MANAGEMENT
Update On CCR5 Inhibitors: Scientific Rationale, Clinical Evidence, and Anticipated Uses
The CCR5 antagonists are a welcome addition to the therapeutic armamentarium available for antiretroviral-experienced patients. Currently, their use in antiretroviral-naive patients should be restricted to enrollment in ongoing or planned clinical trials. The CCR5 antagonist maraviroc is FDA-approved for treatment-experienced patients with R5 virus (only), and no patient should receive maraviroc without first undergoing a tropism assay.
Understanding and Inhibiting Integrase in the Treatment of HIV Disease
Patients who have developed resistance to the 3 currently available classes of HIV medications present a particular treatment challenge. Developments in an entirely new class of HIV antiretroviral therapy, inhibitors of the viral integrase protein, were the focus of discussions at a recent PRN meeting.
New Perspectives in HIV Treatment Interruption: The SMART Study
The advent of highly active antiretroviral therapy in the mid 1990s resulted in a dramatic increase in survival of HIV patients, especially among those with advanced disease,” Dr. Wafaa El-Sadr said in beginning her February 2006 PRN lecture. Follow-up studies, she explained, demonstrated the durability of this effect, with decreasing HIV-associated morbidity and mortality during the late 1990s and early 2000s. She also acknowledged, however, that while combination antiretroviral treatment has changed the face of the HIV epidemic and enabled physicians to provide truly effective therapy, several issues and limitations of these regimens have emerged.
New Antiretrovirals for the Treatment of HIV: The View in 2006
Substantial progress continues to be made in the arena of antiretroviral drug development. PRN is again proud to present its annual review of the experimental agents to watch for in the coming months and years. This year’s review is based on a lecture by Dr. Roy M. Gulick, a longtime friend of PRN, and no stranger to the antiretroviral development pipeline.
Depletion of Latent HIV Infection In Vivo: Moving Towards Eradication of HIV Infection
Dr. Margolis began his October 2005 lecture with a crucial question. Two decades into the HIV/AIDS epidemic, what is to be done in the next decade? The answer, it seems, couldn’t be clearer: the evaluation of novel methods to prevent infection; the ongoing establishment of concrete treatment modalities to prevent disease in the infected; and, of particular interest to Dr. Margolis, continued momentum toward the eradication of infection.
View from the Pipeline: The 2005 Review of Experimental Antiretrovirals
There are 20 unique medications approved for the treatment of HIV infection. Despite this impressive number, there is an indisputable need for new anti-HIV compounds that have potent and durable efficacy profiles, unique resistance patterns, patient-friendly dosing schedules, and minimal toxicities. What follows is an overview of some the newest antiretroviral contenders, discussed by Dr. Roy M. Gulick during a recent meeting of the Physicians’ Research Network.
Surviving Antiretroviral Drug Resistance: Strategies for Optimal Use of Therapeutic Agents
Constructing effective salvage therapy regimens for HIV-infected patients with highly resistant virus poses a daunting challenge to the practicing clinician. The recent approval of new protease inhibitors (PIs)—tipranavir and darunavir—and the continuing development of new drug classes provide hope that patients can now be salvaged with at least a few active new drugs. This paper reviews the available clinical outcomes data for tipranavir and darunavir as well as the investigational CCR5 antagonists, 2nd-generation nonnucleoside reverse transcriptase inhibitors (NNRTIs), and integrase inhibitors. Also discussed are salvage strategies in treatment-experienced patients with the goal of maximizing the chances of a patient receiving at least 2 active agents in combination. When this is not possible, the continued use of nonsuppressive therapy through de-escalation to a simplified “holding“ regimen may be utilized to maintain less fit HIV mutants until more suppressive treatment options become available.
