Plus Ribavirin Research Articles

PIN32 COST-UTILITY ANALYSIS OF NEW ANTIVIRAL TREATMENTS FOR NON-GENOTYPE 1 HEPATITIS C VIRUS IN CHINA: A SOCIETAL PERSPECTIVE

The arise of direct-acting antivirals (DAAs) has dramatically improved the efficacy and reduced the incidence of adverse events, making it possible to cure hepatitis C. Since 2017, several DAAs have been approved through priority approval procedures in China. Although genotype 1 is the most common in China, non-genotype 1 patients also need our attention. So our aim was to investigate the cost-utility of DAAs for non-genotype 1 patients and to afford some references for decision-making in China. A Markov model was established to estimate the lifetime costs, quality adjusted life years (QALYs) and the incremental cost-utility ratio (ICUR) for DAAs compared with pegylated interferon plus ribavirin (PR) from a societal perspective. The model input came from literatures, key opinion leader interviews, and databases specific to China. Sensitivity analyses were performed to evaluate model robustness and threshold analyses were performed to detect reasonable price for DAAs. For genotype 2, the pan-genotypic regimen sofosbuvir/velpatasvir was the most cost-effective compared with PR. As for genotype 3, the combination of sofosbuvir and daclatasvir was the most cost-effective. All DAA regimens for genotype 6 was cost-saving with sofosbuvir plus ribavirin being the optimal strategy. The incidence of long-term complications decreased significantly for all patients using DAAs. Probabilistic sensitivity analyses showed that the corresponding optimal strategy for each genotype had a probability of 58%, 83%, and 71% of being cost-effective compared with PR, respectively. Threshold analyses showed that the price of DAAs should be reduced by a certain degree to achieve better performance. For non-genotype 1 hepatitis C patients in China, DAAs are more cost-effective than PR, and they produce better health outcomes and higher quality of life. More importantly, reasonable price reduction of DAAs will increase drug affordability and is of great significance for the global strategy to eliminate viral hepatitis.

Sustained virological response to hepatitis C therapy does not decrease the incidence of systemic lupus erythematosus or rheumatoid arthritis

In patients with chronic hepatitis C (CHC), the effects of baseline characteristics, virological profiles, and therapeutic outcome to pegylated interferon plus ribavirin (PR) therapy on autoimmune diseases are unknown. Taiwanese Chronic Hepatitis C Cohort is a nationwide hepatitis C virus registry cohort comprising 23 hospitals of Taiwan. A total of 12,770 CHC patients receiving PR therapy for at least 4 weeks between January 2003 and December 2015 were enrolled and their data were linked to the Taiwan National Health Insurance Research Database for studying the development of 10 autoimmune diseases. The mean follow-up duration was 5.3 ± 2.9 years with a total of 67,930 person-years, and the annual incidence of systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) was 0.03%. Other autoimmune diseases were not assessable due to few events. Body mass index ≥24 kg/m2 was an independent predictor of the low incidence of SLE or RA (hazard ratio 0.40, 95% confidence interval 0.17–0.93, p = 0.034). A sustained virological response (SVR) to PR therapy was not associated with the low incidence of SLE or RA in any subgroup analysis. CHC patients achieving SVR to PR therapy did not exhibit an impact on the incidence of SLE or RA compared with non-SVR patients.

Long-term follow-up of HCV patients with sustained virological response after treatment with pegylated interferon plus ribavirin

BackgroundThe progress of liver diseases may not stop after viral eradication. This study aimed to provide data on long-term prognosis of patients with hepatitis C virus (HCV) infection who underwent pegylated interferon plus ribavirin (PR) regimen and achieved a sustained virological response 24 weeks post-treatment (SVR24). MethodsResponders to the PR regimen in our hospital from January 2011 to June 2014 were enrolled and prospectively followed up. Baseline characteristics were profiled. The incidence of hepatocellular carcinoma (HCC), progression of liver disease (increase in liver stiffness or occurrence of decompensated complication), and HCV recurrence was all monitored. The accumulative and annualized incidence rates (AIRs) of these adverse events were analyzed, and the risk factors were also examined. ResultsIn total, 151 patients reached a median follow-up time of 103 weeks. Among them, two had an incidence of HCC during the surveillance with AIR of 0.68% (95% CI: 0.00-1.63%). Six patients showed progression of liver disease with AIR of 2.05% (95% CI: 0.42%-3.68%). Three patients who had risky behaviors encountered HCV reinfection. The cirrhotic patients faced higher risk of poor prognosis than non-cirrhotic patients, including HCC and progression of liver disease (AIR: 6.17% vs. 1.42%, P = 0.039). ConclusionsThe incidence of HCC and progression of liver disease was evident in PR responders during the long-term follow-up period, but the risk level was low. Cirrhotic responders were more vulnerable to develop HCC post SVR24 compared with non-cirrhotic ones. HCV recurrence was rare in responders with SVR24 who had corrected their risky behaviors.

