CSF-1R-Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy.

J Immunol. 2016 Jul 01;197(1):179-87

Authors: Byrne KT, Leisenring NH, Bajor DL, Vonderheide RH

Abstract
Cancer immunotherapies are increasingly effective in the clinic, especially immune checkpoint blockade delivered to patients who have T cell-infiltrated tumors. Agonistic CD40 mAb promotes stromal degradation and, in combination with chemotherapy, drives T cell infiltration and de novo responses against tumors, rendering resistant tumors susceptible to current immunotherapies. Partnering anti-CD40 with different treatments is an attractive approach for the next phase of cancer immunotherapies, with a number of clinical trials using anti-CD40 combinations ongoing, but the optimal therapeutic regimens with anti-CD40 are not well understood. Pancreatic ductal adenocarcinoma (PDA) is classically resistant to immunotherapy and lacks baseline T cell infiltration. In this study, we used a tumor cell line derived from a genetically engineered mouse model of PDA to investigate alterations in the sequence of anti-CD40 and chemotherapy as an approach to enhance pharmacological delivery of chemotherapy. Unexpectedly, despite our previous studies showing anti-CD40 treatment after chemotherapy is safe in both mice and patients with PDA, we report in this article that anti-CD40 administration <3 d in advance of chemotherapy is lethal in more than half of treated C57BL/6 mice. Anti-CD40 treatment 2 or 3 d before chemotherapy resulted in significantly increased populations of both activated myeloid cells and macrophages and lethal hepatotoxicity. Liver damage was fully abrogated when macrophage activation was blocked using anti-CSF-1R mAb. These studies highlight the dual nature of CD40 in activating both macrophages and T cell responses, and the need for preclinical investigation of optimal anti-CD40 treatment regimens for safe design of clinical trials.

PMID: 27217585 [PubMed - indexed for MEDLINE]

Health regulatory communications of well-established safety-related pharmacogenomics associations in six developed countries: an evaluation of alignment.

Pharmacogenomics J. 2017 Mar;17(2):121-127

Authors: Tan-Koi WC, Lim ES, Teo YY

Abstract
Recommendations on genetic testing are typically conveyed by drug regulatory authorities through drug labels, which are legal requirements for market authorization of drugs. We conducted a cross-sectional study of drug labels focusing on three crucial aspects of regulatory pharmacogenomics communications: (i) intent; (ii) interpretation in the local context; and (iii) implications of the genetic information. Labels of drugs associated with well-established safety-related genetic markers for adverse drug reactions across six developed countries of United States, Canada, United Kingdom, Australia, New Zealand and Singapore were reviewed. We found differing medical advice for genotype-positive HLA-B*15:02, HLA-A*31:01, UGT1A1*28 and CYP2D6 ultra-rapid metabolisers in breastfeeding women. This raises questions on implications to clinical practice between these countries. Varying ways of presenting at-risk population and allele frequencies also raises question in incorporating such information in drug labels. An international guidance addressing these crucial aspects of regulatory pharmacogenomic communications in drug labels is long overdue.

PMID: 26902540 [PubMed - indexed for MEDLINE]

19 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 2017/08/08

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.

21 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 2017/08/08

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.

Evidence and decision algorithm for the withdrawal of antipsychotic treatment in the elderly with dementia and neuropsychiatric symptoms.

Eur J Clin Pharmacol. 2017 Aug 05;:

