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Hepatitis C asociada al abuso de sustancias: nunca tan cerca de un tratamiento sin interferon.

El tratamiento de la hepatitis cronica C va a cambiar en los proximos anos. El cambio es debido a la aparicion de farmacos mas eficaces, mejor tolerados, que apenas generan resistencias farmacologicas y que se administraran durante menos tiempo. Estudios publicados a partir de 2012 muestran la eficacia de algunos de estos farmacos y si ello es asi, se pondra de manifiesto la necesidad de expandir el tratamiento a un mayor numero de pacientes; por lo tanto, deteccion de la infeccion y evaluacion de la hepatopatia seran relevantes si se confirma que la curacion de la infeccion puede ser superior al 90%, independientemente del genotipo viral o de haber fracasado en tratamientos anteriores. Cuando la eficacia de las nuevas terapias se confirme en los ensayos clinicos, el tratamiento de la enfermedad se generalizara y tiempo despues se demostrara su efectividad poblacional; eficacia clinica y efectividad poblacional son conceptos diferentes; se necesita de esta ultima para reducir la enorme carga de enfermedad que provoca el virus de la hepatitis C (VHC) en la sociedad. ?Que tiene que ver todo esto con los usuarios de drogas? Mucho. En el mundo occidental, dos de cada tres nuevas infecciones por VHC se dan en personas que han utilizado o utilizan drogas por via parenteral, pero esta poblacion es, no por casualidad, la que menos se trata de la hepatitis C. Los motivos para no recibir el tratamiento de la hepatitis C en personas con historia de abuso de sustancias son muy diversos y se describen en esta revision, pero uno de los mas invocados es la mala tolerancia al Interferon, un farmaco inmunomodulador que forma parte de la columna vertebral del tratamiento de la hepatitis C desde hace dos decadas. Por otra parte, si se confirman las ventajas de los nuevos farmacos, los pacientes con infeccion por VHC asociada al consumo de sustancias querran tratarse, como ya ocurrio tras la irrupcion de los farmacos antirretrovirales de gran eficacia frente al virus de la inmunodeficiencia humana (VIH).

Epidemiologia de la hepatitis C

La infeccion por VHC es una de las principales causas de enfermedad hepatica en el mundo (Shepard, Finelli, y Alter, 2005). La prevalencia de la infeccion en la poblacion mundial, aunque con marcadas diferencias geograficas, es cercana al 3% lo que equivale a 185 millones de personas afectadas. Se estima que 10 millones de las personas con infeccion por VHC son, o han sido, usuarios de drogas por via parenteral (UDIs)(Nelson et al., 2011; Mohd Hanafiah, Groeger, Flaxman, y Wiersma, 2013).

Globalmente, la prevalencia de la infeccion es mayor en hombres, en el grupo de edad comprendido entre 30 y 49 anos y en niveles socioeconomicos bajos (Alter, 2007). Los factores de riesgo de infeccion varian, aunque las transfusiones de sangre y/o hemoderivados antes de 1992, la utilizacion de material sanitario no desechable y el uso de drogas por via parenteral siguen siendo los mas importantes (Des Jarlais et al., 2003; Memon y Memon, 2002). En EE.UU hay mas de 2 millones de personas que usan drogas por via parenteral y la incidencia de infeccion por VHC se estima entre el 8% y 25% anual entre los mas jovenes; en EE.UU cada ano se diagnostican 30.000 nuevas infecciones y la incidencia de la infeccion es mayor en los nuevos consumidores de drogas y durante el primer ano de consumo (Nelson et al., 2011; Page et al., 2009). Esta demostrado que la transmision del VHC es 10 a 15 veces superior a la del VIH (Page et al., 2009; Page, Morris, Hahn, Maher, y Prins, 2013), lo que indica la facil transmision de la infeccion en esta poblacion.

Por otro lado, las personas con trastorno por uso de alcohol presentan mayor prevalencia de infeccion por el VHC que la poblacion general. Hasta el 20% de una serie de 700 pacientes que solicitan tratamiento de alcoholismo en el area de Barcelona se hallan infectados por el VHC segun un estudio reciente (Rivas et al., 2013).

