Anti‐ulcer agent teprenone inhibits hepatitis C virus replication: potential treatment for hepatitis C

Background: Previously we reported that 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors, statins, inhibited hepatitis C virus (HCV) RNA replication. Furthermore, recent reports revealed that the statins are associated with a reduced risk of hepatocellular carcinoma and lower portal pressure in patients with cirrhosis. The statins exhibited anti‐HCV activity by inhibiting geranylgeranylation of host proteins essential for HCV RNA replication. Geranylgeranyl pyrophosphate (GGPP) is a substrate for geranylgeranyltransferase. Therefore, we examined the potential of geranyl compounds with chemical structures similar to those of GGPP to inhibit HCV RNA replication. Methods: We tested geranyl compounds [geranylgeraniol, geranylgeranoic acid, vitamin K₂ and teprenone (Selbex)] for their effects on HCV RNA replication using genome‐length HCV RNA‐replicating cells (the OR6 assay system) and a JFH‐1 infection cell culture system. Teprenone is the major component of the anti‐ulcer agent, Selbex. We also examined the anti‐HCV activities of the geranyl compounds in combination with interferon (IFN)‐α or statins. Results: Among the geranyl compounds tested, only teprenone exhibited anti‐HCV activity at a clinically achievable concentration. However, other anti‐ulcer agents tested had no inhibitory effect on HCV RNA replication. The combination of teprenone and IFN‐α exhibited a strong inhibitory effect on HCV RNA replication. Although teprenone alone did not inhibit geranylgeranylation, surprisingly, statins' inhibitory action against geranylgeranylation was enhanced by cotreatment with teprenone. Conclusions: The anti‐ulcer agent teprenone inhibited HCV RNA replication and enhanced statins' inhibitory action against geranylgeranylation. This newly discovered function of teprenone may improve the treatment of HCV‐associated liver diseases as an adjuvant to statins.     

A same day ‘test and treat’ model for chronic HCV and HBV infection: Results from two community‐based pilot studies in Egypt

Prompt access to confirmatory viral load testing and staging of liver disease are key barriers in uptake of treatment for chronic hepatitis B and C infection. Our objective was to establish the feasibility of a same day ‘test and treat’ model in two distinct community‐based settings in Egypt through use of key point‐of‐care (POC) portable tools for HCV and HBV viral load assessment and staging of liver disease followed by treatment initiation. Community sites were a village in northern Egypt (site 1) and a government office in Cairo (site 2). The following model was adopted: community awareness raising in the week before project initiation; site assessment to ensure optimal placement and calibration of equipment and clinical care set‐up; transfer of key portable laboratory instruments to the sites (four cartridge GeneXpert, FibroScan and abdominal ultrasound); screening using rapid diagnostic tests for HCV‐Ab and HBsAg, with immediate venous or finger‐stick blood sampling for HCV‐RNA and HBV‐DNA assay, FibroScan staging of liver disease and ultrasound screening for liver cancer. At site 1, 475 individuals were screened over a single day, 125 were positive for HCV‐Ab and 4 for HBsAg, 43 of 56 new HCV diagnoses were HCV RNA positive, and 3 of 4 HBsAg positive were HBV DNA positive, 40 initiated HCV treatment, and one HBV treatment . At site 2, 3188 individuals were screened over 3 days, 157 were positive for HCV‐Ab, and 27 for HBsAg; 38 of 76 new HCV diagnoses were HCV RNA positive, and 15 of 18 HBsAg positive were HBV‐DNA positive. Across both sites, 78 patients were counselled and initiated on treatment for HCV and 12 for HBV within 3 and 4 hours, respectively, of initial positive rapid diagnostic test result. We have shown the feasibility of a same day ‘test and treat’ model for chronic HCV and HBV infection in two community‐based settings in Egypt that achieved high levels of linkage to care and initial treatment.     

Chronic hepatitis C treatment in HIV co‐infection in Portugal: Results from a cohort OF 2133 patients presented by GEPCOI (Portuguese Coinfection Study Group)

