Use of virostatics as a means of targeting Human Immunodeficiency Virus infection
ABSTRACT Current antiretroviral therapy has had a significant impact on HIV associated morbidity and mortality. Despite these positive outcomes current antiretroviral regimens have significant deficiencies which include multiple drug-drug interactions, high pill burdens, and considerable financial expense. Perhaps the greatest shortcoming is the apparent inability of current therapy to disrupt low level viremia in certain cellular reservoirs despite maximal virologic control as determined by polymerase chain reaction detection. These drug-resilient reservoirs preclude the ability to discontinue antiretrovirals while maintaining viral control. Additionally, they may be responsible at least in part for the evolution of drug resistant variants. Various researchers have proposed that certain immune modulating agents known as virostatics (i.e., hydroxyurea (HU), mycophenolate mofetil (MMF), and cyclosporine (CSA)) may have some efficacy in managing HIV disease and/or disrupting resilient reservoirs. These agents may act by reducing the pool of activated CD4+ cells which are susceptible to infection thereby inhibiting the characteristic immune over-activation seen in most HIV infected patients. Virostatics have primarily been studied in patients with advanced HIV disease and as components of trials involving structured treatment interruptions. These trials have demonstrated conflicting results with regard to viral load and CD4+ cell counts as well as potential adverse effects including immune suppression. Before widespread use of these agents can be recommended, larger, well controlled trials will need to be conducted to determine which virostatic agents are appropriate for use in HIV infected patients and the most efficacious time course within which to initiate these agents.
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ABSTRACT: Significant scientific discoveries spanning the last decade have altered the course of human immunodeficiency virus (HIV) infection within industrialized nations. Drug discovery and evidenced-based pharmacotherapeutic interventions have delayed the development of more severe immune destruction and subsequent progression to the acquired immune deficiency syndrome (AIDS) in a majority of patients. Of the most notable contributions to the management of HIV infection has been the advent of the antiretroviral class of protease inhibitors. The incorporation of protease inhibitors into anti-HIV armamentariums has significantly reduced HIV-associated morbidity and mortality. While these achievements have brought hope to individual patients and contributed to retarding the HIV pandemic, current therapies are laden with untoward effects that do not appear capable of complete viral eradication. Therefore, on going research into HIV's mechanisms of disease and the endogenous immunological response to infection are necessary. This issue of Current Pharmaceutical Design will review management recommendations and achievements in drug discovery which are responsible for many of the contemporary advances in clinical management. Also discussed will be progress in the understanding of the immunological phenomenon associated with HIV infection and novel drug targets aimed at inhibiting viral replication. Reviews by Feola et al. and Rumbaugh et al. [1, 2] describe advances in pathogenic aspects of HIV infection. Dr. Rathburn  provides a timely clinical review and synopsis of the most current management guidelines for HIV infection. Papers by Jain et al. and Shibuyama et al . [4, 5] review limitations of current antiretroviral therapies, including but not limited to the adverse event profiles of available agents. Dr. Ian McNicholl  and colleagues describe promising antiretroviral agents currently in various phases of investigation. Dr. Ingrid Markovic  specifically examines advances in the area of HIV-1 entry and coreceptor engagement. HIV-1 entry is currently an area of significant research which provides great insight into the infectious processes used by HIV. Romanelli et al.  combine the latest information regarding the immunopathogenesis of HIV disease and the potential use of virostatics to manage HIV infection. Dr. Slish and colleagues  examine the potential use of therapeutic drug monitoring as a means to exploit currently available therapeutic options. Lastly, Dr. Spearman  describes the ideal profile of an HIV vaccine candidate and discusses the most recent research and prospects for such a product. We hope this special issue not only provides insight into current research and discovery in the area of HIV/AIDS but also provides background and stimulus for on going scholarship in this field. References  Feola DJ, Thornton AC, Garvy BA. Effects of Antiretroviral Therapy on Immunity in Patients with HIV. Curr Pharm Design 2006; 12(9): 1015-1022.  Rumbaugh JA, Nath A. Developments in HIV Neuropathogenesis. Curr Pharm Design 2006; 12(9): 1023-1044.  Rathbun RC, Lockhart SM, Stephens JR. Current HIV Treatment Guidelines - An Overview. Curr Pharm Design 2006; 12(9): 1045-1063.  Jain R, Clark NM, Diaz-Linares M, Grim SA. Limitations of Current Antiretroviral Agents and Opportunities for Development. Curr Pharm Design 2006; 12(9): 1065-1074.  Shibuyama S, Gevorkyan A, Yoo U, Tim S, Dzhangiryan K and Scott JD. Understanding and Avoiding Antiretroviral Adverse Events. Curr Pharm Design 2006; 12(9): 1075-1090.  McNicholl IR, McNicholl JJ. On the Horizon: Promising Investigational Antiretroviral Agents. Curr Pharm Design 2006; 12(9): 1091-1103.  Markovic I. Advances in HIV-1 Entry Inhibitors: Strategies to Interfere with Receptor and CoReceptor Engagement. Curr Pharm Design 2006; 12(9): 1105-1119.  Romanelli F, Hoven AD. Use of Virostatics as a Means of Targeting Human Immunodeficiency Virus Infection. Curr Pharm Design 2006; 12(9): 1121-1127.  Slish JC, Catanzaro LM, Ma Q, Okusanya OO, Demeter L, Albrecht M, Morse GD. Update on the Pharmacokinetic Aspects of Antiretroviral Agents: Implications in Therapeutic Drug Monitoring. Curr Pharm Design 2006; 12(9): 1129- 1145.  Spearman P. Current Progress in the Development of HIV Vaccines. Curr Pharm Design 2006; 12(9): 1147-1167.Current Pharmaceutical Design 02/2006; 12(9):1013-1013. DOI:10.2174/138161206776055831 · 3.29 Impact Factor
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ABSTRACT: A 32-year-old African American man with HIV infection presented with hemoptysis, shortness of breath and renal insufficiency. Serologic testing revealed the presence of anti-glomerular basement membrane antibodies and equivocal levels of anti-myeloperoxidase antibodies. Physical examination, urine and blood analysis, kidney ultrasound, chest radiograph, sputum cultures, bronchoscopy and renal biopsy. Reactivation of tuberculosis infection, immune complex glomerulonephritis, and 'false-positive' anti-glomerular basement membrane and anti-myeloperoxidase antibodies. Directly observed therapy with four-drug anti-tuberculosis therapy and conservative management of chronic kidney disease.Nature Clinical Practice Nephrology 01/2007; 2(12):708-12. DOI:10.1038/ncpneph0324 · 6.08 Impact Factor