CHER trial leads to changes in international guidelines on when to start HIV-infected infants on antiretroviral therapy
Submitting InstitutionUniversity College London
Unit of AssessmentPublic Health, Health Services and Primary Care
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences, Neurosciences, Public Health and Health Services
Summary of the impact
HIV-infected infants are at high risk of disease progression and death.
Until 2008 guidelines recommended waiting until the infant displayed
symptoms, or had a weakened immune system before starting treatment. The
CHER trial found that starting infected infants on antiretroviral therapy
as early as possible substantially reduced mortality compared with waiting
until they developed symptoms or their immune system weakened. These
results led quickly to changes in guidelines for treating HIV-infected
infants issued by the US, World Health Organisation (WHO), Paediatric
European Network for Treatment of AIDS (PENTA) and South Africa. These
revised guidelines, if fully implemented along with early infant
diagnosis, would reduce the number of infant deaths because of HIV by 76%,
saving the lives of approximately 46,800 infants globally each year.
The CHER trial aimed to see if giving a limited course of anti-retroviral
therapy (ART) to babies as soon as possible after their HIV status was
known would have a long-term health benefit, when compared with
HIV-infected babies who are treated after they develop symptoms of HIV, or
when their immune system has become weakened. Babies were randomised into
- delayed ART until their immune system became weak (measured through a
- immediate ART, which was then stopped when the babies reached the age
of one year
- immediate ART which was then stopped when they were two years old.
The trial began in August 2005. In June 2007 the IDMC recommended
modifying the trial to stop enrolment into Arm 1, enrolled infants to be
urgently assessed for ART, immediate release of the results of Arm 1
versus Arms 2 & 3, and trial follow-up to continue. This was because
the interim analysis showed that immediate ART reduced mortality by 76%,
and disease progression by 75% after a median follow-up of 32 weeks [1,2].
Follow-up continued until September 2011, and the final results were
presented at a conference in March 2012 .
This was the first large randomised trial looking at when infants should
Based on the early results, we contributed to a costing study to look at
the costs of early versus deferred ART for infants in South Africa. This
found that early treatment was actually cheaper than deferred ART, mainly
because of the reduction in hospitalisation .
The trial was carried out in collaboration with the Perinatal HIV
Research Unit of the University of Witwatersrand, and the Children's
Infectious Disease Clinical Research Unit of Stellenbosch University, as
part of the CIPRA-SA programme. Professors Di Gibb and Abdel Babiker from
MRC Clinical Trials Unit (now part of UCL) played a major role in
designing the study, were part of the Trial Steering and Management
groups, advised on the execution of the trial, carried out and supervised
the statistical analyses, and wrote the papers with their South African
colleagues, Dr Avy Violari and Professor Mark Cotton.
A Wellcome Trust Fellowship has been awarded for Helen Payne to work with
the Cape Town Group, supervised by Nigel Klein and Robin Callard from the
UCL Institute of Child Health, Di Gibb and Abdel Babiker from MRC CTU, now
part of UCL, and Prof Mark Cotton from Cape Town. This work will provide
very important data on the immunology of early ART initiation in babies as
well as on stopping treatment. In addition following reports of the
`functional cure' of the Mississippi baby, further work is ongoing with
collaborators in US as part of the `cure' agenda.
References to the research
 Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA,
Jean-Philippe P, McIntyre JA; CHER Study Team. Early antiretroviral
therapy and mortality among HIV-infected infants. N Engl J Med. 2008 Nov
 Violari A, Cotton M, Gibb D, Babiker A, Steyn J, Jean-Phillip P,
McIntyre J, on behalf of the CHER Study Team. 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. Special session: 4th IAS Conference
on HIV Pathogenesis, Treatment and Prevention. 2007. Abstract no. WESS103.
 Meyer-Rath Gesine, Violari A., Cotton M., Ndibongo B., Brennan A.,
Long L., Panchia R., Coovadia A., Gibb D.M., Rosen S., (2010). The cost of
early versus deferred paediatric antiretroviral treatment in South Africa:
A comparative economic analysis of the first year of the Children with HIV
Early Antiretroviral Therapy (CHER) trial. XVIII International AIDS
Conference, Vienna, Abstract no. THLBB103.
 Cotton M, Violari A, Gibb D, Otwombe K, Josipovic D, Panchia R,
Jean-Philippe P, Handelsman E, McIntyre J, Babiker A. Early ART Followed
By Interruption is Safe & Associated With Better Outcomes than
Deferred ART: Final Results From the 6-Year Randomized CHER (Children with
HIV Early antiRetroviral) Trial in South Africa. 19th
Conference on Retroviruses and Opportunistic Infections. 2012. Available
 Cotton M, Violari A, Otwombe K, Panchia R, Dobbels E, Rabie H,
Josipovic D, Liberty A, Lazarus E, Innes S, van Rensburg A, Pelser W,
Truter H, Madhi S, Handelsman E, Jean- Philippe P, McIntyre J, Gibb DM.
Early time-limited antiretroviral therapy versus deferred therapy in South
African infants infected with HIV: results from the children with HIV
early antiretroviral (CHER) randomised trial. Lancet 382. 2013. http://dx.doi.org/10.1016/S0140-
The research was funded by a grant from the National Institute of Allergy
and Infectious Diseases of the National Institutes for Health through the
Comprehensive International Program of Research on AIDS network (U19
AI53217); the Departments of Health of the Western Cape and Gauteng, South
Africa; and GlaxoSmithKline. The NIAID grant was awarded after a
competitive process that included peer review.
Details of the impact
HIV-infected infants are at high risk of disease progression and death.
But initiating them on lifelong antiretroviral therapy (ART) is
- it is a lifelong commitment
- it costs money
- the drugs can have side effects
- the earlier infants start treatment the more time there is for
resistance to develop.
