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BackgroundIn Japan, hepatitis C virus (HCV)-infected patients with decompensated cirrhosis currently have no treatment options. In this Phase 3 study, we evaluated sofosbuvir–velpatasvir with or without ribavirin for 12 weeks in patients with any HCV genotype and decompensated cirrhosis [Child–Pugh–Turcotte (CPT) class B or C] in Japan.MethodsPatients were randomized 1:1 to receive sofosbuvir–velpatasvir with or without ribavirin for 12 weeks. Randomization was stratified by CPT class and genotype. Sustained virologic response 12 weeks following completion of treatment (SVR12) was the primary efficacy endpoint.ResultsOf the 102 patients enrolled, 57% were treatment naive, 78% and 20% had genotype 1 and 2 HCV infection, respectively, and 77% and 20% had CPT class B and C cirrhosis, respectively, at baseline. Overall, 61% of patients were female and the mean age was 66 years (range 41–83). SVR12 rates were 92% (47/51) in each group. Among patients who achieved SVR12, 26% had improved CPT class from baseline to posttreatment week 12. Most adverse events (AEs) were consistent with clinical sequelae of advanced liver disease or known toxicities of ribavirin. Four patients (8%) who received sofosbuvir–velpatasvir and seven (14%) who received sofosbuvir–velpatasvir plus ribavirin experienced a serious AE. The 3 deaths (bacterial sepsis, gastric varices hemorrhage, hepatocellular carcinoma) were attributed to liver disease progression.ConclusionSofosbuvir–velpatasvir for 12 weeks provides a highly effective and well-tolerated therapy for Japanese patients with HCV and decompensated cirrhosis. Ribavirin did not improve efficacy but increased toxicity.

Doravirine and islatravir is an investigational, once-daily, single-tablet regimen containing two potent antiretrovirals with complementary mechanisms of action and resistance profiles. We aimed to evaluate the efficacy and safety of switching from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·25 mg) in virologically suppressed adults living with HIV-1. This phase 3, randomised, active-controlled, open-label, non-inferiority trial was conducted at 53 research, community, and hospital-based clinics in eight countries: Australia, Canada, Colombia, Japan, South Africa, Switzerland, the UK, and the USA. Adults (aged ≥18 years) with a viral load of fewer than 50 copies of HIV-1 RNA per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, with no history of treatment failure, known resistance to doravirine, or active hepatitis B infection, were randomly assigned (2:1) according to a computer-generated randomisation schedule (block size three) to receive oral doravirine (100 mg) and islatravir (0·25 mg) once daily or to continue baseline ART for 48 weeks. Randomisation was stratified by the anchor antiretroviral drug class (integrase strand-transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor, or protease inhibitor) in the baseline regimen. The primary endpoint (assessed in all treated participants) was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 (analysed according to the US Food and Drug Administration snapshot approach); non-inferiority would be concluded if the upper bound of the multiplicity-adjusted 95% CI for the treatment difference was less than 4%. The safety analysis population included all randomly assigned participants who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT05631093, and is ongoing but closed to enrolment. Between Feb 20 and Oct 24, 2023, 614 individuals were screened for eligibility, of whom 553 were randomly assigned to receive doravirine and islatravir (n=368) or baseline ART (n=185). 551 participants received at least one dose of allocated medication: 366 in the doravirine and islatravir group and 185 in the baseline ART group. Of these 551 participants, 332 (60%) were assigned male and 219 (40%) were assigned female at birth, and the median age was 51 years (IQR 41–59); 250 (45%) identified as Black or African American and 80 (15%) identified as Hispanic, Latino, or Latina. Doravirine and islatravir showed non-inferiority at week 48, with viral loads of 50 copies per mL or higher in five (1·4%) of 366 participants versus nine (4·9%) of 185 participants on baseline ART (difference −3·6% [multiplicity-adjusted 95% CI −7·8 to −0·8]). Treatment-related adverse events were more common with doravirine and islatravir (44 [12·0%] of 366 participants) than with baseline ART (nine [4·9%] of 185 participants; difference 7·2 [95% CI 2·2 to 11·6]). Rates were similar in the doravirine and islatravir group and the baseline ART group for any adverse event (79·5% [291 of 366 participants] vs 83·8% [155 of 185 participants]; difference −4·3 [−10·7 to 2·8]), serious adverse events (6·3% [23] vs 4·9% [nine]; 1·4 [−3·2 to 5·2]), and discontinuation due to adverse events (0·5% [two] vs 2·2% [four]; −1·6 [−4·9 to 0·2]). One death occurred (in the baseline ART group) and was not considered treatment-related. No participants discontinued treatment as a result of protocol-specified declines in CD4 cell or total lymphocyte counts. Doravirine and islatravir is efficacious and well tolerated and would represent the first non-INSTI-based, two-drug regimen for HIV-1 treatment. With increasing concern over the potential development of widespread INSTI resistance, this once-daily, oral, single-tablet regimen could be a potential option for people living with HIV-1 requiring a change to their antiretroviral regimen. The safety and efficacy findings support the ongoing development of islatravir, a drug with long-acting potential. Merck Sharp & Dohme, a subsidiary of Merck & Co.

