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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The use of antiretroviral drugs to prevent HIV infection has created great hope worldwide, and pre-exposure prophylaxis, or PrEP, is an important addition to prevention efforts for seronegative patients with ongoing risk. It is important for all front-line providers to understand appropriate uses and limitations of PrEP, and to be aware of ongoing research. With her rich knowledge of antiretroviral pharmacokinetics in the anogenital tract, Angel Kashuba returns to PRN to discuss and compare data from clinical trials aimed at reducing the sexual transmission of HIV disease.
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Historical Clues, Physical Signs, Laboratory Diagnosis & Treatment of Oral, Anogenital & Systemic STDs
Knowing when and how to successfully diagnose, treat, and counsel patients with sexually transmitted diseases is a skill that benefits our patients, their sexual partners and the public health. Syphilis, gonorrhea, Chlamydia, LGV, herpes, HPV, and even acute HIV can present in myriad ways, and the more efficient we are at suspecting, diagnosing, and treating these diseases, the better we are at preventing further spread.
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HIV-1 coinfection and superinfection are not that uncommon, but few people talk about it, or the viral evolution that dual infections make possible. Davey Smith does talk about it, and if you have patients who think serosorting is safe, you will be better prepared to advise them about the risks and implications of HIV superinfection.
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HIV-1 dual infection, coinfection or superinfection, happens and that it may happen rather frequently. Dual infection has identifiable consequences affecting clinical care of patients who already have HIV and are at continued risk of superinfection. To make matters worse, recombination can occur when two distinct viral variants infect the same cell, adding to the genetic diversity of HIV worldwide, and further complicating the development of a preventive vaccine.
Non-occupational Post-exposure Prophylaxis and Antiretroviral Pharmacokinetics in the Male and Female Genital Tracts
For sexual transmission, prophylaxis with antiretrovirals before a potential exposure—pre-exposure prophylaxis (PrEP)—or after the exposure occurs (PEP) is controversial and often leaves clinicians unsure of how to provide the best care to their at-risk patients. In March of 2006, Michelle Roland, MD, and Angela Kashuba, PharmD, were invited to a PRN meeting to discuss this complex issue. Dr. Roland discussed the challenges and opportunities she has experienced in PEP research, particularly focusing on the broader context of nonpharmacologic interventions that prevent transmission, and the current state of PEP in the United States and internationally. Dr. Kashuba focused on work being done to determine which antiretrovirals are optimal for PrEP and PEP applications, and to provide a rational framework for further policy making.
Health officials, clinic directors, and individual clinicians have been involved in initiatives to make confidential HIV testing a routine part of medical care with the use of new diagnostic technologies, including rapid HIV assays. These assays have been developed to make point-of-care (POC) HIV testing feasible providing immediate results. “When it comes to these assays,” Dr. Kevin Armington said in his introductory remarks, “if people can get a negative or preliminary positive result in twenty minutes, that’s the test most people are going to want.”
Proven, existing interventions could prevent one-half to two-thirds of HIV infections in New York City. Further reductions in transmission are also feasible through expanded community-based prevention efforts, prevention counseling for individual patients, supporting patients to facilitate return to care, and improving availability of effective treatment. The DOHMH is aware that its expanded public health initiatives may provoke controversy.
New York City remains the epicenter of the HIV/AIDS epidemic in the United States. Though NYC is home to less than 3% of the U.S. population, it accounts for 17% of national AIDS deaths. “We have more cases than Los Angeles, San Francisco, Miami, and Washington, D.C., combined,” Dr. Thomas Frieden noted in his presentation to the Physicians’ Research Network. “Our case rate is 60 times the national target for 2010, four times the U.S. average, and higher than any other city in the U.S.” While current funding levels are insufficient in terms of keeping up with care and prevention needs, Dr. Frieden argues that many of the services and programs currently available in New York City can be made more efficient.
PEPFAR targets $9 billion in new funding over five years to ramp up prevention, treatment, and care services in 15 of the most affected countries of the world, devotes $5 billion over five years to ongoing bilateral programs in more than 100 countries, and increases the U.S. Government’s pledge to the Global Fund by $1 billion over five years. We also intend this program to be sustainable. The heart and soul of PEPFAR is to support national strategies, to build capacity for the future.
The risk of mother to child transmission (MTCT ) of HIV infection can be reduced to below 2% by employing interventions that include antiretroviral therapy given to HIV-infected women during pregnancy and labor, as well as to exposed infants during the first weeks of life; the avoidance of breastfeeding; and delivery by elective Caesarean section. With all of these approaches, there are numerous questions and considerations.
