Pretreatment Hepatitis C Virus RNA Research Articles

1067. Interferon-free Hepatitis C Treatment Increases Surrogates of Cardiovascular Disease Risk in Black Veterans

BackgroundSustained virologic response (SVR) after hepatitis C virus (HCV) treatment with either Interferon (IFN)-based or IFN-free regimens with direct-acting antivirals (DAAs) has been shown to reduce cardiovascular disease (CVD) events in majority white populations stratified by ASCVD score. However, the effect of IFN-free therapy on lipid profiles after SVR, as an indirect measure of CVD risk, is unknown in Black patients.MethodsWe evaluated HCV-infected Veterans from the Baltimore VA who were treated with DAAs between 2015-2019. We performed a retrospective analysis comparing lipid profile changes following SVR among those with early stage (F0-F2) fibrosis and advanced liver disease (ALD, F3-F4 fibrosis) using two-tailed paired t-tests. Independent t-tests were used to assess differences in lipid profiles based on fibrosis stage in patients with HIV and Type II Diabetes Mellitus (DM2).ResultsOf those treated for HCV (n=1,528), 96% (n=1,474) achieved SVR. Demographics are shown in Table 1. Most patients were Black males (75%) and a minority (2.7%) received statin therapy during treatment (Table 1). Of 1,094 patients for whom data was available, an increase in total cholesterol (TC) and LDL (p< 0.01 for both) was seen an average of 17 months after SVR, regardless of fibrosis stage (Figure 1). A significant decrease in triglyceride levels (p=0.04) was also seen in the ALD group after SVR (Figure 1). Mean pre-treatment HCV RNA level was comparable between fibrosis groups (F0-F2: 6.35 logs, F3-F4: 6.37 logs, p=0.46). There were 101 and 436 patients with HIV and DM2, respectively, for whom pre-treatment liver fibrosis data was available. In both groups, there were significant increases in LDL (p=0.008 (HIV), p=0.003 (DM2)) among patients with ALD following SVR.Table 1. Baseline characteristics of treated HCV-infected persons who achieved SVR. Figure 1. Mean lipid profile parameters before and after HCV treatment for patients who achieved SVR. TC was measured a mean of 8.1 months (228 days, SD 333 days) before treatment and 17.4 months (488 days, SD 196 days) after SVR. LDL was measured a mean of 8 months (224 days, SD 284 days) before treatment and 17.5 months (492 days, SD 201 days) after SVR. *=differences in means using paired t-test were statistically significant with p<0.05. HCV= Hepatitis C Virus, SVR= Sustained Virologic Response TC=Total Cholesterol, HDL= High Density Lipoprotein, LDL= Lipoprotein, TG= Triglycerides. ConclusionIn a cohort of mostly Black HCV-infected Veterans, significant increases in TC, driven by increases in LDL, were seen after SVR regardless of fibrosis stage. In addition, patients with ALD and HIV or DM2, who have an inherently higher risk of CVD, had increased LDL levels, suggesting that these patients should be screened and treated for HCV prior to development of ALD. Correlates such as the ASCVD score should be considered in the timing of HCV treatment, in order to reduce the long-term risk of CVD.Disclosures Shyam Kottilil, MD PhD, Arbutus Pharmaceuticals (Grant/Research Support)Gilead Sciences (Grant/Research Support)Merck Inc (Grant/Research Support, Advisor or Review Panel member)

Rapid virologic response in chronic hepatitis C genotype 1: Evaluation of pretreatment factors in patients

Background and study aimsRapid virologic response (RVR) is defined as undetectable hepatitis C virus (HCV) RNA in serum after 4 weeks of treatment for chronic hepatitis C (CHC). Paritaprevir/ritonavir/ombitasvir (PRO) and/or dasabuvir (D), with or without ribavirin [PRO (D) ± ribavirin], which are direct-acting antivirals (DAAs), is the currently approved treatment regimen for CHC genotype 1; this regimen can also be used in patients with end-stage renal failure (ESRF). In this study, we aimed to evaluate the effect of pretreatment factors on RVR in patients treated with PRO (D) ± ribavirin. Patients and methodsThis study included 60 patients with CHC genotype 1 who were treated with PRO (D) ± ribavirin and achieved RVR. Patients’ demographic data; baseline HCV RNA levels; HCV genotype information; biochemical, histologic, and radiologic results; and previous treatment history were recorded. Patients were categorized into two groups: virologic responses achieved in the first week (group 1) and in the first to the fourth week (group 2). Pretreatment factors were compared between the groups. ResultsPatients in group 1 who achieved ultraRVR (undetectable HCV RNA after 1 week of treatment) had significantly lower mean pretreatment HCV RNA levels and lower prevalence of ESRF than patients in group 2. ConclusionsRVR has been indicated to be a robust positive predictor of sustained virologic response. We concluded that some pretreatment factors such as low HCV RNA level and absence of ESRF might lead to faster RVR and shorter treatment duration with DAAs for CHC.

