Reverse Transcriptase Inhibitors
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12 results
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Antiviral Agents
- Authors: Nell S. Lurain, Kenneth D. Thompson
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Source: Manual of Clinical Microbiology, 10th Edition , pp 1687-1709
Publication Date :
January 2011
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Abstract:
The use of antiviral agents for the treatment of viral diseases continues to expand. Most of the agents currently approved by the Food and Drug Administration (FDA) are active against one or more of the following viruses: human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2), hepatitis B and C viruses (HBV and HCV, respectively), the human herpesviruses, and influenza A and B viruses. This chapter is organized according to these virus groups, with cross-referencing for agents with activity against more than one group of viruses. There are now five classes of antiviral agents for treatment of HIV-1: (i) nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs and NtRTIs), (ii) nonnucleoside reverse transcriptase inhibitors (NNRTIs), (iii) protease inhibitors (PIs), (iv) entry/fusion inhibitors, and (v) integrase strand transfer inhibitors (INSTIs). The only antiviral agents that have shown any activity in achieving a sustained virologic response against chronic HCV infection are standard interferon (IFN)-α; 2a and 2b, pegylated IFN-α; (PEG-IFN) 2aµ and 2b, and combinations of these IFNs with ribavirin (RBV). There are two major classes of drugs available to treat HBV: nucleoside and nucleotide analogues and IFNs. Most of the antiviral compounds that are approved to treat the eight human herpesviruses are nucleoside or nucleotide analogues which inhibit DNA replication. The two classes of antiviral agents for the treatment of influenza are M2 protein inhibitors (active only against type A influenza viruses) and neuraminidase inhibitors (activity against both type A and B viruses).
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Genetically Polymorphic Cytochrome P450s and Transporters and Personalized Antimicrobial Chemotherapy
- Author: Hong-Guang Xie
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Source: Molecular Microbiology , pp 803-832
Publication Date :
January 2011
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Abstract:
This chapter summarizes a number of functionally important genetic polymorphisms in drug-metabolizing enzymes and drug transporters and their genotyping methodologies, by which individuals susceptible to drug toxicity or loss of efficacy can be identified or predicted easily in the clinical setting. The human cytochrome P450 (CYP) enzyme system contributing to drug metabolism comprises the CYP families CYP1, CYP2, and CYP3. Among these CYPs, proteins encoded by the human CYP3A genes catalyze the metabolism of nearly half of all currently used drugs, and approximately 40% of all marketed drugs are substrates for CYP2C9, CYP2C19, and CYP2D6. Moreover, the CYP2B6, CYP2C9, CYP2C19, and CYP2D6 enzymes exhibit large variations in the levels of their protein expression and enzymatic activity as a result of frequently occurring, functionally important genetic polymorphisms. Typically, in addition to passive diffusion, a drug is transported into cells by uptake (or influx) transporters, such as organic anion transporters (OATs), organic anion transport peptides (OATPs), and organic cation transporters (OCTs), whereas the drug and its metabolite(s) are removed from the cells by efflux transporters, such as P-glycoprotein (P-gp), multidrug resistance proteins (MRPs), and breast cancer resistance protein (BCRP). Anti-infective drugs may be substrates for some uptake transporters, drug-metabolizing enzymes, and efflux transporters.
