Partners AIDS Researchers Assist South Africans With Nationwide ARV Rollout

In an effort to combat the AIDS pandemic at its epicenter, the Partners AIDS Research Center (PARC) is assisting clinics in one of the hardest hit areas of the global AIDS epidemic to develop life saving pilot AIDS treatment programs. Working in the KwaZulu-Natal Province of South Africa, Partners physicians have been mentoring health care professionals on what will be the largest distribution of antiretroviral therapy (ARV) ever undertaken in medical history.

Over the course of the next 8 months, approximately 20,000 individuals across KwaZulu-Natal Province will receive the same HIV drug “cocktails” that have resulted in a dramatic decrease in AIDS deaths since they were introduced in the US in 1995. Drug therapy will be combined with HIV education, peer-to-peer counseling, appropriate laboratory monitoring, and social support. Patients are being selected on the basis of “ARV readiness,” which is measured by their clinical stability, willingness to sign a treatment contract, and reliable clinic attendance in the past. Underwriting for this unprecedented initiative is being provided by the South African government, with additional funds coming from the Global Fund for AIDS, Tuberculosis and Malaria, as well as the President’s Emergency Plan for AIDS Relief.

“Over the next three years, South Africa plans to open enough treatment sites to meet patient needs in all eleven health districts,” commented Bruce Walker, MD, Director of PARC. “Our goal is to do whatever we can to assist local health care providers during this process.”

For nearly a decade, Dr. Walker and his team have been collaborating with hospitals, universities, and government officials to improve AIDS research. More recently they have been assisting in the development of HIV treatment programs in South Africa. Under Dr. Walker’s leadership, in 2003 PARC and the Nelson Mandela School of Medicine established the first medical research building ever constructed at an African University.

“When we started in South Africa, we were focused exclusively on researching local HIV strains,” Dr. Walker recalls. “Before long, though, we realized that we couldn’t continue down that path in good conscience. In Boston, HIV was becoming an outpatient disease; meanwhile in Durban, our research patients were dying because they had no access to treatment. We had to find a way to help.”

Approximately two years ago, under the local leadership of Dr. Krista Dong from Partners, a pilot treatment program was initiated in a rural area in KwaZulu-Natal, and earlier this year the South African government began a treatment program in the public sector, which will eventually provide care in all health districts.

The World Health Organization estimates that 6 million South Africans have HIV or AIDS; in KwaZulu-Natal, the infection rate is 36%. Prior to the onset of the Partners project, less than 1 percent of the HIV+ patients who needed ARV therapy were receiving it.

“This is a very ambitious program that will save countless lives, keep families intact, and prevent the creation of more orphans. We are honored to play a part in this effort,” Dr. Walker said.

From the Executive Director's Desk

A worldwide alarm sounded recently when a highly resistant, rapidly progressive strain of HIV was detected in a patient from New York City. As this issue of the Global Health Update goes to press, local health officials are uncertain as to whether they have identified a “superstrain” outbreak, or simply an isolated case. Either way, this incident serves as a solemn reminder that the global struggle against AIDS is far from over. Our guest columnist for this special issue on AIDS is William Rodriguez, MD, Associate Director of Operations Research from the Office of International Programs at the Harvard Medical School Division of AIDS.

THE ECONOMICS OF AIDS
More than 35 million people across the world are living with HIV infection. A majority of them must survive on an income of less than $1 per day. Even when their earnings are supplemented with meager government-sponsored health services, the total health spend in dozens of developing countries is only $25 per person per year (By comparison, annual per capita health spending in the US is about $5,200). This $25 is expected to cover vitamins, childhood vaccines, prenatal care for pregnant women, mosquito nets, eyeglasses, antibiotics for malaria or TB, hospital stays for unexpected major illnesses and HIV medications. Bear in mind that the total annual cost of HIV treatment in these same developing countries has slowly come down to a range of about $1,500-$2,000 per person per year – not including prevention measures, such as condoms, or educational materials. How can anyone possibly provide $2,000 worth of services for $25?

Two developments in the past few years have started to address the impossibility of this situation. First, the cost of the HIV drugs has dropped to as little as $150 per person per year, thanks to the efforts of several organizations, including the William Jefferson Clinton Presidential Foundation. Second, international organizations, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria and The World Bank – along with the governments of Great Britain, Canada, many European countries and the US – have funneled billions of dollars per year into global HIV care and treatment.