Effectiveness of Direct-acting Antivirals for the Treatment of Chronic Hepatitis C in Rwanda: A Retrospective Study

Direct-acting antivirals (DAAs) are becoming accessible in sub-Saharan Africa. This study examined the effectiveness of DAAs in patients treated through the Rwandan national health system and identified factors associated with treatment outcomes. This retrospective study used data from the national hepatitis C virus (HCV) program for patients who initiated DAAs between November 2015 and March 2017. Sustained virological response at 12 weeks after treatment (SVR12) was the primary outcome. Logistic regression models were fit to estimate the relationship between patients' clinical and demographic characteristics and treatment outcome. 894 patients started treatment during the study period; 590 completed treatment and had SVR12 results. Among the 304 patients without SVR12 results, 48 were lost to follow-up and 256 had no SVR12 results but clinical data indicated they likely completed treatment; these patients were classified as nonvirological failure because viral clearance could not be determined. In a per-protocol analysis of 590 patients with SVR12 results, SVR12 was achieved in 540 (92%), and virological failure occurred in 50 (8%). Pretreatment HCV RNA above the median split was associated with virological failure. Intention-to-treat analyses including all patients showed that SVR12 was achieved in 540 (60%), with nonvirological failure in 304 (34%) and virological failure in 50 (6%). Patients in Western Province were more likely to experience nonvirological failure than patients in Kigali, likely owing to the 5-7-hour travel required to access testing and treatment. DAAs were effective when implemented through the Rwandan national health system. Decentralization and enhanced financing are underway in Rwanda, which could improve access to treatment and follow-up as the country prepares for HCV elimination.

Genetic associations of vitamin D receptor polymorphisms with advanced liver fibrosis and response to pegylated interferon-based therapy in chronic hepatitis C.

Vitamin D receptor (VDR) modulates host immune responses to infections such as hepatitis C virus (HCV) infection, including interferon signaling. This study aimed to investigate the associations of VDR polymorphisms with advanced liver fibrosis and response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic HCV infection. In total, 554 Thai patients with chronic HCV infection treated with a PEG-IFN-based regimen were enrolled. Six single-nucleotide polymorphisms (SNPs) were genotyped: the IL28B C > T (rs12979860) SNP and five VDR SNPs, comprising FokI T > C (rs2228570), BsmI C > T (rs1544410), Tru9I G > A (rs757343), ApaI C > A (rs7975232), and TaqI A > G (rs731236). In total, 334 patients (60.3%) achieved sustained virological response (SVR), and 255 patients (46%) were infected with HCV genotype 1. The bAt (CCA) haplotype, consisting of the BsmI rs1544410 C, ApaI rs7975232 C, and TaqI rs731236 A alleles, was associated with poor response (in terms of lack of an SVR) to PEG-IFN-based therapy. The IL28B rs12979860 CT/TT genotypes (OR = 3.44, 95% CI [2.12–5.58], p < 0.001), bAt haplotype (OR = 2.02, 95% CI [1.04–3.91], p = 0.03), pre-treatment serum HCV RNA (logIU/mL; OR = 1.73, 95% CI [1.31–2.28], p < 0.001), advanced liver fibrosis (OR = 1.68, 95% CI [1.10–2.58], p = 0.02), and HCV genotype 1 (OR = 1.59, 95% CI [1.07–2.37], p = 0.02) independently predicted poor response. Patients with the bAt haplotype were more likely to have poor response compared to patients with other haplotypes (41.4% vs 21.9%, p = 0.03). The FokI rs2228570 TT/TC genotypes (OR = 1.63, 95% CI [1.06–2.51], p = 0.03) and age ≥55 years (OR = 2.25; 95% CI [1.54–3.32], p < 0.001) were independently associated with advanced liver fibrosis, assessed based on FIB-4 score >3.25. VDR polymorphisms were not associated with pre-treatment serum HCV RNA. In Thai patients with chronic HCV infection, the bAt haplotype is associated with poor response to PEG-IFN-based therapy, and the FokI rs2228570 TT/TC genotypes are risk factors for advanced liver fibrosis.

