Flow-based basophil activation test in immediate drug hypersensitivity. An EAACI task force position paper.

Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) "Basophil activation test in the evaluation of Drug Hypersensitivity Reactions" from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus-based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug-specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti-inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory.

Evaluating virological outcomes in people with HIV on stable antiretroviral therapy with reduced frequency of HIV viral load monitoring during the COVID-19 pandemic.

OBJECTIVES: In response to the COVID-19 pandemic, HIV outpatient attendances were restricted from March 2020, resulting in reduced frequency of HIV viral load (VL) monitoring (previously 6-monthly) in clinically stable and virologically suppressed people living with HIV (PLWH). We investigated virological outcomes during this period of reduced monitoring and compared with the previous year, prior to the COVID-19 pandemic. METHODS: People living with HIV with undetectable VL (<200 HIV RNA copies /mL) on antiretroviral therapy (ART) were identified from March 2018 to February 2019. We determined VL outcomes during the pre-COVD-19 period (March 2019-February 2020) and the COVID-19 period (March 2020-February 2021) when monitoring was restricted. Frequency and longest durations between VL tests in each period were evaluated, and virological sequelae in those with detectable VL were determined. RESULTS: Of 2677 PLWH virologically suppressed on ART (March 2018-February 2019), VLs were measured and undetectable in 2571 (96.0%) and 2003 (77.9%) in the pre-COVID and COVID periods, respectively. Mean (SD) numbers of VL tests were 2.3 (1.08) and 1.1 (0.83) and mean longest duration between VL tests was 29.5 weeks (SD 8.25, 3.1% were ≥12 months) and 43.7 weeks (12.64, 28.4% were ≥12 months), in the pre-COVID and COVID periods, respectively. Of 45 individuals with one or more detectable VL during the COVID-19 period, two developed new drug resistance mutations. CONCLUSION: Reduced VL monitoring was not associated with poorer virological outcomes in the majority of stable individuals receiving ART. One in 20 individuals had not returned for VL testing after ≥31 months and the risk of harm in these individuals is unknown.

Objective and subjective rapid frailty screening tools in people with HIV.

OBJECTIVES: As people with HIV (PWH) age, the prevalence of frailty increases. Rapid screening tests to identify frailty within HIV outpatient settings are required to identify at-risk individuals. We undertook a service evaluation to assess three short frailty assessments in PWH. METHODS: We assessed two objective [gait speed (GS), timed-up-and-go test (TUGT)] and one subjective [the self-reported health questionnaire (SRH)] frailty screening tools in PWH aged > 40 years attending a single HIV outpatient department. Factors associated with positive frailty screening tests (defined as GS < 0.8 m/s, TUGT ≥ 10 s and SRH score < 6) were assessed using logistic regression models. ETHICAL CONSIDERATIONS: This was a service evaluation and was approved as a service evaluation by the Imperial College Healthcare NHS trust HIV clinical research committee (February 2020). All participants were given verbal information and were able to terminate the screening tests at any time. RESULTS: Of 84 PWH approached, 80 individuals completed all screening tests (median age = 56 years, range: 40-80) with a positive frailty screening prevalence in 19%, 33% and 20% for GS, TUGT and SRH, respectively. All tests were considered acceptable to participants. Factors statistically significantly associated with frailty included age (GS and TUGT), detectable HIV RNA (TUGT), number of comorbidities (GS and TUGT), presence of polypharmacy (GS and TUGT) and total number of concomitant medication (GS and SRH). CONCLUSIONS: Rates of positive screening tests for frailty are dependent on screening tool used, with all three tools being acceptable to participants. Objective measures of frailty screening (GS and TUGT) are more closely associated with clinical parameters than is a subjective measure of frailty screening (SRH).

Management of a surgical patient with a label of penicillin allergy: narrative review and consensus recommendations.

