Caution against dividing adult FDCs (Triomune) for young children
Polly Clayden, HIV i-Base
While we await paediatric FDCs, several programmes are treating children with divided fixed dose combinations (FDC) Triomune (d4T+3TC+nevirapine) tablets. Although this strategy is important and included in some national guidelines (including Malawis), this is not a long-term solution as previous studies have found cut up tablets for young children can result in under dosing of nevirapine.
There are limited PK data on nevirapine in children treated with divided tablets and in whom malnourishment is common.
In an oral presentation Dr Lhomme presented findings from a study to determine the extent of the subtherapeutic concentrations (<3.0 mg/L) of the nevirapine component and to investigate predictors of nevirapine concentrations in children treated using this strategy.
This study included 127 HIV positive children aged 3 months – 16 years (median 8.4 years) treated at the Queen Elizabeth Central Hospital, Blantyre, Malawi and the University Teaching Hospital, Lusaka, Zambia who had received divided Triomune at a range of doses (see table one) for at least a month.
Steady-state plasma nevirapine concentrations were determined in the children. Centre-stratified regression with backwards elimination (p<0.1) was used to identify predictors from height-for-age, BMI-for-age, age, sex, post-dose sampling time and dose/m2/day.
The 71 Malawian children were similar ages (median 8.4 years), but more malnourished (BMI-for-age -0.89, height-for-age -3.15) and had longer post-dose sampling times (8.9 hours) than the 56 Zambian children (8.5 years, -0.50, -1.84, 3.5 hours respectively).
Table 1: Triomune tablets and daily nevirapine dose
|Number of Triomune tablets||Total daily dose (mg)||Number of children (n=127)|
|¼ once daily||50||6|
|¼ twice daily||100||9|
|¼ once daily, ½ once daily||150||18|
|½ twice daily||200||52|
|½ once daily, ¾ once daily||250||12|
|¾ twice daily||300||2|
|¾ once daily, whole once daily||350||2|
|whole twice daily||400||23|
Overall, the median nevirapine concentration was 6.0mg/l (IQR 3.8-8.2mg/L) percentage of children receiving sub-therapeutic doses of nevirapine (<3.00mg/L) in this analysis was 18% (see table 2).
Table 2: Percentage of patients with subtherapeutic nevirapine (<3.0mg/L)
- Overall: 18%
- >300mg/m2/day: 3%
- 240-300: 20%
- <240: 25%
The median nevirapine levels were 4.8mg/L [IQR: 2.8, 6.5; range: 0.15,15.4] and 7.0 mg/L [IQR: 5.4,10.5; range 0.15,17.1] in Malawian and Zambian children respectively. Only the children receiving the nearly adult dose (350-400mg nevirapine/day) received the target dose of 300 mg/m2/day (median 337 mg/m2 [IQR 303-366; range 274-454], with only 2% of these children with <3 mg/L (considered subtherapeutic).
Those prescribed 50-200 mg/day (quarter/half tablets) were more frequently underdosed (median 236 mg/m2 [IQR 217,267; range 120- 354], with 21% <3mg/L); as were those prescribed >200-<350mg (median 263 mg/m2 [IQR 260,271; range 245-292], with 21% children <3mg/L.
The investigators found lower height-for-age (indicating stunting) (+0.37 mg/L per unit higher [95% CI – 0.013, +0.75], p=0.06), lower prescribed dose/m2 (+0.67 mg/L per 50mg/m2 higher [+0.014, +1.32], p=0.05) and younger age (+0.15 mg/L per year older [-0.022, +0.31], p=0.09) were independently associated with lower nevirapine levels.
They reported no significant independent effect of lower BMI-for-age (indicating wasting) (-0.33mg/L per unit higher [-0.76, +0.09], p=0.12), although this was a stronger predictor for the Malawian children (-0.51 [-1.01, -0.02], p=0.04).
The investigators concluded that dividing Triomune could put children at risk for nevirapine underdosing. They wrote: To avoid nevirapine underdosing in young children, divided FDC Triomune should be used with caution; the use of quarter tablets is not recommended. Nevirapine levels may be reduced in stunted but increased in wasted children. Further studies investigating these relationships are required.
Lhomme R, Ellis R,J, Ewings F et al. Nevirapine concentrations in HIV-infected children treated with divided fixed dose combination tablets in Malawi and Zambia. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 2.