Phase 1 trial of the safety, pharmacokinetics, and antiviral activity of EDP-514 in untreated viremic chronic hepatitis B patients.

Background/aims: Oral EDP-514 is a potent core protein inhibitor of hepatitis B virus (HBV) replication, which produced a >4-log viral load reduction in HBV-infected chimeric mice with human liver cells. This study evaluated the safety, pharmacokinetics, and antiviral activity of three doses of EDP-514 in treatment-naive viremic patients with HBeAgpositive or -negative chronic HBV infection.

Methods: Patients with HBsAg detectable at screening and at least 6 months previously were eligible.

EDP-514 in healthy subjects and nucleos(t)ide reverse transcriptase inhibitor-suppressed patients with chronic hepatitis B.

Background: Chronic hepatitis B (CHB) remains a major cause of morbidity and mortality. EDP-514 is a potent core inhibitor of hepatitis B virus (HBV) that reduces viral load reduction in HBV-infected chimeric mice. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics (PK) of EDP-514 in healthy subjects and antiviral activity in patients with CHB.

Effects of once-daily darunavir/ritonavir versus atazanavir/ritonavir on insulin sensitivity in HIV-infected persons over 48 weeks: results of an exploratory substudy of METABOLIK, a phase 4, randomized trial.

Background: The phase 4, METABOLIK trial demonstrated that changes in metabolic parameters with darunavir with low-dose ritonavir (DRV/r) were comparable to those observed with atazanavir with low-dose ritonavir (ATV/r). A comprehensive assessment of the effects of these agents on insulin sensitivity will provide additional, relevant clinical information.

Methods: In this substudy of METABOLIK, HIV-1-infected, antiretroviral agent-naïve male subjects aged ≥18 years with a viral load of >1,000 copies/mL were randomized to receive DRV/r 800/100 mg once daily (qd) or ATV/r 300/100 mg qd, both with a fixed dose of tenofovir disoproxil fumarate/emtricitabine 300/200 mg qd.

Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study.

Unlabelled: Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients. The phase 2 COSMOS study reported high SVR rates in treatment-naive and prior null-responder HCV genotype (GT) 1-infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST-1 (NCT02114177) was a multicenter, randomized, open-label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1-infected treatment-naive and treatment-experienced patients without cirrhosis.

Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2).

Unlabelled: Hepatitis C virus (HCV)-infected patients with cirrhosis are historically a difficult-to-treat population and are at risk of hepatic decompensation. In the phase 2 COSMOS study that evaluated simeprevir (HCV NS3/4A protease inhibitor) + sofosbuvir (HCV nucleotide analogue NS5B polymerase inhibitor) ± ribavirin for 12 or 24 weeks in HCV genotype (GT)1-infected patients, high rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were achieved, including in patients with cirrhosis (METAVIR score F4). This phase 3, open-label, single-arm study (OPTIMIST-2 [NCT02114151]) evaluated the efficacy and safety of 12 weeks of simeprevir + sofosbuvir in HCV GT1-infected treatment-naive or treatment-experienced patients with cirrhosis.

Simeprevir (TMC435) with pegylated interferon/ribavirin in patients coinfected with HCV genotype 1 and HIV-1: a phase 3 study.

Background: Simeprevir is an oral, once-daily, hepatitis C virus (HCV) NS3/4A protease inhibitor for the treatment of chronic HCV genotype 1 infection. Human immunodeficiency virus (HIV) coinfection accelerates progression of liver disease. This uncontrolled, open-label trial explored the safety and efficacy of simeprevir in patients with HCV genotype 1/HIV type 1 (HIV-1) coinfection.

Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial.

Background: Although the addition of the HCV NS3/4A protease inhibitors boceprevir and telaprevir to pegylated interferon (peginterferon) alfa plus ribavirin has improved sustained virological response (SVR) in treatment-naive and treatment-experienced patients infected with hepatitis C virus (HCV) genotype 1, the regimens have a high pill burden and are associated with increased rates and severity of adverse events, such as anaemia and rash. The efficacy and safety of the combination of simeprevir, a one pill, once-daily, oral HCV NS3/4A protease inhibitor, plus peginterferon alfa 2a plus ribavirin were assessed in treatment-naive patients with HCV genotype 1 infection.

Methods: In QUEST-1, a phase 3, randomised, double-blind multicentre trial undertaken in 13 countries (Australia, Europe, North America, Puerto Rico, and New Zealand), 394 patients (aged ≥18 years) with chronic HCV genotype 1 infection and no history of HCV treatment, stratified by HCV subtype and host IL28B genotype, were randomly assigned in a 2:1 ratio with a computer-generated allocation sequence to receive simeprevir (150 mg once daily, orally) plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (simeprevir group), or placebo orally plus peginterferon alfa 2a plus ribavirin for 12 weeks, followed by peginterferon alfa 2a plus ribavirin (placebo group).

Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial.

Background: Pegylated interferon (peginterferon) alfa 2a or 2b plus ribavirin regimens were the standard of care in patients with hepatitis C virus (HCV) infection, but the sustained virological response can be suboptimum in patients with HCV genotype 1 infection. The efficacy, safety, and tolerability of the combination of simeprevir, a one-pill, once-daily, oral HCV NS3/4A protease inhibitor versus placebo, plus peginterferon alfa 2a or 2b plus ribavirin was assessed in treatment-naive patients with HCV genotype 1 infection.

