Pharmacokinetic and virological evaluations after stopping NNRTIs in children: a substudy of the PENTA 11 (TICCH) Trial
Polly Clayden, HIV i-Base
There are currently limited paediatric pharmacokinetic (PK) data to guide stopping NNRTIs safely.
Marc Lallemant and co-workers from the PENTA 11 study group (evaluating the role of planned treatment interruptions) in Thailand and western Europe presented preliminary findings from a small substudy to assess the PK of antiretrovirals with long half lives and their association with development of resistance within this context.
In PENTA 11, children aged 2-15 years with viral load <50 copies/mL and CD4 percentage of >33% (ages 2-6 years) or CD4 percentage of >32.5% and CD4 >350cells/mm3 (ages 7-15 years) are randomised to planned treatment interruption or continuous therapy.
Between November 2004 and January 2006, 70 children have been randomised of whom 13 (aged 5-15 years; 6 girls) have interrupted nevirapine-based ART and 9 (aged 5-14 years; 6 girls) have stopped efavirenz-based ART.
The choice of stopping strategy was at the discretion of the clinician and was to either stagger stop (stop NNRTI first, continue remaining regimen for 7-14 days) or replace the NNRTI (switch to PI and stop all drugs after 7-14 days).
Nevirapine and efavirenz plasma drug concentrations were measured by High Performance Liquid Chromatography (HPLC) with a limit of detection between 0.05 0.15mg/L for NVP and 0.05 0.2mg/L for EFV. In this evaluation >/= 0.15 for NVP and >/= 0.2 mg/L were considered detectable.
The investigators reported median pre-interruption drug levels of 4.8 mg/L (range: 2.2-15.1) in 11 children interrupting NVP and 3.2 mg/L (range: 0.9-3.5) in 7 children interrupting EFV.
They found that at week one, no children had detectable NVP levels, but they noted that of 2/5 samples tested with a more sensitive assay (lower limit of detection <0.05mg/L) had detectable levels, and three children had detectable EFV levels: 0.61, 0.54 and 0.2mg/mL. At week two, no children had detectable NVP levels and three had detectable EFV levels: 0.26, 0.32 and 0.29 mg/L. At week four no children had detectable levels of either drug.
The investigators also noted that following the results for the first 6 children interrupting EFV, the stagger stop/replace recommendation was increased to two weeks.
Additionally they found that viral rebound following treatment interruption was similar between stopping strategies and that the majority of children had detectable viral load by four weeks.
All 11 children receiving NVP were tested for resistance and one child was found to have detectable K103N mutations at four weeks. The investigators explained though that this child had detectable viral load (700 copies/mL) and detectable K103N at the time of interruption. The investigators reported no resistance in the eight children evaluated to date receiving EFV.
In their conclusion, they wrote that these preliminary data suggest that to avoid the development of resistance in children with undetectable viral loads interrupting an NNRTI based regimen, the adoption of a staggered stop or replacement strategy of: 7-10 days of children interrupting nevirapine; and at least 2 weeks for children interrupting efavirenz; may be sufficient to prevent the selection of resistant mutations. However, they added that more sensitive assays may be required to detect very low level resistance.
Data to guide stopping drugs with long half lives are important. There were concerns following the news from the SMART study of the short-term risk of intermittent therapy in adults that to continue PENTA 11 would be unwise.
The trial was stopped temporarily but its DSMB, having reviewed all the relevant data, recommended resuming enrolment to the study with a few safety amendments on the grounds that
- Likely duration of treatment and immune reconstitution very different in children compared to adults.
- No data on planned treatment interruptions in children.
- PENTA 11 treatment interruption strategy uses CD4 criteria for restart/stop of ART, which are already higher than SMART so should have lower risk.
- In addition, the strategy can be modified to reduce risk of disease progression even further:
- children with CD4 within 2% or 50 cells/mm3 of the restart threshold should be monitored more intensely, to ensure that CD4 do not fall much below the restart thresholds;
- children to spend no more than 48 weeks off ART, and at least 24 weeks back on ART after interruption;
- children whose CD4 drop rapidly after first interruption and restart within 10 weeks of stopping ART should not re-interrupt;
- detailed immunology and virology in children interrupting ART essential to understand viral and host dynamics.
Pharmacokinetic and virological evaluations after stopping NNRTIs in children: a substudy of the PENTA 11 (TICCH) Trial. XVI International AIDS Conference, Toronto, Canada. 13 – 18 August 2006. Poster abstract MOPE0206.