Ronald Nahass

Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection

BACKGROUND Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. METHODS We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).

Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study.

Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)‐infected patients. The phase 2 COSMOS study reported high SVR rates in treatment‐naive and prior null‐responder HCV genotype (GT) 1‐infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST‐1 (NCT02114177) was a multicenter, randomized, open‐label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1‐infected treatment‐naive and treatment‐experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence or absence of NS3 Q80K polymorphism [GT1b, GT1a with Q80K, GT1a without Q80K]), prior HCV treatment history, and IL28B GT [CC, non‐CC]) to simeprevir 150 mg once daily+sofosbuvir 400 mg once daily for 12 or 8 weeks. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. Enrolled were 310 patients, who were randomized and received treatment (n = 155 in each arm). SVR12 with simeprevir+sofosbuvir for 12 weeks (97% [150/155; 95% confidence interval 94%‐100%]) was superior to the historical control (87%). SVR12 with simeprevir+sofosbuvir for 8 weeks (83% [128/155; 95% confidence interval 76‐89%]) was not superior to the historical control (83%). The most frequent adverse events were nausea, headache, and fatigue (12‐week arm: 15% [23/155], 14% [22/155], and 12% [19/155]; 8‐week arm: 9% [14/155], 17% [26/155], and 15% [23/155], respectively). No patients discontinued treatment due to an adverse event. One (1%, 12‐week arm) and three (2%, 8‐week arm) patients experienced a serious adverse event (all unrelated to study treatment). Conclusion: Simeprevir+sofosbuvir for 12 weeks is highly effective in the treatment of HCV GT1‐infected patients without cirrhosis, including those with Q80K. (Hepatology 2016;64:370‐380)

Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy a randomized trial

Background Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID). Objective To evaluate elbasvir-grazoprevir in treating HCV infection in PWID. Design Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688). Setting Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States. Patients 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT). Intervention The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks. Measurements The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events. Results The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event. Limitation These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID. Conclusion Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT. Primary Funding Source Merck & Co.

Infectious Diseases Specialty Intervention is Associated with Decreased Mortality and Lower Healthcare Costs

BACKGROUND Previous studies, largely based on chart reviews with small sample sizes, have demonstrated that infectious diseases (ID) specialists positively impact patient outcomes. We investigated how ID specialists impact mortality, utilization, and costs using a large claims dataset. METHODS We used administrative fee-for-service Medicare claims to identify beneficiaries hospitalized from 2008 to 2009 with at least 1 of 11 infections. There were 101 991 stays with and 170 336 stays without ID interventions. Cohorts were propensity score matched for patient demographics, comorbidities, and hospital characteristics. Regression models compared ID versus non-ID intervention and early versus late ID intervention. Risk-adjusted outcomes included hospital and intensive care unit (ICU) length of stay (LOS), mortality, readmissions, hospital charges, and Medicare payments. RESULTS The ID intervention cohort demonstrated significantly lower mortality (odds ratio [OR], 0.87; 95% confidence interval [CI], .83 to .91) and readmissions (OR, 0.96; 95% CI, .93 to .99) than the non-ID intervention cohort. Medicare charges and payments were not significantly different; the ID intervention cohort ICU LOS was 3.7% shorter (95% CI, -5.5% to -1.9%). Patients receiving ID intervention within 2 days of admission had significantly lower 30-day mortality and readmission, hospital and ICU length of stay, and Medicare charges and payments compared with patients receiving later ID interventions. CONCLUSIONS ID interventions are associated with improved patient outcomes. Early ID interventions are also associated with reduced costs for Medicare beneficiaries with select infections.

Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials

BACKGROUND & AIMS Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). METHODS In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. RESULTS In POLARIS-2, 95% (95% confidence interval [CI], 93%-97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%-99%; difference in the stratum-adjusted Mantel-Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%-99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%-1%). CONCLUSIONS In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.