Real-world virological efficacy and safety of daclatasvir/asunaprevir/beclabuvir in patients with chronic hepatitis C virus genotype 1 infection in Japan.

The virological efficacy and safety of the direct-acting antiviral (DAA) regimen consisting of daclatasvir, asunaprevir, and beclabuvir (DCV/ASV/BCV) for patients chronically infected with hepatitis C virus (HCV) genotype 1 have not been previously evaluated in Japanese real-world settings. In a Japanese nationwide multicenter study, the rate of sustained virologic response (SVR) and safety were analyzed in 91 patients who started the DCV/ASV/BCV regimen between November 2016 and July 2017. SVR rates were compared based on baseline patient characteristics. More than 60% of patients had a history of failure to achieve SVR with interferon (IFN)-free DAA therapy. Overall, 50 of 91 patients (54.9%) achieved SVR. Multivariate analysis identified a history of failure with IFN-free DAA therapy and pretreatment HCV RNA levels as factors significantly associated with treatment failure. Whereas the SVR rate in patients without a history of IFN-free DAA therapy was 91.7% (33 of 36 patients), it was only 30.9% (17 of 55 patients) among patients with a history of IFN-free DAA therapy. The rate of discontinuation due to an adverse event was 4.4%. Many patients treated with the DCV/ASV/BCV regimen have a history of a failure to achieve SVR with previous IFN-free DAA therapy. SVR rate was not as high as that in pre-approval clinical trial of this regimen in IFN-free DAA-naïve patients. In addition, most patients with a history of failure with IFN-free DAA therapy, particularly the DCV/ASV regimen, showed resistance to this regimen.

Observed increases in CD4:CD8 and TIGIT expression during sofosbuvir-based therapy in a longitudinal hepatitis C cohort

Abstract Chronic hepatitis C virus (HCV) infection reduces immune function through exhaustion and repertoire reduction. Sofosbuvir-based direct-acting antiviral (DAA) therapies offer &amp;gt;90% sustained virologic response (SVR) for HCV infection, but the extent of immune recovery and relationship with clinical factors are unknown. The longitudinal Alaska Hepatitis C Cohort provides an opportunity to evaluate immune recovery following sofosbuvir-based DAA and determine the influence of an extensive clinical and laboratory history. Forty-two persons (genotype 1; mean age 50 ± 12 years; 69% female) received 8 or 12-week sofosbuvir-based DAA therapy. Mean HCV RNA detection date was 2007 (range: 1994–2017). Pre-treatment HCV RNA levels averaged 4.9×106 IU/L (range: 4.9×104–2.4×107), were not detectable in any person after 4-weeks of therapy, and all achieved SVR. 18% (n=7) of persons had a fibrosis score of ≥F2 (moderate fibrosis to cirrhosis). Peripheral blood mononuclear cells (PBMCs) were evaluated at four time points: Pre-treatment (Pre), 4-weeks treatment (4wk), End of Treatment (EOT), and SVR post 12-weeks EOT (SVR-12) by flow cytometry to evaluate memory, exhaustion, and functional immune markers. Initial analysis revealed a significant increase in the CD4:CD8 from 4wk to EOT (p=0.007). Regulatory T-cells significantly increased at EOT and SVR-12 compared to 4wk (p=0.04 and 0.03, respectively). TIGIT showed a significant increasing trend in T-cells and NK cells throughout sampling timeline. Preliminary analysis indicates sofosbuvir-based DAA supports immune recovery to some extent. Additional analysis of immune recovery markers, determination of estimated date of HCV infection, and correlation of morbidity factors continues.

Stevens-Johnson Syndrome in a Chronic Hepatitis C Patient Treated With Zepatier (Elbasvir/Grazoprevir)

