People with HIV are growing old—and society isn't ready for it

by Susan Gallagher, Duke University

Credit: iStock.

The good news is that people with HIV are living much longer than they used to; it's estimated that by 2020, 70 percent of people living with HIV in the United States will be age 50 and older, compared to 10 percent during the first 20 years of the epidemic. The bad news? With this longevity come challenges that our healthcare system isn't prepared to address.

15 jun 2019--"When I began my career as a nurse in the late 1980s, HIV was pretty much a death sentence," says Michael Relf, a professor of nursing and global health. "People living with HIV were told, 'We'll keep you as healthy as possible, but you need to get your affairs in order.'"

But when combination antiretroviral therapy (ART) was introduced in the mid-1990s, the outlook for these individuals went from bleak to bright. And over time, as ART has become increasingly effective with fewer harmful side effects, the odds of longer survival continue to improve, necessitating a new focus on healthy aging for people living with HIV.

In 2014, the Joint United Nations Programme on HIV/AIDS established "90-90-90," a treatment target to end the HIV epidemic: by 2020, 90 percent of people living with HIV will know their HIV status, 90 percent of people diagnosed with HIV will receive ART, and 90 percent of people receiving ART will have viral suppression. Some HIV researchers, clinicians, and persons living with HIV refer to healthy aging with HIV as "the fourth 90," signifying the importance of addressing the particular challenges this population faces.

Many people living with HIV have higher rates of risk factors for cancer and chronic illnesses, such as cardiovascular disease and diabetes, than the general population. These factors include smoking, alcohol and drug use and poor nutrition, as well as other factors related directly to the disease and its treatment.

"The sustained inflammation from HIV over time, even when viral loads are suppressed, creates pathways in the body that increase the risk for cardiovascular disease, and some of the earlier antiretrovirals profoundly increased the risk for lipid disorders, insulin resistance and endocrine disorders," says Relf, who studies HIV and aging.

HIV also heightens the body's susceptibility to poor bone health. Conditions such as avascular necrosis—the death of bone tissue due to interruption of the blood supply—disproportionately affect people living with HIV and can lead to the need for a hip replacement.

And people living with HIV are prone to cognitive and neurological problems such as earlier onset of dementia. One study found that the epigenetic age of the brain of a person with HIV was more than seven years older than those who don't have HIV.

But the HIV-related challenges of aging extend beyond physical health. Loneliness, isolation, intersectional stigma and depressive symptoms are common among older adults living with HIV and can negatively impact their ability to access the health and social services they need. "Many people aging with HIV have been socially isolated from their families and communities," says Relf, who also studies HIV-related stigma. "Many older gay men, for example, lost a significant portion of their social network when their friends and partners died in the early days of the HIV epidemic."

In fact, insights Relf gleaned through his research on HIV stigma are what prompted him to delve deeper into HIV and aging. When he and his collaborators were studying internalized stigma among women in the southeastern United States, many of the participants reported experiencing different types and sources of stigma as they age. For example, one woman reported tearfully that her son—who had learned of her HIV status as a child and had been supportive of her throughout his childhood—doesn't allow her to use his dinner plates or go to the bathroom at his house out of fear that his children might contract HIV.

Unfortunately, Relf says, health systems in the U.S. and across the world aren't ready for the aging population in general, let alone older adults with these unique needs. He's among the proponents of a holistic approach to helping people living with HIV age successfully. Relf recently co-authored an update to a model that considers the interplay of biological, cognitive, mental and social factors in the aging process for people living with HIV. The model promotes a lifespan perspective that takes into account historical behaviors and lifestyle factors that affect one's aging process and quality of life as they get older. It also suggests that healthcare practitioners should screen patients with HIV for geriatric problems such as functional impairment and frailty at an earlier age because many of these symptoms occur prematurely in this population.

Relf also thinks healthcare professionals need to develop cross-disciplinary expertise. "HIV specialists need to be able to take care of the geriatric issues, gerontologists should be able to tackle HIV issues and primary care providers should be able to do both," he says. "In most places, we're not quite there yet."

Nurses, Relf says, are poised to play an important role in improving care for older adults with HIV—particularly in rural areas, where they're often the sole healthcare providers. "Because nurses who live and work in a community understand the community's norms, culture and values, they're well-positioned to help design and tailor effective prevention initiatives, testing and counseling programs, and treatment efforts," he says. "But often, they're functioning outside their skill set out of necessity, especially in the global setting."

Relf is working on changing that. As a member of an expert advisory panel of the Association of Nurses in AIDS Care, he's helping to create a series of professional development modules for nurses and nurse practitioners on issues associated with aging among people with HIV. The project is one of several funded by Gilead Sciences, Inc., a leading manufacturer of ART, to support innovative approaches to preparing healthcare and other systems to better serve older adults with HIV.

This "graying of the HIV epidemic" also calls for more sweeping changes in healthcare. In an editorial for a special issue of the Journal of the Association of Nurses in AIDS Care, Relf and his co-editors write, "individual-level interventions and redesigns of health care systems will be needed to meet the unique prevention, care, and treatment needs of older persons at risk of, living with, and/or affected by HIV."

In June 2021, the world will commemorate 40 years of the epidemic, and while significant challenges persist, Relf is hopeful. "Although there is still not a cure, it's tremendous progress that we're now focusing on the 'fourth 90' to help individuals living with HIV age successfully," he says.

More information: David E. Vance et al. Revisiting Successful Aging With HIV Through a Revised Biopsychosocial Model, Journal of the Association of Nurses in AIDS Care (2019). DOI: 10.1097/JNC.0000000000000029

Provided by Duke University 

First diagnosed case of Alzheimer's disease in HIV-positive individual reported

R. Scott Turner, M.D., Ph.D., Director, Georgetown Memory Disorders Program. Credit: Georgetown University

Georgetown University researchers are reporting the first case of Alzheimer's disease diagnosed in an HIV-positive individual. The finding in a 71-year-old man triggers a realization about HIV survivors now reaching the age when Alzheimer's risk begins to escalate.

17 april 2016--Published online in the open access journal Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, neurologist R. Scott Turner, MD, PhD, diagnosed the patient after a PET scan showed deposition of amyloid in the brain. Until this point, Turner says, clinicians thought that individuals with HIV may not develop AD because HIV-related inflammation in the brain may prevent amyloid clumps from forming.
"This patient may be a sentinel case that disputes what we thought we knew about dementia in HIV-positive individuals," says Turner, who leads the Memory Disorders Program at Georgetown University Medical Center.
In addition, Turner says the finding suggests that some older HIV-positive patients with dementia may be misdiagnosed with HIV-associated neurocognitive disorders (HAND) when they may be developing AD. It also may be possible that some patients experience HAND and AD—a new type of mixed dementia, Turner says. "Chronic HIV infection and amyloid deposition with aging may represent a "double-hit" to the brain that results in progressive dementia."
"While it may be challenging to diagnose the cause of dementia in an HIV-positive patient, the diagnosis matters because HAND and AD are treated differently," he says. "For Alzheimer's disease, we now have four FDA-approved drugs and more effective treatments are on the way. For HAND, we prescribe anti-retroviral drugs that have a better chance of penetrating the brain. So getting a correct diagnosis is important, and a critical first step in advancing the field."
HAND will develop in 30-50 percent of individuals with long-term HIV infections. But HAND symptoms are identical to those with AD, Turner says. He adds, "The medical community assumes that dementia with HIV is caused by HAND. Physicians haven't considered Alzheimer's, so it's possible that a number of older HIV-positive individuals may be misdiagnosed."
Published studies to date point to only five individuals with HAND who have undergone amyloid PET imaging, and all were negative; however, the oldest of these patients was 67, Turner says.
Diagnosis of dementia in older HIV-infected individuals is on the rise. HIV-infected adults over 55 comprise the fastest growing age group in the HIV-positive population.
According to the most recent CDC HIV Surveillance Report with data through 2013, 53,000 people in the U.S. living with HIV are 65 and older, the age when Alzheimer's disease risk begins to escalate. That number is expected to double in less than 10 years and doesn't include those who have not been diagnosed. Worldwide, more than 37 million people are living with HIV.
"This case report reveals important new insights into the specific issue of HIV-related neurological impairment," says Jeffrey Crowley, MPH, program director of the National HIV/AIDS Initiative at the O'Neill Institute for National and Global Health Law at Georgetown Law. Crowley is former director of the White House Office of National AIDS Policy and senior advisor on disability policy. "This finding must lead to additional population-based studies, as well as timely clinical and programmatic interventions to better support individuals with HIV who are facing neurological decline."


