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BACKGROUND: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. METHODS: We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. FUNDING: Bristol-Myers Squibb. FINDINGS: This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responde

Introduction: The all-oral combination of daclatasvir (DCV; pangenotypic NS5A inhibitor), asunaprevir (ASV; NS3 protease inhibitor), and BMS-791325 (non-nucleoside NS5B inhibitor) - DCV 3DAA regimen - was evaluated without ribavirin in HCV genotype (GT) 1-infected treatment-naive and -experienced patients without cirrhosis in a Phase 3, open-label, international clinical trial. Method(s): Patients received a fixed-dose combination (FDC) of DCV 30 mg, ASV 200 mg, and BMS-791325 75 mg twice daily for 12 weeks. SVR12 rates in the treatment-naive and -experienced cohorts were evaluated separately as key efficacy outcomes. Result(s): SVR12 was achieved by 92% of treatment-naive patients (Table). Among treatment-experienced patients, 89% achieved SVR12. Virologic failure occurred in 34 (8%) patients overall. Baseline characteristics were comparable between the treatment-naive (N=312) and treatment- experienced (N=103) cohorts. Overall, patients were 58% male and 26% IL28B (rs1297860) CC genotype; 73% were infected with GT 1a and 27% with GT 1b. One death reported posttreatment was considered not related to study treatment. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 (<1%) adverse events leading to treatment discontinuation. The most common adverse events (in >10% of patients) were headache, fatigue, diarrhea, and nausea. Conclusion(s): In this Phase 3 study of 415 patients, 12 weeks of alloral treatment with DCV/ASV/BMS-791325 FDC achieved high SVR12 rates in patients with chronic HCV GT 1 infection and was well tolerated. These findings demonstrate the potent antiviral activity, safety, and tolerability of the DCV 3DAA regimen in treatment-naive and treatmentexperienced patients without cirrhosis. [TABLE PRESENTED].

People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. Conclusion(s): Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017;66:1794-1804).Copyright © 2017 by the American Association for the Study of Liver Diseases.

Background: The efficacy of some HCV regimens is influenced by the presence of certain NS5A resistance associated variants (RAVs). To investigate if the pretreatment prevalence of NS5A RAVs in genotypes (GT) 1a and 1b varied by country, race or ethnicity, comprehensive analyses were performed using deep sequencing of NS5A from more than 5000 patients from 17 countries. Method(s): NS5A deep sequencing analysis with a 1% cut-off was performed. GT1a RAVs were defined as K24G/N/R, M28A/G/T/V, Q30H/G/R/E/K, L31any, P32L, S38F, H58D, A92K/T, Y93any, and GT1b RAVs were L31any, P32L, P58D, A92K, Y93any. Result(s): Pretreatment samples from 5046 patients were analyzed. Prevalence of NS5A RAVs was similar between the different regions for both GT1a and GT1b HCV infected patients (Table). In addition, no significant differences were observed in NS5A RAV prevalence between patients with different race or ethnicity. In the subset of patients who were treated with LDV/SOF for 12 weeks, SVR12 rates were similar in GT1b patients with and without pretreatment NS5A RAVs across all regions. In GT1a patients with pretreatment RAVs, SVR12 rates in North America were 91% (75/82) compared to 98% without NS5A RAVs. All seven GT1a patients who relapsed had pretreatment NS5A RAVs conferring >1000-fold reduced susceptibility to LDV (H58D, Y93H/N/F or multiple RAV combinations). However, 18 GT1a patients with similar RAVs conferring >1000-fold reduced susceptibility achieved SVR12 after LDV/SOF for 12 weeks. Conclusion(s): No significant difference in prevalence of NS5A pretreatment RAVs was observed between different regions, races or ethnicities. Overall, high SVR12 rates (91-100%) were observed in patients with or without NS5A RAVs with LDV/ SOF. In GT1a patients, lower SVR rate (72%) was observed in patients with pretreatment NS5A RAVs conferring high level (>1000-fold) resistance to NS5A inhibitors. (Table Presented).

