The expanding epidemic of HIV in young people, and their eventual move to the adult setting, poses many challenges to the quality and continuity of their medical care. In this program Joe Cervia targets the special needs and models of care that may ease the transitional challenges.
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Each year the number of HIV infected youth is increasing. Join us to hear Donna Futterman describe the trends of this accelerating epidemic in young people, efforts to improve early diagnosis of HIV and other STIs in youth, and treatment challenges pertinent to optimal adolescent HIV care.
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Almost everybody has heard of the "Berlin Patient" and many may have also seen him on morning talk shows, but how many clinicians have had an opportunity to meet and listen to his doctor from Berlin? In this video you will hear Gero Hütter tell about his rationale for performing a bone marrow transplant with CCR5 deficient hematopoietic stem cells, the long term outcomes for his patient, further research to understand if he has been "cured," and attempts to repeat this unique success. Please also see PRN's video of Pablo Tebas, who spoke on gene therapy and other research based on Gero Hütter's "Berlin patient."
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Can HIV disease be cured? If a cure is defined as the permanent remission of HIV disease and its consequences in the absence of antiretroviral therapy, then Timothy Brown, the "Berlin patient,"was cured. (Also see the PRN video of Gero Hütter's detailed discussion of his Berlin patient.) And even though this remains an isolated case, the priority of NIH funding for HIV research has since shifted to a cure. In this presentation, Pablo Tebas highlights new research, in the aftermath of the Berlin patient, to identify HIV reservoirs and ways to eliminate them, gene therapy approaches that mimic the benefits of CCR5 deficient stem cell transplantation, and boosting the immune response with therapeutic vaccines an immune modulators. Yes, there is hope again, for a cure after all.
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The initiation and management of antiretroviral therapy is constantly improving, and periodic review of new data as well as changing treatment guidelines are imperative. In this lecture, Trip Gulick discusses important clinical studies that have led to changes in current guidelines as well as ongoing studies that may expand treatment options in the future.
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There is great excitement about the introduction of directly acting agents for the treatment of chronic hepatitis C, and due to the experience that HIV clinicians already have with the use of antiretroviral agents, co-management of these diseases is optimal for patent care. In this lecture Andy Talal reviews recent advances in HCV monotherapy and implications for HIV-HCV coinfection.
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The ability of HIV to bond to different coreceptors for cell entry is known as tropism. After attaching to CD4, HIV must also bind to one of two additional coreceptors. The predominant coreceptor is CCR5, especially early in the course of infection; alternately HIV may be able to bind to CXCR4, either instead of or in addition to CCR5. Viral and host cell factors determine viral tropism and the dynamics of viral attachment prior to cell entry. Tropism has critical implications for HIV care. This article explains tropism and explores how it may influence decisions regarding the use of CCR5 antagonists for disease management.
The PRN Notebook reports on sessions from the 2005 Treatment and Management of HIV Infection in the United States Conference. Comorbidities have become significant issues for hiv-positive people as they live longer, and patients face social and emotional obstacles as they chart their long lives with hiv infection. Dr. Sharon Lee discusses the need for chronic and lifelong care, and Marjorie Williams discusses social and emotional considerations in HIV.
The integrase inhibitors are a welcome addition to the treatment armamentarium for HIV/AIDS in treatment-experienced patients failing available antiretroviral regimens. The promising efficacy and tolerability profile of the integrase inhibitors, absence of cross-resistance with other antiretroviral classes, and demonstrated synergism of the integrase inhibitors in combination with approved antiretroviral agents place them in a position to become important components of effective combination antiretroviral regimens in individuals living with HIV/AIDS.
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.
In light of the inability of HIV to propagate itself without integration of its genome into chromosomal DNA, the viral integrase protein has become an important potential therapeutic target. It is distinct mechanistically, independent of the catalytic activities of the viral protease, reverse transcriptase, or of virus cell fusion. It therefore has the potential for synergistic activity in combination with available protease and reverse transcriptase inhibitors, and with entry inhibitors now in development. In addition, because of their novel molecular structure, the cost of production of the new families of integrase inhibitors may be less than that of some of the current antiretrovirals which rely on protein-like compounds or nucleoside derivatives for their activity.