Direct‐acting antiviral drugs (DAAs) have recently changed the paradigm of hepatitis C therapy, significantly improving treatment response rates, patient life expectancy and quality of life. In Portugal, sofosbuvir (SOF) and SOF/ledipasvir (SOF/LDV) were fully reimbursed by the National Health System since early 2015 and generalized use of interferon‐free DAA based regimens became current practice. During 2016, the remaining DAAs were sequentially added and covered by the same health access policy. The Portuguese Study Group of Hepatitis and HIV Co‐infection (GEPCOI) collected data from 15 clinical centres in Portugal, pertaining to the HCV treatment experience with DAA regimens. A cohort of 2133 patients was analysed, representing one of the largest DAA treated HCV/HIV co‐infected individuals. The global sustained virologic response (SVR) achieved was 95% in this real‐life cohort setting. Linear regression analysis showed significant differences in treatment response rates when using SOF plus ribavirin (RBV) combination in genotype 2 or 3 infected individuals (P < .002) and in those with liver cirrhosis (P < .002). These findings corroborate that early treatment is mandatory in HIV/HCV co‐infected patients, as response rates may be negatively influenced by higher fibrosis stages and suboptimal DAA regimens. The current national Portuguese health policy should continue to promote wider treatment access and individualized therapy strategies, aiming at the elimination of HCV infection in this high‐risk co‐infected population.     

Treatment outcomes and costs of a simplified antiviral treatment strategy for hepatitis C among monoinfected and HIV and/or hepatitis B virus‐co‐infected patients in Myanmar

Access to hepatitis C virus (HCV) testing and treatment is limited in Myanmar. We assessed an integrated HIV and viral hepatitis testing and HCV treatment strategy. Sofosbuvir/velpatasvir (SOF/VEL) ± weight‐based ribavirin for 12 weeks was provided at three treatment sites in Myanmar and sustained virologic response (SVR) assessed at 12 weeks after treatment. Participants co‐infected with HBV were treated concurrently with tenofovir. Cost estimates in 2018 USD were made at Yangon and Mandalay using standard micro‐costing methods. 803 participants initiated SOF/VEL; 4.8% were lost to follow‐up. SVR was achieved in 680/803 (84.6%) by intention‐to‐treat analysis. SVR amongst people who inject drugs (PWID) was 79.7% (381/497), but 92.5% among PWID on opioid substitution therapy (OST) (74/80), and 97.4% among non‐PWID (298/306). Utilizing data from 492 participants, of whom 93% achieved SVR, the estimated average cost of treatment per patient initiated was $1030 (of which 54% were medication costs), with a production cost per successful outcome (SVR) of $1109 and real‐world estimate of $1250. High SVR rates were achieved for non‐PWID and PWID on OST. However, the estimated average cost of the intervention (under the assumption of no genotype testing and reduced real‐world effectiveness) of $1250/patient is unaffordable for a national elimination strategy. Reductions in the cost of antivirals and linkage to social and behavioural health services including substance use disorder treatment to increase retention and adherence to treatment are critical to HCV elimination in this population.     

A hepatitis C outbreak preceded the HIV outbreak among persons who inject drugs in Athens,Greece: Insights from a mathematical modelling study

People who inject drugs (PWID) comprise one of the major transmission risk groups for human immunodeficiency virus (HIV) and hepatitis C virus (HCV). In 2011, Athens experienced a large HIV outbreak among PWID. Significant public health interventions were implemented in response to the HIV outbreak. The aims of this study were to estimate the indirect effects of the HIV interventions on HCV infection and to evaluate the concept of the association between HCV and HIV infections in the case of Athens. A dynamic, stochastic, individual‐based model was developed to simulate HCV transmission among PWID. We calibrated the model to reproduce the observed HCV prevalence among PWID in Greece. Two years prior to the HIV outbreak, an undetected HCV outbreak has occurred. In 2009, the incidence of HCV infection increased from 640 (495, 842) cases in 2008 to 1260 (1060, 1500). The mean time from initiation of injecting drug use to HCV acquisition decreased from 29 months in 2008 to 13 months in 2009. After HIV interventions, HCV incidence declined by 64.8% in 2012, compared to 2009. The averted HCV incidence cases attributed to the HIV‐implemented interventions were 2200 (1950, 2480), during 2012‐2015. The cumulative number incident HCV cases in Athens during 2002‐2015 was about 9900 (7800, 12 100). Our results highlight that before the 2011 HIV outbreak in Athens, an HCV outbreak occurred in 2009. Prevention measures for HIV that took place in the Athens metropolitan area in 2012 reduced significantly the incidence of HCV.     

