[Proinsulin: physiology, measurement, and interest in clinical biology]. / La pro-insuline : physiologie, dosage et intérêt en biologie clinique.

The proinsulin molecule results from the cleavage of pre-pro-insulin, produced in pancreatic beta cells. Its subsequent -cleavage allows the release of insulin, the key hormone of glycemia regulation and C-peptide in equimolar proportions. During fasting trial, insulinoma diagnosis relies on inadequately high insulin and C-peptide serum levels concomitant with an hypoglycemia. In this context, proinsulin assay can be interesting in the cases of discrepancy between the two parameters. In diabetes, endoplasmic reticulum stress and beta cells inflammation, lead to the secretion of misfolded proinsulin molecules. Thus, in type 2 diabetes, proinsulin/insulin ratio increases with the degree of insulin resistance. In type 1 diabetes, proinsulin/C-peptide ratio could predict the onset of diabetes in relatives. In our practice, serum pro-insulin determined using an Elisa immunoassay (Millipore®) during fasting trial can be complementary to C-peptide and insulin assays in relation to glycemia to label an hypoglycemia. In case of glucose intolerance and diabetes, proinsulin could thus be measured.

Immunogenicity and safety of a fourth homologous dose of NVX-CoV2373.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has significantly reduced the efficacy of some approved vaccines. A fourth dose of NVX-CoV2373 (5 µg SARS-CoV-2 recombinant spike [rS] protein + 50 µg Matrix-M™ adjuvant; Novavax, Gaithersburg, MD) was evaluated to determine induction of cross-reactive antibodies to variants of concern. A phase II randomized study (NCT04368988) recruited participants in Australia and the United States to assess a primary series of NVX-CoV2373 followed by two booster doses (third and fourth doses at 6-month intervals) in adults 18-84 years of age. The primary series was administered when the SARS-CoV-2 ancestral strain was prevalent and the third and fourth doses while the Alpha and Delta variants were prevalent in AUS and US. Local/systemic reactogenicity was assessed the day of vaccination and for 6 days thereafter. Unsolicited adverse events (AEs) were reported. Immunogenicity was measured before, and 14 days after, fourth dose administration, using anti-spike serum immunoglobulin G (IgG) and neutralization assays against ancestral SARS-CoV-2 strain and Omicron sublineages. Among 1283 enrolled participants, 258 were randomized to receive the two-dose primary series, of whom 104 received a third dose, and 45 received a fourth dose of NVX-CoV2373. The incidence of local/systemic reactogenicity events increased after the first three doses of NVX-CoV2373 and leveled off after dose 4. Unsolicited AEs were reported in 9 % of participants after dose 4 (none of which were severe or serious). Anti-rS IgG levels and neutralization antibody titers increased following booster doses to a level approximately four-fold higher than that observed after the primary series, with a progressively narrowed gap in response between the ancestral strain and Omicron BA.5. A fourth dose of NVX-CoV2373 enhanced immunogenicity for ancestral and variant SARS-CoV-2 strains without increasing reactogenicity, indicating that updates to the vaccine composition may not be currently warranted.

Safety of the NVX-CoV2373 COVID-19 vaccine in randomized placebo-controlled clinical trials.

