Efficacy and safety of dolutegravir-based regimens in advanced HIV-infected naïve patients: results from a multicenter cohort study.

Antiviral Res. 2019 09;169:104552

Authors: Rossetti B, Baldin G, Sterrantino G, Rusconi S, De Vito A, Giacometti A, Gagliardini R, Colafigli M, Capetti A, d'Ettorre G, Celani L, Lagi F, Ciccullo A, De Luca A, Di Giambenedetto S, Madeddu G

Abstract
The aims were to describe efficacy and tolerability of regimens containing dolutegravir (DTG) in advanced ART-naïve people living with HIV (PLHIV) from the clinical practice. The frequency of Immune Reconstitution Inflammatory Syndrome (IRIS), the estimated time of discontinuation of the first ART regimen and the time to reach virological suppression in a multicenter cohort of AIDS-presenters or late-presenters with CD4 <350/μL were assessed. We included 272 PLHIV: 120 (44%) AIDS-presenters and 152 (56%) late-presenters. The most frequent AIDS-defining event was Pneumocystis jirovecii pneumonia in 41 (34%). One hundred-thirty-two PLHIV (48%) started first-line cART regimens including DTG and 140 PLHIV (52%) were treated with cART regimens without DTG. One-hundred-eighty-two (67%) individuals discontinued their first-line regimen: 109 (60%) for simplification, 32 (18%) for toxicities, 4 (2%) for drug-drug interactions, 37 (20%) for other reasons. DTG was interrupted in 19/132 (14%) PLHIV: 13 (68%) for adverse events (5 intolerance, 4 gastrointestinal disorders and 4 neurological symptoms), 2 (11%) for proactive switch and 4 (21%) for medical/individual choice. IRIS was reported in 13 (5%) AIDS-presenters without differences between arms. During a median observation time of 16 months (IQR 5-24), HIV-1 RNA<50 copies/mL was achieved in 95/132 (72%) individuals on DTG-based regimen and in 92/140 (66%) individuals with other regimens. The 12-month estimated probability of DTG interruption was 14% (95% CI 11-17). The results demonstrated the low risk for IRIS and the high potency, good tolerability and safety of DTG in our population of advanced naïve PLHIV.

PMID: 31283942 [PubMed - indexed for MEDLINE]

Vulnerabilities to antiepileptic drug (AED) side effects in youth with epilepsy.

Epilepsy Behav. 2019 08;97:22-28

Authors: Wagner JL, Mueller M, Kellermann T, Griffin M, Smith G, Soliven M, Guilfoyle SM, Junger KF, Mucci G, Huszti H, Barrett L, Zupanc M, Modi AC

Abstract
OBJECTIVE: The objective of the study was to investigate the relationship between sociodemographic, seizure-related, behavioral health, and antiepileptic drug (AED) adverse effect variables. The aim of this study was to examine whether there were significant differences on AED adverse effects between youth with normative and subclinical/clinical depressive and/or anxiety symptoms.
METHODS: As part of a larger multisite validation study, 231 youth age 5 to 18 years diagnosed with epilepsy and their caregivers were recruited to participate for the current study. Youth ages 8 and older and caregivers of all youth completed the Behavior Assessment System for Children-2 (BASC-2). Caregivers also completed the Pediatric Epilepsy Side Effects Questionnaire (PESQ) and a Background Questionnaire. Medical chart review provided information regarding epilepsy diagnosis and treatment.
RESULTS: No differences were observed in the mean scores on AED adverse effects between the group with subclinical/clinical BASC-2 Depressive symptoms and those with average/low depressive symptoms. In contrast, the proportion of youth with subclinical/clinical versus average/low depressive symptoms via caregiver report was significantly different for the cognitive, behavioral, general neurological, and total scale of the PESQ. There was also a larger proportion of youth with self-reported subclinical/clinical depressive symptoms who experienced general neurological adverse effects compared with youth with average/low depressive symptoms who experienced general neurological adverse effects. Findings were consistent for anxiety symptoms.
SIGNIFICANCE: Identifying potentially modifiable behavioral health symptoms that exacerbate the expression of AED adverse effects could provide alternative solutions for improved AED tolerability to achieve optimum treatment outcomes.

