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HIV Drug Maraviroc Effective for Drug-Resistant Patients 

NewYork-Presbyterian Hospital/Weill Cornell Medical Center's Dr. Roy Gulick Is Lead Investigator of Phase 3 Multicenter Trial; Results in Oct. 2 New England Journal of Medicine

New Class of HIV Medication Takes Upper Hand Against Drug Resistance

NEW YORK (Oct. 2, 2008) -- As many as one quarter of HIV patients have drug resistance, limiting their treatment options and raising their risk for AIDS and death. Now, maraviroc, the first of a new class of HIV drugs called CCR5 receptor antagonists, has been shown to be effective over 48 weeks for drug-resistant patients with R5 HIV-1, a variation of the virus found in more than half of HIV-infected patients.

Results of the two Phase 3 multicenter MOTIVATE (Maraviroc Plus Optimized Therapy in Viremic Antiretroviral Treatment Experienced Patients) studies led by NewYork-Presbyterian Hospital/Weill Cornell Medical Center's Dr. Roy Gulick and published in the October 2 issue of the New England Journal of Medicine (NEJM) find that the drug, taken with an optimized standard HIV drug regimen, resulted in significantly greater suppression of the virus at 48 weeks, with concurrent increases in immune system T-cell counts, when compared with placebo. Rates of side effects were not different between the maraviroc and placebo groups. 

Preliminary results of these studies led to FDA approval of maraviroc in August 2007. 

Because it is from a new class of HIV medications known as HIV entry inhibitors, people living with HIV generally will not have resistance to maraviroc because they have not been exposed to any drugs from the class previously. Unlike earlier HIV drugs that target the virus, maraviroc acts on the human T-cell, binding to it in such a way that prevents HIV from binding and subsequently infecting the T-cell.

"It is now possible to expect that a majority of treatment-experienced patients who experience failure on their current HIV drugs will regain control of their HIV infection with maraviroc combined with other newer antiretroviral drugs. This is an important step forward," says study principal investigator Dr. Roy Gulick, who is professor of medicine and director of the Cornell HIV Clinical Trials Unit of the Division of International Medicine and Infectious Diseases at Weill Cornell Medical College, and a practicing physician at NewYork-Presbyterian Hospital in New York City. "Suppressing virus levels and increasing immune system T-cells with HIV treatment regimens helps HIV-infected people live longer, healthier lives."

The double-blind study followed 1,049 of patients with advanced HIV and resistance to three antiretroviral drug classes. Patients were randomized to receive maraviroc once-daily, twice-daily or placebo. Safety and efficacy were assessed at 48 weeks. The MOTIVATE studies comprised two identical arms: MOTIVATE1 was conducted in Canada and the U.S., while MOTIVATE2 was conducted in Australia, Europe and the U.S.

More patients receiving maraviroc once- or twice-daily versus placebo achieved HIV-1 RNA <50 copies/mL (43-46% vs. 17%). CD4 counts increased more with maraviroc once- or twice-daily versus placebo (+116-124 vs. +61 cells/L). Frequencies of side effects and toxicities were similar across groups. 

Operations Research Promises Continued Gains for HIV Treatment in Resource-Limited Countries

New Weill Cornell Collaboration Uses Computer-Modeling Techniques to Help Resolve Bottlenecks in Drug Distribution and Medical Personnel Staffing

NEW YORK (Aug. 22, 2008) — In the past 10 years, the global campaign to expand treatment for millions of people with AIDS living in resource-limited countries, especially in sub-Saharan Africa, has gained substantial commitments in public and private financing, and has made major strides in making treatment available to those who need it. A new collaborative study by researchers at Weill Cornell Medical College and the Clinton Foundation HIV/AIDS Initiative explores how to combine engineering science with medical care to guarantee the long-term success of these treatment programs.

In an article published online this month in the BMC Health Services Research journal, the researchers show how the use of sophisticated mathematical modeling approaches used in the field of operations research can help maximize the efficient use of limited resources, notably antiretroviral drugs and medical personnel.

