2021 marks the 18th year of the European AIDS Conference, this year in London. Juergen Rockstroh, a past president of EACS, provides compelling conference updates, focussing on epidemiology, diagnostics, treatments, aging and the impact of COVID-19 on people living with HIV in Europe.
This program presented by David Hardy is a review of highlights from the Virtual IAS Conference on HIV Science 2021, including clinically relevant advances in antiretroviral therapy, metabolic effects, as well as investigational agents for HIV treatment and prevention.
Chronic inflammation caused by herpesviruses (especially CMV) and by sex differences, leads to end-organ morbidities in HIV disease despite optimal treatment of HIV. In this presentation, Peter Hunt explores the causes and consequences of persistent immune activation in treated HIV infection, including its impact on age-related morbidity and mortality as well as HIV persistence.
Marina Caskey provides a comprehensive update of broadly neutralizing antibodies (bNAbs) in the treatment and prevention of HIV. Learn the latest on outcomes from recent engineered HIV bNAbs clinical trials, prevention efficacy studies, as well as new HIV bNAb delivery systems entering clinical evaluation.
Long-acting antiretroviral formulations for HIV treatment and prevention - if nobody has asked you about why they are important and how they work, don’t miss this program, which will help you prepare. Nanoformulations, erodable and non-erodable implant formulations, and other mechanisms for making drugs work longer are on the way, and Charles Flexner will discuss all of them in this engaging program.
Every year the Conference on Retrovirology and Opportunistic Infections (CROI) is packed with important new information in HIV medicine and this year including COVID-19 as well. Don’t miss this engaging review by Trip Gulick on CROI 2021 highlights in HIV cure, new drugs, treatment strategies, and prevention, as well as the latest on SARS CoV-2 and COVID-19.
Testosterone is prescribed frequently for hypogonadism in cisgender men living with HIV, aging cisgender men, and for gender-affirming therapy in transgender men. But do we fully understand the benefits? And what do we really know about the risks? This presentation by Todd Brown will bring you up to date on the outcomes from pertinent studies including the Testosterone Trials (TTrials) in older cisgender men and what is presently known about the potential risks in transgender men.
With the waxing and waning of COVID-19 infections, it is vital to stay up-to-date — especially with our patients living with HIV.
In this presentation, Raj Gandhi will review the most recent data on clinical manifestations and treatment considerations for COVID-19 in the general population, including people living with HIV.
We live with the constant fear of a resurgence of the COVID 19 pandemic. When our patients living with HIV ask us about COVID19 and its impact on them, what do we say and how can we best guide them? This comprehensive review of the clinical features and treatment of COVID 19 in the setting of HIV infection by Dr. Roy (Trip) Gulick will address these important questions, vital to our patients’ well-being - whether we see them in-person or virtually.
This program presented by David Hardy is a review of highlights from the 2020 International Aids Conference, including current antiretroviral therapy, ART and pregnancy, metabolic effects, investigational treatments, as well as HIV prevention and cure. Dr. Hardy also discusses issues surrounding COVID-19 that were covered as part of the 2020 International Aids Conference.
Lessons we have learned from the HIV response can guide us moving forward as the new COVID-19 pandemic continues to expand and evolve. In this program, Wafaa El-Sadr, well known for her innovative work in HIV here in New York and around the world, uses her rich background experience to examine the dynamics of COVID19, scrutinize the challenges and successes of the various responses so far, identify populations disproportionately affected, and anticipate future needs with a steady eye on the science, public health and healthcare systems necessary for a more effective response to this devastating new pandemic.
Please join us for a presentation by Dr. Markowitz on the current recommendations for cART, a review of recent long-acting cabotegravir and rilpivirine data, and the exciting use of broadly neutralizing antibodies in the treatment and prevention of HIV.
Do Grindr™ users take more risks? Are Grindr™ users more likely to serosort? Dr. Martin Hoenigl will answer these questions. He will also cover novel ways to use geosocial mobile apps to better reach marginalized populations at risk for HIV/STIs and to promote testing and PrEP use.
ID Week has a wider focus on infectious diseases than CROI or IAS, but there are important research data and clinical pearls of interest to all HIV clinicians, as Michelle Cespedes clearly demonstrates. So, for the latest information from ID Week on long-acting agents, two-drug therapies, clinical considerations in changing regimens, tailoring HIV treatment strategies to the unique needs of your patients, preventing transmission and ending the epidemic, don’t miss this engaging and important summary.
Every 2 years, the International AIDS Society (IAS) holds its Conference on HIV Science, and this time it was in Mexico City, with nearly 6000 people from 130 countries attended IAS 2019. With multiple tracks, over 90 sessions and 1300 abstracts, it is impossible to cover all the information presented, but in this program, Trip Gulick highlights new data from research pertinent to treatment initiation, maintenance therapy, switch studies, and new drugs in development, as well as prevention efforts including pre-exposure prophylaxis and vaccine development. So, if you want to stay up to date and know what is in the horizon, do not miss this important program.
