Current Pharmaceutical Design - Volume 12, Issue 9, 2006

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 [3] 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 [6] and colleagues describe promising antiretroviral agents currently in various phases of investigation. Dr. Ingrid Markovic [7] 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. [8] combine the latest information regarding the immunopathogenesis of HIV disease and the potential use of virostatics to manage HIV infection. Dr. Slish and colleagues [9] examine the potential use of therapeutic drug monitoring as a means to exploit currently available therapeutic options. Lastly, Dr. Spearman [10] 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 [1] Feola DJ, Thornton AC, Garvy BA. Effects of Antiretroviral Therapy on Immunity in Patients with HIV. Curr Pharm Design 2006; 12(9): 1015-1022. [2] Rumbaugh JA, Nath A. Developments in HIV Neuropathogenesis. Curr Pharm Design 2006; 12(9): 1023-1044. [3] Rathbun RC, Lockhart SM, Stephens JR. Current HIV Treatment Guidelines - An Overview. Curr Pharm Design 2006; 12(9): 1045-1063. [4] 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. [5] 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. [6] McNicholl IR, McNicholl JJ. On the Horizon: Promising Investigational Antiretroviral Agents. Curr Pharm Design 2006; 12(9): 1091-1103. [7] Markovic I. Advances in HIV-1 Entry Inhibitors: Strategies to Interfere with Receptor and CoReceptor Engagement. Curr Pharm Design 2006; 12(9): 1105-1119. [8] Romanelli F, Hoven AD. Use of Virostatics as a Means of Targeting Human Immunodeficiency Virus Infection. Curr Pharm Design 2006; 12(9): 1121-1127. [9] 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. [10] Spearman P. Current Progress in the Development of HIV Vaccines. Curr Pharm Design 2006; 12(9): 1147-1167.

Drug therapy for human immunodeficiency virus (HIV) is highly effective in suppressing viral replication and restoring immune function in patients with HIV. However, this same treatment can also be associated with immunotoxicity. For example, zidovudine and various other antiretroviral agents are capable of causing bone marrow suppression. Agents used to treat opportunistic infections in these individuals, including ganciclovir, foscarnet, and sulfamethoxazoletrimethoprim, can cause additional hematotoxicity. Drug-drug interactions must also be considered and managed in order to control iatrogenic causes of immunotoxicity. In this review, we examine the normal immune response to HIV, and the benefits of antiretroviral therapy in prolonging immune function. We then discuss immune-related adverse effects of drugs used to treat HIV and the opportunistic infections that are common among these patients. Finally, we address in vitro, animal, and clinical evidence of toxicity associated with various combination use of these agents.

Despite the fact that neurons are rarely infected by the human immunodeficiency virus (HIV), neuronal loss is common in patients with HIV infection, likely due to the effects of viral proteins and inflammatory mediators on these cells. Despite the widespread use of highly active antiretroviral therapy (HAART), at least in developed nations, cognitive impairment and other neurological complications of HIV infection persist with devastating personal and socioeconomic consequences. Fortunately, we have made important advances in recent years in defining the molecular mechanisms by which HIV infection targets the nervous system for damage. Such understanding has opened numerous therapeutic options, which are only now beginning to be exploited. This review will highlight the current state of thought regarding the neuropathogenesis of HIV infection. It will summarize the most recent research looking at the roles of both viral and host factors in mediating HIV-induced neurological disease. Utilizing this knowledge base, a framework will be outlined for current and future therapeutic trials to prevent or improve neurological complications of HIV infection.

Use of highly active antiretroviral therapy has resulted in significant reductions in HIV-related morbidity and mortality. Current therapeutic approaches target cellular entry, viral transcription, and maturation of newly formed virus. Combination therapy is necessary to provide durable suppression of viral replication and immune reconstitution. A variety of consensus treatment guidelines addressing prophylaxis and treatment of HIV infection and opportunistic infections have been developed to serve as resources for clinicians. A summary of U.S. Department of Health and Human Services Guidelines for Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and International AIDS Society- USA Panel recommendations for Treatment of Adult HIV infection are presented. Considerations for selection of antiretroviral therapy in special populations (e.g., pregnancy, coinfection with tuberculosis, hepatitis B and C virus) are highlighted. U.S. Public Health Service guidelines for management of occupational exposure to HIV and initiation of postexposure prophylaxis are discussed as well as World Health Organization recommendations for use of antiretroviral therapy in resource-limited settings. The pathophysiology of HIV infection, viral load testing methods, viral dynamics, and classification of antiretrovirals are also briefly reviewed.

Significant progress has been made in the field of human immunodeficiency virus (HIV) pharmacotherapy. This is a remarkable achievement given that the virus was first recognized in the United States in 1981 and the first antiretroviral (ARV) agent became available in 1987. There are now 20 medications in 4 different classes approved by the Food and Drug Administration (FDA) for the treatment of HIV and the carefully orchestrated use of these agents has dramatically decreased HIV mortality. However, the currently available agents have concerning limitations. These include potentially life-threatening side effects, drug interactions, loss of effectiveness over time due to resistance and the need for an extremely high level of medication adherence to achieve viral suppression. In the following review, important features of the presently available agents are described, and the characteristics of an ideal ARV agent defined.