Often we hear that these funds are needed to buy HIV drugs, such as the three-drug combination “cocktail” that has saved hundreds of thousands of lives in western countries. Indeed, by most estimates, six million people living in developing countries are in urgent need of antiretroviral therapy. The World Health Organization’s “3 by 5” Initiative has targeted putting three of the six million on treatment by the end of 2005 – a task that requires starting 50,000 patients in care each week for the next year. If you can imagine what a monumental undertaking that would be in the developed world, you’ll also understand that it isn’t as simple as buying more of the expensive HIV medicines, even if the price has dropped to $150 per year.

The real challenge is what development specialists call “capacity building” – constructing health systems where they don’t exist. Medical care, especially for a lifelong, chronic disease like HIV (or diabetes, its nearest analogy), requires clinics and nurses and community health workers and pharmacists and administrators – to say nothing of roads, and trucks, and supply chain management, and training courses, and standard operating procedures. Suddenly, even after drug prices have tumbled in the developing world from $10,000 per person per year (which is what we pay in the US), to $150 per person per year, an extra few billion dollars in annual support for 35 million people doesn’t seem like a lot.

Yet it turns out that one of the major cost drivers in global HIV care and treatment is the cost of blood tests – the equipment and test kits that allow health providers to diagnose HIV in people, and to monitor the disease over time. In the US, lab testing runs more than $1,000 per person per year for HIV care, largely because the machinery involved – spectrophotometers for HIV diagnosis, laser-based flow cytometers for CD4 counts, and thermocyclers for PCR-based viral load measurements – is both complex and enormously expensive. Now that the drugs no longer seem expensive relative to the cost of the lab tests, several groups have recently started attacking this previously overlooked problem. The US Centers for Disease Control, the Clinton Foundation, technology innovators, international patent lawyers, and biotech companies are all trying to work on negotiating lower prices, developing cheaper, accurate tests, and building new laboratories to meet the urgent need. But it is a long, hard slog.

Regardless of these international efforts, 7,000 people are still dying from AIDS every day. Given the death toll on young adults (otherwise known as the labor force), building the global health systems infrastructure necessary to control the AIDS pandemic is a little like building a sandcastle that crumbles with each shovelful of sand, and each new parapet you add. Despite how slow it is to work with sand, the question is whether we can help build and protect a strong enough structure before the tide washes it all away.  -William Rodriguez, MD

Physician Profile: Krista Dong

Krista Dong, MD is an Infectious Disease Fellow specializing in HIV/AIDS at Massachusetts General Hospital and Brigham and Women’s Hospital. She is also a medical researcher at the Partners AIDS Research Center. Dr. Dong treated patients in South Africa from 2001 - 2004.

“My goal is to help HIV+ patients become knowledgeable about their disease,” explains Dr. Krista Dong, “Once patients accept their illness and are empowered to understand it, then they can choose life. Without that, no treatment program will be effective.”

Having recently returned from Durban, South Africa, where she was a founding physician at the iThemba Family Care Center, Dr. Dong is responsible for helping hundreds of destitute HIV+ adults and children to “choose life.”

While serving at iThemba, Dr. Dong developed an intensive 9-hour drug-readiness training course for patients that incorporated local beliefs and cultural practices. She also helped the clinic establish a treatment support initiative in which counselors visit patients at home, acting as the physicians’ eyes and ears, to identify barriers to drug adherence and early drug side-effects. “We had a drug adherence rate of 99.6%,” Dr. Dong recalls, “I don’t know of any clinic, anywhere in the world, with better adherence.”

In testimony to her success, both of these programs are being replicated in other provinces by the South African government.

Originally drawn to the AIDS crisis after the deaths of several friends during the early 1980s, Dr. Dong is interested in continuing her HIV work in developing countries. When asked about her next destination, she quickly offers several possibilities: “Either a return to South Africa or a country like China or India, where the epidemic is emerging… I’ll go wherever I can contribute the most.”

For more information about the Partners AIDS Research Center’s work in South Africa, please visit www.mgh.harvard.edu/aids.

