Severe Liver Impairment Research Articles

Drug-induced liver injury associated with savolitinib: a novel case report and causality assessment

BackgroundSavolitinib, a small molecule inhibitor, has gained approval as the inaugural medication in China that specifically targets MET kinase. Patients with advanced non-small cell lung cancer (NSCLC) who show MET exon 14 skipping now have a new and innovative treatment option available.Case reportIn this case report, we describe a patient who experienced drug-induced liver injury (DILI) due to the administration of savolitinib. After being prescribed with savolitinib (400 mg per day, oral), a 73-year-old male diagnosed with stage IV NSCLC with MET exon 14 skipping mutation experienced an increase in liver enzymes and bilirubin levels according to his laboratory tests conducted one month later. Following a 14-day course of hepatoprotective medication, the liver function reverted back to its normal state. After receiving savolitinib (200 mg per day, oral) for one week, the patient was once again diagnosed with severe liver impairment. Then savolitinib was discontinued and received treatment with hepatoprotective drugs for one week. Following the restoration of normal liver function, another attempt was made to administer a small amount of savolitinib (100 mg per day, oral). Thus far, the patient has been followed up and there has been no recurrence of liver damage. Additionally, the lung CT scan revealed ongoing tumor shrinkage with no apparent indications of spreading or metastasis. The Roussel Uclaf Causality Assessment Method (RUCAM) determined that savolitinib was “highly probable” cause of DILI. Moderate-severe was determined to be the extent of DILI severity.ConclusionTo the best of our understanding, this is the initial instance of DILI resulting from the use of savolitinib as a standalone treatment in a real-world setting. During the administration of savolitinib, healthcare professionals should carefully consider the potential occurrence of DILI. Administering the patient with a small amount of savolitinib resulted in a remarkable response against the tumor, leading us to speculate that the effectiveness of savolitinib might be associated with its plasma concentration. Studying the pharmacokinetics and pharmacodynamics (PK/PD) of savolitinib is beneficial for tailoring and accurately prescribing the medication to each individual.

Abstract PO3-17-07: Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan

Abstract Background: Trastuzumab deruxtecan (T-DXd) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate. T-DXd has shown great efficacy in HER2-positive breast cancer, hence receiving approval in Japan in March 2020. In Japan, all-patient postmarketing surveillance (PMS) is underway to evaluate the risk of interstitial lung disease/pneumonitis (ILD/p) in patients with breast cancer treated with T-DXd. Due to the limited generalizability of results from clinical trials, there is a need for more information about ILD/p in a real-world setting. Herein we present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT1080225197) with an observation period of 18 months that enrolled all patients treated with T-DXd for recurrent/advanced HER2-positive breast cancer. Patients who initiated T-DXd treatment between May 2020 (launch date of T-DXd) and May 2021 were included in the interim analysis to ensure the observation period of 6 months from the initial treatment of T-DXd. This interim analysis is based on safety data from the first 6 months of 1204 patients. Data collected includes baseline characteristics and information on ILD/p. All potential ILD/p (identified based on the AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee. The incidence of ILD/p was calculated from adjudicated drug-related ILD/p. Results: The interim analysis set included 1204 patients with median age of 60 years. Three of the 1204 patients (0.2%) received T-DXd as a first-line treatment, 30 (2.5%) as second-line, 1159 (96.3%) as third- line or later treatment. At baseline, 105 (8.7%) of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, 8 (0.7%) had severe renal impairment (15≤ creatinine clearance (CLcr) < 30 mL/min), 4 (0.3%) had end-stage renal disease (CLcr < 15 mL/min), 5 (0.4%) had severe liver impairment (total bilirubin >4.5 mg/dL), and 32 (2.7%) had comorbid ILD/radiation pneumonitis. Those were defined as exclusion criteria in clinical trials of T-DXd. The median dose at the start of administration of T-DXd was 5.4 mg/kg (range:2.7-5.4). During the first 6 months from the initial treatment, T-DXd was discontinued in 403 (33.5%) of the 1204 patients. The most common reasons for discontinuation were disease progression in 232 (57.6%) of the discontinued 403 patients followed by ILD/p in 97 (24.1%) of the 403 patients. In the first 6 months, the incidence of all grade, grade ≥3, and grade 5 ILD/p were 8.2% (n=99), 1.7% (n=20) and 0.4% (n=5), respectively. The incidence of ILD/p stratified by baseline characteristics identified as potential risk factors of drug-related ILD/p is shown in Table. Conclusion: This is the first report demonstrating real-world experience with T-DXd in Japan. The interim analysis revealed useful information including patient and treatment profiles of T-DXd and the incidence of ILD/p during the first 6 months from the initial treatment in a real-world setting in Japan. The final analysis of the ongoing PMS is warranted for further evaluation. Incidence of interstitial lung disease/pneumonitis by patient baseline characteristics XX XX ILD/p: interstitial lung disease/pneumonitis, 95% CI: 95% confidence interval, CLCr: creatinine clearance using the Cockcroft-Gault equation * includes ILD/p, pulmonary fibrosis, radiation pneumonitis, chronic obstructive pulmonary disease, emphysema, and Asthma (Source: Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 2022;7(4):100554) Citation Format: Junji Tsurutani, Hideki Mizutani, Ayumi Tanabe. Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-07.