We are fortunate in HIV medicine to have robust treatment and prevention guidelines, but there is always room for improvement. The advances we continue to see are driven, in part, by the controversies surrounding optimal prevention, treatment and cure strategies as evidence-based outcomes are continually reassessed. So, don’t miss this up-to-date review of current controversies by Raj Gandhi, focusing on prevention, treatment, complications of treatment, and efforts to find a cure.
Every year the Conference on Retrovirology and Opportunistic Infections (CROI) is packed with important new information and this program focuses on the advances in antiretroviral therapy to improve standards of care and point the way to future advances through emerging research and drug development. Don’t miss this engaging review by Trip Gulick on CROI 2019 highlights in HIV cure, treatment strategies and drug resistance, new drugs and mechanisms of action, HIV prevention, and TB coinfection.
Achieving a scalable and broad-based cure for HIV-infected individuals is a daunting challenge, but Cure research is ongoing, including immune-based strategies that boost the host immune response against the virus. Clinical trials aimed at achieving ART-free HIV-remission will need to include placebo groups and analytical treatment interruption and plasma viremia as an end point. Don’t miss this important presentation on current Cure research and ways that you and your eligible patients may be able to contribute to the science by which research outcomes can be effectively measured.
The treatment and prevention of HIV disease, Hepatitis C and their myriad complications are constantly changing—and the evolution of state-of-the-art management is almost always forecasted by research presented at major scientific meetings both nationally and internationally. In this program, David Hardy targets some of the highlights from AIDS 2018, the International AIDS Society’s conference in Amsterdam, and IDWeek 2018, the Infectious Diseases Society of America’s annual conference. Don’t miss this important review on diverse topics of interest to our primary care audience.
In this program Trip Gulick discusses important events leading up to the International AIDS Society conference - AIDS 2018 - including the 2018 UNAIDS data report on the global AIDS response, the FDA approval of the first PI-based single-tablet regimen for HIV, and the publication in JAMA of the IAS-USA 2018 recommendations for antiretroviral treatment and prevention of HIV infection. With this background, Dr. Gulick proceeds to discuss highlights of the AIDS 2018 meeting in Amsterdam, including new research on HIV treatment initiation, HIV and TB coinfection, and HIV switch studies. Due to the length of this program, we have split this into two parts. Be sure to watch both!
In this continuation of highlights from AIDS 2018 in Amsterdam, Dr. Gulick finishes his review of HIV switch studies, and goes on to discuss drug toxicities, ARVs in pregnancy and pediatrics, drug resistance, PrEP, including important information for PrEP in trans women, and further efforts to discover a cure for HIV infection. Don’t miss either of the two parts of this important and exciting program!
Growing up is always difficult. Remember? But growing up with perinatal HIV infection, adds new dimensions to the physical and psychosocial challenges that children face as they struggle simply to survive, and hopefully thrive. This important presentation by Elaine Abrams will help you identify interventions that may help you improve the outcomes of young people growing up with HIV and care for them with a deeper understanding when they transition to adult medical care.
Every year, the Conference on Retrovirology and Opportunistic Infections (CROI) sets the bar for scientific research and evidence-based clinical advances in the fields of HIV treatment, prevention, and drug development. As anticipated, 2018 was no exception, and in this exciting presentation, Dr. Roy (Trip) Gulick targets “news that you can use” -- highlights from CROI 2018 most likely to affect treatment and prevention strategies, drug choices, and what’s coming soon in the development pipeline. If you are involved in the day-to-day care of people who are living with, or at risk for HIV infection, don’t miss this engaging update.
The extraordinary benefits of antiretroviral therapy -- especially survival, quality of life, and decrease risk for transmission – are just as true globally, as they are here in the USA. This is most important in resource-poor areas of the world hardest hit by the epidemic, where there are many challenges to healthcare delivery that require innovative solutions to maintain and expand HIV diagnosis and treatment. But even with the enormous success of global efforts over the last 15 years, “what got us here” as Wafaa El-Sadr points out, is still not enough to end the global epidemic as we move forward. So what else is needed? Differentiated Service Delivery (DSD) may help, but what is that, you may be asking? Don’t miss this opportunity to learn about this new model for global health initiatives that can increase the precision of public health efforts to end the HIV epidemic worldwide.
We may not have a cure for HIV, but the treatment options keep expanding and improving, and prevention strategies are working better than ever. This program targets the most recent advances in HIV treatment and prevention from the International AIDS Conference in Paris, including updates on what to start, how to switch, second and third line treatment options, and new NUCs, non-NUCs and integrase inhibitors in the drug development pipeline, as well as drugs with new mechanisms-of-action, such as an orally-dosed attachment inhibitor, an entry inhibitor and maturation inhibitor. So if you want to stay up to date and know what is in the horizon, do not miss this important program.
