[Posted 6/Nov/2024]

AUDIENCE: Gastroenterology, Infectious Disease, Internal Medicine

KEY FINDINGS: The results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection.

BACKGROUND: New antiviral approaches that target multiple aspects of the HBV replication cycle to improve rates of functional cure are urgently required. HBV RNA represents a novel therapeutic target. Here, we programmed CRISPR-Cas13b endonuclease to specifically target the HBV pregenomic RNA and viral mRNAs in a novel approach to reduce HBV replication and protein expression.

DETAILS: Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pregenomic RNA. Mammalian cells transfected with replication competent wild-type HBV DNA of different genotypes, a HBV-expressing stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-BFP (blue fluorescent protein) and crRNA plasmids, and the impact on HBV replication and protein expression was measured. Wild-type HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and serum HBsAg was measured. PspCas13b mRNA and crRNA were also delivered to a HBsAg-expressing stable cell line via lipid nanoparticles and the impact on secreted HBsAg determined. The HBV-targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p <0.0001). HBV protein expression was also reduced in a HBV-expressing stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p <0.0001) in vivo. Lipid nanoparticle-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p = 0.0168) in a HBsAg-expressing stable cell line.

Copyright © Elsevier Inc. All rights reserved.

Source: McCoullough, L. C., Fareh, M., Hu, W., et al. (2024). CRISPR-Cas13b-mediated Suppression of HBV Replication and Protein Expression. Journal of Hepatology. 2024; 81(5): 794-805. Published: November, 2024. DOI: 10.1016/j.jhep.2024.05.025.

A Case Report

[Posted 2/Mar/2026]

AUDIENCE: General Surgery, Infectious Disease

KEY FINDINGS: PDT mediated by MB is an effective and affordable approach for treating FEH associated with HPV in immunosuppressed patients, offering favorable outcomes and improved quality of life.

BACKGROUND: Human papillomavirus (HPV) infections are a major cause of oral lesions, and in individuals living with HIV, lesions such as focal epithelial hyperplasia (FEH) may persist or exhibit atypical features, potentially progressing to more severe conditions if untreated. Managing oral HPV lesions in immunocompromised patients is challenging, as conventional therapies may carry higher risks or show limited efficacy.

DETAILS: This study reports the case of a 49-year-old HIV-positive male with valve disease and arthritis, requiring crutches for mobility. He presented with multiple painless oral lesions, diagnosed as FEH associated with oral HPV, and had previously undergone unsuccessful treatments. Photodynamic therapy (PDT) using methylene blue (MB) and a red laser was proposed as a treatment. Topical MB-mediated PDT successfully cleared the FEH lesions, with no recurrence observed over 24 months.

Copyright © Wiley Periodicals LLC. All rights reserved

Source: de Araújo, J. C., Paiva, H. C., Faara, P. M. M., et al. Long-Term Control of Human Papillomavirus-Related Focal Epithelial Hyperplasia in an Human Immunodeficiency Virus-Positive Patient Using Methylene Blue-Mediated Photodynamic Therapy. A Case Report. Lasers in Surgery and Medicine. 2026; 58(2): 70-73. Published: February, 2026. DOI: 10.1002/lsm.70091

A Single-Centre, Open-Label, Randomised, Controlled, Superiority Trial

[Posted 28/Feb/2026]

AUDIENCE: Infectious Disease

KEY FINDINGS: Voriconazole was not superior to itraconazole for treating chronic pulmonary aspergillosis and was associated with a significantly higher incidence of adverse events. Our findings support the continued use of itraconazole as the preferred therapy for chronic pulmonary aspergillosis, although voriconazole remains a reasonable alternative. The choice between the two agents should be guided by factors such as patient tolerance, drug availability, and cost considerations.

BACKGROUND: Both itraconazole and voriconazole are used to treat chronic pulmonary aspergillosis. However, treatment success with itraconazole is only around 65-70%. Voriconazole, with its lower minimum inhibitory concentrations and better oral bioavailability, might offer improved outcomes, but no head-to-head comparison has been conducted to date. We aimed to evaluate whether oral voriconazole is superior to itraconazole in treating chronic pulmonary aspergillosis.