Unsubstantiated penicillin-allergy labels are common in surgical patients, and can lead to significant harm through avoidance of best first-line prophylaxis of surgical site infections and increased infection with resistant bacterial strains. Up to 98% of penicillin-allergy labels are incorrect when tested. Because of the scarcity of trained allergists in all healthcare systems, only a minority of surgical patients have the opportunity to undergo testing and de-labelling before surgery. Testing pathways can be modified and shortened in selected patients. A variety of healthcare professionals can, with appropriate training and in collaboration with allergists, provide testing for selected patients. We review how patients might be assessed, the appropriate testing strategies that can be used, and the minimum standards of safe testing.

Consensus clinical scoring for suspected perioperative immediate hypersensitivity reactions.

BACKGROUND: Grading schemes for severity of suspected allergic reactions have been applied to the perioperative setting, but there is no scoring system that estimates the likelihood that the reaction is an immediate hypersensitivity reaction. Such a score would be useful in evaluating current and proposed tests for the diagnosis of suspected perioperative immediate hypersensitivity reactions and culprit agents. METHODS: We conducted a Delphi consensus process involving a panel of 25 international multidisciplinary experts in suspected perioperative allergy. Items were ranked according to appropriateness (on a scale of 1-9) and consensus, which informed development of a clinical scoring system. The scoring system was assessed by comparing scores generated for a series of clinical scenarios against ratings of panel members. Supplementary scores for mast cell tryptase were generated. RESULTS: Two rounds of the Delphi process achieved stopping criteria for all statements. From an initial 60 statements, 43 were rated appropriate (median score 7 or more) and met agreement criteria (disagreement index <0.5); these were used in the clinical scoring system. The rating of clinical scenarios supported the validity of the scoring system. Although there was variability in the interpretation of changes in mast cell tryptase by the panel, we were able to include supplementary scores for mast cell tryptase. CONCLUSION: We used a robust consensus development process to devise a clinical scoring system for suspected perioperative immediate hypersensitivity reactions. This will enable objectivity and uniformity in the assessment of the sensitivity of diagnostic tests.

No cases of perioperative allergy to local anaesthetics in the Danish Anaesthesia Allergy Centre.

BACKGROUND: Local anaesthetics (LA) are often suspected as possible causes of allergic reactions. The Danish Anaesthesia Allergy Centre (DAAC) is the national reference centre for investigation of perioperative allergic reactions. The purpose of this study was to investigate the incidence of IgE-mediated immediate type perioperative allergic reactions to LA. METHODS: In the period 2004-2013, a total of 409 patients (244 women/165 men; median age 49 years, range 1-86 years) were investigated in DAAC on suspicion of allergy associated with anaesthesia and surgery. A total of 162 (40%) patients were exposed to one or more LA. Suspected allergy to LA was investigated by prick test, intradermal test and subcutaneous provocation with the suspected drug. Patients with positive skin tests still underwent subcutaneous provocation, as false positive skin tests can occur. RESULTS: A total of 203 test series with LA were carried out on 162 patients (89 women/73 men; mean age 49 years, range 2-85 years) with the following drugs: Lidocaine n = 80 (49%), bupivacaine n = 82 (51%), ropivacaine n = 31 (19%) and mepivacaine n = 10 (6%). All 162 patients had negative subcutaneous provocation for all tested LA (95% CI: 0-1.8%). Investigations revealed another allergen in 52 of 162 patients. CONCLUSION: None of the 162 patients with suspected perioperative allergic reactions and exposure to LA reacted on subcutaneous provocation with the relevant LA. Thus, no patients have been diagnosed with allergy to LA in DAAC in the period 2004-2013 and allergy to LA must be considered very rare in this population.

Immediate-type hypersensitivity to polyethylene glycols: a review.

Polyethylene glycols (PEGs) or macrogols are polyether compounds widely used in medical and household products. Although generally considered biologically inert, cases of mild to life-threatening immediate-type PEG hypersensitivity are reported with increasing frequency. Nevertheless, awareness of PEG's allergenic potential remains low, due to a general lack of suspicion towards excipients and insufficient product labelling. Information on immediate-type reactions to PEG is limited to anecdotal reports, and the potential for PEG sensitization and cross-sensitization to PEGylated drugs and structurally related derivatives is likely underestimated. Most healthcare professionals have no knowledge of PEG and thus do not suspect PEG's as culprit agents in hypersensitivity reactions. In consequence, patients are at risk of misdiagnosis and commonly present with a history of repeated, severe reactions to a range of unrelated products in hospital and at home. Increased awareness of PEG prevalence, PEG hypersensitivity, and improved access to PEG allergy testing, should facilitate earlier diagnosis and reduce the risk of inadvertent re-exposure. This first comprehensive review provides practical information for allergists and other healthcare professionals by describing the clinical picture of 37 reported cases of PEG hypersensitivity since 1977, summarizing instances where PEG hypersensitivity should be considered and proposing an algorithm for diagnostic management.