Prevalence of mixed genotype hepatitis C virus infections in the UK as determined by genotype‐specific PCR and deep sequencing

The incidence of mixed genotype hepatitis C virus (HCV) infections in the UK is largely unknown. As the efficacy of direct‐acting antivirals is variable across different genotypes, treatment regimens are tailored to the infecting genotype, which may pose issues for the treatment of underlying genotypes within undiagnosed mixed genotype HCV infections. There is therefore a need to accurately diagnose mixed genotype infections prior to treatment. PCR‐based diagnostic tools were developed to screen for the occurrence of mixed genotype infections caused by the most common UK genotypes, 1a and 3, in a cohort of 506 individuals diagnosed with either of these genotypes. The overall prevalence rate of mixed infection was 3.8%; however, this rate was unevenly distributed, with 6.7% of individuals diagnosed with genotype 3 harbouring genotype 1a strains and only 0.8% of samples from genotype 1a patients harbouring genotype 3 (P < .05). Mixed infection samples consisted of a major and a minor genotype, with the latter constituting less than 21% of the total viral load and, in 67% of cases, less than 1% of the viral load. Analysis of a subset of the cohort by Illumina PCR next‐generation sequencing resulted in a much greater incidence rate than obtained by PCR. This may have occurred due to the nonquantitative nature of the technique and despite the designation of false‐positive thresholds based on negative controls.     

Homocysteine levels and sustained virological response to pegylated‐interferon α2b plus ribavirin therapy for chronic hepatitis C: a prospective study

Background: Chronic hepatitis C affects about 3% of the world's population. Pegylated interferon (IFN) α plus ribavirin is the gold standard treatment. Methylenetetrahydrofolate reductase(MTHFR) is a key enzyme in the metabolism of homocysteine. MTHFR gene polymorphisms and high levels of homocysteine are associated with a high degree of steatosis and fibrosis, conditions associated with a low sustained virological response (SVR) rate. Aims: To evaluate whether MTHFR polymorphisms and homocysteine levels are predictors of the outcome of treatment in 102 prospectively enrolled patients with chronic hepatitis C naive to treatment. Methods: Patients were treated with pegylated interferon α‐2b plus ribavirin. All patients underwent blood tests, assessment of homocysteine, vitamin B₁₂, folate, hepatitis C virus (HCV)‐RNA levels, screening for MTHFR gene polymorphisms and liver ultrasound examination. Results: Homocysteine levels were deranged (>16 μmol/L) in 10.5% of MTHFR wild‐type patients vs 40.3% of non‐wild‐type patients (P=0.015). Homocysteine levels were 14.4 μmol/L in SVR patients and 15.5 μmol/L in non‐SVR patients (P=0.049). The SVR rate was 40.0% in MTHFR wild‐type patients, 52.0% in heterozygote mutants and 39.3% in homozygote mutants (P=0.467). At logistic regression analysis, genotypes 2 and 3 (odds ratio: 12.328, 95% confidence interval: 3.390–44.837, P=0.0001), homocysteine <16 μmol/L (odds ratio: 3.397, 95% confidence interval: 1.033–11.177, P=0.044) and aspartate aminotransferase (AST) levels <48 U/L (odds ratio: 3.262, 95% confidence interval: 1.125–9.458, P=0.029) were independent predictors of SVR. Conclusions: In patients with chronic hepatitis C, homocysteine levels are associated with the outcome of pegylated‐IFNα plus ribavirin treatment, while polymorphisms of MTHFR are not.     

Hepatitis C cure improved patient‐reported outcomes in patients with and without liver fibrosis in a prospective study at a large urban medical center

Patient‐reported outcomes (PROs) are important measures of quality of life. Direct‐acting antiviral (DAA) drugs for hepatitis C virus (HCV) improved PROs in clinical trials. We prospectively evaluated the impact of DAA‐based HCV cure on PROs and liver‐related outcomes in real‐world patients at a large urban medical center. The short form (SF)‐36 and three additional validated instruments were used. F3‐4 fibrosis was defined as > 9.6 kPa by transient elastography (TE); S2‐3 steatosis was defined as > 270 dB/m by TE‐controlled attenuation parameter (CAP). Data were analysed by paired and unpaired t tests. Patients (n = 16) who did not achieve a sustained virologic response at 12 weeks (SVR12) were excluded. The study achieved its primary endpoint and showed a significant 30% improvement in the SF‐36 vitality score, measured baseline to SVR12: 63 versus 82, P < .001 (n = 111). Scores in 24 of 25 PRO domains improved at SVR12 (P < .05). Nearly all gains exceeded 5%, indicating their clinical significance. Transaminase values and liver stiffness improved (decreased) significantly, baseline to SVR12 (P < .005), but steatosis was unchanged (P = .58). Patients with baseline F0‐2 fibrosis and those with F3‐F4 fibrosis both improved in 22 domains. Patients with baseline S0‐S1 steatosis improved in more domains (23) than patients with S2‐S3 steatosis (19). At baseline, patients with F3‐F4 fibrosis and patients with S2‐3 steatosis had worse scores in certain PRO domains than patients with F0‐2 fibrosis or S0‐S1 steatosis, but this difference resolved by SVR12. HCV cure led to meaningful gains in PROs, and these findings may encourage patients to seek treatment.     