Introduction: Stevens-Johnson syndrome (SJS) is an acute life threatening skin reaction involving mucocutaneous membranes. About 80 to 90% cases are drug induced. The recent introduction of new direct acting antiviral (DAA) agents has commenced a new era of safe and effective treatment of chronic Hepatitis C - previously known to be a difficult-to-treat lifelong infection. While SJS has been reported with the use of first generation DAA agents such as telaprevir, no known cases have been reported till date for patients on Zeptaier (Elbasvir/Grazosprevir combination therapy) for chronic Hepatitis C virus (HCV) infection. We report a case of SJS induced by Elbasvir/Grazosprevir in a patient with Chronic Hepatitis C and HIV.Figure: Mucocutaneous findings.Case Description: A 53-year old male with past history of chronic HCV and HIV presented with a 3-day history of fever, malaise, progressively worsening cutaneous symptoms which included- bilateral periorbital swelling and redness, painful oral ulcers and skin rash. Rash was concentrated on the upper body and was spreading caudally. Rash consisted of erythematous pruritic tender papules and vesicles. Patient had recently started taking Elbasvir/Grazosprevir to treat chronic HCV three weeks ago. He was also on Abacavir/dolutegravir/lamivudine (Triumeq) therapy for HIV with recent non-detectable HIV RNA levels and a CD4 count of 366. His pre-treatment HCV RNA count was 1,780,000 IU/mL (COBAS TaqMan HCV Test version 2.0). He had F3 fibrosis stage via FibroSure testing. Patient's presentation was attributed to early drug induced SJS from Zepatier use. Zepatier was discontinued and patient treated with steroids and antihistamines. He had complete resolution of his symptoms after two weeks. Discussion: Zepatier is a combination drug with Elbasvir, an NS5A inhibitor and Grasoprevir, an NS3/4A protease inhibitor, which was recently approved by the FDA for the treatment of chronic Hepatitis C in patients with genotype 1 and 4. This approval follows several clinical trials establishing the safety and efficacy of Elbasvir/Grasoprevir combination demonstrating a sustained virological response 12 weeks after completing treatment (SVR-12) greater than 92% and a minimal side effect profile. Most common side effects in different trials included headache, nausea and fatigue. In the C-EDGE trial, rash or pruritus was noted in 4% of patients on Elbasvir/Grasoprevir with Ribavirin regimen. However, no rash or pruritus was reported in patients on Elbasvir/ Grasoprevir regimen alone. To the best of our knowledge, serious adverse cutaneous reaction associated with Elbasvir/Grasoprevir therapy has not been previously reported. Possibility of adverse cutaneous drug reaction with Elbasvir/ Grasoprevir use has significant clinical implications. Patients with HIV seem to have a higher incidence of SJS than the general population. Clinicians need to be highly vigilant for cutaneous side effects while treating patients with HIV and HCV with Elbasvir/Grasoprevir combination for chronic HCV treatment. Because of significant mortality associated with SJS - early recognition, offending drug discontinuation and prompt treatment are warranted.

Elbasvir/grazoprevir, Velpatasvir/sofosbuvir, and Eteplirsen

The marketing of sofosbuvir (Sovaldi) in late 2013 and a combination of ledipasvir and sofosbuvir (Harvoni) in late 2014 have represented very important advances in the treatment of chronic hepatitis C virus (HCV) infection, with cure rates exceeding 90%. Ledipasvir/sofosbuvir was initially approved for the treatment of patients with chronic HCV genotype 1 infection, the most common genotype in the United States, and subsequently approved for the treatment of patients with chronic HCV genotypes 4, 5, and 6 infections. Ledipasvir/sofosbuvir is administered once a day, and the duration of treatment for most patients is 12 weeks, although an 8-week course of treatment can be considered for treatment-naïve patients with genotype 1 infection without cirrhosis who have pretreatment HCV RNA less than 6 million IU/mL. In some patients (e.g., treatment-naïve and treatment-experienced with decompensated cirrhosis), ribavirin is also included in the treatment regimen. Daniel A. Hussar, PhD, Remington Professor of Pharmacy, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA William P. Tidwell, BS, Student Pharmacist, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA

Does Epoetin Beta Still Have a Place in Peginterferon Alpha-2a Plus Ribavirin Treatment Strategies for Chronic Hepatitis C?

To investigate the impact of epoetin beta (EPO) on sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients treated with peginterferon-ribavirin (RBV). Controlled, randomized, pragmatic multicenter study to assess 2 strategies, ie, the use (EPO group) or nonuse (control group) of EPO in terms of achieving SVR in treatment-naive, genotype non-2/non-3 HCV-infected patients receiving a 48-week treatment regimen of pegylated interferon α-2a (peg-IFN) plus RBV (randomization 2:1). The single-nucleotide polymorphisms of interferon lambda 3 (IFNL3) (rs12979860 and rs8099917), interferon lambda 4 (IFNL4) (ss469415590), and inosine triphosphatase (ITPA) (rs1127354 and rs7270101) were determined retrospectively. Two hundred twenty-seven patients were included in the study. In the global population (n = 227), the overall SVR rate was 52% (118/227). Nonresponse and relapse occurred in respectively 46/227 (20.3%) and 42/227 (18.5%) patients. In the intention-to-treat analysis, 55.5% of patients with anemia (n = 164) had a SVR, specifically 57.4% in the EPO group versus 52.4% in the control group, but the difference was not statistically significant. In the anemic population, independent factors associated with SVR were IFNL3 and IFNL4 polymorphisms, pretreatment HCV RNA level, iron level, and aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio. EPO has little impact on SVR in patients treated with peg-IFN+RBV and should be recommended only for patients with severe anemia.