Authors: Miarons M, Cabib C, Barón FJ, Rofes L

Abstract
PURPOSE: Antipsychotics (APs) are commonly used to manage neuropsychiatric symptoms (NPS) in elderly patients with dementia, even though several large studies have demonstrated an association between AP treatment and increased morbidity and mortality in people with dementia. The aim of this study is to review the scientific literature of the use of AP in the elderly with dementia and to propose an algorithm to assist in decision-making regarding the withdrawal of APs.
METHODS: A computerized literature search (MEDLINE: 1966 to December 2016, EMBASE: 1982 to December 2016) was used to locate relevant literature. Keywords in the search included terms from Medical Subject Headings (MESH) and EMBASE thesaurus (EMTREE). The following terms were used in the MESH database and EMTREE thesaurus: Aged, Antipsychotic Agents, Behavioral Symptoms and Dementia.
RESULTS: Earlier studies of APs used in elderly patients with dementia suggest that, in most elderly demented patients, APs can be withdrawn with no effect on behaviour. These patients are likely to benefit from the algorithm we propose to assist clinicians in the withdrawal of APs.
CONCLUSIONS: In this paper, we review the potential risks and benefits of discontinuing AP treatment in elderly demented patients with NPS and propose an algorithm to assist in decision-making regarding AP withdrawal.

PMID: 28780696 [PubMed - as supplied by publisher]

[Comparative relevance of declaration of side effects by patients and health professionals].

Therapie. 2017 Jul 08;:

Authors: Lagneau A, Vigier C, Marianna A, Serfaty R, Rocher F, Spreux A, Drici MD

Abstract
INTRODUCTION: Drug-induced adverse events have been accessible to patient's spontaneous reporting in France and such notifications have been steadily increasing since 2011. However, these notifications are still shrouded with medical perplexity and are sometimes subjected to partial caution in their interpretation by the patient's physician. We aimed to evaluate and compare prospectively the relevance of such spontaneous notifications with those provided by healthcare professionals to the French Pharmacovigilance Center of Nice-Alpes-Côte d'Azur.
METHODS: Spontaneous reporting of drug adverse events notified by patients and health care professionals were compared in terms of critical (name, date, effect, drug involved, chronological compatibility) and non-critical (posology, dosage) information, whereas the plausibility of the cases were assessed in weekly multispecialty staffs. Each patient's notification was matched with the immediate pre- and post-notifications declared by health care providers.
RESULTS: Spontaneous notifications from 61 patients were compared with 122 notifications from health care providers. Neither the critical information necessary for declaring the case in the national database (7/61 versus 16/122, P=0.75), nor the uncritical elements allowing to assess the case (30/61 versus 51/122, P=0.22), its plausibility or the causality of the drug (P=0.10) differed significantly between the two groups. 107 cases out of 122 (88%) notified by health care providers were classified as serious, as compared with 19 out of 61 (15%) of patient's ones (P<0.001).
CONCLUSION: Despite concerns from pharmacovigilance specialists in France, the medical relevance of spontaneous reported drug-associated adverse events does not differ from that of health care providers.

PMID: 28780021 [PubMed - as supplied by publisher]

Effect of renal function on antihypertensive drug safety and efficacy in children.

Pediatr Nephrol. 2017 Aug 04;:

Authors: Watt KM, Avant D, Sherwin J, Benjamin DK, Hornik C, Benjamin DK, Li JS, Smith PB

Abstract
BACKGROUND: Hypertension and chronic kidney disease (CKD) are common comorbidities. Guidelines recommend treating hypertension in children with CKD because it is a modifiable risk factor for subsequent cardiovascular disease. Children with CKD are frequently excluded from antihypertensive drug trials. Consequently, safety and efficacy data for antihypertensive drugs are lacking in children with CKD.
METHODS: We determined the incidence of adverse events in 10 pediatric antihypertensive trials to determine the effect of renal function on antihypertensive safety and efficacy in children. These trials were submitted to the US Food and Drug Administration from 1998 to 2005. We determined the number and type of adverse events reported during the trials and compared these numbers in participants with normal renal function and those with decreased function (defined as an estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m(2) calculated using the original Schwartz equation).
RESULTS: Among the 1,703 children in the 10 studies, 315 had decreased renal function. We observed no difference between the two cohorts in the incidence of adverse events or adverse drug reactions related to study drug. Only 5 participants, all with decreased renal function, experienced a serious adverse event; none was recorded by investigators to be study drug-related. Among treated participants, children with decreased renal function who received a high dose of study drug had a significantly larger drop in diastolic blood pressure compared with children with normal renal function.
CONCLUSIONS: These data show that antihypertensive treatment in children with renal dysfunction can be safe and efficacious, and consideration should be given to their inclusion in selected drug development programs.

