Treating HIV-infected infants with antiretroviral therapy (ART) as early as possible, within the first six to 12 weeks of life — rather than waiting until they show signs of immunological or clinical deterioration — dramatically decreases their risk of early death, according to findings from the Children with HIV Early Antiretroviral Therapy (CHER) trial, a South African study presented today at a late-breaker session of the 4th International AIDS Society Conference on HIV Treatment and Pathogenesis in Sydney.
“Starting ART before 12 weeks of age reduces early mortality by 75%,” said Dr Avy Violari of the University of the Witwatersrand in Johannesburg, who, along with Dr Marc Cotton from Cape Town, led the study.
After only 32 weeks of follow-up, the difference between early and deferred treatment was so profound that the study’s Data and Safety Monitoring Board (DSMB) called for the deferred ART arm of the study to be terminated, and urged that infants who weren’t already on treatment “should be urgently recalled and assessed for ART.”
Little information to guide treatment decisions in HIV-infected infants
The CHER findings help address the desperate need for prospective data to inform ART guidelines for children with HIV.
Managing a child with HIV is complicated, particularly in resource-limited settings where the risk of rapid progression and early mortality is very high. One third of HIV-infected infants die before one year of age; half are dead before 2 years of age.
Given these statistics, one might assume that infants should be diagnosed and treated with ART as soon as possible. However, approaches vary.
In the US, treatment is considered for all HIV-infected infants, but in other settings, one concern is that there are only limited treatment options available for children, and using ART in all children from HIV diagnosis might risk the development of resistance and exhaust treatment options that healthier children might only require later in life.
WHO guidance doesn't recommend treating every infant, but instead focuses on those infants at highest risk of progression or death, using clinical or immunological criteria to predict when to treat. Reliance on clinical symptoms is the only option where laboratory infrastructure is limited — and WHO suggests treating all of those with WHO paediatric stage III/IV disease.
But in infants with less severe symptoms, WHO recommends using immunologic criteria, if available. In children under five years of age, the surrogate markers usually used in adults to predict the need for treatment (viral load and/or CD4 cell measurements) are less reliable. So generally, CD4%
But it isn’t clear how well “staging and monitoring” and deferring treatment in healthier children with HIV really works in practice in a resource-limited setting. By the time a child shows clear symptoms of HIV (and gets taken to the clinic), it may be too late for ART to save their lives. And should programmes really wait until an infant is severely immune suppressed to start treatment?
Also, why does treatment of an infant have to be continuous for the rest of its life? While treatment interruption trials have not been shown to work in adults, HIV-infected infants are a unique population. Drs Violari and Cotton hypothesised that early ART might give the infant’s immune system a chance to develop.
CHER
So Drs Violari and Cotton designed a study to see if a limited course of ART given to infants as soon as possible after their HIV status was known, regardless of the immune status, would have a long-term heath benefit compared to HIV-infected infants who are treated only after immunological or clinical deterioration.
HIV was diagnosed using HIV DNA PCR (see below). The study enrolled children between 6 and 12 weeks of life but any infants presenting with a CD4 cell percentage below 25 started treatment immediately and were not included in this analysis.
The remaining infants were randomised to one of three treatment arms:
- Arm 1: deferred treatment until after their CD4 cell percentage fell below 20%, until August 2006 when the protocol was changed to start treatment if CD4% fell below 25% (if aged one year or under) or below 20% (if below two years of age), or based upon clinical staging (CDC stage C).
- Arm 2: immediate treatment lasting until one year of age
- Arm 3: immediate treatment lasting until two years of age
All children received cotrimoxazole and the pneumococcal vaccine. The ART regimen used is AZT/3TC/Kaletra.
After completion of the shorter course of ART in arms 2 and 3, children will be given ART whenever they show signs of immunologic deterioration — and the study plans to follow the children for up to 3.5 years.
DSMB intervention
However, as noted earlier, on June 20, 2007, the DSMB reviewing interim data from the study decided to modify the study, and release the preliminary results comparing arm 1 to arms 2 and 3 combined. Follow-up will continue however.
Results
The analysis reported on 377 infants: 252 infants randomised to arms 2 and 3, and 125 into arm 1. The median age at randomisation was 7.4 weeks and the median CD4 cell percentage was 35% (range 29% - 41%), with no significant differences between arms.
Infants in the study had a median follow-up of 32 weeks (range 20 - 48 weeks). By week 24, 48% of arm 1 had already started ART because of rapid immunological or clinical decline. At the time the deferred arm was suspended, 61% of the infants had begun ART.
The total time on ART was significantly different between the two groups, however. By week 40, infants in groups 2 and 3 had spent 98.6% of the study on ART, compared to only 32% in group 1.
Earlier ART had a clear impact on mortality. 30 infants died: 20 (16%) in the deferred treatment arm and 10 (4%) in the two immediate treatment arms, representing a significantly reduced risk in the immediate treatment group of 76% (hazard ratio 0.24 [95% confidence intervals 0.11 – 0.52]), p=0.0002).
The death rate was higher during the earlier months of follow-up: At month 3, the death rate per 100 person years was 10 for arms 2 & 3 vs 41 for arm 1, from months 3-6, it was 4 vs 23, respectively.
There were various causes of death. Only liver failure and SIDS were higher in those on early treatment (1 each versus none). Notably, there were no cases of pneumonia/sepsis and PCP or CMV in the early treatment arms.
There were 60 episodes of disease progression among the infants, 19 among those on early treatment, 41 among those on deferred treatment. 18 out of the 19 events in those on early treatment were due to “failure to thrive” but the rate was doubled among those on deferred treatment.
In a press release from US National Institute of Allergy and Infectious Diseases (NIAID which sponsored the trial), Dr Anthony S. Fauci said: “The results of this trial could have significant public health implications worldwide.”
However, to have the maximum impact, programmes for the prevention of mother to child (HIV) transmission (PMTCT) will need to be strengthened considerably, and become more closely linked with maternal child health services. Mothers and caregivers providing treatment will need considerable support to deliver these treatments to infants consistently. Paying for treatment expansion in infants will need support from all sectors. And programmes will alo need to expand capacity to provide early diagnosis in infants.
“These results support the need for enhanced pMTCT programmes, early infant diagnosis and effective transition to care,” concluded Dr Violari.
Early diagnosis of HIV infection in infants is especially challenging in many settings. Infant infection is not diagnosable by antibody testing until a child is 18 months old because it may be carrying its mother HIV antibodies but remain uninfected itself. Early diagnosis requires the use of DNA PCR testing, and to be carried out properly, the test needs DNA PCR-skilled technicians and special laboratory equipment.
However, several developing countries have now demonstrated that that it is possible to introduce DNA PCR testing in infants, by collecting dried blood spots on filter paper that can be sent to a central laboratory for testing. At the recent HIV Implementers meeting in Kigali, Rwanda, there was considerable enthusiasm for scaling up dried blood spot testing of infants throughout PEPFAR supported countries.
These issues will be discussed in more depth in a future issue of
Violari A et al. 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. Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis, Sydney, abstract WESS103, 2007.