"Operations research offers a powerful set of tools that have been used successfully in everything from World War II to Wal-Mart-style logistics planning. These tools ought to be used to increase the success of existing programs and to help expand access to HIV care and treatment in resource-limited countries," says lead author Dr. Wei Xiong, instructor in public health at Weill Cornell Medical College. "For example, operations research could help with the planning of a national drug distribution system, or with predicting the demand for services at local clinics and the best ways to staff them."

"To date, HIV treatment scale-up has appropriately focused first on policy-level issues, such as program initiation and costs, and secondarily on operational-level issues," adds co-investigator Dr. Nathaniel Hupert, associate professor of public health at Weill Cornell Medical College and associate attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "Now that many programs are in place, the potential gains from improved planning are great, especially given the high cost of antiretroviral drug therapy."

Another important, looming problem in resource-limited settings, the authors write, is the lack of sufficient health care workers to diagnose and treat the millions of people living with HIV.

Beginning in 2005, the Weill Cornell and the Clinton Foundation researchers created a series of computer simulations to estimate resource requirements and treatment capacity scale-up at an HIV clinic. This year they used a simulation model to predict the amount of physician person-hours saved by shifting some duties to nurses for HIV clinics in Rwanda. This model suggests that if task-shifting were scaled up from a pilot program in three health centers to the national level, it could reduce the demand on public-sector physicians for HIV services by up to 78 percent.

"The analysis suggested that implementation of such a program could allow the government of Rwanda to scale-up HIV treatment without overburdening its existing health-care system," Dr. Xiong comments.

According to the new paper, another area ripe for improvements is the management of laboratory resources, which are often underutilized or not maintained. When there is an equipment breakdown, it often takes a prohibitively long time to get replacement parts or qualified repair technicians.

"The unique advantage of operations research is that it gives us the ability to evaluate and optimize outcomes of various scenarios — such as determining the best approach for the management of lab equipment repair — without impacting patients," explains Dr. Xiong. "Once we have the evidence for a new approach, a good case can be made that it should be implemented as policy, although any initiative should take into account the environments in which the projects are to be carried out, with all necessary ethical, cultural and political considerations."

The need for better resource planning in HIV treatment has been noted by the President's Emergency Plan for AIDS Relief (PEPFAR) program, which writes of the importance of "placing greater emphasis on long-term strategic planning and increasing the attention and resources directed to capacity building for sustainability."

Approximately 95 percent of patients with HIV/AIDS live in developing countries. It is estimated that close to 3 million people, or 31 percent of those living with HIV in resource-limited nations, have access to antiretroviral treatment, a substantial improvement from 5 percent coverage just five years ago.

"While laudable progress has been made, the great majority of HIV patients are still under-treated or untreated," says Dr. Hupert. "We feel that operations research provides one of the tools to make sure progress continues."

"This area of research — and specifically this and other projects led by Drs. Hupert and Xiong — shows how fields such as the engineering sciences can contribute to solving medical and public health problems," says Dr. Alvin I. Mushlin, chairman and Nanette Laitman Distinguished Professor of Public Health at Weill Cornell Medical College, and Public Health Physician-in-Chief at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

Additional co-authors of the study include Eric B. Hollingsworth of Weill Cornell Medical College; Dr. Megan E. O'Brien and Jessica Fast of the Clinton Foundation HIV/AIDS Initiative, Quincy, Mass.; and Dr. William R. Rodriguez of the Partners AIDS Research Center, Massachusetts General Hospital, Boston.

The research was funded, in part, by the Clinton Foundation.

Potential New Drug Target to Fight Tuberculosis Identified

Membrane Protein Is Key to Bacterix's Defense Against Immune Cell Acidification During Infection, According to New Research by Weill Cornell Medical College Scientists

NEW YORK (July 29, 2008) -- With antibiotic resistance on the rise, tuberculosis is emerging as a bigger global health threat than ever before.
      
But now, innovative research at Weill Cornell Medical College suggests that Mycobacterium tuberculosis has an as yet unsuspected weakness -- one that could be a prime target for drug development.
      
