Frecuentación del servicio de urgencias y reingresos no programados durante el primer año del trasplante de hígado y su repercusión en la supervivencia / Emergency department frequentation and unscheduled readmissions within the first year after liver transplantation, and their impact on survival

El objetivo de este estudio fue evaluar la frecuentación de la sala de emergencias, las causas de las visitas y los reingresos no programados dentro del primer año después del alta hospitalaria después del trasplante de hígado. También se evaluó su impacto en la supervivencia del injerto y del paciente. Se trata de un estudio retrospectivo de las historias clínicas de 98 pacientes (edad media, 55,6 ± 8,59 años, 77,6 % varones) que fueron dados de alta hospitalaria de forma consecutiva tras someterse a un primer trasplante hepático en nuestra institución durante 2012-2015. Se analizaron todas las visitas a urgencias durante los primeros años tras el trasplante y se calculó la supervivencia a los dos años tras el trasplante. Cincuenta y seis de los 98 pacientes (57,15 %) acudieron a urgencias en 117 ocasiones durante el primer año postrasplante. Fiebre (n = 34; 29,05 %) y síntomas digestivos (n = 32; 27. 35 %) fueron las causas más comunes de consulta y dieron lugar a más de la mitad de las visitas. Treinta y cinco de estos 56 pacientes (62,5 %) requirieron un reingreso urgente durante 50 de las 117 (42,7 %) visitas. Esto se debió principalmente a complicaciones infecciosas (44 %) de diversas causas (neumonía bacteriana, colangitis, colitis por Clostridium difficile) y problemas relacionados con las vías biliares. La probabilidad de reingreso aumentó del 11,22 % a los 30 días del alta al 22,4 % a los 90 días del alta. La supervivencia de los pacientes al año y 2 años después del trasplante fue menor para los pacientes que reingresaron (88,4 % y 80,7 %, respectivamente) en comparación con los que no reingresaron (95,56 % y 91,17 %, respectivamente, p = 0,002). (AU)

Benefits of hepatitis C cure with antivirals: why test and treat?

Chronic hepatitis C virus (HCV) infection is one of the major causes of death worldwide due to infectious agents. The advent of direct-acting antivirals has dramatically improved the chance of HCV elimination, even for patients with decompensated cirrhosis. Along with HCV cure, benefits are recognized in terms of regression of liver fibrosis and risk of hepatocellular carcinoma. Furthermore, beyond hepatic outcomes, several extrahepatic benefits may result from sustained HCV eradication, including improvements in the neurocognitive function and reduced cardiovascular disease risk. Finally, there is no doubt that the individual success of direct-acting antivirals is largely contributing to halt HCV transmission globally, in the absence of an effective HCV prophylactic vaccine.

Regression of liver fibrosis after curing chronic hepatitis C with oral antivirals in patients with and without HIV coinfection.

BACKGROUND: Treatment with direct-acting antivirals (DAA) eradicates hepatitis C virus (HCV) from most chronic carriers. Information on regression of liver fibrosis and the influence of HIV is scarce in cured patients. METHODS: All consecutive HCV-infected individuals treated with DAA at our institution were examined. Hepatic elastography was performed at baseline and at the time of SVR12. Liver fibrosis regression was defined as a shift from advanced fibrosis (Metavir F3-F4) to null-mild fibrosis (F0-F2) and/or a reduction greater than 30% kPa. AST to platelet ratio index (APRI) and fibrosis 4 (FIB-4) scores were calculated in parallel. RESULTS: A total of 260 patients were treated with DAA. All but 14 achieved SVR12 and represented the study population. HIV confection was present in 42%. At baseline, 57.2% had advanced liver fibrosis with a median of 11 kPa, FIB-4 of 2.4, and APRI of 0.95. At the time of SVR12, a median reduction of 2.1 kPa (P < 0.001) was recognized using elastography. A significant fibrosis regression was seen in 40%, being more frequent in patients with baseline advanced fibrosis than in those with null-mild fibrosis (52.3 vs. 22.5%; P < 0.001). Even so, 41.2% of patients with baseline F3-F4 kept within cirrhotic scores. In multivariable analysis, only baseline stiffness was significantly associated with the extent of liver fibrosis regression. CONCLUSION: HCV cure with DAA is associated with regression of liver fibrosis in most patients treated with DAA, as measured using elastography, FIB-4 and APRI. This benefit is more pronounced in patients with baseline advanced fibrosis and cirrhosis. The dynamics of liver fibrosis regression are not influenced by HIV coinfection.