Provided by Georgetown University Medical Center

More Older Americans Living With HIV

01 nov 2010-- Better treatments are extending the lives of people with HIV, but aging with the AIDS-causing virus takes a toll that will challenge the health care system, a new report says.

A survey of about 1,000 HIV-positive men and women ages 50 and older living in New York City found more than half had symptoms of depression, a much higher rate than others their age without HIV.

And 91 percent also had other chronic medical conditions, such as arthritis (31 percent), hepatitis (31 percent), neuropathy (30 percent) and high blood pressure (27 percent). About 77 percent had two or more other conditions. About half had progressed to AIDS before they got the HIV diagnosis, the report found.

"The good news is antiretroviral therapies are working and people are living. If all goes well, they will have life expectancies similar to those without HIV," said Daniel Tietz, executive director of the AIDS Community Research Initiative of America.

"But a 55-year-old with HIV tends to look like a 70-year-old without HIV in terms of the other conditions they need treatment for," he said Wednesday at a meeting of the Office of National AIDS Policy at the White House in Washington, D.C.

The research included interviews with 640 men, 264 women and 10 transgender people. Dozens of experts on HIV and aging attended the meeting, which was intended to identify the needs of older adults with HIV and to explore ways to improve services to them.

Currently, about 27 percent of those with HIV are over 50. By 2015, more than half will be, said the report.

Because of their special needs, this poses challenges for public health systems and organizations that serve seniors and people with HIV, Tietz said.

HIV can be isolating, Tietz said. Seventy percent of older Americans with HIV live alone, more than twice the rate of others their age, while about 15 percent live with a partner, according to the report.

The survey found that loneliness was higher among HIV-positive adults than for other older Americans. One reason is that many men and women conceal the condition from friends and family for fear of stigma or rejection, both real and imagined, Tietz said.

Lack of social and family support increases the likelihood of needing costly health care, such as home health aides and nursing homes as they get older, Tietz said.

Dr. Amy Justice, an HIV researcher who also attended the meeting, spoke of the need for health care professionals to learn about specific issues facing HIV-positive seniors.

HIV organizations tend to gear messages toward younger people, and senior services organizations often don't know much about the needs of HIV-positive seniors, said Justice, principal investigator of the Veterans Aging Cohort Study. This ongoing study involves some 40,000 veterans with HIV and 80,000 without HIV from 10 Veterans Affairs medical centers nationwide.

"There are a lot of people with HIV who are 60 or 65 and even 80 or 85," Justice said. "Those individuals feel older than their stated age and may have some of the same problems people 10 or 15 years older would normally experience."

Many older Americans with HIV are still sexually active and should be encouraged to practice safe sex, Justice said. While 57 percent of older Americans with HIV said they disclosed their HIV status to sexual partners, about 16 percent didn't, the report found.

About half the survey participants were black, one-third were Hispanic and 14 percent were white. About 67 percent considered themselves heterosexual, 24 percent were gay and 9 percent bisexual.

Why people with HIV are more likely to have other chronic diseases is still unclear, Tietz said. The cause could be the HIV itself or long-term side effects from taking multiple medications, he said. Early HIV drugs were especially toxic, he added.

Premature Aging of the Brain Seen in HIV Patients

02 feb 2010-- Premature aging is striking the brains of people infected with the virus that causes AIDS, new research suggests.

It's not clear if the virus or the drugs that treat it -- or both -- are contributing to the aging. But one thing is clear: The blood flow in HIV patients is about the same as in those of uninfected people who are 15 to 20 years older.

"The graying of the AIDS patient community makes this infection's effects on the brain a significant source of concern," study author Dr. Beau Ances, an assistant professor of neurology at Washington University in St. Louis, said in a university news release.

"Patients are surviving into their senior years, and a number of them are coming forward to express concerns about problems they're having with memory and other cognitive functions," Ances said.

An estimated 14 percent to 18 percent of all AIDS patients in the United States are more than 50 years old, and older people face one of the highest rates of new infections. By 2015, people over the age of 50 may account for more than half of all AIDS patients.

In the study, researchers used MRI scans to study the blood flow in the brains of 26 HIV-infected people and 25 other people who weren't infected. The average age and education level of the participants were similar.

The researchers found reduced blood flow in the brains of younger HIV-infected patients who were infected recently, not just the older ones.

The study was released online in advance of publication in the Feb. 1 print issue of the Journal of Infectious Diseases.

Radioimmunotherapy: Promising treatment for HIV infection and viral cancers

Novel therapy presented in featured lecture at AAAS Annual Meeting

BRONX, NY, 16 feb 2009— Scientists at Albert Einstein College of Medicine of Yeshiva University have piggybacked antibodies onto radioactive payloads to deliver doses of radiation that selectively target and destroy microbial and HIV-infected cells. The experimental treatment — called radioimmunotherapy, or RIT — holds promise for treating various infectious diseases, including HIV and cancers caused by viruses. The research was presented today at the annual meeting of the American Association for the Advancement of Science (AAAS), the world's largest general scientific society and the publishers of the journal Science.

The talk, part of the AAAS Topical Lecture Series, was delivered by Ekaterina Dadachova, Ph.D., a leading RIT researcher at Einstein. Dr. Dadachova is the Olnick Faculty Scholar in Cancer Research, as well as an associate professor of nuclear medicine and of microbiology & immunology at the College of Medicine.

RIT, which is currently used in cancer treatment, capitalizes on the fact that each type of antibody is programmed to seek out just one type of antigen in the body. Thus, by attaching radioactive material to a particular antibody, radiation can be targeted at specific cells that express the corresponding antigen, minimizing collateral damage to other tissues. This level of specificity is not possible with existing forms of radiation therapy.

RIT was originally developed as a therapy for cancer treatment and has been the most successful so far in treatment of non-Hodgkin lymphoma, a cancer that originates in cells of the immune system. Over the last few years, in collaboration with Dr. Arturo Casadevall, Chair and Forchheimer Professor of Microbiology & Immunology at Einstein, Dr. Dadachova has adapted the technique for fighting fungal, bacterial, and viral infections. Drs. Dadachova and Casadevall performed these studies in conjunction with scientists at Einstein and NYU, and at the European Commission Joint Research Centre; the latter of which supplied some of the important radionuclides for arming the antibodies.

Since viruses are quite different from cancer cells, devising radioimmunotherapy for HIV posed significant challenges. Viruses are tiny bits of DNA or RNA wrapped in a thin protein coat. Simple, tough, and resilient, viruses easily shrug off radiation directed at them and can readily repair any damage that might occur. Complicating matters, HIV can hide in immune cells keeping the virus beyond the reach of antibodies.

"Our approach is not to target the virus particles themselves, but rather lymphocytes that harbor the virus," says Dr. Dadachova. "Fortunately, lymphocytes are among the most radiosensitive cells in the body."

The RIT devised by Einstein researchers consists of an antibody for glycoprotein 41 (gp41) and a radioactive isotope called Bismuth-213, bound together with a special molecule known as a ligand. The gp41 antibody was selected because its corresponding gp41 antigen is reliably expressed on the surface of cells infected with HIV. In addition, unlike other HIV-related glycoproteins, gp41 antigen usually is not shed into the bloodstream, which would lead many of radioactive-labeled antibodies to miss their target. Bismuth-213 was chosen because of several characteristics, including a half-life, or decay rate, of 46 minutes. Such a short half-life rate allows just enough time for the treatment to be administered and for the radioactive antibodies to do their job. After four hours, Bismuth-213 radioactivity falls to negligible levels.