Virologic Response Rates to Fixed-Dose Combination Ledipasvir/Sofosbuvir for 8 or 12 Weeks With Baseline Viral Load

Introduction: Ledipasvir/Sofosbuvir (LDV/SOF) is approved to treat patients infected with hepatitis C virus (HCV) genotype 1 (GT1). Based on the LDV/SOF U.S Prescribing Information, 8 weeks can be considered in treatment-naïve patients without cirrhosis who have pre-treatment HCV RNA less than 6 million IU/mL. A post-hoc analysis of the phase 3, ION-3 study, showed that patients with baseline viral load < 6 million IU/ml achieved high response rates with 8 or 12 weeks of LDV/SOF, 97% and 96% SVR12, respectively. Here we evaluate traditional negative predictors of response in patients with baseline viral loads < 6 million IU/ml who received LDV/SOF for 8 weeks or 12 weeks. Methods: This was a retrospective analysis of all patients treated with LDV/SOF for 8 or 12 weeks in the ION-3 trial, who had a baseline viral load < 6 million IU/mL. SVR12 rates are compared for patients with and without traditional negative predictors of response, including: age, gender, race, GT1 subtype, BMI, IL28B status, and fibrosis status based on biopsy and/or Fibrotest score. Results: Two-hundred forty-nine HCV GT1, treatment naïve, non-cirrhotic patients, with baseline viral load < 6 million IU/mL were included in the analysis. SVR12 data for patients who received LDV/SOF for 8 vs 12 weeks are reported in table 1. Conclusion: High response rates were achieved in treatment naïve, non-cirrhotic, GT1 patients with baseline HCV RNA < 6 million IU/mL patients treated with either 8 or 12 weeks of LDV/SOF, regardless of the presence of baseline characteristics traditionally associated with a poor response to IFN-based regimens. These results suggest that 8 weeks of LDV/SOF provides a safe, simple and efficacious treatment option for this patient group.Table 1: Virologic Response Rates in Traditional Negative Predictive Factors

Impact of Hepatitis B Virus Integration Into Liver Tissue on the Efficacy of Peginterferon and Ribavirin Therapy in Hepatitis B Virus-negative Chronic Hepatitis C Patients

Integration of hepatitis B virus (HBV) DNA into host hepatic DNA is found in patients without HBV surface antigen (HBsAg). We investigated the prevalence of HBV integration and its association with the outcome of peginterferon (PEG-IFN) and ribavirin combination therapy in HBsAg-negative chronic hepatitis C patients. We analyzed 157 patients chronically infected with hepatitis C virus (HCV) with viral load ≥5.0 log10 IU/mL, who underwent PEG-IFN and ribavirin combination therapy. HBV integration was measured by an Alu-PCR assay with liver specimens obtained by needle biopsy before treatment. HBV integration was identified in 54 of the 157 (34.4%) patients. There were no significant differences between patients with and without HBV integration with regard to baseline characteristics including liver histology, pretreatment HCV RNA levels, and genetic polymorphisms near the IL28B gene. In patients with HCV genotype 1b (n=91), a more favorable viral response was observed in patients with HBV integration during therapy, with higher rates of rapid and complete early virologic response. The rate of sustained virologic response (SVR) was significantly higher in patients with HBV integration than those without (P=0.0098). Multivariate analysis identified HBV integration and IL28B polymorphisms as independent factors associated with SVR. HBV integration was associated with favorable viral responses and a higher SVR rate to combination therapy with PEG-IFN and ribavirin in patients infected with HCV genotype 1b. Further studies will be required to confirm this association and elucidate its underlying mechanisms.