Background: An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. Method(s): We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. Finding(s): This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, int

Background: Five years of tenofovir DF (TDF) treatment of HBeAgand HBeAg + chronic HBV patients (Studies 102 and 103) resulted in sustained viral suppression and no TDF resistance; in addition, either halting or regression of fibrosis was seen in 96% of patients. Here we present 6 year results from these 2 ongoing 8 year studies. Method(s): After completing 48 weeks of double-blind comparison of TDF to adefovir, all patients were eligible to continue open-label TDF. Patients were assessed every 3 months for safety and efficacy with annual resistance surveillance and annual assessments of bone mineral density (BMD) by DXA (starting Year 4). Result(s): Of 641 patients randomized and treated, 585 (91%) entered the TDF extension phase; 466 (73%) remain on study at year 6. In an on-treatment analysis (missing = excluded), 99.6% and 99% of patients HBeAg- and HBeAg + patients, respectively, had HBV DNA<400 copies/mL and ALT normalization was achieved by 86% and 78% of HBeAg- and HBeAg + patients; 50% of HBeAg + patients achieved HBeAg loss and 37% experienced anti-HBe seroconversion. HBsAg loss and seroconversion (Kaplan-Meier %) was observed in 11% and 8% of HBeAg + patients, respectively; 1 HBeAg- patient had sustained HBsAg loss/seroconversion at Year 5 (Week 240). TDF was well tolerated over the 6 year evaluation period. Less than 2% discontinued TDF due to an adverse event, and <= 1.5% experienced a confirmed renal event (>= 0.5 mg/dL increase in serum creatinine, phosphorus<2 mg/dL, or CrCL<50 mL/min). BMD (T scores) was stable over 2 years of evaluation. No resistance to TDF was detected through Year 6. Conclusion(s): In these two trials, TDF remains safe and effective over a 6 year treatment period, with no detectable TDF resistance; a relatively low rate of renal events and no evidence of clinically relevant bone loss were also observed.

Rare interstitial lung disease cases have been reported with albinterferon alfa-2b (albIFN) and pegylated interferon alfa-2a (Peg-IFNalpha-2a) in chronic hepatitis C virus (HCV) patients. Systematic pulmonary function evaluation was conducted in a study of albIFN q4wk vs Peg-IFNalpha-2a qwk in patients with chronic HCV genotypes 2/3. Three hundred and ninety-one patients were randomly assigned 4:4:4:3 to one of four, open-label, 24-week treatment groups including oral ribavirin 800 mg/d: albIFN 900/1200/1500 mug q4wk or Peg-IFNalpha-2a 180 mug qwk. Standardized spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) were recorded at baseline, weeks 12 and 24, and 6 months posttreatment, and chest X-rays (CXRs) at baseline and week 24. Baseline spirometry and DLCO were abnormal in 35 (13%) and 98 (26%) patients, respectively. Baseline interstitial CXR findings were rare (4 [1%]). During the study, clinically relevant DLCO declines (<=yen;15%) were observed in 173 patients (48%), and were more frequent with Peg-IFNalpha-2a and albIFN 1500 mug; 24 weeks posttreatment, 57 patients (18%) still had significantly decreased DLCO, with a pattern for greater rates with albIFN vs Peg-IFNalpha-2a. One patient developed new interstitial CXR abnormalities, but there were no clinically relevant interstitial lung disease cases. The risk of persistent posttreatment DLCO decrease was not related to smoking, alcohol, HCV genotype, sustained virologic response, or baseline viral load or spirometry. Clinically relevant DLCO declines occurred frequently in chronic HCV patients receiving IFNalpha/ribavirin therapy and commonly persisted for <=yen;6 months posttherapy. The underlying mechanism and clinical implications for long-term pulmonary function impairment warrant further research. © 2013 Blackwell Publishing Ltd.

