Hepatitis C Virus Treatment Response Research Articles

Sex-Specific Risk Factors and Health Disparity Among Hepatitis C Positive Patients Receiving Pharmacotherapy for Opioid Use Disorder: Findings From a Propensity Matched Analysis.

The incidence of opioid-related fatality has reached unparalleled levels across North America. Patients with comorbid hepatitis C virus (HCV) remain the most vulnerable and difficult to treat. Considering the unique challenges associated with this population, we aimed to re-examine the impact of HCV on response to medication assistant treatment for opioid use disorder and establish sex-specific risk factors affecting care. This study employs a multi-center prospective cohort design, with 1-year follow-up. Patients aged ≥18, receiving methadone for opioid use disorder were recruited from a network of outpatient opioid addiction treatment centers across Southern Ontario, Canada. Patients with ≥50% positive opioid urine screens over 1 year of follow-up were classified as poor responders. The prognostic impact of HCV on response was established using a propensity score matched analysis. Sex-specific regression models were constructed to evaluate risk factors for treatment response. Among participants eligible for inclusion (n = 1234), HCV was prevalent in 25% (n = 307). HCV patients exhibited significantly higher rates of high-risk opioid consumption patterns 35.29% (standard deviation 0.478). Sex-specific examination revealed females with HCV incur a 2 times increased risk for high-risk opioid consumption behaviors (female odds ratio: 1.95, 95% confidence interval 1.23, 3.10; P = 0.01). Findings from this study establish the link between HCV and poor treatment response, with differentially higher risk among female patients. In light of the high potential for overdose among this population, concerted efforts are required for distinguishing the source for sex-based disparities, in addition to establishing trauma and gender informed treatment protocols.

RELATION BETWEEN DEGREE OF LIVER STIFFNESS AND DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS C VIRUS PATIENTS

Background: Hepatocellular carcinoma is the fifth most common tumor worldwide and the second most common cause of cancer-related death. Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and hence the development of hepatocellular carcinoma (HCC). Egypt has the highest HCV prevalence worldwide. The introduction of new direct acting antiviral agents in the past 5 years has dramatically improved the outcomes of HCV treatment response with > 90% of patients achieving a sustained virological response (SVR) after 12 weeks of end treatment. However, the effect of direct-acting antivirals (DAAs) induced HCV clearance on HCC recurrence after HCC treatment has emerged as a topic of controversy. Objective: To evaluate the relation between liver stiffness as measured by fibro scan and development of HCC in chronic HCV patients. Patients and methods: A prospective study was done at Kafar Alshaykh National Hepatology Institute conducted in collaboration with the Gastroenterology Unit Department of Internal Medicine, Al-Hussein University Hospital, and Cairo Egypt. The study included 150 patients with proven liver cirrhosis secondary to chronic hepatitis C (CHC) they were further sub classified into three equal groups: Group I with chronic hepatitis C, liver cirrhosis and HCC, Group II with CHC and HCC that appeared after treatment with DAA, and Group III (control group) with cirrhotic chronic hepatitis C (CHC) without HCC. Results: In this study, there was a statistically significant difference between group I (30.38 ± 11.32 kPa) and controlled group (25.0 ± 13.34 kPa), regarding fibro scan results (P = 0.004). On other hand there was no significant difference between group II (23.24 ± 7.69 kPa) and controlled group regarding LS. Conclusion: Fibro scan can be a good technique for detection of HCC high-risk cirrhotic patients not treated by DAA and can be of great added value if incorporated in the current HCC screening protocols in hepatitis C cirrhotic patients. On the other hand, LS tended to decrease dramatically after the treatment with DAA. Using TE in these patients would therefore be misleading liver stiffness measurement (LSM), the risk of HCC remains because advanced fibrosis or cirrhosis, which is the most important risk factor for liver cancer, not completely resolved by antiviral treatment. As a matter of fact, the degree of liver fibrosis seems to be a strong predictor of the risk of HCC development.

