Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients

BACKGROUND AND AIMS: Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine protease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection. METHODS: The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, double-blind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6). RESULTS: Viral RNA reductions of 2-3 log 10 copies/mL were achieved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction > or =3 log(10) copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or compensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies. CONCLUSIONS: BILN 2061 is a well-tolerated and very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity issues.     

Antiviral strategies in hepatitis C virus infection

Resolution of the three-dimensional structures of several hepatitis C virus (HCV) proteins, together with the development of replicative cell culture systems, has led to the identification of a number of potential targets for direct-acting antiviral (DAA) agents. Numerous families of drugs that potently inhibit the HCV lifecycle in vitro have been identified, and some of these molecules have reached early to late clinical development. Two NS3/4A protease inhibitors, telaprevir and boceprevir, were approved in Europe and the United States in 2011 in combination with pegylated interferon (IFN)-α and ribavirin for the treatment of chronic hepatitis C related to HCV genotype 1, in both treatment-na?ve and treatment-experienced patients. Sustained virological response rates in the range of 6675% and 5966% (2988% if the response to the first course of therapy is taken into account) have been achieved in these two patient populations, respectively, with treatment durations of 24 to 48 weeks. A number of other DAAs are at the clinical developmental stage in combination with pegylated IFN-α and ribavirin or with other DAAs in IFN-free regimens, with or without ribavirin. They include second-wave, first-generation, and second-generation NS3/4A protease inhibitors, nucleoside/nucleotide analogue inhibitors and non-nucleoside inhibitorsof HCVRNA-dependent RNA polymerase, inhibitors of nonstructural protein 5A (NS5A) and host-targeted compounds, such as cyclophilin inhibitors and silibinin. The proof of concept that IFN-free regimens may lead to HCV eradication has recently been brought. However, new drugs may be associated with troublesome side effects and drugdrug interactions, and the ideal IFN-free DAA combination remains to be found.     

Antiviral activity of telaprevir and boceprevir for the treatment of hepatitis C virus infection in treatment-experienced patients

Around 50% of hepatitis C virus (HCV)-positive patients infected with genotype 1 are nonresponders to the combination of pegylated interferon (pegIFN) and ribavirin, including relapsers, and partial and null responders and, as such, are exposed to the risk of progression to cirrhosis and its complications, resulting in HCV-related morbidity and mortality. Repeat treatment using the same combination in such patients results in <5% viral eradication and there are no therapeutic prospects for patients who fail, as maintenance therapy has not proved efficacious. The triple association of direct-acting antivirals specific of HCV, and especially the first-generation protease inhibitors boceprevir and telaprevir, increases this percentage to around 65%, with variations according to the previous response to therapy of patients (85% of relapsers, 50% of partial responders and 30% of null responders). These encouraging results extend the therapeutic indications and costs of therapy during virological follow-up, and influence the rules of discontinuation. Information on the management of these new molecules also allows a larger number of patients to be cured and reduces the occurrence of viral resistance. Thus, the aim of the present review is to summarize the efficacy of the triple association of pegIFN, ribavirin and telaprevir or boceprevir in treatment-experienced patients who failed to respond to dual pegIFN and ribavirin therapy.     

Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C

BILN-2061, a specific and potent peptidomimetic inhibitor of the HCV NS3 protease, has recently been shown to markedly lower serum hepatitis C virus (HCV)-RNA levels in patients chronically infected with HCV genotype 1 in three 2-day proof of principle studies. The aim of the current study was to assess the antiviral efficacy of BILN-2061 in patients with genotypes 2 and 3 HCV infection. The antiviral efficacy, pharmacokinetics, and tolerability of 500 mg twice-daily BILN-2061 given as monotherapy for 2 days in 10 patients chronically infected with non-genotype 1 HCV (genotype 2: n = 3; genotype 3: n =7) and minimal liver fibrosis (Ishak score 0-2) were assessed in a placebo-controlled (placebo n = 2), double-blind pilot study. HCV-RNA levels decreased by > or =1 log(10) copies/mL in 4 of 8 patients treated with BILN-2061. One patient showed a weak response of <1 log(10) copies/mL. Three of 8 treated patients showed no response. There was no correlation between baseline viral concentration or genotype and response. BILN-2061 exhibited good systemic exposure after oral administration and was well tolerated. In conclusion, the antiviral efficacy of the HCV serine protease inhibitor BILN-2061 is less pronounced and more variable in patients with HCV genotype 2 or 3 infection compared with previous results in patients with HCV genotype 1. A lower affinity of BILN-2061 for the NS3 protease of genotypes 2 and 3 HCV is most likely a major contributor to these findings.     