Treatment and prevention of HIV infection with long-acting antiretrovirals.

INTRODUCTION: Current antiretroviral therapy allows to achieve and sustain maximal suppression of HIV replication in most treated patients. As result, the life expectancy of HIV-infected persons has improved dramatically and is nowadays similar to that of the HIV-negative population. However, oral antiretrovirals have to be taken daily and indefinitely to avoid resumption of HIV replication and selection of drug resistance. Unfortunately, drug adherence is often suboptimal and tends to decline over time. Areas covered: New drugs, formulations and delivery systems are being developed for extended-release of antiretrovirals. At this time, intramuscular cabotegravir and rilpivirine, dapivirine vaginal rings and tenofovir alafenamide subdermal implants are the products in more advanced stages of clinical development. Their pharmacokinetics/dynamics and safety/efficacy are reviewed. Expert commentary: In the absence of eradicative therapy for individuals with HIV infection and protective vaccines for persons at risk, long-term antiretroviral therapy is the best approach for preventing disease progression in patients and halting transmissions, either as result of 'treatment as prevention' for HIV carriers or 'pre-exposure prophylaxis' for uninfected individuals at risk. In all these scenarios, the advent of long-acting antiretrovirals will expand options for overcoming the challenge of suboptimal drug adherence and reduce the burden of HIV infection.

Baseline NS5A resistance associated substitutions may impair DAA response in real-world hepatitis C patients.

Oral DAA have demonstrated high efficacy as treatment of hepatitis C. However, the presence of resistance-associated substitutions (RAS) at baseline has occasionally been associated with impaired treatment response. Herein, we examined the impact of baseline RAS at the HCV NS5A gene region on treatment response in a real-life setting. All hepatitis C patients treated with DAA including NS5A inhibitors at our institution were retrospectively examined. The virus NS5A gene was analyzed using population sequencing at baseline and after 24 weeks of completing therapy in all patients that failed. All changes recorded at positions 28, 29, 30, 31, 32, 58, 62, 92, and 93 were considered. A total of 166 patients were analyzed. HCV genotypes were as follows: G1a (31.9%), G1b (48.2%), G3 (10.2%), and G4 (9.6%). Overall, 69 (41.6%) patients were coinfected with HIV and 46.7% had advanced liver fibrosis (Metavir F3-F4). Sixty (36.1%) patients had at least one RAS at baseline, including M28A/G/T (5), Q30X (12), L31I/F/M/V (6), T58P/S (25), Q/E62D (1), A92 K (7), and Y93C/H (15). Overall, 4.8% had two or more RAS, being more frequent in G4 (12.5%) followed by G1b (6.3%) and G1a (1.9%). Of 10 (6%) patients that failed DAA therapy, five had baseline NS5A RAS. No association was found for specific baseline RAS, although changes at position 30 were more frequent in failures than cures (22.2% vs 6.4%, P = 0.074). Moreover, the presence of two or more RAS at baseline was more frequent in failures (HR: 7.2; P = 0.029). Upon failure, six patients showed emerging RAS, including Q30C/H/R (3), L31M (1), and Y93C/H (2). Baseline NS5A RAS are frequently seen in DAA-naïve HCV patients. Two or more baseline NS5A RAS were found in nearly 5% and were significantly associated to DAA failure. Therefore, baseline NS5A testing should be considered when HCV treatment is planned with NS5A inhibitors.

Evaluation of sofosbuvir, velpatasvir plus voxilaprevir as fixed-dose co-formulation for treating hepatitis C.

INTRODUCTION: The fixed-dose combination of three direct-acting antivirals (DAA), namely sofosbuvir, velpatasvir and voxilaprevir is the first pangenotypic, single tablet regimen developed for the treatment of HCV infection. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy and safety of the co-formulation are reviewed. Information on drug absorption, distribution, metabolism and excretion of each of the three antivirals is evaluated. Finally, antiviral activity, safety and potential for drug interactions in phase II/III clinical trials in distinct patient populations are discussed. Expert opinion: The triple co-formulation of sofosbuvir-velpatasvir-voxilaprevir represents a major step towards HCV eradication. It depicts high efficacy even in patients infected with viruses harboring resistance-associated substitutions (RAS), including those selected after DAA failures. Likewise, very high success rates and good tolerance are seen in special patient populations, including decompensated cirrhotics, HIV coinfection, organ transplantation or renal insufficiency. A pill once daily for 8 weeks gives SVR rates above 95%. In prior DAA failures, extending treatment to 12 weeks maximizes SVR rates.