Until 2008, national and international guidelines recommended initiation
of antiretroviral therapy on the basis of a low CD4 percentage or count, a
high viral load, or the presence of clinical symptoms, whereas the
treatment of asymptomatic infants with high CD4 values was not mandated.
The early results of CHER were released at the 4th
International AIDS Society Conference on Pathogenesis, Treatment and
Prevention in July 2007. In response to these results, a number of key
national and international guidelines were changed.
In February 2008 US national guidelines were changed to recommend
immediate treatment of HIV-infected infants [a].
WHO held a meeting in April 2008 to look at the evidence from CHER in
relation to their guidelines, and launched new interim guidelines in June
2008, recommending immediate treatment of HIV- infected infants. These
were then incorporated into the full guidelines when they were revised in
The Paediatric European Network for Treatment of AIDS (PENTA) changed
their guidelines to recommend immediate treatment of HIV-infected infants
in November 2008 [c].
WHO guidelines are very influential for national HIV policy, particularly
in African countries, where most HIV-positive infants live. A survey of
national HIV policymakers, carried out in 2008, found that WHO was an
important and frequent source of information to inform HIV policymaking in
Africa [d]. Therefore the incorporation of recommendations from
the CHER trial into WHO policy has had a knock-on effect on national
guidelines in Africa. Following the changes to WHO guidance, individual
countries began to follow suit by changing their national guidelines. For
example, in South Africa the Essential Drug List Committee approved the
recommendation in November 2008, and it was included in the national
guidelines issued in December 2010, following the costing study [e].
The Malawi Ministry of Health updated their guidelines in April 2008 [f],
and the Uganda Ministry of Health updated their guidelines in June 2009 on
when to start infants on treatment [g].
National guidelines are very important determinants of the treatments
given in practice in low- income settings. In many African settings most
children are treated by clinical officers rather than doctors. These
clinical officers have less training than doctors, and therefore use
national guidelines as the basis of how they treat patients to a much
greater extent than doctors in high- income countries.
One paediatrician working in Zambia describes the impact of the trial as
follows: "These changes were quickly adapted by many African countries
including Zambia, a step that enabled many HIV infected children to be
started early on ART and not only have these children survived but they
have been able to lead a relatively normal childhood. Currently it is
estimated that about 43,000 children 0-14 years old are receiving ART in
Zambia, a 50% increase from the 21,120 in 2009 (WHO, UNAIDS, UNICEF
Progress Report 2010). The impact of the CHER trial has not only been on
outcome of children but the findings have also helped push for improved
laboratory diagnostic services in order to initiate early treatment in
as many infants and children as possible in Zambia...Deaths from
HIV/AIDS have dramatically dropped in infants and children, as most of
the children are identified early and commenced on treatment. The CHER
trial results have had a great impact on treatment of HIV infected
infants and children, subsequently on survival, hospital admissions and
ultimately cost of treatment and care for HIV infected infants and
As the results have led to changes in guidelines for HIV-infected infants
worldwide, the research has had a global impact on infants living with HIV
in both high and low-income settings. It is difficult to say exactly how
many children have benefited as a result of this research, as the routine
data collected by most countries does not disaggregate ART coverage
figures into small enough age- bands. We can, however, extrapolate how
many lives could potentially be saved based on global figures. Each year
around 390,000 children are infected with HIV [i]. The vast
majority of these children were vertically-infected infants. CHER found
that early ART reduced infant mortality from 16% to 4%. If we assume that
the WHO guidelines were fully implemented worldwide, the results of this
trial would lead to around 46,800 lives being saved each year (although
the number of infected infants will decline with the scale-up of
Prevention of Mother To Child Transmission programmes).
The costing study found that early ART for infants had lower costs per
child to the health system than deferred ART or the strategy that was
routine care at the time in South Africa ($1,387 vs $2,440 vs $3,008
respectively) [ref 3, above]. This means that the health system in
South Africa (and possibly other settings) will benefit through reduced
costs of treating HIV-infected infants, as they require less
hospitalisation. In 2011 there were approximately 29,000 new infections in
children in South Africa. If all these newly-infected infants had been
treated early, it could save the South African health system as much as 47
Sources to corroborate the impact
[a] US national guidelines: Working Group on Antiretroviral Therapy and
Medical Management of HIV-Infected Children. Guidelines for the Use of
Antiretroviral Agents in Pediatric HIV Infection. Rockville, MD: National
Institutes of Health, US, 2008.
[b] WHO guidelines: WHO (2010): ANTIRETROVIRAL THERAPY FOR HIV INFECTION
IN INFANTS AND CHILDREN: TOWARDS UNIVERSAL ACCESS Recommendations for a
public health approach 2010 revision.
[c] PENTA guidelines: PENTA Steering Committee (2009): PENTA 2009
guidelines for the use of antiretroviral therapy in paediatric HIV-1
infection. HIV Medicine 10: 591-613 DOI:
[d] Parkhurst JO, Hyde A, South A, Brehmer L, Miller A, Newell JN.
Improving communication of research findings - identifying the sources of
information most important to national disease control officers in low and
middle income countries. Tropical Medicine and International Health
[e] Department of Health, Republic of South Africa (2010): The South
African Antiretroviral Treatment Guidelines.
[f] Malawi Ministry of Health (2008): Treatment of AIDS: Guidelines for
the use of antiretroviral therapy in Malawi. Third Edition, April 2008.
[g] Uganda Ministry of Health (2009): National Antiretroviral Treatment
Guidelines for Adults, Adolescents, and Children http://www.idi-makerere.com/docs/guidelines%202009.pdf
[h] Letter from Paediatrician, University Teaching Hospital, Lusaka,
Zambia. Copy available on request.