PMID: 31181425 [PubMed - indexed for MEDLINE]

The Possibility of Therapeutic Drug Monitoring of the Most Important Interactions in Nursing Homes.

Curr Clin Pharmacol. 2019;14(2):152-156

Authors: Schjøtt P, Šutovská M, Schjøtt J

Abstract
BACKGROUND: Therapeutic drug monitoring is a relevant tool in drug treatment of elderly patients. The aim of this study was to assess the possibility of therapeutic drug monitoring of the most important potential interactions in nursing homes.
METHODS: A material of prescribed drugs to 446 patients in three nursing homes in Bergen, Norway from a single day in March 2016 was analysed. Clinically relevant drug interactions (pharmacodynamic or pharmacokinetic) were identified and classified with Stockley`s Interaction Alerts. The most important interaction among several in each patient were ranked by recommended action > severity > evidence according to Stockley`s. The possibility of therapeutic drug monitoring of drug combinations involved in the most important interactions was retrieved from a database of all laboratories performing clinical pharmacology in Norway (the Pharmacology Portal).
RESULTS: Two or more drugs were used by 443 (99.3%) of 446 patients. Three-hundred and eightyfour patients (86.1%) had > 1 interaction. About 95% of the most important interactions were pharmacodynamic. In 280 (72.9%) of these interactions, Stockley`s recommended adjust dose or monitoring. Among the 384 most important interactions, 93% involved one drug and 41% involved two drugs available for therapeutic drug monitoring.
CONCLUSION: In this pilot study, therapeutic drug monitoring was possible in the majority of the most important interactions in Norwegian nursing homes. This option is of importance since adjust dose or monitoring were frequently recommended actions associated with these interactions.

PMID: 30585548 [PubMed - indexed for MEDLINE]

15 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2020/07/07

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Cancer, immune suppression and Coronavirus Disease-19 (COVID-19): Need to manage drug safety (French Society for Oncology Pharmacy [SFPO] guidelines).

Cancer Treat Rev. 2020 Jun 23;88:102063

Authors: Slimano F, Baudouin A, Zerbit J, Toulemonde-Deldicque A, Thomas-Schoemann A, Chevrier R, Daouphars M, Madelaine I, Pourroy B, Tournamille JF, Astier A, Ranchon F, Cazin JL, Bardin C, Rioufol C

Abstract
The Coronavirus disease (COVID-19) pandemic is disrupting our health environment. As expected, studies highlighted the great susceptibility of cancer patients to COVID-19 and more severe complications, leading oncologists to deeply rethink patient cancer care. This review is dedicated to the optimization of care pathways and therapeutics in cancer patients during the pandemic and aims to discuss successive issues. First we focused on the international guidelines proposing adjustments and alternative options to cancer care in order to limit hospital admission and cytopenic treatment in cancer patients, most of whom are immunocompromised. In addition cancer patients are prone to polypharmacy, enhancing the risk of drug-related problems as adverse events and drug-drug interactions. Due to increased risk in case of COVID-19, we reported a comprehensive review of all the drug-related problems between COVID-19 and antineoplastics. Moreover, in the absence of approved drug against COVID-19, infected patients may be included in clinical trials evaluating new drugs with a lack of knowledge, particularly in cancer patients. Focusing on the several experimental drugs currently being evaluated, we set up an original data board helping oncologists and pharmacists to identify promptly drug-related problems between antineoplastics and experimental drugs. Finally additional and concrete recommendations are provided, supporting oncologists and pharmacists in their efforts to manage cancer patients and to optimize their treatments in this new era related to COVID-19.

PMID: 32623296 [PubMed - as supplied by publisher]

Definitive chemoradiotherapy plus cetuximab for cancer in the oesophagus or gastro-oesophageal junction.