Background Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease among infants and young children worldwide, especially in low- and middle-income countries (LMICs). RSM01 is a novel, highly potent, half-life-extended anti-RSV monoclonal antibody (mAb) candidate primarily being developed for LMICs. Here we present the preclinical characterisation and results of a phase 1 trial of RSM01. Methods Preclinical characterisation of RSM01 was conducted using in-vitro neutralization assays and cotton rat models. In the first-in-human, double-blind, phase 1 trial, 56 healthy adults were randomised 6:1 within dose cohorts to receive a single dose of RSM01 ( n  = 48) or placebo ( n  = 8): 300 mg intravenously (IV), 300 mg intramuscularly (IM) or 1000 mg IV (parallel cohorts), 3000 mg IV, and an expansion cohort of 600 mg IM. Systemic solicited adverse events (AEs) were assessed through day 7; unsolicited AEs were collected through day 151. Pharmacokinetics and anti-drug antibodies (ADA) to RSM01 were assessed using immunoassays. A population pharmacokinetics model predicted paediatric pharmacokinetics parameters using allometric scaling and age-specific population weight statistics of North American and African infants. Results RSM01 exhibited highly potent neutralizing activity in the single ng/mL range (0.7–6.4) against diverse RSV-A and RSV-B isolates in vitro. RSM01 also demonstrated prophylactic efficacy in cotton rat models with both RSV subtypes. In the phase 1 clinical trial, the most common unsolicited AEs were COVID-19 (2/48), headache (2/48), and nausea (2/48), all in RSM01-treated participants. The only systemic solicited AEs reported were headache (5/48) and tiredness (2/48) in participants receiving RSM01. No serious AEs or deaths were reported. The half-life of RSM01 was 78 days with dose-proportional increases in T max and AUC last after IV administration. Among RSM01-treated participants, 2/48 were ADA positive at baseline, and 1/48 seroconverted to ADA-positive post-baseline. Conclusions RSM01 is a highly potent, half-life-extended, RSV-neutralising mAb candidate that was shown to be well tolerated in healthy adults. The rate of ADA to RSM01 was low. The long half-life of RSM01 and pharmacokinetics profile support further development of RSM01 as a potential single dose per season prophylaxis to prevent RSV disease in infants. Trial registration Clinicaltrials.gov NCT05118386, Nov 12, 2021.