АНТИКОАГУЛЯНТНАЯ ТЕРАПИЯ У БОЛЬНЫХ С ФИБРИЛЛЯЦИЕЙ ПРЕДСЕРДИЙ И ЦИРРОЗОМ ПЕЧЕНИ

Atrial fibrillation is one of the most common arrhythmias. In patients with liver cirrhosis, the presence of atrial fibrillation is accompanied by additional risks of thromboembolic complications and death. Prevention of thromboembolic events in patients with liver dysfunction presents significant difficulties due to the presence of coagulopathies, which contribute to an increased risk of thrombus formation and hemorrhagic events. Warfarin and direct oral anticoagulants in patients with mild to moderate liver dysfunction and concomitant atrial fibrillation are comparable in effectiveness in reducing the risk of ischemic stroke, but direct oral anticoagulants demonstrate a better safety profile due to reduced risk of bleeding. Clinical trials evaluating the efficacy and safety of anticoagulants rarely include patients with severe liver impairment (Child-Pugh class C), and the benefit of anticoagulant therapy in this population requires further study.

Determinants of clinical response to empirical antibiotic treatment in patients with cirrhosis and bacterial and fungal infections-Results from the ICA "Global Study" (EABCIR-Global Study).

The administration of an appropriate empirical antibiotic treatment is essential in cirrhosis and severe bacterial infections. We aimed to investigate the predictors of clinical response of empirical antibiotic treatment in a prospective cohort of patients with cirrhosis and bacterial and fungal infections included in the International Club of Ascites "Global Study." Patients hospitalized with cirrhosis and bacterial/fungal infection were prospectively enrolled at 46 centers. Clinical response to antibiotic treatment was defined according to changes in markers of infection/inflammation, vital signs, improvement of organ failure, and results of cultures. From October 2015 to September 2016, 1302 patients were included at 46 centers. A clinical response was achieved in only 61% of cases. Independent predictors of lack of clinical response to empirical treatment were C-reactive protein (OR = 1.16; 95% CI = 1.02-1.31), blood leukocyte count (OR = 1.39;95% CI = 1.09-1.77), serum albumin (OR = 0.70; 95% CI = 0.55-0.88), nosocomial infections (OR = 1.96; 95% CI = 1.20-2.38), pneumonia (OR = 1.75; 95% CI = 1.22-2.53), and ineffective treatment according to antibiotic susceptibility test (OR = 5.32; 95% CI = 3.47-8.57). Patients with a lack of clinical response to first-line antibiotic treatment had a significantly lower resolution rate of infections (55% vs. 96%; p < 0.001), a higher incidence of second infections (29% vs. 15%; p < 0.001), shock (35% vs. 7%; p < 0.001) and new organ failures (52% vs. 19 %; p < 0.001) than responders. Clinical response to empirical treatment was an independent predictor of 28-day survival ( subdistribution = 0.20; 95% CI = 0.14-0.27). Four out of 10 patients with cirrhosis do not respond to the first-line antibiotic therapy, leading to lower resolution of infections and higher mortality. Broader-spectrum antibiotics and strategies targeting systemic inflammation may improve prognosis in patients with a high degree of inflammation, low serum albumin levels, and severe liver impairment.

Daridorexant, an Orexin Receptor Antagonist for the Management of Insomnia.

Insomnia is a common sleep disorder that is diagnosed primarily by patients' subjective reported symptoms. Daridorexant is a new dual orexin receptor antagonist that was recently approved by Food and Drug Administration for insomnia characterized by difficulty falling asleep and/or maintaining sleep. The orexin neuropeptide signaling system plays a role in wakefulness, and blocking the wake-promoting neuropeptides results in diminished wake signaling, thus exerting a sedative effect using an entirely different mechanism of action than the classical sleep promoting agents. The drug has quick onset of action, high volume of distribution, and high protein binding. Pharmacokinetics and pharmacodynamic parameters were similar in patients of different sex and age and were not significantly affected by race, body size, or mild-to-moderate kidney impairment. Dose limitation to 25 mg in moderate liver impairment and no use in severe liver impairment are recommended. The drug undergoes hepatic CYP3A4 metabolism; thus, caution with strong CYP3A4 inhibitors and inducers is warranted. The drug was approved based on phase 3 trials involving study 1 and study 2. Study 1 noted daridorexant at doses of 25 and 50 mg demonstrated a statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time against placebo at months 1 and 3. Similarly in study 2, compared with placebo, the 25 mg dose demonstrated statistically significant improvement in wake time after sleep onset, latency to persistent sleep, and self-reported total sleep time at months 1 and 3. Treatment-emergent adverse events were similar for daridorexant and placebo, with nasopharyngitis and headache most frequently reported. Daridorexant is a novel agent with demonstrated efficacy in sleep onset and maintenance and decrease in daytime sedation. Preliminary results from a 1-year extension study note similar incidences of mild-to-moderate side effects as noted in previous trials. Further studies are needed to establish its place in the pharmacological treatment of insomnia.