"Using novel techniques, we have identified a key membrane protein that's essential to the defense that M. tuberculosis mounts against the acidic environment of immune cells called macrophages. Without this protein, called Rv3671c, the bacterium becomes vulnerable to acidification and is killed," explains lead author Omar H. Vandal, a postdoctoral fellow in the lab of study co-senior author Dr. Sabine Ehrt, associate professor of microbiology and immunology at Weill Cornell Medical College.
      
"M. tuberculosis does not depend on Rv3671c under standard growth conditions in the test tube, so it has been overlooked as a candidate drug target," says Dr. Carl F. Nathan, also a senior author of the study and the R.A. Pritchett Professor of Microbiology. He is also chairman of the Department of Microbiology and Immunology at Weill Cornell.
      
Drs. Ehrt and Nathan co-supervised Dr. Vandal in this work while Dr. Vandal was a student at the Weill Cornell Graduate School of Medical Sciences. "However, when M. tuberculosis infects the host, then the Rv3671c protein becomes essential," added Dr. Ehrt. "This is an example of a new class of potential targets for anti-infective agents," continues Dr. Nathan, "those that the pathogen only needs in order to survive in the host environment."
      
The research was just published in Nature Medicine.
      
In numerous papers published in leading journals, Dr. Nathan has long pushed for an innovative approach to the development of anti-infective agents that goes beyond the traditional antibiotic paradigm. "That's exactly what we sought to do in this research," he says.
      
One of the study's innovations involved the examination of M. tuberculosis as it interacted with bone marrow–derived macrophages during the infective process.
      
"That's a huge change from standard anti-infective research, which typically deals with the pathogen simply replicating in culture," explains Dr. Vandal. "In our experiments, we wanted to see if biochemical actors would emerge in the infective process that might be inoperative in the usual in vitro setting."
      
The team specifically focused on changes in the pH (acidity) of the phagosome -- a structure that macrophages use to consume and destroy pathogens, including bacteria.
"As part of this process, the phagosome becomes acidic, which is thought to contribute to its ability to break down and destroy the pathogen," Dr. Ehrt explains. "However, M. tuberculosis appears to survive the acidification process, keeping its own internal pH stable."
      
How does the bacteria do this, despite being surrounded by the more highly acidic phagosome? To find out, the team used a kind of genetic tweaking that effectively disabled M.tuberculosis' ability to produce a key protein lying at its membrane -- a protease (enzyme) called Rv3671c.  
      
They then watched how the organism fared without it.
      
"What we observed was pretty amazing -- without functioning Rv3671c, the mutant bacterium was easily destroyed in a low-pH environment, both in culture and inside the more acidic environment of the macrophage," says Dr. Vandal. "This revealed a new point of vulnerability for the bacterium."
      
The experiment also broke new ground because the researchers were able to accurately gauge the bacterium's internal pH with the organism lying inside a host cell.
      
"The ability to make those kinds of measurements will expand research into this type of host-pathogen interaction," Dr. Nathan believes.
      
The next step is to find out why Rv3671c is so crucial to M. tuberculosis' defense.  
      
"Right now, we have very little idea of the mechanism at work here. Perhaps as an enzyme Rv3671c cleaves a transcription regulator that then turns on some kind of defensive program within the bacterium. Only further study will reveal those secrets," says Dr. Ehrt.
      
"What is clear is that by targeting an element involved directly in the infective process, we may develop a line of drugs that work in collaboration with, rather than in difference to, the host environment, including host immune responses," Dr. Nathan says. "Hopefully, this kind of approach can help solve the ongoing problem of bacterial drug resistance."
      
The new study is also another example of an interdisciplinary approach -- this time among biochemists, microbiologists, immunologists and cell biologists.
      
"In the ideal collaboration, each participant brings key insights from their particular discipline to the table," Dr. Nathan says. "The results are discoveries like these."
      
This work was funded by the U.S. National Institutes of Health and the I.T. Hirschl Trust.
      
Co-researchers include Dr. Lynda M. Pierini and Dr. Dirk Schnappinger, also of Weill Cornell Medical College.