Objective: To discuss prevention and management of adverse drug reactions which result from antiretroviral use in patients infected with HIV. Background: There are four classes of antiretroviral agents used in the treatment of HIV/AIDS. Side effects to medications are common place and often difficult to avoid. In many cases, research is not able to identify the exact cause of an event. The severity of adverse reactions varies greatly, and some may be difficult to manage; typically, prevention is more desirable than treatment. However, this is not always true. This paper will review class-wide and individual side effects from antiretrovirals and, in some cases, the mechanism of action that results in the event. Class-wide side effects for nucleoside/ tide reverse transcriptase inhibitors (NRTIs) include lactic acidosis, peripheral neuropathy and lipoatrophy. Adverse reactions from individual NRTIs, such as abacavir-induced hypersensitivity reactions, will also be discussed. Classwide side effects to non-nucleoside reverse transcriptase inhibitors include rash and hepatotoxicity, while efavirenz has its own unique CNS reactions. Protease inhibitor side effects include hyperglycemia, lipoaccumulation, dyslipidemia, and gastrointestinal (GI) intolerance. We will also review specific side effects caused by indinavir, ritonavir, and atazanavir. Finally, adverse reactions from the fusion inhibitor, enfuvirtide, will be mentioned. Conclusion: Antiretrovirals are an important break-through in the treatment of HIV/AIDS. However, adverse reactions from these drugs can range from mild to life-threatening, and determining which agent is the cause is frequently difficult to discern. Fortunately, side effects can be monitored, treated and in many cases, prevented.

Human immunodeficiency virus (HIV) infection affects close to 40 million individuals worldwide. Since 1981 when the first case reports of individuals dying from a then rare opportunistic infection were published, twenty million people have died from this epidemic. With 3 or more antiretrovirals as the standard of care, the prevalence of single, double and triple-class resistant HIV strains has increased significantly over the last 5 years due to the tremendous replicative capacity of HIV and selective drug pressure. With greater resistance comes the need for novel and effective antiretrovirals to treat these resistant strains. The purpose of this review is to highlight the most promising agents and classes in Phase IIIII drug development by assessing the clinical efficacy, pharmacology, resistance and tolerability. Three out of the four existing antiretroviral classes (nucleosides, non-nucleosides, protease inhibitors) with agents in clinical trials will be discussed such as nucleoside reverse transcriptase inhibitors (D-d4FC, SPD754), non-nucleoside reverse transcriptase inhibitors (capravirine, TMC125) and protease inhibitors (tipranavir, TMC114). In the next several years, antiretrovirals from novel pharmacologic classes will enter the HIV armamentarium. Based on the early clinical studies, these promising agents will be reviewed from the following classes: attachment inhibitors (TNX-355, BMS-488043), CCR5 coreceptor antagonists (SCH-D, UK-427857, GW 873140) and a maturation inhibitor (PA-457). It is hoped that these agents will represent a therapeutic advance and better activity against HIV resistant strains by providing effective therapy that will reduce viral load, increase the CD4+ cell count and ultimately, prolong survival with minimal adverse effects.

The present armamentarium of 19 antiretroviral drugs licensed for treatment of HIV-1 infection in the U.S. exemplifies preponderance of scientific evidence, which led to improved understanding of the structural and functional, viral and cellular attributes driving HIV-1 infection. The majority of approved drugs (with exception of enfuvirtide), however, focus on two steps of the viral life cycle: reverse transcription and viral maturation. Therefore, it appears there is ample opportunity for the development of a third drug class that has been extensively researched in recent years known as entry inhibitors. Currently, this class of compounds targets steps involved in virion attachment to CD4 or to an appropriate chemokine receptor on the cell surface as well as subsequent conformational rearrangements induced in the envelope glycoprotein (gp120/gp41; Env). These inhibitors preclude the fusion of the virion envelope with the host cell membrane thereby preventing the release of viral capsid into the cytosol. Antiviral agents interfering with receptor (i.e., CD4) or coreceptor (e.g., CCR5 and/or CXCR4) engagement comprise a special subset of viral entry inhibitors. While drugs targeting viral entry offer certain advantages over other classes of compounds, they also pose specific challenges. This review focuses on compounds blocking viral attachment to CD4, CCR5 or CXCR4, highlights the challenges they present, and attempts to offer possible solutions.

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.

The observed inter-individual variation in antiretroviral pharmacokinetics (PK) that results in a wide range of drug exposures from fixed-dose regimens has led to increasing interest in the clinical use of therapeutic drug monitoring (TDM) to individualize dosing of antiretroviral therapy (ART). The focus of this review is to provide an overview of literature available to support therapeutic drug monitoring among the current classes of antiretrovirals, suggest patient populations that may benefit from TDM and bring forth some of the limitations that may exist for widespread use of TDM in a traditional clinical setting.

The greatest hope for controlling the expanding HIV epidemic is the development of a preventive HIV vaccine. Despite almost twenty years of effort, the search for an effective HIV vaccine continues at the present time. Advances in the understanding of HIV immunopathogenesis, and especially viral immune evasion mechanisms, have provided important insights into HIV vaccine design. HIV vaccine approaches based solely on recombinant monomeric envelope glycoproteins have failed dramatically and have been discarded. Modern vector technologies with the potential for generating protective cellular immune responses against HIV are undergoing intensive evaluation in clinical trials. Adenoviral vector systems appear to be very promising for this purpose, while the ability of poxvirus-based regimens to elicit potent HIVspecific cellular immune responses in humans is less certain. A number of novel live vector-based approaches are in development. This review presents the current state of the HIV vaccine field, with an emphasis on those vaccines that are in clinical trials or in an advanced stage of preclinical testing. The HIV vaccine field is a very active and challenging one that will continue to push forward our understanding of basic immunology and drive the development of new vaccine technologies. New breakthroughs in methods to generate effective neutralizing antibody responses against HIV are urgently needed.