Need to initiate early ARV therapy in all infants

Although ART therapy is expanding impressively in many countries in Sub-Saharan Africa, several countries still need urgent action towards the elimination of HIV infection among children. Without effective antiretroviral therapy, children with HIV have a very high risk of death, write VALÉRIANE LEROY and FRANÇOIS DABIS for THE LANCET Infectious Diseases journal. The Southern Times carries excerpts of the report.

HIV develops very rapidly among infants and children and without treatment, more than a third of children infected with HIV will die of AIDS before their first birthday.
In 2010, there were 250 000 AIDS-related deaths in the under-15 age group, most of which could have been prevented through early diagnosis and effective treatment.
In many high-income countries, children who were infected with HIV at birth in the 1980s and 1990s are now entering adulthood as a result of access to antiretroviral treatment. However, although the number of children receiving antiretroviral therapy (ART) has increased significantly in recent years, at the end of 2010, only 23 percent of the 2.02 million children in need of ART in low- and middle-income countries were receiving it.
The World Health Organisation (WHO) now recommends that all diagnosed infants and children less than two years old should begin antiretroviral therapy regardless of the child's clinical or immunological stage. Infants, who are presumed by clinicians to have severe HIV, and have been given a diagnosis on this basis, should also begin treatment, but confirmation of infection should be obtained as soon as possible.
A study that was influential in the above WHO recommendations was 'The Children with HIV Early Antiretroviral Therapy' (CHER) study of infants (aged six to 12 weeks) in South Africa.
The study compared the outcomes of those starting limited treatment immediately with those deferring treatment until CD4 percentage dropped below certain levels or severe disease occurred. It found the risk of death for infants who began treatment immediately was 76 percent lower than the deferred treatment group.
The 2009 guidelines produced by the Paediatric European Network for Treatment of AIDS (PENTA) also advocate treatment for all infected infants, regardless of clinical or immunological stage. Other countries’ guidelines may be revised to reflect WHO recommendations and the CHER study’s findings.
The publication that’s based on research done by pediatricians caring for children living with HIV and researchers was responding to the question to when therapy should begin for children infected with HIV.
The publication suggests that antiretroviral therapy started as soon as possible after birth and before immunosuppressant and clinical characteristics of AIDS had developed could strikingly reduce infant mortality.
According to the research, the risk of death could be reduced by 76 percent with immediate antiretroviral therapy compared with deferred antiretroviral therapy. The publication further points out that the risk of death could be reduced by 76 percent with immediate antiretroviral therapy compared with deferred antiretroviral therapy.
Meanwhile, in The Lancet Infectious Diseases journal, Thanyawee Puthanakit and colleagues report the results of the Paediatric Randomised Early versus Deferred Initiation in Cambodia and Thailand (PREDICT) trial. This superiority trial aimed to assess whether antiretroviral therapy could be deferred until CD4 percentages declined to less than 15 percent without affecting AIDS-free survival and neurodevelopment. The study population of this multicentre, randomised, open-labelled trial targeted (for the first time) children older than one year infected with HIV.
Three hundred children infected with HIV were enrolled. Participants were aged a median of 6.4 years, with only 26 percent younger than three years and 6 percent aged 1-2 years. Children were randomly assigned to early or deferred antiretroviral therapy started when CD4 percentages declined to less than 15 percent. Sixty-nine children (46 percent) in the deferred treatment group started antiretroviral therapy during the study. Overall, the risk of progression to AIDS by three years was low, with only five Centers for Disease Control and Prevention (CDC) category C events and one death overall. AIDS-free survival did not differ between groups (98.7percent in the deferred treatment group versus 97.9 percent in the early treatment group; p=0.6). Immediate antiretroviral therapy did not significantly improve neurodevelopment outcomes (measured by the Beery visual motor integration test) compared with deferred antiretroviral therapy. Rates of hospital admission were much the same in the two groups. Tolerance did not differ significantly: 17 percent of children in the early treatment group developed grade three and four adverse events related to antiretroviral therapy compared with 10 percent in the deferred treatment group. Conversely, CD4 percentages and height-for-age Z scores were higher in the early treatment group than they were in the deferred treatment group at end of the 144 weeks of follow-up.
Although the results of this trial fill an important gap in the knowledge, their clinical implications might be restricted because the study findings were mostly inconclusive. Although the length of follow-up was substantial, the study was underpowered to detect a significant difference between the two groups because of a low event rate and, therefore, the authors concluded that additional follow-up of study participants or future studies were needed to fully answer this clinical question. Moreover, the study population was highly selected because children had survived the first years of their lives without antiretroviral therapy (until 6 years for the median age at enrolment) and thus might have been long-term survivors, with a probable slow disease progression whatever the time of initiation of antiretroviral therapy. The subgroup of children younger than three years was too poorly represented to make any meaningful conclusion for this age category.
As the WHO guidelines are revised and consolidated in 2013, the results from PREDICT7 will be quite useful for the formulation of the recommendations on when to start treatment in children after their first birthday. To delay the start of therapy would reduce costs in low-resource settings. However, targeting of treatment efforts to children infected with HIV surviving beyond 1-2 years would favour a truncated population and many opportunities for early access to antiretroviral therapy would be missed in low-resource settings. Clinical trials are difficult to do.
The PREDICT trial, like the CHER trial in the past, provides important insights for the management of children living with HIV but cannot address all the pertinent questions to the shaping of the public health approach and clinical guidelines of paediatric HIV infection. Their results should be completed by cost-effectiveness modelling to inform the competing demands for restricted funds and resources to improve efficiency of paediatric antiretroviral therapy programmes.

November 2012
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