El VHC es la principal causa de trasplante hepatico y de carcinoma hepatocelular (CHC) en paises occidentales (Freeman et al., 2008; Yang et al., 2011). De hecho, CHC y cirrosis hepatica han aumentado en los ultimos anos entre las personas infectadas por el VHC, y se preve que ambas enfermedades aumenten significativamente en las proximas decadas (Mehta et al., 2010; Rein et al., 2011). Un estudio en EE.UU pone de manifiesto el numero creciente de muertes en personas infectadas por VHC, que ya supera las atribuidas al VIH/ Sida (Ly et al., 2012); el mismo estudio indica que las muertes relacionadas con el VHC se producen mayoritariamente en el grupo de edad comprendido entre 45 y 64 anos (Ly et al., 2012), lo que ha llevado a las autoridades sanitarias de aquel pais a aconsejar que la poblacion general de esa edad se realice una prueba diagnostica del VHC. Se ha estimado ademas, que un millon de personas con infeccion por el VHC moriran en EE.UU por las complicaciones relacionadas la enfermedad si no reciben tratamiento (Rein et al., 2011, 2012).

En Espana, se estima que el numero de personas con infeccion por el VHC es de alrededor de 430.000, siendo los mayores de 50 anos los que muestran mayor prevalencia de infeccion; en ese sentido, es probable que la pasada epidemia de uso de heroina endovenosa haya repercutido en la elevada prevalencia de infeccion en la poblacion (Cornberg et al., 2011).

Historia natural de la Hepatitis C

El VHC provoca una infeccion aguda que cursa de forma asintomatica en la mayoria de los casos. Cerca del 20-25% de los pacientes con abuso de sustancias eliminaran espontaneamente la viremia en los 6 meses siguientes a la infeccion (Grebely et al., 2012; Page et al., 2009). Entre los factores que se asocian a la curacion espontanea de la infeccion esta el sexo femenino, la infeccion por el genotipo 1 (el mas frecuente en nuestro entorno) y ser homocigoto para el gen de la Interleukina-28 (IL-28B), gen que codifica la proteina Interleukina-23, involucrada en la replication del VHC (Liu, Fisher, Thomas, Cox, y Ray, 2012; Page et al., 2009). Por otro lado, el 75-80% de los infectados desarrollaran una infeccion cronica y el riesgo de desarrollar cirrosis hepatica, CHC, u otras complicaciones extra-hepaticas puede ser relativamente elevado a medio y largo plazo (Grebely, deVlaming, Duncan, Viljoen, y Conway, 2008), sobre todo si tenemos en cuenta que la mayoria de los pacientes con historia de abuso de sustancias se infectan a edades muy tempranas.

En la infeccion cronica por el VHC, la alteracion histologica hepatica se caracteriza por la necro-inflamacion portal y lobular. En la tercera parte de los pacientes, la infeccion tendra un curso indolente pero en el resto, habra un progresivo aumento de la fibrosis hepatica, que se manifestara clinicamente con el paso de los anos (Afdhal, 2004). La progresion de la fibrosis hepatica no es un proceso lineal ya que factores como la infeccion por el VIH, el VHB, consumo de alcohol y otros pueden acelerarla (Muga et al., 2012; Carton et al., 2011); edad en el momento de la infeccion, sexo masculino, obesidad, diabetes mellitus y esteatosis hepatica tambien se han visto asociadas a mayor riesgo de progresion de la fibrosis (Afdhal, 2004; Poynard, Bedossa, y Opolon, 1997). Una vez establecida la fase final de la enfermedad o cirrosis hepatica, la probabilidad de presentar una descompensacion es del 5% el primer ano y del 30% a los 10 anos del diagnostico, mientras que el riesgo de aparicion de CHC es del 1-4% por ano (Dore, Freeman, Law, y Kaldor, 2003; Raimondi, Bruno, Mondelli, y Maisonneuve, 2009). En lineas generales se acepta que la mediana de la supervivencia de pacientes que presentan una primera descompensacion de la cirrosis hepatica es de 5 anos (Dore et al., 2003).

Diagnostico y evaluacion

La fibrosis hepatica es el principal marcador de evolucion de la enfermedad hepatica (Thomas y Seeff, 2005). La biopsia hepatica se ha considerado el metodo mas fiable para evaluar la presencia de fibrosis en el higado y, por tanto, la herramienta idonea para seleccionar los candidatos al tratamiento. Sin embargo, en los ultimos anos se han desarrollado metodos no invasivos para evaluar el grado de fibrosis sin necesidad de un procedimiento invasivo. Elastografia hepatica y marcadores bioquimicos adquieren cada vez mayor protagonismo en la evaluacion de la fibrosis hepatica (de Ledinghen et al., 2006; Sanvisens et al., 2009; Sterling et al., 2006; Wai et al., 2003).

