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Preclinical and clinical data suggest that fibroblast growth factor 21 (FGF21) is anti-fibrotic, improves metabolic status and has potential to treat non-alcoholic steatohepatitis (NASH). We assessed the safety and efficacy of efruxifermin, a long-acting Fc-FGF21 fusion protein, for the treatment of NASH. BALANCED was a randomized, placebo-controlled study in patients with NASH conducted at 27 centers in the United States (ClinicalTrials.gov NCT03976401 ). Eighty patients, stratified by hepatic fat fraction (HFF) and fibrosis stage, were randomized using a centrally administered minimization algorithm 1:1:1:1 to receive placebo ( n  = 21) or efruxifermin 28 mg ( n  = 19), efruxifermin 50 mg ( n  = 20) or efruxifermin 70 mg ( n  = 20) via weekly subcutaneous injection for 16 weeks. The primary endpoint—absolute change from baseline in HFF measured as magnetic resonance imaging–proton density fat fraction at week 12—was met. For the full analysis set, the least squares mean absolute changes (one-sided 97.5% confidence interval) from baseline in HFF were −12.3% (−infinity (−inf), −10.3), −13.4% (−inf, −11.4) and −14.1% (−inf, −12.1) in the 28-, 50- and 70-mg groups, respectively, versus 0.3% (−inf, 1.6) in the placebo group, with statistically significant differences between efruxifermin groups and placebo ( P  < 0.0001 each). Overall, 70 of 79 patients who received the study drug (89%) experienced at least one treatment-emergent adverse event (TEAE), with the majority grade 1–2 (64 (81%)), five (6%) grade 3 and one grade 4. The most commonly reported drug-related TEAEs were grade 1–2 gastrointestinal (36 (46%)). Treatment with efruxifermin significantly reduced HFF in patients with F1–F3 stage NASH, with an acceptable safety profile. Results from BALANCED, a phase 2a, multicenter, randomized controlled trial testing efruxifermin (a long-acting Fc-FGF21 fusion protein) over 16 weeks, demonstrated significant reductions in the hepatic fat fraction in patients with F1–F3 stage non-alcoholic steatohepatitis.

Lenacapavir is a first-in-class capsid inhibitor for the treatment of multidrug-resistant HIV-1 infection. In this initial trial, patients who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo.

Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19–1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06–0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19–0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. Gilead Sciences.

In two randomized, open-label trials, the combination of glecaprevir and pibrentasvir given once daily for 8 or 12 weeks achieved high rates of sustained virologic response in patients with HCV genotype 1 or 3 infection who did not have cirrhosis.

Twice-yearly subcutaneous lenacapavir has been shown to be efficacious for prevention of human immunodeficiency virus (HIV) infection in cisgender women. The efficacy of lenacapavir for preexposure prophylaxis (PrEP) in cisgender men, transgender women, transgender men, and gender-nonbinary persons is unclear. In this phase 3, double-blind, randomized, active-controlled trial, we randomly assigned participants in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF). The primary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with the background HIV incidence in the screened population. The secondary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with that in the F/TDF group. Among 3265 participants who were included in the modified intention-to-treat analysis, HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years; 95% confidence interval [CI], 0.01 to 0.37) and in 9 participants in the F/TDF group (0.93 per 100 person-years; 95% CI, 0.43 to 1.77). The background HIV incidence in the screened population (4634 participants) was 2.37 per 100 person-years (95% CI, 1.65 to 3.42). The incidence of HIV infection in the lenacapavir group was significantly lower than both the background incidence (incidence rate ratio, 0.04; 95% CI, 0.01 to 0.18; P<0.001) and the incidence in the F/TDF group (incidence rate ratio, 0.11; 95% CI, 0.02 to 0.51; P = 0.002). No safety concerns were identified. A total of 26 of 2183 participants (1.2%) in the lenacapavir group and 3 of 1088 (0.3%) in the F/TDF group discontinued the trial regimen because of injection-site reactions. The HIV incidence with twice-yearly lenacapavir was significantly lower than the background incidence and the incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 2 ClinicalTrials.gov number, NCT04925752.).

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis 1 – 5 . However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance 6 . In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment—which contributes to virologic failure, resistance generation and viral transmission—as well as of pre-exposure prophylaxis, leading to new infections 1 , 2 , 4 , 7 – 9 . Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence 10 . Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log 10 -transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV. The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.

Among patients coinfected with HIV-1 and HCV, a sustained HCV virologic response was reported in 97% of patients treated with 12 weeks of daclatasvir plus sofosbuvir. Liver disease is a leading cause of death among patients with human immunodeficiency virus type 1 (HIV-1) infection. 1 Coinfection with HIV-1 and hepatitis C virus (HCV) appears to accelerate the course of HCV-associated liver disease 2 – 5 and is widespread, particularly among injection-drug users. 6 The effect of HIV-1 coinfection on the course of HCV disease is reduced but not eliminated by antiretroviral therapy. 7 , 8 Adoption of interferon-based HCV treatments has been low among HIV–HCV coinfected patients 9 , 10 owing to a high adverse-event burden. 11 Furthermore, the rate of sustained virologic response to interferon–ribavirin is lower among patients with HIV–HCV coinfection than among . . .