Impact of Occult Hepatitis B Virus Infection or Hepatitis B Virus DNA Integration on Efficacy of Chronic Hepatitis C Treatment With Peginterferon and Ribavirin

Impact of Occult Hepatitis B Virus Infection or Hepatitis B Virus DNA Integration on Efficacy of Chronic Hepatitis C Treatment With Peginterferon and Ribavirin

Characteristics and Outcomes of HCV Genotype-1-Infected Patients Treated with Peginterferon and Ribavirin Combination Therapy with Discordant HCV Responses 4 and 12 Weeks after Starting Therapy

Objective: Some patients with chronic hepatitis C virus (HCV) infection fail to achieve complete early virologic response (EVR) despite a marked decrease in HCV RNA at 4 weeks. We investigated the characteristics and final treatment outcomes of this patient subpopulation. Methods: A total of 516 patients with HCV genotype 1 were enrolled. Background characteristics and final outcomes were compared between patients who achieved complete EVR and those who did not among patients whose HCV RNA levels decreased 3.0 log₁₀ or more at 4 weeks. Results: 78 of 334 patients (23.4%) with a ≥3.0 log₁₀ reduction in HCV RNA levels at 4 weeks failed to achieve complete EVR. Female sex, higher pretreatment HCV RNA levels and lower baseline alanine aminotransferase (ALT) activity were independently associated with failure of complete EVR. The rate of sustained virologic response (SVR) in patients without complete EVR was 47.4%, significantly lower than that in patients with complete EVR (89.7%, p < 0.0001). Conclusions: Female patients, patients with higher pretreatment HCV RNA levels and patients with lower baseline ALT have a high likelihood of failure of complete EVR even when they had a ≥3 log₁₀ reduction of HCV RNA at 4 weeks, resulting in a significantly lower SVR rate.

Effect of Functional Interleukin-10 Polymorphism on Pegylated Interferon-α Plus Ribavirin Therapy Response in Chronic Hepatitis C Virus Patients Infected With 3a Genotype in Pakistani Population

Dear Editor, Pakistan is a low socio economic country having more than 10 million people infected with hepatitis C Virus (HCV) with a major genotype of 3a (GT 3a) (1). Due to high rate of resistance to standard Interferon plus Ribavirin therapy, it is highly needed to identify new marker for response prediction to therapy. Interleukin 10 (IL-10) is a key member of Cytokine, which regulates Th1/Th2 Cytokine balance, a major part of immune system against infection (2). IL-10 production varies inter individually based on functional polymorphism (-1082 G/A, -819 C/T and -592 C/A) in its promoter region. Previously we have shown that IL-10 polymorphic variants play important role in HCV susceptibility/prevention (2). Recently we conducted a study to analyze the impact of functionally important IL-10 polymorphism on outcomes of standard Interferon-α plus Ribavirin therapy. The results of current study strengthen previous findings that IL-10 polymorphism effect disease susceptibility in Pakistan (2-4). Our results showed that high IL-10 producing -1082 GG genotype (P = 0.02; OR = 0.4; 95% CI = 0.2-0.8) and GTA haplotype (P = 0.03; OR = 0.55; 95% CI = 0.3-1) were significantly higher in HCV patients as compared to healthy subjects, while IL-10 -1082 GA genotype (P = 0.03; OR = 1.95; 95% CI = 1.1-3.4) showed protective effect against HCV infection. The current data failed to show any significant corelation between IL-10 polymorphism inheritance and standard therapy response in HCV patients. Age and pretreatment viral load are the parameters which influence therapy response; Patients with sustained virological response (SVR) were younger and had lower pretreatment HCV RNA levels. No gender-based statistical difference was found between chronic hepatitis C patients who achieved SVR or failed to respond. To our knowledge this is the first report from Pakistan to evaluate the role of IL-10 polymorphism on the outcomes of standard antiviral therapy. We are unable to find any corelation between IL-10 polymorphic variants and interferon therapy outcomes, may be due to small number of subjects. This study is a preliminary and is on small scale. We believe that our effort may stimulate some additional personal genetic makeup based studies on larger scale using these and new multi-locus analysis approaches for a deeper analysis of the epistatic interaction of the pro- and anti -inflammatory molecules toward hepatitis C progression. Better understanding of genetic factors that have effect on hepatitis C progression and pathogeneses will provide scientific basis for the development of new immunomodulatory treatments for chronic hepatitis C patients and will also help health care workers about the standard therapy effectiveness.

Distribution of Hepatitis C Virus Genotypes in Kayseri Region, in Turkey: Unexpected Rate of Genotype 4

