Peginterferon-alfa mono-therapy in the treatment of acute hepatitis C in HIV-infection.

The ongoing epidemic of acute hepatitis C (AHC) infection among MSM highlights the need to identify factors allowing for optimal treatment outcome in HIV co-infected individuals. Cohort study of 105 HIV-infected patients with AHC infection from five centres in two European countries was carried out. Choice of treatment with pegIFN-alfa alone (group 1; n = 36) or pegIFN-alfa and ribavirin (RBV) (group 2; n = 69) was at the discretion of the investigator. Outcome was evaluated as RVR and SVR. Fisher's exact and Mann Whitney U tests were used for statistical analysis. All patients were male, median age was 39 years, main route of transmission MSM (91%). In 69% of patients, clinical signs of acute hepatic infection were missing, dominant HCV genotypes were 1 (64%) and 4 (16%) and mean baseline HCV-RNA was 3.559.085 IU/mL. 60% received HAART and CD4 cell count was 469/mm(3) . Overall SVR rate was 64.8% (68/105). SVR was reached in 69% of treated patients in group 1 and in 63% of treated patients in group 2 (P = 0.67) while RVR was seen in 61% and 49%, respectively (P = 0.35). Interestingly, by univariate analysis, SVR rates in group 1 were significantly higher in patients initiating therapy within 4 weeks of AHC diagnosis compared to patients initiating therapy within 5-36 weeks after diagnosis (P = 0.03). PegIFN-alfa alone or in combination with ribavirin results in similar response rates in HIV-infected patients with AHC. In particular, when treatment is initiated within 4 weeks of diagnosis, pegIFN mono-therapy might be sufficient to allow for an optimal treatment response.

Cefiderocol either in monotherapy or combination versus best available therapy in the treatment of carbapenem-resistant Acinetobacter baumannii infections: A systematic review and meta-analysis.

BACKGROUND: The best treatment for carbapenem-resistant Acinetobacter baumannii (CRAB) infections is still a matter of debate. OBJECTIVES: To describe the outcomes of patients treated with cefiderocol for CRAB infections, and to compare the efficacy of cefiderocol versus best available therapy (BAT). DATA SOURCES: We searched MEDLINE, the Cochrane Library and EMBASE to screen original reports published up to September 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials (RCTs) and observational studies investigating 30-day mortality, clinical failure, microbiological failure or rate of adverse drug reactions of patients treated with cefiderocol or BAT. PARTICIPANTS: Patients with infections due to CRAB. INTERVENTIONS: Cefiderocol in monotherapy or in combination with other potentially active agents or BAT. ASSESSMENT OF RISK OF BIAS: We used the Cochrane Risk of Bias Tool for RCTs, and the Newcastle Ottawa scale for observational studies. METHODS OF DATA SYNTHESIS: We conducted a meta-analysis pooling risk ratios (RRs) through random effect models. RESULTS: We screened 801 original reports, and 18 studies (2 RCTs, 13 cohort studies and 3 case-series) were included in the analysis, for a total 733 patients treated with cefiderocol, and 473 receiving the BAT. Among patients receiving cefiderocol, the 30-day mortality rate was 42% (95% CI 38-47%), the rate of microbiological failure 48% (95% CI 31-65%), the clinical failure rate 43% (95% CI 32-55%), and the rate of ADRs was 3% (95% CI 1-6%). A lower mortality rate was observed among patients receiving cefiderocol monotherapy as compared to those treated with combination regimens (RR: 0.64; 95% CI: 0.43-0.94, p = 0.024). We found a significantly lower mortality rate (RR: 0.74; 95% CI: 0.57-0.95, p = 0.02) and a lower rate of ADRs (RR: 0.28; 95% CI: 0.09-0.91, p = 0.03) in the group treated with cefiderocol as compared to BAT. No difference was observed in microbiological and clinical failure rate. CONCLUSIONS: Our data strengthen the efficacy and safety profile of cefiderocol in CRAB infections.

