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The warm heart of Africa – 30 years of research in Karonga

14 Jul, 2009
Leprosy remains a health issue. Although new cases of disease have become infrequent, long-term disability in old cases remains a sizeable problem and the Karonga Prevention Study continues to follow up these individuals.

Leprosy remains a health issue. Although new cases of disease have become infrequent, long-term disability in old cases remains a sizeable problem and the Karonga Prevention Study continues to follow up these individuals.

The Karonga Prevention Study in Malawi is one of the largest and longest running epidemiology research projects in the world, delivering key insights into diseases such as leprosy, tuberculosis and HIV/AIDS. Mun-Keat Looi looks back on 30 years of the project.

At first glance, Malawi’s northern Karonga district is a remarkably isolated place: a single road over mountains to the south, and a bridge north to Tanzania are the only connections to the outside world for the population of farmers, fishermen and small traders. But look again, for this is home to one of the largest and longest running field research sites in the world.

The Karonga Prevention Study has been running for more than 30 years, covering a population of some 250 000 people over a 150-kilometre area, with isolation actually its primary advantage.

“The lack of roads meant less movement in and out of the population, offering lots of potential for epidemiological studies,” says Professor Paul Fine, Director of the project for 28 years until 2006.

“It was a unique opportunity and there’s never been another study like it. Establishing it was a bold step and I don’t think anybody would ever do it again. Much credit is owed to LEPRA [the British Leprosy Relief Association] for having had the vision to support the study from the beginning.”

Leprosy and luck

The study was, as Professor Fine puts it, a “serendipitous accident of history”. Conceived in the late 1970s, the project was born of the then newly established World Health Organization TDR (Tropical Disease Research) Programme and a revolution in leprosy research stemming from the discovery that armadillos could be used to culture Mycobacteria leprae, the bacterium that causes the disease.

TDR was developing skin and serological tests to detect M. leprae infection and potential vaccines. What it needed was somewhere to evaluate them. Leprosy was endemic in Karonga, which was under the jurisdiction of LEPRA, and the site presented an ideal opportunity to conduct clinical trials and study the epidemiology of the disease on a scale never previously attempted.

Karonga district, six hours drive from Lilongwe

Karonga district, six hours drive from Lilongwe

Together with the London School of Tropical Medicine and Hygiene, the project conducted two comprehensive surveys of the entire Karonga population – some 112 000 people, rising to 133 000 by the second survey – over ten years.

“We had the most intense case study finding and control programme ever carried out on leprosy,” says Professor Fine. “Every suspect was biopsied, our treatment programme was as rigorous as any in the world, and we ended up vaccinating the whole population with BCG.”

Establishing the Study was a tremendous physical, logistical and administrative task. The fieldwork, led by the London School’s Dr Jorg Pönnighaus, was conducted on foot with information collected on paper, long before computers, GPS and decent roads were available.

The researchers set up systems that would allow them to recognise individuals and households. And because leprosy clusters in families, the project in effect drew a huge pedigree, mapping out the entire district’s population in genetic terms.

That the surveys went smoothly is testament to the amicable nature of the Karonga people.

“We took our time, nothing was forced, and people were always examined in a discrete way. Rarely did we have difficulties. After all, a nickname for Malawi is the ‘warm heart of Africa’,” says Professor Fine.

Beyond leprosy

Tuberculosis had been studied concurrently almost from the start of the project – unsurprising given that the disease-causing bacteria are of the same genus (Mycobacterium), require the same laboratory stains and are susceptible to the same drugs. For many years, the Karonga Prevention Study was the only laboratory in Malawi doing sputum culture for tuberculosis.

“We collected detailed data on patterns of drug sensitivity and of exposure to various mycobacterial antigens and their implications for leprosy and tuberculosis risk, which has made an important contribution to the current discussion of mycobacterial vaccines,” says Professor Fine.

There was evidence that BCG – the primary vaccine for tuberculosis – had some efficacy against leprosy. One of the project’s major findings was that a booster BCG vaccine – cheap and easy to roll out – increased protection against leprosy by as much as 50 per cent. This was a major success for Professor Fine and his team, who had fought to test this hypothesis at a time when many leprosy researchers were more interested in new cocktail vaccines of killed leprosy bacteria and BCG (subsequently shown to offer no increase in protection over BCG alone).

Specimen collection: A local resident talks to a Study counsellor at home.

Specimen collection: A local resident talks to a Study counsellor at home.

The discovery of HIV in the early 1980s brought concern that weakened immune systems would lead to a resurgence in leprosy cases. But a case control study in Karonga was the first to show that HIV is not associated with leprosy.

“Because we were interested in a serological test for leprosy, we had collected around 60 000 blood samples dating back to the early 1980s,” says Professor Fine. “This included samples from every leprosy and tuberculosis case we saw, along with accompanying information on all these people. That was a tremendous resource.”

That allowed the researchers to re-examine their samples, showing that HIV was present in Karonga as far back as 1981, and to track its increase over time through the district and the resulting patterns of morbidity and mortality.