Hepatitis C virus (HCV) is an important cause of chronic liver disease. There are six genotypes and more than 80 subtypes of HCV. The aim of this study was to investigate the distribution of HCV genotypes in Middle Anatolia in Turkey, and the association of HCV genotypes with pre-treatment HCV RNA viral load, serum transaminase levels, and histopathological grade of liver fibrosis. A total of 160 patients (103 female, 57 male) with chronic hepatitis C were retrospectively evaluated. HCV RNA level was determined by commercial real time PCR method. HCV RNA positive sera were genotyped by the Abbott Real Time HCV Genotype II assay and sequenced by the ABI Prism 310 Genetic Analyzer. Gender, age, serum ALT, AST, HCV RNA viral load, and fibrosis staging of liver were determined in all patients. Genotype 1b was the most frequent (64.7%) followed by genotype 4d (28.3%), 2 (4.4%), and la (2.5%). The HCV genotype results were found consistent with both methods. The gender distribution of the 160 HCV infected patients was 57 male/103 female. Log HCVRNA was significantly higher in genotype 1b compared to genotype 4 and 1a. Stage of liver fibrosis, histology activity index, serum ALT and AST levels did not differ between groups depending on genotypes. Advanced liver fibrosis (Group 2) was found in 36 (76.6%) patients with genotype 1b and in 10 (21.3%) patients with genotype 4 and only in 1 patient (2.1%) with genotype 1a. HCV genotype 1b is the most frequent type (64.7%) in this region. Prevalence of genotype 4 in this region is higher than the national HCV genotype distribution. Serum transaminase levels and liver fibrosis scores are not associated with HCV genotypes.

Significance of a reduction in HCV RNA levels at 4 and 12 weeks in patients infected with HCV genotype 1b for the prediction of the outcome of combination therapy with peginterferon and ribavirin

BackgroundThe importance of the reduction in hepatitis C virus (HCV) RNA levels 4 and 12 weeks after starting peginterferon (PEG-IFN) and ribavirin combination therapy has been reported to predict a sustained virologic response (SVR) in patients infected with HCV genotype 1. We conducted a multicenter study to validate this importance along with baseline predictive factors in this patient subpopulation.MethodsA total of 516 patients with HCV genotype 1 and pretreatment HCV RNA levels ≥5.0 log10 IU/mL who completed response-guided therapy according to the AASLD guidelines were enrolled. The reduction in serum HCV RNA levels 4 and 12 weeks after starting therapy was measured using real-time PCR, and its value in predicting the likelihood of SVR was evaluated.ResultsThe area under the receiver operating characteristics (ROC) curve was 0.852 for 4-week reduction and 0.826 for 12-week reduction of HCV RNA levels, respectively. When the cut-off is fixed at a 2.8-log10 reduction at 4 weeks and a 4.9-log10 reduction at 12 weeks on the basis of ROC analysis, the sensitivity and specificity for SVR were 80.9% and 77.9% at 4 weeks and were 89.0% and 67.2% at 12 weeks, respectively. These variables were independent factors associated with SVR in multivariate analysis. Among 99 patients who showed a delayed virologic response and completed 72-week extended regimen, the area under ROC curve was low: 0.516 for 4-week reduction and 0.482 for 12-week reduction of HCV RNA levels, respectively.ConclusionsThe reduction in HCV RNA levels 4 and 12 weeks after starting combination therapy is a strong independent predictor for SVR overall. These variables were not useful for predicting SVR in patients who showed a slow virologic response and experienced 72-week extended regimen.

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa‐2a/ribavirin

It is unclear whether the current threshold for 'high' hepatitis C virus (HCV) RNA level (800,000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono-infected and 176 HIV-HCV co-infected patients treated with peginterferon alfa-2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono-infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400,000 IU/mL was used and 16% (59%vs 43%) when 800,000 IU/mL was used. In HIV-HCV genotype 1 co-infected patients, the difference was 51% (71%vs 20%) when 400,000 IU/mL was used and 43% (61%vs 18%) when 800,000 IU/mL was used. A lower threshold (200,000 IU/mL) was identified for genotype 1 mono-infected patients with 'normal' alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400,000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1-infected individuals with elevated ALT.

Impact of Peginterferon Alpha and Ribavirin Treatment on Lipid Profiles and Insulin Resistance in Hepatitis C Virus/HIV-Coinfected Persons: The AIDS Clinical Trials Group A5178 Study

