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Overton E.T.,University of Alabama at Birmingham | Arathoon E.,Clinica Familiar Luis Angel Garcia | Baraldi E.,Trialtech Clinical Research | Tomaka F.,Tibotec Inc
HIV Clinical Trials | Year: 2012

Highly active antiretroviral therapy regimens, consisting of a ritonavir-boosted protease inhibitor (PI) and 2 nucleoside reverse transcriptase inhibitors, are established first-line regimens for HIV-infected patients. However, a common adverse effect in patients receiving PIs is dyslipidemia, characterized by increases in plasma levels of triglycerides, low-density lipoprotein cholesterol, and total cholesterol (TC). These lipid changes, as well as other well-described risk factors, may predispose patients to the development of cardiovascular disease, an important comorbidity, especially as the lifespan of HIV-infected patients has increased dramatically in recent years. Among PIs, ritonavir-boosted atazanavir (ATV/r) and, more recently, ritonavir-boosted darunavir (DRV/r) have demonstrated potent antiviral efficacy with more favorable lipid profiles than other PIs. This review provides an overview of the lipid effects of DRV/r. Studies with DRV/r in healthy volunteers and in both treatment-naïve and -experienced patients have demonstrated that changes in tri-glycerides and TC are comparable to those seen with ATV/r. © 2012 Thomas Land Publishers, Inc.


Foster G.R.,University of London | Hezode C.,University Paris Est Creteil | Bronowicki J.,University of Lorraine | Carosi G.,University of Brescia | And 6 more authors.
Gastroenterology | Year: 2011

Background & Aims: We evaluated antiviral activity of 2 weeks therapy with telaprevir alone, peginterferon alfa-2a and ribavirin (PR), or all 3 drugs (TPR) in treatment-nave patients with chronic hepatitis C virus (HCV) genotype 2 or 3 infections. Methods: We performed a randomized, multicenter, partially blinded study of patients (23 with HCV genotype 2, 26 with genotype 3) who received telaprevir (750 mg every 8 h), placebo plus PR (peginterferon, 180 μg, once weekly and ribavirin, 400 mg, twice daily), or TPR for 15 days, followed by PR for 22 or 24 weeks. Plasma levels of HCV RNA were quantified. Results: Levels of HCV RNA decreased in all patients with HCV genotype 2, including those who received telaprevir monotherapy. The decrease was more rapid among patients who received telaprevir. By day 15, 0% (telaprevir), 40% (TPR), and 22% (PR) of patients with HCV genotype 2 had undetectable levels of HCV RNA; rates of sustained virologic response were 56%, 100%, and 89%, respectively. Overall, 6 of 9 HCV genotype 2 patients that received only telaprevir had viral breakthrough within 15 days after an initial response. HCV RNA levels decreased slightly among patients with HCV genotype 3 who received telaprevir and decreased rapidly among patients given PR or TPR (telaprevir had no synergistic effects with PR). Sustained virologic response rates were 50%, 67%, and 44% among patients given telaprevir, TPR, or PR respectively; 7 patients with HCV genotype 3 relapsed after therapy (2 given telaprevir, 3 given TPR, and 2 given PR) and 3 patients with HCV genotype 3 had viral breakthrough during telaprevir monotherapy. The incidence of adverse events was similar among groups. Conclusions: Telaprevir monotherapy for 2 weeks reduces levels of HCV RNA in patients with chronic HCV genotype 2 infections, but has limited activity in patients with HCV genotype 3. © 2011 AGA Institute.


Molina J.-M.,University Paris Diderot | Cahn P.,Fundacion Huesped | Grinsztejn B.,Institute Pesquisa | Lazzarin A.,Vita-Salute San Raffaele University | And 7 more authors.
The Lancet | Year: 2011

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. © 2011 Elsevier Ltd.


