Virological Response In Genotype Research Articles

Effect of vitamin D supplementation on sustained virological response in genotype 1/4 chronic hepatitis C treatment-naïve patients from India.

Background & objectives:The effect of vitamin D supplementation on response to antiviral therapy in hepatitis C virus (HCV) genotype 1 and 4 infection still remains unclear, with studies yielding inconsistent results. The aim of the present study was to assess the effect of vitamin D supplementation on treatment outcome in patients with genotype 1/4 chronic hepatitis C (CHC) infection.Methods:Sixty consecutive, treatment-naïve, genotype 1 and 4 chronic HCV patients were included in the study. The patients were randomized into two groups: Vitamin D supplemented group received pegylated (PEG)-interferon α-2a 180 μg per week plus ribavirin (RBV) (1000-1200 mg/d) together with vitamin D3 (2000 IU/d) and control group received identical therapy without vitamin D (32 patients).Results:There were no significant differences between the two groups in terms of age, sex, body mass index and baseline laboratory values. Lower vitamin D levels were associated with higher grades of fibrosis in liver histology (vitamin D >20 ng/ml - 70% vs vitamin D <20 ng/ml - 37%, P<0.05). Vitamin D supplemented group had similar rapid viral response (40 vs 28%, P=0.36), complete early viral response (53.2 vs 40%, P=0.34), end of treatment response (64 vs 46%, P=0.17) and sustained virological response (SVR) (60 vs 44%, P=0.19) as compared to control group. Interleukin 28B polymorphism [odds ratio (OR)-15.37, 95% confidence interval (CI)-2.32-101.76, P=0.04] and baseline serum vitamin D levels (OR-6.36, 95% CI-1.36-29.61 P=0.02) were independent predictors of SVR in genotype 1/4 CHC. Vitamin D supplementation was not found to be predictor of response in genotype 1/4 CHC on multivariate analysis (OR-2.79, 95% CI- 0.63-12.34, P=0.74).Interpretation & conclusions:The present study showed that addition of vitamin D to PEG/RBV combination therapy in treatment-naïve patients who were infected with HCV genotype 1/4 had no effect on the rates of rapid, early and sustained viral responses.

Role of Interleukin-10, Interleukin-12 in the Response Prediction during Combined PEG Interferon-alpha 2a and Ribavirin Therapy in Patients with Chronic Hepatitis C

Background: Egypt has the highest prevalence of adult HCV infection in the world, averaging 15%-25% in rural communities. Sustained virological response in genotype 4 Egyptian patients treated with PEG-IFN alfa-2a and ribavirin was estimated around 60%. It is of major interest for both patient care and economic approach to predict failure of response. Several factors have been shown to influence response to antiviral treatment. Cytokines play an important role in the pathogenesis, progression and treatment outcome of HCV infection. Aim: The current study was designated to assess serum interleukin-10 and interleukin-12 levels in CHC genotype 4 patients and investigate their benefit as predictors of antiviral response. Methods: This study was conducted on a total number of 70 participants admitted to Hepatology and Gastroenterology Department in NHTMRI (National Hepatology & Tropical Medicine Research Institute). The participants of this study were divided into two groups as following; Group I: 20 healthy subjects (as controls), while the cases in Group II: 50 patients with chronic hepatitis C (CHC) genotype 4. Results: Our results showed that IL-12 and IL-10 levels were higher in patients with HCV infection than in control participants and were significantly higher in the group of the sustained responders, compared with non-responders. Serum IL-10 level showed a sensitivity and specificity of 76.7% and 73.3% respectively while serum IL-12 level showed sensitivity and specificity of 90% and 75% respectively. Conclusion: These results demonstrate the beneficial role ofIL-10, IL-12 in achieving an SVR during IFN-alpha and ribavirin therapy

Impact of host IL28B rs12979860, rs8099917 in interferon responsiveness and advanced liver disease in chronic genotype 3 hepatitis C patients.