Where is no shortage of data suggesting that people with primary HIV infection (PHI) are, unknowingly, significant contributors to the spread of HIV. In turn, public health initiatives surrounding PHI—whether its aggressive testing and counseling of acutely infected individuals, stepped-up contact tracing efforts, or the use of HAART—need to be considered carefully in the larger context of HIV/AIDS prevention efforts
The HIV medical community received an official wakeup call on July 30, 1998, when Dr. Frederick M. Hecht —a frequent PRN lecturer—and his colleagues published the first documented case of high-level protease inhibitor resistance in a recently infected, treatment-naïve, HIV-positive individual. Since this initial report, a number of researchers with close ties to primary HIV infection cohorts have not only confirmed that transmission of drug-resistant HIV is possible, but that it is occurring in up to 20% of all new HIV infections identified in North America in recent years (Little, 2002).
Advancing HIV Prevention: New CDC Strategies for a Changing Epidemic A Report from the U.S. Centers for Disease Control
In several U.S. cities, recent outbreaks of primary and secondary syphilis among men who have sex with men (MSM) (CDC, 2002), along with increases in newly diagnosed HIV infections among MSM and heterosexuals, have created concern that HIV incidence might be increasing. In addition, declines in HIV morbidity and mortality during the late 1990s attributable to HAART appear to have ended.
On the last day of the 7th Conference on Retroviruses and Opportunistic Infections in San Francisco in February 2000, shockwaves reverberated through the Moscone Convention Center. No, it was not an earthquake attributed to the cantankerous San Andreas Fault but rather an earth-shattering case report stemming from a Canadian HIV clinic situated 2500 miles away (Angel, 2000). The case report, presented by Dr. Jonathan Angel and his colleagues from the University of Ottawa, involved an antiretroviral-naïve HIV-positive male (patient A) who experienced rapid disease progression and high levels of viral resistance to multiple drugs after engaging in unprotected sexual activity with another HIV-positive male harboring a drug-resistant, possibly more virulent strain of HIV (patient B). Dr. Angel concluded that "Patient A was very likely infected with a resistant strain of HIV by Patient B," and went on to say: "I think there's enough information here to raise awareness regarding HIV superinfection and to say that this should be a public health issue if we can prove it."
The basic premise of the immune system is simple: to coordinate the activities of various cell types in order to provide extended, if not lifelong, protection against disease-causing pathogens. Usually, this system works flawlessly, quashing infections before they can kill their host and sparking immunity to provide protection against future attacks. Sometimes, however, the system fails and infection prevails--and there is, perhaps, no greater example of this than HIV, a pathogen that almost always succeeds in circumventing and manipulating the body's immune defense to facilitate its own survival. Immunology is still a relatively young research field, and there is still much to learn about its function, particularly as it relates to specific pathogens. One of the least-understood members of the immune system family is the dendritic cell. Accounting for only about 1% of all immune system cells, dendritic cells are nevertheless vital to both the initiation and control of immune responses.
Ever since HIV was first discovered in 1985, the bulk of research conducted has focused primarily on the pathogenesis of this virus in peripheral blood mononuclear cells (PBMCs). However, the mucosal-associated lymphoid tissues (MALT) are the largest source of lymphocytes, macrophages, and dendritic cells in the body, rendering them among the most important--and least understood--repositories of HIV. The significance of mucosal surfaces in the pathogenesis of HIV cannot be overstated. Mucosal surfaces--including those in the alimentary tract--are an important route by which HIV may gain access to blood and lymphoid tissue during heterosexual, homosexual, and perinatal transmission. What's more, the mucosa may be involved in the initial selection of viruses that are transmitted to adults and infants and may be a site where virus replication persists and drug-resistant viruses evolve during HAART.
At the ground-breaking 1996 international conference on AIDS in Vancouver, Drs. Martin Markowitz and David Ho, leading researchers at the Aaron Diamond aids Research Center (ADARC), gave presentations charting the gradual depletion of HIV reservoirs in a small group of patients treated with antiretroviral regimens. Dr. Ho went on to suggest that it might be possible to completely eradicate HIV by initiating aggressive antiretroviral, focusing first on a unique population of patients: individuals in the acute stages of HIV infection. The public consideration of what would be, in essence, a cure was met with enormous enthusiasm—and occasional criticism— by the international media, HIV-treating physicians and, of course, people living with HIV.