Detection of residual HCV-RNA in patients who have achieved sustained virological response is associated with persistent histological abnormality

BackgroundWhether achieving sustained virological response (SVR) in patients with hepatitis C attains complete elimination of hepatitis C virus (HCV) is unknown, because occult HCV infection (OCI), defined as the detection of HCV-RNA in hepatocytes or peripheral blood mononuclear cells (PBMC) in absence of serum HCV-RNA, may occur. We thus investigated the prevalence and clinical relevance of OCI. MethodsSubjects from three hospitals who had achieved serum HCV clearance, including 60 of Direct-acting antiviral agents (DAAs) induced SVR, 50 of pegylated interferon plus ribavirin (PR) induced SVR, and 30 of spontaneous resolution, were subjected to detect HCV-RNA in liver by robust RNAscope assay and PBMC by qPCR. Paired liver biopsies at baseline and at SVR24 were analyzed. ResultsOCI was detected in 16 of 140 subjects (11.4%), with 15.0% in DAA-based group, 10.0% in PR group and 6.7% in spontaneously resolved group. In DAA-based subgroups, the incidence of OCI was gradually increased in group of solely DAA(s) therapy, combining DAA and PR therapy and combining DAA and ribavirin therapy. OCI is more frequent in patients with genotype 3. No correlation between baseline viral load, interleukin-28B genotype, baseline transaminases, post-SVR transaminases and OCI were found. However, OCI was significantly linked with severity of fibrosis and active inflammation at post-SVR, even considering basal fibrosis status. In addition, both the magnitude and the frequency of fibrosis regression were lower in patients with OCI than in those without OCI. In the multivariate analysis, PR therapy was identified an independent negative prognostic factor for both hepatic inflammation (P = .022) and fibrosis regression (P = .015). Importantly, we found HCV relapse in one of the OCI patients at 48 weeks after the end of PR treatment. ConclusionsHCV-RNA can persist in hepatocytes and/or PBMC in a certain of patients who achieved spontaneous or treatment-induced HCV RNA clearance from serum and associated with persistent histological abnormality. Our findings provide new insights into cure of HCV and could influence the following-up scenario after SVR.

Detection of Residual HCV RNA in Patients Who Have Achieved Sustained Virological Response Is Associated with Persistent Histological Abnormality

Background: Whether achieving sustained virological response (SVR) in patients with hepatitis C attains complete elimination of hepatitis C virus (HCV) is unknown, because occult HCV infection (OCI), defined as the detection of HCV-RNA in hepatocytes or peripheral blood mononuclear cells (PBMC) in absence of serum HCV-RNA, may occur. We thus investigated the prevalence and clinical relevance of OCI. Methods: Subjects from three hospitals who had achieved serum HCV clearance, including 60 of Direct-acting antiviral agents (DAAs) induced SVR, 50 of pegylated interferon plus ribavirin (PR) induced SVR, and 30 of spontaneous recovery, were subjected to detect HCV-RNA in hepatocytes and PBMC. Paired liver biopsies at baseline and post-SVR were analyzed. Results: OCI was detected in 16 of 140 subjects (11.4%), with 15.0% in DAA-based group, 10.0% in PR group and 6.7% in spontaneously resolved group. OCI is more frequent in patients with genotype 3. No correlation between baseline viral load, interleukin-28B genotype, baseline transaminases, post-SVR transaminases and OCI were found. However, OCI was significantly linked with severity of fibrosis at post-SVR, even considering basal fibrosis status. In addition, both the magnitude and the frequency of fibrosis regression were lower in patients with OCI than in those without OCI. In the multivariate analysis, PR therapy was identified an independent negative prognostic factor for both hepatic inflammation (P = 0.022) and fibrosis regression (P = 0.015). Conclusions: HCV-RNA can persist in hepatocytes and/or PBMC in a certain of patients albeit achieving serum resolution of hepatitis C and associated with persistent histological abnormality. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (NNSFC) (No. 81673654) (to J.Zhao); NNSFC (No. 31770186) (to Y. Wang); NNSFC (No. 81802020) (to Y. Wang); and the National S&T Major Project for Infectious Diseases (No. 2017ZX10302201001007) (to J.Zhao). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was done in accordance with the ethical principles of the Declaration of Helsinki as revised in 2013 and was approved by the Ethics Committee by each institution’s human research committee, Peking University People’s Hospital, the first Hospital of Jilin University and Chinese PLA General Hospital. Informed consent was obtained from all participants prior to enrolment. Written informed consent was received from participants prior to inclusion in the study.

