Children in rich and poor countries doing equally well on HIV drugs

The effectiveness of one year of antiretroviral treatment in treatment-naive children in resource-limited settings is comparable to that of children in resource-rich settings, report Andrea Ciaranello and colleagues in a study published in the December 15 edition of Clinical Infectious Diseases.

This is in spite of advanced disease at the start of treatment, a predominantly non-nucleoside reverse transcriptase inhibitor (NNRTI) based regimen and multiple barriers to ART delivery.

Comprehensive and clear reporting on the reasons for missing data and loss to follow-up are key in the evaluation of paediatric antiretroviral treatment programmes in resource-limited settings, the authors note.

While combination antiretroviral therapy in resource-rich settings is effective in reducing morbidity and mortality among HIV-infected children, 90% of the estimated 2.1 million children infected globally live in resource-limited settings.

Reported outcomes from programmes in Africa, Asia and the Caribbean of clinical, virologic and immunologic responses to antiretroviral treatment vary considerably.

According to the authors the calculation of single combined estimates of suppression of viral load (HIV RNA

• Pooled estimates consist of useful sets of information for comparison of outcomes from individual programmes and new treatment strategies when multiple randomised trials are lacking.
• These estimates allow comparison with published antiretroviral treatment outcomes in children in resource-rich countries.

The authors carried out a systematic review and meta-analysis of published reports of HIV viral load (RNA) and CD4 cell count outcomes 12 months after initiating antiretroviral treatment in treatment-naïve, HIV-infected children aged from 0-17 years of age in resource-limited settings (Africa, Asia and the Caribbean).

Data from nine studies representing 1097 children with complete follow-up data contributed to a pooled estimate of 70% viral load suppression (HIV RNA

Data from 12 studies and 1839 children with complete data contributed to a pooled estimate of 13.7% gain in CD4 percentage.

The authors note these are comparable to reported antiretroviral treatment outcomes for treatment naïve children in the United States and Europe with 12 month viral load suppression rates (HIV RNA

In addition, the authors note, clinically significant growth gains (height and weight) were observed after 12 months.

These findings support outcomes from other systematic reviews (in Africa) highlighting the similarity of outcomes, following the provision of ART, among treatment-naïve children in resource-poor and resource-rich settings, note the authors.

This is in spite of significant disadvantages in resource-limited settings, including: advanced stage of disease at the start of treatment as well as a higher proportion of children over the age of five, a predominantly NNRTI-based regimen compared to protease inhibitor-based regimens, and the many difficulties of antiretroviral treatment delivery.

While the authors found no direct association between these differences and virologic and immunologic outcomes, their ability to complete a more in-depth analysis was limited by the relatively small number of studies.

In addition, missing or incomplete data meant they were unable to look at the effects on outcomes of: getting treatment for prevention of mother-to-child transmission, nutritional status, pharmacy stockouts, free provision of medications, and prevalence or incidence of tuberculosis, malaria, anaemia, and diarrhoeal disease.

The authors note several limitations.

• Only published reports were included because of the inconsistent quality of conference proceedings which, the authors note meant more recent antiretroviral treatment outcomes were left out.
• Only 12-month treatment outcomes were included since 12 months of data was available in the largest number of reports.
• Programmes made use of HIV RNA tests with different limits of detection. True rates of suppression to
• Included studies did not report on links between gains in CD4 percentages or suppression of HIV RNA and the risks of AIDS-related morbidity. However, these can serve as reliable markers for such events. (The authors note that anticipated individual patient data from a large paediatric cohort in lower-income countries—-KIDS-ART-LINC—will avoid the limitations of meta-analysis http://ije.oxfordjournals.org/cgi/content/full/37/3/474 ).

Strengths noted include:

• Inclusion of studies from resource-limited settings outside of Africa.
• An analysis that provides for the first time pooled estimates of viral load suppression rate and gain in CD4 percentages for children receiving ART in resource-limited settings.

In addition, sensitive analyses were carried out that show the effect that missing data can have on interpreting reports on the effectiveness of antiretroviral treatment and success of ART programmes.

Of 5928 children who began ART 81% did not have 12-month HIV RNA data and 69% did not have 12-month CD4 percentage data.

The authors suggest that children without follow-up data are more likely to have died than those followed-up and so would have poorer virological and immunological outcomes. If so, the authors suggest the pooled estimates will have overestimated the benefits of ART.

Yet they argue that lack of HIV RNA or CD4 percentage data may not represent true loss to follow-up. For example, start of antiretroviral treatment may have begun less than 12 months before data reporting, in children over five years of age CD4 cell count may have been preferred to CD4 percentage, or laboratory testing may not have been available at the time of the visit.

Sensitivity analyses that excluded studies with considerable missing data did not significantly change outcomes. However, when the authors assumed that all children who had died or did not have 12 month data had viral loads >400 copies/ml then the pooled estimate of viral suppression decreased to 53%.

Similarly when children with missing CD4 percentage were assumed to have no change in CD4 percentage then the pooled estimate dropped to 8.5%. The authors further note that it is possible that children who died or were lost to follow-up may actually have a loss in CD4 percentage rather than no change bringing the true CD4 percentage even lower.

Yet the authors note that with increasing age there is some expected decrease in CD4 percentage meaning that small gains may actually represent improved immune function.

“Definitions and reporting of loss to follow-up and clear descriptions of reasons for missing data are therefore important considerations in interpreting reports of paediatric ART effectiveness and the success of ART programmes”, the authors stress and conclude “As paediatric ART programmes are expanded worldwide, clear and comprehensive reporting of these data will be crucial to interpreting and comparing the effectiveness of ART in resource-limited settings.“