The results of the SMART study showed that intermittent therapy compared with continuous therapy, was associated with increased risks of HIV disease progression or death, serious HIV disease progression, and severe complications. “These results were not affected by gender, race, baseline CD4+ cell count, or nadir CD4+ cell count… Episodic use of antiretroviral therapy based on CD4+ cell counts, as utilized in the SMART study design, is inferior to continuous antiretroviral therapy for the management of antiretroviral-experienced patients,” Dr. El-Sadr said. She added that an insufficient number of antiretroviral-naïve patients (5%) were included to make a conclusion about the use of intermittent therapy in this patient population.
To date, twenty-two antiretrovirals have been approved by the FDA for the treatment of HIV infection. In addition to the development of new drugs and drug classes with unique potency advantages, a number of older antiretrovirals have been reformulated to allow for more simplified dosing. Additionally, the development of fixed-dose combination tablets have considerably improved treatment acceptance. For the first time, a widely used complete drug regimen is available to take as one pill once per day. Even with increasingly simplified treatment regimens, challenges still remain in finding products with minimal toxicity and optimized resistance profiles. To achieve optimal viral suppression, there is also a need for agents that penetrate viral reservoirs and target new portions of the HIV lifecycle. Fortunately, the antiretroviral drug pipeline contains several promising agents that may address these needs.
The discussion of eradication is certainly not new to the pages of The PRN Notebook. Early treatment, intensified treatment regimens, and immune-based therapies to achieve this goal have all been pursued—with limited success—and discussed in detail over the past ten years. Just as it seemed as if the possibility of eradicating HIV was nothing more than a pipe dream, exciting new research has emerged utilizing a truly novel approach and exploiting a very common compound—valproic acid—bringing the possibility of a cure to the forefront once again. PRN was pleased to host Dr. Margolis at its October meeting to explain the theory behind, and the data supporting, continued evaluation of this approach.
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.
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—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, 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.
A great deal of research has established potent antiretroviral therapy as a 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, but 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.
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. But now, pharmacokinetic “boosting”—primarily the use of ritonavir (Norvir) to boost concentrations of other protease inhibitors—has, in effect, rendered many of these drugs easier to take and more effective.
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. Very little has been published regarding the actual pharmacologic mechanisms responsible for host- and drug-related pharmacokinetics and pharmacodynamics 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 to discuss the latest developments and future directions of pharmacology in the much larger arena of HIV treatment research.
Drug resistance of HIV to antiretroviral drugs is one of the most common causes for therapeutic failure in people infected with HIV. Fortunately, therapy can now be individualized, based on our evolving knowledge of drug resistance, drug-resistance testing, and state-of-the-art treatment approaches.
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.
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.
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.
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.
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 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. This article summarizes a lecture focusing on acute and early HIV diagnosis and treatment delivered by Dr. Marty Markowitz, as well as data from the Massachusetts General Hospital primary HIV infection structured treatment interruption study, presented by Dr. Bruce Walker.
Efforts are underway to better understand the pharmacology of antiretroviral therapy and how best to individualize treatment of HIV and AIDS to yield the safest, most effective results. According to Dr. David Back, this goal is evident in the recent move toward once daily regimens to simplify dosing as well as boosted protease inhibitor (PI) regimens to both simplify and improve the effectiveness of treatment. Most recently, there has also been growing interest in the potential role for host genotyping, stemming from the fascinating study of pharmacogenetics.
Pharmacokinetic “boosting”—the use of ritonavir to boost concentrations of other protease inhibitors—has, in effect, rendered many of these drugs easier to take and more effective. Research is also emerging regarding the use of two protease inhibitors—both boosted using low-dose ritonavir—as a therapeutic option, which appears to hold promise, particularly for patients who have tried and failed protease inhibitor therapy in the past.
