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Immediate Antiretrovirals Cut Death Risk by 76% in Infected Infants in South Africa Study
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4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention
July 22-25, 2007
Sydney, Australia
Mark Mascolini
South African children who began triple antiretroviral therapy (ART) before 12 weeks of age had a 76% lower risk of death than children who delayed treatment, according to results of a randomized trial presented at the 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention [1].
CHER trial investigators randomized 6- to 12-week-old HIV-infected infants to one of three strategies: (1) treatment with lopinavir/ritonavir plus AZT/3TC delayed until the CD4% fell below 20% (or below 25% after August 2006), (2) immediate treatment with the same regimen and planned interruption at 1 year of age, or (3) immediate treatment with planned interruption at 2 years. All children received cotrimoxazole prophylaxis and Pneumococcal vaccine. Children with a CD4% already below 25% were not randomized because they all began ART according to World Health Organization guidelines.
Regimens to prevent mother-to-child transmission in randomized children included nevirapine in 62%, AZT plus nevirapine in 20%, AZT alone in 3%, and triple therapy in 2%, while the rest received no antiretrovirals. Median age at randomization stood at 7.4 weeks, 59% of the children were girls, and median CD4% measured 35%.
Following a safety panel review after a median of 32 weeks (interquartile range 20 to 48 weeks), the investigators compared mortality in 125 infants randomized to delay ART and 252 infants randomized to begin treatment immediately (in either arm 2 or 3). During that time 30 infants died, 20 (16%) in the delayed-treatment group and 10 (4%) in the immediate-treatment group. Mortality per 100 patient-years measured 25.3 deaths in the delayed-therapy group and 6.0 deaths in the immediate-therapy group. That meant the risk of death was 76% lower in the immediately treated children (hazard ratio 0.24, 95% confidence interval 0.11 to 0.52, P = 0.0002). Kaplan-Meier analysis determined that time to death was significantly faster in the deferred-therapy arm (P = 0.0002).
Of the 18 children who died in the hospital with a known cause, 8 died of gastroenteritis, 5 of sepsis or pneumonia, 3 of Pneumocystis pneumonia or cytomegalovirus infection, 1 of sudden infant death syndrome, and 1 of liver failure. The investigators counted 41 cases of clinical progression in 38 infants in the delayed-therapy arm, compared with 19 cases in 19 infants in the immediate arm.
The CHER team is beginning treatment for all children randomized to delayed therapy. But they still plan to go ahead with treatment interruptions in the immediately treated children.
Reference
1. Violari A, Cotton M, Gibb D. Antiretroviral therapy initiated before 12 weeks of age reduces early mortality in young HIV-infected infants: evidence from the Children with HIV Early Antiretroviral Therapy (CHER) Study. 4th IAS Conference on HIV Pathogenesis, Treatment, and Prevention. July 22-25, 2007. Sydney. Abstract WESS103.
NIH Press Release
U.S. Department of Health and Human Services NATIONAL INSTITUTES OF
HEALTH NIH News National Institute of Allergy and Infectious Diseases
(NIAID)
Wednesday, July 25, 2007, 12:01 a.m. EDT
TREATING HIV-INFECTED INFANTS EARLY HELPS THEM LIVE LONGER South African
Clinical Trial Modified Because of Initial Data
Hundreds of thousands of babies around the world are born each year with
HIV -- more than half a million in 2006 alone. Caring for these children is complicated by the fact that their immune systems are not fully
developed in the first year of life, which makes them especially susceptible to rapid HIV disease progression and death. The current standard of HIV care in many parts of the world is to treat infants with antiretroviral therapy -- but only after they show signs of illness or a weakened immune system.
Now the initial results of an ongoing clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), suggests that more HIV-infected infants survive if they are given therapy early on, regardless of their apparent state of health.
This trial, called the "Children with HIV Early Antiretroviral Therapy" (CHER) study, is a phase III, randomized clinical trial led by Avy Violari, M.D., FCPaed (SA), of the University of the Witwatersrand in Johannesburg, South Africa, and Mark Cotton, MBChB, MMed, of the University of Stellenbosch in Cape Town, South Africa. Dr. Violari will present these findings on Wednesday, July 25 at the 2007 International AIDS Society Conference in Sydney, Australia.