P37 A retrospective audit of molnupiravir prescribing in the virtual hospital via the CMDU pathway

Abstract Background In December 2021, COVID-19 medicine delivery units (CMDU) were launched across NHS hospitals in England. They offered treatment to non-hospitalized patients who tested positive for COVID-19 and were at high risk of progression to severe disease. At the time of auditing (November 2022), NHS England had commissioned four different treatment options. Even though each of them was not directly compared in clinical trials at the time, NHSE clearly specified the order in which treatment option should be considered. Nirmatrelvir boosted with ritonavir or sotrovimab was first line. Then, remdesivir and finally molnupiravir are the last options.1,2,3 Even though molnupiravir has less drug–drug interactions and can be used with patients in all stages of renal impairment, NHSE recommended it last because at the time, it appeared to be the least effective of all four therapies.3 Objectives To review current prescribing practice of COVID-19 medicines in the virtual hospital and to improve stewardship within the Acute Medical Unit virtual hospital. Standards (i) 100% of patients prescribed molnupiravir had a confirmed SARS-CoV-2 infection, (ii) 100% of patients prescribed molnupiravir were ineligible for treatment with nirmatrelvir/ritonavir due to severe liver impairment or kidney disease, (iii) 100% of patients prescribed molnupiravir were ineligible for treatment with nirmatrelvir/ritonavir due to significant drug–drug interactions and (iv) 100% of patients prescribed molnupiravir should have a documented reason in EPR as to why they were ineligible for treatment with sotrovimab. The criteria and standards above were set using the Interim Clinical Commissioning Policy: Antivirals or neutralizing monoclonal antibodies for non-hospitalized patients with COVID-19. Methods All patients admitted to the virtual hospital via the CMDU pathway during the 9-month period from 1 January to 30 September 2022 were included in audit. A total of 602 patients were prescribed molnupiravir during this period, and 34 patients were selected randomly. The data collection involved a retrospective case note review of 34 electronic patient records (EPR) over one working week between 24 October and 28 October 2022. Data from 3 patients were excluded from the audit as liver and/or function tests were unavailable in EPR; thus, N = 31. The data collection was recorded on a Microsoft Excel data toolkit, which included the confirmation of SARS-CoV-2 infection, date of treatment commenced, nirmatrelvir/ritonavir drug interactions1, liver and renal function tests2–3 (ALT, ALP, bilirubin, eGFR/CrCl and CKD) and consideration of sotrovimab as alternative first-line treatment with documented reason. The data was then analysed and graphs were generated to draw results. All standards were set at 100%. This study did not require ethical approval. Results The results after data collation revealed that 100% patients prescribed molnupiravir had a confirmed SARs-CoV-2 infection; 29% patients were ineligible for treatment with nirmatrelvir/ritonavir due to stage 3–5 CKD; 29% patients were ineligible for treatment with nirmatrelvir/ ritonavir due to significant drug–drug interactions; 22.6% patients had a documented reason in their electronic record as to why they were ineligible for treatment with sotrovimab. Discussion and action plan Majority (71%) of patients prescribed molnupiravir did not have severe CKD or severe liver impairment. They were eligible for treatment with nirmatrelvir/ritonavir, provided that these patients did not have significant drug interactions with concomitant medications. Although most cases had documented the interactions with concomitant medications, 64.5% patients had potential interactions that could have been worked around. Documentation was poor as to why sotrovimab was not considered as first-line alternative treatment and this was fed back to the virtual hospital team to document rationale for treatment going forward. Nirmatrelvir/ritonavir could have been co-administered with concomitant medications in most cases. The team now have access to a dedicated antimicrobial pharmacist when they need advice. Limitations Both liver function tests and renal function tests were unavailable at the time when molnupiravir treatment was commenced. Hence, lab results within 1 year were used as part of this audit. Due to time constraints, only a small part of patients prescribed molnupiravir was studied. Conclusions Majority of patients were inappropriately prescribed molnupiravir, as their renal function/liver function was not poor enough to exclude them from treatment with nirmatrelvir/ritonavir. The poor documentation means we do not know why the other first-line and second-line options were not considered. Whilst a lot of patients were on medicines that interacted with nirmatrelvir/ritonavir, the majority were not significant and could have been worked around.

