By James Neaton
The University of Minnesota is a leader in several areas of global health, from emerging infectious diseases to long-standing issues such as HIV/AIDS, tuberculosis and malaria. A prime example of this leadership is the research carried out by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), a network involving several hundred sites in 37 countries throughout the world who take part in clinical trials for the treatment of HIV. The leadership group and statistical and data management center for INSIGHT is located in the U of M’s Division of Biostatistics of the School of Public Health. INSIGHT is funded largely by the National Institutes of Health (NIH), though several governments around the world also contribute research funding.
Today, more than 35 million people are currently living with HIV/AIDS and more than 39 million have died of AIDS-related causes since the first cases were reported in 1981. While the disease exists all over the world, the majority of people living with HIV live in low-and middle-income countries; more than two-thirds (70 percent) live in sub-Saharan Africa. Only 12.9 million (37 percent) of people living with the virus have access to antiretroviral therapy (a treatment regimen that usually consists of three or more drugs that can effectively suppress the HIV virus in the blood). These sobering data illustrate the scale and scope of HIV, which remains one of the world’s largest global health crises.
Through INSIGHT, an interdisciplinary team of U of M researchers collaborate with hundreds of investigators around the world through coordinating centers in London (MRC Clinical Trials Unit), Copenhagen (University of Copenhagen), Sydney (Kirby Institute, University of New South Wales) and Washington D.C., (Veterans Affairs Medical Center and George Washington University). U of M researchers, together with investigators from these international coordinating centers and from hundreds of clinical sites around the world, have designed and completed the largest HIV treatment trials done to date.
Findings from INSIGHT clinical trials have been significant and have had wide-ranging impacts on clinical care for people diagnosed with HIV/AIDS throughout the world. In 2006, the INSIGHT group reported the results of a large trial called SMART (Strategies for Management of Antiretroviral Therapy). Over 5,000 participants were enrolled in SMART by 318 sites around the world. The study, which immediately changed treatment guidelines, showed that interrupting antiretroviral treatment was associated with an increased risk of AIDS as well as end organ diseases such as cardiovascular, renal and liver disease and cancer (serious non-AIDS conditions).
In 2009, the INSIGHT group reported the results of two large international trials of a drug called interleukin-2. The trials enrolled nearly 6,000 participants with HIV. These trials showed that while interleukin-2 dramatically improved markers of immune suppression it had no clinical benefit – it did not extend survival or reduce the risk of AIDS.
Currently, INSIGHT investigators are conducting a large, international randomized trial called START (Strategic Timing of Antiretroviral Treatment) for people with HIV who have no symptoms associated with their HIV and who are at very low risk of developing AIDS. Enrollment in this trial is complete; 4,688 participants with a CD4 count (a marker of immune suppression) that was still in the normal range were enrolled by 215 clinical sites in 35 countries (see figure). Follow-up with START will continue until 2016.
The trial is addressing some simple pragmatic questions: “When should antiretroviral therapy be initiated?” “Should treatment be initiated when the CD4 count is still very high or can it safely be deferred until the CD4 count declines to a level where risk of AIDS increases?” The questions were motivated by the results of the INSIGHT SMART trial. The findings from SMART indicated that the risk of a serious non-AIDS event could be greater among people not taking treatment compared to those taking treatment even when the CD4 count was high. Before SMART was conducted, it was widely believed that some antiretroviral drugs were associated with serious toxicities. While that may be the case, it is uncertain whether the risk of serious non-AIDS events is greater for those on or off antiretroviral treatment. The START trial will determine the risk/benefit of early treatment and the results will potentially affect the care of millions of people around the world.
While the NIH funding was originally to design and carry out large, international randomized trials on treatment strategies for HIV, in 2009, the research scope of INSIGHT expanded to studies of pandemic influenza and after that to other respiratory viruses. Influenza is a major cause of death each year around the world. Better treatments are needed especially for severe influenza infection. With the expansion of the mission of INSIGHT over five years ago to other infectious diseases, INSIGHT began conducting large cohort studies aimed at understanding the incidence and determinants of outcomes of people diagnosed with influenza who seek outpatient care or require hospitalization. To date over 8,000 people have been enrolled in the INSIGHT influenza studies.
In addition to ongoing observational studies, an international randomized trial of a new treatment for patients hospitalized for influenza is about to begin in the northern hemisphere this October. It will continue in the southern hemisphere next year. The novel treatment under investigation is a blood product produced from people who donated blood with high influenza antibodies – either from influenza vaccination or who had recovered from a recent influenza infection. This randomized international clinical trial aims to determine whether an intravenous infusion of the blood product can reduce disease severity and the duration of influenza illness.
In the near future, INSIGHT plans to expand its research portfolio to include the study of treatments for post-transplant infections.
Once an infrastructure like INSIGHT is built, it can be efficiently adapted to the study of other major diseases. While there remain many logistical and regulatory challenges to the conduct of international clinical trials, this is an exciting area that will only continue to grow. At the same time, challenges in the treatment and prevention of disease transcend national borders. Our knowledge concerning optimal strategies for improving health can be accelerated with international collaborations. Furthermore, such collaborations will result in new ways of looking at global problems, more efficient use of resources, and research findings that are more broadly applicable.
James Neaton is a professor in the University of Minnesota’s School of Public Health, Division of Biostatistics. He has research interests in the design, conduct and analysis of clinical trials. Neaton leads the international HIV clinical trials group INSIGHT and remains involved in clinical trials aimed at the prevention of cardiovascular disease.