Improving outcome in patients with hepatitis C virus genotype 4

Several factors influence treatment outcomes among patients with chronic hepatitis C. A trend is growing to adapt an individualized treatment approach to optimize treatment outcomes among chronic hepatitis C patients. Hepatitis C virus (HCV) genotype is an important factor that determines treatment outcomes among patients with chronic hepatitis C. HCV has six genotypes, and genotype 4 (G4) accounts for 20% of all global HCV infections. Patients with G4 are underrepresented in clinical trials involving patients with chronic hepatitis C because most patients infected with G4 are in Egypt, Africa, and Middle Eastern countries. Therefore, there is little information about the predictors of response to standard treatment among chronic hepatitis C patients with HCV G4. Initial evidence suggested that patients with G4 HCV are as difficult to treat as patients with G1; however, recent evidence suggests that the response rates to treatment among patients with G4 may be better than those with G1 but not those with G2 or G3. This review discusses the clinical data among patients with G4 and assesses the impact of an individualized approach on improved treatment outcomes in these patients.     

Antiviral effect of lymphoblastoid interferon-alpha on hepatitis C virus in patients with chronic hepatitis type C

Abstract To study the antiviral effect of lymphoblastoid alpha interferon (IFN) on hepatitis C virus (HCV) we conducted a randomized, controlled trial on 80 patients with chronic hepatitis C using three different doses. Patients were randomly assigned to treatment with 1, 3 or 6 million units of lymphoblastoid IFN-alpha daily for 2 weeks. To assess the antiviral effect of IFN, the amount of HCV present in the serum was estimated by competitive nested polymerase chain reaction (PCR) before and after 2 weeks of treatment. The multiple logistic analysis was used to evaluate factors associated with virus clearance, adjusting the imbalance in predictive factors among patients. Hepatitis C virus became negative as assessed by nested PCR after therapy in 26, 50 and 63% of patients receiving 1, 3 and 6 mega units, respectively. Hepatitis C virus was cleared more often in patients having initially low (< 10⁵/mL) amounts of virus. No significant decrease in the amount of virus was observed in the untreated, control group. Patients without bridging fibrosis in liver histology and with HCV genotypes other than K1 (type II) tended to respond well. These results indicate that lymphoblastoid IFN-alpha suppresses HCV in a dose dependent manner. Higher initial virus amounts, bridging fibrosis and genotype K1 were factors associated with poor response.     

HBV/HCV重叠感染的抗病毒治疗

从全球范围看,乙型肝炎病毒(hepatitis B virus,HBV)和丙型肝炎病毒(hepatitis C virus,HCV)重叠感染估计约有700-2000万人口感染.重叠感染和单一HBV或HCV感染比较,更易发展为肝硬化、肝细胞癌甚至肝衰竭的比例也高,HBV和HCV重叠感染可有四种不同的临床模式,即HCV活动...     

Characterization of naturally occurring protease inhibitor-resistance mutations in genotype 1b hepatitis C virus patients

Background and aims

Protease inhibitor (PI)-resistant hepatitis C virus (HCV) variants may be present in substantial numbers in PI-untreated patients according to recent reports. However, influence of these viruses in the clinical course of chronic hepatitis C has not been well characterized.

Methods

The dominant HCV nonstructural 3 (NS3) amino acid sequences were determined in 261 HCV genotype 1b-infected Japanese patients before pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, and investigated the patients?? clinical characteristics as well as treatment responses including sustained virological response (SVR) rate. HCV-NS3 sequences were also determined in 39 non-SVR patients after completion of the therapy.

Results

Four single mutations (T54S, Q80K, I153V, and D168E) known to confer PI resistance were found in 35 of 261 patients (13.4%), and double mutations (I153V plus T54S/D168E) were found in 6 patients (2.3%). Responses to PEG-IFN/RBV therapy did not differ between patients with and without PI-resistance mutations (mutation group, SVR 48%; wild-type group, SVR 40%; P?=?0.38). On the other hand, two mutations appeared in two non-SVR patients after PEG-IFN/RBV therapy (I153V and E168D, 5.1%).

Conclusions

PI-resistance-associated NS3 mutations exist in a substantial proportion of untreated HCV-1b-infected patients. The impact of these mutations in the treatment of PIs is unclear, but clinicians should pay attention to avoid further development of PI resistance.     

Antiviral activity of amantadine in elderly patients with chronic hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) infection is a worldwide problem of public health. Epidemiological studies have shown a significant higher prevalence of infection in the elderly. Amantadine is an antiviral agent active against the influenza A virus that has been used in cases of chronic hepatitis C. OBJECTIVES: To evaluate the antiviral activity and the safety of amantadine (200 mg daily for 6 months) in elderly patients with chronic hepatitis C. METHODS: The study group consisted of 23 consecutive patients over 65 years suffering from chronic hepatitis C. Aminotransferase (ALT) levels were tested at baseline, at 15 days and then monthly until the end of therapy. HCV genotype was determined at baseline. A quantitative HCV-RNA measurement was performed at baseline, at 15 days and at the 1st, 3rd and 6th month of treatment. RESULTS: 13 males and 10 females were enrolled (mean age 70.1 +/- 3.4 years; range: 65-75). The mean ALT levels did not change significantly during therapy except in 1 patient subsequently returned normal. The HCV-RNA remained detectable in all patients, but a significant difference in response was observed in patients infected by genotype 1b. CONCLUSIONS: Our results confirm the antiviral activity of amantadine against HCV, mainly for genotype 1b with initial high viral load. No consistent effects on aminotransferases were observed.     