Sofosbuvir plus pegylated interferon and ribavirin in patients with genotype 1 hepatitis C virus in whom previous therapy with direct‐acting antivirals has failed

Retreatment of patients who have not achieved sustained virological response (SVR) after treatment with investigational direct‐acting antiviral agents (DAAs) has not been extensively studied. We conducted an open‐label trial to assess the efficacy and safety of sofosbuvir (SOF) plus pegylated interferon (Peg‐IFN) and ribavirin (RBV) in patients with genotype 1 hepatitis C virus (HCV) who participated in previous studies of one or more Gilead investigational DAAs in combination with RBV with or without Peg‐IFN. We enrolled 80 patients at 40 sites. All patients received SOF 400 mg once daily plus Peg‐IFN‐α 180 μg/week and weight‐based ribavirin (1,000 or 1,200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 80 patients enrolled, 36 (45%) had received two or more courses of earlier treatment for HCV and 74 (93%) had at least one resistance‐associated variant (RAV) at baseline. SVR12 was achieved by 63 of the 80 patients (79%) treated. Rates of SVR12 were similar across patient subgroups. Presence of RAVs at baseline did not appear to be associated with treatment failure. Seventy‐one of eighty patients (89%) experienced at least one adverse event (AE), but most events were mild to moderate in severity. The most common AEs were fatigue, headache, and nausea. No patients discontinued all treatment because of AEs. Conclusion: These findings suggest that SOF plus Peg‐IFN and RBV for 12 weeks is effective and safe in patients who have not achieved SVR with earlier regimens of one or more DAAs plus Peg‐IFN and RBV. (Hepatology 2015;62:129‐134)

Safety and efficacy of the fixed-dose combination regimen of MK-3682/grazoprevir/ruzasvir in cirrhotic or non-cirrhotic patients with chronic HCV GT1 infection who previously failed a direct-acting antiviral regimen (C-SURGE)

193 • HCV NS3/4A protease inhibitor • 50 mg per tablet • HCV NS5A next-generation inhibitor • 30 mg per tablet • HCV NS5B polymerase nucleotide inhibitor • 225 mg per tablet Ruzasvir (MK-8408) Grazoprevir (MK-5172) MK-3682 C-SURGE: MK-3682/Grazoprevir/Ruzasvir • MK3 is a three-drug regimen formulated into a fixed-dose combination tablet. The regimen is given as two tablets, once-daily, without regard to food • Triplet also called MK-3682B Lawitz E, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 110. C-SURGE: Study Design • This multicenter, open-label trial randomized 94 HCV GT1infected patients who relapsed after a regimen of LDV/SOF or EBR/GZR (randomized 1:1; stratified by GT1a/1b and cirrhosis) MK-3682 + GZR + RZR + RBV† (16 weeks), n=45 MK-3682 + GZR + RZR (24 weeks), n=49 TW8 TW16 TW24 FW12 D1 SVR12 1° Endpoint Wyles D, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 193. C-SURGE: Study Demographics Demographics 16 Weeks + RBV, n=44* 24 Weeks without RBV, n=49 Overall GT1 N=93* Male, n (%) 37 (84) 43 (88) 80 (86) Age, median years, (range) 61.0 (33 to 70) 60.0 (25 to 71) 60.0 (25 to 71) Race, White, n (%) 31 (71) 37 (76) 68 (73) HCV Genotype 1a, n (%) 40 (90) 40 (82) 80 (86) Non-cirrhotic, n (%) Cirrhotic, n (%) 25 (57) 19 (43) 29 (6) 20 (41) 54 (58) 39 (42) NS5A RAVs at baseline, n (%)† NS3 RAVs at baseline, n (%)‡ 32 (79) 25 (57) 46 (94) 35 (71) 78 (84) 60 (65) Baseline HCV RNA >800,00 IU/mL, n (%) 35 (80) 44 (90) 79 (85) Median baseline HCV RNA (log10 IU/mL) 6.5 6.4 6.5 Previously failed: 12 – 24 weeks of LDV/SOF 8 weeks of LDV/SOF 12 weeks of EBR/GZR 26 (59) 9 (21) 9 (21) 31 (63) 5 (10) 13 (27) 57 (61) 14 (15) 22 (24) RAVs detected by next generation sequencing performed with a 15% sensitivity threshold. * Does not include 1 patient in the 16 week + RBV arm who withdrew prior to beginning treatment. Cirrhosis = Liver biopsy at any time showing cirrhosis, Fibroscan result of >12,5kPa within 12 months of enrollment, or Fibrotest >0.75 and APRI >2 at time of enrollment † NS5A RAVs = any change from wild-type at 4 positions (28, 30, 31, or 93) ‡ NS3 RAVs = any change from wild-type at 14 positions ( 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, or 175) Wyles D, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 193. C-SURGE: Results – Efficacy (Full Analysis Set) Wyles D, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 193. 91 98 98 92 100 100 0 10 20 30 40 50 60 70 80 90 100 TW4 SVR4 SVR8 Pe rc en t o f P at ie nt s w ith H C V R N A <1 5 IU /m L 16 Weeks + RBV 24 Weeks without RBV C-SURGE: Efficacy (mFAS*) TW =treatment week; SVR4 = % of patients with HCV RNA <15 IU/mL at 4 weeks after end of treatment *Excludes 1 patient from the 16-week + RBV arm who withdrew after receiving 3 doses of study medication 93 100 100 92 100 100 0 10 20 30 40 50 60 70 80 90 100 TW4 SVR4 SVR8 Pe rc en ta ge o f P at ie nt s w ith H C V R N A <1 5 IU /m L 16 Weeks + RBV 24 Weeks without RBV 40 43 45 49 43 43 38 38 43 43 30 30 Wyles D, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 193. C-SURGE: No Impact of Baseline NS5A or NS3 RAVs on SVR4 (Resistance Analysis Population) 100% 100% 100% 100% 100% 100% 100% 100% 0% 20% 40% 60% 80% 100% 16 Weeks + RBV 24 Weeks 16 Weeks + RBV 24 Weeks SV R 4 Patients without RAVs Patients with RAVs 35 35 3 3 28 28 10 10 31 31 12 12 24 24 19 19 Wyles D, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 193. No RAVS 12/43 28% RAVs 31/43 72% No RAVS 19/43 44% RAVs 24/43 56% No RAVS 10/38 26% RAVs 28/38 74% PR EV A LE N C E NS5A NS3 16 Weeks + RBV 16 Weeks + RBV 24 Weeks 24 Weeks