The treatment of patients in the acute stage of HIV infection has long been a contentious subject. While some data seem to indicate that the initiation of HAART during PHI is associated with few or no long-term advantages—which appears to have been the experience of Dr. Martin Markowitz and his colleagues at the Aaron Diamond aids Research Center (see page 16)—other research teams have gained extremely encouraging results, most notably Dr. Eric Rosenberg and his colleagues with the Partners AIDS Research Center at Massachusetts General Hospital (MGH). Not only has this research at mgh helped to define the immunologic significance of PHI, it has also led to a greater appreciation of the immune-boosting potential of antiretroviral therapy.
Reams of epidemiological and biological data are now available to suggest that people in the primary stages of HIV are, unknowingly, significant contributors to the spread of HIV and, consequently, the proliferation of the aids epidemic. However, the precise extent to which individuals with phi play into this unfortunate scenario remains unclear. To help make sense of the data that have emerged thus far—and to comment on its relevancy within the realm of public health—Dr. Christopher Pilcher shared his ongoing experiences and thoughts with PRN.
Without a doubt, public health initiatives surrounding PHI—whether it’s aggressive testing and counseling of acutely infected individuals, stepped-up contact tracing efforts, or the use of HAART—need to be considered carefully in the larger context ofHIV/AIDS prevention efforts. Yet our understanding of the public health consequences of “unchecked” viremia and risky sexual behavior during phi is still in its infancy, and even less is known about the cost-effectiveness of intervention programs, particularly when pricey diagnostic tests and antiretroviral therapies are involved.
As discussed throughout this special edition of THE PRN NOTEBOOK, a number of experts suggest that phi is a unique window of opportunity with respect to treatment, since it may be the optimal time to initiate haart to alter the long-term course of HIV disease. On a public-health level, correct diagnosis and medical intervention during PHI—a period in which viral load is exceptionally high—may be useful in halting the unintentional spread of the virus when someone is hypothesized to be most infectious. But, to take advantage of either the possible therapeutic or public health opportunities during phi, clinicians face a daunting task right from the start: actually connecting with and correctly diagnosing individuals in the initial throes of acute infection. While it is true that a growing number of people are likely to seek care immediately after possible exposure, given that the stigma and general sense of pessimism surrounding HIV infection has lessened, the most likely scenario involves patients who appear in the clinic only after symptoms of phi have surfaced— not necessarily aware that they may be connected to acute retroviral syndrome.
Just as the breakthroughs in basic research continue to pave the way for pharmaceutical companies and technology firms to develop novel therapeutics and laboratory tests, the advances of clinical research should serve as a reminder to all clinicians that the management of hiv disease is a work in progress and that new approaches in the diagnosis and care of hivpositive people are always on the horizon. This is certainly the case with primary hiv infection (phi). Chalked up by many as a relatively inconsequential period in the overall natural history of hiv disease, phi has now come to be recognized by some as a veritable window of opportunity for individuals fortunate enough to be diagnosed during the earliest stage of their infection.
The clinical syndrome of primary HIV infection was recognized and documented in 1985, about two years after the initial identification of the causative agent of aids. By 1991 it was known that this symptomatic period is associated with an explosive replication of the virus, which is then partially controlled as the illness resolves spontaneously. Reports in 1993 further showed the population of HIV during this early period of infection to be quite homogeneous, in distinct contrast to the diverse quasispecies that are typically found in chronically infected persons. This observation suggested not only the presence of selective forces operating during HIV transmission, but also the greater likelihood of therapeutic success in treating early infection.
Most HIV patients are diagnosed after the acute stage—primary HIV infection (PHI)—has come and gone. While the individual benefit of initiating HAART during PHI is uncertain, Drs. Christopher Pilcher & Jim Koopman arguet that there may also be unique public health advantage from the rapid diagnosis and treatment of PHI. “HIV shedding in genital secretions during the initial stage of infection is a major concern,” Dr. Pilcher said during his opening remarks at a meeting of PRN in NYC. “If we can step in with counseling and contact tracing, along with antiretroviral therapy, we may be able to diminish HIV shedding and, most importantly, interrupt epidemic spread in sexual networks.”
What factors increase and decrease the risk of transmission of HIV in discordant heterosexual couples? This review of an important meeting of the Physicians' Research Network in NYC points out the roles that male circumcision, control of concomitant sexually transmissible diseases, and decreased HIV viral load may have on HIV transmission risk.
What are the initial signs and symptoms of new HIV infection, how can HIV be diagnosed in its earliest stage of infection, and how risky is oral sex for HIV transmission? These and related issues are reviewed in detail by Dr Frederick Hecht at a meeting of the Physicians’ Research Network in New York.