Background We report on the safety and immunogenicity of V591, a measles vector-based SARS-CoV-2 vaccine candidate. Methods In this multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial, healthy adults with no history of COVID-19 disease were assigned to intramuscular injection of V591 or placebo (4:1 ratio). In part 1, younger adults (18-55 years) received V591 median tissue culture infectious dose (TCID50)-levels of 1 105 pound or 1 106 pound or placebo, 56 days apart. In part 2, younger and older (>55 years) adults received a single dose of one of four (104/ 105/106/107) or one of two (105/106) V591 TCID50 levels, respectively, or placebo. Primary outcome: safety/tolerability. Secondary outcome: humoral immunogenicity. ClinicalTrials.gov: NCT04498247. Findings From August-December 2020, 444 participants were screened and 263 randomised (210 V591; 53 placebo); 262 received at least one and 10 received two doses of V591 or placebo. Adverse events were experienced by 140/209 (67.0%) V591 dose-group participants and 37/53 (69.8%) placebo-group participants following injection 1; most frequent were fatigue (57 [27.3%] vs 20 [37.7%]), headache (57 [27.3%] vs 19 [35.8%]), myalgia (35 [16.7%] vs 10 [18.9%]), and injection-site pain (35 [16.7%] vs 4 [7.5%]). No deaths nor vaccine-related serious adverse events occurred. At Day 29, no anti-SARS-CoV-2 spike serum neutralising antibody and IgG-responses were identified in placebo or the three lower V591 dose-groups; responses were detected with V591 1 107 pound TCID50, although titres were lower than convalescent serum. Interpretation V591 was generally well tolerated, but immunogenicity was insufficient to warrant continued development. Copyright (c) 2022 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA and The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license

Various oral interferon- and ribavirin-free regimens are becoming available to treat chronic hepatitis C virus (HCV) infection. This phase 3 trial evaluates the effectiveness and tolerability of a ...

BACKGROUND & AIMS:Hepatitis C virus (HCV) genotype (GT) 4 infection is prevalent in sub-Saharan Africa and the Middle East, particularly in Egypt. This study evaluated the safety and efficacy of elbasvir/grazoprevir administered for 8 and 12 weeks in participants with HCV GT4 infection. METHODS:In this partially randomized, open-label multicentre study conducted in France (NCT03111108; Protocol MK5172-096), treatment-naive participants with GT4 infection and F0-F2 fibrosis were randomized 2:1 to elbasvir (50 mg)/grazoprevir (100 mg) for 8 or 12 weeks. Treatment-naive participants with F3-F4 fibrosis and all treatment-experienced participants (F0-F4) were assigned to elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response (SVR) 12 weeks after the end of therapy. RESULTS:One hundred and seventeen participants were enrolled. Among treatment-naive participants with F0-F2 fibrosis, SVR was achieved by 94% (50/53) and 96% (26/27) of those receiving elbasvir/grazoprevir for 8 or 12 weeks, respectively, and four participants relapsed. In the 12-week arm, 95% (35/37) achieved SVR and two participants relapsed. NS5A resistance-associated substitutions were present at baseline and virologic failure in five of the participants with relapse. Drug-related adverse events occurred in 42% (n = 22) and 50% (n = 32) of participants receiving 8 and 12 weeks of treatment, respectively. No participant discontinued treatment owing to an adverse event. CONCLUSION:These data confirm the efficacy of elbasvir/grazoprevir administered for 12 weeks in treatment-experienced individuals with HCV GT4 infection and those with advanced fibrosis. Treatment-naive individuals with mild fibrosis can be treated effectively with an 8-week regimen.

Direct‐acting antiviral treatments for chronic hepatitis C virus (HCV) infection are generally safe; however, understanding the safety profile of each regimen is essential for their continued use. Safety data were pooled from 12 clinical trials of elbasvir/grazoprevir (EBR/GZR) that enrolled adult participants with HCV infection. Pooled analyses are presented for participants receiving EBR/GZR for 12 weeks and those receiving EBR/GZR plus ribavirin (RBV) for 16‐18 weeks. Safety data are also presented for participants with comorbidities receiving EBR/GZR for 12 weeks in individual clinical trials (chronic kidney disease [CKD] stage 4/5, inherited blood disorders [IBLD] or receiving opioid agonist therapy [OAT]). Among 1743 participants receiving EBR/GZR for 12 weeks, 1068 (61.3%) reported ≥1 adverse event (AE) and 491 had AEs (28.2%) considered drug‐related. The most frequent AEs were headache (10.6%), fatigue (8.7%), nasopharyngitis (5.8%), nausea (5.1%) and diarrhoea (5.0%). Serious AEs were reported by 37 participants (2.1%), and 12 (0.7%) discontinued treatment due to an AE. In populations with CKD 4/5 or IBLD or receiving OAT, safety was similar in participants receiving EBR/GZR for 12 weeks and those receiving placebo. Some AEs occurred at higher frequencies in participants receiving RBV compared with those receiving EBR/GZR alone: fatigue (32.7% vs 8.7%); headache (21.6% vs 10.6%); and nausea (15.8% vs 5.1%). Safety was similar in participants with and those without cirrhosis. Grade 3/4 alanine aminotransferase elevations were reported in 0.7% participants. EBR/GZR is a safe treatment option for individuals with HCV genotype (GT) 1 or GT4 infections, even those with challenging comorbidities such as CKD or IBLD and those receiving OAT.