PMID: 28779238 [PubMed - as supplied by publisher]

Drug-Induced Hypersomnolence.

Sleep Med Clin. 2017 Sep;12(3):383-393

Authors: Pagel JF

Abstract
Daytime somnolence is among the most commonly reported drug side effects. The United States has the highest rate of motor vehicular accident (MVA) deaths with sedating drug use a factor in more than 30%. Sedating drug use extends beyond drugs of abuse to sedating medications. This paper presents pharmacodynamics, performance and driving tests, and MVAs for somnolence inducing agents classified as hypnotics, sedatives, and/or sedation as a side effect. This classification, based on the drug tendency to induce next-day sedation after nighttime use, can be cogently used by prescribers, pharmacists, regulatory agencies, and in direct to consumer marketing.

PMID: 28778236 [PubMed - in process]

Amantadine for Antipsychotic-Related Weight Gain: Meta-Analysis of Randomized Placebo-Controlled Trials.

J Clin Psychopharmacol. 2017 Jun;37(3):341-346

Authors: Zheng W, Wang S, Ungvari GS, Ng CH, Yang XH, Gu YH, Li M, Xiang YQ, Xiang YT

Abstract
PURPOSE: Weight gain associated with antipsychotics in schizophrenia has been an ongoing concern. This meta-analysis examined the efficacy and safety of amantadine as an adjunctive treatment of weight gain in schizophrenia by systematically searching and analyzing randomized controlled trials (RCTs). RCTs comparing adjunctive amantadine with placebo in adult patients with schizophrenia were included in the meta-analysis.
METHODS: Two independent investigators searched the literature and extracted data. Weighted and standardized mean differences (WMDs/SMDs) and risk ratio ± 95% confidence intervals were calculated.
RESULTS: Five RCTs (n = 265) with double-blinded design lasting 8.2 ± 5.9 weeks were included in the analysis. Amantadine outperformed placebo regarding weight reduction with moderate effect size (trials, 3; n = 205; WMD -2.22 kg; P = 0.001, I = 45%). Amantadine also outperformed placebo at endpoint in the negative symptom (the Positive and Negative Syndrome Scale [PANSS] [1 trial] and the Scale for the Assessment of Negative Symptoms [1 trial]) scores (trials, 2; n = 84; SMD, -0.56; P = 0.01, I = 12%), but not in the PANSS total scores (trials, 2) (SMD, -0.31; P = 0.16, I = 0%) and the positive symptom (PANSS [1 trial] and the Scale for the Assessment of Positive Symptoms [1 trial]) scores (SMD, 0.13; P = 0.54, I = 0%). Except for insomnia (P = 0.007; number needed to harm, 6; 95% confidence interval, 4-16), all-cause discontinuation (risk ratio, 1.12; P = 0.54, I = 0%) and other adverse events were similar between the amantadine and placebo groups.
CONCLUSIONS: According to this meta-analysis of 5 RCTs, adjunctive amantadine seems to be an effective option for attenuating antipsychotic-related weight gain in patients with schizophrenia. More RCTs are needed to inform clinical recommendations.

PMID: 28383359 [PubMed - indexed for MEDLINE]

Lithiumeter: Version 2.0.