The combination of doravirine and islatravir is under investigation as a fixed-dose, single-tablet regimen for the treatment of HIV-1. We aimed to assess the efficacy and safety of switching to doravirine (100 mg) and islatravir (0·25 mg) from bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV-1. This phase 3, randomised, controlled, double-blind, non-inferiority trial was conducted at 49 research, community, and hospital-based clinics in six countries: Australia, Chile, Israel, Japan, the UK, and the USA. Adults aged 18 years or older with HIV-1, who were virologically suppressed (with a viral load of HIV-1 RNA <50 copies per mL) for at least 3 consecutive months on bictegravir, emtricitabine, and tenofovir alafenamide and had no history of treatment failure or known resistance to doravirine, were eligible for the study. Participants were randomly assigned, in a 2:1 ratio according to a computer-generated randomisation schedule with a block size of three, to switch to oral doravirine (100 mg) and islatravir (0·25 mg) or to continue bictegravir, emtricitabine, and tenofovir alafenamide, once daily. Participants, investigators, study staff, and sponsor personnel were masked to study treatment; sponsor personnel directly involved in this analysis were unmasked at week 48. The primary endpoint, which was assessed in all randomly assigned participants who received at least one dose of study treatment, was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 according to the US Food and Drug Administration snapshot approach; non-inferiority would be concluded if the upper bound of the multiplicity-adjusted 95% CI for the treatment difference was less than 4%. The trial is registered at ClinicalTrials.gov, NCT05630755, and is ongoing but closed to enrolment. Between Feb 17 and Nov 17, 2023, 585 individuals were screened, of whom 514 were randomly assigned and 513 treated: 342 participants were switched to doravirine (100 mg) and islatravir (0·25 mg) and 171 continued bictegravir, emtricitabine, and tenofovir alafenamide. The median age of the 513 participants was 47 years (IQR 37–58), 403 (79%) were assigned male and 110 (21%) were assigned female at birth, 158 (31%) were Black or African American, and 117 (23%) were Hispanic, Latino, or Latina. At week 48, doravirine and islatravir showed non-inferiority to bictegravir, emtricitabine, and tenofovir alafenamide (viral load ≥50 copies per mL in five [1·5%] of 342 vs one [0·6%] of 171 participants) with a treatment difference of 0·9% (multiplicity-adjusted 95% CI −1·9 to 2·9). The rates of adverse events (74·6% [255 of 342 participants] vs 71·3% [122 of 171 participants]; difference 3·2 [95% CI −4·7 to 11·6]), treatment-related adverse events (10·2% [35] vs 9·4% [16]; 0·9 [−5·1 to 6·0]), serious adverse events (4·4% [15] vs 6·4% [11]; −2·0 [−7·1 to 1·9]), and discontinuations due to adverse events (2·9% [ten] vs 1·8% [three]; 1·2 [−2·3 to 3·9]) were similar in the doravirine and islatravir group and the bictegravir, emtricitabine, and tenofovir alafenamide group, and no deaths were reported. The combination of doravirine (100 mg) and islatravir (0·25 mg) has similar efficacy and safety profiles to bictegravir, emtricitabine, and tenofovir alafenamide, and could provide a two-drug, once daily, oral single-tablet option without an integrase strand-transfer inhibitor for adults who are virologically suppressed and want to switch to a different ART regimen. Merck Sharp & Dohme, a subsidiary of Merck & Co.

Hepatitis C virus (HCV) exhibits great genetic diversity and is classified into 7 genotypes (GTs), with varied geographic prevalence. Until the recent development of pangenotypic direct-acting antiviral regimens, the determination of HCV GT was necessary to inform optimal treatment. Plasma samples with unresolved GT using standard commercial genotyping methods were subjected to HCV full-genome sequencing, and phylogenetic analysis was performed to assign GT. Four patients, previously classified as GT5 by LiPA or Abbott RealTime polymerase chain reaction assays, were identified as infected with a novel HCV GT. This novel HCV GT, GT8, is genetically distinct from previously identified HCV GT1-7 with >30% nucleotide sequence divergence to the established HCV subtypes. All 4 patients were originally from Punjab, India, but now reside in Canada and are epidemiologically unlinked. Despite presence of baseline resistance-associated substitutions within the GT8 virus of all 4 patients (NS3: V36L, Q80K/R; NS5A: Q30S, Y93S), all patients achieved a sustained virologic response; 2 treated with sofosbuvir/velpatasvir/voxilaprevir for 8 weeks, 1 with sofosbuvir/ledipasvir plus ribavirin for 24 weeks and 1 with sofosbuvir plus daclatasvir for 12 weeks. The discovery of a novel HCV GT8 confirms the circulation of this newly identified lineage in the human population.

Type 3 secretion systems (T3SSs) of bacterial pathogens translocate bacterial effector proteins that mediate disease into the eukaryotic cytosol. Effectors traverse the plasma membrane through a translocon pore formed by T3SS proteins. In a genome-wide selection, we identified the intermediate filament vimentin as required for infection by the T3SS-dependent pathogen S. flexneri . We found that vimentin is required for efficient T3SS translocation of effectors by S. flexneri and other pathogens that use T3SS, Salmonella enterica serovar Typhimurium and Yersinia pseudotuberculosis. Vimentin and the intestinal epithelial intermediate filament keratin 18 interact with the C-terminus of the Shigella translocon pore protein IpaC. Vimentin and its interaction with IpaC are dispensable for pore formation, but are required for stable docking of S. flexneri to cells; moreover, stable docking triggers effector secretion. These findings establish that stable docking of the bacterium specifically requires intermediate filaments, is a process distinct from pore formation, and is a prerequisite for effector secretion. Binding of type 3 secretion system translocons to host intermediate filaments mediate Shigella , Salmonella and Yersinia docking and facilitate effector translocation.