Predictive Biomarkers of Immune Checkpoint Inhibitor-Based Mono- and Combination Therapies for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the most frequent and deadly human cancers worldwide. It has been shown that interaction between immune checkpoint receptors and ligands plays a crucial role in inhibition of T cell-mediated anti-tumor immune responses, thereby assisting tumor cells to evade the host immune surveillance. Therefore, several immune checkpoint inhibitors (ICIs) that selectively block immune checkpoint receptors or ligands have been developed as clinically effective and safe immunotherapeutic agents for treating HCC, including the inhibitors targeting cytotoxic T lymphocyte-associated antigen 4, programmed death 1, and programmed death ligand 1. In addition, various combinations of ICIs and other ICIs or tyrosine kinase inhibitors or vascular endothelial growth factor inhibitors have also emerged as clinically beneficial treatments for HCC. However, the overall response rates of ICI mono-therapy and combination therapy in HCC patients remain unsatisfied, highlighting the urgent need for discovering valuable predictive biomarkers to achieve personalized therapy. This review comprehensively summarizes the literature-based evidence validating a variety of biomarkers with predictive significance for treatment responses and outcomes in HCC patients receiving various ICI-based mono- and combination therapies.

Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial.

Background: Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. Methods: This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. Findings: Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. Interpretation: Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. Funding: This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.

Clindamycin Mono-Therapy of Hidradenitis Suppurativa Patients: A Single-Center Retrospective Study.

BACKGROUND: A rifampicin (RF)-clindamycin (CL) combination therapy is recommended as the first-line treatment for moderate to severe hidradenitis suppurativa (HS). Although the long-term use of RF requires caution due to the possibility of developing resistant bacteria, only a few studies have investigated alternatives for this combination therapy. OBJECTIVE: To evaluate the efficacy of systemic CL mono-therapy and assess the prevalence and CL resistance of bacterial growth in HS patients. METHODS: A total of 53 HS patients treated with CL mono-therapy were included. The efficacy was evaluated by identifying the rate of HS Clinical Response (Hi-SCR) achievers and comparing HS Physician's Global Assessment (HS-PGA) before (W0) and after (W8) the treatment. Purulent material from HS skin lesions was collected on the W0. Bacterial flora and antibiotic sensitivity were determined by bacterial cultures. RESULTS: Of 53 HS patients, 34 were eligible for evaluation of the efficacy of the therapy. Twenty-one patients (61.76%) achieved Hi-SCR. The mean scoring of HS-PGA had significantly decreased from 3.24 to 2.15 (p=0.001). The prevalence of CL resistance was 15.00%. No significant differences in the efficacy of the therapy according to the presence of CL-resistant bacteria on the W0 were observed (p=0.906). Adverse events occurred in 26.42% of patients. CONCLUSION: Systemic CL mono-therapy may be a safe and useful alternative to RF-CL combination therapy, and no significant difference in the efficacy of the therapy depending on the presence of CL-resistant bacteria was observed.

Mono- and poly-therapy with benzodiazepines or Z-drugs: Results from a tertiary-care Addiction Unit study.

BACKGROUND: Using benzodiazepines (BZDs) or Z-drugs in poly-therapy is a critical issue. OBJECTIVE: Identifying factors influencing the use of BZDs/Z-drugs in poly- vs mono-therapy in patients with or without substance use disorders (SUDs). METHODS: 986 inpatients were analysed. Socio-demographic and clinical variables were collected. BZD/Z-drug doses were compared via the Defined Daily Dose (DDD) and standardized as diazepam dose equivalents. Mann-Whitney, Chi-square, Fisher test, hierarchical multivariate regression analyses were run referring to the whole sample and to subjects with current SUDs, lifetime SUDs, current and lifetime SUDs, non-SUDs. RESULTS: In the whole sample the variance of being mono- vs poly-therapy users was explained by BZD/Z-drug formulation, DDD, duration of treatment, age of first BZDs/Z-drugs use (ΔR2 = 0.141, p < 0.001). Among those with current SUDs (ΔR2 = 0.278, p = 0.332) or current and lifetime SUDs (ΔR2 = 0.154, p = 0.419), no variables explained the variance of being mono-vs poly-therapy users. Among lifetime SUDs subjects, the variance of being mono- vs poly-therapy users was explained by BZD/Z-drug formulation and age of first BZD/Z-drug use (ΔR2 = 0.275, p < 0.001). Among non-SUDs subjects, the variance of being mono- vs poly-therapy users was explained by DDD and duration of treatment (ΔR2 = 0.162, p = 0.001). CONCLUSIONS: Tablets, high drug doses, long duration of treatment, and early age of first use were more likely associated to poly- than mono-therapy. This suggests that patients have different clinical features and a pharmacological prescription should be tailored to them also based on the variables here analysed.

