This fight is personal

October 7, 2005

Having seen Aids claim family members, Paula Munderi applied her medical skills to fight the disease. Becky McCall found her working on a clinical trial that offers a lifeline to devastated communities

It was 1986 and Lydia, a 22-year-old Ugandan woman with a husband and a young baby, had just graduated from university. She had also just been given a diagnosis of a new infection called HIV. The doctor who made the diagnosis was Paula Munderi, fresh out of training and working in a missionary hospital in Kampala. She was Lydia's cousin. Lydia was the first of five children in their family who would receive the same diagnosis and lose their lives to Aids.

The story of a family devastated by Aids is commonplace in Africa, but Munderi's personal experience of the tragedy led her to enlist her medical skills in the fight against HIV. She is now co-principal investigator for a large-scale trial into the use of antiretroviral therapy (ART) in Africa and head of the Medical Research Council Entebbe research site in Uganda.

At 24, Munderi entered medical practice at the start of a new era in research and clinical practice for which no medical school could have prepared her. Her daily ward rounds in Kampala brought her face to face with HIV at its worst. The beds were 70 per cent full of patients little different in age or background from Munderi.

"When I diagnosed Lydia with HIV, I could not tell our family about it. At that time, anyone with the diagnosis was stigmatised," she recalls. "On top of this, treatment for HIV was non-existent. I could only treat the opportunistic infections such as oral candida and pneumonia, from which Lydia died in the end."

Munderi, who was born and brought up in Uganda, studied medicine at the University of Makerere before working in the US and Kenya. After receiving accreditation from the Royal College of Physicians in London, she felt the time had come to go home.

"Returning to Uganda from the UK felt like travelling back in time in terms of clinical practice. I married and had my first child, but life was far from normal. HIV had changed the landscape of life in Uganda for ever," she says.

Surrounded by death and despair, Munderi had little choice but to take on the challenge. Her optimism cut through the overwhelming despondency felt by her colleagues.

In fact, Uganda is often held up as a prime example of how an African country can manage the burgeoning crisis of HIV. Its Government took a stand and gave people clear direction about how to prevent and control disease. Radio stations, newspapers and schools provided vital information to the population.

Munderi became a lecturer in clinical medicine at Makerere University after a spell in clinical practice at Nairobi Hospital, Kenya. "I wanted them to see beyond the obvious limitations and make the most of the tools available. We have good clinical training in Uganda because the best teachers are patients - and of these there is no shortage."

But she knew that help from outside Africa was needed. In the mid-1990s, doctors in Europe and the US had begun to control Aids with combination drugs. ART was clearly beginning to make an impact where it was available, affordable and well resourced.

ART is a complicated regimen of drug therapy that usually involves three drugs known as Haart (highly active antiretroviral therapy), proven effective in postponing the development of full-blown Aids. But drug availability is only part of the burden of providing therapy. A good infrastructure and trained personnel are needed to carry out the laboratory tests that accompany treatment.

Munderi and her colleagues in Kampala struggled on with considerable success, but they were fighting an epidemic with one hand tied behind their backs. The most effective treatment was unavailable where it was needed most desperately.

When the World Health Organisation in Geneva advertised a vacancy for an HIV clinical care adviser, Munderi didn't hesitate. She spent three and a half years meeting the people responsible for influencing treatment protocols and funding trials to help people in poor countries get access to essential medicines.

Eventually, people in high places began to respond to the needs of doctors and HIV patients in Africa. With partners from the Department for International Development, the Rockefeller Foundation and the Medical Research Council, Munderi's team rallied support for a study of the use of ART in Africa. The Dart (Development of Antiretroviral Therapy) trial got the go-ahead in 2001.

"It took five years from the initial negotiations to the first patient receiving treatment," Munderi says. "Drug availability was the biggest stumbling block. We fought for free drugs and money for the trial and finally received free drug supplies from GlaxoSmithKline, Boehringer Ingelheim and Gilead Pharmaceuticals."

Just over 3,000 adults, spread across two sites in Uganda and one in Zimbabwe, have begun ART for the first time. They will be followed over the next five years to see if therapy without sophisticated laboratory tests still reduces disease progression and death rate. The trial is also investigating whether treatment can be successful if given intermittently rather than continuously. In reality, it is not unusual for patients to stop and start treatment owing to the drugs' toxicity and what is termed "pill fatigue".

