Antiretroviral therapy initiated before 12 weeks of age reduces early mortality in young infants; interim results from the CHER study
Polly Clayden, HIV i-Base
Avy Violari from the Perinatal HIV Research Unit, University of Witwatersrand, South Africa presented the first results from the Children with HIV Early Antiretroviral Therapy (CHER) Study as an oral late breaker.
Young infants have a high risk of disease progression and are notoriously difficult to treat. Guidelines and opinion differ and, to date, there are no randomised trials on antiretroviral therapy (ART) started before 12 weeks of age.
The CHER study looked at whether early limited ART until a childs first or second birthday will have long term benefit by delaying disease progression and/or delay the time when long term continuous ART needs to be initiated.
In this trial infants aged 6-12 weeks with CD4% >25 (n=375) were randomised to three arms: Arm 1: Deferred treatment – ART when the CD4% declined to <20% (25% if <1year; based on WHO guidelines) (n=125); Arm 2: Short course (to first birthday) – ART with planned interruption at age 1year and Arm 3: Long course (to second birthday) – ART with planned interruption at age 2 years. ART started or restarted in all arms when CD4%, <20% (25% in infants from August 2006), CD4 count <1000 cells/mm3 if age <12 months, or clinical event.
The median age of the infants was: Arm 1 – 7.1 (IQR: 6.4-8.9) weeks; Arm 2/3 7.4 weeks (IQR: 6.6-8.9). 59% and 58.3% of infants were female in Arms 1 and 2/3 respectively. All infants were drug-naive except for PMTCT (either NVP single dose to mother and baby – 68% Arm 1; 64.3% Arms 2/3 – or NVP plus short course AZT – 21% Arm1; 20.2% Arms 2/3. And all received AZT + 3TC +LPV/r.
Dr Violari presented interim data, following a DSMB review on the 20th June 2007, after the trial was fully recruited and at a median follow-up of 32 weeks. The DSMB recommended modification to the study and the release of the results of Arm 1 vs. Arms 2/3 combined. They recommended that infants in Arm 1 should be recalled urgently and assessed for ART initiation and that the trial follow-up should continue.
In the study 252 infants were randomised to Arms 2/3 and 125 to Arm 1. After a median follow-up of 32 (20-48) weeks, 10 (4%) infants in Arms 2/3 and 4 (3.2%) were lost to follow up. Whereas 250 (99%) started ART in arms 2/3, by May 2007, 61 (59%) infants had initiated ART in Arm 1. By the time of the DSMC, a total of 30 infants had died: 10 (4%) in Arms 2/3 and 20 (16%) in Arm 1 (HR 0.24 [95% CI 0.11 0.52]; p = 0.0002).
Of the infants who died, 12 died at home/unknown; of 18 infants dying in hospital, causes of death were gastroenteritis (4, Arm 1; 4 Arms 2/3), sepsis/pneumonia (5 Arm1; 0 Arms 2/3), PCP/CMV (3 Arm1; 0 Arms 2/3), SIDS (0, Arm1; 1 Arms 2/3), liver failure (0 Arm 1,1 Arms 2/3).
The investigators found that starting ART before 12 weeks of age reduced early mortality by 75%. They noted that these findings have implications for guidelines on initiation of ART in early infancy. They concluded: These results support the need for enhanced PMTCT programmes, early infant diagnosis and effective transition to care.
These results raise big issues about what happens next.
Running 100 PCR viral load tests in order to diagnose 7-8 HIV-positive babies early enough to benefit from immediate treatment is just not going to be feasible in many places (eg Malawi). The ratio drops further if AZT and NVP are used together, as currently happens in the Western Cape, South Africa.
The question then of more effective PMTCT (and treating the mothers) becomes important again, and some have suggested that this may actually be both more cost effective, and paradoxically, easier to implement.
Violari A, Cotton M, Gibb D 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. Abstract WESS103.