928. Barriers to Hepatitis C Elimination in an Urban Clinic Offering Integrated HIV/HCV Treatment

BackgroundTreatment of Hepatitis C virus (HCV) infection for persons with Human Immunodeficiency Virus (HIV) is dependent on consistent outpatient follow-up. We sought to identify factors that are associated with lower HCV treatment rates in HIV/HCV co-infected patients followed at Rutgers Infectious Diseases Practice (IDP), an integrated urban clinic.MethodsRetrospective chart reviews were conducted for HIV/HCV co-infected patients treated at IDP in Newark, New Jersey between January 2017 and July 2018. We assessed factors associated with lack of HCV treatment in this practice. Data collected included demographics, HIV disease markers, liver function tests, HCV treatment history and response. Factors with p< 0.05, age and race were included in the multivariate analysis.ResultsWe included 317 HIV/HCV co-infected patients with at least one visit between January 2017 and July 2018. Fifty eight percent were male, 79% black, 10% hispanic, 6% white, and 5% other; 21% reported heterosexual and 79% drug use (injection and non-injection) as their HIV risk factor The median CD4 was 522 cells/cm3, and 74% of patients had HIV viral load (VL) < 40 copies/ml. HCV treatment was started at IDP in 142 (45%) and of those 87% were cured. Data are awaited on 6%. Univariate analyses showed those not treated for HCV were more likely to be born female (57% vs 42%), have a CD4 count < 200 cells/cm3 (9% vs 27%), HIV VL >40 copies/ml (43% vs 17%), currently (58% vs 30%) or previously (89% vs 74%) used drugs, and have a higher APRI score (0.43 vs 1.6). Multivariate logistic regression showed that patients with untreated HCV were more likely to be female (OR 2.93, p< 0.001), report current drug/alcohol use (OR 2.43, p=0.004), and have HIV VL ≥40 copies/ml (OR 2.11, p< 0.001).Table 1: Demographics/Risk Factors of Study Group Table 2: Laboratory Studies Table 3: Logistic Regression of Significant HCV Treatment Factors ConclusionOur results show that despite the availability of integrated treatment programs, concerted efforts need to be made for patients at high risk for not receiving HCV treatment, and who therefore remain at high risk for complications from HCV. Provider perceptions may play a role in withholding treatment for those with high HIV VL and current drug or alcohol use; whereas the rationale for why women were less likely to be treated is less clear and may be related to trauma and other factors not captured by this project that may negatively impact their access to care.Disclosures All Authors: No reported disclosures

Hepatitis C Direct-Acting Antiviral Treatment Selection, Treatment Failure, and Use of Drug-Drug Interactions in a State Medicaid Program.

Newer hepatitis C virus (HCV) treatments often provide high success rates with fewer adverse events, although the extent of all potential drug interactions is not fully known. To assess outcomes of receiving HCV treatment and subsequent sustained virologic response (SVR) based on patient and clinical characteristics, including direct-acting antiviral (DAA) drug-drug interactions (DDIs), in Medicaid members with chronic HCV. Comprehensive medical and pharmacy claims and prior authorization data were collected for HCV patients requesting treatment between January 2014 and June 2015. Outcomes of receiving treatment with DAAs and treatment failure based on SVR were analyzed according to demographics, prior/current HCV treatment, severity of DDIs, advancing liver disease, and comorbidities. Multivariable generalized linear models were employed, including a Bayesian sensitivity analysis. Among 3,412 Medicaid members with HCV, 13.6% received DAAs (n = 464), averaging 53.6 ± 10.0 years, with 52.8% female. Multivariable analyses indicated that higher odds of DAA treatment initiation were associated with older age, prior HCV treatment, and advancing liver disease. Some 4.8% of treatment failures occurred among 168 patients with reported SVRs, wherein a 3.218 times higher adjusted odds of treatment failure was associated with concomitant use of medications with DDIs classified as significant or potentially clinically significant by the University of Liverpool HEP Drug Interactions resource (P = 0.001). In a cohort of state Medicaid members with chronic HCV, a markedly higher adjusted odds of treatment failure was independently associated with DDIs classified as significant or potentially clinically significant, warranting continued inquiry and potential alternate treatments concerning conditions that require their use. This research was funded by an unrestricted research grant by Gilead Sciences. During the course of this study, all authors were either employed by the Oklahoma HealthCare Authority or engaged in contractual work for this employer. Keast, Holderread, and Skrepnek report unrelated research grants from AbbVie, Otsuka, and Amgen. Keast and Skrepnek acknowledge funding from Purdue Pharma for an unrelated research fellowship grant. Posters based on this work were presented at HepDart 2015 on December 6-10, 2015, in Grand Wailea, HI, and at Academy of Managed Care Nexus 2015 on October 26-29, 2015, in Orlando, FL.

