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Early vs Standard HAART Start in Haiti Randomized Study NEJM - pdf attached
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"In conclusion, early antiretroviral therapy decreased the rate of death by 75% in HIV-infected adults who had a CD4+ T-cell count that was greater than 200 and less than 350 per cubic millimeter. Access to antiretroviral therapy should be expanded to all HIV-infected adults who have a CD4+ T-cell count of less than 350 per cubic millimeter, including those who live in locations with limited resources........Our finding that early antiretroviral therapy improves the rate of survival is consistent with data from observational studies.25,26 The When To Start Consortium examined outcomes for more than 24,000 HIV-infected patients in 15 cohorts in Europe and North America. This study showed that with initiation of antiretroviral therapy when the CD4+ T-cell count was lower than 350 per cubic millimeter, as compared with initiation when the CD4+ T-cell count was 350 or higher, the hazard ratio for death was 1.4 to 2.0.26 Our prospective study validates these observational findings in a randomized, controlled trial. Furthermore, the effect size in our trial, with a hazard ratio of 4.0, was larger than the effect size seen in the observational cohorts. One possible reason for the large effect size in our study is that it was conducted in a resource-poor setting, where high rates of tuberculosis, malnutrition, and coinfections with tropical diseases may exacerbate the effect of deferred therapy. Early antiretroviral therapy also decreased the incidence of tuberculosis by 50% in our study. "
"The median CD4+ T-cell count in the early-treatment group increased from 280 per cubic millimeter at enrollment to 520 per cubic millimeter at month 36. The median CD4+ T-cell count in the standard-treatment group declined from 282 per cubic millimeter at baseline to 270 per cubic millimeter at month 36.....
Antiretroviral therapy was initiated in 160 of the 408 participants in the standard-treatment group (39%). In 147 of these participants, the CD4+ T-cell count fell to 200 per cubic millimeter or less; in 7 participants, an AIDS-defining illness developed; and in 3 participants, both an AIDS-defining illness developed and the CD4+ T-cell count fell to 200 per cubic millimeter or less. In addition, antiretroviral therapy was initiated in three pregnant women to prevent transmission of HIV infection to their offspring. Among the 160 participants in the standard-treatment group in whom antiretroviral therapy was initiated, the median CD4+ T-cell count at the start of antiretroviral therapy was 166 per cubic millimeter (interquartile range, 130 to 190)."
Early versus Standard Antiretroviral Therapy for HIV-Infected Adults in Haiti
NEJM July 15 2010
Patrice Severe, M.D., Marc Antoine Jean Juste, M.D., Alex Ambroise, M.D., Ludger Eliacin, M.D., Claudel Marchand, M.D., Sandra Apollon, B.S., Alison Edwards, M.S., Heejung Bang, Ph.D., Janet Nicotera, R.N., Catherine Godfrey, M.D., Roy M. Gulick, M.D., Warren D. Johnson, Jr., M.D., Jean William Pape, M.D., and Daniel W. Fitzgerald, M.D.
From Groupe Haitien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO), Port au Prince, Haiti (P.S., M.A.J.J., A.A., L.E., C.M., S.A., J.W.P.); the Departments of Public Health (A.E., H.B.) and Medicine (R.M.G., W.D.J., J.W.P., D.W.F.), Weill Cornell Medical College, New York; the Department of Pediatrics, Vanderbilt University, Nashville (J.N.); and the National Institute of Allergy and Infectious Diseases, Bethesda, MD (C.G.).
ABSTRACT
Background - For adults with human immunodeficiency virus (HIV) infection who have CD4+ T-cell counts that are greater than 200 and less than 350 per cubic millimeter and who live in areas with limited resources, the optimal time to initiate antiretroviral therapy remains uncertain.