Dynamics of plasma levels of specific IgE in chlorhexidine allergic patients with and without accidental re-exposure.

BACKGROUND: Chlorhexidine is an effective disinfectant, which may cause severe allergic reactions. Plasma level of specific IgE to chlorhexidine (ImmunoCAP(®) ) has high estimated sensitivity and specificity when measured within 6 months of allergic reaction, but knowledge of the dynamics over longer time periods is lacking and it is unknown whether levels fall below <0.35 kUA/L in patients with previously elevated levels. It is also unclear whether re-exposure influences levels of specific IgE. OBJECTIVE: To investigate the dynamics of specific IgE in chlorhexidine allergic patients with and without re-exposure. METHODS: All patients diagnosed with chlorhexidine allergy in the Danish Anaesthesia Allergy Centre January 1999 to March 2015 were invited to participate. The study included blood samples from the time of reaction and time of investigation and blood samples drawn prospectively over several years. RESULTS: Overall, 23 patients were included. Specific IgE within hours of reaction was available in eight patients and was >0.35 kUA/L in six of these. During allergy investigations, usually 2-4 months later, specific IgE was >0.35 kUA/L in 22 of 23 patients. In the following months/years specific IgE declined <0.35 kUA/L in 17 of 23 patients (most rapidly within 4 months). Nine re-exposures in the healthcare setting were reported by seven patients (35%). Most re-exposures caused symptoms and were followed by an increase in specific IgE. Two patients with specific IgE <0.35 kUA/L reacted upon re-exposure. CONCLUSIONS & CLINICAL RELEVANCE: Time from reaction should be considered when interpreting specific IgE results. Specific IgE is >0.35 kUA/L in most patients at time of reaction but should be repeated after a few weeks/months if negative. The optimal sampling time seems to be >1 month and <4 months. A value <0.35 kUA/L neither excludes allergy nor implies loss of reactivity in previously sensitized patients. Re-exposures are common, often iatrogenic, and can cause a rebound in specific IgE.

Differences in hospital attendance for anaphylaxis between immigrants and non-immigrants: a cohort study.

BACKGROUND: The impact of migration on the risk of anaphylaxis remains unknown. We hypothesized that non-Western immigrants have a lower incidence of anaphylaxis compared to Danish-born. We investigated variations in hospital attendance for anaphylaxis between immigrants and Danish-born including time- and age- trends. METHODS: A register-based, historical prospective cohort design. Refugees or family reunified immigrants (n = 127 250) who, between January 1, 1994 and December 31, 2010, obtained residency permits in Denmark were included and matched in a 1 : 6 ratio on age and sex with Danish-born individuals (n = 740 600). Personal identification numbers were cross-linked to the Danish National Patient Registry identifying all first-time hospital attendances for anaphylaxis from January 1, 1994 and December 31, 2010. Incidence rate ratios were estimated, stratified for sex and region of birth, adjusting for age using a Cox regression model including the influence of duration of residence and age when residence was obtained. RESULTS: In total 1053 hospital attendances for anaphylaxis were identified: 89 among non-Western immigrants, 9 among Western immigrants and 955 among Danish-born patients. Both male (RR = 0.65; 95%CI: 0.46;0.90) and female (RR = 0.64; 95%CI: 0.48;0.85) non-Western immigrants had a significantly lower risk ratio of hospital attendance for anaphylaxis compared to Danish-born. Compared to Danish-born, non-Western immigrants living in Denmark during the entire follow-up period also showed a decreased risk (RR = 0.65; 95%CI: 0.34;1.25). Compared to Danish-born, non-Western immigrants who obtained residence permission as children had a decreased risk of hospital attendance for anaphylaxis (RR = 0.48; 95%CI: 0.25;0.91). CONCLUSION: This Danish register-based study using nationwide data revealed fewer hospital attendances for anaphylaxis among non-Western immigrants compared to Danish-born; however this protection was lost over time.