Background and AimsGenetic polymorphisms near interleukin 28B gene are associated with spontaneous and treatment induced clearance of hepatitis C virus (HCV). Our objective was to evaluate the impact of interleukin 28B single nucleotide polymorphism (rs12979860, rs8099917) variability in HCV genotype 3 infected populations.Methods400 hepatitis C seroreactive patients from different population groups in Eastern and North Eastern part of India were assessed for host and viral genotypic analysis. 83 HCV genotype 3 infected patients were administered pegylated interferon- ribavirin therapy. Viral genotyping was performed using nested reverse transcriptase-PCR followed by direct sequencing methods. Host interleukin 28B genotyping was performed using real-time PCR based single nucleotide polymorphism analysis.ResultsOut of 400 hepatitis C seroreactive individuals, 73.25% were found to be RNA positive. HCV genotype 3 (65.87%) was found to be the major circulating strain in this region followed by genotype 1 (32.08%). rs12979860 CC genotype was significantly associated with sustained virological response in HCV genotype 3 infected population. In patients achieving rapid virological response, favourable CC/TT allele at rs12979860, rs8099917 was found to be predominant at both the alleles at 77%, 73.2% respectively; whereas in case of patients with relapsed HCV infection CT, TG alleles were found to be predominant. Additionally, CC genotypes at rs12979860 were found to be associated with sustained virological response in patients with high viral load (OR = 6.75, 0.05<p). HCV unfavourable rs12979860 TT, rs8099917 GG alleles were present in 34%, 27.6% patients with relapsed HCV infection respectively. Also unfavourable CT, TG genotypes were found to be predominant in patients with advanced stages of liver disease.ConclusionCC, TT the two favourable markers at SNPs rs12979860 and rs8099917 are strongly associated with sustained virological response in genotype 3 infected populations. This information will aid clinicians to effectively design response based treatment regimen.

Aminoadamantanes for chronic hepatitis C.

Aminoadamantanes for chronic hepatitis C.

Predictive value of FIB-4 and APRI versus METAVIR on sustained virologic response in genotype 1 hepatitis C patients.

Advanced liver fibrosis is a negative predictor of virologic response in genotype 1 chronic hepatitis C (CHC) patients. Biopsy, however, is invasive, costly, and carries some risk of complications. Using data from the prospective, international cohort study PROPHESYS, we assessed two alternative noninvasive measures of fibrosis, the FIB-4 and AST-to-platelet ratio index (APRI), to predict virologic response in CHC patients. CHC genotype 1, monoinfected, treatment-naive patients prescribed peginterferon alfa-2a (40KD)/ribavirin in accordance with country-specific legal and regulatory requirements and who had baseline METAVIR, FIB-4, and APRI scores (N=1,592) were included in this analysis. Patients were stratified according to the baseline METAVIR, FIB-4, or APRI score to assess virologic response [hepatitis C virus (HCV) RNA <50IU/mL] by week 4 of treatment (rapid virologic response) and 24weeks after untreated follow-up ]sustained virologic response (SVR)]. Baseline predictors of SVR were explored by multiple logistic regression, and the strength of the association between each fibrosis measure and SVR was evaluated. Both FIB-4 and APRI scores increased with increasing levels of biopsy-assessed fibrosis. The association between FIB-4 and SVR (p<0.1×10(-30)) was stronger than that between METAVIR (p=3.86×10(-13)) or APRI (p=5.48×10(-6)) and SVR. Baseline factors significantly associated with SVR included male gender, lower HCV RNA, lower FIB-4 score, no steatosis, and higher alanine aminotransferase ratio. The FIB-4 index provides a valuable, noninvasive measure of fibrosis and can be used to predict virologic response in patients treated with peginterferon alfa-2a (40KD)/ribavirin.

End treatment response and sustained viral response in hepatitis C virus genotype 3 among Pakistani population