Cancer Treat Res Commun. 2020 Jun 27;24:100187

Authors: von Döbeln GA, Wagenius G, Holtved E, Jacobsen AB, Nilsson M, Yu J, Baeksgaard L

Abstract
BACKGROUND: Chemoradiotherapy is standard treatment for localized oesophageal cancer unsuitable for surgery. We aimed to evaluate the efficacy of cetuximab in combination with chemoradiotherapy.
METHODS: This non-randomised multicentre phase II trial recruited patients aged 18-75 with WHO performance status 0-2 having squamous cell carcinoma or adenocarcinoma in the oesophagus or gastro-oesophageal junction, T2-4, N0-3, M0 not suitable for surgery. Chemotherapy was three 21-day cycles of fluorouracil 750 mg/m2 D1-5 and oxaliplatin D1 (cycle 1:130mg/m 2, cycle 2-3:85 mg/m 2). Radiotherapy was 50Gy in 2Gy/fraction, 5 days a week, concurrent with cycle 2 and 3 and weekly cetuximab. The primary objective was loco-regional control at one year.
RESULTS: 52 patients were included. 51 were eligible for toxicity and survival analysis and 46 for recurrence analysis. Full radiotherapy dose was delivered to 80%, 75% received all three cycles of chemotherapy and 75% received four or more doses of cetuximab. The most common related grade III-IV adverse events were gastro-intestinal(16), hypersensitivity(6) and infection(5). There were two drug-related deaths. Within six months from the end of treatment, six patients died from complications from fistulas. The loco-regional control rate at one year was 47.3%(95%CI 30.9%-62.1%). Overall survival at three years was 29.1%(95% CI 17.4-41.9%).
CONCLUSIONS: Oxaliplatin and fluorouracil given concurrent with radiotherapy and cetuximab had an acceptable safety profile and showed a clinical response in patients with locoregionally advanced oesophageal cancer unsuitable for surgery. However, the primary end-point was not met, and the addition of cetuximab to definitive chemoradiotherapy cannot be recommended.

PMID: 32619832 [PubMed - as supplied by publisher]

Predicting potential adverse events using safety data from marketed drugs.

BMC Bioinformatics. 2020 Apr 29;21(1):163

Authors: Daluwatte C, Schotland P, Strauss DG, Burkhart KK, Racz R

Abstract
BACKGROUND: While clinical trials are considered the gold standard for detecting adverse events, often these trials are not sufficiently powered to detect difficult to observe adverse events. We developed a preliminary approach to predict 135 adverse events using post-market safety data from marketed drugs. Adverse event information available from FDA product labels and scientific literature for drugs that have the same activity at one or more of the same targets, structural and target similarities, and the duration of post market experience were used as features for a classifier algorithm. The proposed method was studied using 54 drugs and a probabilistic approach of performance evaluation using bootstrapping with 10,000 iterations.
RESULTS: Out of 135 adverse events, 53 had high probability of having high positive predictive value. Cross validation showed that 32% of the model-predicted safety label changes occurred within four to nine years of approval (median: six years).
CONCLUSIONS: This approach predicts 53 serious adverse events with high positive predictive values where well-characterized target-event relationships exist. Adverse events with well-defined target-event associations were better predicted compared to adverse events that may be idiosyncratic or related to secondary target effects that were poorly captured. Further enhancement of this model with additional features, such as target prediction and drug binding data, may increase accuracy.

PMID: 32349656 [PubMed - indexed for MEDLINE]

Adverse Drug Reaction Risk Measures: A Comparison of Estimates from Drug Surveillance and Randomised Trials.