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Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives
- Authors: Linos P. R. Vandekerckhove, Frauke Christ, Zeger Debyser, Andrew Owen, David Back, Arnout Voet, Jonathan Schapiro, Dirk Vogelaers
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Source: Antiviral Research , pp 71-96
Publication Date :
January 2009
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Abstract:
This chapter describes the unique role of integrase (IN) in the human immunodeficiency virus type 1 (HIV-1) replication cycle and its interaction with different cellular proteins. It addresses the efficacy and toxicity data of the new drugs targeting IN, along with their biochemical, pharmacokinetic, and pharmacodynamic characteristics. It also discusses clinical perspectives and viral resistance against IN inhibitors as well as recently identified new antiviral targets in HIV IN. Since retroviral integration is a multistep process, the different cofactors can theoretically play a role during one of the following steps: (i) catalysis, (ii) nuclear import of the PIC, (iii) target site selection, and (iv) repair of the DNA gaps. The chapter gives an overview of the search for HIV-1 IN inhibitors, and discusses current IN inhibitors in clinical development. The major mechanism of clearance of MK-0518 (raltegravir) in humans is UDP-glucuronyltransferase (UGT) isoform, 1A1-mediated glucuronidation. In a multicenter, double-blind, randomized study (MK-0518 protocol 005), the safety and efficacy of MK-0518 versus placebo, both regimens also using optimized background therapy (OBT), were evaluated. This study was designed to include highly antiretroviral therapy (ART)-experienced patients with a documented genotypic/phenotypic resistance for more than one drug in each of the three classes (NNRTI, NRTI, and PI) with HIV RNA levels of >5,000 copies and CD4 counts of >50 cells/mm3. Resistance to IN inhibitors has been relatively well defined for a new class of antiretroviral agents. IN has only been recently validated in clinical trials as a target for antiretroviral therapy.
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INDEX
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Source: Antiviral Research
Publication Date :
January 2009
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No descriptions available.
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Human Genetic Factors Involved in Viral Pathogenesis
- Authors: Lennart Svensson, Elin Kindberg
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Source: Cellular Signaling and Innate Immune Responses to RNA Virus Infections , pp 177-193
Publication Date :
January 2009
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Abstract:
This chapter reviews genetic traits associated with susceptibility and resistance to several RNA viruses. HIV is an enveloped retrovirus that has caused more than 25 million deaths worldwide. CCL3L1 is a duplicated variant of CCL3 (MIP-1-α), and this chemokine is the most potent chemokine receptor 5 (CCR5) agonist and hence the most effective competitive inhibitor of R5 HIV-1 entry. Volunteer challenge studies have concluded that (i) nonsecretors are resistant to infection, (ii) susceptibility occurs despite repeated challenge with identical virus, and (iii) short-term protective immunity can develop. Studies from authentic outbreaks show that protection from symptomatic norovirus infection is strongly associated with the G428A nonsense mutation in FUT2. There are four different dengue virus serotypes circulating (1 to 4), each being able to cause both asymptomatic and severe disease. A study that compared the genotypes of 87 unrelated Thai children who had been hospitalized because of dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) was followed and reviewed by others, of which several found associations with HLA class I genotypes and some also with an HLA class II antigen. There is limited information regarding human genetic susceptibility factors associated with tick-borne encephalitis virus (TBEV). An interesting example comes from the pharmacokinetics of an HIV medicine, in which abacavir, a nucleoside reverse transcriptase inhibitor, can induce hypersensitivity that limits its use. Investigators identified a particular HLA haplotype that greatly increases the risk of abacavir hypersensitivity.
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Distal Sensory Polyneuropathy and Other Selected Neuropathies in HIV Infection
- Authors: Lydia Estanislao, Anthony Geraci, David Simpson
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Source: The Spectrum of Neuro-AIDS Disorders , pp 75-86
Publication Date :
January 2009
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Abstract:
This chapter discusses the clinical features, diagnosis, and management of HIV distal sensory polyneuropathy (DSP); toxic neuropathies, with emphasis on the antiretroviral (ARV)-associated neuropathies; and other neuropathies found in HIV-infected individuals. Subjects were classified as having asymptomatic DSP if they only had neurologic signs or as having symptomatic DSP if they also had paresthesias or pain in a study by Schifitto and coworkers. The study showed that use of these drugs was not a significant risk factor for incident symptomatic DSP. Such an effect may be related to preservation of immune function, forestalling the potential occurrence of neurotoxicity. This study also addressed the important issue of whether the presence of asymptomatic DSP is a risk factor for incident symptomatic DSP. Thus, it is not surprising that patients with advanced HIV infection and severe immunosuppression remain at the greatest risk of neurotoxicity due to ARV agents. The incidence, severity, progression, and reversibility of peripheral neuropathy from zalcitabine (ddC), as with other toxic neuropathies, are dose dependent. Unlike other toxic neuropathies, dapsone-induced peripheral neuropathy involves primarily motor nerves. Mononeuropathy multiplex (MM) is an infrequent manifestation of HIV infection. A reduced number of oxytocin neurons in the paraventricular nucleus of the hypothalamus have also been described, although the clinical significance of this is unclear. It has been suggested that the pathophysiological mechanism may be due to HIV infection itself as well as an autoimmune mechanism. It may arise from HIV itself or from medications used to treat HIV infection and other concomitant infections.