Advances in Immune-Based Therapies for HIV Disease
A great deal of research conducted over the past ten years has established potent antiretroviral therapy as a tried and true way of drastically reducing HIV replication. Less is known about strategies to enhance T-cell production to preserve or restore immune function in HIV-infected patients. This is not to say that immune-based research and evaluation is not being conducted. Work completed at the Gladstone Institute of Virology and Immunology—not to mention the numerous other immunology labs throughout the world—is a testament to this. As the Gladstone Institute’s Dr. Laura Napolitano affirmed at the January PRN meeting, much progress has been made. Not only do we better understand the mechanisms by which CD4+ cells are lost in HIV-infected individuals and then gained in response to antiretroviral therapy, research in this regard has given rise to a number of potential pharmacologic strategies that continue to be explored in studies.
From Concept to Care: Pharmacokinetic Boosting of Protease Inhibitors
Protease inhibitors have played an instrumental role in decreasing mortality and morbidity among people with HIV infection. At the same time, this class of antiretrovirals has been associated with a number of disadvantages. First, protease inhibitor therapy often comes with a high pill burden, complex dosing schedules, and careful dietary considerations. Second, they are associated with a growing number of short- and long-term side effects, including a variety of metabolic complications. Third, cross-resistance remains a central concern; a simple switch from one protease inhibitor to another—if protease mutations are documented—often yields lackluster results.
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XEN and the Art of Pharmacology: New Learning from an Old Science
The future development of effective and safe antiretroviral agents—and the continued study of ways to maximize the utility of currently available therapies—are highly dependent on a scientific field that has evolved in recent years at an incredible rate: pharmacology. While The PRN Notebook has published numerous articles focusing on the issues of pharmacokinetics (PK) and pharmacodynamics (PD) as they apply to antiretroviral therapy, very little has been published in these pages regarding the actual pharmacologic mechanisms responsible for host- and drug-related PK and PD variability. To help explain the science of drug metabolism and drug interactions—and how it is translating into new treatment strategies—PRN turned to Dr. Charles Flexner, a longtime supporter and friend, to discuss the latest developments and future directions of pharmacology in the much larger arena of HIV treatment research.
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Mother-to-Child HIV Transmission: National and International Progress and Challenges
According to estimates by the World Health Organization (WHO), approximately 700,000 children were infected with HIV in 2003, with greater than 95% of these infections occurring in resource-poor nations. Conversely, new HIV infections in children are becoming increasingly rare in many parts of world, most notably wealthy nations. The vast majority of children with HIV acquire the infection through mother-to-child transmission (MTCT) of the virus, which can occur in utero, during labor and delivery, and while breastfeeding (estimates of the timing of MTCT are illustrated in Figure 1). In the absence of any intervention, the risk of MTCT is 15% to 30% in non-breastfeeding populations. In the setting of breastfeeding, the risk increases by 5% to 20%, to a total of 20% to 45% (De Cock, 2000).
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Mechanisms of HIV Drug Resistance: A Primer
Resistance of HIV to antiretroviral drugs is one of the most common causes for therapeutic failure in people infected with HIV. Sadly, the emergence of drug-resistant HIV variants is a common occurrence—even under the best of circumstances—given that no antiretroviral drug combination studied as of yet is completely effective in shutting down viral replication.
Bangkok 2004: Progress In Spite of Protest?
When PRN approached Veronica Miller, PhD, Director of the Forum for Collaborative HIV Research, to write a summary of the recent XV International AIDS Conference in Bangkok, we knew that this would be a daunting task. For those interested in reading up on some of the basic science; clinical research, treatment, and care; and epidemiology and prevention data presented at the conference, we encourage readers to review the expert summaries posted on Medscape and Clinical Care Options. What Dr. Miller provides us with here has not been readily available through other clinician-based publications: a personal viewpoint of the IAC and, with it, a report on some of the Forum for Collaborative HIV Research activities at the highly charged conference.