Pharmaceut Med. 2019 08;33(4):331-339

Authors: Beau-Lejdstrom R, Crook S, Spanu A, Yu T, Puhan MA

Abstract
BACKGROUND: Most drug regulatory agencies and pharmaceutical companies hold databases of spontaneous reports of suspected adverse drug reactions (ADRs). Detection systems for ADR signals have been created by specialists to analyse such reports, based on the concept of disproportionality, in order to support safety decision making. However, these measures are often misinterpreted by non-specialists in pharmacovigilance.
OBJECTIVES: Our aim was to assess agreement between estimates of risk from spontaneous reports of suspected ADRs and estimates of risks of ADRs from randomised controlled trials (RCTs).
METHODS: From 150 drugs randomly selected from the US Food and Drug Administration's Adverse Event Reporting System (FAERS), we identified drugs where FAERS provided reporting odds ratios (RORs) and corresponding systematic reviews from the Cochrane database gave (pooled) odds ratios (ORs) for the same drugs and adverse reactions. We assessed agreement between (ln) RORs and (ln) ORs using the Pearson correlation coefficient and the Bland-Altman agreement method, and performed sensitivity analyses.
RESULTS: We identified 6 drugs and 125 ADRs. Overall, there was a weak correlation (r = 0.20) between RORs (FAERS) and ORs (RCTs). However, we observed a stronger correlation (r = 0.78) between RORs and ORs for one drug (roflumilast) that received market approval relatively recently (2011).
CONCLUSIONS: Spontaneous reporting of suspected ADRs is an important tool for regulatory agencies and pharmaceutical companies in making decisions and detecting drug safety signals. Although there was moderate-to-strong agreement between ADR risk estimates from drug surveillance and RCTs for one drug, this study illustrates the current recommendations not to use disproportionality measures as valid proxies for risk estimates.

PMID: 31933187 [PubMed - indexed for MEDLINE]

Association of Adverse Drug Events with Hospitalization Outcomes and Costs in Older Adults in the USA using the Nationwide Readmissions Database.

Pharmaceut Med. 2019 08;33(4):321-329

Authors: Riaz M, Brown JD

Abstract
BACKGROUND: Adverse drug events (ADEs) are a primary cause of significant morbidity, mortality, and healthcare utilization in older adults.
OBJECTIVE: The objective of this study was to evaluate the clinical outcomes and cost of ADEs during hospitalization in older adults.
METHODS: Discharges for patients aged 65 years or older were identified in the 2014 Nationwide Readmissions Database. ADEs were selected based on a previously developed algorithm of 442 unique diagnoses and external causes of injury codes. Patients were categorized into ADE or non-ADE groups. Regression models were used for a multivariable analysis for each outcome metric, which included all-cause readmission, in-hospital mortality, length of stay, and costs.
RESULTS: The study included 3,832,322 patients. Among these patients, 203,432 (5.3%) had at least one ADE during hospitalization. The majority of ADEs were related to broad categories of "medications affecting blood constituents" (22%) and "adverse effects of biological and medicinal substances in therapeutic use" (23%). In adjusted models, older adults with ADEs during hospitalization had a 25% (p < 0.0001) and 9% (p < 0.0001) higher odds of readmission and in-hospital mortality, respectively, as compared with those without ADEs. A 17% (p < 0.0001) increase in the length of stay was estimated in the ADE group and 1% point estimate (p > 0.05) rise in cost was observed in the ADE group when compared with the non-ADE group.
CONCLUSIONS: ADEs have a substantial burden on in-patient care of older adults both clinically (increased readmission, in-hospital mortality, and length of stay) and financially. Targeted interventions can help to prevent ADEs and, consequently, the associated clinical and economic burden.

PMID: 31933184 [PubMed - indexed for MEDLINE]

Adverse dose-dependent effects of morphine therapy in acute heart failure.

Int J Cardiol. 2020 05 01;306:146

Authors: Caspi O, Naami R, Halfin E, Aronson D

PMID: 31839427 [PubMed - indexed for MEDLINE]

Emerging Role of Organ-on-a-Chip Technologies in Quantitative Clinical Pharmacology Evaluation.