“Over the years, we developed a programme of research emphasising genetics, leprosy and tuberculosis,” says Professor Fine. “The HIV work has grown over time to be an important part of the roll-out of antiretroviral therapies (ARTs) in the district. And it all grew out of those samples collected for leprosy.”

Karonga at present

With new funding from the Wellcome Trust, the Study’s work expanded in the 2000s to include sophisticated immunological work, investigations of the mode of action of BCG, as well as a continuous population surveillance survey, monitoring fertility and mortality in the south of Karonga district. The project received £3 million of core funding from the Trust in 2006, with a further £2.3 million in 2009 to keep it running until 2011.

According to Dr Neil French, Director of the Study since 2006, the demographic work, though expensive to run, provides the platform for the project’s wide variety of studies. “Because the survey is already a part of our work, we don’t have to collect any extra socio-demographic information on children and families to do new work. We get a very efficient use of resources.”

Pneumococcal research is a new interest, looking at the limitations of pneumococcal vaccines and the implications of introducing conjugate vaccines into a population with a high prevalence of HIV.

The HIV testing team preparing to go out for daily duty.

The HIV testing team preparing to go out for daily duty.

“Because pneumococcal disease is significantly more common in Africa than elsewhere, there is assumed to be far more transmission of the bacteria, which may be exacerbated by HIV,” explains Dr French.

“We’re using Karonga’s strengths to follow a cohort of children from birth, building up a pattern of pneumococcal transmission in newborn babies and their immediate household members, and measuring that in the context of HIV-affected and unaffected families, and how this will change when pneumococcal vaccines are rolled out in an immunization programme.”

The project is also doing major work assessing ARTs for HIV, investigating demographic change and the effect of ART use on reducing HIV transmission.

“Clearly ARTs are very expensive and have an individual benefit. But if they have a preventative benefit then that gives a substantially greater reason to continue the funding and intensive investment in ARTs here,” says Dr French.

“Karonga is, in a sense, ahead of the game. For the last three years we’ve been looking at what can be achieved in terms of reduction of HIV transmission with the current level of ART coverage. That provides meat for more modelling exercises: what might you get if you increase the level of coverage?”

“And we’re not just following a cohort of people that come to a clinic, but people who don’t go to a clinic. This allows us to see what happens at the community level, which is essential to control HIV and to ensure that people with HIV stay alive. Karonga offers a real grassroots, community level assessment of what’s going on.”

They are also building on the Study’s legacy of tuberculosis research: in a long-term case control study, researchers are collecting data on tuberculosis patients who have also received ART to treat HIV.

“Because of our strong historical data, we’re able to start making statements on what the impact of ARTs is on tuberculosis transmission,” says Dr French. “That has implications for how we’re going to tackle tuberculosis control; whether we should be giving prophylaxis against the disease to everybody who is infected with HIV when they start their ARTs.”

Community led

The study still has its challenges. The lack of a major hospital link restricts its capacity for clinical research and teaching, and its rural location can be a problem for attracting clinical scientists.

Yet because of its local community, the Karonga Prevention Study continues to succeed.

“The strength of Karonga is the longevity of what we’ve been doing, and a big part of that is how we’re involved with the community,” says Dr French.

“Many other sites have faced problems doing research in difficult healthcare systems and where HIV continues to take its toll. But the Karonga Prevention Study has a legacy from the reduction and disappearance of leprosy. The community’s trust in what the Study does has been strengthened by that.”

Professor Fine agrees: “The Study is an integrated part of the community and not some sort of Northern establishment plumped in the middle of rural Africa. I’m happy we were able to establish an important resource for tropical medicine, and in a way that was appropriate to, and appreciated by, the local population.”

Image credits: Karonga Prevention Study

References

Pönnighaus JM et al. The Lepra Evaluation Project (LEP), an epidemiological study of leprosy in Northern Malawi. Lepr Rev 1987;58:359-75.

Pönnighaus JM et al. Is HIV infection a risk factor for leprosy? Int J Lepr Other Mycobact Dis 1991;59:221-28.

Fine PEM et al. Delayed-type hypersensitivity, mycobacterial vaccines and protective immunity. Lancet 1994;344:1245-49.

Karonga Prevention Trial Group. Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. Lancet 1996;348:17-24.

Fine PEM et al. Household and dwelling contact as risk factors for leprosy in northern Malawi. Am J Epidemiol 1997;146:91-102

Glynn JR et al. Patterns of initial and acquired antituberculosis drug resistance in Karonga District, Malawi. Lancet 1995;345:907-10.

Glynn JR et al. The development of the HIV epidemic in Karonga District, Malawi.AIDS 2001;15:2025-29.

Black GF et al. BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies. Lancet 2002;359:1393-1401.

Crampin AC et al. Long term follow-up of HIV positive and negative individuals in rural Malawi. AIDS 2002;16:1545-1550.

Glynn JR et al. Trends in tuberculosis and the influence of HIV infection in northern Malawi, 1988-2001. AIDS 2004;18:1459-63.

Jahn A et al. Population level-impact of HIV on adult mortality and early evidence of reversal after introduction of antiretroviral therapy in Malawi. Lancet 2008;371: 1603-11.

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