Bipolar Disord. 2016 Dec;18(8):631-641

Authors: Malhi GS, Gershon S, Outhred T

Abstract
BACKGROUND: The Lithiumeter was developed as a visual and practical guide for determining lithium levels in the management of bipolar disorder (BD). It appears to have been well received, as evidenced by its increasing popularity amongst doctors as a deskside clinical aide, and adoption and reproduction of the schematic in clinical guidelines and texts. However, since its publication 5 years ago, key basic neuroscience and clinical research developments pertaining to lithium have significantly advanced our understanding, necessitating further refinement of guidance concerning the practicalities of lithium therapy.
METHODS: Literature concerning the indications for, and therapeutic levels of, lithium and the associated acute and chronic risks of therapy was scrutinized as part of updating clinical practice guidelines. We have reviewed these updates and identified significant areas of change with respect to the previous Lithiumeter (version 1.0).
RESULTS: Since 2011, updated clinical practice guidelines have narrowed the indicated plasma lithium concentration for maintenance therapy, suggesting that additional guidance is necessary for optimizing treatment. Relevant updated clinical guidance was integrated to constitute the Lithiumeter 2.0, which provides a more comprehensive overview of the practical aspects of lithium therapy while maintaining a focus on optimization of lithium levels, such as differential titration of lithium depending on the current mood state.
CONCLUSIONS: The Lithiumeter 2.0 is an update that clinicians will find useful for their practice. By addressing some of the issues faced in clinical practice, translational clinical research will continue to inform the Lithiumeter in future updates.

PMID: 28063207 [PubMed - indexed for MEDLINE]

[Follow-up of patients treated by VKA: Interest of a pharmaceutical link between the hospital and the retail pharmacies].

Ann Pharm Fr. 2017 Jan;75(1):45-53

Authors: Bidon D, Lecoeur A, Segui E, Seguette N, Le Mercier F, Bauler S

Abstract
Vitamin K antagonists (VKA) are used by 1,7% of the French population. Patient education and monitoring can decrease the number of iatrogenic hospitalizations due to VKA. We assessed the impact of a communication between hospital and retail pharmacists about patient's knowledge on VKA. The aim of our study has been to evaluate the value added by the link between the hospital pharmacist and the community pharmacist on the follow-up of patients treated by vitamin K antagonist. Patient information about VKA treatment is offered to inpatients in our hospital. An information form is filled for each patient treated by VKA. Patient's knowledge is assessed on the document (Name of VKA, cause of treatment, monitoring, risks of overdose, compliance…). This form is sent to the community pharmacist after the training when the patient leaves the hospital (by fax or by email). The form is sent back by the community pharmacist after the second training. Sixty-eight patients received the training, 48 forms have been sent to the retail pharmacists and 43 forms have been sent back to the hospital. Seven retail pharmacists replied spontaneously. Twenty-eight patients increased their knowledge (in average+21%) and 12 patients stabilized their knowledge. The best-known concepts were the INR target, the time of drug intake, the risks of overdose and the information of the family. The improvement of knowledge is significant for the name of VKA, the cause of treatment, efficacy assessment and signs of overdose. The implementation of a communication between the hospital and the retail pharmacies is time-consuming but the follow-up of those patients seems essential to keep a good knowledge.

PMID: 27234455 [PubMed - indexed for MEDLINE]

Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island.

J Gerontol A Biol Sci Med Sci. 2016 Jul;71(7):841-9

Authors: Arriola Apelo SI, Lamming DW

Abstract
Rapamycin (sirolimus) is a macrolide immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) protein kinase and extends lifespan in model organisms including mice. Although rapamycin is an FDA-approved drug for select indications, a diverse set of negative side effects may preclude its wide-scale deployment as an antiaging therapy. mTOR forms two different protein complexes, mTORC1 and mTORC2; the former is acutely sensitive to rapamycin whereas the latter is only chronically sensitive to rapamycin in vivo. Over the past decade, it has become clear that although genetic and pharmacological inhibition of mTORC1 extends lifespan and delays aging, inhibition of mTORC2 has negative effects on mammalian health and longevity and is responsible for many of the negative side effects of rapamycin. In this review, we discuss recent advances in understanding the molecular and physiological effects of rapamycin treatment, and we discuss how the use of alternative rapamycin treatment regimens or rapamycin analogs has the potential to mitigate the deleterious side effects of rapamycin treatment by more specifically targeting mTORC1. Although the side effects of rapamycin are still of significant concern, rapid progress is being made in realizing the revolutionary potential of rapamycin-based therapies for the treatment of diseases of aging.

