Nuevos antivirales frente al VHC: actualidad y perspectivas / New direct acting antiviral for hepatitis C: future perspectives

Aproximadamente 175 millones de personas están infectadas por el virus de la hepatitis C (VHC), lo que representa un 3% de la población mundial. En ausencia de tratamiento eficaz, un 25% de los pacientes desarrollan complicaciones hepáticas tras 25 años de hepatitis crónica C. Hasta hace poco, la única opción terapéutica en estos pacientes era la combinación de interferón pegilado (peg-IFN) y ribavirina (RBV). Alcanzaban la erradicación del VHC un 30-40% de los pacientes infectados con el genotipo 1 del VHC. Recientes avances han permitido desarrollar replicones y sistemas de cultivo tisulares para el VHC. Esto ha facilitado el diseño de fármacos antivirales directos (DAA) que inhiben específicamente la replicación del VHC. Los dos primeros inhibidores de la proteasa del VHC fueron aprobados en mayo de 2011. Permiten obtener tasas de curación en el 70% de los pacientes infectados con el genotipo 1 sin experiencia previa a interferón. La respuesta es menor en pacientes con fracasos previos, excepto en los recidivantes, en los que tasa de curación es del 90%...

Approximately 175 million people worldwide are chronically infected with the hepatitis C virus (HCV), representing 3% of the total world population. In the absence of successful therapy nearly 25% of these patients will develop hepatic complications within 25 years. Until recently, the only available therapeutic option for these patients was the combination of peginterferon-a plus ribavirin. Overall it allowed achievement of eradication in only 30-40% of patients infected by HCV genotype 1. The development of HCV replicons and the chance of producing infectious viral particles in culture systems have both enabled the rational design of direct-acting antivirals (DAA) that specifically inhibit HCV replication. The first two HCV protease inhibitors were marketed in May 2011. Triple therapy has increased the response rate to 70% in HCV genotype 1 carrier naïve to interferon. Although response rates are lower in prior failures, 90% sustained virological response rates are achieved in prior relapsers...

[The pharmacogenetics of response to antiretroviral therapy]. / Farmacogenética de la respuesta al tratamiento antirretroviral.

The plasma concentrations of most antiretroviral drugs show wide interindividual variability, which may lead to differences in response rate and toxicity. Among the factors determining this variable exposure to antiviral drugs are differences in metabolism, interactions due to the use of concomitant medication, problems in treatment adherence, underlying diseases, and host genetic factors. Pharmacogenetics analyzes the genetic bases of interindividual variation in the bioavailability and response to drugs. The aim is to establish the foundations for individualized therapy. Among the genetic factors that are in some way involved in antiretroviral treatment response are those that directly or indirectly affect antiviral plasma concentrations, as is the case of drug transport proteins and metabolizing enzymes. Some host factors also influence antiviral response, such as interleukins and major histocompatibility complex. The present article analyzes the most important genetic markers associated with antiretroviral treatment response.

Farmacogenética de la respuesta al tratamiento antirretroviral / The pharmacogenetics of response to antiretroviral therapy

Existe una elevada variabilidad interindividual en las concentraciones plasmáticas de la mayoría de antirretrovirales, que puede condicionar diferencias en la tasa de respuesta y toxicidad. Entre los factores determinantes de esta exposición variable a los antivirales figuran diferencias en el metabolismo, interacciones por el uso de varias medicaciones, problemas en la adherencia al tratamiento, enfermedades subyacentes y factores genéticos del huésped. La farmacogenética es la disciplina que analiza las bases genéticas de la variación interindividual en la biodisponibilidad y respuesta a los fármacos. Su objetivo es proporcionar las bases para una individualización de la terapia. Entre los factores genéticos asociados de alguna forma con la respuesta al tratamiento antirretroviral se encuentran aquellos que directa o indirectamente afectan a las concentraciones plasmáticas de los antivirales. Es el caso de las proteínas de transporte de los fármacos y las enzimas metabolizadoras. Por otro lado se encuentran factores relacionados con el huésped que influyen en la respuesta antiviral, como las interleucinas y el complejo mayor de histocompatibilidad. En el presente capítulo se analizan los marcadores genéticos más relevantes asociados con la respuesta al tratamiento antirretroviral(AU)