Drs. Dadachova and Casadevall and their colleagues have demonstrated that the treatment can effectively eliminate HIV-infected human cells in both laboratory and animal studies, the latter involving two different models of mice with HIV. The team is now conducting pre-clinical testing of the therapy's efficacy and safety in preparation for a Phase I clinical trial in HIV-infected patients.

RIT also has potential as a therapy for cancers that are preceded by viral infections, such as cervical cancer (certain forms of which are associated with human papilloma virus) and hepatocellular carcinoma (associated with hepatitis B virus). Such cancers account for almost a quarter of all cancers. "Many virus-associated cancer cells continue to express viral antigens," Dr. Dadachova explains. "As these antigens are not found anywhere else in the body, RIT of viral cancers promises exquisite specificity of treatment and very low toxicity to the patient."

HIV tests not yet as routine as cholesterol checks

By LAURAN NEERGAARD
WASHINGTON, 22 nov 2008 – Two years after the government urged making HIV tests as common as cholesterol checks, there are small gains but still one in five people infected with the AIDS virus doesn't know it, scientists said Thursday.

Eleven states that once required special consent for HIV testing have changed their laws, a key step to making an HIV test part of the standard battery that patients expect.

But HIV specialists meeting Thursday said other barriers include physician confusion about the ease of today's rapid tests, which can cost as little as $15 — although many patients seem to accept them.

No more than 100 of the nation's 5,000 emergency rooms routinely test for HIV in patients who aren't critically ill, said Dr. John Bartlett of Johns Hopkins University, who co-chaired the Forum for Collaborative HIV Research meeting. Yet because so many HIV patients are poor or uninsured, ERs are the health-care setting most likely to find them.

And while every pregnant woman is supposed to be tested so steps can be taken to protect her unborn baby, about 40 percent aren't, he added.

"Those are what we call missed opportunities," Bartlett said. Today, the test is "much better, it's much easier, it's much cheaper. The treatment is really great now."

Just over 1.1 million Americans are estimated to have HIV and 232,000 don't know it, according to the Centers for Disease Control and Prevention.

The CDC for years recommended routine testing mainly for people at high-risk, such as intravenous drug users. Then, finally, came drugs potent enough to keep HIV patients healthy for years, postponing the slide into full-blown AIDS. Yet nearly half of new infections still were being discovered too late for patients to benefit. Not to mention that people who don't know they're infected unwittingly spread the virus.

So in September 2006, the CDC recommended routine testing for everyone ages 13 to 64, whether they think they're at risk for HIV or not.

There is no nationwide data yet on the new guidelines' impact, CDC's Dr. Bernard Branson told The Associated Press.

But Branson listed encouraging signs:

_New York City's Health and Hospitals Corporation, the nation's largest municipal health system, has nearly tripled HIV testing — and late diagnoses dropped by about a third.

_New York's state Medicaid program has increased testing by 30 percent.

_Early results from a federal survey suggest 2.4 million more people in 2007 said they had ever been tested for HIV than said so in 2006.

_President George W. Bush in October signed a law allowing Veterans Administration clinics to ease testing requirements.

"I don't think anyone at CDC anticipated that we would test the whole country in a single year," Branson said.

But in pilot projects around the country, "people are taking the recommendations to heart and implementing them as much as was feasible for them," he added. Moreover, "we find people are very receptive to being tested, and there was concern about that before."

Indeed, studies presented Thursday suggest more than 80 percent of emergency-room patients were amenable to an HIV test while most ER workers opposed testing them. Why? Presumably because ERs are so busy and there's confusion about how much HIV counseling is needed.

But Bartlett demonstrated how to quickly give people a chance to either opt out or request counseling: "Mr. Jones, you're going to have a cholesterol test, a blood count, and an HIV test — and by the way we do the HIV test on everybody because that's what the CDC has recommended. Is there any part of this that you want more information about or you don't want to have?"

___

On the Net:

State HIV testing laws: http://www.nccc.ucsf.edu/StateLaws/Index.html

Nobel Prize Eludes American in Long-Running HIV Dispute

12 oct 2008--This year's Nobel Prize awards discoveries of two viruses causing severe human diseases.
Harald zur Hausen went against current dogma and postulated that oncogenic human papilloma virus (HPV) caused cervical cancer, the second most common cancer among women. He realized that HPV-DNA could exist in a non-productive state in the tumours, and should be detectable by specific searches for viral DNA. He found HPV to be a heterogeneous family of viruses. Only some HPV types cause cancer. His discovery has led to characterization of the natural history of HPV infection, an understanding of mechanisms of HPV-induced carcinogenesis and the development of prophylactic vaccines against HPV acquisition.
Françoise Barré-Sinoussi and Luc Montagnier discovered human immunodeficiency virus (HIV). Virus production was identified in lymphocytes from patients with enlarged lymph nodes in early stages of acquired immunodeficiency, and in blood from patients with late stage disease. They characterized this retrovirus as the first known human lentivirus based on its morphological, biochemical and immunological properties. HIV impaired the immune system because of massive virus replication and cell damage to lymphocytes. The discovery was one prerequisite for the current understanding of the biology of the disease and its antiretroviral treatment.
Discovery of human papilloma virus causing cervical cancer
Against the prevailing view during the 1970s, Harald zur Hausen postulated a role for human papilloma virus (HPV) in cervical cancer. He assumed that the tumour cells, if they contained an oncogenic virus, should harbour viral DNA integrated into their genomes. The HPV genes promoting cell proliferation should therefore be detectable by specifically searching tumour cells for such viral DNA. Harald zur Hausen pursued this idea for over 10 years by searching for different HPV types, a search made difficult by the fact that only parts of the viral DNA were integrated into the host genome. He found novel HPV-DNA in cervix cancer biopsies, and thus discovered the new, tumourigenic HPV16 type in 1983. In 1984, he cloned HPV16 and 18 from patients with cervical cancer. The HPV types 16 and 18 were consistently found in about 70% of cervical cancer biopsies throughout the world.
Importance of the HPV discovery
The global public health burden attributable to human papilloma viruses is considerable. More than 5% of all cancers worldwide are caused by persistent infection with this virus. Infection by the human papilloma virus is the most common sexually transmitted agent, afflicting 50-80% of the population. Of the more than 100 HPV types known, about 40 infect the genital tract, and 15 of these put women at high risk for cervical cancer. In addition, HPV is found in some vulval, penile, oral and other cancers. Human papilloma virus can be detected in 99.7% of women with histologically confirmed cervical cancer, affecting some 500,000 women per year.
Harald zur Hausen demonstrated novel properties of HPV that have led to an understanding of mechanisms for papilloma virus-induced carcinogenesis and the predisposing factors for viral persistence and cellular transformation. He made HPV16 and 18 available to the scientific community. Vaccines were ultimately developed that provide ≥95 % protection from infection by the high risk HPV16 and 18 types. The vaccines may also reduce the need for surgery and the global burden of cervical cancer.
Discovery of HIV
Following medical reports of a novel immunodeficiency syndrome in 1981, the search for a causative agent was on. Françoise Barré-Sinoussi and Luc Montagnier isolated and cultured lymph node cells from patients that had swollen lymph nodes characteristic of the early stage of acquired immune deficiency. They detected activity of the retroviral enzyme reverse transcriptase, a direct sign of retrovirus replication. They also found retroviral particles budding from the infected cells. Isolated virus infected and killed lymphocytes from both diseased and healthy donors, and reacted with antibodies from infected patients. In contrast to previously characterized human oncogenic retroviruses, the novel retrovirus they had discovered, now known as human immunodeficiency virus (HIV), did not induce uncontrolled cell growth. Instead, the virus required cell activation for replication and mediated cell fusion of T lymphocytes. This partly explained how HIV impairs the immune system since the T cells are essential for immune defence. By 1984, Barré-Sinoussi and Montagnier had obtained several isolates of the novel human retrovirus, which they identified as a lentivirus, from sexually infected individuals, haemophiliacs, mother to infant transmissions and transfused patients. The significance of their achievements should be viewed in the context of a global ubiquitous epidemic affecting close to 1% of the population.
Importance of the HIV discovery
Soon after the discovery of the virus, several groups contributed to the definitive demonstration of HIV as the cause of acquired human immunodeficiency syndrome (AIDS). Barré-Sinoussi and Montagnier's discovery made rapid cloning of the HIV-1 genome possible. This has allowed identification of important details in its replication cycle and how the virus interacts with its host. Furthermore, it led to development of methods to diagnose infected patients and to screen blood products, which has limited the spread of the pandemic. The unprecedented development of several classes of new antiviral drugs is also a result of knowledge of the details of the viral replication cycle. The combination of prevention and treatment has substantially decreased spread of the disease and dramatically increased life expectancy among treated patients. The cloning of HIV enabled studies of its origin and evolution. The virus was probably passed to humans from chimpanzees in West Africa early in the 20th century, but it is still unclear why the epidemic spread so dramatically from 1970 and onwards.
Identification of virus−host interactions has provided information on how HIV evades the host’s immune system by impairing lymphocyte function, by constantly changing and by hiding its genome in the host lymphocyte DNA, making its eradication in the infected host difficult even after long-term antiviral treatment. Extensive knowledge about these unique viral host interactions has, however, generated results that can provide ideas for future vaccine development as well as for therapeutic approaches targeting viral latency.
HIV has generated a novel pandemic. Never before has science and medicine been so quick to discover, identify the origin and provide treatment for a new disease entity. Successful anti-retroviral therapy results in life expectancies for persons with HIV infection now reaching levels similar to those of uninfected people.