DETAILS: This single-centre, prospective, open-label, superiority trial was conducted at the chest clinic of a tertiary care hospital in Chandigarh, India. We enrolled treatment-naive adults aged 18 years or older with chronic cavitary pulmonary aspergillosis or chronic fibrosing pulmonary aspergillosis. We excluded those who denied consent, received any antifungal azoles for more than 3 weeks in the previous 6 months, or had other forms of aspergillosis. Participants were randomly assigned 1:1 to receive 200 mg twice daily of oral itraconazole or oral voriconazole for 6 months, using a computer-generated randomisation sequence with variable block sizes (4-8). Participants, staff administering the interventions, clinical outcome assessors, and data analysts were not masked to treatment assignment; a radiologist masked to clinical details and treatment allocation evaluated chest images. The primary outcome was the proportion of participants achieving a favourable response (clinical and radiological stability or improvement) at 6 months in the modified intention-to-treat population, which included all participants who received at least one dose of the allocated treatment. The safety analyses (a secondary outcome) were also performed in the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT04824417) and is complete. Between April 15, 2021, and May 31, 2024, 150 individuals were screened, and 116 were randomly assigned to receive itraconazole (n=58) or voriconazole (n=58). Of the 116 participants, 74 (64%) were men, 42 (36%) were women, and the mean age was 45.9 years (SD 14.4). All participants received at least one dose of the study drug and were included in the primary analysis. The proportion of participants achieving a favourable response at 6 months was similar in both groups (69% [40 of 58] receiving voriconazole vs 67% [39 of 58] receiving itraconazole; absolute risk reduction -0.02 [95% CI -0.2 to 0.15], p=0.84). Voriconazole was associated with significantly more treatment-related adverse events than itraconazole (55% [32 of 58] of participants receiving voriconazole vs 34% [20 of 58] receiving itraconazole, p=0.025). There were four deaths, all in the voriconazole group; none were directly attributable to the treatment.

Copyright © 2025 Elsevier Ltd. All rights reserved.

Source: Sehgal, I. S., Agarwal, R., Dhooria, S., et al. Oral Itraconazole Versus Oral Voriconazole for Treatment-Naive Patients With Chronic Pulmonary Aspergillosis in India (VICTOR-CPA Trial): A Single-Centre, Open-Label, Randomised, Controlled, Superiority Trial. The Lancet Infectious Diseases. 2026; 26(3): 239-249 Published: March, 2026. DOI: 10.1016/S1473-3099(25)00537-7.

A Welsh General Population-Based Cohort Study

[Posted 26/Feb/2026]

AUDIENCE: Internal Medicine, Gastroenterology

KEY FINDINGS: At risk thresholds often used for referral, liver fibrosis markers had prohibitively high false positive rates unless restricted to subgroups at increased risk of developing severe liver disease.

BACKGROUND: Liver disease is on the increase worldwide, with cirrhosis and liver cancer accounting for around 3.5% of all deaths. Investigate the prognostic utility of three non-invasive liver fibrosis markers in the Welsh primary care population for identification of those at risk of cirrhosis or hepatocellular carcinoma (HCC).

DETAILS: Using the Secure Anonymised Information Linkage (SAIL) Databank at Swansea University (2000–2017), we identified people with liver blood tests allowing calculation of three commonly used liver fibrosis markers: aspartate transaminase to alanine transaminase (AST/ALT) ratio, AST to platelet ratio index (APRI) and fibrosis-4 index (FIB-4). We modelled 10-year risk of cirrhosis/HCC across a range of thresholds using competing risk survival analysis and compared their prognostic value using decision curve analysis (DCA). Blood tests enabling calculation of FIB-4, APRI and AST/ALT were available for 203,005 people. At commonly utilized cut-points to detect advanced fibrosis/cirrhosis of 3.25, 1.5 and 1.0 for FIB-4, APRI and AST/ALT, respectively, the 10-year risks of cirrhosis/HCC were 4.7%, 16% and 1%. DCA demonstrated the APRI has the greatest net benefit for estimating cirrhosis/HCC risk over 10 years, in a general population compared to AST/ALT or FIB-4. In higher risk subgroups, a greater proportion of at-risk patients were captured for fewer referrals. This was also observed in groups with combinations of risk factors.

Copyright © John Wiley & Sons, Inc. All rights reserved

Source: Hill, T. A., West, J., Morling, J. R., et al. Identifying Subjects at Risk of Liver Cirrhosis via a Range of Thresholds for Common Fibrosis Markers: A Welsh General Population-Based Cohort Study. Journal of Internal Medicine. 2026; 299(3): 398-413. Published: February, 2026. DOI: 10.1111/joim.7006.

[Posted 25/Feb/2026]

AUDIENCE: Gastroenterology, Oncology

KEY FINDINGS: NPH contributed to discrepancies between IA and FA in IMbrave050. Robust IA require a minimum follow-up duration or event count before prematurely stopping RCTs in the presence of NPH.

BACKGROUND: Non-proportional hazards (NPH) can lead to discrepancies between interim (IA) and final analyses (FA) in randomized controlled trials (RCTs) of hepatocellular carcinoma (HCC). We assessed the impact of NPH in pivotal HCC trials and proposed strategies for more robust analyses.