Entre los marcadores bioquimicos, el indice APRI (AST-to-Platelet Ratio Index) o el FIB-4 (edad, AST, ALT y plaquetas) son faciles de usar, ya que para su calculo se necesitan parametros que forman parte de la evaluacion clinica rutinaria de un paciente con enfermedad hepatica. Estos dos indices son los que recomienda la Organizacion Mundial de la Salud (OMS) en la recientemente publicada Guia sobre diagnostico, atencion y tratamiento a pacientes con VHC (World Health Organization, 2014) y ademas, han sido validados en pacientes con VHC (Mallet et al., 2009; Vallet-Pichard et al., 2007; Wong et al., 2010), si bien su validez en pacientes con consumo cronico de alcohol estaria limitada.

Conocer la magnitud del dano hepatico en este grupo de pacientes con hepatitis cronica C es de vital importancia ante la llegada de nuevos regimenes terapeuticos. En nuestra experiencia, la prevalencia de fibrosis hepatica moderada y severa es del 40% y 17%, respectivamente en esta poblacion (Sanvisens et al., 2011).

Situacion actual del tratamiento de la hepatitis C en pacientes con abuso de sustancias

La prevalencia de infeccion por VHC en personas que consumen drogas por via parenteral es muy elevada (50%-80%) y, los genotipos mas comunes son el 1a, 1b y 3 (Robaeys et al., 2013). A pesar de tratarse de la poblacion de mayor riesgo de infeccion, estos pacientes suelen quedar al margen del tratamiento de la hepatitis cronica C. Segun la Union Europea, el numero de pacientes tratados de hepatitis C no alcanza el 0,5% de las 700.000 personas que actualmente reciben tratamiento de metadona (Observatorio Europeo de las Drogas y las Toxicomanias, 2011).

En general, el tratamiento vigente de la hepatitis C se mantiene entre 24 y 48 semanas y los farmacos empleados son Interferon-alfa pegilado (PEG-IFN), Ribavirina (RBV) y Boceprevir o Telaprevir, estos ultimos como inhibidores de la proteasa de primera generacion (World Health Organization, 2014). El tratamiento con PEG-IFN consiste en la administracion de inyecciones subcutaneas semanales y los efectos secundarios son bien conocidos incluyendo sintomas gripales, ansiedad, depresion, astenia y citopenias que, si afectan a la serie roja, pueden requerir eritropoyetina (Chung, 2012). El objetivo final del tratamiento de la hepatitis C es la erradicacion del virus; la llamada respuesta viral sostenida (RVS) indica que el RNA del VHC se mantiene indetectable a los 6 meses de finalizar el tratamiento. Por sus efectos adversos, en mayor medida sobre el SNC, una parte de los pacientes que reciben PEG-IFN deben anadir antidepresivos al tratamiento de la hepatitis C.

En pacientes con historia de abuso de sustancias, la realidad asistencial del tratamiento de la hepatitis C es que solo una minoria son tratados (Grebely et al., 2008; Mehta et al., 2008); los motivos para no recibir el tratamiento son multiples aunque tres de ellos destacan sobre los demas: riesgo de mal cumplimiento terapeutico, de reinfeccion y de agravamiento de la co-morbilidad psiquiatrica (Edlin, 2002; Kramer et al., 2011).

A nivel asistencial todavia existen otras barreras para acceder al tratamiento de la hepatitis cronica C como la falta de entornos asistenciales adecuados para el tratamiento de esta poblacion o la insuficiente formacion clinica en el manejo de la enfermedad hepatica y en el abuso de sustancias (Grebely y Tyndall, 2011; Litwin et al., 2007; Reimer y Haasen, 2009). En nuestro pais, aunque el cribado de la prueba diagnostica es elevado, la evaluacion del abuso de sustancias y de la co-morbilidad medica y psiquiatrica es heterogenea y concierne a varias especialidades; ademas, los circuitos asistenciales de evaluacion de la toxicomania, psicopatologia y hepatopatia son interminables y en nada favorecen la retencion de estos pacientes en el sistema sanitario. La falta de conocimiento de la enfermedad por los propios afectados y de soporte social tambien se han descrito como barreras de acceso al tratamiento (Alavi et al., 2013). La tabla 1 muestra un resumen de las principales barreras de acceso al tratamiento del VHC.