Harald zur Hausen, born 1936 in Germany, German citizen, MD at University of Düsseldorf, Germany. Professor emeritus and former Chairman and Scientific Director, German Cancer Research Centre, Heidelberg, Germany.
Françoise Barré-Sinoussi, born 1947 in France, French citizen, PhD in virology, Institut Pasteur, Garches, France. Professor and Director, Regulation of Retroviral Infections Unit, Virology Department, Institut Pasteur, Paris, France.
Luc Montagnier, born 1932 in France, French citizen, PhD in virology, University of Paris, Paris, France. Professor emeritus and Director, World Foundation for AIDS Research and Prevention, Paris, France.

How STDs increase the risk of becoming infected with HIV

06 sept 2008--Individuals who have a sexually transmitted disease (e.g., genital herpes, gonorrhea, syphilis, and chlamydia) and women with yeast and bacterial vaginal infections have an increased risk of becoming infected with HIV if exposed to the virus through sexual contact. Although several explanations have been proposed, exactly how and why STDs have this effect has not been clear. Now, Teunis B.H. Geijtenbeek and colleagues, at VU University Medical Center, The Netherlands, have described a way in which STDs can increase acquisition of HIV-1 infection in an ex vivo human skin explant model that they hope might be amenable to therapeutic modulation to prevent HIV transmission.
In the ex vivo human skin explant model, although immature immune cells known as Langerhans cells (LCs) captured HIV, they did not efficiently transmit the virus to T cells, something that is essential for the initiation of full disease. By contrast, efficient virus transmission was observed if LCs were activated by inflammatory stimuli. As the infectious agents that cause the STDs thrush and gonorrhea triggered the same inflammatory stimuli in vaginal and skin explants, the authors suggest that in the presence of an STD-causing infectious agent, LCs might become activated, thereby increasing an individual's risk of becoming infected with HIV. Further, these data suggest that antiinflammatory therapies might provide a way to prevent HIV transmission.
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TITLE: TNF-alpha and TLR agonists increase susceptibility to HIV-1 transmission by human Langerhans cells ex vivo
AUTHOR CONTACT: Teunis B.H. Geijtenbeek VU University Medical Center, Amsterdam, The Netherlands. Phone: (31) 20-4448080; Fax: (31) 20-4448081; E-mail: T.Geijtenbeek@vumc.nl.

IAC: Raltegravir (Isentress) Matches Standard Initial Care at 96 Weeks

By Michael Smith
MEXICO CITY, 07 aug 2008-- In patients starting HIV therapy, the integrase inhibitor raltegravir (Isentress) had a long-lasting benefit and was well tolerated, a researcher said here. After 96 weeks of treatment, raltegravir had a virological effect that was almost identical to standard therapy with efavirenz (Sustiva), according to Marty Markowitz, M.D., of the Aaron Diamond AIDS Research Center in New York city. The findings extend earlier results from the industry-sponsored phase II randomized trial, Dr. Markowitz told an oral abstract session at the
The drug was approved last year for use in patients whose HIV is resistant to drug therapy and the earlier results from this trial suggested it was of equal benefit in treatment-naive patients.
But clinicians have been watching for the 96-week results to satisfy themselves that the effect is both durable and does not come with any unexpected side effects, said Cal Cohen, M.D., research director of the Boston-based treatment and research group CRI of New England.
"It was good news -- we didn't see a problem" on either front, said Dr. Cohen, who was not part of the study.
The drug is now widely used in treatment-experienced patients, he said, and to some extent in those beginning therapy who can't tolerate efavirenz.
"This will, to some extent, justify that," he said.
The study enrolled 198 treatment-naive patients and randomized them in a blinded fashion to one of four doses of raltegravir -- 100, 200, 400, and 600 milligrams twice a day -- or to 600 milligrams a day of efavirenz.
At week 48, the raltegravir patients were all put on 400 milligrams twice daily.
Dr. Markowitz said that at week 96, 83% of the 160 patients in the raltegravir group had a viral load of fewer than 50 copies of HIV RNA per milliliter of blood.
In the 38 efavirenz patients, the rate was 84%, he said.
The rates were also similar when the researchers considered a higher viral cut-off of 400 copies, he said.
Only two patients relapsed from week 48 through week 96, Dr. Markowitz said, one each in the raltegravir and efavirenz groups.
Interestingly, the patient who relapsed in the raltegravir arm appeared to do so without developing any resistance mutations. "He had wild-type virus on genotyping," Dr. Markowitz said.
On the other hand, the efavirenz patient who relapsed had developed well-known mutations that lead to drug resistance, he said.
Overall, he said, adverse events were generally similar between the two medications, but drug-related adverse events (mainly neuropsychiatric issues) were higher in the efavirenz arm, where 74% of patients reported them, compared with 50% for raltegravir.
There were three malignancies in the raltegravir arm, compared with one among efavirenz patients, but the difference was not significant.
Raltegravir had a generally neutral effect on lipids, he said.
The study was sponsored by Merck & Co. Dr. Markowitz made no disclosures.
Primary source: International AIDS ConferenceSource reference:Markowitz M, et al "Sustained antiretroviral efficacy of raltegravir as part of combination ART in treatment-naive HIV-1 infected patients: 96-week data" IAC 2008; Abstract TUAB0102.

