Antibiotic Reduces Death in HIV Patients By Michael Smith, North American Correspondent, MedPage Today Published: March 29, 2010 Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston. A cheap and widely available antibiotic markedly reduced mortality when added to antiretroviral therapy in Africa, researchers said. Co-trimoxazole (known as trimethroprim-sulfamethoxazole in the U.S. and sold under several brand names worldwide) reduced the risk of death by 35% among people starting combination antiretroviral therapy, according to Sarah Walker, PhD, of the MRC Clinical Trials Unit in London, and colleagues. The effect was even higher in the first three months of HIV therapy and was sustained for another 60 weeks, but was not seen after that, Walker and colleagues reported online in The Lancet. The World Health Organization recommends the prophylactic use of the drug in all symptomatic adults in resource-limited settings whose CD4-positive T-cell count is lower than 350 cells per microliter, the researchers noted. Despite those guidelines, prophylaxis with the drug is often omitted, the researchers said, because many physicians think it will have little benefit and might reduce adherence to antiretroviral therapy. To add to the information about the drug, Walker and colleagues looked at data collected during the DART randomized trial of different approaches to monitoring HIV patients. The trial, run in four African centers, included 3,316 participants who started antiretroviral therapy at a CD4 count of less than 200 cells per microliter. The 3,179 participants eligible for this analysis had variable exposure to co-trimoxazole, with 10% never getting the drug, 62% taking it when they started antiretroviral medications, and the rest starting co-trimoxazole while they were already on anti-HIV therapy. Co-trimoxazole treatment was not randomized, so the researchers used marginal structural modeling to assess cause and effect. Marginal structural models are causal models designed to adjust for time-dependent confounding in observational studies of time-varying treatments. Analysis of the data showed: * Overall, prophylaxis significantly reduced mortality during an average of 4.5 years of follow-up. The odds ratio was 0.65, with a 95% confidence interval from 0.50 to 0.85, which was significant at P=0.001. * During the first 12 weeks, the reduction was greater, with an odds ratio of 0.41 and a 95% confidence interval from 0.27 to 0.65. * The reduction in mortality risk was still present and significant from 12 weeks through 72, with an odds ratio of 0.56 and a 95% confidence interval from 0.37 to 0.86. * After 72 weeks, there was no evident reduction of mortality risk from co-trimoxazole prophylaxis. * On the other hand, prophylaxis reduced the frequency of malaria and that effect was maintained over time. The odds ratio was 0.74 with a 95% confidence interval from 0.63 to 0.88, which was significant at P=0.0005. * There was no effect on new WHO stage 4 AIDS-defining events, CD4 cell count, or body mass index. The variation in mortality risk over time was not accounted for either by time on co-trimoxazole or by current CD4 cell count, the researchers said. The investigators stated that the reasons co-trimoxazole administration reduced mortality were unclear. Because the study was observational, Walker and colleagues noted, "we cannot guarantee that the results are free from bias." But they added that their systematic approach means it's hard to identify the direction or size of any remaining biases. Indeed, the study shows that "important practical questions about HIV management can be answered with cohort data," according to Xavier Anglaret, MD, PhD, of Universit Victor Segalen Bordeaux 2 in Bordeaux, France, and Serge Eholie, MD, of CHU de Treichville in Abidjan, Cte d'Ivoire. In an accompanying editorial, they said the study results "clearly suggest" two things: starting combination antiretroviral therapy should not be a reason either for failing to start or for stopping co-trimoxazole, and that prophylaxis should be maintained for a year or more after starting anti-HIV medications. The study had support from the U.K. Medical Research Council, the U.K. Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories. The researchers said they had no conflicts. Anglaret and Eholie, the editorial writers, said they had no conflicts. Primary source: The Lancet Source reference: Walker AS, et al "Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort" Lancet 2010; DOI: 10.1016/S0140-6736(10)60057-8. Additional source: The Lancet Source reference: Anglaret X, Eholie S "Co-trimoxazole, cART, and non-AIDS infectious diseases" Lancet 2010; DOI: 10.1016/S0140-6736(10)60200-0.