First-generation Protease Inhibitors Research Articles

Inhibition of human DNA alkylation damage repair enzyme ALKBH2 by HIV protease inhibitor ritonavir

The human DNA repair enzyme AlkB homologue-2 (ALKBH2) repairs methyl adducts from genomic DNA and is overexpressed in several cancers. However, there are no known inhibitors available for this crucial DNA repair enzyme. The aim of this study was to examine whether the first-generation HIV protease inhibitors having strong anti-cancer activity can be repurposed as inhibitors of ALKBH2. We selected four such inhibitors and performed in vitro binding analysis against ALKBH2 based on alterations of its intrinsic tryptophan fluorescence and differential scanning fluorimetry. The effect of these HIV protease inhibitors on the DNA repair activity of ALKBH2 was also evaluated. Interestingly, we observed that one of the inhibitors, ritonavir, could inhibit ALKBH2-mediated DNA repair significantly via competitive inhibition and sensitized cancer cells to alkylating agent methylmethane sulfonate (MMS). This work may provide new insights into the possibilities of utilizing HIV protease inhibitor ritonavir as a DNA repair antagonist.

Elimination of hepatitis C virus in a prison: An 18-year experience

IntroductionDespite the decrease of hepatitis C in Spanish prisons in the last years, it still remains a reservoir for infection. The aim of this work is to analyze the characteristics of these patients and the response to antiviral treatment over the last 18 years. MethodsRetrospective observational study in inmates of Araba penitentiary center diagnosed with HCV infection between 2002 and 2020.A descriptive analysis of patient characteristics and the response to the three antiviral treatment modalities was performed: peg-interferon and ribavirin, peg-interferon, ribavirin and a first-generation protease inhibitor and different combinations of direct-acting antivirals. ResultsA total of 248 antiviral treatments were prescribed. Treatment response rate up to 2015 was 65% and 93,7% after that year. Interferon non-responders were the main cause of non-response to treatment in periods 1 and 2 (40%–50%). Conversely, in period 3 viral breakthrough (67%) was the main culprit. ConclusionAfter 18 years, active hepatitis C infection in prison inmates has resolved with treatment according to clinical criteria. Therefore, the stay in prison may represent an opportunity to reduce the reservoir of the disease in the community, together with continued health care for those released from prison.

In-silico guided design, screening, and molecular dynamic simulation studies for the identification of potential SARS-CoV-2 main protease inhibitors for the targeted treatment of COVID-19

COVID-19, the disease responsible for the recent pandemic, is caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (Mpro) of SARS-CoV-2 is an essential proteolytic enzyme that plays a number of important roles in the replication of the virus in human host cells. Blocking the function of SARS-CoV-2 Mpro offers a promising and targeted, therapeutic option for the treatment of the COVID-19 infection. Such an inhibitory strategy is currently successful in treating COVID-19 under FDA’s emergency use authorization, although with limited benefit to the immunocompromised along with an unfortunate number of side effects and drug-drug interactions. Current COVID vaccines protect against severe disease and death but are mostly ineffective toward long COVID which has been seen in 5–36% of patients. SARS-CoV-2 is a rapidly mutating virus and is here to stay endemically. Hence, alternate therapeutics to treat SARS-CoV-2 infections are still needed. Moreover, because of the high degree of conservation of Mpro among different coronaviruses, any newly developed antiviral agents should better prepare us for potential future epidemics or pandemics. In this paper, we first describe the design and computational docking of a library of novel 188 first-generation peptidomimetic protease inhibitors using various electrophilic warheads with aza-peptide epoxides, α-ketoesters, and β-diketones identified as the most effective. Second-generation designs, 192 compounds in total, focused on aza-peptide epoxides with drug-like properties, incorporating dipeptidyl backbones and heterocyclic ring motifs such as proline, indole, and pyrrole groups, yielding 8 hit candidates. These novel and specific inhibitors for SARS-CoV-2 Mpro can ultimately serve as valuable alternate and broad-spectrum antivirals against COVID-19. Communicated by Ramaswamy H. Sarma

Eliminación del virus de la hepatitis C en un centro penitenciario: una experiencia de 18 años