Clinical and Economic Impact of Empirical Extended-Infusion Piperacillin-Tazobactam in a Community Medical Center

Background: Current medical center practice allows for the automatic conversion of all piperacillin/tazobactam orders from intermittent to extended infusion (EI). Objective: To compare the clinical and cost impact of empirical extended-infusion piperacillin/tazobactam. Methods: All consecutive patients treated with piperacillin/tazobactam for >48 hours were reviewed for inclusion. Patients were stratified into 2 groups: (1) traditional infusion (TI), preprotocol implementation, and (2) EI, postprotocol implementation. Patient demographics and primary and secondary diagnoses were extracted from the hospital discharge database. All patients were assessed for the primary end point of all cause 14-day in-hospital mortality. Secondary outcomes included length of hospital stay, duration of antibiotic therapy, cost per treatment course, and occurrence of Clostridium difficile infection. Results: A total of 2150 patients were included (EI = 632; TI = 1518). After adjusting for comorbidity, length of stay, and age, 14-day in-hospital mortality was similar between groups (odds ratio = 1.16; 95% CI = 0.85-1.58; P = 0.37). Length of stay was similar between the EI group versus TI (mean ± SD: 12.5 ± 9.58 days vs 11.8 ± 9.58 days, respectively; P = 0.10) after adjusting for age and Chalson-Deyo comorbidity index. Total cost per treatment course was reduced in the EI group by 13% compared with the TI group (

Efficacy of 12 or 18 weeks of elbasvir plus grazoprevir with ribavirin in treatment-naïve, non-cirrhotic HCV genotype 3-infected patients

565.90 ±

Linkage to Care for Suburban Heroin Users with Hepatitis C Virus Infection, New Jersey, USA.

257.70 vs