Peter O'Donnell

This prospective study of HIV-infected persons under active follow-up has been underway since 1999, based on multinational cohort collaboration. When it started, the study was designed as a collaborative review of the cardiovascular safety and metabolic and body composition changes possibly associated with HIV treatment.

The scope of the study was extended in 2005 to include investigation of liver-related safety. It now includes data from 33,308 patients in 11 ongoing HIV cohorts in Europe, Australia, and the United States.

DAD in the details

The data collection for DAD takes place at least every eight months. Each cohort gathers and computerizes its data, subsequently merging it into a database at the Copenhagen HIV Programme (CHIP), a research unit at the Faculty of Health Sciences University of Copenhagen.

The core data in the study is information on cases of cardiovascular disease, which are reported immediately to the local cohort coordinating office, using event reporting forms. The data collection also includes information on risk factors for cardiovascular disease, such as previous myocardial infarction or stroke, hereditary tendency, smoking status, diabetes mellitus, dyslipidemia, and hypertension.

An association between antiretroviral combination therapy and myocardial infarction was identified in 2003. Further follow-up established that this was mainly explained by cumulative exposure to protease inhibitors. More recently an association with the recent use of abacavir and didanosine was found and is being further investigated.

The study will also be expanded to consider whether antiretroviral medicines affect the risk of contracting non-AIDS defining cancers and end-stage kidney disease, as well as to examine patterns of causes of death over time and laboratory markers of liver and kidney function.

Although marketing authorization holders of antiretroviral medicines contribute to the funding of the study, it is run in scientific independence, ensured by an independent scientific steering committee, which takes all scientific and procedural decisions.

The Oversight Committee for The Evaluation of Metabolic Complications of Highly Active Antiretroviral Therapy (which includes representatives of academia, patient organizations, the European Medicines Agency (EMEA), and U.S. FDA administers the funds for studies, follows their progress, and ensures their completion.

European pride

The EMEA greeted the decision to continue the study with particular enthusiasm. As it points out, "the DAD study was started in response to a request from the EMEA to all marketing authorization holders of antiretroviral medicines." In addition, the oversight committee reports to the EMEA on progress.

The renewed commitment of the sponsors should ensure that the study continues at least until 2012 and "will remain one of the most powerful pharmacovigilance tools to monitor the long-term safety of antiretroviral medicines."

The announcement of the extension in early February came days after the January meeting of EMEA's Committee for Medicinal Products for Human Use—at which representatives of the oversight committee and steering committee presented the achievements made over the past 10 years and the plans for the study's continuation.

There is no doubt in the EMEA's mind about the importance of the study. "Due to its large size and long follow-up, the DAD study has had a pioneering role in drug safety, helping to address existing and new emerging safety concerns, as well as to learn more about HIV infection itself," the agency said in a statement. And looking ahead further, it added: "This is likely to serve as a model for future collaborative observational studies that will analyze the safety of whole therapeutic classes of medicines."