José Ramón Arribas López

Tenofovir disoproxil fumarate–emtricitabine coformulation for once-daily dual NRTI backbone

Truvada® is the coformulation of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) in a single tablet, providing the nucleotide backbone for once-daily dosing, as a component of highly active antiretroviral therapy (HAART). TDF (the bioavailable prodrug of tenofovir) is hydrolyzed to tenofovir intracellularly and phosphorylated to the active metabolite, tenofovir diphosphate. Tenofovir is a nucleotide analog of deoxyadenosine monophosphate, with activity against HIV-1, -2 and hepatitis B virus. FTC, the fluorinated derivative of lamivudine, is an analog of deoxycitidine, active against HIV-1, -2 and hepatitis B virus. Their long half-lives in plasma and in peripheral blood mononuclear cells allow once-daily dosing. Both are eliminated renally. Resistance mutation K65R is selected for by tenofovir and confers a two- to fourfold reduced susceptibility to this drug. The incidence of K65R is low (3%) and has not been observed in clinical trials with the concomitant use of tenofovir a...Truvada® is the coformulation of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) in a single tablet, providing the nucleotide backbone for once-daily dosing, as a component of highly active antiretroviral therapy (HAART). TDF (the bioavailable prodrug of tenofovir) is hydrolyzed to tenofovir intracellularly and phosphorylated to the active metabolite, tenofovir diphosphate. Tenofovir is a nucleotide analog of deoxyadenosine monophosphate, with activity against HIV-1, -2 and hepatitis B virus. FTC, the fluorinated derivative of lamivudine, is an analog of deoxycitidine, active against HIV-1, -2 and hepatitis B virus. Their long half-lives in plasma and in peripheral blood mononuclear cells allow once-daily dosing. Both are eliminated renally. Resistance mutation K65R is selected for by tenofovir and confers a two- to fourfold reduced susceptibility to this drug. The incidence of K65R is low (3%) and has not been observed in clinical trials with the concomitant use of tenofovir and FTC. FTC selects for M184V mutation less frequently than lamivudine. Tenofovir drug interactions include increased exposure to didanosine and inferior immmune recovery that preclude their concomitant use. Boosted protease inhibitors increase exposure to tenofovir without dose adjustment required. FTC has no significant drug interactions. They are not metabolized by cytochrome P450, which confers little potential for interactions with drugs metabolized by these enzymes. As tenofovir and FTC are renally eliminated, drugs eliminated by tubular secretion must be avoided. Both antiretrovirals, as individual agents and in coadministration have evidenced antiviral potency in clinical trials. Pivotal study 934 evidenced superior efficacy of the combination TDF/FTC/efavirenz (EFV) versus zidovudine/FTC/EFV. The toxicity profile of tenofovir and FTC has been extensively studied. Lipid profile is more favorable with tenofovir than thymidine analog. Tenofovir requires surveillance of glomerular filtration rate and dosing interval adjustment when creatinine clearance is less than 50 ml/min and avoidance less than 30 ml/min. Fat loss is less likely with tenofovir than with thymidine analog. Clinical trials have assessed the performance of the coformulation of TDF and FTC.

Transient elastography to rule out esophageal varices and portal hypertensive gastropathy in HIV-infected individuals with liver cirrhosis.

Background/aims:It is recommended that patients with cirrhosis undergo endoscopic screening to rule out the presence of gastroesophageal varices: a noninvasive predictive method to identify cirrhotic patients with a very low risk of esophageal varices could potentially avoid unnecessary endoscopies. Methods:We studied in 85 HIV-infected patients with cirrhosis the association between the absence of esophageal varices and portal hypertensive gastropathy, assessed by endoscopy, and liver stiffness measurement by transient elastography. We analyzed other parameters related to portal hypertension and hepatic function. Results:Values of transient elastography and platelet count were significantly associated with absence of esophageal varices/portal hypertensive gastropathy. The area under the receiver operating characteristics curve [95% confidence interval (CI)] of transient elastography for the prediction of the absence of esophageal varices/portal hypertensive gastropathy was 0.7 (0.58–0.81). A liver stiffness measurement value less than 20 kPa was highly predictive of the absence of esophageal varices and portal hypertensive gastropathy. The combination of transient elastography (<20 kPa) and platelet count (>120 × 109 cells/l) had the highest negative predictive value (100%, CI 95% 77.2–100) for absence of esophageal varices and portal hypertensive gastropathy. Conclusion:Transient elastography combined with platelet count is useful for predicting the absence of esophageal varices and portal hypertensive gastropathy and, therefore, avoid unnecessary diagnostic endoscopies in HIV-infected patients with liver cirrhosis.

