While antiretroviral therapy is a lifesaving intervention recommended for all HIV-positive infants in resource-limited settings, younger children who begin antiretroviral therapy do not appear to be as likely to suppress viral load as children who begin treatment at a later age, according to findings of a South African study presented at the International AIDS Conference in Mexico City on August 4th.
The researchers were not suggesting that treatment be deferred — because the benefits of early treatment are so profound.
“We need to determine the reason why younger children fail to suppress HIV, in order to improve the chances of a durable and sustained response” said Vincent Kgakgadi, the Senior Administration Clerk of the Empilweni HIV Clinic at Coronation Hospital in Johannesburg, South Africa.
Antiretroviral therapy for children in resource-limited settings
“Effective therapies for HIV in children and aggressive treatment recommendations have prolonged life and quality of life,” said Dr Lynne Mofenson of the US National Institutes of Health who chaired the session on Clinical Issues in HIV-Infected Children. She noted that in the US, the median age of HIV-infected children followed at paediatric clinical trial sites is now 14.8 years. “Children in low-resource countries respond to [antiretroviral therapy] as well as children in high-resource countries,” she added.
But in resource-limited settings, the risk of progression to illness and death is much greater, with up to half of young children dying by the age of two. Last year, however, the Children with HIV Early Antietroviral Therapy (CHER) study reported that when antiretroviral therapy was given immediately to children with HIV between six and twelve weeks of age, there was a 76% reduction in risk of death compared to when treatment was deferred until the CD4 percentage fell below 25%.
In response to this and other studies, the World Health Organization revised its guidelines on “When to Start Antiretroviral Therapy in HIV-Infected Children” recommending antiretroviral therapy in all children under 12 months of age with a confirmed HIV diagnosis or with presumptive severe HIV. In older children however, clinical or immunological criteria should guide the decision on when to start antiretroviral therapy: for children between one and four years of age, treatment initiation is recommended when CD4 percentage is ≤20%, or absolute CD4 cell counts 3 from 12-35 months, or 3.
However, in her overview Dr Mofenson reported that several studies have shown children can have very different responses to antiretroviral therapy based on the immunological status when they start, or their age. For instance, a number of studies note that normalisation of CD4 cell percentage to >25% is uncommon in children in resource-limited settings, though this may be because children began treatment either late or with a low CD4 percentage.
A recent analysis of responses in over 1200 children in PACTG 219, by Patel et al in Clinical Infectious Diseases (46:507-15,2008 in press), reported that the more immunodeficient children are when they begin antiretroviral therapy, the less likely they are to recover their immune status. Dr Mofenson noted that another recent review of paediatric treatment studies in Africa by Sutcliffe in Lancet Infectious Diseases, found that the median CD4 percentage at start of antiretroviral therapy was only 6-15%, with 53 studies reporting a median of
In addition, another study (in the UK and Ireland) has previously reported that immunological and virological response to antiretroviral therapy varies by age at initiation of treatment (Walker AS et al. AIDS;18:1915-24,2004). In this study, younger children were more likely to have good immunological responses — however, there was a slower time to viral load suppression and lower rates of suppressed viral load in children beginning antiretroviral therapy at a younger age.
Starting HIV treatment in children at Coronation Hospital
“In South Africa, progression of HIV in children is rapid,” said Kgakgadi. So the policy at Coronation Hospital is to test neonates, infants and children as early as possible and to treat them before there is severe disease. However, “data on how the age at initiation of ART affects viral load suppression is needed to identify intervention strategies that ensure the success of ART in young children in resource-limited settings,” Kgakgadi said.
So Kgakgadi and colleagues reviewed the three, six and 18 month viral load results for all the HIV-positive children put on antiretroviral therapy at their clinic. Results were correlated with age at initiation of treatment, grouped by 0-18 months, 19-60 months and older than 60 months. Full suppression was considered to be a viral load of less than 25 copies/ml.
Results
Of the 1179 children who started antiretroviral therapy, 49-57% had viral load results available at each timepoint. The suppression rate at three and six months was significantly lower (p
The long-term suppression rate seemed to be dependent upon the initial suppression rate. If HIV was not suppressed by six months, this seemed predictive of it not being suppressed at 18 months (p
Kgakgadi speculated on a few reasons why complete viral load suppression seems more difficult in young children including higher baseline viral loads than in older children, intolerance of the antiretroviral formulations (or willingness to swallow which could lead to inadequate drug levels in the child), concurrent TB (which could increase viral load) or TB treatment (which could also lower antiretroviral drug levels) and poor socio-economical circumstances.
In addition to TB, it is also possible that a subset of younger children may be “rapid progressors” inherently less capable of controlling viral load. Without treatment, these children are the most likely to die — and thus would not be part of the cohort of older children. In other words, older children may achieve better suppression because they are a cohort of survivors.
However, immune restoration — and improved survival — is really the most critical aspect of treating young infants. This study did not report on the baseline immune status of these children or analyse the impact of therapy on it. However, there is a chance that children who fail to suppress viral load will become resistant to treatment and if anti-HIV efficacy is not improved, the response may not be sustainable.
“The long-term outcomes in “saved” infants must be monitored to ensure healthy progress to adolescence and adulthood,” said Kgakgadi, “and further studies are required regarding the relationship between age at initiation of ART and time to virological suppression to elucidate the underlying causes that make the younger age group more vulnerable to suppression failure.”