Effect of HCV treatment response on insulin resistance: A systematic review and meta-analysis.

Sustained virological response (SVR) in hepatitis C virus (HCV) patients treated with pegylated interferon α-2a and ribavirin is associated with reduced insulin resistance (IR), measured as a reduction of homeostasis model assessment (HOMA) scores after 24 weeks of therapy, and reduced fasting serum insulin and serum glucose levels. The present meta-analysis aimed to evaluate the effect of HCV treatment response on IR in HCV patients who achieved SVR and those who did not (non-SVR) after receiving interferon (IFN)-based therapy. The PubMed, Cochrane and Embase databases were searched using combinations of the following search terms: ‘HCV’, ‘hepatitis C’, ‘interferon’, ‘antiviral’, ‘treatment response’ and ‘insulin resistance’. The incidence of IR, HOMA-IR and HOMA-β, as well as fasting glucose and fasting insulin levels, were summarized in terms of basal values and values after the end of treatment for each study. A total of 8 studies were included in the final analysis. There was no significant difference in the reduction in IR between the SVR and non-SVR groups (odds ratio, 0.995; 95% CI=0.613–1.616; P=0.984). However, the SVR group had a significantly higher mean reduction in HOMA-IR (difference in means=−0.485; 95%CI=−0.713 to −0.256; P<0.001) and HOMA-β (difference in means=−15.448; 95%CI=−23.326 to −7.570; P<0.001) compared to the non-SVR group. In conclusion, HCV patients who achieved SVR after IFN-based therapy exhibited improvement in HOMA-IR and HOMA-β. The present results suggest that clinical management of IR and serum glucose levels may be an important way to impact the therapeutic response in HCV patients.

IFNL4 haplotype, linkage disequilibrium and their influence on virological response to hepatitis C virus infection in Indian population.

Type III interferon (IFNs) encoded by IFN lambda (IFNL) genes induce antiviral activity. The IFNL clusters include IFNL1/IL29, IFNL2/IL28A, IFNL3/IL28B and IFNL4 genes. The single nucleotide polymorphisms (SNPs, rs12979860 and rs8099917) associated with virological responses against hepatitis C virus (HCV) infections are recently mapped to IFNL4 gene. The IFNL gene polymorphisms also plays role in immune clearance, inflammation and risk of developing hepatocellular carcinoma. There is significant genetic heterogeneity of IFNL4 polymorphisms among ethnic populations that need to be regionally studied for viral infection, treatment response and relapse. The IFNL4 risk allele, genotype and haplotype frequencies across north Indian cohort were determined among chronic hepatitis C (CHC) cases (n = 141) and healthy controls (n = 111) by allele specific real-time PCR. Odds ratio was calculated for HCV exposure and treatment response using dominant and minor allele/genotype as reference. Non-random associations of these two SNP loci were evaluated by linkage disequilibrium plot. The minor allele (T) frequency of rs12979860C/T is 0.241 and 0.229; and minor allele (G) frequency for SNP rs8099917T/G is 0.174 and 0.171 among CHC cases and healthy control respectively. Coefficient of linkage disequilibrium (D') of these two SNPs is very high (D' = 0.98, r2 > 0.6) in CHC group than in healthy control (D' = 0.76, r2 = 0.39) which indicate that both SNPs are strongly linked in CHC population than healthy control. Favorable association of IFNL4 haplotype (C-T), genotype (CC for rs12979860 and TT for rs8099917) with anti HCV therapy were found significant (p = 0.009, 0.021 and 0.001) for SVR. Favorable genotypes are also found to be predominant across the Indian study population.

HCV Screening and Treatment Uptake Among Patients in HIV Care During 2014-2015.

