New WHO guidelines for children (July 2010)
Polly Clayden, HIV i-Base
The new WHO 2010 paediatric guidelines Antiretroviral Therapy for HIV Infection in Infants and Children: Towards Universal Access – also summarised on their website in a preliminary version for programme planning in June, were released at IAS 2010.
Lynne Mofenson provided an excellent summary of the new guidelines at the paediatric meeting and Shaffiq Essajee in the Early Infant Diagnostics (EID) session at IAS. [1,2] We will review developments in diagnostics including EID in the next issue of HTB.
When to start
Universal treatment is recommended for all infants and young children under two years irrespective of CD4 or clinical indication. The recommendation is strong for less than 12
months and conditional for 12-24 months.
Data to guide when to start for children one to five years old are scant and this is reflected in differences in recommendations between guidelines (see statement from PENTA in the comment below). After five years of age, guidance is similar to that for adults (see Table 1). Table 2 shows a comparison between the 2006 and 2010 WHO guidelines.
|Age||WHO 2010 Guidelines|
|Less than 24 months|
|Clinical||Stage 3 or 4|
|Immunological*||< 25% or < 750|
|5 years and older|
|Clinical||Stage 3 or 4|
*CD4 percentage/absolute CD4 count mm3
|2006||Immune marker||Age specific recommendations to initiate ART||Clinical criteria|
|<12 months||12-35 months||36-59 months||≥5 years|
|CD4 percent||All||<20%||<20%||<15%||Stage 4 disease
Stage 3 disease (ART initiation may be delayed in some cases)
|CD4 count/mm3||All||<750 cells||<350 cells||<200 cells|
|TLC/mm3||All||<3000 cells||<2500 cells||<2000 cells|
|2010||Immune marker||Age specific recommendations to initiate ART||Clinical criteria|
|<24 months||24-59 months||>5 years|
|CD4 percent||All||<25%||Stage 3 and 4 disease|
|CD4 count/mm3||All||<750 cells||<500 cells|
Adapted from WHO 2010 revision. Essajee S.
PENTA have published a letter in support of the new guidance for resource limited settings and are continuing to recommend PENTA guidance ie universal treatment for infants less than 12 months and immunological and clinical criteria for those above for treating children in Europe. In the letter they write:
Both PENTA 2009 and WHO 2010 guidelines considered the same body of evidence, and several experts took part in the drafting of both sets of recommendations. The universal treatment of infants is based on evidence from the CHER study, children over five are treated at adult thresholds in both guidelines, based on comparisons between the HPPMCS child cohort and CASCADE adult seroconverter cohort. The recommendations for children aged between 2 and 5 are based on cohort data, largely from the HPPMCS study.
The new recommendations in the WHO guidance for children between age one and five are based on programmatic considerations, in particular the ability to closely monitor a child clinically and by repeat CD4 count measurement if they are not started on ART. Such monitoring is available in Europe, and in many settings outside Europe. It is also noted that the evidence basis for these recommendations is weak or very weak, and that studies expected to publish results soon may shed more light on the subject. We endorse WHOs recommendation to treat early where the ability to provide monitoring is limited, as well as the call for more research to provide RCT evidence for treatment initiation thresholds after infancy. We continue to recommend PENTA 2009 guidance as appropriate for European and other settings with the facility to monitor closely children in whom treatment is deferred.
What to start with
Recommended regimens are:
- For children less than two not exposed to maternal or infant nevirapine or whoseexposure status is unknown: nevirapine plus two NRTIs.
- For children exposed to maternal or infant nevirapine or other NNRTIs used for maternal treatment or PMTCT: lopinavir/ritonavir plus two NNRTIs (with the caveat that nevirapine is better than nothing).
- For children over two but under three: nevirapine plus two NRTIs.
- All others (irrespective of nevirapine exposure): nevirapine or efavirenz (efavirenz preferred for TB treatment)
- Under three and needs TB treatment: nevirapine plus two NRTIs or abacavir plus lamivudine plus zidovudine/stavudine.
- Adolescents over 12 with hepatitis B: tenofovir plus lamivudine/emitricitabine plus efavirenz/nevirapine (can take FDC of lamivudine/emitricitabine plus efavirenz if this is available).
- Adolescents with hepatitis C: preferred regimen is efavirenz plus two NRTIs.
The guidelines also recommend a preferential order of NRTIs (zidovudine/lamivudine > abacavir/lamivudine > stavudine/lamivudine).
They recommend that any child with active TB begin TB treatment immediately and start ART in the first eight weeks of TB treatment.
For children already on ART who develop TB, they recommend that ART regimens may need to be adjusted to decrease the potential for toxicities and interactions: if on nevirapine substitute for efavirenz if over three years; if under three ensure nevirapine is at high dose (2 mg/m2) and if on lopinavir/ritonavir consider adding ritonavir to a 1:1 ratio lopinavir/ritonavir to achieve the full therapeutic dose of ritonavir.
The guidelines recommend solid in preference to liquid formulations, use of heat stable FDCs or co-packaged formulations wherever possible and dosing in accordance with WHO weight band tables.
When to switch
Switching to second line treatment is recommended when clinical, immunological or
virological failures occur.
- Clinical failure is defined as the appearance (or reappearance) of WHO clinical stage 3 or 4 events at least 24 weeks on ART and child is adherent.
- Immunological failure is defined as returning to age related thresholds in a treatment adherent child: CD4 count of <200 cells/mm3 or CD4 percentage <10% for a child over two and less than five years of age; CD4 count of <100 cells/mm3 for a child of five years or more.
- Virological failure is defined as a persistent viral load above 5000 copies/mL after at least 24 weeks on ART for a treatment adherent child.
What to switch to
Choice of second line ART is dependent on the first line regimen received:
- After failure on an NNRTI: boosted PI plus 2NRTIs. Lopinavir/r is preferred.
- After failure on zidovudine or stavudine plus lamivudine: abacavir plus lamivudine is the preferred NRTI backbone, abacavir plus didanosine is an alternative.
- After failure on abacavir plus lamivudine, zidovudine plus lamivudine is the preferred NRTI backbone; zidovudine plus didanosine is an alternative.
These guidelines represent a liberalisation of criteria and if they are followed should ensure that many more children are identified and treated.
They are available on the WHO website. 
Annexe E has updated weightband dosing tables and formulations that are needed. We also look at paediatric formulations in the TAG/i-Base Pipeline Report. 
- Mofenson L. Whats new in WHO Pediatric Treatment Guidelines? 2nd International Workshop on HIV Pediatrics. July 2010, Vienna, Austria. http://regist2.virology-education.com/2ndHIVPed/docs/I_04Mofenson.pdf
- Essajee S. Scaling up early infant diagnosis of HIV as the bridge between prevention, care and treatment: successes, challenges and potential solutions. Special session SUSS03. http://pag.aids2010.org/session.aspx?s=150
- World Health Organisation. Antiretroviral therapy for HIV infection in infants and children : Recommendations for a public health approach (2010 revision) http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html
- Clayden P. Paediatric antiretroviral pipeline. TAG 2010 Pipeline Report. July 2010. https://i-base.info/htb/13436