Mortality in HIV‐infected injection drug users with active vs cleared hepatitis C virus‐infection: a population‐based cohort study

Summary. Acute hepatitis C virus (HCV) infection may lead to chronic HCV‐infection with detectable HCV RNA or to spontaneous clearance with no HCV RNA, but detectable HCV antibodies. It is unknown whether HCV RNA status is associated with mortality in HIV‐infected injection drug users (IDUs). We conducted a nationwide population‐based cohort study to examine the impact of HCV RNA status on overall and cause‐specific mortality in HIV‐infected IDUs. We computed cumulative mortality and used Cox Regression to estimate mortality rate ratios (MRR). We identified 392 HIV‐infected patients of whom 284 (72%) had chronic HCV‐infection (HCV RNA positive patients) and 108 (28%) had cleared the HCV‐infection (HCV RNA negative patients). During 1286 person‐years of observation (PYR), 157 persons died (MR = 122/1000 PYR, 95% CI: 104–143). The estimated 5‐year probabilities of survival were 0.58 (95% CI: 0.51–0.65) in the chronically HCV‐infected and 0.52 (95% CI: 0.40–0.63) in the cleared HCV group. Chronic HCV‐infection was not associated with overall mortality: MRR 0.85, 95% CI: 0.59–1.21. In HIV‐infected Danish IDUs, chronic HCV‐infection is not associated with increased mortality compared to patients who have cleared the infection.     

Sofosbuvir,velpatasvir and voxilaprevir combination for the treatment of hepatitis C

Introduction: The advent of direct-acting antiviral (DAA) treatments for chronic hepatitis C virus (HCV) infection has dramatically increased rates of cure. However, there remain difficult-to-treat populations, including patients with genotype 3 infection and cirrhosis, and limited salvage treatment options for those that have failed first-line DAA therapy.

Areas covered: This is a review of the preclinical and clinical development of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX), an interferon-free, oral, once daily, pangenotypic treatment for chronic HCV infection. All relevant literature from 2015 through June of 2017 is included.

Expert commentary: Voxilaprevir, a second-generation HCV protease inhibitor, in combination with the already approved combination of sofosbuvir and velpatasvir, was evaluated in the POLARIS trials and found to be a safe and effective regimen. Patients with prior DAA treatment failure, genotype 3, cirrhosis and/or unfavorable resistance profiles all achieved cure rates of 96% or greater. The most distinctive role for this potent regimen may prove to be as a salvage regimen for patients who have failed previous DAA therapy.     

Insulin resistance and hepatitis C virus: a case–control study of non‐obese,non‐alcoholic and non‐steatotic hepatitis virus carriers with persistently normal serum aminotransferase

Background/Aims: Recent studies using transgenic mouse models have demonstrated that the presence of hepatitis C virus (HCV) singularly induces insulin resistance (IR). When evaluated in humans, the exclusion of other factors influencing IR, such as obesity, alcohol intake, hepatic inflammation and steatosis is needed, but only few studies have been performed to these ends. Therefore, we aimed at exploring the singular effects of HCV on glucose metabolism through analysis of HCV carriers with persistently normal serum aminotransferase. Methods: Non‐obese, non‐diabetic and non‐alcoholic HCV carriers (n=30) were enrolled with 30 hepatitis B virus carriers matched by age, gender, body mass index and waist‐to‐hip ratio. All patients maintained normal serum aminotransferase (<30 U/L), hyaluronic acid (<50 ng/ml) and platelet count (>150 × 10³/μl) for more than 5 years without additional treatments, and had no signs of steatosis. We then compared fasting plasma glucose, serum insulin and adiponectin, and homoeostasis model assessment of IR (HOMA‐IR) and HOMA‐β indices between the groups. Results: There were no significant differences in IR/secretion‐associated markers or serum adiponectin. Multivariate analysis demonstrated that the presence of HCV was not an independent predictor of IR. HOMA‐IR was strongly correlated with waist circumferences and serum γ‐glutamyltransferase in HCV carriers, but not with serum aminotransferase, high‐sensitivity C‐reactive protein, hyaluronic acid or HCV core antigen. Conclusions: These results suggest that the presence of HCV alone does not affect IR. Coexistence of hepatitis, steatosis and/or fibrosis may be important to the pathogenesis of IR induced by chronic HCV infection.