Drug allergy passport and other documentation for patients with drug hypersensitivity - An ENDA/EAACI Drug Allergy Interest Group Position Paper.

The strongest and best-documented risk factor for drug hypersensitivity (DH) is the history of a previous reaction. Accidental exposures to drugs may lead to severe or even fatal reactions in sensitized patients. Preventable prescription errors are common. They are often due to inadequate medical history or poor risk assessment of recurrence of drug reaction. Proper documentation is essential information for the doctor to make sound therapeutic decision. The European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology have formed a task force and developed a drug allergy passport as well as general guidelines of drug allergy documentation. A drug allergy passport, a drug allergy alert card, a certificate, and a discharge letter after medical evaluation are adequate means to document DH in a patient. They are to be handed to the patient who is advised to carry the documentation at all times especially when away from home. A drug allergy passport should at least contain information on the culprit drug(s) including international nonproprietary name, clinical manifestations including severity, diagnostic measures, potential cross-reactivity, alternative drugs to prescribe, and where more detailed information can be obtained from the issuer. It should be given to patients only after full allergy workup. In the future, electronic prescription systems with alert functions will become more common and should include the same information as in paper-based documentation.

No evidence for contraindications to the use of propofol in adults allergic to egg, soy or peanut†.

BACKGROUND: Propofol is thought to be a potential cause of allergic reactions in patients allergic to egg, soy or peanut, since current formulations contain an emulsion that includes egg lecithin and soybean oil. However, other than six case reports lacking in confirmatory evidence of an allergic reaction, there is no evidence linking the two types of allergies. The aim of this study was to examine the frequency of propofol allergy and to investigate if patients with specific immunoglobulin E (IgE) to egg, soy or peanut tolerated propofol. METHODS: Study A examined the frequency of propofol allergy in 273 patients systematically investigated for suspected perioperative allergic reactions. Of these, 153 had been exposed to propofol and underwent skin tests and intravenous provocation. Study B retrospectively investigated propofol exposure and tolerance in 520 adult patients with a positive specific IgE to egg, soy or peanut. RESULTS: Four of the 153 propofol-exposed patients (2.6%) investigated in study A were diagnosed with propofol allergy. Of these, three tested positive only on intravenous provocation. None of the four had allergic symptoms when eating egg, soy or peanut and none had detectable levels of specific IgE to egg or soy in their serum. In study B we found no signs of allergic reactions towards propofol in 171 retrieved anaesthetic charts from 99 patients with specific IgE to egg, soy or peanut. CONCLUSION: No connection between allergy to propofol and allergy to egg, soy or peanut was found. The present practice of choosing alternatives to propofol in patients with this kind of food allergy is not evidence based and should be reconsidered.

Oxytocin use during Caesarean sections in Denmark - are we getting the dose right?

BACKGROUND: In Denmark, an iv bolus of 10 IU oxytocin was traditionally given after delivery to prevent atony during caesarean sections. Randomized controlled trials have shown that lower iv bolus doses have same efficacy with fewer side effects and many countries now recommend a 5 IU maximum dose. The aims of this study were to investigate whether patients referred for allergy testing after oxytocin exposure had dose-related side effects to oxytocin rather than true allergic reactions and to investigate whether updated international recommendations on lower bolus doses had been implemented in practice. METHODS: Medical notes of patients tested with oxytocin as part of investigations in the Danish Anaesthesia Allergy Centre from May 2004 to January 2014 were reviewed retrospectively. A telephone survey of on-duty obstetricians at all Danish obstetric departments was performed and most recent online recommendations from the Danish societies of obstetrics and anaesthesia about the use of oxytocin were identified. RESULTS: In total 30 women were tested with oxytocin as part of investigations. None were allergic to oxytocin but 19 had symptoms consistent with dose-related side effects on iv provocation. The telephone survey revealed that iv doses of 10 IU oxytocin were still used and recommendations on the websites were not updated. CONCLUSION: Too high oxytocin doses are still used in Denmark leading to dose-related side effects mimicking allergic reactions. Coordination between obstetricians and anaesthesiologists on producing common updated guidelines on the administration of oxytocin and dissemination of this information to obstetric and anaesthetic departments in Denmark is needed.