Despite the high prevalence of hepatitis C virus (HCV) among persons living with HIV (PWH), the prevalence of HCV screening, treatment, and sustained virologic response (SVR) is unknown. This study aims to characterize the continuum of HCV screening and treatment among PWH in HIV care. Adult patients enrolled at 12 sites of the HIV Research Network located in 3 regions of the United States were included. We examined the prevalence of HCV screening, HCV coinfection, direct-acting antiretroviral (DAA) treatment, and SVR-12 between 2014 and 2015. Multivariate logistic regression was performed to identify characteristics associated with outcomes, adjusted for site. Among 29,071 PWH (age 18-87, 74.8% male, 44.4% black), 77.9% were screened for HCV antibodies; 94.6% of those screened had a confirmatory HCV RNA viral load test. Among those tested, 61.1% were determined to have chronic HCV. We estimate that only 23.4% of those eligible for DAA were prescribed DAA, and only 17.8% of those eligible evidenced initiating DAA treatment. Those who initiated treatment achieved SVR-12 at a rate of 95.2%. Blacks and people who inject drugs (PWID) were more likely to be screened for HCV than whites or those with heterosexual risk. Persons older than 40 years, whites, Hispanics, and PWID [adjusted odds ratio (AOR) 8.70 (7.74 to 9.78)] were more likely to be coinfected than their counterparts. When examining treatment with DAA, persons older than 50 years, on antiretroviral therapy [AOR 2.27 (1.11 to 4.64)], with HIV-1 RNA <400 [AOR 2.67 (1.71 to 4.18)], and those with higher Fib-4 scores were more likely to be treated with DAA. Although rates of screening for HCV among PWH are high, screening remains far from comprehensive. Rates of SVR were high, consistent with previously published literature. Additional programs to improve screening and make treatment more widely available will help reduce the impact of HCV morbidity among PWH.

Risk of Hepatitis B Virus Reactivation Among Patients Treated With Ledipasvir-Sofosbuvir for Hepatitis C Virus Infection.

Direct acting antiviral (DAA) agents are the standard of care for treatment of hepatitis C virus (HCV)-infected individuals. Hepatitis B virus (HBV) reactivation during HCV treatment has been reported, the incidence and clinical outcome remains unclear. The aim of our study is to examine the risk of HBV reactivation in actively infected or previously exposed patients during or after HCV treatment with DAAs. Adults with chronic HCV infection previously exposed or actively infected with HBV and treated with DAAs between December 2015 to 2016 were included. Electronic medical records were reviewed for HCV treatment dates, HCV treatment response, DAA used, HBV status, and concurrent HBV treatment. Primary end-point was to determine the risk of HBV reactivation during or up to 3 months after DAA treatment. We identified 283 patients, and 100% of patients completed HCV treatment with ledipasvir-sofosbuvir. 93% had HCV genotype-1 of whom 91% achieved sustained viral response at 12 weeks posttreatment (SVR-12). In total, 7% had HCV genotype-4 who achieved SVR-12 of 84%. Mean (±SD) age was 59.7 (±7) years, and 58% were male. A total of 45% of patients had hepatitis B core antibody (HBcAb) positive and hepatitis B surface antigen (HBsAg) negative. In total, 55% of patients had a positive HBsAg before HCV DAA treatment. No HBV reactivation was encountered in the (HBcAb) positive HBsAg-negative cohort nor in the (HBsAg) positive group with 95% confidence interval (0-0.023) and (0-0.019), respectively. In our study of patients with HCV and isolated hepatitis B core or HBsAg positivity, no HCV patients treated with DAA experienced HBV reactivation.

Association of CXCR2 genotype variations with HCV clearance in a Chinese population.

Chemokines are known to play a vital role in guiding and regulating the immune response to viral infections. The chemokine CXC subfamily is a major subfamily in the chemokine family. Outcomes of hepatitis C virus (HCV) infection, as well as the response to treatment, depend on virus and host factors. Here we recruited chronic hepatitis C (CHC) patients to perform an association study between three single nucleotide polymorphisms (SNPs) (CXCR2 rs1126579, CXCL10 rs8878 and CXCL10 rs3921) and HCV infection outcomes and treatment responses among a Chinese population, using primarily a TaqMan assay. Multivariate logistic regression analysis was performed to identify the influencing factors on HCV infection outcome and treatment response. The results showed that subjects with the CXCR2 rs1126579 TT genotype had a significantly increased possibility of HCV spontaneous clearance (Dominant model: adjusted OR = 1.32, 95% CI = 1.06-1.64; P = 0.013). Additionally, CHC patients carrying the CXCR2 rs1126579 TT genotype were also more likely to achieve a sustained virological response (SVR) (Dominant model: adjusted OR = 0.49, 95% CI = 0.29-0.84; P = 0.010). We also established a predictive model for HCV treatment response including the CXCR2 rs1126579 SNP status, albumin (ALB) levels and baseline HCV RNA levels, which produced an area under the curve (AUC) of about 0.660. These findings highlight that variant CXCR2 rs1126579 genotypes are associated with HCV clearance within the Chinese population.