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View from the pipeline: The 2004 Review of Experimental Antiretrovirals
There are 26 medications approved for the treatment of HIV infection. This latest tally includes 19 unique antiretroviral agents, three prodrug/extended-release formulations of older drugs, and four fixed-dose combinations (including the most recent arrivals: Gilead’s Truvada and GlaxoSmithKline’s Epzicom). Despite these impressive numbers, there is an indisputable need for new anti-HIV compounds that have potent and durable efficacy profiles, unique resistance patterns, patient-friendly dosing schedules, and minimal toxicities. What follows is an overview of some the newest antiretroviral contenders, including some of the more recently approved agents and a number of the experimental agents in various stages of development.
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HIV Drug Resistance: New Insight and Updated Practices
Over the past 18 months, significant amounts of data presented at scientific conferences have shed additional light on the mechanisms and clinical significance of antiretroviral drug resistance. These include new reports from studies evaluating the incidence and lingering consequences of transmitted drug-resistant HIV, the significance of the K65R mutation in reverse transcriptase, the persistence of minor HIV variants harboring drug-resistance mutations, the selection of TAM pathways, as well as some heartening data indicating that lamivudine retains some activity against HIV carrying the M184V mutation. To discuss these and other emerging data, Dr. Daniel Kuritzkes graciously accepted PRN’s offer to speak at the May 2004 meeting, the proceedings from which are reviewed here.
Antiretrovirals for the World: Needs and Challenges
At the XIII International AIDS Conference, held in 2002 in Barcelona, the World Health Organization (WHO) challenged the global HIV/AIDS community to expand access to care and treatment to at least half of those in immediate need—to put antiretroviral therapy into the hands of three million people in resource-limited settings by the end of 2005. On World AIDS Day 2003, WHO released a detailed and concrete plan to achieve this ambitious goal. The “3 by 5 Initiative,” as it has come to be known, has been heralded as the first big step towards universal access to AIDS care and treatment.
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Update on the Treatment of Acute and Early HIV Infection
The treatment of patients in the acute and early stage of HIV infection has long been a subject of intensive investigation. A handful of studies have evaluated immediate, short-term antiretroviral therapy—with and without structured treatment interruptions and/or immune-based therapies—during acute and early HIV infection in an effort to perturb the virus-host equilibrium with the intent of achieving long-term virologic control in the absence of antiretroviral therapy. However, when it comes to this approach, there are still more questions than answers. But this is not to say that the identification and careful handling of individuals in the acute and early stages of HIV infection is not important. There are both established and potential benefits associated with the early diagnosis and management of acute HIV infection. And for the lingering questions to be answered correctly, clinical trials must continue, which requires clinicians to remain on their toes and to refer patients to ongoing studies in an effort to capitalize on what is still believed to be a potential window of opportunity.
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Pharmacokinetics, Pharmacogenetics, and HIV: The Aim to Optimize Antiretroviral Therapy
There are hundreds of thousands of HIV-infected individuals, around the world, who are benefiting virologically, immunologically, and clinically from antiretroviral therapy. But without doubt, many of these individuals grapple with an array of short- and long-term side effects and virtually all of them are at risk of —or are currently dealing with the realities of—drug resistance and therapeutic failure. Fortunately, plans to remedy these situations are not simply based on the development of antiretrovirals with unique resistance patterns or adjunctive therapies to counteract side effects. Efforts are underway to better understand the pharmacology of antiretroviral therapy and how best to individualize treatment to yield the safest, most effective results.
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Protease Inhibitor Therapy: Boosted and Double-Boosted Options to the Fore
In April 1999, Dr. Schlomo Staszewski had a simple message for clinicians attending his first PRN lecture: that protease inhibitors were a less-than-ideal therapeutic option and that focus should be placed on prescribing protease inhibitor-sparing regimens, whenever possible. “We were seeing problems with dosing, with side effects, with dietary restrictions, with resistance and cross resistance,” Dr. Staszewski said upon returning to PRN in November 2003.