Clinical and diagnostic features of perioperative hypersensitivity to cefuroxime.

INTRODUCTION: The Danish Anaesthesia Allergy Centre (DAAC) investigated 89 adult patients with suspected perioperative cefuroxime-associated hypersensitivity reactions between 2004 and 2013. The goals were to determine whether the time to index reaction after cefuroxime exposure could be used to implicate cefuroxime as the cause of the reactions and explore different test modalities in diagnosing cefuroxime hypersensitivity. METHOD: Skin tests, in vitro tests, and titrated provocations were used to determine cefuroxime hypersensitivity. Patients were deemed cefuroxime positive on the basis of at least two positive tests and/or a positive provocation. RESULTS: One or more tests were positive for cefuroxime in 24 of 89 (27.0%) patients. One was only specific IgE positive and was deemed cefuroxime negative. Twenty-three (25.8%) were deemed cefuroxime positive. There were four specific IgE-, 4 histamine release test-, 13 skin test-, and 14 provocation positive patients. There were eight (34.8%) patients who were only provocation positive. Data on time to index reaction after cefuroxime exposure were available for 80 patients (22 in the positive group and 58 in the negative group), 22 of 22 (100%) of positive patients reacted in <15 min vs. only 38 of 58 (65.5%) of negative patients. CONCLUSION: All patients with confirmed hypersensitivity to cefuroxime reacted within 15 min of administration, but so did 65.5% of Cefuroxime negative patients, making timing of administration an unreliable predictor of causation in the perioperative setting. Provocations were always positive when carried out in skin test positive patients; however, eight patients had positive provocations only, highlighting the need for provocation in skin test negative patients.

Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper.

Mastocytosis is a clonal disorder characterized by the proliferation and accumulation of mast cells (MC) in different tissues, with a preferential localization in skin and bone marrow (BM). The excess of MC in mastocytosis as well as the increased releasability of MC may lead to a higher frequency and severity of immediate hypersensitivity reactions. Mastocytosis in adults is associated with a history of anaphylaxis in 22-49%. Fatal anaphylaxis has been described particularly following hymenoptera stings, but also occasionally after the intake of drugs such as nonsteroidal anti-inflammatory drugs, opioids and drugs in the perioperative setting. However, data on the frequency of drug hypersensitivity in mastocytosis and vice versa are scarce and evidence for an association appears to be limited. Nevertheless, clonal MC disorders should be ruled out in cases of severe anaphylaxis: basal serum tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation.

Standardized testing with chlorhexidine in perioperative allergy--a large single-centre evaluation.

BACKGROUND: Perioperative allergic reactions to chlorhexidine are often severe and easily overlooked. Although rare, the prevalence remains unknown. Correct diagnosis is crucial, but no validated provocation model exists, and other diagnostic tests have never been evaluated. The aims were to estimate (i) the prevalence of chlorhexidine allergy in perioperative allergy and (ii) the specificity and sensitivity for diagnostic tests for chlorhexidine allergy. METHODS: We included all patients investigated for suspected perioperative allergic reactions in the Danish Anaesthesia Allergy Centre during 2004-2012. The following tests were performed: specific IgE (Immunocap® ; Phadia AB, Sweden), histamine release test (HR) (RefLab ApS, Denmark), skin prick test (SPT) and intradermal test (IDT). Positivity criteria were as follows: specific IgE >0.35 kUA/l; HR class 1-12; SPT mean wheal diameter ≥3 mm; IDT mean wheal diameter ≥ twice the diameter of negative control. Chlorhexidine allergy was post hoc defined as a relevant clinical reaction to chlorhexidine combined with two or more positive tests. Based on this definition, sensitivity and specificity were estimated for each test. RESULTS: In total, 22 of 228 patients (9.6%) met the definition of allergy to chlorhexidine. Estimated sensitivity and specificity were as follows: specific IgE (sensitivity 100% and specificity 97%), HR (sensitivity 55% and specificity 99%), SPT (sensitivity 95% and specificity 97%) and IDT (sensitivity 68% and specificity 100%). CONCLUSIONS: In patients investigated for suspected perioperative allergic reactions, 9.6% were diagnosed with allergy to chlorhexidine. Using our definition of chlorhexidine allergy, the highest combined estimated sensitivity and specificity was found for specific IgE and SPT.