Moreno C.,Free University of Colombia | Berg T.,University of Leipzig | Tanwandee T.,Mahidol University | Thongsawat S.,Chiang Mai University | And 6 more authors.
Journal of Hepatology | Year: 2012

Background & Aims: TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-nave patients infected with HCV genotypes 2-6. Methods: The study consisted of 7 days of monotherapy with TMC435 (200 mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from day 8 with a follow-up period up to days 37-42. Results: Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary end point at day 8, the mean (± standard error) change in plasma HCV ribonucleic acid (log 10 IU/ml) from baseline was the greatest for genotypes 6 (-4.35 ± 0.29) and 4 (-3.52 ± 0.43), followed by genotypes 2 (-2.73 ± 0.71) and 5 (-2.19 ± 0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period. Conclusions: The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


Crauwels H.,Tibotec BVBA | Vingerhoets J.,Tibotec BVBA | Ryan R.,Tibotec Inc. | Witek J.,Tibotec Therapeutics | Anderson D.,Tibotec Therapeutics
Antiviral Therapy | Year: 2012

Background: Rilpivirine and efavirenz share metabolic pathways (CYP3A), potentially leading to drug-drug interactions. We report the pharmacokinetics, ex vivo antiviral activity and safety of rilpivirine, following efavirenz treatment. Methods: HIV-negative adults received in fixed sequence: treatment A (rilpivirine 25 mg once daily for 14 days, followed by a washout), treatment B (efavirenz 600 mg once daily for 14 days), immediately followed by treatment C (rilpivirine 25 mg once daily for 28 days). Rilpivirine pharmacokinetic profiles were determined on days 1 and 14 of treatment A and days 1, 14, 21 and 28 of treatment C. Ex vivo antiviral activity was measured in treatments A and C using an exploratory assay. Safety was evaluated throughout. Results: From days 1 to 21, higher mean rilpivirine exposure was observed with treatment A compared with treatment C. The area under the concentration-time curve (AUC 24 h) least squares (LS) means ratio (90% CI) for treatment C versus treatment A was 0.54 (0.46, 0.64; Day 1), 0.82 (0.75, 0.89; Day 14) and 0.84 (0.74, 0.94; Day 21). By day 28 of treatment C, the main rilpivirine pharmacokinetic parameters were similar to day 14 of treatment A (AUC 24 h LS means ratio [90% CI], 0.91 [0.82, 1.01]), except for the minimum plasma concentration. At each time point in treatment C, samples of >80% of subjects demonstrated similar ex vivo antiviral activity compared with treatment A. All adverse events were grade 1 or 2. Conclusions: These results provide useful information supporting a clinical study evaluating HIV-1-positive subjects switching from efavirenz to rilpivirine. ©2012 International Medical Press.


Kakuda T.N.,Tibotec Inc. | Scholler-Gyure M.,Tibotec BVBA | Hoetelmans R.M.W.,Tibotec BVBA
Clinical Pharmacokinetics | Year: 2011