Anti-HIV therapy boosts life expectancy more than 13 years
Improvements due to modern antiretroviral cocktails

BIRMINGHAM, Ala., 26 july 2008 – The life expectancy for patients with human immunodeficiency virus (HIV) has increased by more than 13 years since the late 1990s thanks to advancements in antiretroviral therapy, according to researchers at the University of Alabama at Birmingham (UAB) and Simon Fraser University in Vancouver, British Columbia.
Improved survival has led to a nearly 40 percent drop in AIDS deaths among 43,355 HIV-positive study participants in Europe and North America, bolstering the call for improved anti-HIV efforts worldwide, the study authors said.
The study is published in the British medical journal The Lancet. It was compiled by The Antiretroviral Therapy Cohort Collaboration, which includes UAB, Simon Fraser University and more than a dozen other research sites around the world.
The authors looked at changes in life expectancy and mortality among the 43,355 HIV patients taking a cocktail of drugs called combination antiretroviral therapy (cART). Data was compiled from a total of 14 studies in Europe and North America.
"Since their introduction in 1996 cART regimens have become more effective, better tolerated and easier to follow," said Michael Mugavero, M.D., an assistant professor in UAB's Division of Infectious Diseases and a co-author on the study.
"We are now seeing the benefits of years of research, hard work and efforts to make these medications widely available. This has led to dramatic improvements in life expectancy, but patients who start cART with more advanced HIV infection do not have the same level of benefit," Mugavero said.
The new Lancet study found cART yielded a 13.8-year life-expectancy increase – from 36.1 years in study participants who began therapy during the 1996-1999 period, to 49.9 years in participants who began therapy during the 2003-2005 period.
Despite the good results, the study found life expectancy for HIV patients is far lower on average than the general population, which includes all those with other chronic illnesses. For example, an HIV-positive patient starting cART at age 20 will live to 63, about 20 years shorter than the average life span of non-infected adults.
With nearly half of all patients diagnosed with advanced HIV infection, the life expectancy benefits of cART are not fully realized, said Mugavero and lead study author Robert Hogg, Ph.D., of Simon Fraser University. Improved AIDS testing and increased access to care is needed.

HIV Life Expectancy Approaching Normal

By Michael Smith
NEW YORK, 28 june 2008-- In the early days of the HIV pandemic, patients could expect only a few years between diagnosis and a final fatal AIDS-associated illness. Now, people with HIV in the developed world are living long enough that other causes of death -- such as cardiovascular disease -- are starting to assume an ever-greater importance.Indeed, some physicians counsel new patients that they can expect an essentially normal lifespan -- as long as they keep taking their HIV medication and don't drop dead of something else.
At the 2006 World AIDS Conference in Toronto, for instance, Stefano Vella, M.D., a former president of the International AIDS Society, told reporters: "Today, I can tell my patients with HIV that they can have a normal life expectancy."
The most recent analyses show that Dr. Vella is wrong -- but not by much.
A computer simulation, using data from U.S. sources, calculated the median lifespan of an adult entering HIV care to be 24.2 years, according to Bruce Schackman, Ph.D., of Weill Medical College of Cornell University, and colleagues. The study appeared in Medical Care in November 2006.
In the study, the median age for entering care was 39, which yields a potential lifespan of 63 years, Dr. Schackman said. On the other hand, a 39-year-old without HIV can probably expect to live well into his or her 70s, he said.
In fact, according to the CDC's national Vital Statistics Report, issued June 11, a 40-year-old American can expect to live another 40.2 years.
"There's still a gap," Dr. Schackman said, but it's a far cry from 1993, when one study estimated a lifespan of just 6.4 years for an HIV patient entering care with a CD4 T cell count of about 500 cells per microliter of plasma.
The major difference is highly active antiretroviral therapy (HAART). Its use began in 1996 and it caused an immediate and precipitous decline in HIV/AIDS mortality, Dr. Schackman said.
But even compared with the first years of HAART, that 24.2 years is a huge jump: a 1997 analysis suggested that the early HAART regimens would add only four years of life expectancy.
By 2006, however, the number of drugs available had expanded and their ease of use -- often a barrier -- had increased, to the point where some patients are able to suppress HIV replication with just one pill a day.
Indeed, Dr. Schackman said, the available drugs and drug regimens "have only gotten better since then."
In an analysis that took a different tack, researchers in British Columbia looked at the life expectancy of a 20-year-old starting HAART in one of three periods -- 1996 through 1999, 2000 through 2002, and from 2003 through 2005.
Rather than using a simulated cohort, as Dr. Schackman and colleagues did, Robert Hogg, M.D., of the University of British Columbia and colleagues looked at more than 26,000 people who started HAART in those periods.
As might be expected, they found that the years of life available to their standardized 20-year-old increased over time -- from 24.3 years in the earliest period to 27.1 in 2000-2002 and 33.2 in 2003-2005.
Living to your early 50s is a far cry from a normal life span, but it is a far cry from not making it out of your 20s.
Dr. Hogg and colleagues reported their findings at the 2007 Conference in Retroviruses and Opportunistic Infections, held a few months after Dr. Schackman and colleagues published their analysis.
Although the exact figures aren't identical to those of Dr. Schackman -- and the starting point of care is different -- they're in the same ballpark.
But even the 24 years suggested by the computer simulation is probably an underestimate, if you consider only medication issues, Dr. Schackman said.
"We were being overly conservative by not considering the fact that innovation will continue in the future," he said. "We could only focus on the technology that existed in 2006, but 24 years from now, there will probably be many new ideas."
In another analysis by Dr. Schackman and colleagues, antiretroviral medications accounted for 70% of the lifetime costs of HIV medical care.
On the other hand, Dr. Schackman said, the researchers also did not consider some of the implications of a long life with HIV -- such as the increased risk of cardiovascular disease.
Indeed attendees at the 2006 AIDS meeting were told that 9% of HIV patients now die from heart disease, 15% from liver disease, and 8% from cancer.
The interaction between HIV, the medications, and the human body is still not well understood and it will require years of study on large numbers of patients to work out the details, Dr. Schackman said.
"There may be things about HIV disease itself that affect the risk of other chronic diseases," he said, and what those are will only emerge with time.
Luckily, for people with HIV who have access to HAART, time is what they have.
The study was supported by the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, and the Agency for Healthcare Research and Quality. Dr. Schackman did not report any conflicts.
Primary source: Medical CareSource reference:Schackman BR, et al "The lifetime cost of current human immunodeficiency virus care in the United States" Med Care 2006; 44: 990-997. Additional source: CROI 2007Source reference: Hogg R, at al "Life expectancy of persons at the time of initiating cART in high-income countries" 14th Conference on Retroviruses and Opportunistic Infections 2007; Abstract 972.

Study: Treating herpes doesn't prevent HIV

By MARIA CHENG
21 june 2008--Doctors have long suspected that people with herpes are more likely to catch HIV. So they thought that by treating herpes, they could also cut a person's HIV risk. But a new study that tested this strategy found the assumption may have been wrong.
"It's a significant, disappointing finding," Francis Ndowa, coordinator of the sexually transmitted infections control team at the World Health Organization, said in an interview.
Ndowa was not connected to the research, published Friday in the medical journal The Lancet.
The finding may spark a rethinking of HIV prevention strategies in Africa, where controlling sexually transmitted diseases such as herpes is usually part of general AIDS prevention plans.
Researchers tracked more than 3,000 men and women infected with herpes in Africa, Peru and the United States. Roughly half were treated with aciclovir, an antiviral that stops herpes ulcers.
After a year and a half, the scientists found that 75 people out of the 1,581 who had been receiving aciclovir were later infected with HIV. Of the 1,591 people who received placebo pills, 64 contracted HIV.
In the trial, researchers chose participants who had herpes and who faced similar risks of getting AIDS. The study also questioned the participants during monthly visits about risky sexual behavior with their recent partners.
The study was paid for by the United States' National Institute of Allergy and Infectious Diseases, other U.S. government institutes, and by GlaxoSmithKline PLC, which sells aciclovir as Zovirax.
A small study in Tanzania last year also suggested that treating herpes didn't help reducing HIV susceptibility.
But that doesn't necessarily mean that the theory of treating herpes to avoid HIV is incorrect, experts said.
"It's probably likely that we need considerably more potent interventions than we have," Connie Celum, a professor of global health and medicine at the University of Washington who led the Lancet study, told The Associated Press.
Experts said there was a complex relationship between the two viruses that is still not entirely understood.
When herpes ulcers erupt, that draws white blood cells to the skin to fight the virus. Unfortunately, those white blood cells also have receptors for HIV.
Ndowa said it was possible that even without the telltale ulcers, herpes might have lingered while patients were taking the aciclovir, allowing HIV to gain a foothold.
In an accompanying commentary in the Lancet, Ronald H. Gray and Maria J. Wawer of Johns Hopkins University said it was questionable whether controlling sexually transmitted infectious could work to prevent HIV.
"It is time to reassess the hypothesis and to adjust prevention policy accordingly," they wrote.
But Ndowa and Celum said the strategy of fighting herpes to prevent AIDS might work, if a different dosage or more powerful drug was tried.
"We don't exactly know why this didn't work, but this approach still has potential," Ndowa said. "Maybe it was just too much to expect from a tablet taken twice a day that it could be effective against HIV."