The annual Conference on Retroviruses and Opportunistic Infections (CROI) is known worldwide for its leadership in fostering and showcasing advances in the basic sciences, immunology, drug development, and clinical research for the prevention, treatment, and cure of HIV disease, as well as HIV-related coinfections and cancers. Don’t miss this important update from Tim Wilkin, focusing on the highlights from CROI 2017 that are most pertinent for our audience of HIV primary care providers.
The field of HIV management is dynamic and staying up-to-date can be challenging. There are new questions and new answers to old questions that we must consider. Should all HIV-infected patients be treated, including elite controllers? Should HIV-infected patients initiate ART on the day of diagnosis? Should all newly-diagnosed HIV-infected patients be started on an integrase inhibitor-based regimen? Should TAF replace TDF for all patients? How should an ART regimen be chosen in patients with specific comorbidities or conditions? What regimen should you choose for a patient who cannot take ABC, TDF and TAF? Don't miss this important and thorough presentation on the art of initiating ART.
Fresh from the International AIDS Conference in Durban, Trip Gulick gives an engaging overview of new research in HIV treatment and prevention strategies, new formulations of existing antiretroviral drugs, new agents in the development pipeline, and better understanding of pharmacokinetics. Don’t miss this important review of new research that will contribute to the ever-changing, and improving field of HIV treatment and prevention.
Don’t miss this engaging review of the recent Conference on Retroviral and Opportunistic Infections (CROI 2016) spotlighting the latest research in HIV treatment and prevention strategies. Topics include prophylaxis, initiation of antiretroviral therapy in newly-diagnosed patients, switch-therapy to decrease toxicities, and choosing new therapeutic combinations for treatment-experienced patients with suboptimal responses. Also, new drugs in the development pipeline that may soon expand therapeutic options for our patients suffering from treatment failure are discussed, as well as research in longer-acting drugs for PrEP and other prevention modalities.
It is encouraging that both national and international HIV treatment guidelines support early initiation of antiretroviral drugs, regardless of CD4 count, for the best long-term outcomes, and to decrease transmission. And the guidelines continue to evolve to support efficacy, tolerability and simplicity, while acknowledging scenarios where alternative regimens may be needed. Of course there are comorbidities, drug resistance, and immune failure to consider when choosing or changing regimens. And newer, safer drugs are still coming! Don’t miss this important review on the state-of-the-art and future of antiretroviral therapy for HIV.
Isn’t it time to start treating HIV disease like the urgent medical and public health problem it is, rather than losing people step after step after step after step in a drawn-out cascade to treatment? In other words, why not start empiric treatment immediately on the same day as point-of-care diagnosis? In this presentation you will hear about the innovative work being done in San Francisco to hasten access to antiretroviral treatment in an effort to decrease loss-to-follow-up, speed treatment to undetectability and reduce transmission.
With an estimated prevalence of up to 14% in HIV-infected patients, diabetes is a leading cause of cardiovascular disease, blindness, end-stage renal disease, amputations, and hospitalizations for our patients. Regular screening for diabetes is important, and extra diagnostic caution must be taken in people living with HIV. When diagnosed, changes in lifestyle are critical, and medical management requires individualization. This clinically oriented lecture focuses on therapeutic options including recently approved drugs from new classes of drugs for glycemic control, as well as treatment strategies for optimal management of diabetes and prevention of diabetic morbidities in HIV medicine.
HIV disease is likely associated with a 50% increased risk for cardiovascular disease, but independent HIV-related risk factors suggest that early and continuous antiretroviral therapy may reduce atherosclerotic cardiovascular disease risk in HIV, especially type 1 myocardial infarctions caused by atherosclerotic plaque rupture. In addition to the direct relation of HIV disease to atherosclerotic disease, questions about reported associations of certain antiretroviral drugs with myocardial infarctions, and the potential use of statins to decreased inflammation and promote plaque regression are discussed in this important program.
The annual Conference on Retrovirology and Opportunistic Infections (CROI) is the most important international meeting on HIV. This year Trip Gulick reports on some of the highlights of CROI 2015 including the most up-to-date strategies for when to start treatment, what to start with, when to change and what to change to. In addition, he also touches on controversies of intolerance and toxicities, drug resistance, new drugs in the development pipeline, and finishes off with the most recent advances in HIV prophylaxis. If you are interested in the treatment and prevention of HIV disease, do not miss this engaging presentation.