IntroductionDespite the decrease of hepatitis C in Spanish prisons in the last years, it still remains a reservoir for infection. The aim of this work is to analyze the characteristics of these patients and the response to antiviral treatment over the last 18 years. MethodsRetrospective observational study in inmates of Araba penitentiary center diagnosed with HCV infection between 2002 and 2020.A descriptive analysis of patient characteristics and the response to the 3 antiviral treatment modalities was performed: peg-interferon and ribavirin, peg-interferon, ribavirin and a first-generation protease inhibitor and different combinations of direct-acting antivirals. ResultsA total of 248 antiviral treatments were prescribed. Treatment response rate up to 2015 was 65% and 93,7% after that year. Interferon non-responders were the main cause of non-response to treatment in periods 1 and 2 (40-50%). Conversely, in period 3 viral breakthrough (67%) was the main culprit. ConclusionAfter 18 years, active hepatitis C infection in prison inmates has resolved with treatment according to clinical criteria. Therefore, the stay in prison may represent an opportunity to reduce the reservoir of the disease in the community, together with continued health care for those released from prison.

Ombitasvir/paritaprevir/ritonavir & dasabuvir \xb1 ribavirin following protease inhibitors failure - a prospective multi-centre trial

BackgroundHepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65–75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs.MethodsAn investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants.ResultsThirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3–4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P < 0.001). Seven patients (17.9%) experienced serious adverse events (3 Psychiatric admissions, 1 pneumonia, 1 ankle fracture, 2 palpitations), and 12 patients (30.8%) experienced self-reported adverse events, mostly weakness.Conclusion3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment.Trial registrationNCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

A decade of hepatitis C at the University of Cape Town/Groote Schuur Hospital Liver Clinic, South Africa, in the pre-direct-acting antivirals era.

Hepatitis C virus (HCV) in South Africa (SA) is incompletely characterised and understood. Epidemiological and clinical data will better inform our understanding and assist national policy decision-making. Against the background of more than two decades of clinical challenges in HCV management, the advent of direct-acting antivirals (DAAs) now makes HCV elimination plausible. To better understand the base from which we come, we elected to review and characterise our HCV experience at Groote Schuur Hospital (GSH), Cape Town, SA, in the pegylated interferon (Peg-IFN) and ribavirin (RBV) management era. Patients with chronic HCV infection attending the GSH Liver Clinic from 2002 to 2014 were included in the analysis. Relevant data were extracted from a registry and existing clinical records were accessed. Two brands of Peg-IFN were available, and patients treated with the first-generation add-on protease inhibitor telaprevir were included. A total of 238 patients were included in the analysis (median (interquartile range) 47 (37 - 58) years, 60.5% males). Males were significantly younger than females (43.5 (35 - 52) years v. 55 (42 - 64) years, respectively) (p&lt;0.0001). The majority were white (55.9%) or of mixed ancestry (21.8%), 16.4% were HIV co-infected, 3.7% were hepatitis B virus (HBV) co-infected, and 1 patient (0.4%) was triple-infected with HCV, HBV and HIV. The most likely mode of HCV acquisition was blood or blood product exposure prior to 1992 (32.8%) and injecting drug use (17.6%), while 30.3% of patients had no clear risk factor identifiable. Genotypes (GTs) 1 - 5 were observed, with GT-1 (34.9%) predominating. Of patients who were biopsied (n=90), 30.0% had ≥F3 fibrosis, with 15.6% cirrhotic. With IL28B polymorphisms, the heterozygous CT (23.9%) and CC (15.5%) genotypes were most frequent. Of the patients, 32.6% accessed Peg-IFN/RBV-based therapy, 6.5% (n=5) with add-on telaprevir. GT-1 (35.1%) was most prevalent in the treatment group, followed by GT-3 (26.0%) and GT-5 (18.2%); 10.0% were HIV co-infected. The overall sustained virological response (SVR) rate was 75.3%, with 37.0% of GT-1 patients not achieving SVR. Of the patients treated, 49.4% experienced adverse events, including cytopenias (32.5%) and depression (15.6%), and 23.4% required cell support in the form of erythropoietin and/or granulocyte-macrophage colony-stimulating factor. HCV patients in the Peg-IFN/RBV management era typified the epidemiology of HCV. GT distribution was pangenotypic, and treatment outcomes were encouraging despite treatment challenges. Patient selection, IL28B and sensible support of cytopenias probably accounted for these favourable outcomes. However, numbers treated were limited, and the DAA era of therapy allows for rapid expansion of therapy with now growing numbers of patients and a changing local epidemiology.