Etravirine (formerly TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant strains of HIV-1. Etravirine has been approved in several countries for use as part of highly active antiretroviral therapy in treatment-experienced patients.In vivo, etravirine is a substrate for, and weak inducer of, the hepatic cytochrome P450 (CYP) isoenzyme 3A4 and a substrate and weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. An extensive drug-drug interaction programme in HIV-negative subjects has been carried out to assess the potential for pharmacokinetic interactions between etravirine and a variety of non-antiretroviral drugs.Effects of atorvastatin, clarithromycin, methadone, omeprazole, oral contraceptives, paroxetine, ranitidine and sildenafil on the pharmacokinetic disposition of etravirine were of no clinical relevance. Likewise, etravirine had no clinically significant effect on the pharmacokinetics of fluconazole, methadone, oral contraceptives, paroxetine or voriconazole. No clinically relevant interactions are expected between etravirine and azithromycin or ribavirin, therefore, etravirine can be combined with these agents without dose adjustment.Fluconazole and voriconazole increased etravirine exposure 1.9- and 1.4-fold, respectively, in healthy subjects, however, no increase in the incidence of adverse effects was observed in patients receiving etravirine and fluconazole during clinical trials, therefore, etravirine can be combined with these antifungals although caution is advised.Digoxin plasma exposure was slightly increased when co-administered with etravirine. No dose adjustments of digoxin are needed when used in combination with etravirine, however, it is recommended that digoxin levels should be monitored. Caution should be exercised in combining rifabutin with etravirine in the presence of certain boosted HIV protease inhibitors due to the risk of decreased exposure to etravirine. Although adjustments to the dose of clarithromycin are unnecessary for the treatment of most infections, the use of an alternative macrolide (e.g. azithromycin) is recommended for the treatment of Mycobacterium avium complex infection since the overall activity of clarithromycin against this pathogen may be altered when co-administered with etravirine. Dosage adjustments based on clinical response are recommended for clopidogrel, HMG-CoA reductase inhibitors (e.g. atorvastatin) and for phosphodiesterase type-5 inhibitors (e.g. sildenafil) because changes in the exposure of these medications in the presence of co-administered etravirine may occur.When co-administered with etravirine, a dose reduction or alternative to diazepam is recommended. When combining etravirine with warfarin, the international normalized ratio (INR) should be monitored. Systemic dexamethasone should be co-administered with caution, or an alternative to dexamethasone be found as dexamethasone induces CYP3A4. Caution is also warranted when co-administering etravirine with some antiarrhythmics, calcineurin inhibitors (e.g. ciclosporin) and antidepressants (e.g. citalopram). Co-administration of etravirine with some antiepileptics (e.g. carbamazepine and phenytoin), rifampicin (rifampin), rifapentine or preparations containing St Johns wort (Hypericum perforatum) is currently not recommended as these are potent inducers of CYP3A andor CYP2C and may potentially decrease etravirine exposure. Antiepileptics that are less likely to interact based on their known pharmacological properties include gabapentin, lamotrigine, levetiracetam and pregabalin.Overall, pharmacokinetic and clinical data show etravirine to be well tolerated and generally safe when given in combination with non-antiretroviral agents, with minimal clinically significant drug interactions and no need for dosage adjustments of etravirine in any of the cases, or of the non-antiretroviral agent in the majority of cases studied. © 2011 Adis Data Information BV. All rights reserved.


Kakuda T.N.,Tibotec Inc. | Scholler-Gyure M.,Tibotec BVBA | Hoetelmans R.M.W.,Tibotec BVBA
Antiviral Therapy | Year: 2010

Etravirine is an effective and well-tolerated recently approved non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV type-1-infected patients with previous antiretroviral treatment experience. Considering the importance of combining antiretrovirals for their optimal use in treating HIV, a number of drug-drug interactions with etravirine and other antiretrovirals have been evaluated. Etravirine is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C9/CYP2C19 and P-glycoprotein, and although etravirine is metabolized by the CYP enzyme system, the extent of clinically relevant interactions with other antiretrovirals is limited. Etravirine can be combined with all currently available nucleoside/nucleotide reverse transcriptase inhibitors without dose adjustments, but not with other NNRTIs. Available data indicate that etravirine can be coadministered with most of the currently available ritonavir-boosted HIV protease inhibitors. Coadministration with tipranavir/ritonavir or unboosted HIV protease inhibitors is not recommended because of clinically relevant changes in exposure to etravirine or the coadministered HIV protease inhibitor, respectively. Etravirine can be coadministered with the integrase inhibitors elvitegravir/ritonavir or raltegravir, and with the fusion inhibitor enfuvirtide, without dose adjustments. Dose adjustment of the C-C chemokine receptor type-5 antagonist maraviroc is required, with the type of adjustment depending on whether a boosted HIV protease inhibitor is included in the regimen. In conclusion, etravirine can be combined with most antiretrovirals, with no clinically meaningful effect on drug exposure or safety/tolerability profiles. ©2010 International Medical Press.


Tambuyzer L.,Tibotec BVBA | Nijs S.,Tibotec BVBA | Daems B.,Tibotec BVBA | Picchio G.,Tibotec Inc. | Vingerhoets J.,Tibotec BVBA
Journal of Acquired Immune Deficiency Syndromes | Year: 2011

The contribution of E138 mutations to etravirine resistance was investigated. Amino acids at position E138 after failure with etravirine in DUET were A (n = 1), G (n = 5), K (n = 3), P (n = 1), Q (n = 5), and V (n = 2). At baseline, only E138A and Q were found at 3.0% and 2.5%, respectively. Virologic response (less than 50 copies/mL) was observed in six of 12 and eight of 10 patients with E138A and E138Q, respectively. Site-directed mutants harboring E138A/G/K/Q/R or S showed etravirine fold change values of 2.9, 2.4, 2.6, 3.0, 3.6, and 2.8, respectively. E138G, K, and Q were added to the existing etravirine-weighted genotypic score including 17 etravirine resistance- associated mutations. Copyright © 2011 Lippincott Williams & Wilkins.