Methods: In the QUEST-2, phase 3 study, done at 76 sites in 14 countries (Europe, and North and South Americas), patients with confirmed chronic HCV genotype 1 infection and no history of HCV treatment were randomly assigned with a computer-generated allocation sequence in a ratio of 2:1 and stratified by HCV genotype 1 subtype and host IL28B genotype to receive simeprevir (150 mg once daily, orally), peginterferon alfa 2a (180 μg once weekly, subcutaneous injection) or 2b (according to bodyweight; 50 μg, 80 μg, 100 μg, 120 μg, or 150 μg once weekly, subcutaneous injection), plus ribavirin (1000-1200 mg/day or 800-1400 mg/day, orally; simeprevir group) or placebo (once daily, orally), peginterferon alfa 2a or 2b, plus ribavirin (placebo group) for 12 weeks, followed by just peginterferon alfa 2a or 2b plus ribavirin.

Comparison of illumina and 454 deep sequencing in participants failing raltegravir-based antiretroviral therapy.

Background: The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs.

Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial.

Background & Aims: Simeprevir is an oral, once-daily inhibitor of hepatitis c virus (HCV) protease NS3/4A. We investigated the safety and efficacy of simeprevir with peg-interferon α-2a and ribavirin (PR) in a randomized, double-blind, placebo-controlled, phase 3 trial of patients with HCV genotype 1 infection who relapsed after previous interferon-based therapy.

Methods: Patients were assigned randomly (2:1) to groups given simeprevir (150 mg, once daily) and PR (n = 260) or placebo and PR (n = 133) for 12 weeks.

Discovery and development of simeprevir (TMC435), a HCV NS3/4A protease inhibitor.

Hepatitis C virus is a blood-borne infection and the leading cause of chronic liver disease (including cirrhosis and cancer) and liver transplantation. Since the identification of HCV in 1989, there has been an extensive effort to identify and improve treatment options. An important milestone was reached in 2011 with the approval of the first-generation HCV NS3/4A protease inhibitors.

Virological analysis of once-daily and twice-daily darunavir/ritonavir in the ODIN trial of treatment-experienced patients.

Background: The aim of this analysis was to characterize viral resistance in the Phase III, randomized ODIN trial, which demonstrated non-inferiority of once-daily darunavir/ritonavir (DRV/r) 800/100 mg to DRV/r 600/100 mg twice daily, each combined with an optimized background regimen in treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening.

Methods: Virological failure (VF) was defined as never achieving or losing confirmed virological suppression after week 12, with patients being classed as 'never suppressed' (never achieved HIV-1 RNA<50 copies/ml) or 'rebounders' (achieved two consecutive HIV-1 RNA<50 copies/ml but then ≥ 50 copies/ml). Phenotypes and genotypes of plasma HIV-1 viruses, using population-based sequencing and Antivirogram(®), were determined at screening/baseline and on samples from VFs with HIV-1 RNA ≥ 50 copies/ml.

Pharmacokinetics and Pharmacodynamics of Darunavir and Etravirine in HIV-1-Infected, Treatment-Experienced Patients in the Gender, Race, and Clinical Experience (GRACE) Trial.

Objectives. Evaluation of pharmacokinetics and pharmacodynamics of darunavir and etravirine among HIV-1-infected, treatment-experienced adults from GRACE, by sex and race. Methods.

Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks.

We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd.

Effects of darunavir/ritonavir-based therapy on metabolic and anthropometric parameters in women and men over 48 weeks.

Gender-based differences in lipids have been noted in antiretroviral clinical trials. We present the metabolic and anthropometric data from the GRACE (Gender, Race And Clinical Experience) study by gender. Treatment-experienced adults received darunavir/ritonavir (DRV/r) 600/100 mg twice daily, plus a background regimen, over 48 weeks.

Pharmacoeconomics of darunavir.

Darunavir boosted with ritonavir (DRV/r) in combination with other antiretrovirals (ARVs) was initially approved in 2006 for the treatment of HIV infection in ARV treatment-experienced adults and has subsequently been approved for use in treatment-naive adults in 2008. Clinical studies have shown that DRV/r in combination with other ARVs achieves superior levels of undetectable plasma HIV RNA and generates significant CD4 increases, which reduce the risk of HIV disease progression. Economic evaluations, based on data from controlled clinical trials, found DRV/r combination therapy to generate savings in hospital costs and other non-ARV costs of care in treatment-experienced patients, to maximize the number of patients reaching undetectable plasma HIV RNA, to improve health-related quality of life and quality-adjusted life expectancy, and to be cost effective across different patient populations.

Darunavir outcomes study: comparative effectiveness of virologic suppression, regimen durability, and discontinuation reasons for three-class experienced patients at 48 weeks.

Several new antiretroviral (ARV) agents for treatment experienced HIV-infected patients have been approved since June 2006, including darunavir (DRV) and raltegravir (RAL). While efficacious in clinical trials, the effectiveness, durability, and tolerability of these new ARVs remains understudied in the context of routine clinical care. The Darunavir Outcomes Study is a prospective cohort study of three-class ARV-experienced patients changing regimens at the 1917 Clinic after 1/7/2006.

A case of Strongyloides stercoralis and mesenteric tuberculous infection with acute abdominal pain in an HIV-positive patient.

We describe an HIV-positive female patient who had acute abdominal pain as the initial presentation of Strongyloides stercoralis infection. The diagnosis was established by identifying rhabditiform larvae in stool. She also had intra-abdominal tuberculosis without intestinal perforation.