The effect of peginterferon alpha/ribavirin (PEG-IFN/RBV) and hepatitis C virus (HCV) clearance on lipid and insulin resistance (IR) profiles in HCV/human immunodeficiency virus (HIV) coinfection is unknown. We measured fasting total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoproteins (HDL-C), triglycerides (TG), glucose, and insulin at defined intervals in the A5178 study (N = 329), a prospective treatment trial in HCV/HIV coinfection. Changes from baseline and the relation between baseline values of these variables to sustained virologic response (SVR) were determined. Of 182 subjects with metabolic data, 98 achieved early virologic response (EVR) and continued PEG-IFN/RBV. Among those, median pretreatment HCV RNA was 6.6 log(10 )IU/mL; 73% had HCV genotype 1. Median pretreatment TC was 176 mg/dL (interquartile range [IQR],150-205]; median LDL-C was 99 mg/dL (IQR, 79-123); median HDL-C was 40 mg/dL (IQR, 31-47); and median TG was 147 mg/dL (IQR, 101-221). Median homeostasis model assessment of IR (HOMA-IR) was 3.3 (IQR, 1.7-5.3). The EVRs demonstrated a decline in TC, LDL-C, and HDL-C, whereas TG increased on treatment but returned to near baseline 24 weeks after end of treatment (EOT). The HOMA-IR decline from entry to 24 weeks after EOT was significant among non-sustained virologic responders and nonsignificant among sustained virologic responders; this difference was offset after adjusting for higher HOMA-IR at baseline among the former. Among all 182 subjects, entry LDL-C was associated with SVR in a joint logistic model adjusted for HCV genotype, race, and prior IFN (odds ratio, 1.17 per 10 mg/dL increase; 95% confidence interval, 1.03-1.32), but TC, HDL, TG, and IR were not. Peginterferon alpha and RBV can significantly affect lipid profile and IR in HCV/HIV-coinfected persons. Although the lipid profile returns to near pretreatment levels after completion of treatment, our data suggest persistent modest improvement in IR with treatment. Clinical Trials Registration. NCT00078403.

Analysis of the complete open reading frame of hepatitis C virus in genotype 2a infection reveals critical sites influencing the response to peginterferon and ribavirin therapy

A proportion of patients infected with genotype 2a hepatitis C virus (HCV) cannot achieve a sustained virological response (SVR) to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV) but the reason remains unclear. The present study aimed to clarify the possible correlation between viral sequence variations and final outcome. The pretreatment complete open reading frame (ORF) sequences of genotype 2a HCV were determined by direct sequencing for two independent groups of patients (43 patients as test; group 1 and 35 as validation; group 2), and the correlation with the final outcome was explored. Patients with SVR (n=58) and with non-SVR (n=20) differed significantly in pretreatment HCV RNA level (p=0.002), fibrosis score (p=0.047), and cumulative RBV dosage (p=0.003). By comparison of all amino acid positions in the complete HCV ORFs, threonine at amino acid (aa) 110 in the core region was remarkably frequent in SVR (p=0.01 for group 1, p=0.004 for group 2, and p=5E-05 for combined). A sliding window analysis revealed that the total number of amino acid variations within the NS5A aa 2258-2306 region were significantly high in SVR compared to non-SVR patients (p=0.01 for group 1, p=0.006 for group 2, and p=0.0006 for combined). Multivariate analyses revealed that core aa 110 (p=0.02), NS5A aa 2258-2306 (p=0.03), and cumulative RBV dosage (p=0.02) were identified as independent variables associated with the final outcome. The outcome of PEG-IFN/RBV therapy is significantly influenced by variation in the core and NS5A regions in genotype 2a HCV infection.

Abbott RealTime PCR assay is useful for evaluating virological response to antiviral treatment for chronic hepatitis C

This study was done to evaluate the utility of the Abbott RealTime PCR assay (ART) for the monitoring of chronic hepatitis C patients. The serum samples of 183 patients infected with hepatitis C virus (HCV) genotype 1b who had completed a 48-week period of pegylated interferon (PEG-IFN) alpha-2b plus ribavirin treatment were prospectively analyzed. Serum HCV RNA levels were measured both by ART and by the Roche COBAS Amplicor Monitor test, version2.0 (CAM) at baseline and at weeks 4, 12, 24, 36, and 48 of treatment, and at 24weeks after the end of treatment (EOT). A significant positive correlation of pretreatment HCV RNA levels was found between ART and CAM (r=0.595, P<0.0001). Of the 183 patients, 66 (36.0%) achieved a sustained virological response (SVR). The logarithmic decline of the HCV RNA level from the pretreatment level determined by ART in SVR patients was significantly higher than that in non-SVR patients at all time points tested. The logarithmic decline determined by CAM in SVR patients was significantly higher than that in non-SVR patients only at week 4, but there was no significant difference at other weeks. Of 124 patients who were HCV RNA-negative at EOT by ART, 58 (46.8%) had a relapse of viremia at 24weeks after EOT, whereas 77 of 143 patients (53.8%) who were HCV RNA-negative at EOT by CAM had a relapse. The relapse rate was lower when determined by ART than by CAM, but not significantly so. ART is more useful than CAM for evaluating the virological response to antiviral treatment for chronic hepatitis C.