June 8, 2009
CIPRA HT 001 is a randomized, controlled, open-label clinical trial. It was designed to test the hypothesis that HIV-infected people with early HIV disease and CD4+ T cell counts -- a measure of immune health -- of 200 to 350 cells per cubic millimeter (mm3) have better survival rates when they begin antiretroviral therapy (ART) immediately as opposed to beginning treatment when their CD4+ T cell counts drop below 200 cells/mm3 or they receive an AIDS diagnosis. The study tested this hypothesis in a resource-limited setting where the standard of care is to provide ART when CD4+ T cells drop below 200 cells/mm3 or there is a diagnosis of clinical AIDS.
The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is the study sponsor. NIAID is funding the study through the Comprehensive International Program of Research on AIDS (CIPRA). The trial was carried out by the Haitian Group for the Study of Kaposi's Sarcoma and Immune Deficiency Disorders (GHESKIO) Centers in Port-au-Prince, Haiti. The principal investigator is Jean William Pape, M.D., the director of the GHESKIO Centers and a professor of medicine at Weill Medical College of Cornell University in New York.
The participants are 816 HIV-infected men and women ages 18 and older who had HIV disease (WHO Stage I, II or III (www.who.int/entity/hiv/pub/guidelines/HIVstaging150307.pdf)) and a CD4+ T cell count between 200 and 350 cells/mm3 upon enrollment in the study.
Study participants were assigned at random to begin ART either within two weeks of enrollment or when they were diagnosed with clinical AIDS (WHO Stage IV (www.who.int/entity/hiv/pub/ guidelines/HIVstaging150307.pdf)) or their CD4+ T cell count dropped below 200 cells/mm3. The first-line ART regimen used in the study consists of the drugs efavirenz, lamivudine and zidovudine.
In Haiti, the standard of care for treating HIV-infected individuals is to administer ART when an individual is diagnosed with clinical AIDS or their CD4+ T cell count drops below 200 cells/mm3.
A data and safety monitoring board (DSMB) is an independent committee composed of clinical research experts, statisticians, ethicists and community representatives to provide additional oversight of NIAID clinical trials.
DSMBs regularly review study data while a clinical trial is in progress to ensure the safety of participants and that any benefits found in the study are quickly made available to all participants. A DSMB may recommend that a trial, or part of a trial, be stopped if there are safety concerns or if the trial objectives have either been achieved or are unlikely to be achieved. The DSMB looks at analyses that are not available to the investigators or to anyone else.
CIPRA HT 001 was monitored annually by a DSMB. Given the recent publication of epidemiologic cohort studies indicating that earlier ART reduces overall risk of death, the study team asked the DSMB to conduct an earlier review than originally planned. The DSMB met on May 28, 2009.
During its May 28 review, the DSMB found overwhelming evidence that starting ART at CD4+ T cell counts between 200 and 350 cells/mm3 improves survival compared with deferring treatment until CD4+ T cells drop below 200 cells/mm3. Six participants in the early treatment group had died, while 23 participants in the standard-of-care group had died -- nearly four times as many. The DSMB also found that among participants who began the study without tuberculosis (TB) infection, 18 people in the early treatment group developed TB, while 36 people -- twice as many -- in the standard-of-care group developed TB. These results were statistically significant.
Because there was overwhelming evidence that starting ART earlier than the current standard of care in Haiti improves survival among HIV-infected individuals, the DSMB recommended that NIAID end the trial immediately so that all study participants could begin ART at CD4+ T cell counts between 200-350 cells/mm3. Ending the trial early also allowed the study team to share the DSMB's findings with other countries and public health organizations around the world. Many resource-limited countries have standards for HIV treatment similar to Haiti's, so the results of CIPRA HT 001 could be applicable elsewhere.
The study team is offering ART to all participants in the standard-of-care group who have fewer than 350 CD4+ T cells/mm3. The study team also will continue to follow all participants for approximately 12 more months and will make every effort to ensure that participants receiving ART continue their therapy.
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