July 25, 2007

1.		What is the CHER study?
		The Children with HIV Early Antiretroviral Therapy (CHER) study is a phase III, randomized clinical trial in South Africa to evaluate different approaches for treating HIV-infected infants under three months of age and determine the optimal time to begin antiretroviral (ARV) therapy.
2.		Who is sponsoring and conducting the trial?
		The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), is sponsoring the trial through the Comprehensive International Program of Research on AIDS (CIPRA) program.  Additional support is also provided by the MRC Clinical Trials Unit in London, the Departments of Health of the Western Cape and Gauteng, South Africa, and GlaxoSmithKline. The CHER study, part of the CIPRA-SA collaborative research program, is being conducted by an international team of scientists, led by Dr. Avy Violari of the University of the Witwatersrand in Johannesburg and Dr. Mark Cotton of the University of Stellenbosch in Cape Town.
3.		When did the trial start and where is it taking place?
		The trial, which began in July 2005, is being conducted at two locations in South Africa: the Perinatal HIV Research Unit of the University of the Witwatersrand and the Children’s Infectious Diseases Clinical Research Unit of the University of Stellenbosch, Cape Town.
4.		What is the primary objective of the trial?
		This trial was designed to evaluate whether early ARV therapy given over a limited period of time in infants infected with HIV would delay progression of disease compared to those treated when the immune system begins to decline.
5.		What is the design of this study?
		The trial recruited and enrolled 377 infants with confirmed HIV infection without advanced immune suppression between six and 12 weeks of age who had CD4 cell percentages equal to or greater than 25 percent.  Parents or guardians received detailed information about the study, the drug, and requirements for participation prior to signing a written informed consent form. Eligible infants were randomly enrolled in one of three groups—those receiving immediate antiretroviral therapy (Zidovudine (AZT) + Lamivudine (3TC) + Lopinavir/Ritonavir (LPV/r)) for 40 weeks, those receiving immediate antiretroviral therapy for 96 weeks, and a control group whose treatment was only initiated after doctors observed signs of clinical or immunological progression (e.g. CD4 cell percentage decline) toward the development of AIDS.  Deferring therapy until an infant has clinical or immunologic decline is the current standard of care in South Africa and throughout most of the world; however, the specific immunologic and clinical criteria for starting therapy in this study were slightly different from South African or World Health Organization (WHO) guidelines and have changed over time to reflect changing standards of care.  In this study, treatment is started or restarted when CD4 cell percentages dropped below 20 percent for infants greater than one-year old or 25 percent for infants less than one-year old or if symptomatic and severe disease occurs as defined by U.S. Centers for Disease Control and Prevention (CDC) criteria. All participants follow a schedule of regular clinical visits for a minimum of 3.5 years, with the clinical team available 24 hours a day for consultation, referrals and advice.
6.		What was the rationale for early treatment of HIV in infants?
		Children infected with HIV typically have a more rapid disease progression within the first years of life due to their developing immune system and susceptibility to other serious infections. In many developed countries, most infants receive ARV therapy immediately after being diagnosed with HIV, which has shown to be safe and effective.  This approach, however, raises concerns about side effects, adherence and resistance, and may be difficult to sustain in resource-poor countries. Therefore, this study was designed to evaluate whether early ARV therapy given over a limited period of time would delay disease progression.  This approach would 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.
7.		What is the data and safety monitoring board, and how does it monitor this study?
		The data and safety monitoring board (DSMB) is an independent committee composed of clinical research experts, statisticians, ethicists, and community representatives from Africa, Europe and the United States, set up by NIAID to provide additional oversight of the study. The DSMB regularly reviews data while a clinical trial is in progress to ensure the safety of participants and that any benefits shown 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. The CHER study was monitored at least twice annually by an NIAID DSMB.
8.		What were the results of the most recent DSMB review?