Management of hepatitis C virus genotype 4

Hepatitis C virus (HCV) genotype 4 is predominantly found in the Middle East and North Africa. Because most of the large randomized controlled trials of antiviral therapy for chronic hepatitis C were conducted in North America and Europe, little is known about management of patients with this particular genotype. Based on the available data, sustained virological response rates to interferon-based therapies appear to be intermediate between the relatively resistant HCV genotype 1 and the readily responsive genotypes 2 and 3. Several large prospective studies of pegylated interferon plus ribavirin combination therapy, the current gold-standard treatment, have recently been completed and will be reviewed.     

大连地区丙型肝炎病毒亚型的分布状态

HCV是输血后肝炎的主要病因,具有较高的慢性化比例,并与肝硬化和原发性肝癌的发生关系密切,严重威胁人类健康.不同的基因型对流行病学,疫苗研制、临床抗病毒治疗及预后等方面有着明显影响.     

Significance of hepatitis C virus coinfection with persistently normal alanine aminotransferase levels in HIV-1-infected patients

ObJECTIVES: To assess the prevalence of chronic hepatitis C virus (HCV) infection with persistently normal alanine aminotransferase (ALT) levels in HIV-1-infected patients, together with its clinical, biological and histological characteristics and predictive factors. METHODS: We retrospectively studied all HCV/HIV-coinfected patients treated in our Infectious Diseases Department, for whom data on both HIV and HCV infection were available. We compared the demographic characteristics and parameters of HIV and HCV infection between cases, defined by persistently normal ALT levels (<45 IU/L) and detectable serum HCV-RNA (determined by PCR), and controls with high ALT levels and HCV PCR positivity during the previous 3 years. RESULTS: Among the 815 HIV-infected patients assessed for this study, 179 (22%) were HCV-coinfected, of whom 155 were eligible for this analysis. Of these 155 HCV-coinfected patients, 137 (88%) were HCV-PCR-positive, of whom 39 (28.5%) had persistently normal ALT levels (cases) and 98 (71.5%) had high ALT levels (controls). Relative to controls, cases had a significantly lower fibrosis score and a lower fibrosis progression rate (2.2 vs. 1.3, P=0.004; 0.3 vs. 0.2, P=0.006, respectively). Three factors associated with persistently normal ALT levels were identified, namely: HBsAg negativity (P=0.003), HCV genotype 4 (P=0.01) and female sex (P=0.05). CONCLUSION: Persistently normal ALT levels may be considered as a marker of slow HCV disease progression in HIV-coinfected patients, with significantly less severe hepatic lesions.     

Antiviral therapy in hepatitis C virus cirrhotic patients in compensated and decompensated condition

The main goals of treating cirrhotic patients with antiviral therapy are to attain sustained viral clearance （SVR）, halt disease progression, and prevent reinfection of the liver graft. However, while the medical need is great, the use of interferon and ribavirin might expose these patients to severe treated-related side effects as a large proportion of them have pre-existing hematological cytopenias. We have reviewed potential benefits and risks associated with antiviral drugs in patients with liver cirrhosis, due to hepatitis C virus （HCV） infection. In cases presenting with bridging fibrosis or cirrhosis, current regimens of antiviral therapy have attained a 44%-48% rate of SVR. In cirrhotic patients with portal hypertension, the SVR rate was 22% overall, 12.5% in patients with genotype 1, and 66.7% in those with genotypes 2 and 3 following therapy with low doses of either Peg-IFN alpha- 2b and of ribavirin. In patients with decompensated cirrhosis, full dosages of Peg-IFN alpha-2b and of ribavirin produced a SVR rate of 35% overall, 16% in patients with genotype 1 and 4, and 59% in those with genotype 2 and 3. Use of hematological cytokines will either ensure full course of treatment to be accomplished with and prevent development of treatment-associated side effects. Major benefits after HCV eradication were partial recovery of liver metabolic activity, prevention of hepatitis C recurrence after transplantation, and removal of some patients from the waiting list for liver transplant. Several observations highlighted that therapy is inadvisable for individuals with poor hepatic reserve （Child-Pugh- Turcotte score ≥ 10）. Although SVR rates are low indecompensated cirrhotics due to hepatitis C, these patients have the most to gain as successful antiviral therapy is potentially lifesaving.     

Should we test hepatitis C virus genotype and viraemia level in patients with chronic hepatitis C?

Hepatitis C is a major health problem and at present, interferon-α is the only therapy of proven use. Two viral factors, namely HCV genotype and viraemia levels, have been studied extensively for their possible role in the clinical management of patients with chronic hepatitis C virus infection. This review attempts to summarize our current understanding of these two viral factors and provide recommendations as to how these two parameters should be used by general practitioners, practising gastroenterologists/hepatologists, and investigators in 1997.