bi-201335 and telaprevir

Hepatitis C virus (HCV)-related liver disease is a major source of mortality in HIV-infected patients. Approximately one third of all patients with HIV are co-infected with HCV. Patients co-infected with HIV/HCV have shown lower rates of sustained virologic response with pegylated-interferon and weight-based ribavirin as well as more rapid progression of fibrosis than those with HCV mono-infection. Several direct-acting antiviral agents (DAAs), developed originally for HCV mono-infection, are being reevaluated for HIV/HCV co-infection. In addition, entirely new DAAs are being developed, including, interferon-free regimens with fewer side effects, allowing novel treatment opportunities for difficult-to-treat patients. In order for HCV DAAs to be successfully used in the HIV/HCV co-infected population several hurdles must be overcome, including adverse event management and drug-drug interactions. The aim of this review is to discuss the results of trials for new HCV therapies being developed for HIV/HCV co-infected patients and the impact of interferon-free regimens on treatment in the future.

Topics: Aminoisobutyric Acids; Antiviral Agents; Coinfection; Hepatitis C; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Interferons; Leucine; Oligopeptides; Proline; Protease Inhibitors; Quinolines; Simeprevir; Sulfonamides; Thiazoles; Viral Nonstructural Proteins

In recent years, several studies have clearly shown that sustained virological response (SVR) achieved by interferon-based therapies may delay or reduce the risk of hepatocellular carcinoma, liver decompensation and all-causes of mortality in all categories of patients with HCV-related cirrhosis, a condition characterized by a wide heterogeneity of clinical features, especially in patients with compensated disease. Unfortunately, the advanced fibrosis stage has been shown to be associated with poor SVR rates and poor tolerance with Peg-interferon and ribavirin. Therefore, on the basis of its risk/efficacy evaluation, most patients are considered to be ineligible for antiviral therapy with these molecules. Recently, improvement in the knowledge of the HCV life-cycle, has resulted in the rapid development of many direct-acting antivirals (DAAs). Two first generation DAAs, boceprevir (BOC) and telaprevir (TVR), have been approved, and more than 40 new small molecules are still in development. However, only a few individuals with compensated cirrhosis were included in the phase III studies assessing the safety and efficacy of BOC or TVR in naïve and chronic hepatitis C genotype 1 patients in whom treatment had failed, and patients with either decompensation or end-stage liver disease were excluded. Therefore, the information available in these patients, which have shown significantly lower SVR compared with patients with mild to moderate fibrosis, are not fully reliable. In addition, in real practice, some studies that have not yet been fully published have shown that triple therapy with these two molecules was associated with low SVR and high serious adverse events (SAEs).

Topics: Algorithms; Aminoisobutyric Acids; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Leucine; Liver Cirrhosis; Oligopeptides; Proline; Quinolines; Simeprevir; Sofosbuvir; Sulfonamides; Thiazoles; Time Factors; Uridine Monophosphate

Treating hepatitis C virus (HCV) in HIV/HCV co-infected patients is a challenge. Even if the benefits of achieving a sustained virological response are clear, the rates achieved with the combination of pegylated-interferon and ribavirin are disappointing. The addition of direct acting antiviral agents (DAAs) to the treatment of hepatitis C is revolutionizing the treatment of HCV in mono-infected patients. Even if there have not been any agents approved for the treatment of co-infected patients, many studies specifically designed for this population are ongoing. This article reviews available data on the use of DAAs in co-infected patients and the challenges associated with these new drugs.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carbamates; Coinfection; Drug Interactions; Drug Therapy, Combination; Hepacivirus; Hepatitis C; HIV Infections; Humans; Imidazoles; Leucine; Oligopeptides; Proline; Pyrrolidines; Quinolines; Sofosbuvir; Thiazoles; Treatment Outcome; Uridine Monophosphate; Valine

Infection with the hepatitis C virus (HCV) is a major cause of chronic liver disease and a leading indication of liver transplantations worldwide. The current standard of care for chronic hepatitis C is a combination of pegylated interferon-α and ribavirin that is effective in slightly more than half of cases and is associated with significant side effects. The first directly acting antivirals recently reached the US market, but will have shortcomings that should in part be overcome by the second-wave PIs that are in development. This article gives an overview of the compounds that will soon be available.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carrier Proteins; Cyclopropanes; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Intracellular Signaling Peptides and Proteins; Isoindoles; Lactams; Lactams, Macrocyclic; Leucine; Oligopeptides; Proline; Protease Inhibitors; Quinolines; Simeprevir; Sulfonamides; Thiazoles; Viral Nonstructural Proteins

