Abstract and Introduction
Abstract
Objectives The aim of the study was to compare the neuropsychiatric safety and tolerability of rilpivirine (TMC278) vs. efavirenz in a preplanned pooled analysis of data from the ECHO and THRIVE studies which compared the safety and efficacy of the two drugs in HIV-1 infected treatment naïve adults.
Methods ECHO and THRIVE were randomized, double-blind, double-dummy, 96-week, international, phase 3 trials comparing the efficacy, safety and tolerability of rilpivirine 25 mg vs. efavirenz 600 mg once daily in combination with two background nucleoside/tide reverse transcriptase inhibitors. Safety and tolerability analyses were conducted when all patients had received at least 48 weeks of treatment or discontinued earlier. Differences between treatments in the incidence of neurological and psychiatric adverse events (AEs) of interest were assessed in preplanned statistical analyses using Fisher's exact test.
Results At the time of the week 48 analysis, the cumulative incidences in the rilpivirine vs. efavirenz groups of any grade 2–4 treatment-related AEs and of discontinuation because of AEs were 16% vs. 31% (P < 0.0001) and 3% vs. 8% (P = 0.0005), respectively. The incidence of treatment-related neuropsychiatric AEs was 27% vs. 48%, respectively (P < 0.0001). The incidence of treatment-related neurological AEs of interest was 17% vs. 38% (P < 0.0001), and that of treatment-related psychiatric AEs of interest was 15% vs. 23% (P = 0.0002). Dizziness and abnormal dreams/nightmares occurred significantly less frequently with rilpivirine vs. efavirenz (P < 0.01). In both groups, patients with prior neuropsychiatric history tended to report more neuropsychiatric AEs but rates remained lower for rilpivirine than for efavirenz.
Conclusions Rilpivirine was associated with fewer neurological and psychiatric AEs of interest than efavirenz over 48 weeks in treatment-naïve, HIV-1-infected adults.
Introduction
Effective control of HIV replication using antiretroviral (ARV) medication requires long-term treatment adherence of ≥ 95%. Reasons for adherence levels below this threshold are complex. Several causal relationships have been suggested for suboptimal HIV treatment adherence, including complicated treatment regimens, patient-specific factors and treatment-related adverse events (AEs).
Under current guidelines, the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) is recommended as a preferred component of ARV regimens for treatment-naïve patients. EFV has good overall tolerability but has been associated with some AE-related concerns, particularly neuropsychiatric symptoms that typically begin shortly after therapy initiation. An analysis of four phase 2/3 controlled clinical trials has shown that 53% of EFV vs. 25% of control recipients reported central nervous system AEs (all grades). While EFV-associated neuropsychiatric AEs are often transient, symptoms such as abnormal dreams, dizziness, somatization, irritability and stress can persist in some instances for several months to years, and patients may experience symptoms of depression at any time during treatment.
Several studies have compared the incidences of neuropsychiatric AEs with EFV-based vs. non-EFV-based ARV regimens. Maintenance of virological control and significant improvement in neuropsychiatric AEs were demonstrated by switching from an EFV- to a nevirapine-based ARV regimen in a retrospective analysis of patients changing ARV therapy. A higher incidence of neuropsychiatric AEs was also observed in patients receiving EFV compared with the integrase inhibitor raltegravir in the randomized, controlled STARTMRK trial in treatment-naïve patients (52% vs. 20%, respectively, at week 8, P < 0.0001, with a significant difference between treatment groups maintained at week 48). Also, a randomized, open-label study comparing the safety, tolerability and ARV activity of EFV with those of atazanavir plus ritonavir, each given with placebo-controlled abacavir (ABC)/lamivudine (3TC) or tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), reported a higher incidence of grade 3 or 4 neuropsychological symptoms in the EFV-based groups (6% vs. 3%, respectively). More recently, the NNRTI etravirine has been shown in a randomized, double-blind clinical trial in treatment-naïve patients to be associated with a significantly lower incidence of neuropsychiatric AEs compared with EFV.
Rilpivirine (RPV; TMC278), like etravirine, is a diarylpyrimidine NNRTI, which has recently been approved in several countries worldwide including in the USA, Canada and Europe in combination with other ARVs for the treatment of HIV-1-infected ARV-naïve adult patients. Two double-blind, phase 3 clinical trials, ECHO (TMC278-C209; ClinicalTrials.gov Identifier: NCT00540449) and THRIVE (TMC278-C215; NCT00543725), were conducted to compare the efficacy and safety of RPV with those of EFV, each in combination with a background regimen of two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs], in HIV-1-infected treatment-naïve patients over 96 weeks. The primary, 48-week analyses of both trials confirmed noninferior efficacy of RPV 25 mg once a day (qd) to EFV 600 mg qd.
The aim of the present analysis was to compare the neuropsychiatric safety and tolerability of RPV with those of EFV in a preplanned pooled analysis of ECHO and THRIVE.
*Data described in this manuscript have been presented in part at the 18th Conference on Retroviruses and Opportunistic Infections, Boston, USA, 27 February–2 March 2011 (Mills A et al., Abstract 0–306) and at the 4th International Symposium on HIV and Psychiatry, Barcelona, Spain, 5–6 May 2011.