Magnetic Resonance Imaging for Monitoring of Hepatic Disease Induced by Ebola Virus: a Nonhuman Primate Proof-of-Concept Study.

Severe liver impairment is a well-known hallmark of Ebola virus disease (EVD). However, the role of hepatic involvement in EVD progression is understudied. Medical imaging in established animal models of EVD (e.g., nonhuman primates [NHPs]) can be a strong complement to traditional assays to better investigate this pathophysiological process in vivo and noninvasively. In this proof-of-concept study, we used longitudinal multiparametric magnetic resonance imaging (MRI) to characterize liver morphology and function in nine rhesus monkeys after exposure to Ebola virus (EBOV). Starting 5 days postexposure, MRI assessments of liver appearance, morphology, and size were consistently compatible with the presence of hepatic edema, inflammation, and congestion, leading to significant hepatomegaly at necropsy. MRI performed after injection of a hepatobiliary contrast agent demonstrated decreased liver signal on the day of euthanasia, suggesting progressive hepatocellular dysfunction and hepatic secretory impairment associated with EBOV infection. Importantly, MRI-assessed deterioration of biliary function was acute and progressed faster than changes in serum bilirubin concentrations. These findings suggest that longitudinal quantitative in vivo imaging may be a useful addition to standard biological assays to gain additional knowledge about organ pathophysiology in animal models of EVD. IMPORTANCE Severe liver impairment is a well-known hallmark of Ebola virus disease (EVD), but the contribution of hepatic pathophysiology to EVD progression is not fully understood. Noninvasive medical imaging of liver structure and function in well-established animal models of disease may shed light on this important aspect of EVD. In this proof-of-concept study, we used longitudinal magnetic resonance imaging (MRI) to characterize liver abnormalities and dysfunction in rhesus monkeys exposed to Ebola virus. The results indicate that in vivo MRI may be used as a noninvasive readout of organ pathophysiology in EVD and may be used in future animal studies to further characterize organ-specific damage of this condition, in addition to standard biological assays.

Acute Liver Failure Guidelines.

Acute liver failure (ALF) is a rare, acute, potentially reversible condition resulting in severe liver impairment and rapid clinical deterioration in patients without preexisting liver disease. Due to the rarity of this condition, published studies are limited by the use of retrospective or prospective cohorts and lack of randomized controlled trials. Current guidelines represent the suggested approach to the identification, treatment, and management of ALF and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence was reviewed using the Grading of Recommendations, Assessment, Development and Evaluation process to develop recommendations. When no robust evidence was available, expert opinions were summarized using Key Concepts. Considering the variety of clinical presentations of ALF, individualization of care should be applied in specific clinical scenarios.

Quanduzhong capsules for the treatment of grade 1 hypertension patients with low-to-moderate risk: A multicenter, randomized, double-blind, placebo-controlled clinical trial.

Background: Duzhong [DZ (Eucommia ulmoides Oliv.)] is regarded as a traditional Chinese medicine with a history dating back more than 2000years. This herb is considered a nourishing herb in China and is commonly used as a tonic to strengthen muscles and bones, nourish the kidneys and liver, and soothe miscarriages. Moreover, there is evidence that DZ is capable of regulating blood pressure (BP), and several compounds isolated from DZ have been shown to have a BP-lowering effect. Quanduzhong capsules contain an extract of DZ [Eucommia ulmoides Oliv. (Eucommiaceae; Eucommiae cortex)] that is effective in treating hypertension. This multicenter, randomized, double-blind, placebo-controlled clinical trial sought to evaluate the clinical efficacy of Quanduzhong capsules in the treatment of low-to-moderate risk grade 1 hypertension patients. Materials and methods: A total of 60 patients from 3 centers with documented low-to-moderate risk grade 1 hypertension were randomly assigned in a 1:1 ratio to the test group or the control group. After a 1week lead-in period using sham Quanduzhong capsules, all patients who met the entry criteria (29 cases in the test group and 29 cases in the control group) entered the 4week test period. The test group took Quanduzhong capsules, and the control group continued to take sham Quanduzhong capsules. The primary endpoints [24-h mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) determined via 24-h ambulatory blood pressure monitoring (ABPM); office SBP and DBP] and secondary endpoints [mean arterial pressure; mean pulse; daytime mean SBP and DBP; nocturnal mean SBP and DBP; SBP and DBP load; area under the blood pressure (BP) curve; morning peak BP; early morning SBP and DBP; smoothness index of SBP and DBP; 24h BP mean coefficient of variation (CV); percentage of patients with circadian restoration in ABPM; home BP; quality of life evaluated by WHO Quality of Life-BREF questionnaire; grading and quantitative evaluation of hypertension symptoms; values of plasmatic renin activity, angiotensin II, aldosterone, β-2 microglobulin and homocysteine] were assessed following the treatment. Drug-related adverse events and adverse drug reactions were also compared. Results: After a 4week test period, a significant difference in the DBP CV between the two groups was observed (-2.49 ± 4.32 vs. 0.76 ± 4.3; p < .05). Moreover, the mean office SBP change was -7.62 ± 9.32mmHg, and the mean DBP change was -4.66 ± 6.03 (p < .05). Among the three subjects with abnormal homocysteine levels in the test group, homocysteine levels decreased by 6.23 ± 9.15μmol/L after treatment. No differences were observed between the two groups in any other indicators. After 4weeks of treatment, there were no significant differences between the groups in terms of safety indicators (p > .05). No abnormal vital signs (except BP) or severe liver or renal function impairment were observed during the treatment periods; in addition, adverse events and drug reactions were mild. Conclusion: Treatment with Quanduzhong capsules reduced office SBP and DBP as well as DBP CV determined by 24-h ambulatory BP monitoring in patients with grade 1 hypertension at low-to-moderate risk. Clinical Trial Registration: https://www.chictr.org.cn/showproj.aspx?proj=32531, identifier ChiCTR1900021699.