BACKGROUND AND OBJECTIVESThis study aimed to determine the end treatment response (ETR) and sustained viral response (SVR) to interferon (IFN) and ribavirin in hepatitis C virus (HCV) genotype 3 in the Pakistani population.DESIGN AND SETTINGSThis is an interventional study conducted from January 2010 to December 2012 in Lyari General Hospital and Abbasi Shaheed Hospital, Karachi, outpatients department.METHODSAll patients with chronic hepatitis C genotype 3 infections were included. Patients with decompensated chronic liver disease, or having coexisting hepatitis B virus/human immunodeficiency virus were excluded. All patients received IFN alpha, 3 million international units (MIU), subcutaneously 3 times weekly and ribavirin >800 mg/d for a period of 6 months. Outcome parameters included ETR (negative polymerase chain reaction [PCR] at the end of therapy), SVR (negative PCR both at the end of treatment and 6 months later), and relapse (PCR negative at the end of treatment but positive 6 months later) were determined.RESULTSA total of 1170 patients were included with a female to male ratio of 1.64:1 and a mean age of 31.6 (8.4) years. Among 1170 patients, 985 completed the therapy as per the protocol, 119 were defaulted (treatment abandoned before completion), and 66 had to stop treatment due to side effects. ETR was 74.1%, SVR was 98%, relapse rate was 1.5%, and 10.1% were nonresponders. SVR was seen only in patients who had achieved an ETR (n=867). SVR was achieved in 848 patients (out of 867) (98%), relapse was seen in 13 (1.5%), and 6 (0.7%) patients lost follow-up after stopping treatment. Patients achieving ETR and SVR had a mean serum alanine aminotransferase of 71.3 (57.1) and 71.0 (56.5), respectively, which is approximately twice the upper normal limit.CONCLUSIONThe conventional IFN and ribavirin therapy in genotype 3 chronic HCV-infected patients gives an ETR and SVR of 74.1% and 98%, respectively.

Impact of the peginterferon‐α 2a and ribavirin plasma levels on viral kinetics and sustained virological response in genotype 1 HCV/HIV‐co‐infected patients with the unfavourable non‐CC IL28B genotypes

Studies on the association between the peginterferon-α and ribavirin levels and sustained virological response (SVR) have shown yielded conflicting results, but most of them were performed before the influence of IL28B polymorphisms was known. Our aim was to assess the effects of peginterferon-α 2a and ribavirin plasma levels on viral kinetics and SVR in hepatitis C virus genotype 1 HCV-1/HIV-co-infected patients according to IL28B genotype. This was a cohort study of HCV-1/HIV-co-infected patients who were HCV-treatment naïve and for whom the efficacy of peginterferon-α 2a plus ribavirin was evaluated by per-protocol analysis. The peginterferon-α 2a and ribavirin levels were measured by ELISA and HPLC-UV, respectively. The relationships among host and viral factors, the trough drugs levels and virological responses were analysed by multivariate regression analyses. A total of 131 Caucasian patients were included (cirrhosis:38.9%). Overall, SVR rate was 39.6%. In patients with CC IL28B genotype, SVR was related neither to peginterferon-α 2a nor to ribavirin plasma levels, while higher levels of both drugs were the only variables independently associated with SVR in individuals with CT/TT IL28B genotypes (OR, 5.02; CI95 , 1.45-17.1; P=0.001 and 4.0; CI95 , 1.08-14.7; P=0.038, respectively). Moreover, faster viral declines were observed in CT/TT patients when pegIFN-α 2a and ribavirin plasma levels were greater than 3400pg/mL and 1.6μg/mL, respectively. In contrast to the results for CC patients, the results in patients carrying the unfavourable CT/TT IL28B genotypes showed that plasma levels of both drugs have significant effects on viral kinetics and SVR.

Prevalence of insulin resistance and its relationship with virologic response rate in genotype 3 HCV patients

Background and Aim: Changes in carbohydrate metabolism have been reported in hepatitis C virus (HCV) infection, resulting in insulin resistance and accelerated progression of hepatic fibrosis. Only a few studies have looked at the association of insulin resistance with virologic response in genotype 3 HCV infection. Hence a prospective study was conducted to determine prevalence of insulin resistance in genotype 3 HCV and it's the relationship between rapid virologic response (RVR).

Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin Increased Sustained Virologic Response in Genotype 1 Chronic HCV and Allowed for Shorter Treatment Duration in Treatment-naïve and Prior Relapser Patients: 2011 ACG Presidential Poster

Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin Increased Sustained Virologic Response in Genotype 1 Chronic HCV and Allowed for Shorter Treatment Duration in Treatment-naïve and Prior Relapser Patients: 2011 ACG Presidential Poster

New anti HCV drugs in the pipeline

Several novel therapeutic approaches are currently in the pipeline for HCV treatment. They include new target host immune system as novel interferon, toll-like receptor agonists, therapeutic vaccines or interleukins, new target cell replication drug as ribavirin analogues, cyclophilin inhibitors, alpha glucosidase inhibitors, dephosphorylationinhibitors of eukaryotic initiation factors 2alpha, antisense molecule, entry inhibitors and specifically targeted antiviral therapy (STAT-C) such as viral enzyme inhibitor ( protease and polymerase). Several STAT-C molecules are currently in development and will soon be at hand and will offer new treatment opportunities to patients infected with hepatitis C. Promising results leading to more than 70% of sustained virological response in genotype 1 naive patients have been reported with two proteases inhibitors (telaprevir and boceprevir) in combination with pegylated interferon and ribavirin that are currently in phase III. These studies also demonstrated the potential to shorten treatment duration in those with a rapid viral response and the realistic hope for retreatment (40 and 75%) in previous non responders or relapsers to interferon based therapies. In addition there is indication that STAT-C drugs may help to overcome negative host factors that have historically been associated with poor response rates (such as ethnicity, insulin resistance, steatosis and cirrhosis). However these trials also emphasize the limitations of protease inhibitors and viral resistance data have provided important new lessons for small molecule drug development. In the near feature, it is likely that IFN-based therapy plus ribavirin will remain the backbone of the treatment of chronic hepatitis C. PEG-IFN and ribavirin are needed in order to prevent HCV resistance to STAT-C drugs and subsequently increase SVR. Genotypic and phenotypic resistance tests will also enter the therapeutic arena. Once several STAT-C agents without cross resistance become available, treatment strategies will include a combination of several drugs with different mechanisms of action (protease inhibitors and polymerase inhibitors) that could hopefully results in IFN and/or ribavirin sparing regimen. The first dual -- combination clinical trial with oral antiviral is still ongoing. Patients receiving this combination for 14 days had undetectable HCV RNA in 63% of naive genotype1 patients. This early success has moved IFN-free regimen a step closer to reality for patients. In the future, there might be combinations of antivirals having additive potency, lacking cross resistance and with a good safety profile.

Interleukin-28B Polymorphism Improves Viral Kinetics and Is the Strongest Pretreatment Predictor of Sustained Virologic Response in Genotype 1 Hepatitis C Virus

We recently identified a polymorphism upstream of interleukin (IL)-28B to be associated with a 2-fold difference in sustained virologic response (SVR) rates to pegylated interferon-alfa and ribavirin therapy in a large cohort of treatment-naive, adherent patients with chronic hepatitis C virus genotype 1 (HCV-1) infection. We sought to confirm the polymorphism's clinical relevance by intention-to-treat analysis evaluating on-treatment virologic response and SVR. HCV-1 patients were genotyped as CC, CT, or TT at the polymorphic site, rs12979860. Viral kinetics and rates of rapid virologic response (RVR, week 4), complete early virologic response (week 12), and SVR were compared by IL-28B type in 3 self-reported ethnic groups: Caucasians (n = 1171), African Americans (n = 300), and Hispanics (n = 116). In Caucasians, the CC IL-28B type was associated with improved early viral kinetics and greater likelihood of RVR (28% vs 5% and 5%; P < .0001), complete early virologic response (87% vs 38% and 28%; P < .0001), and SVR (69% vs 33% and 27%; P < .0001) compared with CT and TT. A similar association occurred within African Americans and Hispanics. In a multivariable regression model, CC IL-28B type was the strongest pretreatment predictor of SVR (odds ratio, 5.2; 95% confidence interval, 4.1-6.7). RVR was a strong predictor of SVR regardless of IL-28B type. In non-RVR patients, the CC IL-28B type was associated with a higher rate of SVR (Caucasians, 66% vs 31% and 24%; P < .0001). In treatment-naive HCV-1 patients treated with pegylated interferon and ribavirin, a polymorphism upstream of IL-28B is associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.

