Dose escalation or immediate full dose when switching from efavirenz to nevirapine-based highly active antiretroviral therapy in HIV-1-infected individuals?

Efavirenz induces the metabolism of co-administered drugs through the induction of CYP 3A4. It is often necessary to switch from efavirenz to nevirapine because of intolerance or toxicity. In a pharmacokinetic study we determined whether to dose-escalate nevirapine or start the full dose when switching from efavirenz. It was found that when changing from efavirenz to nevirapine individuals should commence on 200 mg twice a day, as this dose is associated with therapeutic plasma drug levels. The non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz, is commonly used as a component of combination antiretroviral therapy in HIV-1-infected individuals. Many clinicians would now consider efavirenz-containing antiretroviral regimes to be the first line treatment of choice [1]. Efavirenz is metabolized in the liver by cytochrome P450 3A4. It acts as an inducer of this enzyme, increasing the metabolism of other co-administered drugs that are metabolized by this route, resulting in lower plasma drug levels. Side-effects of efavirenz are common, but are generally well tolerated. Central nervous system side-effects are reported in 58% of individuals [2]. The majority improve with time. A total of 3.2% of individuals have been reported to develop a drug-related rash [3]. Studies have reported 9% of individuals stopping efavirenz as a result of intolerance and toxicity [4]. Individuals intolerant of efavirenz are commonly switched to nevirapine, another NNRTI. After stopping any enzyme-inducing drug the effects on enzyme levels will persist for some time afterwards. If this is so, when switching from efavirenz to nevirapine the residual enzyme induction from efavirenz could lead to reduced plasma levels of nevirapine. The potential implication of low nevirapine plasma levels is the development of drug resistance. The recommended dose of nevirapine is initially 200 mg for 14 days, with an increase to 200 mg twice a day thereafter. Dose escalation is necessary secondary to nevirapine inducing its own metabolism through CYP 3A4. Veldkamp et al. [5] reported on the steady-state pharmacokinetics of efavirenz and nevirapine when used in combination. Nevirapine levels were unaffected by the co-administration of efavirenz, whereas efavirenz levels were significantly reduced. However, that study, which measured steady-state pharmacokinetics 28 days after nevirapine 400 mg a day was added to individuals established on efavirenz, did not look at interim drug levels and efavirenz continued to be taken. When switching from efavirenz to nevirapine it is unknown whether nevirapine should be commenced at the standard 200 mg once daily dose or at the full dose (e.g. 200 mg twice a day), because of possible efavirenz-related enzyme induction. The objective of this pharmacokinetic study was to explore whether to dose-escalate nevirapine or commence at the full dose when switching from efavirenz. Individuals established on efavirenz for at least one month, who were changing to nevirapine as a result of toxicity or intolerance of efavirenz, were eligible for this observational pharmacokinetic study. Individuals were randomly assigned on a 1 : 1 basis to either dose escalation (200 mg a day for 2 weeks then 200 mg twice a day; group 1 ) or the full dose (200 mg twice a day; group 2) of nevirapine. The protocol was approved by the local ethics committee. Blood samples were taken one hour before the morning nevirapine dosage on days 2, 8, 15, 22 and 29 to determine drug concentrations, as were liver function tests, CD4 cell counts and viral load estimations. Drug analysis was performed by the Department of Pharmacology, Liverpool University. The trough concentration of nevirapine considered to be the minimum effective concentration was 3000 ng/ml [6]. This was a pharmacokinetic observational study with trough drug levels the outcome measure. The study was powered to 80% certainty and 5% significance, assuming that 12 patients completed the study. Differences between group comparisons were made using non-parametric statistical methods. All P values quoted are two sided. Fifteen individuals were randomly selected. Full data from 12 are available. Three patients were lost to follow-up before the first study visit. Six individuals were randomly assigned to dose escalation (group 1) and six were randomly assigned to full-dose nevirapine (group 2). All 12 individuals were switched from efavirenz as a result of intolerable central nervous system side-effects. All were men, with no significant differences in age, baseline CD4 cell counts or time on efavirenz between each group (Table 1). Five individuals in both groups were currently receiving combivir and efavirenz. The other two individuals were receiving efavirenz with other nucleoside backbones. No individual in either group was receiving other enzyme-inducing or inhibiting drugs.Table 1: Clinical parameters, laboratory parameters and drug levels in group 1 versus group 2.The mean trough nevirapine levels up to day 15 in group 1 were below the recommended level associated with virological success of 3000 ng/ml. Mean trough nevirapine levels in group 2 were above this threshold except for day 2, but were significantly higher than group 1 on this day. Efavirenz levels were also measured on day 8. Individual nevirapine levels for day 8 are shown (Table 1). From these data, on day 8, no individual had a continuing therapeutic level of efavirenz. In group 1, four out of six individuals had sub-therapeutic nevirapine levels and in the remaining two patients nevirapine levels were only marginally above the therapeutic level. Drug levels in group 2 show therapeutic nevirapine levels in four individuals with one level not obtained and one just below the therapeutic level. There was no increased incidence of raised alanine aminotransferase in either group. Viral loads were undetectable to less than 50 copies/ml in five out of six individuals in both groups at baseline. One patient in each group had a viral load blip at baseline, in both of whom the previous viral load measurements were below the level of detection. Further viral load blips were observed throughout the study. However, in both groups viral loads were undetectable for all individuals at 3 months post-switch. We have shown that individuals changing from efavirenz to nevirapine should commence on 200 mg twice a day to ensure therapeutic plasma drug levels. This regimen reduces the length of time when subtherapeutic drug levels are present. This study did not demonstrate any virological failure in those being given lower-dose nevirapine over the time period studied, but there is a potential for virological failure and the associated risk of developing drug-resistant mutants. Individuals given higher-dose nevirapine may potentially be at a greater risk of hepatotoxicity. This was not demonstrated in our cohort. The highest alanine aminotransferase (serum glutamate-pyruvate transaminase) level observed was 161 IU/ml (less than five times the upper limit of normal, grade 2 reaction). Toxic concentrations of nevirapine were also not demonstrated in our cohort for those switching to 200 mg twice a day; the highest nevirapine level observed was 5667 ng/ml (upper limit 8000 ng/ml). For individuals with pre-existing liver disease, if nevirapine 200 mg twice a day is commenced the close monitoring of liver function tests is mandatory. Because of its long plasma half-life, one may have expected efavirenz levels to remain therapeutic for the initial period of the switch, protecting from the potential sub-therapeutic levels of nevirapine. However, by day 8 no therapeutic levels of efavirenz were observed. This may partly be be caused by the effect nevirapine has on reducing efavirenz plasma levels [5]. When switching from an efavirenz-based regimen as a result of toxicity or intolerance, physicians may choose to switch to nevirapine, a protease inhibitor-based regimen or a triple nucleoside regimen [7]. If nevirapine is chosen, from these pharmacokinetic data, it should be given at the full dose without the 2 week dose escalation.