Clin Transl Sci. 2019 03;12(2):113-121

Authors: Isoherranen N, Madabushi R, Huang SM

Abstract
The recently enacted Prescription Drug User Fee Act (PDUFA) VI includes in its performance goals "enhancing regulatory science and expediting drug development." The key elements in "enhancing regulatory decision tools to support drug development and review" include "advancing model-informed drug development (MIDD)." This paper describes (i) the US Food and Drug Administration (FDA) Office of Clinical Pharmacology's continuing efforts in developing quantitative clinical pharmacology models (disease, drug, and clinical trial models) to advance MIDD, (ii) how emerging novel tools, such as organ-on-a-chip technologies or microphysiological systems, can provide new insights into physiology and disease mechanisms, biomarker identification and evaluation, and elucidation of mechanisms of adverse drug reactions, and (iii) how the single organ or linked organ microphysiological systems can provide critical system parameters for improved physiologically-based pharmacokinetic and pharmacodynamic evaluations. Continuous public-private partnerships are critical to advance this field and in the application of these new technologies in drug development and regulatory review.

PMID: 30740886 [PubMed - indexed for MEDLINE]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2020/07/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Patients' perception about opioids and addiction in South Korea.

Korean J Pain. 2020 Jul 01;33(3):234-244

Authors: Kim CL, Hong SJ, Lim YH, Jeong JH, Moon HS, Choi HR, Park SK, Kim JE, You H, Kim JH

Abstract
Background: Chronic pain affects approximately 22% of the world's population. Opioids can be useful in chronic pain management. However, some patients have negative perception of opioids. The purpose of this research was to evaluate patients' perception about opioids and investigate problems associated with prescribing and taking opioids in South Korea.
Methods: Patients who visited a pain clinic in 14 university hospitals of South Korea from September through October 2018 were asked to complete anonymous questionnaires about taking opioids.
Results: Of the 368 patients that were surveyed (female 53.3%, male 46.7%), 56.8% were prescribed opioids. In the opioid group, 92.8% patients had heard of opioids from their doctor and 72.6% of them had a positive perception about opioids. The side effects associated with opioid use were constipation (35.4%), dizziness (24.6%), nausea and vomiting (17.4%), dysuria (6.2%), and addiction (2.0%). In the no opioid group, the primary sources of information about opioids were doctors (49.2%), mass media (30.8%), and the internet (16.2%). The main reasons why 39.0% patients did not take opioids were fear of addiction (57.7%) and side effects (38.5%). There were 71.5% and 60.9% patients in the opioid and no opioid group, respectively, who wished to take opioids when their numeric rating scale pain score was ≥ 7.
Conclusions: Perception of opioids among patients who take them was either neutral or positive. However, 39.0% patients who have not been prescribed opioids did not want an opioid prescription, citing fear of addiction and side effects as the primary reasons.

PMID: 32606268 [PubMed]

Updates on Vaccine Safety and Post-Licensure Surveillance for Adverse Events Following Immunization in South Korea, 2005-2017.

Yonsei Med J. 2020 Jul;61(7):623-630

Authors: Yoon D, Kim JH, Lee H, Shin JY

Abstract
PURPOSE: Vaccine hesitancy is among the top ten threats to global health, and access to precise data on adverse events following immunization (AEFIs) is imperative to alleviate public concerns surrounding vaccines. This study aimed to present the overall trends of AEFIs reported in South Korea.
MATERIALS AND METHODS: We evaluated the trends of AEFIs using the Korea Institute of Drug Safety & Risk Management-Korea Adverse Event Reporting System database between January 2005 and December 2017. AEFIs were classified into five categories to evaluate associations between vaccines and AEFIs through a case-non-case study: neurologic reactions, general systemic reactions, local reactions, allergic reactions, and others.
RESULTS: Among 54378 reported adverse events (AEs) associated with all vaccines approved in South Korea, more than half (56.7%) occurred following influenza vaccination, followed by the pneumococcal (11.6%) and Bacillus Calmette-Guérin (BCG) vaccines (5.0%). After immunization with most vaccines, general systemic reactions were most common, followed by local and neurologic reactions. Adjusted reporting odds ratios were calculated for all neurologic, general, local, and allergic reactions: of all vaccines, rotavirus [neurologic 2.43, 95% confidence interval (CI), 2.25-2.62], BCG (general; 2.20, 95% CI, 1.91-2.53), BCG (local; 3.15, 95% CI, 2.69-3.68), and Japanese encephalitis (allergic 2.38, 95% CI, 1.98-2.87) vaccines showed the highest values.
CONCLUSION: The majority of reported AEFIs were non-serious and mostly general systemic reactions. Sufficient knowledge on the AEFIs would secure public confidence on the safety of vaccines, thereby reducing public health burden from vaccine-preventable diseases.