Drug interactions in HIV-infected patients treated for hepatitis C.

INTRODUCTION: The introduction of direct-acting antivirals (DAA) has revolutionized the hepatitis C field. Most hepatitis C patients can now be cured, including those coinfected with HIV. However, drug-drug interactions (DDI) between DAA and antiretrovirals (ARV) should be known to prevent either toxicity due to drug overexposure or treatment failures due to low drug concentrations. Areas covered: Clinically significant DDI may be classified as major (when co-administration should be contraindicated) or minor (when they require close monitoring, changes in drug dosage or in timing). Strategies for preventing and managing DDI influence response rates in HIV/HCV-coinfected patients. Pharmacokinetic evidence of interactions from clinical trials and reports from real-world experience are discussed. Expert opinion: The most frequent DDI between DAA and ARV affect drug metabolism by CYP450 induction/inhibition, leading to abnormal drug exposures. Throughout this mechanism interact HCV and HIV boosted protease inhibitors, and most non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide analogue polymerase inhibitors, most HCV NS5A inhibitors and HIV integrase inhibitors (e.g., dolutegravir), do not or only marginally affect CYP450, and therefore are relatively free of DDI. Exposure to some HIV and HCV nucleos(t)ide analogues (e.g., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (e.g., P-glycoprotein) and requires special attention in patients with renal insufficiency.

Treatment of hepatitis C with new fixed dose combinations.

INTRODUCTION: The advent of oral direct-acting antivirals (DAA) has revolutionized the hepatitis C virus (HCV) therapeutic landscape providing cure rates over 90%. However, a subset of patients remains at higher risk for treatment failure, including those infected with: i) genotype 3 and cirrhosis; ii) resistance-associated substitutions (RAS) occurring either as natural polymorphisms or selected after prior DAA failure; and iii) poor drug adherence associated with social disabilities (homeless, psychiatric illnesses, injection drug use, alcoholism, etc.). Whereas discovery of new DAA with increased antiviral activity across all genotypes and over RAS may enhance efficacy, development of fixed dose combinations (FDC) may be the best way to improve drug adherence in difficult-to-treat HCV populations. Areas covered: Three FDC regimens are in the last steps of clinical development for treating hepatitis C. Two distinct nucleotide analogues that inhibit the HCV polymerase, sofosbuvir and uprifosbuvir, are part of the FDC from Gilead and Merck, respectively. The AbbVie dual FDC does not include a polymerase inhibitor. All three new FDC include second-generation NS3 protease inhibitors and NS5A inhibitors active across all HCV genotypes and over common RAS. Expert opinion: Hepatitis C cure rates over 95% are expected with all three next-coming DAA, even in the most difficult-to-treat and/or cure patient populations. These regimens would be particularly needed for the growing number of prior DAA failures. Co-formulations and 8-week shorter treatment lengths will help to overcome drug adherence challenges in certain populations.

Dual antiretroviral therapy for HIV infection.

INTRODUCTION: For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens. Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naïve and in treatment-experienced patients with viral suppression (switch strategy). Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions. The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction-maintenance.

Impact of ITPA gene polymorphisms on the risk of ribavirin-induced haemolytic anaemia using interferon-free antivirals for chronic hepatitis C.