Perplexing Results of Failed HIV Vaccine Grow More Puzzling

SEATTLE, Nov. 8 -- HIV vaccine researchers remain puzzled by the results of the ill-starred STEP trial, halted in September because of a lack of efficacy.
New results just released also hint that the vaccine might have slightly increased the risk of HIV infection.
Volunteers who had a high level of pre-existing immunity to the adenovirus vector used in the vaccine seemed to be more vulnerable to HIV infection, the researchers revealed in a special forum here.
But the researchers also said the data are complex and will require more in-depth analysis before it's clear what happened.
"It will take some time before we understand why the vaccine did not work and why there was a trend toward more cases of infection in volunteers who received the vaccine," said Keith Gottesdiener, M.D., of Merck Research Laboratories, which was developing the vaccine.
The vaccine includes three viral genes delivered by an adenovirus-5 vector, and in earlier clinical trials appeared to generate a significant HIV-specific cell-mediated immune response.
It was being tested in two large phase IIb trials, STEP in North and South America, the Caribbean, and Australia and Phambili in South Africa. Both trials stopped vaccinating volunteers after the STEP data safety monitoring committee found the vaccine wasn't efficacious. (See: Hopes Dashed Again for HIV Preventive Vaccine)
But in a special open scientific meeting of the HIV Vaccine Trials Network, researchers revealed more details of the ill-fated trial.
The key finding that led to halting the trial was that among volunteers with low pre-existing immunity to the adenovirus vector who were HIV-negative at the start of the trial, 24 of the 741 who got the vaccine developed an HIV infection, compared with 21 in the 762 who got placebo.
When the researchers restricted the analysis to those who got at least two of three planned vaccinations and who remained HIV-negative for at least the first 12 weeks of the trial, they found 19 HIV infections in the 672 volunteers who got the vaccine and 11 in the 691 who got placebo.
In the whole study population, including cases recorded after the trial was stopped, there were 49 cases of HIV infection among the 914 men in the vaccine group compared with 33 cases among the 922 in the placebo group.
The vaccine also failed to achieve its secondary endpoint -- reducing the HIV viral levels among volunteers who got infected despite the vaccine.
When the trial was stopped, researchers said that the HIV RNA levels approximately eight to 12 weeks after diagnosis of infection were generally similar in the two groups -- but with a trend toward higher levels in those who got the vaccine.
HIV RNA levels in the blood were about 40,000 copies per milliliter among volunteers in the vaccine group who developed HIV infection and approximately 26,000 copies per milliliter in infected volunteers in the placebo group.
When the entire study population was taken into account, including male volunteers with both low and high levels of immunity to Ad5, the geometric means of HIV RNA levels were approximately 29,000 copies/mL for the vaccine group (based on 46 infections) and approximately 38,000 copies/mL in the placebo group (based on 30 infections).
The study wasn’t designed to look at the effect of immunity to adenovirus on HIV acquisition, but a post hoc analysis showed that HIV infection among volunteers with high Ad5 immunity was more pronounced among those who received the vaccine compared to those who received placebo.
Among the 778 male volunteers who had high levels of pre-existing immunity, there were 21 cases of HIV infection in the vaccine group and nine in the placebo group.
The researchers also said that among volunteers who had no or limited pre-existing immunity to adenovirus, there was little difference in the HIV infection rate.
Researchers outside the trial emphasized that there remain large knowledge gaps.
"We know the Merck vaccine didn't work," said Seth Berkley, M.D., president of the New York-based International AIDS Vaccine Initiative. "We don't know why."
"We know that more people who got the Merck [vaccine] candidate than got the placebo wound up becoming HIV infected," he said in a statement. "We don't know if that had anything to do with the candidate or not."
He added that the trend was not statistically significant, so "it could have been chance. And if the vaccine was a factor, we don't know why."
Dr. Berkley said many in the vaccine community were not surprised by the result.
"The failure of the Merck product to prevent HIV infection is not unexpected," he said, because the vaccine -- like nearly all of those in the pipeline -- aimed at producing cell-mediated immunity.
But T cells only attack infected cells, so that "many scientists, including those at IAVI, think T-cell vaccines are unlikely to protect individuals from becoming infected."
Likely to be more effective, Dr. Berkley said, would be vaccines aimed at producing an antibody response and thus preventing HIV particles from entering the body.

FDA Approves First-in-Class Integrase Inhibitor for Treatment-Resistant HIV-1

WHITEHOUSE STATION, N.J., Oct. 15 -- The FDA has approved raltegravir (Isentress) as part of a combination regimen for treatment for multiresistant HIV-1 infection in adults, according to an announcement from Merck.
The company said the approval emerged from analyses of plasma HIV-1 RNA levels up through 24 weeks in two controlled studies of raltegravir (400 mg tablet bid) plus optimized background therapy. It is the first drug approved in a new class of antiretroviral agents called integrase inhibitors.
The drug works by inhibiting the insertion of HIV DNA into human DNA via the integrase enzyme, which blocks the ability of the virus to replicate and infect new cells.
The studies were conducted in clinically advanced patients with virus resistant to agents three antiretroviral classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors). In those studies, patients randomized to raltegravir plus optimized background therapy achieved significant reductions in HIV RNA viral load and increased CD4 cell counts compared with placebo plus optimal therapy.
The company said, however, that the safety and efficacy of raltegravir has not been established in treatment-naïve patients, nor are there data demonstrating an effect on clinical progression of HIV-1 infection.
Joseph J. Eron, Jr., M.D., of the University of North Carolina in Chapel Hill, who was an investigator for the company-sponsored trials, called the approval a "significant milestone in the history of HIV/AIDS therapy because we now have a drug that's potent against another key enzyme essential for viral replication."
Dr. Eron said, however, that it was important to recognize that the drug should not be used as monotherapy, but must always be used in combination with other active agents.
The most commonly reported adverse events were diarrhea, nausea, headache, and fever.
Additionally, creatine kinase elevations were observed in patients who received raltegravir. Both myopathy and rhabdomyolysis have been reported, although the relationship of raltegravir to these events is not known. The company said the drug should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.

Drinking Linked to HIV Progression

BOSTON, Aug. 21 -- Heavy alcohol use appears to speed HIV progression, researchers here said.
But the effect is modest and is only seen in HIV-infected people not getting anti-retroviral therapy (ART), according to Jeffrey Samet, M.D., of Boston University, and colleagues.
Nevertheless, the finding suggests that people with HIV should avoid heavy alcohol consumption, they reported online in the Journal of Acquired Immune Deficiency Syndromes.
"HIV-infected persons who drink alcohol heavily and are not on ART might decrease their risk of disease progression if they abstain from alcohol use," the researchers said.
The finding emerged from two prospective observational cohort studies, which ran consecutively from 1997 through 2001 and 2001 through 2006, to investigate links between alcohol use and HIV progression.
Some of the participants in the first study were also recruited for the second, and the combined cohort included 595 people. Participants had HIV and either past or current alcohol problems at enrollment.
The researchers defined heavy drinking as:
More than 14 drinks a week or at least five drinks on a single occasion for men younger than 66.
More than seven drinks a week or at least four drinks on a single occasion for men 66 or older.
More than seven drinks a week or at least four drinks on a single occasion for all women.
Moderate alcohol use was defined as any drinking less than heavy amounts.
The participants were assessed at study enrollment and then every six months for CD4 cell counts and HIV RNA levels and for alcohol use within the previous 30 days.
Overall, the researchers said, 30% of participants were heavy consumers, 10% were moderate, and 59% were abstinent. Among those who reported drinking in the 30 days before an assessment, the average daily alcohol consumption was 5.4 drinks.
When the researchers looked at those not on ART, they found that the adjusted mean CD4-positive T-cells averaged 48.6 cells per microliter lower for those with heavy alcohol use than for those who were abstinent. The difference was statistically significant at P=0.03.
On the other hand, there was no difference in viral load, Dr. Samet and colleagues found. Also, there was no association between moderate drinking and disease progression.
Heavy alcohol use is known to lessen adherence to therapy, which in turn increases the risk of HIV progression, the researchers noted.
But among study participants on ART -- when the researchers controlled for adherence to therapy -- there was no association between drinking and either disease progression marker.
One explanation for that might be that the large beneficial effect of the therapy outweighs the small negative effect of the alcohol, Dr. Samet and colleagues said.
The study is unable to say much about moderate drinking, the researchers said, because only 10% of participants reported that level of alcohol consumption.
That's not surprising, given that the study included people with alcohol problems: "Individuals with current or past alcohol dependence are likely to abstain or drink heavily," the researchers said.
The research was supported by the National Institute of Alcohol Abuse and Alcoholism. The authors made no statement regarding possible conflicts.Primary source: Journal of Acquired Immune Deficiency SyndromesSource reference: Samet JH et al. "Alcohol Consumption and HIV Disease Progression." J Acquir Immune Defic Syndr 2007.

