Anna Maria Peri

Switching to unboosted atazanavir reduces bilirubin and triglycerides without compromising treatment efficacy in UGT1A1*28 polymorphism carriers

OBJECTIVES Hyperbilirubinaemia is a frequent complication of atazanavir-containing antiretroviral therapy and its severity is related to UDP-glucuronosyl transferase (UGT) 1A1*28 polymorphism. The aim of this study was to evaluate the safety and outcome of unboosted atazanavir-containing regimens based on the genetic constitution. METHODS Fifty-one HIV-1-infected patients on boosted atazanavir were prospectively enrolled in the study. Twenty-five patients with a UGT1A1*28 allele switched to 400 mg of unboosted atazanavir. RESULTS At baseline, UGT1A1 heterozygous and homozygous patients had significantly higher bilirubin levels than wild-type (P = 0.012 and P < 0.001, respectively). After ritonavir removal, a reduction was observed in total bilirubin (from 4.09 to 1.82 mg/dL; P < 0.001), γ-glutamyl transpeptidase (P = 0.015), triglycerides (P = 0.03) and total cholesterol (P = 0.05). No significant changes in CD4 T cell count and no increases in viral load were observed 12 months after unboosting. Plasma drug monitoring after ritonavir removal revealed the presence of therapeutic atazanavir concentrations in all patients except one with poor therapy adherence. CONCLUSIONS UGT1A1*28 is significantly related to hyperbilirubinaemia in HIV-1 patients receiving atazanavir. Genotyping before the initiation of antiretroviral therapy can reduce the emergence of severe hyperbilirubinaemia. Unboosted atazanavir-containing therapy is safe and efficacious in patients with an undetectable viral load with a UGT1A1*28 polymorphism, allowing the use of atazanavir in patients otherwise likely unable to receive it.

SLC29A1 polymorphism and prediction of anaemia severity in patients with chronic hepatitis C receiving triple therapy with telaprevir

OBJECTIVES The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the SLC29A1 gene, encoding ENT1, may influence ribavirin-associated anaemia, which is observed at a higher incidence with telaprevir in combination with pegylated-IFNα and ribavirin than with pegylated-IFNα and ribavirin alone. In this study, we investigated the role of the rs760370 SLC29A1 variant in ribavirin-induced anaemia in chronic hepatitis C patients treated with telaprevir-based triple therapy. METHODS Forty patients infected with hepatitis C virus (HCV) genotype 1 and starting anti-HCV therapy with telaprevir in combination with pegylated-IFN/ribavirin were prospectively evaluated for SNPs at the SLC29A1 gene and inosine triphosphatase (ITPA) genes using a real-time PCR system. RESULTS 40% of patients developed severe anaemia with a haemoglobin (Hb) decline ≥ 5 g/dL from the pretreatment value. The SLC29A1 rs760370 GG genotype was associated with the severity of Hb decrease as expressed by the median (IQR) Hb nadir change from baseline [-5.4 (-5.6; -5.0) g/dL in GG versus -4.2 (-5.1; -3.4) in AA/AG genotype; P=0.05] and by the Hb decrease ≥ 5 g/dL by week 12 (77.8% of GG carriers versus 24% of AA/AG; P<0.01). In multivariate analysis, older age (P=0.03), lower baseline Hb concentration (P=0.02) and SLC29A1 rs760370 GG (P=0.02) were associated with the development of severe anaemia during treatment, whereas no association was found with ITPA SNPs in our population receiving telaprevir-based therapy. CONCLUSIONS In patients with chronic hepatitis C receiving telaprevir-based therapy, SNP rs760370A>G at the SLC29A1 gene influences the severity of ribavirin-induced anaemia, possibly mirroring the erythrocyte uptake of ribavirin.