BACKGROUND: Single nucleotide polymorphisms (SNPs) at the ITPA gene are associated with haemolytic anaemia in chronic hepatitis C patients treated with pegylated interferon-ribavirin (RBV). Information in patients treated with interferon-free, direct-acting antivirals (DAA) is scarce. METHODS: Median haemoglobin (Hb) levels were compared at baseline and at week 4, when ribavirin concentration achieves steady state, in all consecutive chronic hepatitis C patients treated with oral DAA plus RBV at our clinic. RESULTS: Median Hb drop in 55 patients was greater in rs1127354-CC than -CA/AA (1.8 versus 0.7 g/dl; P=0.029), and in rs6051702-AA than -AC/CC carriers (2.2 versus 1.1 g/dl; P=0.016). Eleven (20%) patients experienced severe anaemia, defined as Hb drop >3 g/dl or to <10 g/dl. All of them were rs6051702-AA. CONCLUSIONS: Baseline testing of rs6051702 may identify the subset of patients at greatest risk for RBV-induced anaemia using interferon-free hepatitis C therapies.

Rate and predictors of treatment failure to all-oral HCV regimens outside clinical trials.

BACKGROUND: Cure rates above 90% have been reported in most Phase III clinical trials using distinct all-oral direct-acting antivirals (DAAs) in chronic hepatitis C patients. Preliminary results in real-world patients have confirmed this, although efficacy tends to be lower. METHODS: All consecutive chronic hepatitis C patients treated with all-oral DAA regimens at three hepatitis clinics in Spain were retrospectively examined. Host and viral factors were tested as predictors of treatment failure. RESULTS: A total of 363 chronic hepatitis C patients had completed a course of all-oral DAA therapy outside clinical trials up to the end of 2015. All but 14 (4%) patients achieved sustained virological response. There were 10 failures that occurred after 12 weeks of sofosbuvir-ledipasvir, despite 5 of them being on ribavirin. All failures but one were relapses. The only patient with viral breakthrough selected NS5B L159F and NS5A Y93H. In multivariate analyses, only advanced liver fibrosis (Metavir F3-F4) and HIV coinfection were significantly associated with treatment failure. A trend towards lower response was seen for HCV genotype 4. CONCLUSIONS: Treatment failures outside clinical trials are roughly seen in 4% of chronic hepatitis C patients who complete a course of all-oral DAA therapy, resembling what is seen in registration trials. In our series, outcomes were not significantly influenced by ribavirin addition, IL28B polymorphisms, HCV genotype, high baseline HCV RNA or prior interferon failure. However, advanced liver fibrosis and HIV coinfection were significantly associated with treatment failure. Our findings support that there is still room for individualization of current DAA therapy.

Prevention and management of treatment failure to new oral hepatitis C drugs.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection has become a curable disease. Sustained virologic response rates above 90% have been achieved with recommended direct-acting antiviral (DAA) combinations in most registration trials. However, outcomes in real-world patients are lower. In patients experiencing DAA failure, resistance-associated variants (RAVs) are almost universally selected. At this time it is unclear when and how to re-treat hepatitis C in patients with prior DAA failure. AREAS COVERED: The rate of DAA failure and predictors of lack of treatment response using distinct DAA combinations are analyzed. We discuss the management of HCV treatment failure and the impact of RAVs on re-treatment strategies. EXPERT OPINION: Failure to DAA combinations occurs more often in chronic hepatitis C patients with baseline predictors of poor response, such as those with RAVs, genotypes 3 or 1a, advanced liver cirrhosis, elevated serum HCV-RNA and perhaps HIV coinfection. Impaired antiviral efficacy is more frequent when multiple factors are present. On-treatment predictors of DAA failure are poor drug adherence and development of side effects. Extending the length of therapy, adding ribavirin and/or using DAA from other drug families may allow successful re-treatment of most prior DAA failures.

High serum HCV RNA in chronic hepatitis C patients coinfected with HIV despite successful antiretroviral therapy.

BACKGROUND: Baseline serum HCV RNA predicts treatment success in chronic hepatitis C patients. Thresholds at 0.8, 2, 4 and 6 million IU/ml discriminate treatment outcomes using distinct antiviral regimens. Compared to the general population, immunosuppressed individuals exhibit greater viral load values. This has been confirmed in HIV-HCV-coinfected patients, although little is known about the influence of antiretroviral therapy. METHODS: Serum HCV RNA results recorded from all chronic hepatitis C patients who consecutively attended at our clinic were analysed. RESULTS: A total of 813 patients with detectable HCV RNA were identified. HIV coinfection was present in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 467 (57%), 273 (34%), 170 (21%) and 127 (16%) had HCV RNA >0.8, >2, >4 and >6 million IU/ml, respectively. These high viral load values were found in 60%/36%/23%/18% of HIV-positive versus 47%/25%/11%/6% of HIV-negative individuals (P<0.01), respectively. In multivariate analysis, the greatest HCV RNA values were only significantly associated with HIV coinfection and HCV genotypes-1 or -4. Greater HCV RNA values were paradoxically found in HIV patients on than off antiretroviral therapy. CONCLUSIONS: Serum HCV RNA values above 0.8, 2, 4 and 6 million IU/ml are roughly seen in 47%, 25%, 11% and 6% of chronic hepatitis C monoinfected patients, respectively. Despite being on antiretroviral therapy, the corresponding figures are 1.3- to 3.0-fold greater in HIV-HCV-coinfected patients, who may benefit less frequently from shorter oral HCV treatment lengths.