Genetic variants in chemokine CC subfamily genes influence hepatitis C virus viral clearance.

Chemokine genes may influence both hepatitis C virus (HCV) spontaneous clearance in acute infection and treatment response in chronic infection. We conducted this study to evaluate whether the genetic variants in several CC family genes influence HCV spontaneous clearance and treatment response. The current research genotyped eight SNPs, including CCR1 rs3733096, rs13096371, CCR5 rs746492, rs1800874, CCL3 rs1130371, CCL5 rs3817656, CCL8 rs1133763, CCL14 rs854625, to explore their associations with HCV spontaneous clearance and response to treatment in two populations. We identified that the CCR1 rs3733096 (dominant model: adjusted OR = 2.29, 95% CI = 1.49-3.53, additive model: adjusted OR = 2.21, 95% CI = 1.50-3.25) and CCL5 rs3817656 (dominant model: OR = 1.37, 95% CI = 1.10-1.70, additive model: OR = 1.33, 95% CI = 1.12-1.58) were associated with HCV spontaneous clearance in Chinese Han population, while we found no association with treatment response. Moreover, the expression quantitative trait loci (eQTL) analysis showed that the risk alleles of rs3817656 were significantly associated with downregulated expression of CCL5 in whole blood (P < 0.001). The polymorphism of CCR1 rs3733096 and CCL5 rs3817656 are associated with spontaneous clearance of HCV in Chinese Han population.

Association between human leucocyte antigen-DO polymorphisms and interferon/ribavirin treatment response in hepatitis C virus type 1 infection in Chinese population: a prospective study

ObjectiveThe human leucocyte antigen-DO (HLA-DO) gene located in the HLA non-classical class-II region may play a role in treatment response to hepatitis C virus (HCV). This study was conducted to...

Efficacy of response-guided directly observed pegylated interferon and self-administered ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: The ACTIVATE study

BackgroundThere are few data on treatment for hepatitis C virus (HCV) infection among people with ongoing injecting drug use. This study evaluated the efficacy of response-guided therapy for chronic HCV genotypes 2/3 infection among people with ongoing injecting drug use or receiving opioid substitution therapy (OST). A secondary aim was to identify predictors of HCV treatment response. MethodsACTIVATE was a multicentre clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Participants were recruited from drug treatment clinics, private practices, hospital clinics and community clinics in Australia, Canada, and five countries in Europe. The primary study outcome was sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). ResultsAmong 93 people with ongoing injecting drug use or receiving OST treated for HCV genotype 2/3, 59% had recently (past month) injected drugs, 77% were receiving OST and 56% injected drugs during therapy. Overall SVR was 66% (61/93). SVR was 84% in those with undetectable HCV RNA at week 4 (12 weeks) compared to 38% in those without (24 weeks). In adjusted analysis, cirrhosis vs. no/mild fibrosis [adjusted OR (aOR) 0.33, 95% CI 0.13, 0.86] predicted reduced SVR, while response at week 4 was associated with increased SVR [aOR 8.11, 95% CI 2.73, 24.10]. Recent injecting drug use at baseline or during therapy was not associated with SVR. ConclusionThis study demonstrates that people with recent injecting drug use or OST with chronic HCV can achieve responses to interferon-based therapy similar to other populations, despite injecting drugs prior to or during therapy. Cirrhosis was predictive of reduced response to HCV therapy, while response at week 4 (despite shortened therapy) was predictive of improved response.

The Impact of Interleukin-28B rs12979860 Polymorphism on Peginterferon-alpha and Ribavirin Combination Therapy in Iranian Patients with Hepatitis C Virus Genotype 1 Infection

