First-line treatment with two nucleoside reverse transcriptase inhibitors (NRTIs) plus efavirenz (EFV) 600 mg daily is the standard of care in HIV infection. Some patients benefit from an EFV dose reduction, and a Phase II study carried out during the development of EFV supported use of a lower dose . ENCORE 1, a randomized, blinded, placebo-controlled trial comparing EFV at the standard dose of 600 mg versus 400 mg in 630 patients treated for 48 weeks, has started , but results will not be available until 2013.
We describe our experience of EFV dose reduction in a clinical setting (Infectious Diseases Outpatient Clinic, University of Verona, Verona, Italy) in 33 HIV-infected patients treated with two NRTIs plus EFV. Blood samples collected 9–16 hours after the last dose intake were stored for subsequent measurement of EFV plasma levels .
Three groups of patients were included in the study (Table 1). In group 1 patients, EFV was reduced to 400 mg after 33–119 months (mean 66.4 months) on the full dose and when HIV RNA was <50 HIV-1 RNA copies/mL. EFV was reduced, because of sleep disturbances and on the basis of pharmacokinetic data, to 400 mg in all but one patient (who switched to 200 mg). After a mean of 12.6 months, all the patients continue to have undetectable HIV RNA, and side effects have disappeared. Mean EFV plasma levels decreased by 65.9% at 6 months, and in five subjects the post-dose reduction EFV concentration was below 1000 ng/mL, i.e. the supposed minimum effective concentration (MEC) .
|Patient group||Total number of patients||Numbers of female/male patients||Numbers of Caucasian/African patients||Mean age (range) (years)||Mean CD4 count before EFV dose reduction (cells/μL)||Mean CD4 count after EFV dose reduction (cells/μL); range of time on reduced dose (months)||Mean (range) EFV Ctrough before dose reduction (ng/mL)||Mean (range) EFV Ctrough 6 months after starting reduced dose (ng/mL)|
Group 2 patients had a mean treatment duration of 35.4 months (range 21–60 months) and HIV RNA <50 copies/mL before a reduction of EFV to 400 mg by the physicians in charge because of sleep disturbances and prior to having knowledge of the pharmacokinetic data. Ten to twelve months after the reduction of EFV, all patients continue to have undetectable HIV RNA, with no side effects. Mean EFV plasma levels decreased by 34.4% at 6 months, and in five subjects the post-dose reduction EFV concentration was below the MEC.
Group 3 patients were naïve to antiretrovirals, and had a pretreatment mean HIV RNA level of 104 529 copies/mL. Four patients were started on EFV 400 mg by the physicians in charge, and four had decided to take only 400 mg and two only 200 mg despite being prescribed the full dose. The latter six patients informed physicians of their decision after a few months on the reduced doses, and then pharmacokinetic analysis was performed. After 9–86 (mean 30) months on reduced doses, all patients have undetectable HIV RNA. The mean EFV level was 1579.9 ng/mL at 6 months.
Although 10 patients (in groups 1 and 2) had EFV levels that were below the MEC after dose reduction, no virological failure was observed over a follow-up period of up to 15 months. These results confirm those of previous studies that questioned the relationship between plasma levels and efficacy and are consistent with those of the FOTO study , suggesting that the long-term maintenance phase of an EFV-containing fully suppressive first-line regimen could require lower pharmacological pressure.
In conclusion, a dose reduction of EFV to 400 mg once daily warrants further investigation as a therapeutic option. Although our results were obtained largely in Caucasian male patients, if they are replicated in other populations a dose reduction may be indicated, leading to considerable cost savings which could be very important, especially in resource-limited countries.