Ameliorative Effects of Propolis and Royal Jelly against CCl4 -Induced Hepatotoxicity and Nephrotoxicity in Wistar Rats.

Carbon tetrachloride (CCl4 ) is known to have hepatotoxic and nephrotoxic effects. During the two-month CCl4 exposure of Wistar rats, propolis extract (PE) and royal jelly (RJ) were added in order to test the potential protective effect against hepato-renal injury. Ketonuria, proteinuria, high creatinine and urea levels are the result of CCl4 -induced nephrotoxicity. Severe disorders of hematological indicators indicate anemia; high values of leukocytes indicate inflammatory condition. Cytogenetic impairments in hepatocytes, aggregation of platelets, and hypoproteinemia indicate severe liver impairment. Results suggest a more significant protective role of RJ compared to PE. Both extracts regulated proteinuria, ketonuria, hypoproteinemia and reduced platelet aggregation in the hepatic circulation. The increase in the number of erythrocytes (RBC) suggest protective effects against anemia; the decrease in the number of leukocytes can be linked to anti-inflammatory effects. PE and RJ have a beneficial effect against hepato-renal injury, anemia and anti-inflammatory conditions caused by CCl4 .

Real-world effectiveness of early molnupiravir or nirmatrelvir–ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.2 wave: a retrospective cohort study

BackgroundData on the effectiveness of oral antivirals in patients with mild-to-moderate COVID-19 are urgently needed. This retrospective cohort study aimed to evaluate the clinical and virological outcomes associated with molnupiravir or nirmatrelvir–ritonavir use in hospitalised patients with mild-to-moderate COVID-19 during a pandemic wave dominated by the omicron BA.2 subvariant.MethodsWe analysed data from a territory-wide retrospective cohort of patients in Hong Kong who were hospitalised with a confirmed diagnosis of SARS-CoV-2 infection between Feb 26 and April 26, 2022. Data were extracted from the Hospital Authority, the Department of Health, and the Hong Kong Death Registry. Patients were eligible for inclusion if their admission date was within 3 days before or after confirmation of their COVID-19 diagnosis. Those who were admitted to hospital more than 5 days after symptom onset, were younger than 18 years, had a history of oral antiviral use before admission, required supplemental oxygen on admission, had drug-related contraindications to nirmatrelvir–ritonavir use, or had severe renal or severe liver impairment were excluded. Patients who received the oral antivirals molnupiravir or nirmatrelvir–ritonavir were matched with controls using propensity-score matching in a ratio of 1:1. The primary outcome was all-cause mortality and secondary outcomes included a composite outcome of disease progression (all-cause mortality, initiation of invasive mechanical ventilation [IMV], intensive care unit [ICU] admission, or the need for oxygen therapy) and each of these individual disease progression outcomes, and time to reaching a low viral burden (RT-PCR cycle threshold value ≥30). For each event outcome, crude incidence rates were calculated and hazard ratios (HRs) estimated using Cox regression models.FindingsWe identified 40 776 patients hospitalised with SARS-CoV-2 infection during the study period, with a mean follow-up of 41·3 days (total 925 713 person-days). After exclusions and propensity-score matching, we included 1856 molnupiravir recipients and 1856 matched controls, and 890 nirmatrelvir-ritonavir recipients and 890 matched controls. A lower risk of all-cause mortality was observed in molnupiravir recipients (crude incidence rate per 10 000 person-days 19·98 events [95% CI 16·91–23·45]) versus matched controls (38·07 events [33·85–42·67]; HR 0·48 [95% CI 0·40–0·59], p<0·0001) and in nirmatrelvir–ritonavir recipients (10·28 events [7·03–14·51]) versus matched controls (26·47 events [21·34–32·46]; HR 0·34 [0·23–0·50], p<0·0001). Oral antiviral recipients also had lower risks of the composite disease progression outcome (molnupiravir HR 0·60 [95% CI 0·52–0·69], p<0·0001; nirmatrelvir–ritonavir 0·57 [0·45–0·72], p<0·0001) and need for oxygen therapy (molnupiravir 0·69 [0·57–0·83], p=0·0001; nirmatrelvir–ritonavir 0·73 [0·54–0·97], p=0·032) compared with controls. Time to achieving a low viral burden was significantly shorter among oral antiviral recipients than matched controls (molnupiravir HR 1·38 [95% CI 1·15–1·64], p=0·0005; nirmatrelvir–ritonavir 1·38 [1·07–1·79], p=0·013). Significant differences in initiation of IMV and ICU admission were not found.InterpretationDuring a wave of SARS-CoV-2 omicron BA.2, initiation of novel oral antiviral treatments in hospitalised patients not requiring oxygen therapy on admission showed substantial clinical benefit. Our findings support the early use of oral antivirals in this population of patients.FundingHealth and Medical Research Fund (Health Bureau, Government of the Hong Kong Special Administrative Region).TranslationFor the Chinese translation of the abstract see Supplementary Materials section.