Infections during extracorporeal membrane oxygenation: epidemiology, risk factors, pathogenesis and prevention

Extracorporeal membrane oxygenation (ECMO) is a life support technique used in patients with respiratory and/or cardiac failure. The ECMO circuit consists of vascular cannulae, a pump and an artificial lung. Infections are among the most common complications associated with ECMO and have a significant impact on the mortality rate. Here we present a narrative literature review regarding the epidemiology, risk factors, pathogenesis and prevention of infectious complications during ECMO support. The prevalence of hospital-acquired infections during ECMO is 10-12% and their occurrence is likely to be more frequent compared with other critically ill patients. Coagulase-negative staphylococci, Candida spp., Enterobacteriaceae and Pseudomonas aeruginosa are the most frequently involved pathogens. A high incidence of ventilator-associated pneumonia was reported (24.4 cases/1000 ECMO days), with a major role unexpectedly played by Enterobacteriaceae. The infectious risk was shown to increase along the duration of the ECMO run, which represents the most important risk factor for the development of infections. Other ECMO-specific factors predisposing to infections include the severity of illness in ECMO patients, the high risk of bacterial translocation from the gut, and ECMO-related impairment of the immune system. Another important issue could be microbial colonisation of catheters, ECMO cannulae and the oxygenator, which is consistent with most commonly observed aetiologies.

Global prevalence of carbapenem resistance in neutropenic patients and association with mortality and carbapenem use: systematic review and meta-analysis.

Background: Carbapenem-resistant Gram-negative bacteria are recognized as a cause of difficult-to-treat infections associated with high mortality. Objectives: To perform a systematic review of currently available data on distribution, characteristics and outcome associated with carbapenem-resistant bloodstream infections in adult neutropenic patients. Methods: Included studies were identified through Medline, Embase and Cochrane databases between January 1995 and April 2016. Random effect meta-analysis was used to quantify the association between carbapenem resistance and mortality and between carbapenem exposure and resistance. Results: A total of 30 studies from 21 countries were included. Overall carbapenem resistance varied from 2% to 53% (median 9%) among studies. Infections due to carbapenem-resistant Pseudomonas spp. were reported in 18 (60%) studies showing high median resistance rates (44% of all carbapenem-resistant Gram-negatives and 19% of Pseudomonas isolates). Resistance of Enterobacteriaceae was less commonly reported and bloodstream infections due to carbapenem-resistant Klebsiella spp. were mainly documented from endemic areas (Greece, Italy, Israel). Carbapenem resistance in Acinetobacter spp. was reported in 9 (30%) studies (median resistance 58% of Acinetobacter isolates). Mortality rates ranged from 33% to 71% (median 50%) in patients with carbapenem-resistant infections. Carbapenem resistance appeared to correlate with mortality (OR 4.89, 95% CI 3.30–7.26) and previous exposure to carbapenems (OR 4.63, 95% CI 3.08–6.96). Conclusions: Carbapenem resistance represents a threat to neutropenic patients. In this group, resistance is likely promoted by previous carbapenem use and leads to high mortality rates. The knowledge of resistance patterns is crucial and can direct clinicians in the use of alternatives to carbapenem-based regimens.

Central nervous system nocardiosis in Queensland: a report of 20 cases and review of the literature

AbstractNocardia infection of the central nervous system (CNS) is an uncommon but clinically important disease, often occurring in immunocompromised individuals and carrying a high mortality rate. We present 20 cases of microbiologically proven CNS nocardiosis diagnosed in Queensland from 1997 to 2015 and review the literature from 1997 to 2016.Over 50% of cases occurred in immunocompromised individuals, with corticosteroid use posing a particularly significant risk factor. Nine (45%) patients were immunocompetent and 3 had no comorbidities at time of diagnosis. Nocardia farcinica was the most frequently isolated species (8/20) and resistance to trimethoprim–sulfamethoxazole (TMP-SMX) was found in 2 isolates. Overall, 35% of our patients died within 1 year, with the majority of deaths occurring in the first month following diagnosis. Interestingly, of the 7 deaths occurring at 1 year, 6 were attributed to N farcinica with the seventh isolate being unspeciated, suggesting the virulence of the N farcinica strain.