Although oral PrEP can be highly successful in preventing HIV infection, more options for chemoprophylaxis are needed to meet the diverse needs of varying populations. The development of vaginal and rectal microbicides has been a bumpy road, and so far none have been licensed, but progress is being made. In this program, Ian McGowan, a leading researcher in the field, discusses the science and the studies that will hopefully lead to a variety of licensed microbicides for the prevention of vaginal and rectal transmission.
The early diagnosis and treatment of HIV during the acute or primary stage of infection has lasting benefits for each individual that starts and adheres to antiretroviral therapy, but there are also public health advantages for the community. Tracing the phylogenetics of HIV transmission networks provides insight to contagiousness, length of infection and severity, and transmission of drug resistant variants of HIV. In this exciting lecture, Susan Little, who runs the primary HIV infection program at UCSD demonstrates how early diagnosis and treatment of HIV interrupts network transmission, which may be the most powerful key to ending the HIV epidemic that we currently have.
Transgender women are at extraordinarily high risk for HIV infection for a number of reasons. We will never be able to end the HIV epidemic if we cannot better serve the needs of transgender individuals in ways that are both culturally sensitive and inclusive. In this thought-provoking lecture, Dr. Radix targets the many challenges our transgender patients face and how we can improve the management and prevention of HIV in this most vulnerable population.
Now that we are all routinely testing for HIV-2 as part of the new HIV testing algorithm, it will be helpful to know more about how HIV-2 differs from HIV-1 pathogenically, and how treatment fro HIV-2 differs from standard therapy of HIV-1. And who could teach us better than the researcher who first discovered HIV-2, Fancois Clavel, in this fascinating lecture.
Is testosterone replacement for hypogonadism overprescribed in the United States? Is it safe? The diagnosis of hypogonadism is not uncommon in aging HIV-infected men. So understanding the optimal screening recommendations as well as the potential risks and benefits of testosterone therapy, particularly in older men, is extremely important to their well-being. Join us for this important update by Todd Brown.
Awareness of drug-drug interactions between agents used to treat HIV, coinfections such as hepatitis C, and co-morbidities such cardiovascular, renal, respiratory and metabolic disease, has never been more important. And the risk of adverse interactions of polypharmacy will increase as our patients age and their problem lists get longer. This comprehensive view from David Back, known world-wide for his extensive work in drug interactions at the University of Liverpool, is a must for anybody caring for people living with HIV.
Who, among your HIV-positive patients, may be at higher risk for kidney disease? And what about your HIV-negative patients who have started or are thinking about PrEP? This program will help you recognize the limitations of current screening tests for kidney disease in your patients with and at risk for HIV disease, and understand the diagnosis and management of antiretroviral-associated nephrotoxicity.
The advances in the management of chronic HIV disease have been extraordinary, but only one person—the Berlin patient—has ever achieved a “functional cure.” HIV cure research is a complicated yet exciting field, with recent setbacks, such as the failure of cure in the Mississippi baby. Purging latent reservoirs is necessary if the chronically infected are to ever be completely free of HIV infection. David Margolis, a leader in the field of cure research updates what is presently known as well as current research that may someday make eradication of HIV more easily achievable.
Hot on the heels of CROI 2014, this up-to-date review of HIV treatment and prevention strategies, antiretroviral initiation, options for treatment failure, and new agents in development, is not to be missed. Even if you attended this live meeting, we hope you will find this presentation by Trip Gulick helpful in your day-to-day decision-making.
In this program, Tae-Wook Chun reviews the mechanism by which HIV reservoirs persist in infected individuals on antiretroviral therapy and advances in HIV Cure research, followed by Mike Sneller who discusses a new therapeutic HIV vaccine trial, the THERAVAX Study, now enrolling HIV-infected individuals who were diagnosed and started on cART during the acute/early stage of HIV infection. If you have any patients that were diagnosed and initiated treatment during the acute/early stage of HIV disease, please view this program-- the NIAID/NIH needs your help to enroll this important trial.
Rarely, some individuals are able to control HIV without medication, while the overwhelming majority of people with HIV infection will progress to AIDS and death without lifelong antiretroviral therapy. But for this majority who are unlikely to control HIV spontaneously, is it possible to induce HIV control and prevent progression of disease without medication? The VISCONTI Study implies that this may be so. This important study in France has shown that very early diagnosis and initiation of combination antiretroviral therapy eventually led to virologic control after treatment interruption in a higher-than-expected proportion of study participants. Join us for Dr. Sáez-Cirión’s discussion of this important study and its contribution to research for a cure.
Antiretroviral therapy of HIV disease requires life-long adherence for optimal treatment outcomes and to prevent further transmission to uninfected partners. It is important for all prescribing clinicians to understand the principles of durable antiviral suppression, guidelines for initiating and changing antiretroviral regimens, and alternative strategies when these fail. Understanding the research behind alternative strategies is often necessary for long-term management of HIV-infection in the real world.
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.
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.
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."
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.
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.
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.
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.