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Mitochondrial Dysfunction and Lactic Acidosis in HIV Disease
- Authors: Ashok Verma, Jorge Pardo
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Source: The Spectrum of Neuro-AIDS Disorders , pp 87-93
Publication Date :
January 2009
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Abstract:
Mitochondria differ from other subcellular organelles in that they contain their own DNA (mitochondrial DNA [mtDNA]). In mitochondrial disorders, not only does energy failure in tissues and organs result, with a variety of clinical symptoms, but the metabolic block at the end of the anaerobic glycolysis can also lead to excessive pyruvate and lactate accumulation. Lactic acidosis, therefore, can be a manifestation of mitochondrial dysfunction. Symptomatic hyperlactatemia associated with antiretroviral therapy is linked to the mitochondrial respiratory-chain impairment in HIV disease. The recent availability of antiretroviral drugs has substantially reduced HIV-associated mortality and morbidity through decreased viral burden and immune restoration. Mitochondria are the site of generation of most of the cellular ATP pool. The conversion of one molecule of glucose to pyruvate or lactate is associated with the net formation of two molecules of ATP. Nucleoside analog reverse transcriptase inhibitors (NRTI)-related mitochondrial toxicity appears to be the major factor responsible for hyperlactatemia and lactic acidosis in patients with HIV disease. All metabolic acidoses have profound effects on the respiratory, cardiac, and nervous system. It seems essential to discontinue all antiretroviral drugs at the time of NRTI-associated lactic acidosis (NALA) diagnosis; however, surviving patients often need to continue antiretroviral therapy.
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Mood Disorders, Delirium, and Other Neurobehavioral Symptoms and Disorders in the HAART Era
- Authors: Stephen J. Ferrando, Todd Loftus
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Source: The Spectrum of Neuro-AIDS Disorders , pp 393-410
Publication Date :
January 2009
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Abstract:
This chapter reviews of the epidemiology, diagnosis, and treatment of the major psychiatric aspects of HIV infection, in addition to somatic symptoms such as sleep disorder, fatigue, sexual dysfunction, and HIV-associated lipodystrophy, all of which have substantial quality of life impact. Benzodiazepines should be avoided in patients with cognitive impairment and delirium. Delirium is common among hospitalized HIV/AIDS patients. Most studies documenting rates of delirium were conducted in the pre-highly active antiretroviral therapy (HAART) era and were restricted to subsets of patients seen in psychiatric consultation. Sleep disorders, primarily insomnia disorders, are prevalent in the HIV-infected population. Hepatitis C virus (HCV) infection is increasingly recognized as a significant comorbid condition that affects the clinical outcome of patients with substance abuse disorders and HIV disease. Fatigue is common among patients with HIV/AIDS and may contribute to impairment in physical function and disability. With the advent of nucleoside analog reverse transcriptase inhibitors (NRTIs) (e.g., zidovudine), nonnucleoside analog reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz), and PIs (e.g., indinavir) as part of HAART, there has been heightened interest in the issue of drug interactions in the context of HIV psychopharmacology. HIV-associated lipodystrophy is an increasingly recognized complication of prolonged treatment with HAART that may have significant impact on the psychological well-being and quality of life of those affected.