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Rapid Syphilis Testing in Haiti Will Prevent Congenital Disease and Stillbirths
Weill Cornell and GHESKIO Research Also Finds Rapid Testing To Be Cost Effective

NEW YORK (May 28, 2007) — Congenital syphilis is a major preventable public health problem in many developing countries, frequently causing stillbirths or neonatal death and disabling children who survive. Often undiagnosed or untreated, syphilis is passed from mother to child — even when mothers take part in prenatal programs to prevent the spread of HIV.

Now, new research from Weill Cornell Medical College and the Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) published in the May issue of the open-access journal PLoS Medicine finds that integrating a new rapid syphilis test into prenatal HIV testing programs in Haiti can prevent more than 2,000 cases of stillbirth, neonatal death or congenital syphilis.

"We have shown that by working with the HIV prevention program infrastructure, we can better prevent transmission of syphilis from mother to child at minimal incremental cost. These findings not only give guidance to public health efforts in Haiti, but may serve as a model for projecting the benefits of similar efforts in Africa and in other resource-poor settings," says Dr. Bruce R. Schackman, lead author of the study and associate professor and chief of the Division of Health Policy in the Department of Public Health at Weill Cornell Medical College.

Researchers compared three strategies for screening pregnant women for syphilis. The first strategy, the standard of care in rural Haitian areas without access to syphilis laboratory testing, is assessing symptoms and treating if symptoms are found. The second, considered the standard in urban areas, is a blood test for antibody response to the syphilis bacterium — an approach that requires a one-week waiting period for follow-up and treatment. The third strategy is rapid testing that permits immediate diagnosis and treatment initiation at a single clinic visit.

According to the World Health Organization (WHO), there are more than 20 rapid syphilis tests commercially available. Four of the tests were evaluated in a field trial at the GHESKIO Center in Port-au-Prince, Haiti, and found to be simple to administer, offering easy-to-interpret results within 30 minutes. Haiti is one of several developing countries where in pregnant women infection with untreated syphilis is as common as infection with HIV.

"Relying on the appearance of symptoms allows for many syphilis cases to be missed. And for most rural women, making even one repeat visit to a clinic to learn the results of a test and be treated is too much of a personal burden. Requiring only one clinic visit, rapid testing followed by immediate treatment proved to be definitely the best strategy," says co-author Dr. Jean W. Pape, founder and director of GHESKIO and professor of medicine in the Division of International Medicine and Infectious Diseases at Weill Cornell Medical College.

Dr. Pape, an internationally renowned infectious disease expert who is from Haiti, founded GHESKIO more than 25 years ago. The organization is dedicated to the battle against HIV/AIDS, childhood diarrhea and tuberculosis. Since its inception, GHESKIO has worked closely with Weill Cornell Medical College in championing education, health care and HIV research in Haiti. The work of GHESKIO and its partners has led to a 50 percent decrease in infant mortality in Haiti and a similar decrease in the national HIV prevalence.

Researchers evaluated cost-effectiveness by predicting the health outcomes for each strategy as "disability-adjusted life years" (DALYs) — reflecting the number of years of healthy life lost due to congenital syphilis among newborn babies, the number of stillbirths and the number of neonatal deaths. While rapid testing was found to be more expensive than other approaches, its value compared to current syphilis screening standards of care in rural and urban areas was represented by cost-effectiveness ratios of $7-$10 per DALY. This is similar to or better than the value for programs to prevent mother-to-child transmission of HIV that have been studied in Africa.

"If immediate syphilis testing were provided as part of HIV-testing programs for all pregnant women in Haiti who currently have access to prenatal care, over 1,000 cases would be avoided each year, along with over 1,000 stillbirths and neonatal deaths, at a very reasonable additional cost of slightly more than half a million dollars," says senior author Dr. Daniel W. Fitzgerald, assistant professor of medicine at Weill Cornell Medical College and assistant attending physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. "This study provides a convincing case for adding rapid syphilis testing to current global campaigns aimed at reducing mother-to-child transmission of HIV."

Additional co-authors include Weill Cornell's Christopher P. Neukermans and GHESKIO's Dr. Sandy N. Nerette Fontain, Dr. Patrice Joseph and Claudine Nolte.

The study was funded by the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, and by the U.S. National Institutes of Health.

Contact Info
Andrew Klein
ank2017@med.cornell.edu
 


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