DETAILS: Phase III pivotal HCC RCTs (2008–2024) were reviewed. Proportional hazards were tested using the Grambsch-Therneau method. For trials with NPH, we proposed an optimal IA timing (twice the estimated median of the primary endpoint in the control arm) or a minimum event threshold (>=60%). In NPH scenarios, the MaxCombo test, restricted mean survival time (rRMST), and piecewise hazard ratios were applied. NPH was present in 4/20 (20%) phase III trials in HCC, all involving immunotherapies, and displayed three patterns: 1) diminishing effects, 2) delayed effects, and 3) crossing hazards. Two RCTs (IMbrave050, LEAP-012) reported positive IA results with diminishing effects. In IMbrave050, discrepancies were observed when comparing IA and FA using MaxCombo analysis (p = 0.02 and p = 0.33, respectively), rRMST at 12 and 36 months (1.11 [p <0.001] and 1.08 [p = 0.08], respectively) and piecewise hazard ratios before vs. after 12 months (0.59 [95% CI 0.43-0.73] vs. 1.12 [95% CI 0.88-1.37]). In LEAP-012, results were consistent across 12 and 24 months (MaxCombo test p <0.001) and rRMST (1.20 [p <0.001) and 1.27 [p <0.001]). HIMALAYA and Checkmate 9DW reported positive results, which were confirmed by MaxCombo test. HIMALAYA showed delayed effects (rRMST at 12 and 36 months: 1.04 [p = 0.13] and 1.15 [p = 0.004]), while CheckMate 9DW displayed crossing hazards (rRMST at 12 and 36 months: 0.95 [p = 0.07] and 1.12 [p = 0.03]).

Copyright © Elsevier Inc. All rights reserved.

Source: Mauro, E., de Castro, T., Zeitlhoefler, M., et al. Strategies to Address Non-Proportional Hazards Between Survival Curves - Lessons From Phase III Trials in Hepatocellular Carcinoma. Journal of Hepatology. 2026; 84(3): 567-577. Published: March, 2026. DOI: 10.1016/j.jhep.2025.08.042.

[Posted 19/Feb/2026]

AUDIENCE: Hematology

KEY FINDINGS: This phase 2 clinical trial of a novel FD inhibitor met its primary efficacy endpoint because treatment with vemircopan led to a clinically meaningful increase in Hgb after 12 weeks of therapy in participants who were PNH treatment–naïve and participants who remained anemic despite treatment with eculizumab. Despite these improvements, inconsistent and suboptimal control of IVH resulted in 82 BT-IVH events reported by over half of the participants, which led to the early termination of the trial. Strategies to mitigate the critical risk of BT-IVH with dual inhibition with a terminal complement inhibitor may be warranted.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, debilitating, and potentially life-threatening hematologic disease characterized by uncontrolled terminal complement activation on red blood cells (RBCs), white blood cells, and platelets, resulting in intravascular hemolysis (IVH), thrombosis, and organ damage. Thrombotic events associated with PNH contribute to significant patient morbidity and mortality. Patients may also experience considerable fatigue and impaired health-related quality of life (QOL).

DETAILS: Authors present the results of a phase 2, open-label clinical trial of vemircopan monotherapy in patients with PNH to explore the efficacy and safety of inhibiting the complement alternative pathway via factor D. Adults (aged >=18 years) with PNH who were treatment-naïve and switched from eculizumab with hemoglobin (Hgb) of 10 g/dL or rolled over from danicopan monotherapy (ACH471-103 trial; ClinicalTrials.gov identifier: NCT03181633) were enrolled. The trial comprised a 60-day screening period, 12-week treatment period, and 148-week long-term extension. Participants received vemircopan 120 mg twice daily, with potential escalation to 180 mg twice daily. The primary endpoint was change in Hgb from baseline to week 12. Safety endpoints included treatment-emergent adverse events (TEAEs) and serious AEs. Twenty-nine participants were enrolled (treatment-naïve, n = 12; eculizumab-switch, n = 11; and danicopan-rollover, n = 6); all completed the 12-week treatment period, and 1 danicopan-rollover participant completed the long-term extension. Clinically meaningful improvements from baseline to week 12 in Hgb (change of >=2 g/dL) were reported in the treatment-naïve (mean, 3.6 [standard deviation [SD], 1.5]) and eculizumab-switch (mean, 3.3 [SD, 2.0]) cohorts and maintained through the end of the trial. Eighty-two breakthrough intravascular hemolysis (BT-IVH) events in 25 participants were reported. Twenty-eight participants reported TEAEs, and 14 reported serious AEs; most were unrelated to vemircopan. No deaths occurred. This trial evaluating vemircopan monotherapy met its primary efficacy endpoint; however, concerns regarding BT-IVH risk and suboptimal, inconsistent control of IVH emerged, leading to early trial termination.

Copyright © The American Society of Hematology. All rights reserved.

Source: Kulasekararaj, A., Browett, P., Risitano, A. M., et al. Efficacy and Safety of Vemircopan as Monotherapy in Patients With Paroxysmal Nocturnal Hemoglobinuria. Blood Adv.. 2026; 10(3): 540-554. Published: February, 2026. DOI: 10.1182/bloodadvances.2025017731.