Hepatitis C Virus Elimination is Not Attained in a Certain of Immunocompetent Patients Who Achieved Sustained Viral Response to Direct-Acting Antiviral Agents

Background: Direct-acting antiviral agents (DAAs) have opened a new era for treating chronic hepatitis C virus (HCV) infection. However, whether DAA induced SVR attains real cure and complete eradication of HCV RNA is unknown, because occult HCV infection (OCI), as defined the detection of HCV RNA in hepatocytes or peripheral blood mononuclear cells (PBMC) in absence of serum of HCV RNA, may occur despite SVR and the clinical significance is yet to be established. We thus investigated the prevalence and provisional outcome of OCI in patients who achieved spontaneous or therapy-induced resolution of hepatitis C. Methods: Chronic HCV subjects from three tertiary hospitals who had achieved serum viral clearance, including 60 of DAAs treatment, 50 of pegylated interferon plus ribavirin (PR) treatment, and 30 of spontaneous recovery, were subjected to detect HCV RNA in hepatocytes by in suit hybridization as well as in PBMC by PCR. Liver function testes, HCV genotypes, and paired liver biopsies of pre- and post-treatment for each patient were acquired for comparison analysis. Findings: 16 of 140 subjects (11·4%) were found to have OCI, with the highest (15·0%) rate in DAA-based treated subjects, 10·0% in PR treated subjects and 6·7% in spontaneously resolved cases. Rates of OCI were 16·7% and 11·1% among patients with PR-free regimen and PR-based regimen, respectively. The existence of intermediate negative strand of HCV genome in all PBMCs of OCI patients suggested ongoing viral replication. The occurrence of OCI is more frequent in patients with genotype 3 HCV but less in patients with genotype 1. No correlation between baseline HCV viral load, interleukin-28B genotype, baseline transaminases, post transaminases and occurrence of OCI was found. While notably, OCI patients had more advanced liver fibrosis and active inflammation at both baseline and post- treatment. In addition, fibrosis scores were significantly decreased after SVR only in patients without OCI (P <0·001), but not in OCI subjects (P = 0·385). Patients with OCI have less incidence of fibrosis regression than in those without OCI after SVR. Importantly, we found two cases of HCV reactivation in OCI patients during 48 weeks to three-year follow up. Interpretation: HCV RNA can persist as ongoing replicative virus after treatment-induced or spontaneous serum resolution of hepatitis C, with highest incidence in patients with PR-free regimen induced SVR. The existence of OCI is associated with persistent pathological abnormality and likely to result in HCV relapse. Funding Statement:This study is supported by grants from National Natural Science Foundation of China (NNSFC) (No. 81673654) (to J.Zhao); NNSFC (No. 31770186) (to Y. Wang); the National S&T Major Project for Infectious Diseases (No. 2017ZX10302201001007). Declaration of Interests: The authors have declared that no competing interests exist. Ethics Approval Statement: This study was done in accordance with the ethical principles of the Declaration of Helsinki as revised in 2013 and was approved by the Ethics Committee by each institution’s human research committee. Informed consent was obtained from all participants prior to enrollment. All patients were recruited from three tertiary hospitals, Peking University People’s Hospital, the first Hospitalof Jilin University and Beijing 302 hospital.

Cost-effectiveness of daclatasvir plus asunaprevir for chronic hepatitis C genotype 1b treatment-naïve patients in China.