Intestinal lymphangiectasia and reversible high liver stiffness

Primary intestinal lymphangiectasia (PIL) is a protein‐losing enteropathy characterized by tortuous and dilated lymph channels of the small bowel. The main symptoms are bilateral lower limb edema, serosal effusions, and vitamin D malabsorption resulting in osteoporosis. We report here a case of long‐lasting misdiagnosed PIL with a peculiar liver picture, characterized by a very high stiffness value at transient elastography, which decreased with clinical improvement. The complex interplay between lymphatic and hepatic circulatory system is discussed. (Hepatology 2014;60:759–761)

Nosocomial Infections During Extracorporeal Membrane Oxygenation: Incidence, Etiology, and Impact on Patients’ Outcome

Objective: To study incidence, type, etiology, risk factors, and impact on outcome of nosocomial infections during extracorporeal membrane oxygenation. Design: Retrospective analysis of prospectively collected data. Setting: Italian tertiary referral center medical-surgical ICU. Patients: One hundred five consecutive patients who were treated with extracorporeal membrane oxygenation from January 2010 to November 2015. Interventions: None. Measurements and Main Results: Ninety-two patients were included in the analysis (48.5 [37–56] years old, simplified acute physiology score II 37 [32–47]) who underwent peripheral extracorporeal membrane oxygenation (87% veno-venous) for medical indications (78% acute respiratory distress syndrome). Fifty-two patients (55%) were infected (50.4 infections/1,000 person-days of extracorporeal membrane oxygenation). We identified 32 ventilator-associated pneumonia, eight urinary tract infections, five blood stream infections, three catheter-related blood stream infections, two colitis, one extracorporeal membrane oxygenation cannula infection, and one pulmonary-catheter infection. G+ infections (35%) occurred earlier compared with G– (48%) (4 [2–10] vs. 13 [7–23] days from extracorporeal membrane oxygenation initiation; p < 0.001). Multidrug-resistant organisms caused 56% of bacterial infections. Younger age (2–35 years old) was independently associated with higher risk for nosocomial infections. Twenty-nine patients (31.5%) died (13.0 deaths/1,000 person-days of extracorporeal membrane oxygenation). Infected patients had higher risk for death (18 vs. 8 deaths/1,000 person-days of extracorporeal membrane oxygenation; p = 0.037) and longer ICU stay (32.5 [19.5–78] vs. 19 [10.5–27.5] days; p = 0.003), mechanical ventilation (36.5 [20–80.5] vs. 16.5 [9–25.5] days; p < 0.001), and extracorporeal membrane oxygenation (25.5 [10.75–54] vs. 10 [5–13] days; p < 0.001). Older age (> 50 years old), reason for connection different from acute respiratory distress syndrome, higher simplified acute physiology score II, diagnosis of ventilator-associated pneumonia, and infection by multidrug-resistant bacteria were independently associated to increased death rate. Conclusions: Infections (especially ventilator-associated pneumonia) during extracorporeal membrane oxygenation therapy are common and frequently involve multidrug-resistant organisms. In addition, they have a negative impact on patients’ outcomes.

Pharmacokinetic interactions between telaprevir and antiretroviral drugs in HIV/HCV-coinfected patients with advanced liver fibrosis and prior HCV non-responders

Complex drug-drug interactions have been reported with concurrent administration of telaprevir (TVR) and human immunodeficiency virus (HIV) protease inhibitors (PIs), leading to relevant limitations of the therapeutic options for patients coinfected with hepatitis C virus (HCV) and HIV. However, little is known about the pharmacokinetics and drug interactions between TVR and antiretrovirals in HIV/HCV-coinfected patients with advanced liver fibrosis. Here we report the pharmacokinetics of TVR and antiretrovirals in a cohort of HIV/HCV genotype 1-coinfected patients with advanced liver fibrosis treated with TVR-based triple anti-HCV therapy. No significant differences were observed in the pharmacokinetics of atazanavir, amprenavir or tenofovir at baseline and at Day 15 of TVR, whereas the AUC0-4h of darunavir was 36% lower in the presence of TVR (AUC0-4h 15007ngh/mL and 9563ngh/mL at baseline and at Day 15 of TVR administration, respectively). Noteworthy, the AUC0-4h, Cmin and Cmax of raltegravir were reduced by 61%, 50% and 64%, respectively. However, none of the patients plasma levels of tenofovir, atazanavir, amprenavir or raltegravir declined below their minimum effective concentrations even in association with TVR, and no HIV treatment failure occurred. A non-significant trend for lower TVR exposure was seen in patients concomitantly given amprenavir versus those given atazanavir (AUC0-4h, 9840ngh/mL and 13345ngh/mL, respectively). In conclusion, this study highlighted the feasibility of maintaining the current antiretroviral regimen in HIV/HCV-coinfected patients, even when significant interactions with TVR are predictable, whenever a change of HIV PIs is not deemed appropriate.