Azacitidine Treatment in Patients with Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia Type 2 and Acute Myeloid Leukemia According to their Cytogenetic Findings

Abstract Introduction: Azacitidine is one of the hypomethylating agents available for the treatment of elderly patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). It is also used as an appropriate treatment of chronic myelomonocytic leukemia (CMML) in the real life setting. As treatment of AML and CMML is not curative, and allogeneic stem cell transplantation (allo-SCT) remains traditionally the only option, significant clinical benefits by hypomethylating agents have been reported. According to the available data, 16% of subjects with MDS who received azacitidine had a complete or partial normalization of blood cell counts and bone marrow morphology, while two-thirds of patients who required blood transfusions no longer needed them. Nevertheless, it can also be hepatotoxic in patients with severe liver impairment and extensive liver tumors. Aim: to summarize the effect of azacitidine treatment in patients in the light of their general condition, blood count parameters, toxicity (general and hematologic), as well as the presence of cytogenetic aberrations. Materials and Methods: Twenty-seven patients of which 15 patients with MDS, 9 patients with CMML and 3 patients with AML received azacitidine treatment. The blood count levels and toxicity were followed for a period of twelve months. Results: 22.2% of our patients (6 of 27) of different hematologic diagnoses showed genetic aberrations in their DNA. All they showed quick disease progression and fatal outcome, four of them also developed hematologic toxicity. The remaining 77.8% had no cytogenetic findings. Of all the cohort, 19.05% developed toxicity during the course of the treatment, 38% – decreased leucocyte levels, 14.3% – decreased thrombocyte levels and 18.2% – decreased hemoglobin level. The erythrocyte levels were not substantially influenced by the treatment. The majority of the patients sustained stable levels of red blood cells, as well as of platelets and hemoglobin without remarkable changes between month 0 and month 6 of the treatment. Conclusion: Our results showed, that the main disadvantage of azacitidine treatment in our patients were progressive leucopenia (in 10/27 patients or 37% of cases) and toxicity (8/27 or 29.6% of cases).

Hemorrhage risk and countermeasures of acupuncture treatment in patients undergoing administration of anticoagulants and antiplatelets

Acupuncture therapy is widely used in the treatment of various clinical problems, but has some contraindications which should be highly noted. For example, patients with potential hemorrhagic tendency owing to administration of necessary anticoagulants and antiplatelets should be paid more attention when acupuncture therapy was performed. Usually, anticoagulants and antiplatelets combined with nonsteroidal anti-inflammatory hormones, antibiotic agents and vasodilators significantly increased the risk of bleeding. Chinese herbal medicines for activating blood circulation to arrest pain, and improper medication including the dosage and frequency should be avoided. Patients with chronic liver diseases, acute and severe liver and kidney function impairment due to inability to secrete coagulation factor in time to initiate coagulation mechanism are also unsuitable for acupuncture the-rapy. For this reason, we put forward some necessary countermeasures: a) collecting the patient's medical history in detail, b) paying attention to the coagulation related tests, c) taking the patient's blood volume and platelet related parameters seriously, and d) enacting reasonable diagnosis and treatment ideas.