Core-Shell Palladium Telluride Quantum Dot-Hemethiolate Cytochrome Based Biosensor for Detecting Indinavir Drug.

Indinavir is a first-generation HIV protease inhibitor anti-retroviral (ARV) drug. Due to interindividual differences in the rate of indinavir metabolism, clinicians and pharmacologists have expressed urgent need for sensor devices that will enable real time determination of appropriate dosage. In this study, an indinavir biosensor was developed by the functionalization of a cysteamine-modified gold (Cyst|Au) electrode with biocompatible core-shell 3-mercaptopropionic acid (3-MPA)-capped palladium telluride quantum dot (PdTeQD) and the heme-thiolate cytochrome P450-3A4 (CYP3A4) enzyme. The PdTeQD was capped with 3-mercaptopropionic acid (3-MPA) to improve its reactivity, biocompatibility and thermal stability. Small angle X-ray scattering (SAXS) studies revealed that the 3-MPA-PdTeQD particles formed core-shells with diameters of 4.7 nm. Fourier transformed infrared spectroscopy (FTIR) experiments confirmed the formation of 3-MPA-PdTeQD by the presence of specific COOH and CH₂ FTIR signature bands. Ultraviolet-visible (UV-Vis) spectrophotometric analysis of the quantum dot, exhibited a broad characteristic band at ~320 nm, corresponding to a band gap energy (Eg) value of 3.87 eV, indicating that the QD is a semiconducting material. Cyclic voltammetry (CV) responses of the biosensor (i.e., CYP3A4|3-MPA-PdTeQD|Cyst|Au) indicated that 0.26 V was the suitable potential for measuring indinavir metabolism. The biosensor has a sensitivity, dynamic linear range (DLR) and limit of detection (LOD) values of 0.0218 μA/nM, 0.0004-0.01 nM (i.e., 3×10-7 -7×10-6 mg L-1) and 0.023×10-7 mg L-1, respectively, for indinavir. The LOD value was lower than the maximum plasma concentration (Cmax) value (0.13-8.6 mg L-1) of indinavir which is normally measure 8 h after intake. The low DLR value makes the biosensor suitable for application at point-of-care, where indinavir concentration is expected to be in ng L-1 level in physiological samples within a few minutes of the drug administration.

Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study

Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27). Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.

Treatment of hepatitis C virus infection in patients with mixed cryoglobulinemic syndrome and cryoglobulinemic glomerulonephritis.

Cryoglobulinemia is a common extrahepatic manifestation of infection with hepatitis C virus (HCV). When signs and symptoms of systemic vasculitis or glomerulonephritis occur in the presence of circulating cryoglobulins, this syndrome is called "mixed cryoglobulinemia syndrome" (MCS). Historically, interferon-based therapies in HCV have been associated with lower rates of viral cure in patients with MCS than in the general HCV-infected population. The advent of direct-acting antiviral therapies have revolutionized the treatment of HCV, dramatically increasing rates of cure. Early studies of first-generation protease inhibitors (telaprevir and boceprevir) in combination with interferon and ribavirin demonstrated HCV cure rates of 67% and complete clinical response rates of vasculitis symptoms in 60% of patients with MCS; however, regimens were poorly tolerated by patients, 22% discontinued treatment early. More recently, all-oral, interferon-free regimens have become available and combination therapies are now being approved for patients with and without renal impairment. Patients with HCV-MCS achieved sustained virologic response in 297 out of 313 patients (95%) treated with direct-acting antiviral therapy, and 85% had a complete or partial clinical response of MCS symptoms. Current direct-acting antiviral therapies are well tolerated in patients with HCV-MCS and only 1.6% discontinued treatment early. Patients with cryoglobulinemic glomerulonephritis also had an excellent cure rate (94%). The majority improved; 17/52 (33%) experienced full remission and 15/52 (29%) experienced partial remission. There were no reports of worsening kidney function in patients treated with direct-acting antiviral therapies. Less than 5% of patients with HCV-MCS treated with IFN-free direct-acting antiviral therapy required immunosuppression. However, patients with severe vasculitis appear to still require concomitant immunosuppression.

Recent Advancement of Direct-acting Antiviral Agents (DAAs) in Hepatitis C Therapy.