New Therapy Benefits Selected
Mesothelioma Patients

David J. Sugarbaker, MD
Chief, Division of Thoracic Surgery, Brigham and Women’s Hospital
Chief, Surgical Services, Dana-Farber Cancer Institute
Richard Wilson Prof. of Surgical Oncology, Harvard Medical School

Bruce E. Johnson, MD
Director, Lowe Center for Thoracic Oncology,
Dana-Farber Cancer Institute
Associate Professor of Medicine, Harvard Medical School

A promising new therapy offers hope for patients with malignant pleural mesothelioma (MPM). MPM, although relatively rare, with an estimated 10,000 new cases diagnosed worldwide every year, is an aggressive, almost uniformly lethal disease. Without treatment, patients can expect to survive for only four to nine months.

Palliative care is the most common therapy for MPM. Single modality therapies have been relatively ineffective, and multimodality treatment has provided the only glimpse of hope. Thus, since 1980, the Brigham and Women’s thoracic surgery group has pursued optimizing surgical therapies and local therapies, which, in concert with external radiation and chemotherapy, have improved survival rates and quality of life for MPM patients.

The innovative therapy, pleurectomy with intraoperative lavage, is offered at the Dana-Farber/Brigham and Women’s Cancer Center, an integrated adult oncology center combining the expertise of Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

Background. In 1991, we described an aggressive surgical procedureextrapleural pneumonectomy (EPP) – in which the lung, pleura, and portions of the pericardium and diaphragm are resected en bloc, and in 1996 we reported on a series of 120 patients treated with EPP as part of a trimodality therapy. The trimodality therapy involves surgical resection, radiation therapy, and chemotherapy. Although it is a complex procedure and therefore not widely performed, our study demonstrated that EPP is effective in reducing the mortality and morbidity of MPM.

Following this series, our colleague from radiation oncology, Elizabeth Baldini, MD evaluated the patients who died from mesothelioma following this three-pronged therapeutic approach. She noted that distant failures outside the chest were uncommon, and the most common failure sites were the same-side chest and abdomen. This phenomenon may have been caused by tumor cells shed from the pleural surface before surgery or disseminated during surgery, or by residual tumor at the resection margins. In any case, her findings suggested that more effective local control would likely benefit the patient.

We investigated intraoperative heated chemotherapy lavage as a local control strategy. The concept was adapted from a successful treatment strategy for ovarian carcinoma and peritoneal mesothelioma. Cisplatin has demonstrated activity in MPM and a safe history of intracavitary use. Hyperthermia increases cell permeability, enhances drug uptake, and also works synergistically with cisplatin. We have demonstrated this local control strategy could be safely used in conjunction with EPP and in conjunction with pleurectomy for patients who cannot withstand EPP.

Schematic of Heated Lavage System

Pleurectomy with intraoperative lavage. In May 2003, we presented to the American Society for Clinical Oncology the results of a Phase I/II trial of an innovative therapy for MPM patients who were not appropriate candidates for EPP. The treatment involves pleurectomy followed by intraoperative hyperthermic cisplatin lavage into the chest cavity. We found that this aggressive therapy is feasible and well-tolerated, even for this group of very sick patients with limited surgical options.

Patients included in this trial had biopsy-proven MPM and were not
appropriate candidates for pneumonectomy (poor lung function). Of 60 registered patients, 44 were deemed to be resectable, that is, we were able to debulk the tumor, leaving no area of tumor thicker than 1 cm.

We removed both the visceral and parietal pleura, and then performed intraoperative bicavitary lavage with dose-escalated heated cisplatin for one hour. The cisplatin perfusate is pumped through an inflow tube in the apex of the chest, drains through the pelvis, flows through a heat exchanger to maintain a constant temperature of 42 degrees C, and flows back into the chest through the inflow tube. Lavage is followed by intravenous infusion of sodium thiosulfate to bind and inactivate systemic platinum.

We treated three patients at each of several dosages levels-50, 100, 150, 175, 200, 225, and 250 mg/m2. Dose-limiting renal toxicity was noted at 250 mg/m2, and the maximum tolerated dose was established at 225 mg/m2. We treated 23 patients at this level with no toxic effects.

Results. Thirty-day mortality was 11 percent, which was not unexpected in this group of very sick patients. The median survival was 10.5 months, and there was a pronounced improvement in survival and disease-free interval with increases in cisplatin dose. (See charts.)

This benefit applied to both epithelial and sarcomatous/mixed cell type tumors. In studies of other therapies, patients with epithelial cell tumors experienced better survival. Interestingly, in this study, dose appears to trump histology as a predictor of recurrence-free interval. Although patients with epithelial cell tumors did better, those with mixed-cell type tumors also benefited.