BACKGROUND: NVX-CoV2373 (Nuvaxovid™ or the Novavax COVID-19 Vaccine, Adjuvanted), the first protein-based COVID-19 vaccine, received emergency use authorization (EUA) as a primary series/booster and is available globally. NVX-CoV2373 primary series demonstrated efficacy rates of 89.7-90.4 % and an acceptable safety profile. This article summarizes safety in adult recipients (aged ≥ 18 years) of primary series NVX-CoV2373 in four randomized placebo-controlled trials. METHODS: All participants who received NVX-CoV2373 primary series or placebo (pre-crossover) were included according to actual received treatment. The safety period was from Day 0 (first vaccination) to unblinding/receipt of EUA-approved/crossover vaccine, end of each study (EOS), or last visit date/cutoff date minus 14 days. The analysis reviewed local and systemic solicited adverse events (AEs) within 7 days after NVX-CoV2373 or placebo; unsolicited AEs from after Dose 1 to 28 days after Dose 2; serious AEs (SAEs), deaths, AEs of special interest, and vaccine-related medically attended AEs from Day 0 through end of follow-up (incidence rate per 100 person-years). FINDINGS: Pooled data from 49,950 participants (NVX-CoV2373, n = 30,058; placebo, n = 19,892) were included. Solicited reactions after any dose were more frequent in NVX-CoV2373 recipients (local, 76 %/systemic, 70 %) than placebo recipients (local, 29 %/systemic, 47 %), and were mostly of mild-to-moderate severity. Grade 3+ reactions were infrequent, with greater frequency in NVX-CoV2373 recipients (local, 6.28 %/systemic, 11.36 %) than placebo recipients (local, 0.48 %/systemic, 3.58 %). SAEs and deaths occurred with similarly low frequency in NVX-CoV2373 (SAEs: 0.91 %, deaths: 0.07 %) and placebo recipients (SAEs: 1.0 %, deaths: 0.06 %). INTERPRETATION: To date, NVX-CoV2373 has displayed an acceptable safety profile in healthy adults. FUNDING: Supported by Novavax, Inc.

Safety, efficacy, and immunogenicity of the NVX-CoV2373 vaccine.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality worldwide. As SARS-CoV-2 moves into endemic status, vaccination remains a key element in protecting the health of individuals, societies, and economies worldwide. AREAS COVERED: NVX-CoV2373 (Novavax, Gaithersburg, MD) is a recombinant protein vaccine composed of SARS-CoV-2 spike trimer nanoparticles formulated with saponin-based Matrix-M™ adjuvant (Novavax, Gaithersburg, MD). NVX-CoV2373 is authorized for emergency use in adults and adolescents aged ≥12 years in the United States and numerous other countries. EXPERT OPINION: In clinical trials, NVX-CoV2373 showed tolerable reactogenicity and favorable safety profiles characterized by mostly mild-to-moderate adverse events of short duration and by low rates of severe and serious adverse events comparable to those seen with placebo. The two-dose primary vaccination series resulted in robust increases in anti-spike protein immunoglobulin G, neutralizing antibody titers, and cellular immune responses. NVX-CoV2373 vaccination was associated with complete protection against severe disease and a high (90%) rate of protection against symptomatic disease in adults, including symptomatic disease caused by SARS-CoV-2 variants. Additionally, the NVX-CoV2373 adjuvanted recombinant protein platform offers a means to address issues of COVID-19 vaccination hesitancy and global vaccine equity.

Safety, pharmacokinetics and antiviral activity of ABI-H2158, a hepatitis B virus core inhibitor: A randomized, placebo-controlled phase 1 study.

Treatment for chronic hepatitis B virus infection (cHBV) is mostly indefinite, with new finite-duration therapies needed. We report safety, pharmacokinetics and antiviral activity of the investigational HBV core inhibitor ABI-H2158. This Phase 1a/b study (NCT03714152) had three parts: Part A, participants received a single ascending oral dose of ABI-H2158 (5-500 mg) or placebo; Part B, participants received multiple doses of ABI-H2158 300 mg once (QD) or twice (BID) daily or placebo, for 10 days; Part C, cHBV patients received ABI-H2158 (100, 300, or 500 mg QD or 300 mg BID) or placebo, for 14 days. Ninety-three participants enrolled. In Parts A/B, there were no serious adverse events (SAEs) or deaths, and all treatment-emergent AEs (TEAEs) were Grade 1. In Part C, two patients had Grade 3 TEAEs unrelated to ABI-H2158; there were no deaths, SAEs or Grade 4 TEAEs. In Part A, median time to maximum ABI-H2158 plasma concentration (Tmax ) and mean terminal elimination half-life (t½ ) were 1-4 and 9.8-20.7 h, and area under the plasma concentration-time curve increased dose proportionally. In Part B, Day 10 Tmax was 2 h, mean t½ was 15.5-18.4 h, and exposure accumulated 1.7- to 3.1-fold. In Part C, Day 14 Tmax was 1 h, exposure accumulated 1.4- to 1.8-fold, and ABI-H2158 was associated with >2 log10 declines in HBV nucleic acids. In conclusion, ABI-H2158 in cHBV patients following 14 days of dosing was well tolerated and demonstrated potent antiviral activity. Safety and pharmacokinetics supported future QD dosing.