The dramatic reduction of mother-to-child HIV transmission rates has been heralded as one of the most important breakthroughs in the history of HIV research. Yet an estimated 10,000-plus children in the United States were already infected with the virus. 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.
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.
The CDC also recognizes that, if they and other prevention groups are to be successful in stemming the tide of the epidemic, it is necessary to understand the ever-changing trends in HIV transmission. This requires monitoring the incidence of new HIV infections in various at-risk populations. To do this, the CDC has been implementing programs to take advantage of new testing strategies to identify newly infected individuals from among the scores of persons testing positive for HIV. This article intends to shed some light on rapid assays and sensitive/less-sensitive HIV-antibody testing strategies, based on a lecture delivered by Dr. Bernard Branson of the CDC to members of the Physicians’ Research Network in NYC.
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.
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.
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.
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.
Despite the fact that 16 antiretrovirals are approved for use in the United States, 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. To provide PRN with a glimpse of drugs currently snaking their way through the development pipeline—including three drugs currently being reviewed by the U.S. Food and Drug Administration (FDA) for marketing approval—Dr. Scott Hammer returned to the podium at the January 2003 PRN meeting to discuss his observations of data presented over the past few years. A summary of his presentation—along with key data presented at the 10th Conference on Retroviruses and Opportunistic Infections (CROI), held in February in Boston—is provided here.
HIV infection continues to increase among sexually active adolescents and young adults, who account for half of all new HIV infections in the United States and worldwide. However, only a fraction of these young people are actually aware of their HIV serostatus, and an even smaller number have been successfully linked to vital medical care and social services. It’s all about "Gettin’ Busy." The medical establishment, Dr. Donna Futterman argues, has much "Gettin’ Busy" to do. Now, more than ever, there is a great need to identify at-risk adolescents, to introduce them to counseling and testing as a component of HIV prevention, and to bring HIV-infected young people into care. "Gettin’ Busy"—a term that refers to having sex—still has enormous significance in the discourse of young people and it is something teenagers and adolescents are clearly doing. In the process, however, they are engaging in behavior that increases the risk of contracting or spreading sexually transmitted diseases, including HIV. Each year, 25% of sexually active adolescents contract an STD.
Not 20 years since it was identified as the cause of AIDS, the human immunodeficiency virus (HIV) has become the world's leading infectious cause of death. In the United States and other industrialized nations, the success of highly active antiretroviral therapy (HAART) has provided a partial reprieve from the epidemic. Yet in developing nations-home to 90% of those living with HIV in the world-antiretroviral treatment is beyond the reach of most people living with the disease.
Although structured treatment interruptions (STIs) are no longer the most pressing topic among the many researchers who were initially charmed by their multifaceted potential, STIs very much remain in the hearts and minds of clinicians and people living with HIV. And why shouldn’t they? The reasons for wanting to halt therapy, even temporarily, are just as valid today as they once were. Even in this day and age, in which once-daily drug regimens with low pill burdens are plausible, there are countless patients who continue to grapple with adherence issues and treatment “burnout.” There is also the issue of long-term side effects, whether it’s preventing, delaying, or reversing their onset. Immune augmentation still remains a worthwhile goal, although its potential seems limited to those fortunate few diagnosed during the primary stages of infection. Finally, there is the possibility of using STIs to overcome drug-resistant virus in patients running low on fresh treatment options.
Despite the fact that 16 antiretrovirals are approved for use in the United States, 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. To provide PRN with a glimpse of drugs currently snaking their way through the development pipeline, Dr. Roy "Trip" Gulick returned to the podium at the February 2002 PRN meeting to discuss his observations of data presented over the past few years. A summary of his presentation-along with data presented at the 9th Conference on Retroviruses and Opportunistic Infections (CROI), held in February in Seattle-is provided here.
Tim Horn reports on The Forum for Collaborative HIV Research, which seeks and develops consensus from the diverse constituencies represented with the singular goal of moving hiv/aids research forward. Dr. Roy Gulick discusses how The Forum has been very successful in identifying, evaluating, and catalyzing the next steps in the key areas of HIV research.
