Hermione Lyall
Children with advanced HIV at St Marys are also treated with 4-drug combinations in first line, using an NNRTI and three nucleosides. This offers a potent alternative to using 4-drug combinations with all three classes.
Although the use of NNRTIs in first line therapy (without PIs) has not been well studied, this may be an ideal role in which to use them, especially in a four-drug combination.
A preliminary study of the three-drug combination of AZT/3TC/nevirapine in six children (age 2-4 months, baseline viral load 40,000-1,500,000 copies/ml) produced an early reponse to <10,000 copies/ml by day 14 but this was sustained to 24 weeks in only two children. [1] This also highlighted ongoing concerns in paediatric care of previous treatment or exposure to antiretrovial drugs and relatively high levels of viral load replication.
Nevirapine has been available in the UK since late 1997. The liquid formulation is palatable and can be used in once or twice daily regimens.
We have recently reviewed the use of nevirapine in a mixed group of seventy-four children. Only 28 of these children were treatment naive and, as reflects the majority of our cases, about 70-80% of the children were of African origin. Both the naive and pre-treated group were starting from high viral loads and low CD4 counts and low z-scores.
At 24 weeks, 60% of treatment na•ve children were < 400. Now we would be aiming for lower levels still, but at the time this was not too bad. With pretreated children the success rate was much lower (approximately 38% < 400copies/ml). [2]
We then went back through all the case records to see the dosing the children had received. At that time the recommended dosing was 240-300mg/m2/day but many children received lower doses. This analysis revealed a direct relationship between dosing and efficacy with only those children recieving >300mg/m2/day achieving viral load < 400 copies/ml for all the children in that group. This is very important. Underdosing in paediatrics is now increasingly recognised as an important problem.
About 20% of children showed any incidence of rash, with grade 3-4 in 5% of the children. Median time to onset was nine days (range 1-44 days). There was one child who got quite severe transaminitis and five cases of grade 3-4 neutropenia.
In PACTG 383 with efavirenz (plus nelfinavir and at least one RTI), 58% of 18 treatment-experienced children achieved viral loads levels <50 copies/ml at 48 weeks. This may be better but it is still not good enough Ð and again raises the question of the difficulty of a salvage regimen for those children whose treatment did not produce optimal results, and who developed resistance to all three classes.
This study again showed that antiviral effect was related to dosing levels. Importantly in this study there were particular difficulties with dosing for efavirenz and nelfinavir in the ten children who were under two years of age -seven and five of whom had suboptimal levels of efavirenz and nelfinavir respectively. [3]
Although I agree that with advanced children you have to use at least four drugs in a combination, I have serious concerns about using all three classes of drugs in a first-line therapy. I think it is better to only use two classes of drugs, then having the opportunity of one held in reserve for the next time round.
We have a small cohort at St Marys of five children (median age 3 months, range 1-28 mo) who presented with AIDS defining illnesses (4 cases PCP, 2 cases CMV retinitis, 1 case bacterial pnuemonia). With these children we used a four drug combination using two classes of antiretrovirals (nucleoside analoges) abacavir, 3TC, AZT and nevirapine (non-nucleoside analogue).
These children all had very low baseline CD4 counts that have since come into a more or less normal range. All five achieved viral load <100 copies/ml at a median of 19 weeks (editors note: which has since beed sustained for a further four months). They were all underweight and thin before starting treatment and have seen dramatic improvements in their weight. There were three case of rash although this lead to no discontinuations.
Although there are few studies of NNRTIs as first line therapy for children, there is evidence from adult studies that NNRTIs can be included in an effective first-line regimen even with relatively high viral loads.
The advantages of this regimen include easier dosing and achievement of good therapeutic levels. If you are going to be using PIs in children you also need to use therapeutic drug monitoring. The liquid formulations for nevirapine and efavirenz are palatable and nevirapine tablets are crushable, dividable, soluble and easiy to manage.
In general, NNRTIs have less GI side effects and that is obviously important for children who are meant to be eating, growing and gaining weight. There is also a concern with the long term metabolic side effects that we are beginning to see in adults who have been on PI treatment for 2-3 years, particularly related to cardiovascular events, glucose metabolism and more recently osteopenia.
If we are starting small children on these drugs then whats going to happen to these kids when they are teenagers and young adults? This is something that should be an ongoing concern.
| Figs 1-3. Changes in parameters in children [4] | ||
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Dr Hermione Lyall is a consultant in paediatric infectious
diseases at St Marys Hospital, London. Her special interest is prevention of
vertical transmission of HIV, herpesvirus infections and the management of HIV
infected children. She co-wrote the BHIVA guidelines for prevention of mother
to child transmission which are currently being updated. The family clinic at
St Marys is a participating centre in the PENTA studies.
h.lyall@ic.ac.uk
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