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial.

BACKGROUND: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. METHODS: Adults aged 18-84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. RESULTS: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%-88.8%). Vaccine efficacy was 100% (95% CI, 17.9%-100.0%) against severe disease and 76.3% (95% CI, 57.4%-86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein-specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. CONCLUSIONS: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. CLINICAL TRIALS REGISTRATION: EudraCT, 2020-004123-16.

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

Pharmacokinetics of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir in Healthy Chinese Subjects and HCV GT1b-Infected Chinese, South Korean and Taiwanese Patients.

BACKGROUND/PURPOSE: The 3 direct-acting antiviral (3D) regimen of ombitasvir/paritaprevir/ritonavir plus dasabuvir has recently been approved in several Asian geographic regions for the treatment of hepatitis C virus (HCV) genotype (GT) 1 infection. The pharmacokinetics of the components of the 3D regimen with or without ribavirin were evaluated in healthy Chinese subjects and HCV GT1b-infected Chinese, South Korean, and Taiwanese patients, with or without cirrhosis, to determine how the drug exposures in Asian populations compare with historical data in Western populations. METHODS: Participants received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily plus dasabuvir 250 mg twice daily for 14 days (healthy subjects, n = 36) or 12 weeks (HCV patients, n = 754). Patients with compensated cirrhosis also received ribavirin 1000 or 1200 mg divided twice daily, per the local label. Intensive or sparse pharmacokinetic sampling was performed for assessments of plasma drug concentrations. RESULTS: The exposures [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC)] of the components of the 3D regimen were comparable (< 20% difference) in healthy Chinese subjects residing in China or the United States. In addition, the trough plasma concentrations (Ctrough) in HCV GT1b-infected Asian patients were either similar to (ombitasvir) or within 75% of (paritaprevir and dasabuvir) those in Western patients without cirrhosis, or similar to (ombitasvir and paritaprevir) or within 100% of (dasabuvir) those in Western patients with cirrhosis, with widely overlapping ranges of individual values. Generally comparable drug exposures were observed among Chinese, South Korean, and Taiwanese ethnicities for noncirrhotic and cirrhotic patients. CONCLUSION: Collectively, the results of these pharmacokinetic analyses support the use of the same dose of the 3D regimen for Asian and Western patients. CLINICALTRIALS.GOV: NCT02534870, NCT02517515, NCT02517528.

Infectious diarrhea in autologous stem cell transplantation: high prevalence of coccidia in a South American center.

BACKGROUND: Diarrhea is frequently seen in autologous stem cell transplantation. Although toxicity related to conditioning is the most common cause, infectious pathogens can play a distinctive role particularly in certain regions and environments. METHODS: The role of enteropathogens was investigated in 47 patients submitted to autologous stem cell transplantation at a Brazilian center between May 2011 and May 2013. All patients who presented with diarrhea consented to stool sample analysis to identify the etiological agents including coccidia, Strongyloides sp., Clostridium difficile and other pathogenic bacteria. RESULTS: Thirty-nine patients (83%) had diarrhea, among whom seven (17.5%) presented with coccidia, three (7.5%) with Candida sp., one (2.5%) with C. difficile, and one (2.5%) with Giardia lamblia. There was a tendency toward a higher incidence of diarrhea in older patients (p-value = 0.09) and those who received conditioning with lomustine, etoposide, cytarabine, and melphalan (p-value = 0.083). Furthermore, the number of days of neutropenia was higher in patients with diarrhea (p-value = 0.06). CONCLUSIONS: The high frequency of diarrhea caused by coccidia shows the importance of investigating and correctly identifying etiological agents and highlights the possible varieties of intestinal infections in patients who undergo autologous stem cell transplantation.