Entecavir for HBV May Result in HIV Drug Resistance

Emma Hitt, PhD

August 16, 2007 — Use of entecavir (Baraclude) by patients coinfected with HIV and hepatitis B virus who are not already receiving highly active antiretroviral therapy (HAART) may result in resistance to nucleoside reverse transcriptase inhibitors (NRTIs), according to an alert sent today from MedWatch, the US Food and Drug Administration (FDA) adverse event and reporting program. The full prescribing information for entecavir, including the boxed warning, has been updated to include this information.
Entecavir, manufactured by Bristol-Myers Squibb (BMS), is indicated for the treatment of chronic hepatitis B virus in adults who show evidence of active viral replication and who have either histologically active disease or persistent elevations in serum aminotransferases (ALT or AST).
The microbiology section of the entecavir prescribing information was also updated to include a statement about the inhibitory activity of entecavir against HIV-1 isolates. Entecavir selected for an M184I substitution in HIV reverse transcriptase at micromolar concentrations in cell culture, indicating inhibitory pressure at high entecavir concentrations, and HIV variants containing the M184V substitution showed loss of susceptibility to entecavir.
In addition, the warnings section has been updated to state that before starting therapy with entecavir, all patients should be offered HIV antibody testing and that entecavir has not been evaluated for treatment of HIV infection.

Circumcision Not Protective Against HIV Seroconversion in Homosexual Men

Bonnie Darves

August 2, 2007 (Seattle) — Circumcision status may have little effect on whether men who have sex with men go on to develop HIV, according to the results of a new study of more than 1400 homosexual men, presented here at the 17th Meeting of the International Society for Sexually Transmitted Diseases Research. Although several recent randomized controlled trials of heterosexual men have found that adult circumcision reduces the risk of HIV acquisition by 50% or more, little is known about the association between circumcision and HIV risk in homosexual men, said the study's chief author, David Templeton, MD, from the University of New South Wales, Sydney, Australia.
"The data on circumcision and heterosexual men are compelling, but there are few data on circumcision and HIV risk in homosexual men," said Dr. Templeton. "We found no relationship at all between circumcision and HIV seroconversion in this cohort." That lack of association or protective effect, he added, may be because most HIV occurs "following receptive rather than insertive intercourse," but further studies would be needed to confirm that theory.
"Based on these findings, we cannot make a recommendation for circumcision in homosexual men" as a protective measure against HIV seroconversion, Dr. Templeton said.
The longitudinal study of 1427 initially HIV-negative homosexual Australian men, initiated in 2001, found that in the 49 who developed HIV, circumcision status appeared to have no effect (risk ratio was 1.07, with a confidence interval of 95%). At baseline, 66% of participants reported being circumcised, mostly as infants, and circumcision was more prevalent among men aged 45 or older (83%) than in men aged 25 or younger; only 50% of the latter group reported being circumcised. Circumcision status in all participants was later validated by physical examination.
Although the Australian study's results showed no benefit in circumcision for homosexual men as a means of protecting against HIV, the association might merit further study in light of the findings of larger African trials about the potentially protective effect of circumcision overall, said Matthew Hogben, PhD, a research scientist from the Centers for Disease Control and Prevention's National Center for HIV, STD, and TB Prevention, Atlanta, Georgia.
"The Australian study showed that circumcision was not a factor one way or the other in whether [individuals] developed HIV, which probably makes sense," said Dr. Hogben, who moderated the session. He added that although "receptor sex" was "clearly was the manner of acquisition," in the Australian study, it's understandable that "with the findings of the trials that ran in Africa, [researchers] might want to expand study of the association to see to what extent they could take advantage of those findings to look at secondary effects. It might be worthwhile to see whether there's less transmission or 'burden' with a foreskin intervention, but I suspect we would need more data, and more clean data, to confirm this."
Dr. Templeton and Dr. Hogben report no relevant financial relationships.
17th Meeting of the International Society for Sexually Transmitted Diseases Research: Abstract 215. Presented July 30, 2007.

IAS: Darunavir Noninferior to Lopinavir in TITAN trial

SYDNEY, July 27 -- HIV treatment with the newly approved protease inhibitor darunavir (Prezista) was noninferior to the standard-of-care treatment lopinavir/ritonavir (Kaletra) in a year-long trial."This is the first time that any drug has been shown to be superior to lopinavir," said Jose Valdez-Madruga, MD, director of clinical trials for the Sao Paulo AIDS Program in Brazil. "Patients with experienced HIV infection now have an option for treatment."
In a presentation at the International AIDS Society meeting, Dr. Valdez-Madruga said that after 48 weeks of treatment, 71% of HIV-infected participants who were taking darunavir, boosted with ritonavir, had undetectable viral loads, using the <50 copies/mL assay. In comparison, 60% of patients on lopinavir, boosted with ritonavir, achieved the undetectable level on that assay.
The 11% difference in being able to suppress the virus to undetectable levels reached statistical significance (P=.005), Dr. Valdez-Madruga said.
In the TITAN (TMC114/r in Treatment-Experienced patients Naïve to lopinavir) trial, investigators screened 785 patients before enrolling 595 into the group given either darunavir at 600 mg and ritonavir at 100 mg or lopinavir at 400 mg and ritonavir at 100 mg on a twice-daily dosing schedule.
In addition to the protease inhibitors, all patients received an optimized background regimen of at least two antiretrovirals from the nucleoside reverse transcriptase or non-nucleoside reverse transcriptase classes. The use of enfuvirtide (Fuzeon) was not allowed in the trial.
Dr. Valdez-Madruga said that the primary endpoint of the trial was to show that the darunavir regimen was non-inferior to the lopinavir regimen.
The researchers assigned 298 patients to darunavir and 297 were given lopinavir. At the start of the trial, the average viral load in each group was about 40,000 copies/mL. The participants had mean CD-4 positive cell counts of about 230. About 30% of patients in each group were naïve to protease inhibitors.
About 21% of patients in the darunavir arm did not finish the trail, but only four participants (1.3%) dropped out because of virological failure. About 29% of lopinavir patients dropped out, 34 because of virologic failure (11.4%).
The most common adverse event in the trial was diarrhea, reported by 31.8% of darunavir patients and 41.8% of lopinavir patients. Twice as many lopinavir patients had Grade 2-4 diarrhea than darunavir patients. About 16.1% of patients on darunavir reported any kind of rash, compared with 6.7% of patients on lopinavir.
"We also found that darunavir appears to protect the other drugs classes better than lopinavir," Dr. Valdez-Madruga said. He explained that fewer resistance mutations in the nucleoside reverse transcriptase class and in the protease inhibitor class appeared while patients were being treated with darunavir.
"The study shows that darunavir is a better drug than lopinavir," commented Robert Murphy, M.D., of Northwestern in Chicago.
"Whether this trial will change clinical practice, however, may not have anything to do with the science," Dr. Murphy said. He noted that lopinavir/ritonavir can be taken as one pill, but darunavir and ritonavir have to be taken separately. "That means patients have to fill two prescriptions and have two co-pays. Kaletra is a very good drug. I wouldn't switch a patient on the basis of this trial unless there was a reason for doing so."
Dr. Valdez-Madruga concurred. He said that if a patient was experiencing diarrhea on lopinavir, he would consider a switch because diarrhea was less frequent among darunavir patients. Primary source: Abstract Book 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention incorporating the 19th ASHM ConferenceASM ConferenceAJournal
Source reference: Jose Valdez-Madruga et al "TUAB101 - Comparison of 48-week efficacy and safety of darunavir/ritonavir (DRV/r) with lopinavir/ritonavir (LPV/r) in LPV/r-naïve, treatment-experienced patients: a randomised, controlled phase III trial (TITAN)," Abstract Book 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention incorporating the 19th ASHM Conference, 22-25 July 2007, Sydney, Australia; p 91.