BackgroundHepatitis C is the second fastest growing infectious disease in China. The standard-of-care for chronic hepatitis C in China is Pegylated interferon plus ribavirin (PR), which is associated with tolerability and efficacy issues. An interferon- and ribavirin-free, all-oral regimen comprising daclatasvir (DCV) and asunaprevir (ASV), which displays higher efficacy and tolerability, has recently been approved in China.ObjectivesThis study is to estimate the cost-effectiveness of DCV+ASV (24 weeks) for chronic hepatitis C genotype 1b treatment-naïve patients compared with PR regimen (48 weeks) in China.MethodsA cohort-based Markov model was developed from Chinese payer perspective to project the lifetime outcomes of treating 10,000 patients with an average age of 44.5 with two hypothetical regimens, DCV+ASV and PR. Chinese-specific health state costs and efficacy data were used. The annual discount rate was 5%. Base-case analysis and sensitivity analysis were conducted.ResultsFor HCV Genotype 1b treatment-naïve patients, DCV+ASV proved to be dominant over PR, with a cost saving of ¥33,480(5,096 USD) and gains in QALYs and life years of 1.29 and 0.85, respectively. The lifetime risk of compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver-related death was greatly reduced with DCV+ASV. Univariate sensitivity analysis demonstrated that key influencers were the discount rate, time horizon, initial disease severity and sustained virological response rate of DCV+ASV, with all scenarios resulting in additional benefit. Probabilistic sensitivity analysis demonstrated that DCV+ASV has a high likelihood (100%) of being cost-effective.ConclusionDCV+ASV is not only an effective and well-tolerated regimen to treat chronic HCV genotype 1b infection treatment-naïve patients, but also is more cost-effective than PR regimen. DCV+ASV can benefit both the public health and reimbursement system in China.

Clinical value of pegylated interferon-α plus ribavirin-based therapy in antiviral treatment of chronic hepatitis C in China

Chronic hepatitis C virus (HCV) infection is one of the most common causes of liver cirrhosis and hepatocellular carcinoma in China. The older standard treatment regimen for chronic hepatitis C was the pegylated interferon-alfa plus ribavirin(PR). Now newer oral medications called direct antiviral agents (DAAs) has been gradually changed to PR-based DAAs and interferon-free, oral DAAs; making chronic hepatitis C a curable disease. This article intends to expound the advantages and disadvantages of PR-based therapy and provide reference for the treatment of chronic hepatitis C.

Combined Effects of 2 Interleukin 28B Polymorphisms on the Therapeutic Outcome of Hepatitis C Patients With Circulating Cryoglobulins.

Chronic hepatitis C is commonly associated with extrahepatic manifestations. Cryoglobulins are observed in 40% to 60% of such patients and their presence seems to modify response to therapy. The new antivirals are greatly improving the sustained virological response (SVR); however, their high cost limits the use, leaving pegylated interferon plus ribavirin (PR) still the standard-of-care therapy worldwide. Since PR therapy is burdened with several side effects, pretreatment predictions of patients who are unlikely to respond to this regimen may avoid ineffective treatment. Variants of the interleukin-28B (IL28B) gene correlate with an SVR to PR, and combined IL28B polymorphisms may improve the prediction of treatment outcome.The potential role of both rs8099917 and rs12979860 IL28B single nucleotide polymorphisms (SNPs) combined with presence of cryoglobulins in predicting SVR to PR in hepatitis C virus (HCV)-chronically infected patients was analyzed in the present study.Single and combined IL28B SNPs (rs12979860 and rs8099917) were analyzed in 64 chronic HCV patients treated with PR showing circulating cryoglobulins and compared to 108 noncryoglobulinemic subjects to verify the predictive value on the SVR.The association of rs12979860CC or rs8099917TT with SVR was confirmed in the noncryoglobulinemic group but not in cryoglobulinemic patients. Moreover, the combined determination of both SNPs improved the prediction of SVR in noncryoglobulinemic patients but not in the cryoglobulinemic subgroup.We report that both single and combined determination of IL28B rs12979860 and rs8099917 SNPs in chronic HCV patients with circulating cryoglobulins treated with PR may have a reduced predictive value of SVR.

Impact of HIV infection on sustained virological response to treatment against hepatitis C virus with pegylated interferon plus ribavirin.