Infectious diarrhea in autologous stem cell transplantation: high prevalence of coccidia in a South American center

ABSTRACT Background: Diarrhea is frequently seen in autologous stem cell transplantation. Although toxicity related to conditioning is the most common cause, infectious pathogens can play a distinctive role particularly in certain regions and environments. Methods: The role of enteropathogens was investigated in 47 patients submitted to autologous stem cell transplantation at a Brazilian center between May 2011 and May 2013. All patients who presented with diarrhea consented to stool sample analysis to identify the etiological agents including coccidia, Strongyloides sp., Clostridium difficile and other pathogenic bacteria. Results: Thirty-nine patients (83%) had diarrhea, among whom seven (17.5%) presented with coccidia, three (7.5%) with Candida sp., one (2.5%) with C. difficile, and one (2.5%) with Giardia lamblia. There was a tendency toward a higher incidence of diarrhea in older patients (p-value = 0.09) and those who received conditioning with lomustine, etoposide, cytarabine, and melphalan (p-value = 0.083). Furthermore, the number of days of neutropenia was higher in patients with diarrhea (p-value = 0.06). Conclusions: The high frequency of diarrhea caused by coccidia shows the importance of investigating and correctly identifying etiological agents and highlights the possible varieties of intestinal infections in patients who undergo autologous stem cell transplantation.

Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis.

BACKGROUND: The once-daily, all oral, RBV-free, pangenotypic direct-acting anti-viral regimen consisting of co-formulated NS3/4A protease inhibitor glecaprevir and NS5A inhibitor pibrentasvir (G/P), demonstrated high rates of sustained virologic response (SVR) in phase 2 and 3 studies outside Japan. METHODS: CERTAIN-1 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in Japanese patients with chronic HCV GT1 infection. Patients without cirrhosis received 8 weeks of G/P or 12 weeks of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r, 25/150/100 mg); patients with cirrhosis received G/P for 12 weeks. The primary efficacy endpoint was non-inferiority of G/P compared to OBV/PTV/r by assessing SVR at post-treatment week 12 (SVR12) among non-cirrhotic patients without the NS5A Y93H polymorphism. RESULTS: SVR12 was achieved by 128/129 (99.2%; one patient lost to follow-up) non-cirrhotic patients in the 8-week G/P Arm (including 23/23 patients with the NS5A Y93H polymorphism) and 52/52 (100%) patients in the 12-week OBV/PTV/r Arm. No patients from the G/P Arm prematurely discontinued the study drug or experienced a treatment-emergent serious adverse event (TESAE). Three patients from the OBV/PTV/r Arm experienced five TESAEs and one of these patients discontinued the study drug due to TESAEs. All 38 (100%) patients with compensated cirrhosis achieved SVR12; in this group, no TESAEs were reported and one patient discontinued treatment due to an AE. CONCLUSIONS: CERTAIN-1 study results demonstrate high efficacy and favorable tolerability of G/P in GT1-infected Japanese patients including those with the NS5A Y93H polymorphism, with no virologic failures observed.

Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection.