Background: Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection. Method(s): After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (>=2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (>=1 unit decrease by Ishak scoring system). Finding(s): Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0.0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (>=1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0.0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug. Interpretation(s): In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis. Funding(s): Gilead Sciences. © 2013 Elsevier Ltd.

BACKGROUND: Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. METHOD(S): We conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin (207 patients) or matching placebo (71) for 12 weeks. In a second trial, patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks (103 patients) or 16 weeks (98). The primary end point was a sustained virologic response at 12 weeks after therapy. RESULT(S): Among patients for whom treatment with peginterferon was not an option, the rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, -23 percentage points; 95% CI, -35 to -11; P<0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%). CONCLUSION(S): In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Ef

Background: Patients infected with chronic hepatitis C virus (HCV) genotype (GT) 2 and 3 who are ineligible or unwilling to receive interferon or who have failed previous treatment with interferon currently have limited treatment options. The nucleotide HCV polymerase inhibitor sofosbuvir (SOF) in combination with ribavirin (RBV) has provided high rates of response in treatment-naive and treatment experienced patients with HCV GT 2 or 3. Method(s): We conducted 2 phase 3 studies in patients infected with HCV GT 2 and 3. In the POSITRON study, patients who were interferonineligible, -intolerant or -unwilling were randomly assigned (3:1) to receive SOF 400 mg daily and RBV 1000-1200 mg daily for 12 weeks or placebo. In the FUSION study, patients who had failed prior interferon therapy were randomly assigned (1:1) to receive 12 or 16 weeks of SOF 400 mg daily and ribavirin 1000-1200 mg daily. The primary efficacy end point was sustained virologic response (SVR) 12 weeks after the end of treatment. Result(s): In POSITRON, 207 patients (53% GT 2, 47% GT 3) were randomized to SOF+RBV and 71 (48% GT 2, 52% GT 3) received placebo; 54% were male, 16% had compensated cirrhosis, and 45% carried the IL28B CC genotype. In the FUSION study, 103 patients (35% GT 2, 62% GT 3) were randomized to receive SOF +RBV for 12 weeks and 98 patients (33% GT 2, 64% GT 3) were randomized to receive SOF +RBV for 16 weeks; 70% were male, 34% had compensated cirrhosis, and 30% carried the IL28B CC genotype. SVR12 rates are given in table. Extending treatment duration to 16 weeks improved SVR12 rate in patients with genotype 3 HCV infection, whereas the SVR12 rates for patients with GT 2 infection were similar in the 12- and 16-week arms. Relapse accounted for all virologic failure and no S282T variant was observed in patients with relapse. SOF with RBV for 12 or 16 weeks had a safety profile similar to that expected for RBV. There were few SAEs, and rates of discontinuation of the treatment regim

Albinterferon alfa-2b (albIFN) is a fusion protein of recombinant human albumin/recombinant interferon (IFN)-alpha-2b, with a200-h half-life. Safety/efficacy of albIFN q4wk was evaluated in 391 treatment-naive patients with chronic hepatitis C virus (HCV) genotype 2/3. Patients were randomized 3:4:4:4 to one of four open-label treatment groups: pegylated IFN (Peg-IFN)-alpha-2a 180 mug qwk or albIFN 900, 1200 or 1500 mug q4wk, plus oral ribavirin 800 mg/day, for 24 weeks. Primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <20 IU/mL 24 weeks post-treatment). SVR rates were as follows: 85%, 76%, 76% and 78% with Peg-IFNalpha-2a and albIFN 900, 1200 and 1500 mug, respectively (P = NS); corresponding rapid virologic response rates (HCV RNA <43 IU/mL at week 4) were as follows: 78%, 49% (P < 0.001), 60% (P = 0.01) and 71%. SVR rates were not influenced by interleukin 28B genotype, although rapid virologic response rates were greater with interleukin 28B CC (P = NS). Serious adverse event rates were as follows: 4%, 11%, 3% and 3% with Peg-IFNalpha-2a and albIFN 900, 1200 and 1500 mug, respectively. No increase in serious/severe respiratory events was noted with albIFN. Fewer absolute neutrophil count reductions <750/mm3 occurred with albIFN (P = 0.03), leading to fewer IFN dose reductions. Haemoglobin reductions <10 g/dL were less frequent with albIFN 900 and 1200 mug vs 1500 mug and Peg-IFNalpha-2a (P = 0.02), leading to fewer ribavirin dose reductions. albIFN administered q4wk produced fewer haematologic reductions than Peg-IFNalpha-2a, but had numerically lower SVR rates (P = NS) in patients with chronic HCV genotype 2/3. © 2012 Blackwell Publishing Ltd.