"Children with HIV infection frequently show rapid disease progression within the first year of life due to their developing immune systems and susceptibility to other serious infections," says NIH Director Elias A. Zerhouni, M.D. "This is the first randomized clinical trial that shows that infants treated before three months of age will do better than infants who have their treatment delayed."
"The results of this trial could have significant public health implications worldwide," says NIAID Director Anthony S. Fauci, M.D. "Because these findings will cause experts to consider changes in standards of care in many parts of the world, NIAID has released details of the interim results to the World Health Organization, local ethics committees, regulatory authorities and other key stakeholders for their consideration and evaluation for possible implementation."
"Children with HIV infection frequently show rapid disease progression within the first year of life due to their developing immune systems and susceptibility to other serious infections," says NIAID Director Anthony S. Fauci, M.D. "This is the first randomized clinical trial that shows that infants born with HIV do better if you treat them sooner rather than later."
These initial results also highlight the importance of diagnosing HIV infections early -- within the first six to twelve weeks of life," says Edward Handelsman, M.D., chief of the Pediatric Medicine Branch in NIAID's Division of AIDS, which is overseeing the CHER study. Dr. Handelsman stresses, however, that the study results cannot necessarily be generalized to asymptomatic adults or older children because young infants are very different in immune function, time since HIV infection and susceptibility to other serious illnesses.
The evidence came to light last month after a routine review by the trial's data and safety monitoring board (DSMB), an independent committee composed of clinical research experts, statisticians, ethicists and community representatives from Africa, Europe and the United States that regularly reviews interim data from the CHER study to ensure the safety of study participants.
CHER had begun two years earlier to evaluate whether early antiretroviral therapy given over a limited period of time would delay disease progression. The idea was that this approach might allow the immune system to develop and possibly allow the child to stop treatment for a period of time and therefore avoid continuous therapy from an early age.
Starting in July 2005, HIV-infected infants between 6 and 12 weeks old without immune suppression or severe symptoms of clinical disease were enrolled at the Perinatal HIV Research Unit in Soweto and Tygerberg Children's Hospital in Cape Town. By early 2007, 377 babies were enrolled in one of three groups -- those receiving immediate antiretroviral therapy for 40 weeks, those receiving immediate antiretroviral therapy for 96 weeks, and a control group whose treatment was initiated after doctors observed signs of clinical or immunological progression toward the development of AIDS (the current standard of HIV
care in many parts of the world).
The trial is designed to continue through 2011, but after reviewing early trial data on June 20, 2007, the DSMB found a significant increase in survival among infants who received immediate antiretroviral therapy. At the time of the DSMB review, 96 percent of these children were alive, compared to only 84 percent of the children in the control group. Based on this finding, the DSMB concluded that providing early antiretroviral therapy to infants is more effective in preventing early death than delaying treatment until clinical or immunological disease triggers are observed.
The DSMB recommended that no additional infants be placed in the deferred-treatment arm of the study and infants previously enrolled in this arm be evaluated for potential initiation of antiretroviral therapy. NIAID accepted these recommendations and informed the study investigators at each site. The doctors at those sites have been contacting the parents and legal guardians of the infants involved in the study to inform them of the interim findings and call them in for
evaluation. The DSMB also recommended that all infants enrolled in the study be followed for the planned duration of approximately 3.5 years and those in the 40- and 96-week treatment groups continue with the study.
NIAID is sponsoring the CHER trial through the Comprehensive International Program of Research on AIDS (CIPRA) program, which supports research and development efforts in resource-limited areas to create practical, affordable and acceptable ways to prevent and treat HIV/AIDS in adults and children The trial is part of the CIPRA-SA collaborative research program, led by James McIntyre, MBChB, FRCOG, of the Perinatal HIV Research Unit, with additional support provided by the MRC Clinical Trials Unit in London Departments of Health of the Western Cape and Gauteng, South Africa, and GlaxoSmithKline.
U.S. AND INTERNATIONAL REPORTERS: Data from the CHER study will be
presented on Wednesday, July 25 at the 2007 International AIDS Society
Conference in Sydney, Australia. The presentation will be at 1:30 p.m.
local time in the Bayside Auditorium B of the Sydney Convention and
Exhibition Centre.
NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
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