Glecaprevir (nonstructural protein 3/4A protease inhibitor) and pibrentasvir (nonstructural protein 5A inhibitor) (G/P), a coformulated once-daily, all oral, ribavirin (RBV)-free, direct-acting antiviral regimen, was evaluated for safety and efficacy in hepatitis C virus genotype 2 (GT2)-infected Japanese patients, including those with compensated cirrhosis. CERTAIN-2 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in treatment-naive and interferon ± RBV treatment-experienced Japanese patients without cirrhosis but with GT2 infection. Patients were randomized 2:1 to receive 8 weeks of G/P (arm A) or 12 weeks of sofosbuvir (400 mg once daily) + RBV (600-1000 mg weight-based, twice daily) (arm B). The primary endpoint was noninferiority of G/P compared to sofosbuvir + RBV by assessing sustained virologic response at posttreatment week 12 (SVR12) among patients in the intent-to-treat population. SVR12 was also assessed in treatment-naive and interferon ± RBV treatment-experienced patients with GT2 infection and compensated cirrhosis who received G/P for 12 weeks in the CERTAIN-1 study. A total of 136 patients were enrolled in CERTAIN-2. SVR12 was achieved by 88/90 (97.8%) patients in arm A and 43/46 (93.5%) patients in arm B. No patient in arm A experienced virologic failure, while 2 did in arm B. The primary endpoint was achieved. In CERTAIN-1, 100% (18/18) of GT2-infected patients with compensated cirrhosis achieved SVR12. Treatment-emergent serious adverse events were experienced by 2 patients without cirrhosis in each arm and no patient with cirrhosis. Conclusion: The results demonstrate high efficacy and favorable tolerability of G/P in GT2-infected Japanese patients. (Hepatology 2018;67:505-513).

Resistance characterization of hepatitis C virus genotype 2 from Japanese patients treated with ombitasvir and paritaprevir/ritonavir.

Treatment of HCV genotype (GT) 2-infected Japanese patients with paritaprevir (NS3/4A inhibitor boosted with ritonavir) and ombitasvir (NS5A inhibitor) without ribavirin for 12 weeks in the phase 2 study M12-536, and with ribavirin for 16 weeks in phase 3 study GIFT II resulted in SVR rates of 72.2% to 91.5%. Overall, 11 out of 125 patients with GT2a and 37 out of 79 patients with GT2b infection experienced virologic failure. The prevalence of baseline polymorphisms in NS3 and NS5A and their the impact on treatment outcome, as well as the development of viral resistance in GT2-infected patients experiencing virologic failure were evaluated by HCV NS3 and NS5A population and clonal sequence analyses. Baseline polymorphisms in NS3 that confer resistance to paritaprevir were rare in both GT2a- and GT2b-infected patients, while baseline polymorphisms in NS5A that confer resistance to ombitasvir were detected in 11.2% and 14.1% of the GT2a- and GT2b-infected patients, respectively. There was no significant impact of baseline polymorphisms on treatment outcome in Japanese patients. The most common treatment-emergent substitutions at the time of virologic failure occurred at amino acid positions 168 in NS3 and 28 in NS5A in both GT2a- and GT2b-infected patients. Although there was a higher rate of virologic failure in patients with GT2b infection, the resistance analyses presented in this report support the conclusion that testing for baseline resistance-associated polymorphisms is not warranted for HCV GT2-infected patients treated with a regimen of ombitasvir/paritaprevir/ritonavir + ribavirin for 16 weeks.

Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir ± Ribavirin for HCV in Brazilian Adults with Advanced Fibrosis.