Anlotinib in Chinese Patients With Recurrent Advanced Cervical Cancer: A Prospective Single-Arm, Open-Label Phase II Trial.

OBJECTIVE: This phase II, single-arm, prospective study aimed to evaluate the efficacy and safety of anlotinib in Chinese patients with recurrent or metastatic cervical cancer (CC). METHODS: Patients with histologically proven recurrent or metastatic advanced CC were enrolled at Fudan University Shanghai Cancer Center. Patients received 12 mg of oral anlotinib daily before breakfast for 2 weeks of each 3-week (21 days) cycle separated by a 1-week interval. Anlotinib was administered orally until disease progression, patient withdrawal, intolerant toxicity, or death. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors, and the secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Between September 2018 and November 2019, 41 patients were recruited. The median age was 53 years old. The histological results revealed that 82.9% of the recruited patients had squamous cell carcinoma, 14.6% had adenocarcinoma, and 2.4% had other types. At the data cutoff date, six patients were still being treated, and 35 patients had discontinued treatment. Forty (40/41, 97.5%) patients were evaluated for treatment response. The median PFS and OS was 3.2 and 9.9 months, respectively, in patients who received anlotinib treatment. The ORR was 24.4%. In addition, 34.2% (14/41) of patients were confirmed to have stable disease, and 39.0% (16/41) of patients were confirmed to have progressive disease. The DCR was 58.5%. Ten patients (10/41) had a confirmed response during the follow-up period. Most adverse events (AEs) were grade 1 or 2. High-grade AEs (grade 3) included urinary leukocyte positivity (9.8%), hematuria (4.9%), and hypertension (2.4%). CONCLUSION: This is the first study to evaluate the efficacy and safety of anlotinib in Chinese patients with recurrent or metastatic CC. Anlotinib produced durable clinical responses with manageable safety in these patients.

Comparison between single-agent and combination chemotherapy as second-line treatment for advanced non-small cell lung cancer: a multi-institutional retrospective analysis.

PURPOSE: Doublet combination chemotherapy is commonly considered a second-line treatment for advanced non-small cell lung cancer (NSCLC) in China. This multi-institutional retrospective analysis evaluated and compared the efficacy between combination and mono-therapy after platinum-based first-line chemotherapy in Chinese patients with advanced NSCLC. METHODS: We retrospectively reviewed 335 patients who received second-line chemotherapy for advanced NSCLC. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), response rate (RR) and toxicity. Treatment-free interval (TFI) was used for further stratification analysis. The Cox proportional hazards model was used for multivariate analysis. RESULTS: Two hundred and fifty-three patients received doublet combination chemotherapy and 82 received single-agent chemotherapy. PFS was significantly prolonged in combination group compared to single-agent group (median 5.70 vs 3.70 months; HR 0.62; 95% CI 0.45-0.85; p < 0.001). The RR was significantly higher in the combination group than in the single-agent group (29.25% vs. 10.98%; p = 0.001). OS was also prolonged in combination group versus single-agent group (median 13.30 vs. 11.45 months, respectively; HR 0.70; 95% CI 0.52-0.95; p = 0.023). Among patients with TFI of ≥ 6 months, PFS and OS of the combination group were significantly increased than the single-agent group (median PFS, 6.67 vs. 3.80 months, p = 0.002; median OS, 13.60 vs. 11.45 months, p = 0.013). Grade III/IV toxicity was similar between the two groups (p = 0.113). Through multivariate analyses, we found that Eastern Cooperative Oncology Group (ECOG) score (p < 0.001), further-line treatment (p < 0.001) and combination chemotherapy (p = 0.024) were the independent prognostic factors. CONCLUSION: Compared with mono-therapy, combination chemotherapy was a better second-line option for Chinese patients with good performance status, especially in those with TFI of ≥ 6 months.

The emergence of levothyroxine as a treatment for hypothyroidism.