Background: Shortened courses of treatment with pegylated interferon alfa and ribavirin for patients with hepatitis C virus infection who experience rapid virologic response can be effective in appropriately selected patients. The cost-effectiveness of truncated therapy is not known. Objective(s): To assess the cost-effectiveness of response-guided therapy versus standard-duration therapy on the basis of best available evidence. Method(s): We developed a decision model for chronic hepatitis C virus infection representing two treatment strategies: 1) standard-duration therapy with pegylated interferon alfa and ribavirin for 48 weeks in patients with genotype 1 or 4 and for 24 weeks in patients with genotype 2 or 3 and 2) truncated therapy (i.e., 50% decrease in treatment duration) in patients with rapid virologic response. Patients for whom truncated therapy failed began standard-duration therapy guided by genotype. We used a Markov model to estimate lifetime costs and quality-adjusted life-years. Result(s): In the base-case analysis, mean lifetime costs were $46,623 +/- $2,483 with standard-duration therapy and $42,354 +/- $2,489 with truncated therapy. Mean lifetime quality-adjusted life-years were similar between the groups (17.1 +/- 0.7 with standard therapy; 17.2 +/- 0.7 with truncated therapy). Across model simulations, the probability of truncated therapy being economically dominant (i.e., both cost saving and more effective) was 78.6%. The results were consistent when we stratified the data by genotype. In one-way sensitivity analyses, the results were sensitive only to changes in treatment efficacy. Conclusion(s): Truncated therapy based on rapid virologic response is likely to be cost saving for treatment-naive patients with chronic hepatitis C virus infection. Cost-effectiveness varied with small changes in relative treatment efficacy. © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR).

Background: After 5 years of TDF treatment, high rates of virological suppression and reversal of cirrhosis were observed in CHB patients. However, 14% of HBeAg-negative (study 102) and 26% of HBeAg-positive (study 103) patients on treatment did not achieve normal ALT values at Year 5. Method(s): Retrospective pooled analysis of subjects participating in studies 102 and 103 who are continuing on open-label TDF for up to 7 years. The association of baseline (BL) factors that include patient demographics and disease characteristics and on-treatment virologic, serologic, and histologic responses were evaluated for subjects remaining on study at Year 5 (N=471) who achieved normal ALT (n=384) and for those with ALT > ULN (n=87); logistic regression was used to assess the relationship between baseline and efficacy variables and normal ALT at Year 5. Result(s): A higher % of patients with normal ALT at Year 5 were >40 years of age at baseline (58% vs. 42%, p=0.012), HBeAg-negative (66% vs. 47%; p=0.0013), and mean BMI was lower (25 vs. 28 kg/m2; p<0.001); no other demographic differences were observed. Baseline ALT was similar between groups; patients with normal ALT at Year 5 also had a higher mean Knodell score at baseline (8 vs. 7; p=0.001). By multivariable analysis (Table), higher BMI at BL was the strongest independent predictor of a lack of achievement of normal ALT at 5 years in chronic HBV patients treated with TDF. Other factors of significance were HBeAg-positive status, lower BL Knodell score, and lower rate of HBV DNA suppression at Year 5. Conclusion(s): Despite successful virologic and histologic responses, lack of achievement of normal ALT in some patients following long term TDF treatment is likely due to etiologies other than HBV infection (e.g. obesity-related liver disease). Efforts to define the presence of steatosis or steatohepatitis are underway.