Long-Acting HIV Fusion Inhibitor Albuvirtide is A Safe And Effective Treatment in HIV Patients with Severe Liver Impairment, HBV Co-Infection and High HIV RNA Copies

Long-Acting HIV Fusion Inhibitor Albuvirtide is A Safe And Effective Treatment in HIV Patients with Severe Liver Impairment, HBV Co-Infection and High HIV RNA Copies

Chronic tribasic copper chloride exposure induces rat liver damage by disrupting the mitophagy and apoptosis pathways

Despite the fact that copper (Cu) is a vital micronutrient to maintain body function, high doses of Cu through environmental exposure damage various organs, especially the liver, which is the main metabolic organ. To investigate the influence of long-term Cu-induced toxicity on mitophagy and apoptosis in rat liver, 96 seven-month-old male Sprague-Dawley rats were fed TBCC for 24 weeks. The results revealed that exposure to high Cu concentrations could promote oxidative stress liver injury by increasing the hepatic function index (ALT, AST and ALP) and MDA content, while reducing the activity of antioxidant enzymes (T-SOD, GSH-Px and CAT) related to oxidative stress. Consistent with histopathological observations, proper dietary Cu (15–60 mg/kg) could improve antioxidant stress levels and induce a dose-dependent increase in the mRNA expression of mitophagy-related genes, whereas a high Cu concentration (120 mg/kg) could cause severe liver impairment and ultrastructural changes and a reduction in mitophagosomes, accompanied by downregulation of Atg5, Beclin1, Pink1, Parkin, NIX, P62 and LC3B. The expression of apoptosis-related genes (Bax, Bax/Bcl-2, Caspase3, Cytc and p53) and proteins (Caspase3 and p53) was upregulated with the addition of dietary Cu. The results demonstrated that an appropriate dose of TBCC could improve liver function by promoting mitophagy and Cu enzymes that play antioxidative roles, while the accumulation of excess Cu could induce liver lesions by enhancing apoptosis and inhibiting mitophagy pathways.

Complicated COVID-19 in pregnancy: a case report with severe liver and coagulation dysfunction promptly improved by delivery

BackgroundIt has been proposed that pregnant women and their fetuses may be particularly at risk for poor outcomes due to the coronavirus (COVID-19) pandemic. From the few case series that are available in the literature, women with high risk pregnancies have been associated with higher morbidity. It has been suggested that pregnancy induced immune responses and cardio-vascular changes can exaggerate the course of the COVID-19 infection.Case presentationA 26-year old Somalian woman (G2P1) presented with a nine-day history of shortness of breath, dry cough, myalgia, nausea, abdominal pain and fever. A nasopharyngeal swab returned positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Her condition rapidly worsened leading to severe liver and coagulation impairment. An emergency Caesarean section was performed at gestational week 32 + 6 after which the patient made a rapid recovery. Severe COVID-19 promptly improved by the termination of the pregnancy or atypical HELLP (Hemolysis, Elevated Liver Enzymes and Low Platelet Count) exacerbated by concomitant COVID-19 infection could not be ruled out. There was no evidence of vertical transmission.ConclusionsThis case adds to the growing body of evidence which raises concerns about the possible negative maternal outcomes of COVID-19 infection during pregnancy and advocates for pregnant women to be recognized as a vulnerable group during the current pandemic.

High levels of serum interleukin-6 increase mortality of hepatitis B virus-associated acute-on-chronic liver failure.

BACKGROUNDPatients with hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) present a complex and poor prognosis. Systemic inflammation plays an important role in its pathogenesis, and interleukin-6 (IL-6) as a pro-inflammatory cytokine is related with severe liver impairment and also plays a role in promoting liver regeneration. Whether serum IL-6 influences HBV-ACLF prognosis has not been studied.AIMTo determine the impact of serum IL-6 on outcome of patients with HBV-ACLF.METHODSWe performed a retrospective study of 412 HBV-ACLF patients. The findings were analyzed with regard to mortality and the serum IL-6 level at baseline, as well as dynamic changes of serum IL-6 within 4 wk.RESULTSThe serum IL-6 level was associated with mortality. Within 4 wk, deceased patients had significantly higher levels of IL-6 at baseline than surviving patients [17.9 (7.3-57.6) vs 10.4 (4.7-22.3), P = 0.011]. Patients with high IL-6 levels (> 11.8 pg/mL) had a higher mortality within 4 wk than those with low IL-6 levels (≤ 11.8 pg/mL) (24.2% vs 13.2%, P = 0.004). The odds ratios calculated using univariate and multivariate logistic regression were 2.10 (95% confidence interval [CI]: 1.26-3.51, P = 0.005) and 2.11 (95%CI: 1.15-3.90, P = 0.017), respectively. The mortality between weeks 5 and 8 in patients with high IL-6 levels at 4 wk was 15.0%, which was significantly higher than the 6.6% mortality rate in patients with low IL-6 levels at 4 wk (hazard ratio = 2.39, 95%CI: 1.05-5.41, P = 0.037). The mortality was 5.0% in patients with high IL-6 levels at baseline and low IL-6 levels at 4 wk, 7.5% in patients with low IL-6 levels both at baseline and at 4 wk, 11.5% in patients with low IL-6 levels at baseline and high IL-6 levels at 4 wk, and 16.7% in patients with high IL-6 levels both at baseline and at 4 wk. The increasing trend of the mortality rate with the dynamic changes of IL-6 was significant (P for trend = 0.023).CONCLUSIONA high level of serum IL-6 is an independent risk factor for mortality in patients with HBV-ACLF. Furthermore, a sustained high level or dynamic elevated level of serum IL-6 indicates a higher mortality.

