Tolerance of efavirenz in children

Objective: To extend the limited knowledge of efavirenz tolerance in children.

Method: An observational study of 33 children given efavirenz combined with various others agents and followed in a single institution.

Cited Here...: Fifteen (42%) of the children presented at least one clinically discernable side effect, cutaneous (n = 5), nervous system (n = 10), or both (n = 2). Intolerance led to treatment interruption in seven children but the main symptom was transitory dizziness or other signs similar to those observed in adults.

Conclusion: Early, often transient nervous system side effects require careful preparation with the child and his family to avoid premature and inadequate withdrawal from treatment.

Introduction

The association of a non-nucleoside analogue inhibitor of reverse transcriptase and two nucleoside analogues is largely prescribed in adults: it is easier to take, generally better tolerated and probably as effective as a standard tritherapy including a protease inhibitor ^[1]. There has as yet been little experience with the use of non-nucleoside inhibitors to treat HIV-infected children ^[2,3], and further description of both efficacy and tolerance would be valuable. Herein, we present the results for 33 children from a single institution treated with multi-therapy including efavirenz for a median follow-up of 125 days (range, 70-277).

Patients

The general characteristics of the children were unremarkable: median age was 12.5 years (range, 10.4 -14.9); median CD4 cell count was 225 ′ 10⁶ cells/l (range, 0-1262) and median viral load was 4.7 log₁₀ copies/ml (range, 1.3-6.7) (Centers for Disease Control class A, n = 11; class B, n = 8; and class C, n = 14, ^[4]). Twenty-five children had previously been given antiretroviral treatment and 20 of these had received a regimen which included a protease inhibitor. The clinical and immunovirological characteristics of these patients show, as expected, more advanced disease progression for the children previously treated, in particular those having received an antiprotease.

The median dose of efavirenz was 13.3 mg/kg (range, 11.3; 16) administered as a single daily dose in the evening, without any particular recommendation with respect to mealtimes. Capsules of 50, 100 or 200 mg were used according to the child's choice and ability to swallow. For most children, efavirenz was combined with two nucleoside analogues. For a minority of the children (n = 9), all of whom had previously received substantial antiretroviral treatment, including a protease inhibitor, efavirenz was combined with a nucleoside analogue and a protease inhibitor. For all the previously treated children, the drugs associated with efavirenz were chosen according the current recommendations ^[5], and included new drugs as much as possible. For four children, efavirenz simply replaced a protease inhibitor in a combination considered to be effective but poorly tolerated.

Results

Changes in the viral load and CD4 cell count

The overall reduction in the viral load for all the children under treatment was 2.1 log₁₀ copies/ml (range, 0.2-5.3) after 1 month, 2.0 log₁₀ copies/ml (range, 0-4.5) after 3 months and 1.2 log₁₀ copies/ml (range, -0.1 to 4.5) log₁₀ after 6 months (the mean ± SD declines at these times were: 2.1 ± 1.3, 2.0 ± 1.4 and 1.7 ± 1.5 log₁₀, respectively). The viral load was below 200 copies/ml in 12 of 30 children (40%) after 1 month, 13 of 26 (50%) after 3 months and 12 of 25 (48%) after 6 months. A more sensitive test was used for some of the children who had a viral load below 200 copies/ml: the viral load was below 50 copies/ml for six of 12, eight of 12 and nine of 12 children, respectively, at these times. The median increase in the absolute CD4 cell counts for the group as a whole was 46 ′ 10⁶ cells/l (range, -240 to 1270) after 1 month, 96 ′ 10⁶ cells/l (range, -103 to 596) after 3 months and 128 (range, -45 to 414) after 6 months.

Tolerance

Fifteen (42%) of the children suffered clinically discernible side effects (Table 1). Five presented with mild, diffuse cutaneous eruptions around the eighth to tenth days; the intensity led to treatment being stopped in one child. Twenty-five nervous system manifestations were observed in 12 children and led to treatment being stopped in six. Dizziness of varying severity was noted for 11 children following the first administrations. In many cases, these manifestations spontaneously disappeared within a few days, but they persisted in two children. For one child, occasionally changing the time of taking the drug after several months of treatment, caused recurrent dizziness; it is difficult to assess whether these symptoms appeared, or had simply previously been masked by taking the drug in the evening. Five children complained of persistently disturbed sleep, mostly nightmares. Three children presented behavioural problems (with or without dizziness); two of these children had psychiatric histories and the start of treatment was followed by an exacerbation of the existing symptoms, which led to treatment being withdrawn from one child. The third child had no psychiatric history, and appeared to become apathetic and confused following two nights of nightmares and so the parents stopped the treatment. Three children had increased appetite which, because of its intensity, persistence and associated weight gain, was considered by the parents to be an unwanted side effect.

Table 1

In summary, the treatment was stopped for intolerance within days or a few weeks for a total of seven children. The only clinical or biological factor that appeared to be significantly associated with the occurrence of side effects was younger age for children with at least one intolerance symptom: 10.8 years (range, 4.6-12.5) versus 13.3 years (range, 4.4-15.1), (P < 0.04). No long-term side effect potentially caused by efavirenz was detected. No biological modification above Grade II according to the WHO classification for standard parameters (haematology, liver, pancreas, lipid analysis) ^[6] was observed.

Discussion

Paediatric experience with efavirenz is still very limited. The only documentary evidence available is the trial ACTG382, a study of the association of efavirenz with a protease inhibitor (nelfinavir) and one or two nucleoside analogues ^[3]. The present data from an observational study in a single centre reflecting routine practice for this drug, extend the data from trial ACTG382. In contrast to this previous trial, neurological intolerance during the first days of administration was not negligible. The prevalence was of the same order of magnitude as that in adults ^[1]. Furthermore, the parents may react to the symptoms suggestive of inebriety and the troubled sleep by requesting that the treatment be stopped before the end of the habituation period. This period, which lasts for a few days, has been described in adults, and is similarly found with children. Particular attention should be given to children with psychiatric histories, as they may be liable to aggravation of the symptoms. We have no explanation for the notable difference between our findings and the results of trial ACTG382 which includes no evidence of such problems. These symptoms, despite being transitory, should be discussed in advance with the patient and family so as to minimize the risk of premature withdrawal from treatment.

The simplification of multi-therapies would make a major contribution to adherence to treatment. The administration of a single daily dose of efavirenz is undoubtedly important and was greatly appreciated by the experienced children. Although the optimal use of efavirenz in the overall therapeutic strategy remains to be determined precisely, it appears to be a promising and major antiretroviral molecule. Its early, often transient, adverse effects require careful preparation with the child and his family.