PMID: 32608206 [PubMed - in process]

Clinical prospects of biomarkers for the early detection and/or prediction of organ injury associated with pharmacotherapy.

Biochem Pharmacol. 2019 12;170:113664

Authors: Tajima S, Yamamoto N, Masuda S

Abstract
Several biomarkers are used to monitor organ damage caused by drug toxicity. Traditional markers of kidney function, such as serum creatinine and blood urea nitrogen are commonly used to estimate glomerular filtration rate. However, these markers have several limitations including poor specificity and sensitivity. A number of serum and urine biomarkers have recently been described to detect kidney damage caused by drugs such as cisplatin, gentamicin, vancomycin, and tacrolimus. Neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), kidney injury molecule-1 (KIM-1), monocyte chemotactic protein-1 (MCP-1), and cystatin C have been identified as biomarkers for early kidney damage. Hy's Law is widely used as to predict a high risk of severe drug-induced liver injury caused by drugs such as acetaminophen. Recent reports have indicated that glutamate dehydrogenase (GLDH), high-mobility group box 1 (HMGB-1), Keratin-18 (k18), MicroRNA-122 and ornithine carbamoyltransferase (OCT) are more sensitive markers of hepatotoxicity compared to the traditional markers including the blood levels of amiotransferases and total bilirubin. Additionally, the rapid development of proteomic technologies in biofluids and tissue provides a new multi-marker panel, leading to the discovery of more sensitive biomarkers. In this review, an update topics of biomarkers for the detection of kidney or liver injury associated with pharmacotherapy.

PMID: 31606409 [PubMed - indexed for MEDLINE]

Health care utilization and steroid-refractory toxicities from immune checkpoint inhibitors.

Cancer. 2020 01 15;126(2):322-328

Authors: Wang LX, Quach HT, Moodabigil NV, Davis EJ, Sosman JA, Dusetzina SB, Johnson DB

Abstract
BACKGROUND: Anti-programmed death protein 1 (anti-PD-1) agents have transformed the treatment of advanced melanoma and other cancers, but the rates of steroid-refractory toxicities and health care utilization are not well described. This study assessed these endpoints in patients with melanoma treated with anti-PD-1 with or without ipilimumab.
METHODS: This study retrospectively evaluated 344 patients with metastatic melanoma treated with anti-PD-1 or a combination of ipilimumab and nivolumab at Vanderbilt University Medical Center from 2009 to 2018. The incidence, types, grades, management, and outcomes of immune-related adverse events (irAEs) and hospitalizations for irAEs and disease progression were assessed.
RESULTS: Patients on combination therapy were more likely to develop irAEs than those on monotherapy (72% vs 37%; P < .001) and were more likely to require systemic steroids (61% vs 20%; P < .001), steroid dose re-escalation (23% vs 6%; P < .001), and second-line immunosuppressive use (17% vs 2%; P < .001) and to suffer high-dose steroid-refractory toxicities (23% vs 3%; P < .001). Combination-treated patients were more likely to have any hospitalization (32% vs 7%; P < .001) or multiple hospitalizations for irAEs (11% vs 3%; P = .001) and had a longer average time of hospitalization (mean, 1.92 vs 0.62 days; P = .002). Among 176 hospitalizations related to disease progression in patients who died during evaluable follow-up, 69% occurred within the 90 days before death. Early hospitalizations for disease-related reasons portended a very poor prognosis (median time from admission to death, 58 days).
CONCLUSIONS: Patients treated with a combination of ipilimumab and nivolumab had higher rates of hospitalization and steroid-refractory toxicities than those treated with anti-PD-1 monotherapy. Disease-associated hospitalizations were similar between the 2 groups, portended a poor prognosis, and mostly occurred in the last months of life.