Efectos secundarios asociados al tratamiento con maraviroc y otros antagonistas de CCR5. Impacto potencial del bloqueo del receptor CCR5

Maraviroc es el primer inhibidor de los correceptores CCR5 comercializado como antirretroviral. Los estudios preclinicos y los ensayos de fase 3 han demostrado que su perfil de seguridad es muy favorable. No se ha identificado un efecto adverso caracteristico de maraviroc. En contraste con aplaviroc, cuyo desarrollo clinico fue interrumpido por hepatotoxicidad grave, no se ha demostrado un incremento de toxicidad hepatica en pacientes tratados con maraviroc incluso si estan coinfectados por virus hepatotropos. Tampoco se ha evidenciado un incremento en la incidencia de neoplasias o infecciones graves en pacientes tratados con maraviroc. En un estudio de pacientes naive, maraviroc causo cambios no significativos en colesterol total, lipoproteinas de baja densidad, lipoproteinas de alta densidad y trigliceridos. Aunque los correceptores CCR5 desempenan un papel en la respuesta inmunitaria del organismo, no se ha demostrado que los individuos homocigotos para su delecion (mutacion delta-32) tengan un riesgo incrementado de infecciones graves, con la posible excepcion de la encefalitis por el virus del Nilo occidental. Sin embargo, es necesario un seguimiento a largo plazo de los pacientes tratados con maraviroc para poder descartar una susceptibilidad incrementada a infecciones o neoplasias.

[Carotid revascularisation using angioplasty and stent in 134 consecutive cases in a reference hospital: a risky technique?].

INTRODUCTION Carotid revascularisation (CR) using angioplasty and stent (ASC) is an effective procedure in the prevention of ischaemic stroke, but with a controversial morbidity and mortality in the different studies conducted in this field. METHODS The results of the ASCs performed in the Virgen de la Arrixaca University Hospital (Murcia) between January 2006 and April 2009 were analysed (epidemiology, indication, grade of residual stenosis and procedure complications). All patients subjected to ASC were pre-selected and followed up by neurologists, and they followed a strict medical protocol for performing the procedure. All ASCs were performed by a team consisting of two surgeons, an anaesthetist and a nurse. RESULTS A total of 134 ASC were performed. The mean age of our patients was 72.7 years, with the large majority (75%) being male. The most prevalent diseases were, high blood pressure (81%), smoking (66.4%), and diabetes (38.1%). The most common indications for CR were symptomatic carotid stenosis with a level of stenosis of 75-99%, either in the left (33.6%) or right (32.1%), followed by asymptomatic stenosis combined with risk factors (11.2% in the left side and 10.4% in the right side). A level of stenosis less than 30% was achieved in 132 of the 134 ASC (98.5%). performed. Five patients (3.7%) had complications associated with the procedure, of which four were different clinical presentations of a re-perfusion syndrome and one an asymptomatic thrombosis of the stent. CONCLUSIONS ASC is a complex technique that must be performed by appropriately trained specialists. The performing a minimum number of procedures per year and an admission protocol controlled by Neurology are essential conditions for a low rate of complications. Under these conditions, the morbidity and mortality of the technique is no higher than that of endarterectomy.

Validación prospectiva de un test farmacogenético: estudio PREDICT-1

El ensayo PREDICT-1 tuvo como objetivo comprobar la utilidad clinica del test farmacogenetico que determina el HLA-B*5701 para reducir la incidencia de reaccion de hipersensibilidad (RHS) a abacavir (ABC) diagnosticada clinicamente y con confirmacion inmunologica, asi como para reducir el abandono injustificado de este farmaco. En el estudio PREDICT-1 se aleatorizo a 1.956 pacientes a ser sometidos a cribado de HLA-B*5701 previo a la instauracion de tratamiento con ABC (excluyendo a los sujetos positivos), o bien a recibir ABC con el desconocimiento de su HLA-B*5701 bajo vigilancia clinica convencional. La prevalencia de positividad para HLA-B*5701 fue del 5,7%. En el grupo en que se realizo el cribado prospectivo no se observo ningun caso de RHS a ABC confirmada inmunologicamente (con test epicutaneo positivo) frente a una incidencia de 2,7% en el grupo con vigilancia estandar. La sensibilidad del cribado prospectivo para predecir la RHS a ABC confirmada inmunologicamente fue 100% y su valor predictivo negativo tambien fue del 100%. La RHS a ABC sospechada clinicamente tambien fue inferior en el grupo sometido a cribado; 3,4 frente a 7,8% en el grupo de seguimiento convencional. La realizacion del test epicutaneo como prueba de confirmacion inmunologica demostro una sensibilidad del 100%.