Herta Crauwels

Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial

BACKGROUND Efavirenz with tenofovir-disoproxil-fumarate and emtricitabine is a preferred antiretroviral regimen for treatment-naive patients infected with HIV-1. Rilpivirine, a new non-nucleoside reverse transcriptase inhibitor, has shown similar antiviral efficacy to efavirenz in a phase 2b trial with two nucleoside/nucleotide reverse transcriptase inhibitors. We aimed to assess the efficacy, safety, and tolerability of rilpivirine versus efavirenz, each combined with tenofovir-disoproxil-fumarate and emtricitabine. METHODS We did a phase 3, randomised, double-blind, double-dummy, active-controlled trial, in patients infected with HIV-1 who were treatment-naive. The patients were aged 18 years or older with a plasma viral load at screening of 5000 copies per mL or greater, and viral sensitivity to all study drugs. Our trial was done at 112 sites across 21 countries. Patients were randomly assigned by a computer-generated interactive web response system to receive either once-daily 25 mg rilpivirine or once-daily 600 mg efavirenz, each with tenofovir-disoproxil-fumarate and emtricitabine. Our primary objective was to show non-inferiority (12% margin) of rilpivirine to efavirenz in terms of the percentage of patients with confirmed response (viral load <50 copies per mL intention-to-treat time-to-loss-of-virological-response [ITT-TLOVR] algorithm) at week 48. Our primary analysis was by intention-to-treat. We also used logistic regression to adjust for baseline viral load. This trial is registered with ClinicalTrials.gov, number NCT00540449. FINDINGS 346 patients were randomly assigned to receive rilpivirine and 344 to receive efavirenz and received at least one dose of study drug, with 287 (83%) and 285 (83%) in the respective groups having a confirmed response at week 48. The point estimate from a logistic regression model for the percentage difference in response was -0.4 (95% CI -5.9 to 5.2), confirming non-inferiority with a 12% margin (primary endpoint). The incidence of virological failures was 13% (rilpivirine) versus 6% (efavirenz; 11%vs 4% by ITT-TLOVR). Grade 2-4 adverse events (55 [16%] on rilpivirine vs 108 [31%] on efavirenz, p<0.0001), discontinuations due to adverse events (eight [2%] on rilpivirine vs 27 [8%] on efavirenz), rash, dizziness, and abnormal dreams or nightmares were more common with efavirenz. Increases in plasma lipids were significantly lower with rilpivirine. INTERPRETATION Rilpivirine showed non-inferior efficacy compared with efavirenz, with a higher virological-failure rate, but a more favourable safety and tolerability profile. FUNDING Tibotec.

Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial

BACKGROUND The non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (TMC278; Tibotec Pharmaceuticals, County Cork, Ireland), had equivalent sustained efficacy to efavirenz in a phase 2b trial in treatment-naive patients infected with HIV-1, but fewer adverse events. We aimed to assess non-inferiority of rilpivirine to efavirenz in a phase 3 trial with common background nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). METHODS We undertook a 96-week, phase 3, randomised, double-blind, double-dummy, non-inferiority trial in 98 hospitals or medical centres in 21 countries. We enrolled adults (≥18 years) not previously given antiretroviral therapy and with a screening plasma viral load of 5000 copies per mL or more and viral sensitivity to background N(t)RTIs. We randomly allocated patients (1:1) using a computer-generated interactive web-response system to receive oral rilpivirine 25 mg once daily or efavirenz 600 mg once daily; all patients received an investigator-selected regimen of background N(t)RTIs (tenofovir-disoproxil-fumarate plus emtricitabine, zidovudine plus lamivudine, or abacavir plus lamivudine). The primary outcome was non-inferiority (12% margin on logistic regression analysis) at 48 weeks in terms of confirmed response (viral load <50 copies per mL, defined by the intent-to-treat time to loss of virologic response [TLOVR] algorithm) in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00543725. FINDINGS From May 22, 2008, we screened 947 patients and enrolled 340 to each group. 86% of patients (291 of 340) who received at least one dose of rilpivirine responded, compared with 82% of patients (276 of 338) who received at least one dose of efavirenz (difference 3.5% [95% CI -1.7 to 8.8]; p(non-inferiority)<0.0001). Increases in CD4 cell counts were much the same between groups. 7% of patients (24 of 340) receiving rilpivirine had a virological failure compared with 5% of patients (18 of 338) receiving efavirenz. 4% of patients (15) in the rilpivirine group and 7% (25) in the efavirenz group discontinued treatment due to adverse events. Grade 2-4 treatment-related adverse events were less common with rilpivirine (16% [54 patients]) than they were with efavirenz (31% [104]; p<0.0001), as were rash and dizziness (p<0.0001 for both) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz (p<0.0001). INTERPRETATION Despite a slightly increased incidence of virological failures, a favourable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1. FUNDING Tibotec.

Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials.

Background:Pooled analysis of phase 3, double-blind, double-dummy ECHO and THRIVE trials comparing rilpivirine (TMC278) and efavirenz. Methods:Treatment-naive HIV-1–infected adults were randomized 1:1 to rilpivirine 25 mg once daily or efavirenz 600 mg once daily, with background tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) (ECHO) or TDF/FTC, zidovudine/lamivudine, or abacavir/lamivudine (THRIVE). The primary endpoint was confirmed response [viral load <50 copies per milliliter; intent-to-treat time-to-loss-of-virologic-response (ITT-TLOVR) algorithm] at week 48. The pooled data set enabled analyses of subgroups and predictors of response/virologic failure. Results:Confirmed responses were 84% (rilpivirine) and 82% (efavirenz). The difference in response rates (95% confidence interval) was 2.0% (–2.0% to 6.0%). The incidence of virologic failure was 9% (rilpivirine) versus 5% (efavirenz). Responses in ITT-TLOVR and ITT-snapshot analyses were consistent. Responses were similar for rilpivirine and efavirenz by background regimen, gender, race and clade. Suboptimal adherence and higher baseline viral load resulted in lower responses, higher virologic failure, and development of resistance in both groups; the effects on virologic failure were more apparent with rilpivirine. CD4+ cell count increased over time in both groups. Rilpivirine compared with efavirenz gave smaller incidences of adverse events leading to discontinuation (3% vs. 8%, respectively), treatment-related grade 2–4 adverse events (16% vs. 31%), rash (3% vs. 14%), dizziness (8% vs. 26%), abnormal dreams/nightmares (8% vs. 13%), and grade 2−4 lipid abnormalities. Conclusions:At week 48, rilpivirine 25 mg once daily and efavirenz 600 mg once daily had comparable response rates. Rilpivirine had more virologic failures and improved tolerability versus efavirenz.

Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults.

Objective:Pharmacokinetics, safety, and tolerability of GSK1265744 (744) and rilpivirine (RPV) (TMC278) were assessed after repeat dosing of long-acting (LA) injectable formulations in healthy subjects. Methods:Subjects received a 14-day lead-in of oral 744 (30 mg/d) to assess safety and tolerability before injectable administration. Subjects were randomized into 4 cohorts: 800 mg of 744 LA intramuscularly (IM) followed by 3 monthly doses of (1) 200 mg subcutaneously, (2) 200 mg IM, (3) 400 mg IM, or (4) a second injection of 800 mg IM after 12 weeks. Cohorts 2 and 3 also received IM doses of RPV LA at months 3 (1200 mg) and 4 (900 or 600 mg). Pharmacokinetics and safety were assessed throughout the trial. Results:Forty-seven subjects enrolled; 40 received ≥1 LA injection with 37 completing all planned injections. Seven subjects discontinued 744 oral (non–drug-related, n = 6; dizziness, n = 1). The 744 LA and RPV LA injections were generally well tolerated, with grade 1 injection site reactions most commonly reported. Three subjects discontinued during injection phase (consent withdrawn, n = 2; self-limited rash, n = 1). There were no grade 3 or 4 adverse events and no clinically significant trends in laboratory abnormalities, electrocardiograms, or vital signs. All dose cohorts achieved therapeutically relevant plasma concentrations of each drug within 3 days with prolonged exposure over the dosing interval. Plasma concentrations of 744 exceeded the protein-adjusted IC90 and RPV plasma concentrations and were comparable to steady-state oral RPV 25 mg/d. Conclusions:These data support the potential application of dual-therapy 744 LA and RPV LA for treatment of HIV-1 infection.