IAS: HIV Treatment Requires Cardiac Assessment

SYDNEY, July 24 -- As the long-term prognosis for patients with HIV improves, it becomes more important to assess the patient's risk for cardiovascular disease and other health issues, researchers suggested here.
"In settings where antiretroviral therapy is readily accessible, the long-term prognosis for people living with HIV/AIDS has dramatically improved," Judith Currier, M.D., of the University of California, Los Angeles, told attendees at an industry-sponsored symposium held in conjunction with the International AIDS Society meeting.
"Clinical management of HIV infection now needs to include provision of screening and interventions to reduce morbidity and mortality from other chronic diseases such as cardiovascular disease," she said.
Dr. Currier reviewed a series of clinical studies that attempted to tease out the question of whether HIV itself is responsible for increased risk of cardiovascular disease; whether the problem is rooted in the treatment of HIV disease with highly active antiretroviral therapy (HAART); and which of the components of HAART might be the culprit for increasing the risk of heart disease in patients.
She said that one of the surprising results of the SMART study was that patients with HIV who were assigned to a regimen in which treatment was guided by levels of CD4-positive cells and were able to take less medication actually had worse cardiovascular disease outcomes than did patients who never stopped taking the HAART regimen. (See Interrupting HIV Treatment Raises Cardio Risk)
On the other hand, she noted, data from the DAD study indicated that use of protease inhibitors increased HIV patients' risk of myocardial infarction by about 16% a year. (See Protease Inhibitors Linked to Increased Heart Attack Risk)
Dr. Currier also noted that treatment of cardiovascular disease requires that the physician be aware of interactions between statins and protease inhibitors. For example, fluvastatin and pravastatin appear safe for use in HIV patients, but lovastatin and simvastatin are contraindicated. The other statins have to be used with caution, she said.
While there is reason to consider the cardiovascular risk profile of a patient with HIV, Dr. Currier noted, "The absolute risk of cardiovascular disease in the HIV population remains low (about 2%). Modification of coronary heart disease risk and use of antiretroviral agents less likely to cause metabolic disturbances may be warranted when patients have many options, but the fear of coronary heart disease should not preclude the use of effective HAART," she said.
Peter Reiss, M.D., of the Academic Medical Centre, in Amsterdam, illustrated how the choices of treatment fit into selection of therapy for a patient, noting that the risk of heart disease could be reduced by selecting specific HIV drugs.
However, he said, the best way to get his patient to dramatically reduce his Framingham Heart Score was to get the individual to quit smoking.
"Cardiovascular risk assessment has become an integral component of the care for persons with HIV infection," Dr. Reiss said. "Careful choice of antiretroviral regimens may contribute to optimization of lipid profile. Cardiovascular disease risk reduction, however, involves much more than just paying attention to lipids."
The symposium was sponsored by Bristol-Myers-Squibb.
The International AIDS Society does not require presenters to identify possible financial conflicts of interest. Dr. Currier said she has possible conflicts with Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Merck and Tibotec. Dr. Reiss did not list conflicts, nor did symposium chairman Andrew Carr, MD, professor of medicine at the University of New South Wales, Sydney.Primary source: IAS Conference on HIV Pathogenesis and TreatmentSource reference: "HIV and Cardiovascular Disease -- Minimizing the Risk;" Conference Programme 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention incorporating the 19th ASHM Conference, 22-25 July 2007, Sydney, Australia, p 199.

IAS: Investigative Drugs Zero in on HIV Vulnerabilities

SYDNEY, July 24 -- New compounds that seek ways to disrupt mechanisms of the HIV life cycle were outlined here, reflecting an expanding investigative antiviral pipeline.Among the compounds and investigative agents discussed at a session on new drug development at the International AIDS Society meeting, chaired by Robert Murphy, M.D., of Northwestern, were:
A series of compounds being developed by Panacos Pharmaceuticals of Gaithersburg, Md., that appears to have the ability to prevent fusion of HIV with its target CD4-positive cell. Another entry inhibitor, injectable enfuvirtide (Fuzeon) is on the market, but the Panacos compounds are designed to be taken orally and to block the entry cascade at a different location.
A second-generation maturation inhibitor, also being developed by Panacos. The company's first-generation product bevirimat is phase IIB development. The new molecule, PA1050040, has a different resistance profile and is less likely to bind to protein than bevirimat. Phase I trials are under way.
A series of compounds called dihydroxytropolones that attack the reverse transcriptase enzyme, one of the three key enzymes of the HIV virus. Nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors all attack this facet of the HIV lifestyle.
Small molecule inhibitors of the interaction of HIV-1 Tat-protein with phosphatase-1 prevent HIV-1 transcription . "We have always suggested that finding inhibitors of tat would be a welcome weapon in the AIDS arsenal," said Dr. Murphy.
A molecule that prevents dimerization in the protease enzyme, another of the critical enzymes of the virus.
"We need more antiretroviral drugs to fight HIV infection because no matter how good we are, the virus develops resistance as it evolves," commented Robin Isaacs, M.D., executive director of infectious disease and HIV Vaccine Clinical Research at Merck Research Laboratories in Upper Gwynedd, Pa.
Dr. Isaacs, whose company was not involved in the research presented in the discussion session, said, "We are also going to have to have sufficient drugs to give patients options for treatment for 30 or 40 years. We have not yet reached the point where we have the perfect drug in the sense of tolerance and convenience."
He said that development of an oral fusion inhibitor would answer the question of convenience for those taking enfuvirtide who require twice-daily injections.
Karl Salzwedel, Ph.D., director of drug discovery for Panacos, said that the company has three different groups of compounds that are being studied to see which of the fusion inhibitor molecules would make appropriate drug candidates.
"We expect to seek an investigative new drug application with the FDA by the end of this year, and we may begin clinical trials by the end of 2008," he said.
He said that the molecules in development operate in an area that is upstream in the fusion cascade from enfuvirtide.
Dr. Murphy said that most of the compounds discussed in the session "are a long way down the road, but these chemists that have developed the compounds are from very successful groups."
The International AIDS Society does not require presenters to disclose possible financial conflicts of interest. The presenters at the discussion session did not make any disclosures. Primary source: 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention Abstract Book
Source reference: C. Finnegan et al, MOPDX01 - Discovery of a novel class of orally bioavailable HIV-1 fusion inhibitors.
J. Didierjean et al, MOPDX02 - Mechanism of inhibition of the polymerase activity of HIV-1 reverse transcriptase by dihydroxytropolones
D. Kovalskyy et al, MOPDX03 - Development of small molecule inhibitors of HIV-1 Tat- protein phosphatase-1 interaction as a new anti-HIV-1 retroviral therapeutics
Y. Koh et al, MOPDX04 - Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule protease dimerization inhibitors
N. Kilgore et al, MOPDX05 - Characterization of PA1050040, a second generation HIV-1 maturation inhibitor
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention Abstract Book, 22-25 July 2007, Sydney, Australia, pp. 22-23.