Background: We previously reported that 5 years of tenofovir DF (TDF) therapy in mostly treatment naive patients results in sustained virological suppression with no development of resistance and was associated with either the halting or regression of fibrosis in 96% of patients. Here we present 6 year results from these two ongoing 8 year studies (Studies 102 and 103). Method(s): After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, all patients undergoing liver biopsy were eligible to continue openlabel TDF. Patients were assessed every 3 months for safety and efficacy with annual resistance surveillance; annual assessments of bone mineral density (BMD) of the spine and hip by DXA were added starting at year 4. Result(s): In a total 641 patients who were initially randomized and treated, 585 (93%) entered the TDF extension phase, and at Year 6, 466 (73%) remain on study. Efficacy results at Year 6 are shown in the table. TDF was well tolerated over the 6 year evaluation period. Less than 2% of patients discontinued TDF due to an adverse event, and <=1.5% experienced a confirmed renal event (>=0.5 mg/dL increase in serum creatinine from baseline, phosphorus <2 mg/dL, or CrCL <50 mL/min). BMD (T scores) was stable over 2 years of evaluation. No resistance to TDF has been detected through Year 6. Conclusion(s): In these two trials, TDF remains safe and effective over a 6 year treatment period, with no detectable resistance to TDF; a relatively low rate of renal events and no evidence of clinically relevant bone loss were also observed. (Table Presented).

Background: Albinterferon-alfa-2b (albIFN) is a fusion protein of recombinant human albumin and rIFN-alpha2b with a half-life of 8 days. An active controlled study evaluated the safety and efficacy of albIFN q4w in treatment-naive patients with chronic HCV-2-3 hepatitis. Method(s): 391 patients were randomized 4:4:4:3 to one of 4 open-label treatment groups, in combination with oral ribavirin 800 mg/d: albIFN q4wks 900mug, 1200mug or 1500mug (6 injections) or PEG-IFNalpha2a 180mug q1wk (24 injections) for 24 weeks. An interim safety evaluation was conducted after all patients had completed the end of treatment while the interim efficacy endpoint was HCV RNA < LOD (20 IU/mL) at week 12 after end of treatment (SVR12). Patients were enrolled at 55 sites in Europe, Asia, Australia and Canada. Result(s): Rates of treatment discontinuation due to adverse events were 1.0%, 2.9%, 3.8%, and 1.3% in the alb- IFN 900mug, 1200mu g, 1500mug and PEG-IFNalpha2a groups respectively (p=NS). Serious AEs occurred in 4.9%, 2.9%, 2.9%, and 2.6% respectively (p=NS). No statistically significant increase in serious or severe respiratory events was noted in any albIFN arm as compared to PEG-IFNalpha2a. Rates of cough on albIFN were 21.6%, 21.4% and 26.7% respectively vs 19.2% on PEG-IFNalpha2a (p=NS). Rates of alopecia were 35.3%, 37.9%, 47.6% and 28.2% respectively (p=0.05). Overall, there were fewer hematology reductions on albIFN, leading to fewer IFN and ribavirin dose reductions. ANC reductions <750/mm3 were 5.0%, 13.7% and 8.6% for albIFN 900mug, 1200mug, 1500mug groups vs 17.9% on PEG-IFNalpha 2a (p=0.0279) while hemoglobin reductions <10g/dL were 11.9%, 18.4% 28.6% vs 25.6% respectively (p=0.0175). SVR 12 rates were 76%, 75%, 81% for albIFN 900mug, 1200mug and 1500mug, vs 82% for PEG-IFNalpha2a (intent to treat; p=NS). Corresponding rates of Rapid Virologic Response at week 4 (HCV RNA < 43 IU/mL) were respectively 49% (p<0.0001 vs PEG-IFNalpha2a) 60% (p=0.01), 71% (p=NS) vs 78% for