Elevated interferon-stimulated gene transcription in peripheral blood mononuclear cells occurs in patients infected with genotype 1 but not genotype 3 hepatitis C virus

Hepatitis C virus (HCV) can be classified into seven distinct genotypes that are associated with differing pathologies and respond differently to antiviral therapy. In the UK, genotype 1 and 3 are present in approximately equal proportions. Chronic infection with HCV genotype 3 is associated with increased liver steatosis and reduced peripheral total cholesterol levels, which potentially influences peripheral immune responses. To understand these differences, we investigated host gene transcription in peripheral blood mononuclear cells by microarray and quantitative PCR in patients with genotype 1 (n = 22) or genotype 3 infection (n = 22) and matched healthy controls (n = 15). Enrichment of genes involved in immune response and inflammatory pathways were present in patients infected with HCV genotype 1; however, no differences in genes involved in lipid or cholesterol metabolism were detected. This genotype-specific induction of genes is unrelated to IL28B genotype or previous treatment failure. Our data support the hypothesis that genotype 1 infection drives a skewed Type I interferon response and provides a foundation for future investigations into the host–pathogen interactions that underlie the genotype-specific clinical outcomes of chronic HCV infection

Colitis Following Initiation of Sofosbuvir and Simeprevir for Genotype 1 Hepatitis C.

Sofosbuvir and simeprevir are used for the treatment of chronic hepatitis C (HCV) genotype 1. Both drugs have been well-tolerated, with diarrhea noted in 6% cases with sofosbuvir, 16% with sofosbuvir plus simeprevir, and 0% with simeprevir. No prior reports exist of colitis secondary to either drug or their combination. We report a patient with no prior history of inflammatory bowel disease who developed significant bloody diarrhea within 2 weeks of sofosbuvir/simeprevir initiation. Colonoscopy and biopsy confirmed pancolitis, which responded to mesalamine and completion of sofosbuvir/simeprevir

A cost-utility analysis of different antiviral medicine regimens in patients with chronic hepatitis C virus genotype 1 infection

Background: Despite the introduction of new drug regimens with high effectiveness for the hepatitis C virus (HCV) patients, especially in HCV genotype 1, no cost-effectiveness study on the selection of the superior drug strategy in Iran has been conducted yet. Objectives: This study is aimed to assess the cost-effectiveness of the three drug regimens of pegylated interferon and ribavirin (PR), sofosbuvir (SOF) + PR and ledipasvir and sofosbuvir (LDV/SOF) in patients with HCV genotype 1 in Iran in the year 2014. Methods: A Markov micro-simulation model was used to evaluate the cost-effectiveness of the three drug strategies for a cohort of 10000 patients. Quality-adjusted life-years (QALYs) were extracted from published studies. Cost data was estimated through the review of medical records and obtaining experts opinion. Results: The results showed that the SOF + PR drug compared with PR had a lower cost and was more effective, but compared with the LDV/SOF, in spite of its lower cost, it was less efficient. The QALY values obtained for PR, SOF + PR and LDV/SOF, respectively, were 10.98, 12.08 and 12.28 and their costs were $41,741,$ 7,676 and $46,993. Moreover, the results obtained from acceptability curves showed that SOF + PR were the most cost-effective treatment for thresholds below$ 45,270 PPP. Conclusions: The use of SOF + PR regimen or LDV/SOF can significantly reduce the incidence of complications associated with the disease. For example, short and long-term outcomes are better than the current drug regimens for HCV genotype 1 patients in all stages of the disease

Prevalence of HCV NS3 pre-treatment resistance associated amino acid variants within a Scottish cohort

Background: Protease inhibitors (PI) including boceprevir, telaprevir and simeprevir have revolutionised HCV genotype 1 treatment since their introduction. A number of pre-treatment resistance associated amino acid variants (RAVs) and polymorphisms have been associated with reduced response to treatment. Objectives: We measured the prevalence of RAVs/polymorphisms in a PI treatment-naïve HCV genotype 1 Scottish cohort using Sanger sequencing. Study design: Chronically infected, treatment-naïve, HCV genotype 1 patients (n = 146) attending NHS Greater Glasgow and Clyde clinics were investigated for RAVs/polymorphisms to the PIs boceprevir, telaprevir and simeprevir. The NS3/4A region was amplified by nested polymerase chain reaction. The 1.4 kb amplified product was sequenced using an ABI 3710XL DNA sequencer. Sequence analysis was performed using web-based ReCall (beta 2.10). Amino acid positions 36, 41, 43, 54, 55, 80, 109, 122, 155, 156, 168 and 170 were analysed for RAVs/polymorphisms. Results: Overall, 23.29% (34/146) of patients had an RAV or polymorphism detected. Overall, 13.69% (20/146) of patients had HCV virus that contained the Q8 K polymorphism. Other RAVs detected were: V36 M 0.70% (1/146), V36L 0.70% (1/146), T54S 6.85% (10/146), V55A 3.42% (5/146) and V/I170A 0.68% (1/146). Four patients had dual combinations of mutations (T54S + V36L; T54S + V55A and 2 patients with T54S + Q80K). Conclusions: Q80K was the most prevalent baseline polymorphism detected in the Scottish cohort. Simeprevir treatment is not recommended in patients infected with the Q80K genotype 1a variant. This highlights the need for baseline sequencing prior to administration of this drug in this population

Baseline anti-NS4a antibodies in combination with on-treatment quantitative HCV-RNA reliably identifies nonresponders to pegylated interferon-ribavirin combination therapy after 4 weeks of treatment