Future. The next steps in continuing to develop this therapy include

• Conduct Phase II and III trials utilizing thiosulfate as a cytoprotection agent
• Conduct Phase I trials to investigate other systemic cytoprotection agents
• Investigate strategies to prolong disease-free survival
• Investigate whether pleurectomy with heated cisplatin lavage may be a cure for selected patients
  

Advanced treatment for mesothelioma is also offered at Massachusetts
General Hospital.

The International Mesothelioma Program at Brigham and Women's Hospital

The International Mesothelioma Program at Brigham and Women’s Hospital is a multi-disciplinary initiative that draws clinical, surgical and research expertise from the Dana-Farber Cancer Institute, Harvard Medical School, and the Harvard School of Public Health. Under the leadership of Dr. David J. Sugarbaker (left), a team of surgeons, pulmonologists, medical and radiation oncologists, radiologists and pathologists are all working together to extend the quality of life for patients and to find a cure for this aggressive form of cancer, which grows in the membranes lining the chest cavity, lungs, abdominal cavity or heart.

Genetic Battleground Marked Between HIV and Host

A study in the Dec. 9 Nature provides evidence that a specific genetic region – the human leukocyte antigen B (HLA-B) class I gene – plays a dominant role in shaping the body’s response to HIV infection. The study, led by Philip Goulder and conducted by a multiinstitutional team in the United States, the United Kingdom and South Africa, shows that slight differences in HLA-B proteins can noticeably influence disease outcome.

There are two sides to every infection. The pathogen that is deadly to one person may only be a nuisance to another, depending on the immunological weapons each host carries. In HIV infection, some are better equipped to fight the virus than others, and characterizing this advantage is the best chance for identifying new approaches to making vaccines. A study in the Dec. 9 Nature provides a large-scale snapshot of how genetic differences translate into a faster or slower course of disease in HIV infection. It points to a specific genetic region – the human leukocyte antigen B (HLA-B) class I gene – as having a dominant role in shaping both the body’s response to HIV and the virus’s countermeasures. The study, led by Philip Goulder, Harvard Medical School assistant professor of medicine at Massachusetts General Hospital, was conducted by a multi-institutional team in the United States, the United Kingdom, and South Africa, and demonstrates that slight differences in HLA-B proteins can noticeably influence disease outcome.

CLASS ACT
HLA class I molecules stud the surface of cells and act as warning beacons for roving killer T cells. When a cell is infected by a virus, the viral peptides churned through the cell’s protein processing machinery are bound by HLA molecules, which bring the peptides to the surface of the cell like warning flags. Each type of HLA molecule is capable of binding to only a certain range of peptides.

Humans have three different sets of HLA class I genes – A, B, and Cand each comes in hundreds of possible varieties. “It has been long recognized that this particular region of the human genome is more variable than any other region,” said Goulder, whose time is divided among Oxford, Boston, and Durban. Of the three sets of HLA class I genes, HLA-B is the most diverse, with more than 500 known variations. By keeping a long list of possible HLA molecules to choose from, humans are able to adapt their immune systems over time to meet new challenges from pathogens.

Previous research has suggested that a few specific HLA-B alleles protect certain HIV-infected people against developing AIDS. But the current study shows that the HLA-B genes are a key driver in the success – or failure – of the immune response to HIV in a large population of infected people.

PROFILING
The team studied a group of 375 HIV-infected South Africans who were not being treated for HIV. Using blood samples, the researchers measured the immune responses to more than 400 synthetic peptides that together represent all of HIV’s proteins. The analysis showed a wide diversity of responses; many of the peptides caused no response, and only five were recognized by more than 25 percent of the subjects. Many of the peptide responses could be matched to the occurrence of particular HLA alleles, and HLA-B contributed to more of the associations than did HLA-A or -C.

The team also looked at how the different HLA alleles that people carry can affect the progress of HIV infection to disease. In a group of 700 infected people, the team found that the viral load of the patients varied significantly according to which HLA-B alleles they carried, but not according to their HLA-A or -C alleles. Most of the variants that could be associated with viral load that was better or worse than expected were HLA-B. Certain HLA-B alleles also correlated closely with differences in CD4 T cell counts, used as an additional measure of disease progression since CD4 cells are the target of HIV and are slowly decimated over the course of infection, if left untreated.