Response to pegylated interferon alfa‐2a and ribavirin in chronic hepatitis C genotype 4

The safety and efficacy of pegylated interferon (PEG-IFN) alfa-2a and ribavirin were studied among patients treated for genotype 4 chronic hepatitis C. Ninety-five patients with chronic hepatitis C genotype 4 were treated with PEG-IFN alfa-2a (180 microg/week) plus ribavirin (> or =11 mg/kg/day) for 48 weeks. The primary end point was sustained virological response, defined as non-detectable levels of HCV RNA at the end of follow up (week 72). The proportion with sustained virological response was 58/95 = 61.1% (95% CI = 50.5-70.9%). Side effects were generally mild, well managed by dose reductions (in 62% of patients); in only two patients were side effects sufficiently severe to require treatment interruption. Ninety percent of patients adhered to treatment up to week 12, and their sustained virological response rate was higher compared to non-adherent (65% vs. 22%, respectively, P = 0.012). None of the patients who failed to achieve 1 log reduction of viral load by week 8 (n = 15), or 2 log reduction by week 12 (n = 17), had a sustained virological response. In conclusion, sustained virological response in genotype 4 Egyptian patients treated with PEG-IFN alfa-2a and ribavirin was estimated around 60%, intermediate between sustained virological response observed in genotype 1 and genotype 2-3 patients in Western countries. The early virological response (week 4 or week 8) should be investigated as a criterion to decide whether the patient may benefit from a shorter duration of therapy.

Insulin resistance is a major determinant of sustained virological response in genotype 1 chronic hepatitis C patients receiving peginterferon α‐2b plus ribavirin

Cross-sectional studies suggest insulin resistance is strongly associated with hepatic steatosis and fibrosis in patients with chronic hepatitis C (CHC), which might affect the efficacy of antiviral therapy. Aim To investigate retrospectively the impact of insulin resistance on treatment response in Chinese genotype 1 CHC patients receiving a 24-week course therapy with peginterferon alpha-2b/ribavirin. A total of 133 biopsy-proven CHC patients were enrolled for analyses. Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR). Hepatic fibrosis was graded by the METAVIR scoring system. Mean HOMA-IR progressively elevated along with the severity of hepatic fibrosis (F1-F2 fibrosis: 2.55 +/- 0.16 vs. F3-F4 fibrosis: 3.61 +/- 0.20, P < 0.001). Compared with patients with sustained virological response (SVR), patients without SVR had significantly higher percentages of F3-F4 fibrosis (62.2% vs. 21.6%, P < 0.001) and baseline high viral load (>or=600,000 IU/mL; 64.4% vs. 35.6%, P = 0.038). In addition, patients without SVR had significantly higher plasma levels of insulin (15.03 +/- 0.89 vs. 10.19 +/- 0.55 microU/mL, P < 0.001) and HOMA-IR values (3.76 +/- 0.23 vs. 2.50 +/- 0.15, P < 0.001). Multivariate analyses showed that F1-F2 fibrosis (odds ratio: 4.49, P = 0.001), HOMA-IR < 2 (odds ratio: 7.15, P = 0.005) and pre-treatment hepatitis C virus RNA < 600,000 IU/mL (odds ratio: 3.26, P = 0.012) were the independent factors associated with SVR. Insulin resistance is a major determinant of SVR in genotype 1 CHC patients receiving peginterferon alpha-2b/ribavirin. Strategies to modify insulin resistance may be effective in enhancing SVR before or during anti-viral therapy.

Peginterferon Alfa-2a and Ribavirin for 24 Weeks in Hepatitis C Type 1 and 4 Patients With Rapid Virological Response

This analysis reports the rate of sustained virological response (SVR) in patients infected with hepatitis C virus (HCV) genotype 1 or 4 who were assigned to 24 weeks of treatment with pegylated interferon (peginterferon) alfa-2a 180 mug/wk plus ribavirin 1000/1200 mg/day after achieving a rapid virological response (RVR; HCV RNA level <50 IU/mL) at week 4 in a prospective trial investigating response-guided therapy. Non-RVR patients with an early virological response were randomized to 48 or 72 weeks of therapy (this is a still-ongoing trial). A total of 150 of 516 patients (29%) had an RVR, 143 of whom completed 24 weeks of treatment. Younger patients, leaner patients, and those with an HCV RNA level </=400,000 IU/mL and HCV genotype 4 infection were more likely to achieve an RVR; however, among patients with an RVR, no baseline factor predicted SVR. The SVR rate was 80.4% (115/143; 95% confidence interval [CI], 72.9-86.6) in patients who completed 24 weeks of treatment. The SVR rate was 86.7% (26/30; 95% CI, 69.3%-96.2%) in patients infected with genotype 4 and 78.8% in those infected with genotype 1 (89/113; 95% CI, 70.1%-85.9%; intent to treat: 89/120; 74.2%; 65.4-81.7%). Treatment was well tolerated. This prospective study confirms that a 24-week regimen of peginterferon alfa-2a plus ribavirin 1000/1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy.