Methods - We conducted a randomized, open-label trial of early initiation of antiretroviral therapy, as compared with the standard timing for initiation of therapy, among HIV-infected adults in Haiti who had a confirmed CD4+ T-cell count that was greater than 200 and less than 350 per cubic millimeter at baseline and no history of an acquired immunodeficiency syndrome (AIDS) illness. The primary study end point was survival. The early-treatment group began taking zidovudine, lamivudine, and efavirenz therapy within 2 weeks after enrollment. The standard-treatment group started the same regimen of antiretroviral therapy when their CD4+ T-cell count fell to 200 per cubic millimeter or less or when clinical AIDS developed. Participants in both groups underwent monthly follow-up assessments and received isoniazid and trimethoprim-sulfamethoxazole prophylaxis with nutritional support.
Results - Between 2005 and 2008, a total of 816 participants - 408 per group - were enrolled and were followed for a median of 21 months. The CD4+ T-cell count at enrollment was approximately 280 per cubic millimeter in both groups. There were 23 deaths in the standard-treatment group, as compared with 6 in the early-treatment group (hazard ratio with standard treatment, 4.0; 95% confidence interval [CI], 1.6 to 9.8; P=0.001). There were 36 incident cases of tuberculosis in the standard-treatment group, as compared with 18 in the early-treatment group (hazard ratio, 2.0; 95% CI, 1.2 to 3.6; P=0.01).
Conclusions - Early initiation of antiretroviral therapy decreased the rates of death and incident tuberculosis. Access to antiretroviral therapy should be expanded to include all HIV-infected adults who have CD4+ T-cell counts of less than 350 per cubic millimeter, including those who live in areas with limited resources.
The optimal time to initiate antiretroviral therapy in adults who are infected with human immunodeficiency virus (HIV) remains uncertain. There have been no randomized trials to determine the optimal time to start antiretroviral therapy in adults who have CD4+ T-cell counts that are greater than 200 and less than 350 per cubic millimeter. Furthermore, there are few data on the optimal time to start antiretroviral therapy in persons who live in locations with limited resources, where high rates of tuberculosis, malnutrition, and coinfection with tropical diseases may alter the natural history of HIV disease and the optimal time to initiate therapy. Therefore, international guidelines differ on when to start antiretroviral therapy.1,2,3,4,5,6
In Haiti, following World Health Organization (WHO) guidelines, the first-line regimen of antiretroviral therapy, which consists of zidovudine, lamivudine, and efavirenz, is initiated when the CD4+ T-cell count in a patient with HIV type 1 (HIV-1) infection is 200 per cubic millimeter or less or when clinical acquired immunodeficiency syndrome (AIDS) develops.1,2 Among patients who are treated according to this standard strategy for the initiation of antiretroviral therapy, approximately 80% are alive at 5 years.7,8 We conducted a randomized clinical trial in Haiti to determine whether early initiation of antiretroviral therapy, as compared with the standard timing for the initiation of therapy, improves survival.
Results
Recruitment and Baseline Characteristics
A total of 1066 subjects were screened between August 2005 and July 2008, and 816 were enrolled in the study (Figure 1). The median age of enrolled subjects was 40 years, and 470 (58%) were women. The median CD4+ T-cell count was 281 per cubic millimeter. The baseline characteristics were similar between the two groups (Table 1).
Status at the Time of Analysis
The data and safety monitoring board reviewed the second interim analysis, which included data accumulated up to May 1, 2009; there were 29 deaths at that point. The trial crossed the prespecified stopping boundary for a difference in survival between the groups, and the data and safety monitoring board recommended that the trial be stopped and that all participants in the standard-treatment group be given antiretroviral therapy.
The median length of follow-up was 21 months (range, 1 to 44). Of the 408 participants in the early-treatment group, 383 (94%) continued in follow-up to the end of the study, 6 (1%) died, and 19 (5%) were lost to follow-up. Of the 408 participants in the standard-treatment group, 367 (90%) were included in the follow-up assessments, 23 (6%) died, and 18 (4%) were lost to follow-up.