INTRODUCTION AND AIM: Approximately 650,000 people in Brazil have chronic hepatitis C virus (HCV) infection. We evaluated the safety and efficacy of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus dasabuvir (DSV) with/without ribavirin (RBV) in an openlabel multicenter phase 3b trial in treatment-naive or interferon (IFN) treatment-experienced Brazilian patients with advanced hepatic fibrosis (METAVIR F3/4) and HCV genotype (GT) 1 infection. MATERIAL AND METHODS: All patients received coformulated OBV/PTV/r daily + DSV twice daily (3-DAA). GT1a-infected patients received 3-DAA plus RBV for 12 weeks, except for prior pegIFN/RBV nonresponders with cirrhosis who were treated for 24 weeks. GT1b-infected patients received 3-DAA alone (F3) or in combination with RBV (F4) for 12 weeks. The primary endpoint was sustained virologic response (HCV RNA < 15 IU/mL) at post-treatment Week 12 (SVR12). RESULTS: The study enrolled 222 patients, 214 achieved an SVR12 (96.4%; 95% CI, 93.1-98.2%), one GT1a-infected patient experienced virologic breakthrough, six (5 GT1a) relapsed, and one was lost to follow-up. SVR12 was achieved in 111/ 112 (99.1%) GT1b-infected patients, including 42/43 (97.7%) noncirrhotic, and 69/69 (100%) cirrhotic patients; and in 103/110 (93.6%) GT1a-infected patients, including 44/46 (95.7%) noncirrhotic and 59/64 (92.2%) cirrhotic patients. Overall there was a low rate of serious adverse events (n = 6, 2.7%). One patient experienced a treatment-related serious adverse event and one patient discontinued treatment because of an adverse event. DISCUSSION: The results confirm that the 3-DAA regimen with/without RBV is well tolerated and had a favorable safety profile and is efficacious in GT1-infected patients with advanced fibrosis (METAVIR F3/4).

Correction to: Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection.

Unfortunately, in the original publication of this article, the copyright line was incorrectly published in PDF as "© The Author(s) 2017" instead of "©The Author(s) 2017 This article is an open access publication" and also the CC-BY description was not included. The description should be as follows.

Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection.

BACKGROUND: Once-daily, orally administered, co-formulated glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) (G/P) demonstrated pangenotypic activity and high sustained virologic response (SVR) rates in studies outside Japan. Here we report safety and efficacy in a subset of Japanese patients with chronic HCV infection who received G/P 300/120 mg in a phase 3, open-label, multicenter study (CERTAIN-1). METHODS: This analysis focuses on three difficult-to-treat subgroups: HCV GT1/2-infected patients who failed to achieve SVR after treatment with a direct acting antiviral (DAA)-containing regimen; GT1/2-infected patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2); and GT3-infected patients. Patients in the renal impairment and GT3 cohorts were treatment-naive or interferon treatment-experienced. Noncirrhotic GT1/2-infected, DAA-naïve patients in the renal impairment cohort received G/P for 8 weeks; all other patients were treated for 12 weeks. Primary outcome was SVR (HCV RNA < 15 IU/mL) 12 weeks post-treatment (SVR12). RESULTS: The study enrolled 33 GT1/2-infected patients who failed previous DAA treatment (four with cirrhosis); 12 GT1/2-infected patients with severe renal impairment (two with cirrhosis); and 12 GT3-infected patients (two with cirrhosis). SVR12 was achieved by 31/33 (93.9%), 12/12 (100%), and 10/12 (83.3%) patients, respectively. One serious adverse event (fluid overload, not related to G/P) occurred in a patient on chronic intermittent hemodialysis. CONCLUSIONS: G/P achieved high SVR12 rates and was well tolerated in three difficult-to-treat patient subgroups with limited treatment options in Japan (DAA-experienced patients, patients with severe renal impairment, and GT3-infected patients). These results support the potential suitability of this regimen for these special populations in Japan.

Randomized Phase 3 Trial of Ombitasvir/Paritaprevir/Ritonavir and Ribavirin for Hepatitis C Virus Genotype 2-Infected Japanese Patients.

