction of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors has made this breakthrough possible. However, the long-term therapeutic benefits and safety profiles of these agents are still being evaluated. 

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