Vingerhoets J.,Tibotec BVBA | Tambuyzer L.,Tibotec BVBA | Azijn H.,Tibotec BVBA | Hoogstoel A.,Tibotec BVBA | And 6 more authors.
AIDS | Year: 2010

Objective: To refine the genotypic and phenotypic correlates of response to the nonnucleoside reverse transcriptase inhibitor etravirine. Design: Initial analyses identified 13 etravirine resistance-associated mutations (RAMs) and clinical cutoffs (CCOs) for etravirine. A multivariate analysis was performed to refine the initial etravirine RAM list and improve the predictive value of genotypic resistance testing with regard to virologic response and relationship to phenotypic data. Methods: Week 24 data were pooled from the phase III studies with TMC125 to Demonstrate Undetectable viral load in patients Experienced with ARV Therapy (DUET). The effect of baseline resistance to etravirine on virologic response (<50 HIV-1 RNA copies/ml) was studied in patients not using de-novo enfuvirtide and excluding discontinuations for reasons other than virologic failure (n = 406). Clinical cutoffs for etravirine were established by analysis of covariance models and sliding fold change in 50% effective concentration (EC50) windows (Antivirogram; Virco BVBA, Mechelen, Belgium). Etravirine RAMs were identified as those associated with decreased virologic response/increased etravirine fold change in EC50. Relative weight factors were assigned to the etravirine RAMs using random forest and linear modeling techniques. Results: Baseline etravirine fold change in EC50 predicted virologic response at week 24, with lower and preliminary upper clinical cutoffs of 3.0 and 13.0, respectively. A fold change in EC50 value above which etravirine provided little or no additional efficacy benefit could not be established. Seventeen etravirine RAMs were identified and attributed a relative weight factor accounting for the differential impact on etravirine fold change in EC50. Virologic response was a function of etravirine-weighted genotypic score. Conclusion: The weighted genotypic scoring algorithm optimizes resistance interpretations for etravirine and guides treatment decisions regarding its use in treatment-experienced patients. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Kulkarni R.,Gilead Sciences Inc. | Babaoglu K.,Gilead Sciences Inc. | Lansdon E.B.,Gilead Sciences Inc. | Rimsky L.,Tibotec BVBA | And 5 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2012

Background: The registrational phase III clinical trials of the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) rilpivirine (RPV) in combination with two nucleoside/nucleotide RT inhibitors (NRTIs) found a unique genotypic resistance pattern involving the NNRTI mutation E138K with the NRTI mutation M184I. Eighty percent of subjects used emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF); a single tablet regimen of FTC/RPV/TDF is in development. Methods: HIV-1 with E138K and/or M184V or I mutations were constructed and phenotyped in MT-2 cells and the PhenoSense and Antivirogram assays. Viral fitness was determined using growth competitions. Molecular models of the mutants were constructed from the RT-RPV crystal structure. RESULTS: The E138K mutant showed low-level reduced susceptibility to RPV (2.4-fold), but full susceptibility to FTC and tenofovir (TFV). Viruses with M184V or M184I showed high-level resistance to FTC and full susceptibility to RPV and TFV. Addition of M184I, but not M184V, to E138K, further decreased susceptibility to RPV and maintained FTC resistance. The E138K and M184V or I single and double mutants showed decreased replication fitness compared with wild type. M184V outcompeted M184I when compared directly and in the background of E138K. E138K + M184I was less fit than either E138K or M184I alone. Removing a salt bridge between E138/K101 is implicated in resistance to RPV. Conclusions: The higher frequency of E138K and M184I among RPV + FTC/TDF virologic failures is due to reduced susceptibility of the single mutants to RPV and FTC and the enhanced resistance to RPV for the double mutant at the cost of decreased viral fitness.

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