Dress syndrome : phénotype cutané et atteinte viscérale (étude rétrospective de 62 cas)

BackgroundDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome) is a severe cutaneous drug-induced reaction with a mortality rate that can reach 10%. The major morbidity in DRESS arises from visceral involvement. Although certain factors indicative of a poor prognosis have been suggested, such as pancytopenia, clinical markers of prognosis have not yet been identified. ObjectivesTo describe the epidemiologic and clinical characteristics of DRESS and to investigate the clinical features of patients with DRESS syndrome in order to identify potential prognostic markers. Patients and methodsRetrospective analysis of data collected over a period of 19 years in 62 patients with DRESS syndrome. Clinical features, laboratory findings, responses to treatment and outcomes were investigated. ResultsSixty-two patients were included (33 women, 29 men). Cutaneous involvement was identified as urticated papular exanthem (47 patients), morbilliform erythema (1patient), exfoliative erythroderma (12 patients) and erythema multiforme-like (2 patients). Patients with urticated papular exanthem showed more severe liver impairment but this difference was not statistically significant. Reported visceral involvement comprised liver impairment (75%), renal impairment (25%), pulmonary dysfunction (11%), and cardiac and muscle involvement with lower frequencies. Allopurinol was the most commonly incriminated drug and it was correlated with both renal impairment and high eosinophil levels. Phenobarbital was mainly responsible for liver involvement. ConclusionOur series of DRESS syndrome patients did not reveal any significant correlation between clinical phenotype and degree of systemic involvement. Other studies are needed to investigate prognosis factors and to allow a better medical care.

Short term Outcome of Coronary Artery Bypass Surgery in Patients with Impaired Left Ventricular Systolic Function

Abstract Background: Coronary artery bypass graft surgery (CABG) in patients with left ventricular dysfunction was associated with improved survival compared to medical treatment. We aimed to evaluate the short-term outcome of CABG in patients with an ejection fraction of ≤ 40%. Methods: Forty patients with ejection fraction (EF) ≤40% underwent CABG between December 2015 and August 2019. Patients with moderate to severe mitral regurgitation, concomitant severe liver and kidney impairment, re-operative CABG, who had concomitant procedures with CABG were excluded. The mean age was 56.72±12.44 years; 30 patients (75%) were males. Twenty-six patients (65%) were diabetics, 28 patients (70%) were hypertensive, 18 patients (45%) were dyslipidemic, 22 patients (55%) were smokers and 4 patients (10%) were obese. The preoperative ejection fraction ranged from 20% to 40%, with a mean of 34.62% Results: Mean cardiopulmonary bypass time was 90.8 minutes, and ischemic time was 49.8 minutes. Seventeen patients (42.5%) needed inotropic support intraoperatively, and 16 patients (40%) needed an intra-aortic balloon. Five patients (12.5%) had postoperative ischemia, one patient (2.5%) had re-exploration for bleeding, and one patient (2.5%) had acute renal failure. The mean ICU stay was 70.5± 45.63 hours, hospital stay was 8.9± 4 days, and three patients (7.5%) had operative mortality. After 6 months operatively, the ejection fraction improved to reach a mean value of 39.87± 5.02% compared to the preoperative ejection fraction of 32.8± 8.8%. (p<0.001) Conclusion: Coronary artery bypass grafting can be performed safely in patients with depressed left ventricular function with low short-term morbidity and mortality.

Upadacitinib tartrate in rheumatoid arthritis.

In rheumatoid arthritis (RA) there is an unmet therapeutic need, as a substantial proportion of patients does not achieve low disease activity or remission despite the use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and/or biological DMARDs (bDMARDs). The Janus kinase (JAK) inhibitors are the most recently added drug category in the therapeutic armamentarium in RA. Upadacitinib tartrate (Rinvoq), a selective and reversible JAK1 inhibitor, inhibited interleukin (IL)-6 and IL-7 and ameliorated adjuvant-induced arthritis in preclinical studies. In phase III randomized controlled trials (RCTs), upadacitinib, as monotherapy or in combination with csDMARDs, showed efficacy in RA patients with inadequate response to csDMARDs or bDMARDs. In a head-to-head RCT, upadacitinib 15 mg once daily was superior to adalimumab in achieving remission and in patient-reported outcomes. Upadacitinib has a good safety profile but it may increase the risk for herpes zoster, and as a substrate of cytochrome P450 (CYP) enzyme CYP3A4 it should not be coadministered with strong CYP3A4 inducers. Upadacitinib is contraindicated in patients with active tuberculosis, serious infections, active malignancy and in patients with severe liver impairment. Upadacitinib has been approved for the treatment of moderate to severe RA.