PMID: 31580492 [PubMed - indexed for MEDLINE]

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

Oncologist. 2019 11;24(11):e1148-e1155

Authors: Duma N, Abdel-Ghani A, Yadav S, Hoversten KP, Reed CT, Sitek AN, Enninga EAL, Paludo J, Aguilera JV, Leventakos K, Lou Y, Kottschade LA, Dong H, Mansfield AS, Manochakian R, Adjei AA, Dronca RS

Abstract
BACKGROUND: Immune-related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti-programmed cell death protein 1 (PD-1) therapy.
MATERIALS AND METHODS: All patients with metastatic melanoma and non-small cell lung cancer (NSCLC) treated with anti-PD-1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan-Meier method and log-rank test was used for time-to-event analysis.
RESULTS: In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression-free-survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs.
CONCLUSION: Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations.
IMPLICATIONS FOR PRACTICE: The results of this study suggest that women may be at a higher risk for immune-related adverse events (irAEs) compared with men when treated with anti-programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow-up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment-related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

PMID: 31036771 [PubMed - indexed for MEDLINE]

Exposure to acetaminophen impairs vasodilation, increases oxidative stress and changes arterial morphology of rats.

Arch Toxicol. 2019 07;93(7):1955-1964

Authors: Porto HKP, Grando MD, Ramalho LNZ, Valadares MC, Bendhack LM, Batista AC, Rocha ML

Abstract
Acetaminophen (APAP) is one of the most widely consumed drugs in the world. Studies have shown renal and hepatic damage as the direct result of high oxidative stress induced by APAP. Since the cardiovascular system is sensitive to oxidative stress and literature describes increased cardiovascular dysfunction in APAP consumers, this work aimed to evaluate harmful effects of APAP on the vascular system. Rats were exposed to APAP (400 mg/kg/day in drinking water) for 14 days. Plasma and aortas were collected and stored in - 80 °C and a selection of arteries was prepared for isometric tension recordings, morphological, immunohistochemical and protein expression analysis. The APAP-treated group presented increased transaminases (ALT/AST) and malondialdehyde levels in the plasma compared to controls. Lipid peroxidation, glutathione reductase and superoxide dismutase levels were increased in the plasma and arteries of the APAP group. Nevertheless, glutathione level was reduced as compared to control group. The vasodilation response to acetylcholine and sodium nitroprusside (0.1 nM to 10 µM) was also impaired after APAP treatment; however, the vascular relaxation was restored after treatment with vitamin C (100 µM). Arteries from the APAP group presented reduced wall thickness, collagen deposition, elastic fibers and increased immunoreactivity to nitrotyrosine. eNOS and sGC protein expression remained unchanged and were at similar levels as controls. These findings showed higher oxidative stress and impaired vasodilation in rats exposed to APAP. Furthermore, arteries presented reduced cell layers, collagen, elastin deposition and significantly increased immunoreactivity to nitrotyrosine after APAP treatment.

PMID: 31020376 [PubMed - indexed for MEDLINE]

Echinocandins as alternative treatment for HIV-infected patients with Pneumocystis pneumonia.