Background: Hepatitis C virus (HCV) infection is a global health problem. Most cases of HCV infection do not resolve spontaneously. Combination therapy with pegylated interferon-α (PegIFN-alpha) and ribavirin (RBV) is the standard treatment for patients with HCV infection. The success of treatment is affected by several host, viral, and treatment factors. Available works have demonstrated significant role of interleukin 28B (IL28B) polymorphisms in predicting HCV infection treatment outcomes. This suggests the possibility of tailored therapy in HCV infected patients. HCV is one of the most common causes of liver disease worldwide. If untreated, this infection can develop chronic hepatitis in 50%-85% of patients. The aim of current study is to determine the association of interleukin-28B (IL-28B) rs-12979860 polymorphism in response to peginterferon-alpha (PegIFN-alpha) and ribavirin combination therapy in Iranian patients with chronic hepatitis C genotype 1 infection. Methods: This cross-sectional study was carried out on 70 Iranian patients with chronic hepatitis C infection (genotype 1) receiving PegIFN-alpha and ribavirin. DNA was extracted from blood samples. Specific primers were used to amplify targeted polymorphisms. Results: In this study, 71.4% of patients reached sustained virological response (SVR). The prevalence of CC, CT and TT genotypes were 38.6%, 42.8% and 18.6% respectively. The rate of SVR was 96.3 for CC genotype, whereas this rate was 66.7 for CT and 30.8 for TT genotypes. We found an association between end of treatment response (ETR) and IL-28B genotypes as 100% of patients bearing CC genotype reached ETR, but ETR rate was 45.85% in CT group and 10.2% in TT group. Six months follow-up showed that there was a significant difference between response to treatment in patients IL-28B-CC and TT (P &lt; 0.001). Data regression analysis showed that CC genotype was an independent predicting factor, significantly associated with higher SVR (P = 0.005 (OR=36.1; 95% CI = 3 - 434.2)). In contrast, absence of C allele (TT genotype) was significantly correlated with the failure of response (P = 0.005 (OR = 36.1; 95% CI = 3 - 434.2)). Conclusions: The results showed that IL-28B rs12979860 was an important predictor of HCV treatment response.

Is response to anti-hepatitis C virus treatment predictive of mortality in hepatitis C virus/HIV-positive patients?

Long-term clinical outcomes after hepatitis C virus (HCV) treatment of HIV/HCV patients are not well described. We aimed to compare the risk of all-cause and liver-related death (LRD) according to HCV treatment response in HIV/HCV patients in the multicohort study Collaboration of Observational HIV Epidemiological Research in Europe. All patients who had started pegylated interferon + ribavirin (baseline) and followed for at least 72 weeks after baseline were included. Patients were categorized into three response groups depending on treatment duration and HCV-RNA measured in the window 24-72 weeks after baseline. Patients who received at least 24 weeks of therapy were defined as responders if their last HCV-RNA measured between 24 and 72 weeks after baseline was negative, and having 'unknown response' if HCV-RNA was unknown. Nonresponders were treated for less than 24 weeks or were HCV-RNA+ between 24 and 72 weeks after baseline. Mortality rates were compared using survival analysis, and Cox regression was used to compare hazard ratios of death between response groups. A total of 3755 patients were included: 1031 (27.5%) responders, 1639 (43.6%) nonresponders and 1085 (28.9%) with unknown response. Rates [per 1000 person-years of follow-up, 95% confidence interval (CI)] of all-cause death were 17.59 (14.88-20.78), 10.43 (7.62-14.28) and 11.00 (8.54-14.23) for nonresponders, responders and unknown responders, respectively. After adjustment, the relative hazard (nonresponders vs. responders) for all-cause death, LRD and nonliver-related death was 1.53 (95% CI 1.06-2.22), 3.39 (95% CI 1.32-8.75) and 1.22 (95% CI 0.80-1.84), respectively. HIV/HCV patients with a favourable virological response to pegylated interferon + ribavirin had reduced risk of all-cause and LRD, whereas there was no difference in risk of nonliver-related death when comparing responders and nonresponders.

Epigenetic analysis of the IFNλ3 gene identifies a novel marker for response to therapy in HCV-infected subjects.

Chronic hepatitis C virus (HCV) infection is characterized by high interindividual variability in response to pegylated interferon and ribavirin. A genetic polymorphism on chromosome 19 (rs12979860) upstream of interferon-λ3 (IFNλ3) is associated with a twofold change in sustained virologic response rate after 48weeks of treatment with pegylated interferon/ribavirin in HCV genotype 1 (GT1) treatment-naïve patients. We conducted epigenetic analysis on the IFNλ3 promoter to investigate whether DNA methylation is associated with response to HCV therapy. DNA samples from HCV GT1-infected subjects receiving an interferon-free paritaprevir-containing combination regimen (N=540) and from HCV-uninfected, healthy controls (N=124) were analysed for IFNλ3 methylation levels. Methylation was strongly associated with rs12979860 allele status whether adjusting for HCV status (r=65.0%, 95% CI: [60.2%, 69.5%]), or not (r=64.4%), both with P<2.2×10-16 . In HCV GT1-infected subjects, C/C genotypes had significantly lower methylation levels relative to C/T or T/T genotypes (P<1×10-14 ), with each T allele resulting in a nine-unit increase in mean methylation level. Methylation levels did not correlate with response in subjects treated for 12 or 24 weeks. However, non-C/C subjects with higher methylation levels were more likely to relapse when treatment duration was 8weeks. This analysis suggests that methylation status of the IFNλ3 promoter region may be a useful parameter that identifies patients more likely to relapse following HCV therapy; however, continuing therapy for a sufficient duration can overcome this difference. These findings may provide mechanistic insight into the role of IFNλ3 genetic variants in HCV treatment response.