PMID: 27208895 [PubMed - indexed for MEDLINE]

Etiology and pathogenesis of dental erosion.

Quintessence Int. 2016 Apr;47(4):275-8

Authors: Kanzow P, Wegehaupt FJ, Attin T, Wiegand A

Abstract
The condition of dental erosion is defined as acid-related loss of tooth structure which does not involve microorganisms. Depending on the origin of the acid, extrinsic (usually caused by acids in food) and intrinsic (caused by endogenous acid) erosion can be distinguished. The presence and severity of erosive defects depend on various parameters such as nutrition, saliva, general diseases, and mechanical stress by abrasion and attrition. As an example, dietary habits which involve frequent intake of acidic food and beverages, occupational acid exposure, as well as certain drugs or diseases that affect saliva flow rate are accompanied by an increased risk of erosive dental hard tissue defects. By a thorough clinical examination and an accurate anamnesis, various erosion-related risk factors can be identified and strategies to reduce or eliminate these factors be identified.

PMID: 27022647 [PubMed - indexed for MEDLINE]

Absence of human herpesvirus 6B detection in association with illness in children undergoing cancer chemotherapy.

J Med Virol. 2016 Aug;88(8):1427-37

Authors: Goldfarb J, Borges N, Gowans LK, Kohn D, Worley S, Li L, Yen-Lieberman B, Lach D, Danziger-Isakov L, Yee-Guardino S, Trunick C, Pellett PE

Abstract
The lymphotropic herpesviruses, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6B (HHV-6B) can reactivate and cause disease in organ transplant recipients; the contributions of HHV-6A and HHV-7 to disease are less certain. Less is known about their pathogenic roles in children undergoing treatment for malignancies. Children with newly diagnosed cancer were followed for 24 months. Clinical information and blood samples were collected during routine visits and during acute visits for fever or possible viral infections. Lymphotropic herpesvirus DNA in blood was measured by polymerase chain reaction (PCR). Although HHV-6B DNA was detected at least once in about half of the patients; the other viruses were seldom detected. There was no association between HHV-6B detection and individual acute clinical events, however, HHV-6B detection was more common in children who experienced more frequent acute clinical events. In children being treated for various malignancies, HHV-6B detection was common, but was not associated with individual events of acute illness. Thus, if HHV-6B is not assessed longitudinally, clinical events may be misattributed to the virus. The elevated frequency of detection of HHV-6B in sicker children is consistent with prior reports of its detection during apparently unrelated acute clinical events. J. Med. Virol. 88:1427-1437, 2016. © 2016 Wiley Periodicals, Inc.

PMID: 26815906 [PubMed - indexed for MEDLINE]

Real-world experience of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma.

Oncotarget. 2017 Jul 26;:

Authors: Liang SK, Hsieh MS, Lee MR, Keng LT, Ko JC, Shih JY

Abstract
We evaluated the real-world efficacy and side effects of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. The medical records of patients receiving afatinib as a first-line therapy after National Health Insurance reimbursement between May 2014 and January 2016 were reviewed, and information on patient characteristics and treatment courses were collected consecutively. Rebiopsy tissue was collected for EGFR mutation and MET amplification analyses. MET amplification was detected by fluorescence in situ hybridization and immunohistochemistry. In total, 140 patients were enrolled (median follow-up, 18.0 months). No significant differences in side effects, treatment responses, progression-free survival, or brain metastasis control were observed between patients receiving 40 mg versus < 40 mg of afatinib during the first 6 months. Patients with significant pretreatment weight loss (> 10.0% in 6 months) had a shorter median progression-free survival. Patients with brain metastases had a poorer Eastern Cooperative Oncology Group performance status and were associated with a shorter median progression-free survival. Nine patients (32.1%) had a p.T790M mutation and only 1 patient gained MET amplifications after disease progression. Afatinib is effective as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma. Afatinib dosage does not affect clinical efficacy and drug-related side effects.