Hepatitis C virus (HCV) infection is a major health problem worldwide. Approximately, 170-200 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. A complete eradication of the virus is one of the most important treatment goals for antiviral research. In 2011, the first-generation protease inhibitors boceprevir (BOC) telaprevir (TVR) were approved by FDA as the direct-acting antiviral agents. A number of promising new direct-acting antiviral agents (DAAs) have been developed in the past few years. Due to their increased efficacy, safety, and tolerability, interferon-free oral therapies with DAAs are in use for patients with chronic HCV and cirrhosis patients. In this review, we will discuss the results of clinical trials of several DAAs and the approved combinations, including NS3/4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors. A number of drugs, including Sovaldi®, Harvoni® Viekira Pak®, Epclusa®, Zepatier® have been approved by FDA in the past two-three years. The latest advancement of DAA therapy and related side effects due to the therapy are also discussed.

The association between HIV, antiretroviral therapy, and gestational diabetes mellitus.

The widespread, chronic use of antiretroviral therapy raises questions concerning the metabolic consequences of HIV infection and treatment. Antiretroviral therapy, and specifically protease inhibitors, has been associated with hyperglycemia. As pregnant women are vulnerable to development of hyperglycemia, the objective of this study was to explore existing literature on the relationship between HIV infection, HIV treatment, and gestational diabetes mellitus (GDM). A systematic search was conducted in six databases for articles providing data on HIV-positivity, protease inhibitor exposure, and GDM or glucose intolerance development in pregnancy. The quality of articles was evaluated using an adapted Cochrane Collaboration bias assessment tool. Risk ratios were generated from pooled data using meta-analysis by the Mantel-Haenszel method. Of 891 references screened, six studies on the role of HIV-positivity, 10 on protease inhibitor use, and two on both were included. Meta-analysis showed no significant relationship between HIV infection and the development of GDM [risk ratio 0.80, 95% confidence interval (CI): 0.47-1.37, I = 0%]. Meta-analysis of protease inhibitor exposure showed increased GDM in studies using first-generation protease inhibitors (risk ratio 2.29, 95% CI: 1.46-3.58) and studies using the strictest diagnosis criteria, the National Diabetes Data Group criteria for 3-h oral glucose tolerance test (risk ratio 3.81, 95% CI: 2.18-6.67). Meta-analysis showed no significant association between HIV-positivity and GDM. Significance of protease inhibitor use was limited to studies using the strictest diagnostic criteria for GDM. Results are limited by high risk of bias. Well designed prospective studies are needed to further clarify this relationship and its consequences for clinical practice.

Efficacy and safety profile of boceprevir- or telaprevir-based triple therapy or dual peginterferon alfa-2a or alfa-2b plus ribavirin therapy in chronic hepatitis C: the real-world PegBase observational study.

BackgroundThe aim of the study was to determine the efficacy and safety of triple therapy with a first-generation protease inhibitor (PI; boceprevir, telaprevir) plus peginterferon alfa-2a or -2b plus ribavirin, and dual therapy (peginterferon alfa-2a or -2b plus ribavirin) in patients with chronic hepatitis C (CHC) in routine clinical practice.MethodsPegBase was an international, prospective, observational study in which 4441 patients with CHC were enrolled in 27 countries. This analysis focuses on results in 4100 treatment-naïve and previously treated patients treated with PI-based triple therapy or dual therapy, according to the discretion of the investigator and local standards of practice. The primary efficacy outcome was sustained virological response after 12-week follow up (SVR12).ResultsSVR12 rates in treatment-naïve genotype (G) 1 patients were 56.6% and 62.9% for recipients of boceprevir plus peginterferon alfa-2a/ribavirin and boceprevir plus peginterferon alfa-2b/ribavirin, respectively, and 65.3% and 58.6% for recipients of telaprevir plus peginterferon alfa-2a/ribavirin and telaprevir plus peginterferon alfa-2b/ribavirin, respectively. In previously treated patients assigned to these four regimens, SVR12 rates were 43.6%, 48.3%, 60.3% and 56.1%, respectively. Among treatment-naïve patients assigned to peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin, respectively, SVR12 rates were 49.2% and 41.9% in G1 patients, 75.7% and 83.3% in G2 patients, 65.9% and 65.9% in G3 patients, and 49.7%, and 51.1% in G4 patients. The safety and tolerability of dual and triple therapy were consistent with previous reports.ConclusionThe efficacy and safety of first-generation PI-based triple-therapy and dual-therapy regimens in this real-world cohort were broadly comparable to those of previous studies.