Among patients coinfected with HIV-1 and HCV genotype 1 or 4 who were receiving effective antiretroviral therapy, treatment with 12 weeks of ledipasvir and sofosbuvir was associated with a sustained HCV virologic response in 96% of patients. Globally, an estimated 4 million to 5 million persons are chronically infected with both human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV). 1 Patients who are coinfected with HIV-1 and HCV have higher rates of cirrhosis, hepatocellular carcinoma, and hepatic decompensation than do patients monoinfected with HCV; they also have a higher rate of death from any cause. 2 – 8 In observational cohort studies, treatment-induced clearance of HCV infection has been associated with decreased morbidity and mortality associated with liver disease. 9 , 10 However, treatment of HCV with interferon and ribavirin in patients who are coinfected with HIV-1 and HCV . . .

Sofosbuvir/velpatasvir (SOF/VEL) may be administered with atazanavir, cobicistat, darunavir, dolutegravir, efavirenz (EFV), elvitegravir, emtricitabine, lopinavir, raltegravir, rilpivirine, ritonavir, tenofovir alafenamide, or tenofovir disoproxil fumarate without dose adjustment. Use of SOF/VEL with EFV is not recommended. Abstract Background Combining antiviral regimens in the hepatitis C virus (HCV)/human immunodeficiency virus (HIV)-coinfected population can be complex as they share overlapping mechanisms for elimination that may result in drug interactions. The pharmacokinetics, safety, and tolerability of sofosbuvir/velpatasvir (SOF/VEL) with multiple antiretroviral (ARV) regimens were evaluated. Methods Healthy volunteers were enrolled into 2 phase 1, open-label, randomized, multiple-dose, cross-over studies. SOF/VEL and ARV regimens were administered alone and in combination; ARVs (and pharmacokinetic enhancers) included atazanavir (ATV), cobicistat (COBI), darunavir (DRV), dolutegravir (DTG), efavirenz (EFV), elvitegravir (EVG), emtricitabine (FTC), lopinavir (LPV), raltegravir (RAL), rilpivirine (RPV), ritonavir (RTV), tenofovir alafenamide (TAF), and tenofovir disoproxil fumarate (TDF). Geometric least squares means ratios (coadministration:alone) and 90% confidence intervals were constructed for area under the plasma concentration-time curve over the dosing interval, maximum concentration, and trough, for all analytes. Safety and tolerability were also evaluated. Results In total, 237 participants were enrolled. No clinically relevant differences in the pharmacokinetics (PK) of SOF, SOF metabolite GS-331007, or VEL were observed other than an approximate 50% decrease in VEL exposure when administered with EFV/FTC/TDF. No clinically relevant differences in the PK of ARVs were observed when administered with SOF/VEL. Study treatments were well tolerated, including no observed creatinine clearance changes during evaluation of TDF-containing regimens. Conclusions SOF/VEL and ARV regimens including ATV, COBI, DRV, DTG, EVG, FTC, LPV, RAL, RPV, RTV, TAF, or TDF may be coadministered without dose adjustment. Use of SOF/VEL with EFV-containing regimens is not recommended due to an approximate 50% reduction in VEL exposure.

Mycobacterium marinum, a natural pathogen of fish and frogs and an occasional pathogen of humans, is capable of inducing actin tail formation within the cytoplasm of macrophages, leading to actin-based motility and intercellular spread. Actin tail formation by M. marinum is markedly reduced in macrophages deficient in the Wiskott-Aldrich syndrome protein (WASP), which still contain the closely related and ubiquitously expressed protein N-WASP (neuronal WASP). In fibroblasts lacking both WASP and N-WASP, M. marinum is incapable of efficient actin polymerization and of intercellular spread. By reconstituting these cells, we find that M. marinum is able to use either WASP or N-WASP to induce actin polymerization. Inhibition or genetic deletion of tyrosine phos-phorylation, Nck, WASP-interacting protein, and Cdc42 does not affect M. marinum actin tail formation, excluding the participation of these molecules as upstream activators of N-WASP in the initiation of actin-based motility. In contrast, deletion of the phosphatidylinositol 4,5-bisphosphate-binding basic motif in N-WASP eliminates M. marinum actin tail formation. Together, these data demonstrate that M. marinum subversion of host actin polymerization is most similar to distantly related Gram-negative organisms but that its mechanism for activating WASP family proteins is unique.

In the ION-4 trial, hepatitis C virus relapse was rare, occurring only in African American patients, 80% receiving efavirenz for human immunodeficiency virus infection. We observed no indication that CYP2B6 polymorphisms associated with increased plasma efavirenz exposure explained the relapses.