PMID: 28767414 [PubMed - as supplied by publisher]

Cisplatin and cisplatin analogues perfusion through isolated rat heart: the effects of acute application on oxidative stress biomarkers.

Mol Cell Biochem. 2017 Aug 01;:

Authors: Stojic IM, Zivkovic VI, Srejovic IM, Nikolic TR, Jeremic NS, Jeremic JN, Djuric DM, Jovicic N, Radonjic KG, Bugarcic ZD, Jakovljevic VLJ, Novokmet SS

Abstract
Drug-induced oxidative stress can occur in numerous tissues and organ systems (liver, kidney, ear, nervous system, and cardiovascular system). Cancer therapy with cisplatin is associated with side effects to which oxidative stress may contribute. We have compared the influences of cisplatin (reference compound) and its' analogues (dichloro(1,2-diaminocyclohexane)platinum(II) and chloro(2,2':6',2″-terpyridine)platinum(II)) in a model of isolated rat heart using the Langendorff technique. The production of oxidative stress biomarkers, antioxidant enzymes, myocardial damage, and expression of Bax, OH-1, and SODs were studied. Cisplatin and the analogues were perfused at concentration of 10(-6) and 10(-5) M during 30 min. The results of this study showed that examined platinum complexes had different ability to induce oxidative stress of isolated perfused rat heart. Varying the carrier ligands, such as 1,2-diaminocyclohexane and 2,2':6',2″-terpyridine, related to amino ligands (cisplatin) directly influenced the strength to induce production of oxidative stress biomarkers. Introducing 2,2':6',2″-terpyridine ligands provoked the smallest changes in antioxidant enzymes activity, lipid peroxidation, and expression of heme oxygenase-1, that undoubtedly indicated that this complex had the lowest impact on redox status in heart tissue. These findings may be useful in synthesis of novel platinum analogues with lower potential for oxidative stress induction. However, the fact that platinum complexes could induce toxic effects in the heart by other mechanisms should be taken into the consideration.

PMID: 28766171 [PubMed - as supplied by publisher]

Phase 1 dose-escalation study of the anti-CD70 antibody ARGX-110 in Advanced Malignancies.

Clin Cancer Res. 2017 Aug 01;:

Authors: Aftimos P, Rolfo C, Rottey S, Offner F, Bron DD, Maerevoet M, Soria JC, Moshir M, Dreier T, van Rompaey L, Michot JM, Silence K, Hultberg A, Gandini D, De Haard H, Ribrag V, Peeters M, Thibault A, Leupin N, Awada A

Abstract
PURPOSE: The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies. <br /><br />Experimental Design: <p>Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels (N=26). ARGX-110 was administered intravenously every three weeks until progression or intolerable toxicity. Dose limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected.</p> <br /><br />Results: <p>Dose limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRRs). Of the 20 SAEs reported, 5 events, all IRRs, were considered related to ARGX‑110.</p> <p>ARGX-110 demonstrates dose proportionality over the dose range 1-10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10-13 days.</p> <p>The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose-response related anti-tumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematological malignancies.</p> <br /><br />Conclusions:This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics and preliminary anti-tumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies.

PMID: 28765328 [PubMed - as supplied by publisher]

Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: Recommendation Statement.

Am Fam Physician. 2016 Oct 15;94(8):Online

Authors:

PMID: 27929224 [PubMed - indexed for MEDLINE]

Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients.