Effectiveness and safety of first-generation protease inhibitors in real-world patients with hepatitis C virus genotype 1 infection in Brazil: a multicenter study

OBJECTIVE:To evaluate the effectiveness and safety of first-generation protease inhibitors for the treatment of genotype 1 hepatitis C virus-infected patients at Brazilian reference centers.METHODS:This multicenter cross-sectional study included hepatitis C virus genotype 1 monoinfected patients treated with Peg-interferon, ribavirin, and either boceprevir (n=158) or telaprevir (n=557) between July 2013 and April 2014 at 15 reference centers in Brazil. Demographic, clinical, virological, and adverse events data were collected during treatment and follow-up.RESULTS:Of the 715 patients, 59% had cirrhosis and 67.1% were treatment-experienced. Based on intention-to-treat analysis, the overall sustained viral response was 56.6%, with similar effectiveness in both groups (51.9% for boceprevir and 58% for telaprevir, p=0.190). Serious adverse events occurred in 44.2% of patients, and six deaths (0.8%) were recorded. Cirrhotic patients had lower sustained viral response rates than non-cirrhotic patients (46.9% vs. 70.6%, p<0.001) and a higher incidence of serious adverse events (50.7% vs. 34.8%, p<0.001). Multivariate analysis revealed that sustained viral response was associated with the absence of cirrhosis, viral recurrence after previous treatment, pretreatment platelet count greater than 100,000/mm3, and achievement of a rapid viral response. Female gender, age>65 years, diagnosis of cirrhosis, and abnormal hemoglobin levels/platelet counts prior to treatment were associated with serious adverse events.CONCLUSION:Although serious adverse events rates were higher in this infected population, sustained viral response rates were similar to those reported for other patient cohorts.

PGI12 - Hepatitis C Treatment with First-Generation Protease Inhibitors in A Real-World Cohort: Risk-Benefit Profile and Costs of the Therapy

PGI12 - Hepatitis C Treatment with First-Generation Protease Inhibitors in A Real-World Cohort: Risk-Benefit Profile and Costs of the Therapy

Low Pretreatment Acoustic Radiation Force Impulse Imaging (ARFI) Values Predict Sustained Virological Response in Antiviral Hepatitis C Virus (HCV) Therapy.

BackgroundNon-invasive procedures such as acoustic radiation force impulse imaging (ARFI) shear-wave elastography are currently used for the assessment of liver fibrosis. In the course of chronic hepatitis C, significant liver fibrosis or cirrhosis develops in approximately 25% of patients, which is a negative predictor of antiviral treatment response. Cirrhosis can be prevented by successful virus elimination.In this prospective study, a pretreatment ARFI cutoff value of 1.5 m/s was evaluated in relation to sustained virological response to anti-HCV therapy.Material/MethodsIn 23 patients with chronic hepatitis C, liver stiffness was examined with ARFI at defined times before and under antiviral triple therapy (peginterferon, ribavirin in combination with a first-generation protease inhibitor, and telaprevir or boceprevir). Patients were stratified into 2 groups based on pretreatment ARFI values (<1.5 m/s and ≥1.5 m/s) for the assessment of virological response.ResultsThe liver stiffness at baseline for all patients was 1.57±0.79 m/s (ARFI median ± standard deviation; margin: 0.81 m/s to 3.45 m/s). At week 4 of triple therapy, patients with low pretreatment ARFI values had higher rates of HCV-RNA negativity (69% vs. 43%), reflecting an early rapid virological response (eRVR). Sustained virological response (SVR) was found in 75% (12/16) of patients with an ARFI value <1.5 m/s and only 57% (4/7) of patients with ARFI value ≥1.5 m/s.ConclusionsPatients with chronic hepatitis C and pretreatment ARFI <1.5 m/s showed earlier virus elimination and better response to treatment.

Pharmacogenetics of Ribavirin-Induced Anemia in Hepatitis C

Pharmacogenetics assesses inherited genetic differences in drug metabolic pathways and its role in medicine is growing. Ribavirin (RBV) and peginterferon were the standard of care therapy in hepatitis C virus infection during 15 years, with the addition of first-generation protease inhibitors at the beginning of 2010s. New direct-acting agents are the new standard of care, but RBV remains important in some scenarios. The main adverse effect of RBV is anemia, which requires dose reduction and even stopping treatment in some patients. Pharmacogenetics has identified ITPA and SLC28/29 genes to be closely related to RBV-induced anemia. The routine evaluation of these genes could help to identify those patients at risk of developing anemia during the hepatitis C virus treatment.