Background Early detection of nonresponders to hepatitis C therapy limits unnecessary exposure to treatment and its side-effects. A recent algorithm combining baseline anti-NS4a antibodies and on-treatment quantitative PCR identified nonresponders to a combination of interferon and ribavirin after 1 week of treatment. Aim To validate a stopping rule based on baseline anti-NS4a antibody levels and early on-treatment virological response in treatment-naive genotype 1 chronic hepatitis C patients treated with the current standard pegylated interferon and ribavirin combination therapy. Methods Eighty-nine genotype 1 patients from the Dynamically Individualized Treatment of hepatitis C Infection and Correlates of Viral/Host dynamics Study treated for 48 weeks with standard 180 mu g pegylated interferon (PEG-IFN)-alpha-2a (weekly) and ribavirin 1000-1200mg (daily) were analysed. Baseline anti-NS4a antibody enzyme-linked immunosorbent assay (NS4a AA 1687-1718) was performed on pretreatment serum. Hepatitis C virus-RNA was assessed at days 0, 1, 4, 7, 8, 15, 22, 29, weeks 6, 7, 8, 10, 12 and 6 weekly thereafter until end of treatment. Multiple regression logistic analysis was performed. Results Overall 54 of 89 (61%) patients achieved sustained virological response. A baseline anti-NS4a antibody titre less than 1/1250 correlated with absence of favourable initial viral decline according to variable response types (P=0.015). The optimal algorithm was developed using the combination of the absence of anti-NS4a Ab (= 100.000 IU/ml at week 4. This algorithm has a specificity of 43% and negative predictive value of 100% to detect nonresponse to standard PEG-IFN-alpha-2a and ribavirin therapy at fourth week of therapy (intention-to-treat analysis). Conclusion The decision to stop the therapy in genotype 1 chronic hepatitis C patients treated with PEG-IFN-alpha-2a and ribavirin can be confidently made after 4 weeks of treatment based on the absence of baseline anti-NS4a Ab and a week-4 hepatitis C virus-RNA above 100.000 IU/ml. Eur J Gastroenterol Hepatol 22:1443-1448 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Dasabuvir and Ombitasvir/Paritaprevir/Ritonavir with or without Ribavirin in Patients with HIV-HCV Coinfection. Real Life Interim Analysis of an Italian Multicentre Compassionate Use Program

Background and Aims: An HCV cure is now possible in a large proportion of HIV-HCV patient. We present real life results of a compassionate use program promoted by SIMIT (Infectious and Tropical Diseases Italian Society) of Dasabuvir and Ombitasvir/Paritaprevir/Ritonavir ± Ribavirin for 12 weeks in 213 HIV-HCV genotype 1 patients. Data on efficacy and tolerability of this strategy in HIV patients have been reported until now only in 43 non cirrhotic HIV subjects

Hepatitis C virus NS5A targets the nucleosome assembly protein NAP1L1 to control the innate cellular response

Hepatitis C virus (HCV) is a single-stranded positive-sense RNA hepatotropic virus. Despite cellular defenses, HCV is able to replicate in hepatocytes and to establish a chronic infection that could lead to severe complications and hepatocellular carcinoma. An important player in subverting the host response to HCV infection is the viral non-structural protein NS5A that, in addition to its role in replication and assembly, targets several pathways involved in the cellular response to viral infection. Several unbiased screens identified the nucleosome-assembly protein 1-like 1 (NAP1L1) as an interaction partner of HCV NS5A. Here we confirm this interaction and map it to the C-terminus of NS5A of both genotype 1 and 2. NS5A sequesters NAP1L1 in the cytoplasm blocking its nuclear translocation. However, only NS5A from genotype 2 HCV, but not from genotype 1, targets NAP1L1 for proteosomal-mediated degradation. NAP1L1 is a nuclear chaperone involved in chromatin remodeling and we demonstrate the NAP1L1-dependent regulation of specific pathways involved in cellular responses to viral infection and cell survival. Among those we show that lack of NAP1L1 leads to a decrease of RELA protein levels and a strong defect of IRF3 TBK1/IKKϵ-mediated phosphorylation leading to inefficient RIG-I and TLR3 responses. Hence, HCV is able to modulate the host cell environment by targeting NAP1L1 through NS5A

Atazanavir-Based Therapy Is Associated with Higher Hepatitis C Viral Load in HIV Type 1-Infected Subjects with Untreated Hepatitis C

Comunicación cortaWe assessed the relationship between atazanavir (ATV)-based antiretroviral treatment (ART) and plasma hepatitis C virus (HCV) viral load in a population of HIV/HCV-coinfected patients. HIV/HCV-coinfected patients who received ART based on a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) were included. Patients were stratified by ART drug [ATV/rtv, lopinavir (LPV/rtv), efavirenz (EFV), nevirapine (NVP), and other PIs], HCV genotype (1/4 and 2/3), and IL28B genotype (CC and non-CC). The Kruskal-Wallis test and chi-squared test were used to compare continuous and categorical variables, respectively. Multivariate analysis consisted of a stepwise linear regression analysis. Six hundred and forty-nine HIV/HCV-coinfected patients were included. HCV genotype 1/4 patients who received ATV had higher HCV RNA levels [6.57 (5.9-6.8) log IU/ml] than those who received LPV [6.1 (5.5-6.5) log IU/ml], EFV [6.1 (5.6-6.4) log IU/ml], NVP [5.8 (5.5-5.9) log IU/ml], or other PIs [6.1 (5.7-6.4) log IU/ml] (p=0.014). This association held for the IL28B genotype (CC versus non-CC). The association was not found in patients carrying HCV genotypes 2/3. The linear regression model identified the IL28B genotype and ATV use as independent factors associated with HCV RNA levels. ATV-based therapy may be associated with a higher HCV RNA viral load in HIV/HCV-coinfected patients