Hepatitis C cure with antiviral therapy--benefits beyond the liver.

Liver disease is the major complication of chronic HCV infection. However, extrahepatic complications are common (50-75%), including mixed cryoglobulinaemia and B-cell lymphomas. Given that chronic hepatitis C has become curable using expensive oral direct-acting antivirals (DAAs), it seems worth revisiting the whole spectrum and burden of disease in HCV carriers.Herein, we update the most clinically significant medical complications associated with chronic hepatitis C and the evidence of benefits that would derive from a wide use of curative DAA therapies.Chronic HCV infection is associated with a broad spectrum of clinical conditions, including distinct rheumatic disorders (polyarthritis, sicca syndrome), lymphoproliferative conditions (mixed cryoglobulinaemia, monoclonal gammapathies and B-cell lymphomas) and damage at other organs due to persistent systemic inflammation, leading to renal, bone, neurological and/or cardiovascular disease. Eradication of HCV with DAAs is associated with amelioration and/or resolution of most liver-related and extrahepatic complications. Ultimately, gains in quality of life and survival favour treating everyone with hepatitis C regardless of liver fibrosis stage.

New hepatitis C therapies for special patient populations.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection has become a curable disease. More than 90% sustained virologic response rates have been obtained with 8-24 weeks of treatment with distinct combinations of direct-acting antivirals (DAA) in most registration trials. However, outcomes in real-world patients tend to be lower and treatment of special patient populations is often challenging. AREAS COVERED: We address the treatment of chronic hepatitis C with DAA in major special patient populations, such as HIV-positive persons, transplant recipients, patients with advanced cirrhosis, renal insufficiency, hepatitis B or D coinfection, injection drug users (IDUs) and prior DAA failures. EXPERT OPINION: Drug interactions between DAA and medications given to persons with HIV infection or transplant recipients can result in treatment failure and adverse events. Severe organ dysfunction as in kidney insufficiency or decompensated cirrhosis may lead to DAA overexposure and toxicities. Dysfunctional social circumstances and behavior are associated to poor drug adherence and increased risk for HCV re-infection in active IDUs. Finally, DAA response might be impaired by viral interference in patients with hepatitis B or D coinfection or drug resistance in HCV either at baseline or after prior DAA failures.

Rate and predictors of serum HCV-RNA >6 million IU/mL in patients with chronic hepatitis C.

BACKGROUND: Baseline serum HCV-RNA predicts sustained virological response in chronic hepatitis C patients treated with antiviral therapy. A threshold at 6 million IU/mL has been proposed to best discriminate treatment outcomes on sofosbuvir-based regimens. In comparison with the general population, immunosuppressed individuals exhibit greater viral load values. OBJECTIVES: To estimate the rate and predictors of serum HCV-RNA above 6 millionIU/mL in chronic hepatitis C patients on care outside clinical trials. STUDY DESIGN: Serum HCV-RNA values recorded from all chronic hepatitis C patients consecutively attended at our clinic during the last decade were analyzed. Testing had been performed using the COBAS TaqMan HCV test v2.0. RESULTS: A total of 816 individuals with detectable serum HCV-RNA were identified. The main characteristics of this population were as follows: mean age 48.6 years-old; 73.4% males; mean ALT 82.6IU/L; mean HCV-RNA 6.02logIU/mL; 80.6% HCV genotypes 1 or 4; 34.9% advanced liver fibrosis; 35.4% IL28B-CC alleles. HIV coinfection in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 127 (15.6%) had serum HCV-RNA values >6 millionIU/mL. This high viremia was found in 18.2% of HIV-positive versus 5.7% of HIV-negative subjects (p<0.001). In multivariate analysis, serum HCV-RNA >6 millionIU/mL was only significantly associated with HIV coinfection (OR: 4.03; 95% CI: 1.98-8.19, p<0.01) and HCV genotypes 1 or 4 (OR: 1.88; 95% CI: 1.05-3.37, p=0.03). CONCLUSIONS: Serum HCV-RNA >6 millionIU/mL is roughly seen in 6% of chronic hepatitis C monoinfected patients, and increases up to 18% in HIV coinfection.