Simeprevir-induced severe withdrawal syndrome in an HIV/HCV coinfected patient on long-term maintenance methadone therapy.

Sir, The availability of second-generation direct-acting antivirals (DAAs) has further changed the treatment of chronic hepatitis C virus (HCV) infection [1]. The combination of simeprevir and sofosbuvir with or without ribavirin led to sustained virological response (SVR12 rates) close to 90 % in chronic HCV genotype 1 and 4 infected patients and was overall well tolerated [2, 3]. Similar results have also been recently observed in HCV patients who are coinfected with human immunodeficiency virus (HIV) [4], which are, however, at higher risk of clinically relevant drug-to-drug interactions (DDI). Here, we report a case of an HIV/HCV patient on HAART and stable methadone maintenance therapy who developed symptoms of opioid withdrawal early after starting the combination of simeprevir and sofosbuvir with ribavirin. A 54-year-old white HIV/HCV infected man was admitted to our outpatient service with shakiness, diaphoresis, body aches, abdominal pain, anxiety, insomnia, and asthenia. He reported that the symptoms had started the previous day. Six days before, the patient had started taking simeprevir 150 mg/day, sofosbuvir 400 mg/day, and ribavirin 800 mg/day to treat chronic HCV genotype 4c/4d infection. The patient was on tenofovir/emtricitabine and raltegravir as antiretroviral therapy and was given methadone at 70 mg/day since 1990 for maintenance of former heroin addiction. No other comedications were reported. Liver function tests and haemoglobin were similar to those prior to the start of DAAs. The patient was diagnosed with methadone withdrawal syndrome. A blood sample drawn the same day retrieved a methadone plasma trough concentration of 300 ng/mL, which was in the usual narcotic stabilization range of 50–1000 ng/mL [5]. The patient was stabilized after administration of alprazolam and an increase in methadone dosage to 80 mg/day. Methadone plasma trough concentrations measured 4 days after the increase in the dose was 365 ng/mL. The dosage of methadone was further increased to 90 mg/day in the next weeks and the patient was fully stabilized. The metabolism of methadone, commonly used as opioid substitution in patients with a history of drug addiction, is not completely understood. However, evidence is available that it mainly undergoes oxidative metabolism to inactive metabolites by cytochrome P450 3A (CYP3A), by CYP2D6, and, to a lesser extent, by CYP2C8, CYP2B6, and CYP2C19 [6]. Sofosbuvir and GS-33100, its inactive nucleoside metabolite, neither inhibit nor induce the CYP enzyme system; therefore, these molecules are not expected to affect the concentrations of methadone [7]. Conversely, simeprevir is metabolized primarily by CYP3A, is a substrate for several drug transporters including the organic anion transporting polypeptides, and is a mild inhibitor of CYP1A2 and intestinal CYP3A [7]. It is, therefore, theoretically susceptible to DDIs with drugs that share the same pathways of absorption, transport, or metabolism, * Cristina Gervasoni cristina.gervasoni@unimi.it

Fungal meningitis in England and Wales

www.thelancet.com/infection Vol 14 October 2014 921 cryptococcal meningit is , the diagnosis of fungal meningitis by traditional microbiological methods (ie, cerebrospinal culture) is generally difficult and characterised by low sensitivity. In the case of candida meningitis, a review reported a sensitivity of 44% for the initial culture, increasing to 83% for serial cultures. We would be interested to know how many patients in Okike and colleagues’ study had a clinical diagnosis of candida meningitis made only by positive blood culture. Finally, in view of the abovementioned problems encountered in correctly diagnosing fungal meningitis, the use of galactomannan antigen, 1,3-β-D-glucan antigen, mannan antigen, and anti-mannan antibodies in cerebrospinal fluid is highly recommended.