Background: Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection.Objective: To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients.Design: Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467)Setting: 60 centers in the United States, Europe, Australia, Scandinavia, and Asia.Patients: Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection.Intervention: Oral, once-daily, fixed-dose grazoprevir 100 mg/ elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy.Measurements: Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups.Results: Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% Cl, 92% to 97%[) achieved SVR12, including 144 of 157 (92% [Cl, 86% to 96%]) with genotype 1a, 129 of 131 (99% [Cl, 95% to 100%)) with genotype 1b, 18 of 18(100% [Cl, 82% to 100%]) with genotype 4, 8 of 10(80% [Cl, 44% to 98%]) with genotype 6, 68 of 70 (97% [Cl, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [Cl, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9(2.8%) and 3(2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point (Cl, -5.4 to 3.1 percentage points)); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%).Limitation: The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections.Conclusion: Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection.

BACKGROUND:Raltegravir has demonstrated potent and durable efficacy and a favorable safety profile in 3 phase III studies in treatment-naïve and treatment-experienced patients with HIV-1 infection. This manuscript provides a review of the raltegravir safety profile using data from these and other studies in the clinical development program.METHODS:Comprehensive 96-week safety data from STARTMRK (raltegravir versus efavirenz, each with tenofovir/emtricitabine) and BENCHMRK (raltegravir versus placebo, each with optimized background therapy) are summarized. A cumulative meta-analysis of raltegravir 400 mg bid was conducted across the entire development program.RESULTS:In STARTMRK, drug-related adverse events (AEs) occurred less frequently with raltegravir than efavirenz. In BENCHMRK, the most common drug-related AEs occurred at generally similar frequencies in both groups. Drug-related serious AEs were uncommon. Rash was observed in raltegravir-treated patients at a higher frequency than placebo but a lower frequency than efavirenz. Depression and immune reconstitution inflammatory syndrome occurred at similar rates for raltegravir and comparators. Isolated elevations of creatine kinase were more common with raltegravir than placebo but occurred without clinical manifestations. The frequency of aminotransferase elevations was greater in patients with viral hepatitis co-infection, but similar in the raltegravir and comparator groups. The relative risk (95% CI) of cancer was 0.75 (0.30, 1.91) indicating no difference between raltegravir and comparator. Overall trends in the cumulative meta-analysis were similar to those observed in the phase III studies.CONCLUSIONS:Long-term data from the phase III clinical trials demonstrate that raltegravir was generally well-tolerated in both treatment-naïve and treatment-experienced patients with HIV infection.

BACKGROUND:We analyzed human immunodeficiency virus (HIV) seroresponses from 3 phase I HIV-1 vaccine trials to assess the frequency of vaccine-induced seroconversion. METHODS:HIV-1 and HIV-2 enzyme-linked immunosorbent assay (ELISA) was performed during trials of adenovirus type 5 (Ad5)-vectored clade B HIV-1 monovalent gag and trivalent gag/pol/nef vaccines given to HIV-seronegative adults. Doses were administered at day 1, week 4, and week 26. Results were analyzed by vaccine formulation and dose and were stratified by baseline Ad5 titer. ELISA-positive samples were reflexively tested by Western blotting. RESULTS:Overall, 165 (41%) of 406 evaluable vaccine recipients had positive ELISA results but negative PCR results by week 78. Seroconversion rates were directly related to vaccine dose, were inversely related to baseline Ad5 titer, and were unaffected by vaccine valency. One hundred (89%) of 113 evaluable patients with low baseline Ad5 antibody titers (or=1 dose of vaccine with >or=1 x 10(10) gag-containing Ad5 particles per dose experienced seroconversion. Of 163 vaccine recipients who had positive ELISA results and available Western blot results, 150 (92%) had indeterminate results of Western blot, typically involving bands at p24, p40, and/or p55. Thirteen uninfected patients (8%) had equivocally positive Western blot results, usually because of an additional weak glycoprotein 41 band. Env-specific enzyme immunoassay results were falsely positive for 2 uninfected vaccine recipients. CONCLUSIONS:Positive ELISA results were similarly common for monovalent and trivalent vaccine recipients. Vaccine dose and baseline Ad5 immunity were major determinants of vaccine-induced seroconversion rates. Corresponding Western blots characteristically showed bands directed only at Gag proteins, which helped to distinguish HIV-uninfected vaccine recipients who experienced seroconversion from true HIV-infected patients. If available, an enzyme immunoassay exclusively targeting proteins not expressed by the vaccine should be the screening test of first choice for vaccine recipients.