Dual antiviral therapy for HIV and hepatitis C - drug interactions and side effects.

INTRODUCTION: Roughly 20% of HIV-positive persons worldwide are coinfected with hepatitis C virus (HCV). The recent advent of direct-acting antivirals (DAA) that cure most hepatitis C patients has attracted much attention. Knowledge on drug interactions between DAA and antiretrovirals (ARV) may allow maximizing antiviral efficacy while minimizing drug-related toxicities. AREAS COVERED: We review the most frequent side effects and clinically significant drug interactions between DAA and ARV. We further discuss how they can be prevented and managed in HIV/HCV-coinfected patients. EXPERT OPINION: The safety profile of current DAA and the most recently approved ARV is quite favorable. Interactions between DAA and ARV could be frequent in clinical practice. The most common drug interactions affect drug metabolism by inducing or inhibiting the cytochrome P450 system, leading to abnormal drug exposures. Throughout this mechanism HCV and HIV protease inhibitors interact, especially when co-formulated with ritonavir as a pharmacoenhancer, and non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide polymerase inhibitors, and most HCV NS5A inhibitors (i.e., ledipasvir) and HIV integrase inhibitors (i.e., dolutegravir), do not or only marginally affect CYP450, and therefore are free of significant drug interactions. Exposure to HIV and HCV nucleos(t)ide analogues (i.e., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (i.e., P-glycoprotein).

Drug interactions with new hepatitis C oral drugs.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection has recently become a curable disease with antiviral therapy. The knowledge of drug interactions using direct-acting antivirals (DAA) may permit maximizing antiviral efficacy and avoiding drug-related toxicities. Ageing in the chronic hepatitis C population, along with added co-morbidities that require other medications, has increased the attention on drug interactions using DAA. AREAS COVERED: This review provides an update of the most clinically significant pharmacokinetic and pharmacodynamic drug interactions occurring between currently available DAA and other medications. The review also revisits how drug interactions with DAA can be prevented and managed. EXPERT OPINION: Interactions between DAA and other drugs are frequent in clinical practice. The most frequent drug interactions modify drug metabolism by inducing or inhibiting the cytochrome P450, leading to abnormal drug exposures. Through this mechanism HCV protease inhibitors, especially when co-formulated with ritonavir as pharmacoenhancer, and non-nucleoside HCV polymerase inhibitors interact with other medications. In contrast, NS5B nucleos(t)ide analog inhibitors (i.e., sofosbuvir) and some HCV NS5A inhibitors (i.e., ledipasvir), which do not or only marginally affect CYP450, are relatively free of significant pharmacokinetic interactions. However, exposure to HCV nucleos(t)ide analogs may be influenced by induction/inhibition of drug transporters (i.e., P-glycoprotein) as well as by pharmacodynamic interference with other nucleos(t)ide analogs used as antivirals or cancer drugs. Drug interactions for some NS5A inhibitors (i.e., daclatasvir) are generally moderate and can be managed with dose adjustments.

Correction: Antimicrobial stewardship in patients recently transferred to a ward from the ICU / Asesoramiento antibiótico en pacientes tras estancia en cuidados intensivos