AIDS. 2019 07 01;33(8):1345-1351

Authors: Huang YS, Liu CE, Lin SP, Lee CH, Yang CJ, Lin CY, Tang HJ, Lee YC, Lin YC, Lee YT, Sun HY, Hung CC, Taiwan HIV Study Group

Abstract
OBJECTIVES: Treatment with trimethoprim-sulfamethoxazole for Pneumocystis pneumonia (PCP) is often associated with adverse effects. Echinocandins, by inhibiting the cyst form of Pneumocystis jirovecii, may be an alternative therapy for PCP. However, clinical experience with echinocandins in the treatment of PCP remains limited among HIV-infected patients.
METHODS: From August 2013 to April 2018, data of HIV-infected patients with confirmed PCP who received echinocandins as alternative treatment because of intolerance or unresponsiveness to trimethoprim-sulfamethoxazole were retrospectively reviewed to assess the effectiveness and safety of echinocandins alone or in combination with other agents.
RESULTS: In total, 34 patients were included, with a median CD4 count of 27 cells/μl [interquartile range (IQR), 20-93). Twenty-four patients (70.6%) presented with moderate-to-severe PCP. The most common adverse effects leading to withdrawal of trimethoprim-sulfamethoxazole were hepatotoxicity (29.4%), gastrointestinal upset (23.5%), and rash (17.6%). Nine patients (26.5%) were switched to echinocandins after failure of trimethoprim-sulfamethoxazole. The median interval before switch from trimethoprim-sulfamethoxazole to echinocandins was 9.0 days (IQR 5.0-14.0). The all-cause and PCP-related in-hospital mortality rate of patients receiving echinocandins as alternative therapy was 20.6% (7/34) and 14.7% (5/34), respectively. The all-cause in-hospital mortality was 0% in mild PCP cases and 29% (7/24) in moderate-to-severe PCP cases. Patients who had failed to respond to first-line trimethoprim-sulfamethoxazole treatment tended to have a higher in-hospital mortality rate than those without first-line trimethoprim-sulfamethoxazole failure (44.4% versus 12.0%, P = 0.06).
CONCLUSION: Echinocandin therapy might serve as an alternative option for HIV-infected patients with PCP who are intolerable to trimethoprim-sulfamethoxazole.

PMID: 30932964 [PubMed - indexed for MEDLINE]

Effects of 24-week Toll-like receptor 9 agonist treatment in HIV type 1+ individuals.

AIDS. 2019 07 01;33(8):1315-1325

Authors: Vibholm LK, Konrad CV, Schleimann MH, Frattari G, Winckelmann A, Klastrup V, Jensen NM, Jensen SS, Schmidt M, Wittig B, Zuwala K, Mack K, Olesen R, Hua S, Lichterfeld M, Østergaard L, Denton PW, Tolstrup M, Søgaard OS

Abstract
DESIGN: This was an exploratory, single-arm clinical trial that tested the immune enhancement effects of 24-weeks of Toll-like receptor 9 (TLR9) agonist (MGN1703; Lefitolimod; 60 mg × 2 weekly) therapy.
METHODS: We enrolled HIV-1-infected individuals on suppressive combination antiretroviral therapy. Safety was assessed throughout the study. The primary outcome was reduction in total CD4 T-cell viral DNA levels. Secondary outcomes included safety, detailed immunological and virological analyses, and time to viral rebound (viral load > 5000 copies/ml) after randomization into an analytical treatment interruption (ATI).
RESULTS: A total of 12 individuals completed the treatment phase and nine completed the ATI. Adverse events were limited and consistent with previous reports for MGN1703. Although the dosing regimen led to potent T-cell activation and increased HIV-1-specific T-cell responses, there were no cohort-wide changes in persistent virus (total CD4 T cells viral DNA; P = 0.34). No difference in time to rebound was observed between the ATI arms (log rank P = 0.25). One of nine ATI participants, despite harboring a large replication-competent reservoir, controlled viremia for 150 days via both HIV-1-specific cellular and antibody-mediated immune responses.
CONCLUSION: A period of 24 weeks of MGN1703 treatment was safe and improved innate as well as HIV-1-specific adaptive immunity in HIV-1+ individuals. These findings support the incorporation of TLR9 agonism into combination HIV-1 cure strategies.
TRIAL NAME AND REGISTRATION: TLR9 Enhancement of antiviral immunity in chronic HIV-1 infection: a phase 1B/2A trial; ClinicalTrials.gov NCT02443935.

PMID: 30932955 [PubMed - indexed for MEDLINE]