P.411 The impact of age on sustained virological response in genotype 1 HIV-HCV co-infected patients receiving peginterferon alpha-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®): AIDS PEGASYS ribavirin co-infection trial (APRICOT)

Patterns of gene expression for the facilitative glucose transporters 1–4 (GTs 1–4) were mapped using in situ hybridization on rat brains from embryonic day 11 (E 11) through adulthood. GT2 and GT4 mRNAs were not detected at any stage of development. Prior to the formation of the blood-brain barrier (BBB), GT1 mRNA was localized in the germinal neuroepithelium. During and after formation of the BBB, GT1 mRNA was abundant in brain and spinal cord vascular endothelium and in condensations of mesenchyme forming the meninges. With the gradual disappearance of the germinal neuroepithelium, GT1 mRNA was retained in the ependymal cell layer lining the ventricles. Postnatally, GT1 mRNA appeared in numerous small parenchymal cells, demonstrating characteristic glial cell morphology and distribution, and was not detected in neurons. GT3 mRNA, in contrast, was detected only in differentiated neurons, indicating that there is a switch from GT1 to GT3 gene expression by neuroepithelial cell lineages during the process of terminal neural differentiation. GT3 mRNA increased gradually from E14, attaining adult levels in most regions by postnatal day 20. The highest levels were found in large projection neurons of the olfactory system, hippocampal formation, neocortex (VI), and deep cerebellar, pontine, and brain stem nuclei. The ontogeny and neuroanatomical distribution of GT3 gene expression correlates with developmental and regional patterns of brain glucose utilization, suggesting that—while GT1 may have a role in the transfer of glucose across the BBB—GT3 expression determines brain glucose utilization.

The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients

Background / Aims : Questions remain regarding the etiology of steatosis in hepatitis C, and its impact on disease progression and treatment outcomes. Methods : We evaluated liver biopsies from 574 patients with chronic hepatitis C from a single center. Results : Severity of steatosis was associated with body mass index, HCV genotype 3 infection, age, and duration of infection ( P≤0.01). Serum HCV RNA levels were associated with severity of steatosis in HCV genotype 3 infection ( P≤0.03). In HCV genotype 1 infection, fibrosis was associated with severity of steatosis ( P<0.01), and patients who achieved SVR had lesser degrees of pre-treatment steatosis compared to nonresponders (4.6±1.6 vs. 10.1±1.1%, P=0.02). Genotype 1 infected patients with an early virologic response were more likely to have grade 0 steatosis compared to those without an early response (71 vs. 42%; P=0.003). Evaluation of paired biopsies demonstrated a marked decline in steatosis in genotype 3 patients who achieved SVR ( P<0.01). Conclusions : In conclusion, steatosis is an important cofactor in hepatitis C as it is associated with fibrosis and reduces the likelihood of achieving early and sustained virologic response in genotype 1 infected patients.

Treatment of patients with hepatitis C virus on the waiting list

1. Over 90% of patients with hepatitis C on the waiting list might be candidates for therapy with interferon plus ribavirin. 2. One must exercise caution in the treatment of these patients. Those with Child-Turcotte-Pugh score >11 or Model for End-Stage Liver Disease score >25 should be excluded from treatment. 3. Sustained virologic response (hepatitis C virus RNA-negative) is mainly dependent on viral genotype, with 50% of genotype 2 and 3 patients achieving sustained virologic response. 4. The ability to achieve sustained virologic response in genotype 1 patients is dependent on dose and duration of treatment. 5. Patients rendered hepatitis C virus RNA-negative pretransplantation may not experience posttransplantation recurrence.