High Risk of Infection During Triple Therapy with First-Generation Protease Inhibitors: A Nationwide Cohort Study.

Peginterferon (PegIFN) remains the backbone of therapy for chronic hepatitis C (CHC) in economically constrained regions. However, PegIFN may cause neutropenia and addition of a protease inhibitor can increase the likelihood of neutropenia. The aims of this study were to assess the occurrence of clinically relevant infections during first-generation protease inhibitor based therapy and its risk factors as well as the relation to treatment-induced neutropenia. This multicenter (n=45) retrospective cohort study included CHC patients treated in the Netherlands. Based on absolute neutrophil count, categories of neutropenia were defined as: severe (<500/μL), moderate (500-750/μL) and mild (750-1500/μL). Likewise, infections were classified as severe (intravenous antibiotics/hospitalization) and moderate (anti-infective treatment). We assessed risk factors for infections using multivariable regression analysis with correction for multiple measurements. We included 467 CHC patients, 319 (68%) were male and 111 (24%) had cirrhosis. A total of 185 clinically relevant infections (34 severe) occurred in 145 patients (31%). During treatment 310 patients experienced neutropenia (34 severe). Multivariable analysis identified female sex (OR 1.7, 95%CI 1.2-2.5), chronic obstructive pulmonary disease (COPD) (OR 2.7, 95%CI 1.6- 4.5) and diabetes mellitus (OR 1.7, 95%CI 1.0-3.0) as risk factors for infections. Neutropenia at the previous visit was not associated with infection (univariable analysis: OR 0.9, 95%CI 0.6-1.3). This study shows that therapy with first generation protease inhibitors was complicated by an infection in 31% of patients. Not neutropenia, but female sex, COPD and diabetes mellitus were independent risk factors for infection. These patients should be monitored carefully once a PegIFN regimen is initiated.

JSH Guidelines for the Management of Hepatitis C Virus Infection: A 2016 update for genotype 1 and 2.

JSH Guidelines for the Management of Hepatitis C Virus Infection: A 2016 update for genotype 1 and 2.

Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with Chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60–70% in DYNAMO 1 and of 71–96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI.Trial Registration: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390

Predictors of early treatment discontinuation and severe anemia in a Brazilian cohort of hepatitis C patients treated with first-generation protease inhibitors.

The aim of this study was to determine risk factors for adverse events (AE)-related treatment discontinuation and severe anemia among patients with chronic hepatitis C virus (HCV) genotype 1 infection, treated with first-generation protease inhibitor (PI)-based therapy. We included all patients who initiated treatment with PI-based therapy at a Brazilian university hospital between November 2013 and December 2014. We prospectively collected data from medical records using standardized questionnaires and used Epi Info 6.0 for analysis. Severe anemia was defined as hemoglobin ≤8.5 mg/dL. We included 203 patients: 132 treated with telaprevir (TVR) and 71 treated with boceprevir (BOC). AE-related treatment discontinuation rate was 19.2% and anemia was the main reason (38.5%). Risk factors for treatment discontinuation were higher comorbidity index (OR=1.85, CI=1.05-3.25) for BOC, and higher bilirubin count (OR=1.02, CI=1.01-1.04) and lower BMI (OR=0.98, CI=0.96-0.99) for TVR. Severe anemia occurred in 35 (17.2%) patients. Risk factors for this outcome were lower estimated glomerular filtration rate (eGFR; OR=0.95, CI=0.91-0.98) for patients treated with TVR, and higher comorbidity index (OR=2.21, CI=1.04-4.67) and ribavirin dosage (OR=0.84, CI=0.72-0.99) for those treated with BOC. Fifty-five (57.3%) patients treated with TVR and 15 (27.3%) patients treated with BOC achieved sustained virological response (SVR). Among patients who received TVR and interrupted treatment due to AE (n=19), only 26.3% (n=5) achieved SVR (P=0.003). Higher number of comorbidities, lower eGFR and advanced liver disease are associated with severe anemia and early treatment cessation, which may compromise SVR achievement.