In this phase 3 study involving patients with HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis, treatment with 12 weeks of sofosbuvir and velpatasvir resulted in a sustained virologic response in 99% of patients. The hepatitis C virus (HCV), a single-stranded RNA virus of the family Flaviviridae with six major genotypes, infects up to 150 million people worldwide. 1 , 2 Chronic HCV infection causes progressive liver fibrosis, which can lead to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. 3 , 4 As many as half a million people die annually from liver disease associated with chronic HCV infection. 5 In recent years, the development of drugs that directly interfere with HCV replication has revolutionized HCV treatment. There are now effective combinations of direct-acting antiviral agents for most patients, but in choosing an appropriate regimen, clinicians must take into account . . .

The continuing, randomised, multinational, phase IIB POWER 1 and 2 studies aim to evaluate efficacy and safety of darunavir in combination with low-dose ritonavir in treatment-experienced HIV-1-infected patients. We did a pooled subgroup analysis to update results at week 48 for patients receiving the recommended dose of darunavir-ritonavir compared with those receiving other protease inhibitors (PIs). After 24-week dose-finding phases and primary efficacy analyses, patients randomised to receive darunavir-ritonavir were given 600/100 mg twice daily, and patients receiving control PIs continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background regimen. We assessed patients who had reached week 48 or discontinued earlier at the time of analysis; for the darunavir-ritonavir group, only patients who received 600/100 mg twice daily from baseline were included. Analyses were intention-to-treat. The POWER 2 study (TMC114-C202) is registered with ClinicalTrials.gov ( NCT00071097). At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log 10 copies per mL or greater from baseline (primary endpoint; difference in response rates 46%, 95% CI 35%–57%, p<0·0001). Based on a logistic regression model including stratification factors (baseline number of primary PI mutations, use of enfuvirtide, baseline viral load) and study as covariates, the difference in response was 50% (odds ratio 11·72, 95% CI 5·75–23·89). In the darunavir-ritonavir group, rates of adverse events were mostly lower than or similar to those in the control group when corrected for treatment exposure. No unexpected safety concerns were identified. Efficacy responses with darunavir-ritonavir 600/100 mg twice daily plus optimised background regimen were greater than those with control PI and were sustained to at least week 48, with favourable safety and tolerability in treatment-experienced patients. This regimen could expand the treatment options available for such patients.

Background: Single cell transcriptomics offers an avenue for predicting, with improved accuracy, the gene networks that are involved in the establishment of the first direct cell–cell interactions between the blastocyst and the maternal luminal epithelium. We hypothesised that in silico modelling of the maternal–embryonic interface may provide a causal model of these interactions, leading to the identification of genes associated with a successful initiation of implantation. Methods: Bulk and single cell RNA-sequencing of endometrial epithelium and scRNAseq of day 6 and 7 trophectoderm (TE) were used to model the initial encounter between the blastocyst and the maternal uterine lining epithelium in silico. In silico modelling of the maternal–embryonic interface was performed using hypernetwork (HN) analysis of genes mediating endometrial–TE interactions and the wider endometrial epithelial transcriptome. A hypernetwork analysis identifies genes that co-ordinate the expression of many other genes to derive a higher order interaction likely to be causally linked to the function. Potential interactions of TE with non-ciliated luminal cells, ciliated cells, and glandular cells were examined. Results: Prominent epithelial activities include secretion, endocytosis, ion transport, adhesion, and immune modulation. Three highly correlated clusters of 25, 22 and 26 TE-interacting epithelial surface genes were identified, each with distinct properties. Genes in both ciliated and non-ciliated luminal epithelial cells and glandular cells exhibit significant functional associations. Ciliated cells are predicted to bind to TE via galectin–glycan interaction. Day 6 and day 7 embryonic–epithelial interactomes are largely similar. The removal of aneuploid TE-derived mRNA invoked only subtle differences. No direct interaction with the maternal gland epithelial cell surface is predicted. These functional differences validate the in silico segregation of phenotypes. Single cell analysis of the epithelium revealed significant change with the cycle phase, but differences in the cell phenotype between individual donors were also present. Conclusions: A hypernetwork analysis can identify epithelial gene clusters that show correlated change during the menstrual cycle and can be interfaced with TE genes to predict pathways and processes occurring during the initiation of embryo–epithelial interaction in the mid-secretory phase. The data are on a scale that is realistic for functional dissection using current ex vivo human implantation models. A focus on luminal epithelial cells may allow a resolution to the current bottleneck of endometrial receptivity testing based on tissue lysates, which is confounded by noise from multiple diverse cell populations.