Merck & Co.

The vaccine was generally well tolerated and induced cell-mediated immune responses against human immunodeficiency virus type 1 peptides in most healthy adults. Despite these findings, vaccination in a proof-of-concept trial with use of this vaccine was discontinued because of lack of efficacy.

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 (TCID 50 )-levels of 1×10 5 or 1×10 6 or placebo, 56 days apart. In part 2, younger and older (>55 years) adults received a single dose of one of four (10 4 /10 5 /10 6 /10 7 ) or one of two (10 5 /10 6 ) V591 TCID 50 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 1×10 7 TCID 50 , although titres were lower than convalescent serum. Interpretation V591 was generally well tolerated, but immunogenicity was insufficient to warrant continued development. Funding Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

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.

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.

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; APaT, all participants as treated; APRI, aspartate aminotransferase to platelet ratio index; ART, antiretroviral therapy; AST, aspartate aminotransferase; DAA, direct-acting antiviral; EBR/GZR, elbasvir/grazoprevir; FAS, full analysis set; GT, genotype; HBsAg, hepatitis B surface antigen; LLOQ, lower limit of quantification; mFAS, modified full analysis set; NS5A, non-structural protein 5A; RAS, resistance-associated substitutions; SVR, sustained virologic response; SVR12, sustained virologic response at 12 weeks after the completion of all study therapy. Abstract 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 | 1043 ASSELAH Et AL. 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 treatmentnaive 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. K E Y W O R D S hepatitis C, randomized controlled trial, therapeutics Key points • The combination of two drugs, elbasvir and grazoprevir, was effective in treating hepatitis C virus genotype 4 infection.• Some individuals require these medicines once daily for 12 weeks to achieve a cure, whereas many of those who have not been treated previously and have mild liver disease can achieve cure after treatment for 8 weeks. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Asselah T, Pol S, Hezode C, et al. Efficacy and safety of elbasvir/grazoprevir for 8 or 12 weeks for hepatitis C virus genotype 4 infection: A randomized study.

Chronic hepatitis C virus (HCV) infection afflicts nearly 71 million people worldwide, and left unchecked, and can cause cirrhosis, hepatocellular carcinoma (HCC) and liver-related death. 1 Since 2011, the standard of care treatment for HCV infection has shifted from pegylated interferon (PEG-IFN)-based therapy to direct-acting antiviral (DAA)-based treatments. This change has

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