This paper is a corrigendum to the previously published paper: "Antimicrobial stewardship in patients recently transferred to a ward from the ICU" [Rev Esp Quimioter. 2014 Mar;27(1):46-50.] This corrigendum was prepared in order to correct some erroneous comments included in the discussion section. First, it should be pointed out that there could have been several suitable options for treating many infections and that, therefore, the word "nadequate" was not the most appropriate in this situation. In addition, some comments about the interpretation of microbiological results made by ICU physicians have been removed from the first article because this variable was not included in the study. Finally, another change made to the discussion was to clarify the ICU physicians’ alleged low level of compliance with advice given by infectious disease specialists. This has been suggested in previous studies it cannot be substantiated when analyzing the results of the study. Purpose. Inappropriate use of antibiotics is an important health problem that is related to increasing bacterial resistance. Despite its relevance, many health institutions assign very limited resources to improving prescribing practices. An antimicrobial stewardship programme (APS) centred on patients discharged from the ICU could efficiently undertake this task. Methods. During this six month study the main activity was performing a programmed review of antimicrobial prescriptions in patients transferred to the ward from the ICU. In the case of amendable antimicrobial treatment, a recommendation was included in the medical record. Results. A total of 437 antimicrobial prescriptions for 286 patients were revised during a six month period and a total of 271 prescriptions (62%) in 183 patients were considered to be amendable. In most of these cases, treatment could have been reduced taking into consideration each patient’s clinical improvement and their location in a hospital area with a lower risk of infection due to resistant bacteria. The most common advice was antimicrobial withdrawal (64%), antimicrobial change (20%) and switching to oral route (12%). Proposed recommendations were addressed in 212 cases (78%). There was no significant difference in adherence with respect to the type of recommendation (p=0.417). There was a 5% lower use of antibiotics during the year the study was conducted compared to the previous one. Conclusions. ASPs centred on patients discharged from the ICU may be an efficient strategy to ameliorate antimicrobial use in hospitals

Este artículo es una corrección del artículo previamente publicado: "Antimicrobial stewardship in patients recently transferred to a ward from the ICU" [Rev Esp Quimioter. 2014 Mar;27(1):46-50.] Esta corrección ha sido elaborada para subsanar algunos comentarios erróneos incluidos en la discusión. Primero, hay que señalar que podría haber habido varias opciones adecuadas para el tratamiento de muchas infecciones y que, por tanto, la palabra "inadecuada" no era el más apropiada en esta situación. Además, algunos comentarios sobre la interpretación de los resultados microbiológicos realizados por médicos de la UCI se han eliminado del primer artículo porque esta variable no se incluyó en el estudio. Por último, otro cambio realizado en la discusión fue aclarar que los médicos de la UCI alegaron bajo nivel de cumplimiento con las recomendaciones dadas por los especialistas en enfermedades infecciosas. Esto ha sido sugerido en estudios previos y no puede ser demostrado en el análisis de los resultados de este estudio Objetivos. El uso inapropiado de antimicrobianos es un problema de salud relevante que se relaciona con aumento de la resistencia bacteriana y con el gasto farmacéutico innecesario. A pesar de su relevancia, un número elevado de instituciones sanitarias destinan escasos recursos para mejorar la prescripción antimicrobiana. Un programa de asesoramiento sobre el uso de antimicrobianos centrado en los pacientes dados de alta una unidad de cuidados intensivos (UCI) podría constituir una herramienta eficiente para mejorar este problema. Métodos. Durante este estudio de seis meses de duración se realizó una intervención consistente en una revisión programada, por expertos en enfermedades infecciosas, de las prescripciones antimicrobiana en pacientes trasladados a una sala de hospitalización desde UCI. En el caso de prescripción modificable se realizaba una recomendación en la historia electrónica. Resultados. Se revisaron de 437 prescripciones de antimicrobianos en 286 pacientes. En total, 271 prescripciones (62%) en 183 pacientes se consideraban modificables. En la mayoría de estos casos, el tratamiento podría ser ajustado a la baja teniendo en cuenta la mejoría clínica del paciente y su actual ubicación en un área hospitalaria con menos riesgo de infección por bacterias resistentes. El consejo más común fue retirada a los antimicrobianos (64%), el cambio a los antimicrobianos (20%) y la administración por vía oral (12%). Las recomendaciones propuestas fueron aceptadas en 212 casos (78 %). No hubo diferencia significativa en la adherencia a la recomendación por parte del clínico responsable ni con el tipo de recomendación (p = 0,417). Durante el año en que realizó el estudio se redujo la prescripción antibiótica en un 5% en comparación con el año anterior. Conclusiones. La revisión del tratamiento antimicrobiano en pacientes dados de alta de UCI puede ser una estrategia eficiente para mejorar el uso de estos fármacos (AU)