Formulation and pharmacology of long-acting rilpivirine.

Purpose of review Rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor, is a potent antiretroviral (ARV) effective for HIV treatment at 25 mg daily oral dose. Its physio-chemical and pharmacological properties enable formulation of RPV as a long-acting injectable nanosuspension. This review summarizes these properties supporting the potential of intermittent parenteral administration of rilpivirine long acting (RPV LA) in both treatment and prevention of HIV-1 infection. Recent findings RPV is unusual among ARVs in that its stability and solubility enable aqueous suspensions with high drug loading, so that injection volumes can be minimized. Such innovative nanosuspensions are well tolerated in animals and humans after intramuscular injection and provide sustained drug concentrations in systemic circulation. The pharmacological findings support further investigations of RPV LA injections every 4 or 8 weeks, both as a single agent for potential preexposure prophylaxis and as two-drug all-injectable maintenance therapy with cabotegravir long acting. Summary By building on expertise with long-acting injectable antipsychotic agents, RPV has been formulated as an agent for infrequent intramuscular dosing, in addition to its conventional oral tablet forms. The advantages of adherence to a regimen of intermittent injections may be significant.

Effect of intrinsic and extrinsic factors on the pharmacokinetics of TMC278 in antiretroviral-naïve, HIV-1-infected patients in ECHO and THRIVE

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

The pharmacokinetic (PK) interaction between omeprazole and TMC278, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI)

Purpose of the study TMC278 is a next-generation investigational NNRTI with potent and sustained efficacy through 96 weeks in ARVnaive patients [1]. The current trial evaluated the PK interaction between omeprazole and TMC278. Omeprazole increases gastric pH, which can affect the solubility and gastro-intestinal absorption of TMC278. Furthermore, TMC278 has been shown to induce CYP2C19 in vitro, which may influence the omeprazole PK.

Pooled week 48 safety and efficacy results from the ECHO and THRIVE phase III trials comparing TMC278 vs EFV in treatment-naïve, HIV-1-infected patients

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK

Pharmacokinetics of Total and Unbound Etravirine in HIV-1-Infected Pregnant Women.

Background:Treatment of HIV-1–infected women during pregnancy protects maternal health and reduces the risk of perinatal transmission of HIV-1. However, physiologic changes that occur during pregnancy may affect drug pharmacokinetics. This phase IIIb, open-label study evaluated the effects of pregnancy on the pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor etravirine. Methods:Eligible HIV-1–infected pregnant women (18–26 weeks gestation) on an individualized, highly active antiretroviral therapy regimen including etravirine 200 mg twice daily were enrolled. Blood samples to assess the pharmacokinetics of total and unbound etravirine were obtained at clinic visits during the second and third trimesters (24- to 28-weeks and 34- to 38-weeks gestation, respectively) and 6–12 weeks postpartum. At each time point, plasma concentrations were measured over 12 hours (12-hour time point was obtained before the second daily dose of etravirine); pharmacokinetic parameters were derived using noncompartmental analysis and were compared between pregnancy and postpartum using general linear models. Antiviral and immunologic response and safety were assessed at each visit. Results:Etravirine pharmacokinetic profiles were available for 13 of 15 enrolled women. Exposure to total etravirine was generally higher during pregnancy compared with 6–12 weeks postpartum (1.2- to 1.4-fold); the differences were less pronounced for unbound (pharmacodynamically active) etravirine. Virologic response was generally preserved throughout the study, and no perinatal transmission was observed. Etravirine was generally safe and well tolerated. Conclusions:Etravirine 200 mg twice daily, as part of individualized combination antiretroviral therapy, may be a treatment option for HIV-1–infected pregnant women.

Week 48 results of a Phase IV trial of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected treatment-experienced adults.

In DUET, etravirine (ETR) 200 mg bid had durable efficacy and a favourable safety profile versus placebo, both arms with an optimised background regimen (BR) including darunavir/ritonavir (DRV/r). TMC125IFD3002 (VIOLIN; NCT01422330) investigated ETR plus ARVs other than DRV/r.