OBJECTIVE: To describe the historical refinements, understanding of physiology and clinical outcomes observed with thyroid hormone replacement strategies. METHODS: A Medline search was initiated using the search terms, levothyroxine, thyroid hormone history, levothyroxine mono therapy, thyroid hormone replacement, combination LT4 therapy, levothyroxine Bioequivalence. Pertinent articles of interest were identified by title and where available abstract for further review. Additional references were identified in the course of review of the literature identified. RESULTS: Physicians have intervened in cases of thyroid dysfunction for more than two millennia. Ingestion of animal thyroid derived preparations has been long described but only scientifically documented for the last 130 years. Refinements in hormone preparation, pharmaceutical production and regulation continue to this day. The literature provides documentation of physiologic, pathologic and clinical outcomes which have been reported and continuously updated. Recommendations for effective and safe use of these hormones for reversal of patho-physiology associated with hypothyroidism and the relief of symptoms of hypothyroidism has documented a progressive refinement in our understanding of thyroid hormone use. Studies of thyroid hormone metabolism, action and pharmacokinetics have allowed evermore focused recommendations for use in clinical practice. Levothyroxine mono-therapy has emerged as the therapy of choice of all recent major guidelines. CONCLUSIONS: The evolution of thyroid hormone therapies has been significant over an extended period of time. Thyroid hormone replacement is very useful in the treatment of those with hypothyroidism. All of the most recent guidelines of major endocrine societies recommend levothyroxine mono-therapy for first line use in hypothyroidism.

Benefit of initial dual-therapy on stroke prevention in Chinese hypertensive patients: a real world cohort study.

AIMS: Studies have shown that combination anti-hypertensive therapy is superior to mono-therapy in blood pressure control and prevention of cardiovascular events. However, whether such advantage exists in the prevention of stroke in Chinese hypertensive patients remains unclear. This study aimed to compare the impact of initial combination versus mono-therapy on stroke events in a large cohort of Chinese hypertensive patients. METHODS AND RESULTS: Hypertensive patients with uncontrolled blood pressure and without a history of stroke were screened from the Shanghai Community-dwelling Hypertensive Population Follow-up Database. Based on the initial treatment, individuals were divided into an initial mono-therapy group and initial dual combination group. Patients were followed for 42 months. 32,682 and 4,926 patients were included in the initial mono- and dual-therapy group. The achieved target blood pressure control rates of mono vs. combination groups at 6, 12, 24, and 42 months of follow-up, were 59.47% vs. 60.05%, 78.23% vs. 77.06%, 85.51% vs. 84.02%, and 86.90% vs. 85.44%, respectively. Their corresponding incidence densities of stroke were 0.792 vs. 0.489, 1.49 vs. 1.15, 2.79 vs. 2.38, and 4.25 vs. 4.32 (cases per 100 person-year), respectively. The 6-month incidence of stroke in dual-therapy group was significantly lower than mono-therapy group (adjusted HR 0.64; 95% CI: 0.30-0.93). However, no significant group differences in the incidence density were observed at 12, 24, and 42 months. CONCLUSIONS: Our study demonstrates that, for patients with uncontrolled hypertension, initial dual therapy is more effective in the prevention of stroke during the first 6 months of treatment, but not thereafter. Combination antihypertensive therapy may be a beneficial initial strategy for early stroke prevention.

Efficacy and safety of spironolactone in mono-therapy versus low dose spironolactone in combined-therapy for the treatment of idiopathic hyperaldosteronism / 中华内分泌代谢杂志

Objective The aim of this study was to compare the efficacy and safety of spironolactone in mono-therapy versus low dose spironolactone in combined-therapy for the treatment of idiopathic hyperaldosteronism (IHA). Methods This was a prospective and randomized study. After 2 weeks wash out period, 48 patients confirmed IHA were assigned to either spironolactone mono-therapy or low dose spironolactone combined-therapy groups. All patients underwent adrenal venous sampling and showed no lateralization. The primary outcome was the percentage of patients with blood pressure<140/90 mmHg(1 mmHg＝0.133 kPa) at 16 weeks. The other observatory parameters were: the occurrence of gynecomastia, renal insufficiency, and hyperkalemia. Results At the end of 16 weeks, the patients′blood pressure were normalized in 17 out of 24 patients(70.8%) in mono-therapy group and in 23 out of 24 patients ( 95. 8%) in combined-therapy group ( P<0. 05). There was no hyperkalemia in both groups. 2 patients and 5 patients in mono-therapy group were observed renal insufficiency and gynecomastia respectively, while no patients in combined-therapy group presented with those side effects. Conclusion Low dose spironolactone combined-therapy group is more effective to control blood pressure and hypokalemia without increase the occurrence of renal insufficiency or gynecomastia.