INTRODUCTION: In Japan, hepatitis C virus (HCV) genotype (GT) 2 accounts for approximately 32% of HCV infections. Limited treatment options exist in Japan for HCV GT2-infected patients. GIFT-II was a phase 3, randomized, open-label study evaluating the efficacy and safety of 16- and 12-week regimens of co-formulated ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (r) plus ribavirin (RBV) in Japanese adults with HCV GT2 infection. METHODS: Patients were randomized in a 1:1 ratio to once-daily, co-formulated OBV/PTV/r (25/150/100 mg) with weight-based RBV for 16 or 12 weeks. The primary efficacy endpoint was the sustained virologic response at 12 weeks post-treatment (SVR12) rate in the primary efficacy population of non-cirrhotic treatment-naive patients. RESULTS: A total of 171 patients were randomized to OBV/PTV/r + RBV. In the primary efficacy population, SVR12 rates were 91.5% (43/47; 95% confidence interval 83.5-99.5%) and 75.0% (36/48; 95% confidence interval 62.8-87.2%) in the 16-week arm and 12-week arm, respectively. No patient in the 16-week arm relapsed by post-treatment week 12. Among non-cirrhotic treatment-experienced patients, the overall SVR rate in the 16-week arm was 75.8% (25/33) and was highest [93.8% (15/16)] among those who had relapsed after previous interferon-based therapy. SVR12 rates were consistently higher in patients with HCV GT2a infection versus HCV GT2b infection [16-week treatment arm: 93.9% (31/33) versus 85.7% (12/14) and 93.8% (15/16) versus 56.3% (9/16) among non-cirrhotic treatment-naive and treatment-experienced patients, respectively]. No patient discontinued treatment because of an adverse event. The most common adverse events were anemia, increased blood bilirubin, and nasopharyngitis. CONCLUSIONS: OBV/PTV/r + RBV for 16 weeks resulted in high SVR12 rates in non-cirrhotic Japanese patients infected with HCV GT2 who were treatment-naive or who had relapsed after an interferon-based therapy. Higher SVR12 rates were observed among patients with HCV GT2a infection versus those with GT2b infection. This regimen demonstrated a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02023112. FUNDING: AbbVie.

Drug Interactions Between Hepatoprotective Agents Ursodeoxycholic Acid or Glycyrrhizin and Ombitasvir/Paritaprevir/Ritonavir in Healthy Japanese Subjects.

PURPOSE: The 2 direct-acting antiviral combination (2D) of ombitasvir and paritaprevir (coadministered with ritonavir) is being evaluated for the treatment of chronic hepatitis C virus infection in Japan. Ursodeoxycholic acid (UDCA) and glycyrrhizin (GCR) are hepatoprotective agents widely used in Japan. A drug-drug interaction (DDI) study was conducted to guide dosing recommendations for UDCA and GCR when coadministered with the 2D regimen. METHODS: DDIs between the 2D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg orally once daily) and UDCA (50 mg orally 3 times daily) or GCR (80 mg intravenously once daily) were evaluated in a 2-arm, multiple-dose study in 24 Japanese healthy subjects under fed conditions. Pharmacokinetic and safety evaluations were performed when UDCA or GCR and the 2D regimen were administered alone and during coadministration. Exposures from coadministration of the 2D regimen plus UDCA or GCR versus the 2D regimen, UDCA, or GCR alone were compared using repeated-measures analyses of natural logarithms of the maximum plasma concentration (Cmax) and area under the curve (AUC). FINDINGS: After coadministration of the 2D regimen and UDCA, steady-state exposures (Cmax and AUC) of ombitasvir, paritaprevir, and ritonavir showed a ≤9% change, and UDCA exposures showed a ≤20% change compared with administration alone. When the 2D regimen and GCR were coadministered, steady-state exposures of ombitasvir, paritaprevir, and ritonavir were not affected (≤9% change), GCR AUC increased by 49%, and GCR Cmax was unaffected (<1% change). IMPLICATIONS: No dose adjustment is needed for UDCA, GCR, or the 2D regimen when UDCA or GCR is coadministered with the 2D regimen in hepatitis C virus-infected patients under fed conditions. Clinical monitoring of patients using GCR is recommended due to an approximately 50% increase in GCR AUC when coadministered with the 2D regimen.