Munderi says it puts clinical skills to the test. "As clinicians in rural Africa, we have only our eyes, ears and hands with which to treat patients, so we monitor them purely with our clinical acumen and ability to spot the danger signs of a bad reaction to the drugs."

So far, the results look promising. The Entebbe trial site in Uganda has clinical records on local patients dating back to 1995, so there is a pre-ART benchmark for comparison. "One year into the trial, ART has shown a strong and significant reduction in HIV-related deaths of about 10 per cent among patients with advanced HIV in this Ugandan community," Munderi says.

Seven years' worth of data on 3,000 patients generates a lot of data.

Thousands of miles away, in the MRC Clinical Trials Unit in London, 33-year-old Sarah Walker is trying to make sense of it all. When she was growing up, her mother ploughed through similar statistics relating to tuberculosis trials in Africa. "Having trained in maths, I wanted to do something different from accountancy or teaching, but I still wanted to do what I am good at and to use maths in a way that is socially responsible," she says.

She argues that the scientific predictability that is often associated with statistics is balanced by the unpredictability of the DART trial and HIV itself. "Just when we think we are winning the battle with HIV, something comes along to upset the balance and tip it all over again. As a medical statistician, I have to constantly make sure that we are on track and that we don't end up finding the answer to the wrong question five years down the line."

Few trials in Africa have been run on this scale and with this degree of complexity. Not only will the trial answer essential questions about the delivery of drugs in a resource-starved environment, it will also determine whether it is feasible for patients to have periods off drug treatment and free of the high toxicity associated with the drugs.

But for researchers such as Munderi, the trial is about more than scientific results - it is about the difference between life and death.

With a poignancy that cuts through her professional exterior, she regrets the harsh hand that fate and timing dealt her cousin. "If only it had been a different time, she might have been put into the trial," she says.


Age: 44

Education 1994-99: Makerere University Medical School, Kampala, Uganda

1988-92: Medical training at the Nairobi Hospital, Nairobi, Kenya

Medical work

Currently project leader and co-principal investigator for the Development of Antiretroviral Therapy (Dart) in Africa trial

1999- 2002: Worked in Department of Essential Drugs and Medicines Policy and as medical officer, HIV Care and Support Team, World Health Organisation, Geneva

Focus: AIDS

Women in Africa are to be given the power to defend themselves from sexually transmitted disease as major trials of a potential HIV-protective gel get under way.

Researchers from the Medical Research Council Clinical Trials Unit at Imperial College London and clinical sites in Africa are collaborating on the largest multi-centre trial the continent has seen. The microbicide gels - which are applied intravaginally and designed to protect the body from virus invasion and to prevent transmission to a sexual partner - will be tested on about 12,000 African women.

In parts of Africa, it is common for men to refuse to wear a condom, and cultural and religious beliefs limit a woman's power to protest. The gels were designed to give women more control over their sexual health.

Janet Darbyshire, director of the MRC's Clinical Trials Unit, says: "At present, the only method of preventing HIV transmission is the condom. As an effective HIV vaccine is not yet on the horizon, microbicides offer the best hope of reducing transmission in the short to medium term. Even a partially effective microbicide, if used with condom promotion, could have a significant impact."

Nearly 45 million people are infected with HIV worldwide, and the figure is set to escalate. Most people contract the virus through unprotected sexual relations.

The microbicide could work in three ways: by killing the virus before it enters the body, by serving as a barrier to virus entry, or by preventing the virus from taking hold once in the system.

Each research site for the microbicide trial has a community liaison officer to prepare the local women. Julie Bakobaki, who is co-ordinating the trial across Uganda, Tanzania, Zambia and South Africa, says:

"Widespread adoption of microbicides is dependent on a number of factors, not least of which is their level of acceptance by both partners in a relationship. The trials will not only look at the long-term safety and efficacy of the intervention but also at social and behavioural factors."

About 60 microbicides are in development, and about 14 of them are at the clinical trial stage.

It will no doubt be some time before research arrives at a clinically effective and culturally acceptable product. "Although it is likely to be some years before we have microbicide in commercial production, we should know within the next five years, if there is at least an effective product," Darbyshire says.

Becky McCall

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