		On June 20, 2007, the DSMB reviewed the interim data and found a significant increase in survival among infants who received immediate ARV therapy (96 percent) compared to infants who received therapy later (84 percent) based on declining immune function linked to a defined CD4+ T-cell count and/or clinical progression.  Based on this finding, the DSMB recommended that no additional infants be placed in the deferred-treatment arm of the study and infants in this arm be evaluated for potential initiation of ARV therapy. The DSMB also recommended that all infants enrolled in the study be followed for the planned duration of approximately 3.5 years. On July 2, 2007, NIAID Director Anthony S. Fauci, M.D., concurred with the DSMB recommendations.
9.		What is the current standard of care for HIV-infected infants in South Africa?
		Currently, HIV-exposed infants in South Africa are offered co-trimoxazole for Pneumocystis carinii pneumonia (PCP) prophylaxis started at four to six weeks, free formula for six months if requested by the mother, and diagnostic Polymerase Chain Reaction (PCR) HIV testing beginning at six weeks of age. ARV therapy is offered to HIV-infected children with prolonged or recurrent hospitalization, those children classified with WHO clinical stage 3 or 4 disease, or those with CD4 cell percentages below 20 percent if under 18 months of age. For additional information, the South African pediatric treatment guidelines are available at: www.doh.gov.za/docs/index.html and the WHO document, “Antiretroviral Therapy of HIV Infection in Infants and Children in Resource-Limited Settings: Towards Universal Access, Recommendations for a Public Health Approach”, is available at: http://www.who.int/hiv/pub/guidelines/paediatric020907.pdf.
10.		What is the possible impact of these new findings on the management of HIV disease in children?
		The findings have significant public health implications around the world.  The study has demonstrated that early treatment of young infants infected with HIV in a resource-poor setting can increase their chance of survival, underscoring the importance of diagnosing HIV-infected children in the first six weeks of life and facilitating early access to treatment. While the criteria for starting therapy in the deferred therapy arm in this study was not identical to current WHO or South African guidelines, the study nonetheless suggests that immediately starting ARV treatment in all infants may have benefit over a clinical or CD4-cell guided approach. These results are being released to the WHO, local ethics committees, regulatory authorities and other key stakeholders for their consideration and evaluation for possible implementation.
11.		How will these findings affect the management of HIV disease for older children and adults?
		The interim findings from the CHER study address optimal time for treatment of HIV-infected infants under three months of age.  Since young infants are very different in immune function, time since HIV infection and susceptibility to other serious illnesses, these results cannot necessarily be generalized to adults or older children.  Until additional studies are performed, it is not known whether newly-identified asymptomatic adults or older children with high CD4 cell counts would benefit from earlier treatment.
12.		What will happen to the children on the study?
		The study investigators at each site have been informed of the decision and have contacted the parents and legal guardians of the infants involved in the study to inform them of the interim findings and the changes to the study. All infants who have not started ARV therapy because they did not yet meet the existing criteria for initiation of treatment are being called back for evaluation. At this visit, parents are being fully informed about the latest developments and the changes in the study. Doctors will assess the infants in light of the new information and are making decisions about starting ARV therapy, while taking into consideration the age and the clinical characteristics of the infants and the parents’ wishes. Follow-up of all infants will continue with the aim of evaluating the long-term benefits of early limited ARV therapy, which will provide valuable information to guide future treatment decisions in infants with HIV.
13.		Who approved the study?
		The study was approved by the Ethics Committees of the University of the Witwatersrand and the University of Stellenbosch, the South African Medicines Control Council, the provincial Departments of Health of the Western Cape and Gauteng, community advisory boards at the trial sites, the U.S. Food and Drug Administration and the trial sponsors.
14.		When will this trial be completed?
		The CHER trial is currently scheduled to end in 2011.  At that time, the investigators hope to have further information about the effect of stopping therapy in these infants after one or two years.

Media inquires can be directed to the NIAID OCPL media group at 301-402-1663, niaidnews@niaid.nih.gov.

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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