Patients with HIV receive an abundance of daily medications, often including a triple-drug antiretroviral regimen, primary and/or secondary prophylactic drugs, and other compounds as needed (e.g., lipid-lowering drugs). Clinicians will be the first to admit that the proper use of these drugs has yielded highly desirable effects—including prolonged survival and fewer opportunistic infections—but will also attest to the burgeoning task of monitoring possible drug interactions.
Eradication of HIV has not been possible with currently available reverse transcriptase inhibitors and protease inhibitors; and multiclass drug-resistant mutants of HIV-along with a multitude of disabling and sometimes life-threatening side effects-are a growing threat. Thus, there is a great need for compounds that target non-protease and reverse transcriptase elements of the HIV lifecycle. Not only might such novel therapies increase the potency of initial HIV treatment, but they may also provide hope for patients who have exhausted current treatment options.
With so much emphasis being placed on protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) in recent years, it’s no wonder that key research involving the “old reliables”—the nucleoside reverse transcriptase inhibitors (NRTIs)—is often overlooked while thumbing through the pages of conference abstract books and peer-reviewed medical journals. Yet, just as there are remaining questions regarding how best to use PIs and NNRTIs, there are similar issues facing the NRTIs that have yet to be fully addressed—most notably, how best to sequence their use in light of their individual drug-resistance profiles. Ironically, this particular issue is becoming more complex as time goes on, given recent data suggesting that resistance within this class of drugs may not be as agent-specific as was originally suspected.
At the ground-breaking 1996 International AIDS Conference, Markowitz and Ho, postulated 1.5--3 years of “maximally suppressive” antiretroviral therapy might eradicate HIV infection. Since then, research has shown that HAART may not completely shut down HIV replication, and that infection may persist in reservoirs. “But this does not mean that we should abandon concepts of eradication or remission,” stated Dr Markowitz at a meeting of PRN in NYC, “the shortcomings that we see today, especially the emergence of drug resistance, might be less of a concern if we can maximize the benefits of therapies that are now available, as well as those in development.”
Though much progress has been made in the treatment of HIV disease, most patients develop drug resistance over time, making new active agents necessary in order to sustain treatment success. Dr Joe Eron discusses HIV drugs-in-development in 2000, with attention to those that may benefit treatment-experienced patients with drug resistance and treatment failure on currently available agents.
Life-threatening drug hypersensitivity reactions can occur with drugs used to treat HIV disease and its complications. This discussion of adverse drug reactions by Dr. Elizabeth Phillips, at a meeting of the Physicians’ Research Network in New York, focuses on the diagnosis and management of hypersensitivity to antiretroviral agents, including nevirapine, efavirenz, agenerase and abacavir, as well as to sulfamethoxazole used for treatment and prophylaxis of Pneumocystis pneumonia.
Virologic failure in the treatment of HIV disease, and the emergence of drug-resistant virus, often begins with subtherapeutic antiretroviral plasma concentrations, but the actual pharmacokinetics of individual drugs can also be blamed. Furthermore, plasma concentrations of antiretroviral agents exceeding therapeutic range may be associated with drug toxicity. This review of Dr Richard Hoetelmans’ presentation to the Physicians’ Research Network in New York focuses on the potential role of therapeutic drug monitoring (TDM) in individualizing antiretroviral therapy, preventing virologic failure, and avoiding drug toxicity.
Although structured treatment interruptions (STIs) are no longer the most pressing topic Structured treatment interruptions (STIs) are a clinical concern. Patients with underlying hiv drug-resistance mutations who initiate an STI while experiencing virologic failure on a HAART regimen essentially remove the selective pressure being exerted on the virus. This, in theory, should permit the “optimally fit” wild-type virus to outgrow drug resistant variants, thus having a dominant drug-sensitive phenotypic population. And once therapy is reinitiated, a profound and perhaps durable response to therapy would ensue. This article reviews treatment interruption strategies and studies, as well the benefits and drawbacks to STIs.