It is commonly accepted that human immunodeficiency (HIV) coinfection negatively impacts on the rates of sustained virological response (SVR) to therapy with pegylated interferon plus ribavirin (PR). However, this hypothesis is derived from comparing different studies. The aim of this study was to determine the impact of HIV coinfection on SVR to PR in one single population. In a multicentric, prospective study conducted between 2000 and 2013, all previously naïve hepatitis C virus (HCV)-infected patients who started PR in five Spanish hospitals were analyzed. SVR was evaluated 24 weeks after the scheduled end of therapy. Of the 1046 patients included in this study, 413 (39%) were coinfected with HIV. Three hundred and forty-one (54%) HCV-monoinfected versus 174 (42%) HIV/HCV-coinfected patients achieved SVR (p < 0.001). The corresponding figures for undetectable HCV RNA at treatment week 4 were 86/181 (47%) versus 59/197 (30%), p < 0.001. SVR was observed in 149 (69%) HCV genotype 2/3-monoinfected subjects versus 91 (68%) HIV/HCV genotype 2/3-coinfected subjects (p = 0.785). In the HCV genotype 1/4-infected population, 188 (46%) monoinfected patients versus 82 (30%) with HIV coinfection (p < 0.001) achieved SVR. In this subgroup, absence of HIV coinfection was independently associated with higher SVR [adjusted odds ratio (95% confidence interval): 2.127 (1.135-3.988); p = 0.019] in a multivariate analysis adjusted for age, sex, baseline HCV RNA load, IL28B genotype, fibrosis stage, and type of pegylated interferon. HIV coinfection impacts on the rates of SVR to PR only in HCV genotype 1/4-infected patients, while it has no effect on SVR in the HCV genotype 2/3-infected subpopulation.

Interleukin-28B gene non-TT allele strongly predicts treatment failure for genotype 1 infected chronic hepatitis C patients with advanced fibrosis: a case control study

BackgroundThe role of single nucleotide polymorphisms (SNPs) of interleukin (IL)-28B in predicting therapeutic response of pegylated interferon (peg-IFN) plus ribavirin (PR) for genotype 1 infected chronic hepatitis C patients with advanced fibrosis (AF) is limited. The aim of this study is to assess its role in predicting sustained virologic responses (SVR) to treatment.MethodsForty-two patients with biopsy proven hepatitis C virus (HCV) related AF (group A; Ishak fibrosis score, ≥4) and 126 sex- and HCV genotype-matched patients without AF (group B; Ishak fibrosis score, ≤3) were recruited into study. All patients received PR therapy for 24 weeks. Baseline and on-treatment clinical, virological and host factors were evaluated for treatment efficacy.ResultsThe SVR rate was significantly lower in group A than group B patients with genotype 1 infection (24% vs. 53.3%; p = 0.011). However, it was similar in those with genotype non-1 infection (76.5% vs. 76.5%; p = 1.0). IL-28B rs8099917 genotype TT is the strongest predictor for SVR in genotype 1 infection. Patients who had TT genotype and achieved RVR in group A had similar SVR rates with those in group B (44.4% vs. 53.3%; p = 0.614). One third of patients in group A developed hematological adverse effects and had required modified doses during antiviral therapy.ConclusionsIn HCV genotype 1 infected AF receiving 24 weeks of PR treatment, patients with IL28B rs8099917 genotype TT, achieving RVR had similar SVR rate with those without AF. In contrast, patients with IL-28B rs8099917 non-TT genotype without achieving RVR are suggested to stop therapy.

Predictive factors associated with hepatitis C antiviral therapy response.

Hepatitis C virus (HCV) infection may lead to significant liver injury, and viral, environmental, host, immunologic and genetic factors may contribute to the differences in the disease expression and treatment response. In the early 2000s, dual therapy using a combination of pegylated interferon plus ribavirin (PR) became the standard of care for HCV treatment. In this PR era, predictive factors of therapy response related to virus and host have been identified. In 2010/2011, therapeutic regimens for HCV genotype 1 patients were modified, and the addition of NS3/4a protease inhibitors (boceprevir or telaprevir) to dual therapy increased the effectiveness and chances of sustained virologic response (SVR). Nevertheless, the first-generation triple therapy is associated with many adverse events, some of which are serious and associated with death, particularly in cirrhotic patients. This led to the need to identify viral and host predictive factors that might influence the SVR rate to triple therapy and avoid unnecessary exposure to these drugs. Over the past four years, hepatitis C treatment has been rapidly changing with the development of new therapies and other developments. Currently, with the more recent generations of pangenotipic antiviral therapies, there have been higher sustained virologic rates, and prognostic factors may not have the same importance and strength as before. Nonetheless, some variables may still be consistent with the low rates of non-response with regimens that include sofosbuvir, daclatasvir and ledipasvir. In this manuscript, we review the predictive factors of therapy response across the different treatment regimens over the last decade including the new antiviral drugs.