Pretreatment Predictors of Response to PegIFN-RBV Therapy in Egyptian Patients with HCV Genotype 4.

BackgroundEgypt has the highest prevalence of a difficult to treat chronic hepatitis C virus (HCV), genotype 4. Pretreatment factors could guide individualization of therapy which aids in treatment optimization and interleukin IL28B gene polymorphism has been shown to closely relate to HCV treatment response. Polymorphisms in genes encoding inhibitors of T-cell response, which have role in disease progression as Programmed Cell Death 1 (PD-1), and Cytotoxic T-Lymphocytes Antigen-4 (CTLA-4), could be candidate markers predicting treatment response.MethodsThis cohort study consisted of 200 chronic HCV genotype 4 infected patients treated with PegIFN α-2a and RBV in 2 hepatology centers. Genotyping of the polymorphisms in the IL28B gene region (rs12979860), PD1.3 (rs11568821) and CTLA-4 (rs231775) was performed on DNA collected from each patient using TaqMan® genotyping assay. Groups were classified according to response into sustained virological responders (SVR), or non-responders (NR). A multivariate logistic regression analysis was used to identify potential markers, host pretreatment clinical and viral predictive factors including viral load, insulin resistance, and alpha fetoprotein (AFP) related to treatment response.ResultsOur results showed that in a multivariate analyses IL28B C/C genotype was the most significant predictor for SVR (OR = 10.86; p<0.0001) followed by AFP (OR = 0.915; p = 0.001) then CTLA-4/G genotypes (OR = 1.948; p = 0.022). However, PD-1.3/A genotypes and platelets count were significantly related to response in univariate analysis only (OR = 1.973; p = 0.023; OR = 1.007; p = 0.009 respectively).ConclusionIL28B SNP, AFP level, and CTLA-4 SNP could be used in conjunction to predict treatment response in HCV genotype 4 infected Egyptian patients.

Quantification of Hepatitis C Virus Cell-to-Cell Spread Using a Stochastic Modeling Approach.

It has been proposed that viral cell-to-cell transmission plays a role in establishing and maintaining chronic infections. Thus, understanding the mechanisms and kinetics of cell-to-cell spread is fundamental to elucidating the dynamics of infection and may provide insight into factors that determine chronicity. Because hepatitis C virus (HCV) spreads from cell to cell and has a chronicity rate of up to 80% in exposed individuals, we examined the dynamics of HCV cell-to-cell spread in vitro and quantified the effect of inhibiting individual host factors. Using a multidisciplinary approach, we performed HCV spread assays and assessed the appropriateness of different stochastic models for describing HCV focus expansion. To evaluate the effect of blocking specific host cell factors on HCV cell-to-cell transmission, assays were performed in the presence of blocking antibodies and/or small-molecule inhibitors targeting different cellular HCV entry factors. In all experiments, HCV-positive cells were identified by immunohistochemical staining and the number of HCV-positive cells per focus was assessed to determine focus size. We found that HCV focus expansion can best be explained by mathematical models assuming focus size-dependent growth. Consistent with previous reports suggesting that some factors impact HCV cell-to-cell spread to different extents, modeling results estimate a hierarchy of efficacies for blocking HCV cell-to-cell spread when targeting different host factors (e.g., CLDN1 > NPC1L1 > TfR1). This approach can be adapted to describe focus expansion dynamics under a variety of experimental conditions as a means to quantify cell-to-cell transmission and assess the impact of cellular factors, viral factors, and antivirals. The ability of viruses to efficiently spread by direct cell-to-cell transmission is thought to play an important role in the establishment and maintenance of viral persistence. As such, elucidating the dynamics of cell-to-cell spread and quantifying the effect of blocking the factors involved has important implications for the design of potent antiviral strategies and controlling viral escape. Mathematical modeling has been widely used to understand HCV infection dynamics and treatment response; however, these models typically assume only cell-free virus infection mechanisms. Here, we used stochastic models describing focus expansion as a means to understand and quantify the dynamics of HCV cell-to-cell spread in vitro and determined the degree to which cell-to-cell spread is reduced when individual HCV entry factors are blocked. The results demonstrate the ability of this approach to recapitulate and quantify cell-to-cell transmission, as well as the impact of specific factors and potential antivirals.

