Plasma concentrations and virologic evaluations after stopping NNRTI treatment in PENTA 11
Polly Clayden, HIV i-Base
A paper authored by Tim Cressey and co-workers from the PENTA-11 study group, published in the 15 May 2008 edition of Clinical Infectious Diseases, showed findings from an evaluation plasma concentrations, viral load, and development of drug resistance after a planned treatment interruption of a NNRTI-containing regimen in HIV-positive children.
PENTA-11 is an ongoing, randomised, phase II trial evaluating the role of planned treatment interruptions (PTI) in the treatment of HIV-positive children with a good response to antiretroviral therapy.
In this study children on stable HAART for at least 6 months with viral loads <50 copies/mL and CD4 percentages of 30% (for children aged 2-6years) or CD4 percentages of 25% and CD4 counts of 500 cells/mm3 (for children aged 7-15 years) were randomised to either a PTI or to continuous therapy.
The PTI arm used one of two strategies for stopping NNRTIs:
- Treatment with nevirapine or efavirenz was stopped, and treatment with the remaining drugs was continued for 7-14 days.
- Nevirapine or efavirenz were replaced by a protease inhibitor, and all drugs were stopped after 7-14 days.
Choice between the strategies was at the discretion of the paediatrician.
Sampling for plasma concentrations, viral load, and drug resistance testing were performed on days 0, 7 (drug concentrations only), 14 and 28 after interruption of treatment with an NNRTI.
Of 110 children enrolled in PENTA-11 between November 2004 and December 2006, 56 were randomised to the PTI arm. Of these children, treatment with an NNRTI was stopped for 35 children of which 20 were receiving nevirapine, and 15 were receiving efavirenz). The median age of the children was 8.9 years (range, 3.6-15.9).
Median time from stopping treatment with an NNRTI to stopping all drugs was 9 days (range, 6-15 days) for nevirapine and 14 days (range, 6-18 days) for efavirenz.
The investigators reported that at 7 days, 1/19 (5%) and 4/8 (50%) children had detectable nevirapine and efavirenz concentrations respectively. Efavirenz remained detectable in 3/12 (25%) children at 14 days. At 14 days, viral load was 50 copies/mL in 6/16 (38%) children interrupting treatment with nevirapine (range, 52-7000 copies/mL) and in 2/12 (17%) children interrupting treatment with efavirenz (range, 120-1600 copies/mL).
They found that no new NNRTI or mutations were detected. Additionally, they reported no detection of 3TC-associated mutations.
The investigators concluded that in virologically suppressed children who interrupt an NNRTI-based regimen during their first PTI cycle, staggered or replacement stopping strategies for a median of 9 days for nevirapine and 14 days for efavirenz were not associated with the selection of NNRTI resistance mutations.
They noted that in this study it could not be determined whether a replacement or staggered stopping strategy is preferable. They suggest however that there are theoretical reasons to prefer a replacement stop strategy, particularly for efavirenz.
Cressey TR, Green H, Khoo S et al. Plasma drug concentrations and virologic evaluations after stopping treatment with nonnucleoside reversetranscriptase inhibitors in HIV type 1-infected children. Clinical Infectious Diseases 2008; 46.1601-8.