A pilot study of add-on oral hypoglycemic agents in treatment-naïve genotype-1 chronic hepatitis C patients receiving peginterferon alfa-2b plus ribavirin

Insulin resistance (IR) affects sustained virological response (SVR) to peginterferon alfa plus ribavirin (PR) in patients with chronic hepatitis C (CHC). Whether add-on oral hypoglycemic agents (OHAs) to PR improve SVR remains unclear; therefore, we conducted a prospective, randomized pilot trial on 23 consecutive patients with genotype 1 CHC and IR in Taiwan. Patients were randomized to receive acarbose (Arm A; n = 7) or metformin (Arm B; n = 6) or pioglitazone (Arm C; n = 5) in addition to peginterferon alfa-2b (1.5 μg/kg/week) plus ribavirin (1000-1200 mg/day) or just PR (Arm D; n = 5). The primary end point was SVR, and secondary end points were viral clearance at Weeks 17, 29, and 53. There were no differences among all arms at baseline. Using intent-to-treat analysis, SVR was observed in 66.7% (4/6), 83.3% (5/6), 66.7% (4/6), and 60% (3/5) in Arms A, B, C, and D, respectively. SVR was higher in female patients receiving OHA [90% (9/10)] than in male patients [50% (4/8)]. Results of per protocol analysis showed that SVR was 80.0% (4/5) in Arm A, 100% (5/5) in Arm B, 66.7% (4/6) in Arm C, and 60% (3/5) in Arm D. Patients receiving OHA had a higher rapid virologic response: 11/18 (61%) versus 2/5 (40%). Complete early virologic response was comparable between patients receiving OHA and PR [15/18 (83%) vs. 4/5 (80%)]. Our preliminary data show add-on OHAs to PR might achieve better early viral kinetics and SVR. However, further larger studies are needed to confirm these findings.

Commentary: efficacy and safety of ribavirin plus pegylated interferon‐alpha in geriatric patients with chronic hepatitis C

The study of Hu et al. from Taiwan1 adds evidence on the safety and efficacy of treatment with pegylated interferon-alpha plus ribavirin (PR) in elderly patients with chronic hepatitis C virus (HCV) infection. This topic is of clinical interest, as life expectancy is increasing both in developed and developing countries, anti-HCV positivity in the general population reaches peak prevalence in older age groups, the prevalence of cirrhosis in HCV-infected people above the age of 50 years is climbing and the yearly incidence of HCC reaches somewhere between 2% and 8%.2, 3 However, patients >65 years have been excluded from clinical trials of PR, because of a tendency towards lower sustained virological response (SVR) and a higher rate of treatment discontinuation.4-8 At the same time clinical data encourages the effort of treating chronic HCV in advanced age.9 In this context, the results of the present study support the view that treatment should not be denied to patients based on age, or other unfavourable factors, alone.10 However, because of the small number of cases in the age and HCV-genotype (HCV/G) subgroups, some differences may not have attained statistical significance. Thus, SVR rates were lower in older compared with middle-aged patients but the difference was significant only in HCV/G non-1 infections. Moreover, the duration of treatment was limited to 24 weeks regardless of HCV/G with SVR rates in HCV/G1 similar, or even higher, in comparison with those in patients from Western countries treated for 48 weeks with PR. Race variations, IL28B genotypes or other factors may account for these differences. Therefore, the findings of this Asiatic study are not transferrable, as such, to Western populations either with G1 or non-1 infections. Possibly the development of new all oral HCV therapies with direct-acting antivirals will become the standard of care in the difficult to treat HCV patients, including the elderly. Declaration of personal interests: Dr Hadziyannis has served as an advisory board member for Gilead and Novartis, and has received research funding from Janssen. Declaration of funding interests: None.