Of the 408 participants in the standard-treatment group, 160 (39%) met the criteria for initiation of antiretroviral therapy and began receiving antiretroviral drugs during the course of the study. Of the 408 participants in the standard-treatment group, 118 (29%) received isoniazid prophylaxis because of a positive tuberculin skin test and 400 (98%) received trimethoprim-sulfamethoxazole prophylaxis. Of the 408 participants in the early-treatment group, 99 (24%) received isoniazid prophylaxis and 388 (95%) received trimethoprim-sulfamethoxazole prophylaxis. Of the 327 participants in the early-treatment group who had at least 12 months of follow-up, 294 (90%) were adherent to antiretroviral therapy (i.e., received more than 95% of antiretroviral medications in the first year of antiretroviral therapy); of the 60 participants in the standard-treatment group who received antiretroviral therapy for at least 12 months, 57 (95%) were adherent to the therapy.
Survival
There were 29 deaths during the course of the study - 23 in the standard-treatment group and 6 in the early-treatment group (P=0.001 by the log-rank test). In the Kaplan-Meier analysis, 98% of the participants in the early-treatment group and 93% in the standard-treatment group were alive at 36 months (Figure 2). The unadjusted hazard ratio for the risk of death with standard treatment as compared with early treatment was 4.0 (95% confidence interval [CI], 1.6 to 9.8).
The causes of death among the 23 participants in the standard-treatment group who died were gastroenteritis (7 participants), tuberculosis (5), pneumonia (4), homicide (2), cancer (1), cardiomyopathy (1), cholangitis with sepsis (1), stroke (1), and suicide (1). The causes of death among the 6 participants in the early-treatment group who died were burn injury (1), gastroenteritis (1), myocardial infarction (1), pulmonary embolism after gynecologic surgery (1), stroke (1), and gastrointestinal bleeding (1). There was only 1 death from an infectious disease in the early-treatment group, as compared with 17 deaths in the standard-treatment group.
Antiretroviral therapy had been initiated in 7 of the 23 participants in the standard-treatment group who died. These seven participants died a median of 2 months after starting therapy.
Incident Tuberculosis
Among the 773 participants who did not have tuberculosis at enrollment, 54 received a diagnosis of tuberculosis during the follow-up period. There were 36 cases of incident tuberculosis in the standard-treatment group and 18 in the early-treatment group (P=0.01 by the log-rank test). In the Kaplan-Meier analysis of survival, tuberculosis developed by 36 months in 6% of the participants in the early-treatment group, as compared with 14% in the standard-treatment group (Figure 3). The hazard ratio for the risk of incident tuberculosis with standard treatment as compared with early treatment was 2.0 (95% CI, 1.2 to 3.6). Tuberculosis developed in 31 participants in the standard-treatment group before antiretroviral therapy was initiated and in 5 participants in the standard-treatment group a median of 6 months after the initiation of antiretroviral therapy. None of the participants in the early-treatment group, as compared with five of the participants in the standard-treatment group, died as a result of incident tuberculosis.
CD4+ T-Cell Count
The median CD4+ T-cell count in the early-treatment group increased from 280 per cubic millimeter at enrollment to 520 per cubic millimeter at month 36. The median CD4+ T-cell count in the standard-treatment group declined from 282 per cubic millimeter at baseline to 270 per cubic millimeter at month 36.
Initiation of Antiretroviral Therapy in the Standard-Treatment Group
Antiretroviral therapy was initiated in 160 of the 408 participants in the standard-treatment group (39%). In 147 of these participants, the CD4+ T-cell count fell to 200 per cubic millimeter or less; in 7 participants, an AIDS-defining illness developed; and in 3 participants, both an AIDS-defining illness developed and the CD4+ T-cell count fell to 200 per cubic millimeter or less. In addition, antiretroviral therapy was initiated in three pregnant women to prevent transmission of HIV infection to their offspring. Among the 160 participants in the standard-treatment group in whom antiretroviral therapy was initiated, the median CD4+ T-cell count at the start of antiretroviral therapy was 166 per cubic millimeter (interquartile range, 130 to 190).
An additional 16 participants in the standard-treatment group died before antiretroviral therapy could be initiated. In the Kaplan-Meier analysis, the estimated median survival without antiretroviral therapy in the standard-treatment group was 24 months (Figure 4).
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