A large-scale clinical trial of the use of steroids in treating tuberculosis (TB) pericarditis was already halfway through before it found funding. Even then, it was conducted on a relative shoestring. Nevertheless, the findings will change clinical practice and settle a great unanswered question in the treatment of patients with this condition.
The Investigation of the Management of Pericarditis (IMPI) trial found that the prescription of steroids to patients with TB pericarditis – a dangerous form of TB that can cause fluid build-up and compression of the heart, and kills a quarter of those who contract it – made no difference to their eventual mortality rate. Even more significantly, in HIV-positive patients, steroid treatment increased the risk of cancer. However, steroids were found to offer anti-inflammatory benefit by reducing fibrosis (also called constriction) of the heart and preventing scarring.
“Until now we have had contrasting evidence about this combination therapy, and therefore conflicting recommendations about it,” says lead investigator Professor Bongani Mayosi, Head of Medicine at Groote Schuur Hospital and the University of Cape Town.
This uncertainty had concerned him since he was a trainee specialist at Groote Schuur. Some specialists were believers in the use of steroids, and some were not. “When you were on intake, whether you – the trainee – gave the patient steroids depended on who the specialist was the next day. I reasoned that surely, if steroids worked, that should not depend on the whim of the specialist who was on call.”
However, IMPI settles the question. It is the first multi-national trial on TB pericarditis, and the largest trial of corticosteroids in HIV-associated TB. “Findings from the study suggest it may be reasonable to add steroids to regular treatment in TB pericarditis patients who don’t have HIV infection, to prevent constriction and reduce hospitalisation; but this strategy should be avoided in HIV-infected individuals, because of the increased risk of malignancy,” says Mayosi.
The study, which was presented at the European Society of Cardiology congress (and published simultaneously in the New England Journal of Medicine), enrolled 1 400 patients with pericarditis from 19 hospitals in eight countries in Africa.
African-led study with little funding
The road from idea to findings turned out to be strewn with obstacles, most of them financial. Mayosi, together with colleagues from seven other countries in Africa, began applying for funding, but drew a blank every time. The reason they were most often given was that no-one in the team had the required experience of conducting a large, multi-centre, clinical trial on the scale they were proposing.
However, in 2009, the group met: as it happened, Barack Obama had just been elected President of the USA, and his slogan ‘Yes we can’ was ringing in their ears. “When the group met the next day,” says Mayosi, “we said: we have no money, it is now four years since we’ve been trying to do this study, what are we going to do? And the group said, yes we can! We can do this study, despite the fact that we have no funding.”
Two years later, the group finally received funding from the Canadian Institutes of Health Research (CIHR). By then, they were already halfway through the trial. However, the CIHR enabled them to leverage further funding to expand and complete the trial.
“This was an African-led study with no initial funding that went to places that had never conducted trials before and established capacity there,” says Mayosi. “Yet we set new standards for data quality and completeness of follow-up in large African clinical trials, and challenged the perception that ‘Africans can’t do it’.”
Perhaps the name chosen for the study was significant: “We are named after the Zulu battalions – the Impi – who vanquished the great armies of Queen Victoria at Isandlwana. By that we’re saying that we are putting together a team that will solve this problem by whatever means necessary. The IMPI ‘warriors’ have overcome every obstacle to do the first multi-sector, multi-national clinical trial on the use of steroids in treating TB pericarditis in the history of the world.”
The effect of steroids on HIV
By far the most significant finding of the study was the effect of steroids on patients with HIV. The majority of patients (67.1%) in the study were HIV-positive. According to the World Health Organisation, the risk of developing TB is estimated to be 12 to 20 times greater in people living with HIV, compared to those without HIV.
The increase in HIV-associated cancers is consistent with the results of two previous studies on HIV-associated TB.
“The immune system keeps cancer cells in check to a certain degree, and HIV reduces this protection, which is why HIV-associated cancers occur. Steroids further depress the immune system, thus promoting the occurrence of HIV-associated cancers such as Kaposi sarcoma and non-Hodgkin lymphoma, which occurred in this study.”
Where to next?
Given the implications of these findings, it is perhaps surprising that the study only happened because of the determination of its team. “I go to many meetings where people do global studies,” says Mayosi, “and Africa is the black box – it is often missing, and yet people have the audacity to call those studies ‘global’. There is no longer an excuse now. IMPI has created the railroad – the infrastructure – for doing research studies throughout the sub-Saharan African regions. We have demonstrated that we not only have centres that can do studies of the highest quality, but people who can.”
The IMPI team is now planning to extend these studies to other heart conditions that affect African people, such as high blood pressure, rheumatic heart valve disease and stroke.
“Africa is open for business when it comes to health research,” says Mayosi. “We are ready to engage with the world on the highest level of quality required by science. We are looking for collaborators so that we can work together to solve some of the major health problems that are confronting us.”
PARTNERS and SOURCES OF FUNDING:
Key local partners were UCT, Groote Schuur Hospital, the South African Medical Research Council, the Walter Sisulu University/Nelson Mandela Academic Hospital (in Mthatha in the Eastern Cape) and other South African medical schools, and collaborators from Sierra Leone, Nigeria, Kenya, Uganda, Malawi, Moçambique and Zimbabwe. The key international partner was Professor Salim Yusuf and team from the Population Health Research Institute at Hamilton Health Sciences and McMaster University in Canada. Supported by grants from the Canadian Institutes of Health Research, CANNeCTIN, the Population Health Research Institute, the South African Medical Research Council, the Lily and Ernst Hausmann Research Trust and Cadila Pharma, India. Cadila Pharma also provided the prednisolone tablets used in the study, and supported distribution of the investigational drugs.