Direct-acting antiviral agents (DAAs) have become the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. We aimed to assess treatment uptake and efficacy in routine clinical settings among HIV/HCV coinfected patients after the introduction of the first generation DAAs.. Data on all Swiss HIV Cohort Study (SHCS) participants starting HCV protease inhibitor (PI) treatment between September 2011 and August 2013 were collected prospectively. The uptake and efficacy of HCV therapy were compared with those in the time period before the availability of PIs.. Upon approval of PI treatment in Switzerland in September 2011, 516 SHCS participants had chronic HCV genotype 1 infection. Of these, 57 (11%) started HCV treatment during the following 2 years with either telaprevir, faldaprevir or boceprevir. Twenty-seven (47%) patients were treatment-naïve, nine (16%) were patients with relapse and 21 (37%) were partial or null responders. Twenty-nine (57%) had advanced fibrosis and 15 (29%) had cirrhosis. End-of-treatment virological response was 84% in treatment-naïve patients, 88% in patients with relapse and 62% in previous nonresponders. Sustained virological response was 78%, 86% and 40% in treatment-naïve patients, patients with relapse and nonresponders, respectively. Treatment uptake was similar before (3.8 per 100 patient-years) and after (6.1 per 100 patient-years) the introduction of PIs, while treatment efficacy increased considerably after the introduction of PIs.. The introduction of PI-based HCV treatment in HIV/HCV-coinfected patients improved virological response rates, while treatment uptake remained low. Therefore, the introduction of PIs into the clinical routine was beneficial at the individual level, but had only a modest effect on the burden of HCV infection at the population level.

Topics: Adult; Aminoisobutyric Acids; Antiviral Agents; Cohort Studies; Female; Hepatitis C, Chronic; HIV Infections; Humans; Leucine; Male; Middle Aged; Oligopeptides; Patient Acceptance of Health Care; Proline; Prospective Studies; Protease Inhibitors; Quinolines; RNA, Viral; Switzerland; Thiazoles; Viral Load

BI 201335 is a hepatitis C virus (HCV) NS3-NS4A (NS3 coexpressed with NS4A) protease inhibitor that has been shown to have potent clinical antiviral activity. It is a highly optimized noncovalent competitive inhibitor of full-length NS3-NS4A proteases of HCV genotypes 1a and 1b with K(i) values of 2.6 and 2.0 nM, respectively. K(i) values of 2 to 230 nM were measured against the NS3-NS4A proteases of HCV genotypes 2 to 6, whereas it was a very weak inhibitor of cathepsin B and showed no measurable inhibition of human leukocyte elastase. BI 201335 was also shown to be a potent inhibitor of HCV RNA replication in vitro with 50% effective concentrations (EC(50)s) of 6.5 and 3.1 nM obtained in genotype 1a and 1b replicon assays. Combinations of BI 201335 with either interferon or ribavirin had additive effects in replicon assays. BI 201335 had good permeability in Caco-2 cell assays and high metabolic stability after incubation with human, rat, monkey, and dog liver microsomes. Its good absorption, distribution, metabolism, and excretion (ADME) profile in vitro, as well as in rat, monkey, and dog, predicted good pharmacokinetics (PK) in humans. Furthermore, drug levels were significantly higher in rat liver than in plasma, suggesting that distribution to the target organ may be especially favorable. BI 201335 is a highly potent and selective NS3-NS4A protease inhibitor with good in vitro and animal ADME properties, consistent with its good human PK profile, and shows great promise as a treatment for HCV infection.

Topics: Aminoisobutyric Acids; Animals; Antiviral Agents; Caco-2 Cells; Carrier Proteins; Cell Line, Tumor; Hepacivirus; Humans; Intracellular Signaling Peptides and Proteins; Leucine; Male; Oligopeptides; Proline; Protease Inhibitors; Quinolines; Rats; Thiazoles; Viral Nonstructural Proteins; Viral Proteins; Virus Replication