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Global Issues in Neuro-AIDS and Their Evolution over the Future of the HAART Era
- Author: Bruce J. Brew
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Source: The Spectrum of Neuro-AIDS Disorders , pp 507-523
Publication Date :
January 2009
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Abstract:
In developed countries the effect of highly active antiretroviral therapy (HAART) on the neurological complications in the short term has been well described, but the long-term effects are only just starting to be clarified. These issues are best discussed within a framework that structures the complications according to whether they are direct or indirect. Within this framework this chapter deals briefly with the more significant aspects of nervous system involvement in HIV infection emphasizing three points: possible new complications in developing countries, new complications in HAART-treated patients as well as complications such as progressive multifocal leukoencephalopathy (PML) that have only marginally changed with HAART, and future directions. The direct complications such as dementia and neuropathy are organized according to the degree of advancement of HIV disease and anatomical region involved. With the introduction of HAART, some aspects of investigations have changed; however, this is an evolving area that still needs clarification. There are several myopathies that have been linked to HIV disease. The association seems to be at least in part causal rather than just associative. The two most important are polymyositis and inclusion body myositis. The indirect neurological complications related to HIV disease are many. Only the more important are discussed in the chapter. The most significant aspects of these disorders in the era of HAART are that the incidence of opportunistic infections has significantly declined with HAART and that HAART may induce the clinical expression of previously subclinical disease through the immune reconstitution syndrome.
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Antiretroviral Agents
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Source: Clinical Virology, Third Edition , pp 167-216
Publication Date :
January 2009
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Abstract:
In 1987, zidovudine became the first approved agent in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Two decades later, 24 additional agents in six drug classes had been approved. These include nucleoside analog reverse transcriptase inhibitors (NRTIs), a nucleotide analog reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, and an integrase inhibitor. This chapter describes the major characteristics of antiretroviral agents that are currently approved, or at a promising stage of development, and is organized according to the virus replication cycle. The current therapeutic niche of chemokine receptor 5 (CCR5) inhibitors is as one component of combination regimens for patients with multidrug-resistant R5 virus. In vitro, maraviroc demonstrates no antagonism with existing antiretroviral agents and additive or synergistic activity in combination with enfuvirtide. Vicriviroc is a potent inhibitor of most R5 viruses in vitro, with an IC50 in the range of 20 nM. It demonstrates additive or synergistic activity in combination with other approved antiretroviral agents. Additive or synergistic in vitro inhibition has been reported with double or triple combinations of numerous antiretroviral agents, except for zidovudine-stavudine, which is an antagonistic combination. Stavudine enjoys relatively few drug-drug interactions compared to other antiretroviral agents. The major mechanism of clearance of raltegravir in humans is by hepatic uridine diphosphoglucuronosyl transferase (UGT)-1A1. Amprenavir is additive with a number of other antiretroviral agents (zidovudine, didanosine, abacavir, saquinavir, indinavir, and ritonavir).
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Preface
- Publication Date : January 2007
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No descriptions available.
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Human Immunodeficiency Virus
- Author: Richard L. Hodinka
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Source: Manual of Commercial Methods in Clinical Microbiology , pp 100-127
Publication Date :
January 2002
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Abstract:
This chapter focuses on the various technologies that are currently available from commercial companies for the diagnosis and monitoring of human immunodeficiency virus (HIV) infections, and it is not meant to duplicate more extensive reviews of HIV. Infection with HIV type 1 (HIV-1) results in the induction of a humoral antibody response specific to viral proteins, with the production of immunoglobulin A (IgA), IgM, and IgG. The majority of the automated immunoassay analyzers provide walk-away simplicity to perform assays from sample processing through interpretation of results. The major advantage of Western blot assays over enzyme immunoassays (EIAs) is that the specific interaction of antibody and antigen can be directly visualized. Immunofluorescence assay (IFA) is a very useful and inexpensive alternative to performing Western blot assays for confirmation of HIVspecific antibody responses. The Fluorognost HIV-1 IFA is based on the specific binding of HIV-1 antibodies in a specimen to HIV-1 antigens expressed on the surfaces of immortalized human T- cells fixed to glass slides. Specific antibody-antigen complexes are then detected using an anti-human antibody conjugated with fluorescein isothiocyanate. The development of molecular assays to quantitate the levels of HIV RNA in infected patients has provided one of the most valuable tools to assess the progression of HIV disease, monitor the impact of antiviral therapy, predict treatment failure and the emergence of drug-resistant viruses, and facilitate our understanding of the natural history and pathogenesis of this virus.