Resistance-associated amino acid variants associated with boceprevir plus pegylated interferon-α2b and ribavirin in patients with chronic hepatitis C in the SPRINT-1 Trial F

Resistance to direct-acting antivirals represents a new challenge in the treatment of chronic hepatitis C. SPRINT-1 was a randomized study of treatment-naive patients with genotype (G) 1 hepatitis C infection (n=595) that evaluated the safety and efficacy of boceprevir (BOC) when added to pegylated interferon-α2b plus ribavirin (PR). Plasma samples collected at protocol-specified visits were analysed by population sequencing for detection of BOC-associated resistance-associated variants (RAVs). A total of 17/24 (71%) patients randomized to BOC with baseline RAVs achieved sustained virological response (SVR). V55A/I (n=14), Q41H (n=11) and T54S (n=9) were the most frequently detected polymorphisms at baseline. Seven non-SVR patients with baseline RAVs had V55A (relapse, n=3; breakthrough, n=1; and non-response, n=1) and/or R155K (non-response, n=2). In total, 63/144 (44%) patients with sequenced post-baseline samples (2 SVR, 61 non-SVR) had detectable RAVs after BOC treatment (G1a: R155K [39/49; 80%], V36M [37/49; 76%] and T54S [24/49; 49%]; G1b: T54S [3/11; 27%], T54A [4/11; 35%], A156S [2/11; 18%] and V170A [2/11; 18%]). RAV frequency varied according to the virological response: 90%, 67%, 27% and 37% of breakthrough, incomplete virological response, relapse and non-responder patients, respectively, had post-baseline RAVs present. Similar RAVs were identified in both the PR lead-in and no-lead-in arms and the frequency of post-baseline RAVs was highest in the low-dose ribavirin arm. SVR rates were not compromised among patients with RAVs at baseline; however, a lower starting mg/kg dose of ribavirin was associated with a higher frequency of post-baseline RAVs.

1200 ANTIVIRAL ACTIVITY OF EP-NI266, A POTENT NUCLEOTIDE HCV POLYMERASE INHIBITOR

1198 HCV NS3/4A PROTEASE RESISTANCE-ASSOCIATED VARIANTS (RAVS) IDENTIFIED IN GENOTYPE 1A PATIENTS EXHIBIT DIFFERENCES IN PHENOTYPIC RESISTANCE TO BOCEPREVIR AND TELAPREVIR IN GENOTYPE 1A REPLICON CELLS S. Black, P. McMonagle, R. Chase, S. Curry, R.J.O. Barnard, D.J. Hazuda, A.Y. Howe, J.A. Howe, R.A. Ogert. Merck & Co., Inc., Kenilworth, NJ, USA E-mail: robert.ogert@merck.com Background: The HCV NS3 protease inhibitors boceprevir (BOC) and telaprevir (TPV) in combination with pegylated interferon alpha-2 plus ribavirin (PR) have been approved for treatment of HCV genotype 1 (GT 1) infection. The major RAVs identified in nonsustained virologic response (SVR) GT 1a infected patients were similar for BOC and TPV. These RAVs were analyzed for phenotypic resistance to BOC and TPV using an in-vitro GT 1a replicon assay. Methods: RAVs were detected by population sequencing in samples from SPRINT-2 (treatment naive) and RESPOND-2 (prior nonresponder/relapser) patients. RAVs were engineered into a GT 1a replicon derived from the H77 1a strain. Replicon cell lines were treated with BOC or TPV for 3 days, and HCVRNA was quantified by Taqman real time PCR analysis. Results: For patients treated with BOC, RAVs were detected in 53% of non-SVR patients with NS3 sequences available. In BOC treated, non-SVR HCV GT 1a infected patients; the most common RAVs were V36M, T54S and R155K. T54A and A156S/T were also identified in HCV GT 1a non-SVR treated patients but were observed more frequently in HCV GT 1b. A similar pattern of HCV GT 1a RAVs was identified in TPV treated patients (Bartels DJ, et al. Hepatology. 2011;54(S1):1328). These RAVs were analyzed for resistance to BOC and TPV in a GT 1a replicon assay. T54A and T54S produced similar fold-shifts in EC50 with BOC and TPV. However, V36M, R155K and A156S each produced a larger fold-shift in resistance to TPV than BOC. The fold shift in EC50 for each RAV was 2to 6-fold for BOC and 5to 16-fold for TPV. Also, the V36M + R155K double variant resulted in a >20-fold increase in EC50 for TPV but <10-fold for BOC.