THE PRESSURE POINT
The study “shows us where the action is – it’s happening at HLA-B,” Goulder said. The researchers also analyzed whether HLA-B alleles were exerting a greater evolutionary pressure on the virus. When they looked at all the viral proteins in a cohort of infected people from Perth, Australia, they found a significantly higher rate of viral mutations associated with specific HLA-B alleles than with HLA-A variants.

The evolutionary pressure works both ways; the study found evidence that the Durban population is adapting in response to the pressures of the virus. There was a higher rate of protective HLA-B alleles in HIV-infected mothers than in infants who are infected, suggesting that women with protective alleles are less likely to pass the virus to their offspring.

The study was a multi-site undertaking, with researchers at Harvard, Oxford, and the University of KwaZuluNatal in South Africa, amongother institutions. The findings are the fruit of a unique program led by Bruce Walker, Howard Hughes investigator and HMS professor of medicine at MGH, through the Partners AIDS Research Center and the HMS Division of AIDS. By creating the Doris Duke Medical Research Institute at KwaZuluNatal, the program has allowed South Africans to conduct basic research into HIV. The paper’s first author is South African scientist Photini Kiepiela, who had not conducted research on HIV before the facilities opened. “One of the things that I feel most excited about is that South African researchers, with support from Harvard Medical School, have been able to make a really significant contribution to our understanding of HIV,” Walker said.

One of the implications of the study is that not all immune responses are equal, and it may be that particular responses must be achieved over others. Nor is it known how certain HLA molecules offer better protection against HIV. Though the findings will not translate immediately into a new vaccine strategy, Walker said that the study “gives us much better insight into that battleground between the virus and the host and where the effective skirmishes are taking place.”

This article was written by Courtney Humphries and reprinted with permission from Harvard Medical School.

Partners In the News

At the invitation of Project Hope, a Mass General team consisting of 14 physicians, 25 nurses, two social workers and a nutritionist left Boston on January 24 to provide medical care for victims of the tsunami disaster. Based aboard a navy hospital ship called the USNS Mercy, which was stationed off the coast of Indonesia, the MGH team staffed the ship’s operating rooms and intensive care units, while also providing support to what little remained of the local medical infrastructure. Many of the patients, particularly children, were suffering from “tsunami lung,” which is severe aspiration pneumonia caused by inhaling seawater and mud.

Experts from Brigham and Women’s Hospital also joined the tsunami relief effort. On only a day’s notice, Hilarie Cranmer, MD (at left) departed for Indonesia on January 7th as a member of the International Rescue Committee. She spent the next 4 weeks conducting health assessments and providing medical relief in refugee camps to patients suffering from measles, scabies, respiratory infections and malaria.

Nearly 400 physicians from 18 countries attended the Partners International Cardiovascular Conference in Dubai on December 9 & 10. Chaired by Gilbert H. Mudge, MD of Brigham and Women’s Hospital, the conference emphasized innovative therapeutic strategies as well as the newest concepts in preventive medicine. Sponsored by an educational grant from Pfizer, the conference featured a faculty of five Harvard Medical School professors, who were joined by colleagues from Bugshan Hospital in Jeddah, Al Jazeira Hospital and Al-Mafraq Hospital in Abu Dhabi, as well as Cerrapasa Hospital in Istanbul. A second conference is planned for Fall 2005 in Dubai. For more information, contact Ann McKay, by email at amckay1@partners.org.

December 23, 2004 marked the 50th anniversary of the first successful human organ transplant – a kidney – performed at Peter Bent Brigham, a forerunner of today’s Brigham and Women’s Hospital (BWH). Prior to 1954, such a procedure had never been completed successfully on a human patient and the picture for those with organ failure was bleak. The first transplant – which involved a kidney donated by a 23-year-old man to his identical twin brother – radically altered the practice of medicine and gave new hope to the chronically ill.

Partners was pleased to participate in the 2005 Arab Health Exhibition and Congress. Pictured from left to right are Ann McKay, Middle East Health Services Manager; Jay Pieper, Vice President for Corporate Development and Treasury Affairs; and H.E. Hamad Al-Madfaa, Dubai's Minister of Health.

The Global Health Update is published three times per year by the International Program of Partners HealthCare System, Inc. The International Program develops opportunities for Partners staff to contribute to the improvement of health care around the world.

This publication provides medical news. It is not intended to provide medical advice, which should always be obtained directly from a physician. To subscribe, request additional copies or make comments, please contact us via email at partersinternational@partners.org or by phone at +1 (617) 724-6420.

©2005. Partners HealthCare System, Inc.