Hepatitis C virus: Is it time to say goodbye yet? Perspectives and challenges for the next decade.

The majority of individuals exposed to hepatitis C virus (HCV) establish a persistent infection, which is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. Major progress has been made during the past twenty-five years in understanding the HCV life cycle and immune responses against HCV infection. Increasing evidence indicates that host genetic factors can significantly influence the outcome of HCV infection and the response to interferon alpha-based antiviral therapy. The arrival of highly effective and convenient treatment regimens for patients chronically infected with HCV has improved prospects for the eradication of HCV worldwide. Clinical trials are evaluating the best anti-viral drug combination, treatment doses and duration. The new treatments are better-tolerated and have shown success rates of more than 95%. However, the recent breakthrough in HCV treatment raises new questions and challenges, including the identification of HCV-infected patients and to link them to appropriate health care, the high pricing of HCV drugs, the emergence of drug resistance or naturally occurring polymorphism in HCV sequences which can compromise HCV treatment response. Finally, we still do not have a vaccine against HCV. In this concise review, we will highlight the progress made in understanding HCV infection and therapy. We will focus on the most significant unsolved problems and the key future challenges in the management of HCV infection.

Response-Guided Therapy for Hepatitis C Virus Recurrence Based on Early Protocol Biopsy after Liver Transplantation.

Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is universal and progressive. Here, we report recent results of response-guided therapy for HCV recurrence based on early protocol biopsy after LT. We reviewed patients who underwent LT for HCV related liver disease between 2010 and 2012. Protocol biopsies were performed at 3, 6, and 12 months after LT in HCV recurrence (positive HCV-RNA). For any degree of fibrosis, ≥ moderate inflammation on histology or HCV hepatitis accompanying with abnormal liver function, we treated with pegylated interferon and ribavirin. We adjusted treatment period according to individual response to treatment. Among 41 HCV related recipients, 25 (61.0%) who underwent protocol biopsies more than once were enrolled in this study. The mean follow-up time was 43.1 (range, 23-55) months after LT. Genotype 1 and 2 showed in 56.0% and 36.0% patients, respectively. Of the 25 patients, 20 (80.0%) started HCV treatment after LT. Rapid or early virological response was observed in 20 (100%) patients. Fifteen (75.0%) patients finished the treatment with end-of-treatment response. Sustained virological response (SVR) was in 11 (55.0%) patients, including 5 (41.7%) of 12 genotype 1 and 6 (75.0%) of 8 non-genotype 1 (P = 0.197). Only rapid or complete early virological response was a significant predictor for HCV treatment response after LT (100% in SVR group vs. 55.6% in non-SVR group, P = 0.026). Overall 3-yr survival rate was 100%. In conclusion, response-guided therapy for HCV recurrence based on early protocol biopsy after LT shows encouraging results.

Distribution of genetic polymorphisms associated with hepatitis C virus (HCV) antiviral response in a multiethnic and admixed population

The prevalence of genetic polymorphisms identified as predictors of therapeutic-induced hepatitis C virus (HCV) clearance differs among ethnic groups. However, there is a paucity of information about their prevalence in South American populations, whose genetic background is highly admixed. Hence, single-nucleotide polymorphisms rs12979860, rs1127354 and rs7270101 were characterized in 1350 healthy individuals, and ethnicity was assessed in 259 randomly selected samples. The frequency of rs12979860CC, associated to HCV treatment response, and rs1127354nonCC, related to protection against hemolytic anemia, were significantly higher among individuals with maternal and paternal Non-native American haplogroups (64.5% and 24.2%), intermediate among admixed samples (44.1% and 20.4%) and the lowest for individuals with Native American ancestry (30.4% and 6.5%). This is the first systematic study focused on analyzing HCV predictors of antiviral response and ethnicity in South American populations. The characterization of these variants is critical to evaluate the risk-benefit of antiviral treatment according to the patient ancestry in admixed populations.