Timing is everything when treating patients with both HIV and tuberculosis. Starting HIV therapy in such patients within two weeks of TB treatment, rather than two months as is the current practice, increases survival by 33 percent, according to a large-scale clinical trial in Cambodia led by researchers at Children's Hospital Boston and the Immune Disease Institute (IDI).
The study's results -- reported by Anne Goldfeld, MD, of the IDI and the Program in Cellular and Molecular Medicine at Children's Hospital Boston, and the CAMELIA (Cambodian Early versus Late Introduction of Antiretrovirals) study team in the October 20 issue of the New England Journal of Medicine -- definitively show that immunosuppressed HIV-TB co-infected patients should be started on ART rapidly at two weeks after beginning TB therapy. At the same time, the results strongly suggest that the World Health Organization (WHO) should be more aggressive in its recommendations for treating such patients.
A collaboration of Cambodian, French, and American physicians and researchers, the CAMELIA trial set out to settle a long-standing debate in the medical community over the relative timing of antiretroviral (ART) and anti-TB treatment regimens in co-infected patients. Some have advocated for delaying ART for upwards of two months after initiating anti-TB treatment, arguing that the toxicity of and difficulties in adhering to the two regimens (which together require patients to take seven pills every day), as well as the risk of severe inflammation as the immune system rebounds from HIV's suppressive influence, create undue burden on patients. Those supporting early initiation of ART note that rapid restoration of immune function bolsters the effects of anti-TB treatment.
"Tuberculosis claims the lives of more than half a million people with HIV worldwide every year," said Goldfeld, who holds professorships in medicine at Harvard Medical School and immunology and infectious diseases at Harvard School of Public Health and is co-founder of the Cambodian Health Committee. "This is a tragedy, because TB is completely curable when diagnosed and treated properly even in a patient with advanced HIV, especially if the patient also receives anti-retroviral therapy."
The WHO, in its most recent guidelines, recommended that co-infected patients start ART as soon as possible within eight weeks of initiating anti-TB treatment, but at the time lacked any evidence-based research to provide more fine-grained guidance.
Upon enrollment in the CAMELIA trial, all participants started standard treatment for TB, followed either two weeks or two months later by ART. Patients, all of whom had very weak immune systems, were seen at one of five study sites across Cambodia and followed for as long as four and a half years. By the time enrollment closed, 661 patients had been recruited into the study.
The study's results make a very strong case for starting ART treatment as early as two weeks after initiating treatment for TB. At the end of the study, the survival rate in the early ART arm was 33 percent greater than that in the late ART arm.
The study was also remarkable for its successful level of follow up: Of the trial's 661 participants, only 12 were lost to follow-up over the study period, and participants only missed less than one percent of the study's 8,955 scheduled visits.
"When we started, there was no research infrastructure for conducting such a trial in Cambodia. ART was just being introduced into the country, and HIV and TB were not being treated in an integrated fashion," Goldfeld said. "As side benefits, over the course of the study we helped to establish a center of excellence for HIV and TB care, and a center for treating children with HIV. We also created a national framework in Cambodia for treating patients with multi-drug resistant TB, which is now being replicated in Ethiopia.
"We also want to understand how the immune system is restored when you give HIV drugs while treating TB at the same time," Goldfeld continued. "This trial has created an unprecedented opportunity to gain fundamental insights into the workings of the immune system in the context of HIV and TB. It has many fruits yet to bear."
The study, which was previously reported at the 18th Annual AIDS Meeting in Viennea in 2010, was supported by the National Institute of Allergy and Infectious Diseases and the French National Agency for Research on AIDS and Viral Hepatitis.
- François-Xavier Blanc, Thim Sok, Didier Laureillard, Laurence Borand, Claire Rekacewicz, Eric Nerrienet, Yoann Madec, Olivier Marcy, Sarin Chan, Narom Prak, Chindamony Kim, Khemarin Kim Lak, Chanroeurn Hak, Bunnet Dim, Chhun Im Sin, Sath Sun, Bertrand Guillard, Borann Sar, Sirenda Vong, Marcelo Fernandez, Lawrence Fox, Jean-François Delfraissy, Anne E. Goldfeld. Earlier versus Later Start of Antiretroviral Therapy in HIV-Infected Adults with Tuberculosis. New England Journal of Medicine, 2011; 365 (16): 1471 DOI: 10.1056/NEJMoa1013911
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