HIV Med. 2017 Jan;18(1):56-63

Authors: Hoffmann C, Welz T, Sabranski M, Kolb M, Wolf E, Stellbrink HJ, Wyen C

Abstract
OBJECTIVES: Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is now among the most frequently used antiretroviral agents. However, recent reports have raised concerns about potential neurotoxicity.
METHODS: We performed a retrospective analysis of a cohort of HIV-infected patients who had initiated an INSTI in two large German out-patient clinics between 2007 and 2016. We compared discontinuation rates because of adverse events (AEs) within 2 years of starting treatment with dolutegravir, raltegravir or elvitegravir/cobicistat. We also evaluated factors associated with dolutegravir discontinuation.
RESULTS: A total of 1950 INSTI-based therapies were initiated in 1704 patients eligible for analysis within the observation period. The estimated rates of any AE and of neuropsychiatric AEs leading to discontinuation within 12 months were 7.6% and 5.6%, respectively, for dolutegravir (n = 985), 7.6% and 0.7%, respectively, for elvitegravir (n = 287), and 3.3% and 1.9%, respectively, for raltegravir (n = 678). Neuropsychiatric AEs leading to dolutegravir discontinuation were observed more frequently in women [hazard ratio (HR) 2.64; 95% confidence interval (CI) 1.23-5.65; P = 0.012], in patients older than 60 years (HR: 2.86; 95% CI: 1.42-5.77; P = 0.003) and in human leucocyte antigen (HLA)-B*5701-negative patients who initiated abacavir at the same time (HR: 2.42; 95% CI: 1.38-4.24; P = 0.002).
CONCLUSIONS: In this large cohort, the rate of discontinuation of dolutegravir because of neuropsychiatric adverse events was significantly higher than for other INSTIs, at almost 6% within 12 months. Despite the limitations of this retrospective study, the almost three-fold higher discontinuation rates observed amongst women and older patients underscore the need for further investigation, especially in patient populations usually underrepresented in clinical trials.

PMID: 27860104 [PubMed - indexed for MEDLINE]

Direct-acting antivirals in hepatitis C virus (HCV)-infected and HCV/HIV-coinfected patients: real-life safety and efficacy.

HIV Med. 2017 Apr;18(4):284-291

Authors: Milazzo L, Lai A, Calvi E, Ronzi P, Micheli V, Binda F, Ridolfo AL, Gervasoni C, Galli M, Antinori S, Sollima S

Abstract
OBJECTIVES: Clinical trials of all-oral direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection reported high response rates in HCV/HIV coinfection, similar to those obtained in HCV monoinfection. We evaluated the safety and efficacy of these regimens in a clinical practice setting.
METHODS: In this prospective observational study, all the HCV-monoinfected and HCV/HIV-coinfected patients undergoing HCV treatment with all-oral DAA regimens in a routine clinical setting from December 2014 to December 2015 were included in the analysis. Sustained virological response 12 weeks after the end of therapy (SVR12) and reported adverse events (AEs) were evaluated. Resistance-associated variants (RAVs) were analysed in a subgroup of patients at baseline and at the time of viral rebound in those with virological failure.
RESULTS: One-hundred and nine patients (51 HCV-infected and 58 HCV/HIV-coinfected) were enrolled in the study. Sixty per cent had cirrhosis and 52% were pegylated interferon and ribavirin (pegIFN/RBV)-experienced. Thirty-six per cent received ombitasvir + paritaprevir/ritonavir + dasabuvir, 25% sofosbuvir + daclatasvir, 16% sofosbuvir + simeprevir, 17% sofosbuvir + ribavirin and 6% sofosbuvir + ledipasvir; ribavirin was used in 57% of subjects. The SVR12 rate was 91% and 96% in HIV-infected and uninfected patients, respectively (P = 0.44). The 4-week HCV viral decline was similar in the two groups. RAVs were found at baseline in 23 of 49 patients and did not affect SVR12. No predictors of SVR12 were identified in our cohort.
CONCLUSIONS: Treatment with all-oral DAA combinations of patients infected with HCV and with HCV/HIV under real-life conditions led to high and similar rates of SVR12. Moreover, the historical factors associated with a sustained virological response to pegIFN/RBV were not predictive of the response to all-oral DAAs.

PMID: 27477612 [PubMed - indexed for MEDLINE]