The plasma concentrations of most antiretroviral drugs show wide interindividual variability, which may lead to differences in response rate and toxicity. Among the factors determining this variable exposure to antiviral drugs are differences in metabolism, interactions due to the use of concomitant medication, problems in treatment adherence, underlying diseases, and host genetic factors. Pharmacogenetics analyzes the genetic bases of interindividual variation in the bioavailability and response to drugs. The aim is to establish the foundations for individualized therapy. Among the genetic factors that are in some way involved in antiretroviral treatment response are those that directly or indirectly affect antiviral plasma concentrations, as is the case of drug transport proteins and metabolizing enzymes. Some host factors also influence antiviral response, such as interleukins and major histocompatibility complex. The present article analyzes the most important genetic markers associated with antiretroviral treatment response(AU)

[Diagnostic, clinical and therapeutic implications of viral hepatitides in HIV-infected patients]. / Implicaciones diagnósticas, clínicas y terapéuticas de las hepatitis virales en el paciente infectado por el VIH.

Viral hepatitis B (HBV) and C (HCV) are a significant cause of morbidity and mortality in patients coinfected with human immunodeficiency virus (HIV). In HBV/HIV coinfection, there is a higher frequency of HBV replication, and higher rates of HBV-associated liver disease. The only drugs currently approved for the treatment of HBV infection are lamivudine, adefovir, entecavir, and interferon-a. HIV/HBV coinfection is associated with an increased frequency of hepatotoxicity in patients receiving highly active antiretroviral therapy (HAART), and reactivation of clinical hepatitis is observed upon stopping HBV-active anti-HIV drugs. Liver disease due to HCV infection is currently the leading cause of mortality among HIV-infected patients in the developed world. The treatment of choice of chronic hepatitis C in these patients is based on pegylated interferon in combination with ribavirin, which achieves sustained virological response rates of up to 40%. However, patients with HCV/HIV coinfection show accelerated progression to cirrhosis and are at increased risk of hepatotoxicity from HAART.

Implicaciones diagnósticas, clínicas y terapéuticas de las hepatitis virales en el paciente infectado por el VIH / Diagnostic, clinical and therapeutic implications of viral hepatitides in HIV-infected patients

La coinfección por los virus de la hepatitis B (VHB) o C (VHC) constituye una de las principales causas de morbilidad y mortalidad en los pacientes infectados por el virus de la inmunodeficiencia humana (VIH). Los pacientes con coinfección VHB/VIH presentan un mayor riesgo de cronicidad del VHB, junto con valores mayores de replicación. La lamivudina, junto con el adefovir, el entecavir y el interferón-α son los únicos fármacos aprobados para el tratamiento del VHB. El tratamiento antirretroviral de gran eficacia (TARGA) se acompaña de un incremento de la hepatotoxicidad en estos pacientes, junto con una reactivación de la hepatitis B al interrumpirlo, si incluye fármacos activos frente al VHB. Las complicaciones hepáticas producidas por el virus de la hepatitis C (VHC) son, actualmente, la primera causa de mortalidad en los pacientes coinfectados por el VIH en el mundo occidental. La combinación de interferón pegilado más ribavirina es el tratamiento de elección en la coinfección VHC/VIH. Con esta terapia se consiguen tasas de respuesta viral sostenida de hasta el 40%. Los pacientes coinfectados VHC/VIH presentan una más rápida evolución a cirrosis y un mayor riesgo de toxicidad hepática con el TARGA

Viral hepatitis B (HBV) and C (HCV) are a significant cause of morbidity and mortality in patients coinfected with human immunodeficiency virus (HIV). In HBV/HIV coinfection, there is a higher frequency of HBV replication, and higher rates of HBV-associated liver disease. The only drugs currently approved for the treatment of HBV infection are lamivudine, adefovir, entecavir, and interferon-a. HIV/HBV coinfection is associated with an increased frequency of hepatotoxicity in patients receiving highly active antiretroviral therapy (HAART), and reactivation of clinical hepatitis is observed upon stopping HBV-active anti-HIV drugs. Liver disease due to HCV infection is currently the leading cause of mortality among HIV-infected patients in the developed world. The treatment of choice of chronic hepatitis C in these patients is based on pegylated interferon in combination with ribavirin, which achieves sustained virological response rates of up to 40%. However, patients with HCV/HIV coinfection show accelerated progression to cirrhosis and are at increased risk of hepatotoxicity from HAART