Studies underway on metabolic side effects of antiretrovirals

The Committee for the Evaluation of the Metabolic Complications of HAART recently met to review the status of four research studies it is sponsoring to explore side effects of antiviral medications:

  • A study to develop a case definition of lipodystrophy;
  • A prospective observational study of several patient cohorts from 11 countries in Europe, the US and Australia totalling over 20,000 participants to look for increases in rates of heart attacks, strokes, and diabetes;
  • A meta-analysis of recently initiated metabolic studies of major clinical trials networks and other related studies; and
  • A retrospective review of medical records in the HIV database of the US Veterans Administration system to determine whether there was a significant increase in the rate of heart attacks and strokes following the introduction of HAART.

These efforts are characterized by collaboration, starting with the Committee itself. The Committee was created in response to a request by the European Medical Evaluation Agency (EMEA) for more information regarding the possibility that antiviral medications might cause an increase in rates of heart attacks or strokes. It consists of representatives from eight pharmaceutical manufacturers of HIV antiviral medications, plus members from academia, the European Union (EMEA-CPMP Pharmacovigilance WP), the US Food and Drug Administration, and the community. Committee co-chairs are David Pizzuti, MD, Vice President of Medical Affairs at Abbott Laboratories and Professor Ian Weller, head of the Department of STDs, Royal-Free and University College Medical School, London.

In another example of collaboration, the prospective observational study will combine data from a large number of existing HIV research cohorts, some of which normally compete for research resources and subjects. Finally, the principal investigators of large metabolic studies from several networks are collaborating to harmonize the data collected in each study as much as possible, laying the groundwork for future meta-analysis.

The pharmaceutical companies comprising the Committee are Abbott Laboratories, Agouron Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, DuPont Pharmaceuticals, GlaxoSmithKline, Hoffmann-La Roche and Merck. Collectively, these firms are committing approximately five million dollars to support the four research studies.

Each research study is conducted by an academic researcher as principal investigator and has its own steering committee. Research proposals were subjected to peer review before they were approved and funded by the Committee. The Committee receives regular status reports and critically evaluates progress on the individual studies.

These important research studies are expected to significantly advance our understanding of the side effects associated with HIV antiviral medications but are not intended to provide definitive answers.

Lipodystrophy Case Definition Study

Principal investigator: Andrew Carr, St. Vincent’s Hospital, Sydney

  • Design: Case-control study
  • Objective: Formulate a sensitive, specific, simple, cost-effective and universally applicable tool for diagnosis of lipodystrophy syndrome(s).
  • Sites: 35 clinical sites in Europe, Asia, Australia, and North and South America
  • Expected Recruitment: 800 subjects
  • Projected Completion: 3rd quarter of 2001

This is the first major systematic effort in this area. Four hundred patients with lipodystrophy will be identified along with 400 control patients. The study has a goal of recruiting at least 160 women. A “training dataset” will consist of 250 cases and 250 controls. The study will identify the variables that differentiate the cases from the controls. These variables will be used to develop one or more definitions of lipodystrophy. The definition(s) will then be tested against the “validation dataset” consisting of the remaining 150 cases and 150 controls. This will be the first careful definition of lipodystrophy, and may not apply to special populations such as infants and children or to certain ethnic groups.

Data Collection on Adverse Events of Anti-HIV Drugs (The DAD Study)

Principal investigator: Jens D. Lundgren, MD, Copenhagen HIV Program

  • Design: Prospective cohort study
  • Objective: Attempt to determine whether there is an increased risk for cardiovascular events when patients are receiving HAART
  • Sites:11 cohorts in Europe, the US and Australia
  • Expected Recruitment: Over 20,000 subjects
  • Projected Completion: 3rd quarter of 2002

Subjects will be followed for an average of two years, generating at least 30,000 patient-years of data. Rates of cardiovascular disease events will be compared in time intervals since initiation of antiviral therapy to study whether rates increase with longer exposure to therapy, and further to compare these rates with large studies of the general population. The DAD study is powered to determine whether HAART therapy results in at least a doubling of risk. It will not likely have sufficient power to determine how much each antiviral drug might contribute to cardiovascular risk.

Meta-analysis of metabolic studies

  • Principal investigator: Janet Darbyshire, PhD, Medical Research Council Clinical Trials Unit, London
  • Objective: Attempt to discern whether information gathered previously in already completed trials or in ongoing prospective trials can derive information on the incidence of metabolic abnormalities with specific types of HAART therapy
  • Projected Completion: 2003

This effort is based on the data collected in existing research trials. The more similar the data sets, the more powerful the results of the meta-analysis. A feasibility study will be conducted and include review of some completed and ongoing studies and may produce a first meta-analysis. As part of this effort, the principal investigators of the major metabolic studies in na•ve patients (ACTG384, CPCRA FIRST, INITIO, and ATLANTIC), have collaborated to align the metabolic data they are collecting. This will maximize the power of the meta-analysis and will result in a model dataset for studies of metabolic complications. The major metabolic studies will follow subjects for several years, which will increase the value of the data they produce. The meta-analysis will be conducted following the completion and unblinding of the data sets.

Retrospective review of Veterans Administration database

Principal investigators: Barbara R. Phillips, PhD, and Samuel A. Bozzette, MD, PhD, Veterans Affairs (VA) San Diego Healthcare System, University of California, San Diego, California.

  • Design: Retrospective analysis
  • Objective: Assess the impact of highly active antiretroviral therapy (HAART) and classes of antiretroviral drugs on serious, adverse cardiovascular and cerebrovascular events in the context of a changing force of mortality
  • Data Characteristics: Over 20,000 patient-years
  • Projected Completion: 3rd quarter of 2001

This study has been designed to determine whether there has been a large increase in the rate of heart attacks and strokes among people using HAART. The dataset has certain limitations, including a lack of information about whether patients were smokers or not (a major risk factor for cardiovascular disease) and limited information on other cardiovascular risk factors. Due to the small number of women in the VA system, data will be analysed for men only. This analysis is intended to provide a rapid evaluation of how much HAART therapy increases the risk of these serious events.

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