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The Changing Face of HIV Infection in Children
Our ability to drastically reduce mother-to-child HIV transmission rates has been heralded as one of the most important breakthroughs in the history of HIV research. But try explaining such good fortune to the estimated 10,000-plus children—or their caregivers—in the United States who are already infected with the virus. Yet, as we have been seeing with HIV-positive adults, managing HIV disease progression in our youngest patients has dramatically improved in recent years. Not even ten years ago, a pediatric HIV diagnosis was associated with a dismal prognosis: most infected children would die before their fifth birthday. Today, thanks to early access to care and potent antiretroviral therapy, HIV-infected children can look forward to entering and graduating from high school and beyond. And with more information quickly emerging with respect to how HIV-infected children should be treated, we can expect continued improvements in prognosis.
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Shooting the Messenger: Harnessing RNA Interference to Combat HIV Infection
It all began less than ten years ago, when a team of researchers under the direction of Dr. Rich Jorgensen, who is currently an associate professor in the Department of Plant Sciences at the University of Arizona, was experimenting with petunias (Jorgensen, 1996). Dr. Jorgensen’s group was attempting to deepen the color of these household plants with the use of a pigment-producing gene. However, upon injecting the plants with the gene, the flowers actually lightened considerably, turning white in some cases. After some sleuthing, Dr. Jorgenson’s team suggested that what was being seen was “cosuppression”—the suppression of both the homologous endogenous gene and the introduced pigment-producing gene.
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Understanding and Utilizing New Techniques for HIV Testing
Approximately 40,000 new HIV infections occur every year in the United States. Of even greater concern, however, is the U.S. Centers for Disease Control (CDC) estimation that between 180,000 and 280,000 people in the United States are infected with the virus and don’t know it. In turn, there is a sizeable population of HIV-infected individuals who are unknowingly putting their own health at risk and likely contributing to the spread of HIV. Another concern is the fact that between 27,000 and 30,000 of blood tests conducted at publicly funded testing sites are positive for HIV antibodies. However, approximately 31% of those who test positive do not return to the testing site to receive their results.
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State of the ART: The New DHHS HIV Treatment Guidelines and Current Controversies in Antiretroviral Therapy
Since their original publication on April 24, 1998, the Department of Health and Human Services’ Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents have undergone significant alterations. Research into the optimal times to start and switch therapy, along with the evaluation of both new and older antiretroviral regimens and laboratory assays, has evolved considerably over the past five years—a reflection of scientific discovery that continues to change the standard of care for HIV-infected individuals.
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To Switch or Not to Switch: When Is It A Question?
When the first official Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents were published by the Department of Health and Human Services (DHHS) on April 24, 1998, the HIV treatment landscape was a different world: hitting the virus early still seemed like a logical idea, an apparent never-ending supply of protease inhibitors was flowing out of the drug-development pipeline, non-nucleoside reverse transcriptase inhibitors were coming into vogue as potent backbone options, nucleoside analogues did not appear to suffer much in the way of cross resistance, and an extraordinary percentage of HIV-positive individuals were still doing well on their first triple-drug regimens. In short, treatment options were plentiful and the DHHS was confident in its endorsement of pushing viral load to undetectable levels and keeping it there, using a succession of seemingly endless regimen switches to maintain this goal.
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Understanding Treatment-Resistant HIV
Resistance of HIV to antiretroviral drugs is one of the most common causes for therapeutic failure in people infected with HIV. Sadly, the emergence of drug-resistant HIV variants is usually an inevitable occurrence—even under the best of circumstances—given that no antiretroviral drug combination is completely effective in shutting down viral replication. And there is no shortage of data indicating that the emergence of HIV drug resistance is clearly associated with adverse treatment outcomes.
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HIV AIDS in Resource-Poor Settings: A Province In China
At the dawn of the third millennium, it is clear that humanity is facing one of the most devastating epidemics in human history-an epidemic that threatens development in major regions of the world. Since the 1960s, most countries have made impressive strides in human development. However, such achievements are being undermined as countries lose young, productive people to the epidemic.
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