Transfusion-associated anaphylaxis during anaesthesia and surgery--a retrospective study.

BACKGROUND AND OBJECTIVES: Transfusion-associated anaphylaxis (TAA) is a severe adverse reaction reported to occur in 1:9000-90,000 transfusions. According to the Danish Registration of Transfusion Risks (DART), the frequency is 1:300,000 transfusions, which suggests insufficient reporting of TAA in Denmark. Our aims were to identify possible cases of TAA, to characterize their symptoms and tryptase levels and to investigate the reporting of TAA to the haemovigilance systems. MATERIAL AND METHODS: We reviewed 245 patients with suspected allergic reactions during anaesthesia and surgery, investigated at the Danish Anaesthesia Allergy Centre (DAAC). Based on the outcome of this investigation, the patients were classified as DAAC positive (confirmed hypersensitivity to identified agent, n = 112), or DAAC negative (no confirmed hypersensitivity, n = 133). Data on case history, details of blood transfusion and results of laboratory and clinical investigations were collected. TAA cases were identified according to the recommendations of the International Society of Blood Transfusion (ISBT). RESULTS: Ten possible TAA cases (30% of all transfused patients) were identified, all DAAC negative. The frequency of elevated serum tryptase, hypotension and male sex was significantly higher among these cases compared with the remaining DAAC negative (P < 0·05), but not different from the DAAC-positive patients. One case had been reported to the Blood Bank haemovigilance system and none to DART. CONCLUSION: We identified unreported cases of possible TAA, which resembled the DAAC-positive patients with respect to elevated tryptase and symptoms. By applying the ISBT criteria of adverse transfusion reactions, we conclude that TAA during anaesthesia and surgery is likely to be underreported in Denmark.

Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper.

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity.

Pharmacokinetic and safety profile of raltegravir and ribavirin, when dosed separately and together, in healthy volunteers.

BACKGROUND: Treatment of chronic hepatitis C virus (HCV) infection in HIV-1-co-infected individuals remains challenging due to numerous factors, including drug-drug interactions. The aim of this study was to assess the safety and pharmacokinetic (PK) profile of raltegravir and ribavirin when dosed separately and together. METHODS: Fourteen healthy volunteers [mean (standard deviation) age 35 (10) years, 71% male] entered this phase 1 PK study and received single-dose ribavirin (800 mg) on day 1 (phase 1). Following a washout period, subjects received raltegravir (400 mg twice daily) on days 15-19 (phase 2) and single-dose ribavirin (800 mg) with raltegravir (400 mg) on day 20 (phase 3). Intensive PK sampling was undertaken on days 1, 19 and 20 and differences in geometric mean ratios (GMRs) for PK parameters between study periods were assessed. RESULTS: No statistically significant differences in PK parameters were observed for raltegravir between phases 2 and 3. A statistically significant decrease in maximum plasma concentration (C(max)) and an increase in time to maximum plasma concentration (T(max)) were observed for ribavirin in phase 3 compared with phase 1 [GMR (95% confidence interval) 0.79 (0.62-1.00) and 1.39 (1.08-1.78), respectively], whereas no significant differences in other ribavirin PK parameters were observed between study phases. No clinically significant safety concerns were reported. CONCLUSIONS: The PK profile of ribavirin is altered when administered with raltegravir (reduced C(max) and increased T(max)), with no safety concerns identified. This is unlikely to be of clinical significance or have an impact on the antiviral effects of ribavirin in HIV-1- and HCV-co-infected subjects.