Diferentes estudios indican que el consumo de alcohol o de sustancias no suele comprometer la adherencia al tratamiento de la hepatitis C ni implica peores tasas de respuesta al mismo, si bien se ha observado una mayor dificultad para completarlo (Anand et al., 2006; Grebely y Tyndall, 2011; Hellard, Sacks-Davis, y Gold, 2009). Una revision sistematica reciente sobre usuarios de drogas elegibles para el tratamiento del VHC con PEG-IFN y RBV mostro una RVS global del 56% (37% para genotipos 1/4 y 67% para 2/3) (Aspinall et al., 2013); estas cifras son algo inferiores a las de la mayoria de ensayos clinicos para estos farmacos, si bien son similares a las descritas en dos estudios de efectividad del tratamiento (39%-46% para genotipo 1 y 70%-84% para genotipo 2/3) (Borroni et al., 2008; Innes et al., 2012). En esta misma revision sistematica (Aspinall et al., 2013) se observo una elevada adherencia al tratamiento, del 83%, algo superior a la mostrada en pacientes no usuarios de drogas (McHutchison et al., 2002; Ravi, Nasiri Toosi, Karimzadeh, Ahadi-Barzoki, y Khalili, 2013), si bien las diferencias observadas se explicarian por la propia definicion de adherencia; ademas, la tasa de reinfeccion por VHC fue moderada (2.4 por 100p-a) sugiriendo que esta tiene poco impacto en la efectividad del tratamiento a largo plazo (Aspinall et al., 2013).

Cambio de paradigma; nuevos tratamientos para la hepatitis C libres de IFN

El creciente numero de pacientes que necesitaran tratamiento de la hepatitis C, las contraindicaciones y efectos secundarios del tratamiento actual con IFN y el mejor conocimiento del ciclo vital del VHC han llevado a desarrollar nuevos farmacos. La aparicion de regimenes de tratamiento sin IFN va a suponer un avance fundamental para aumentar el acceso al tratamiento. Todo apunta a que los pacientes con historia de abuso de sustancias y hepatitis C no van a ser la excepcion.

Este cambio de paradigma en el tratamiento de la hepatitis C empieza a ser una realidad desde la aprobacion en los EE.UU de los inhibidores de la proteasa de segunda generacion y del primer inhibidor de la polimerasa del VHC en 2013. El primer paso en la direccion de los nuevos regimenes de tratamiento se dio a partir del 2011 con la introduccion de inhibidores de la proteasa del VHC de primera generacion (Telaprevir y Boceprevir).

La segunda generacion de inhibidores de la proteasa aporta mayor barrera de resistencia farmacologica, menos efectos adversos y actividad farmacologica ampliada contra otros genotipos del VHC (Wendt et al., 2014). Proteasa y polimerasa son proteinas clave en el ciclo vital del VHC, solo conocido con detalle en los ultimos anos. Varias companias farmaceuticas han analizado dianas terapeuticas en zonas clave del virus. La identificacion de estas nuevas dianas terapeuticas, basadas en atacar proteinas no estructurales del virus, ha permitido reconocer mas de 10 Antivirales de Accion Directa (AAD). Estos agentes incluyen inhibidores de la proteasa NS3/4A, inhibidores de la polimerasa NS5B, inhibidores del complejo NS5A, inhibidores de la ciclofilina e inhibidores directos de la polimerasa del RNA viral. Antivirales frente al VHC como Sofosbuvir (Lawitz y Gane, 2013) o Simeprevir (Asselah y Marcellin, 2014) aprobados por la FDA a finales de 2013 y otros como Daclatasvir (Gentile et al., 2013), Asunaprevir (Suzuki et al., 2013), Faldaprevir, Deleobuvir (Zeuzem et al., 2013) o Ledipasvir (Link et al., 2014) son de alta eficacia y pretenden erradicar el virus mediante regimenes terapeuticos orales de 12 semanas en algunos genotipos y con escasos efectos adversos (Gane et al., 2014; Sulkowski et al., 2014). En este sentido, la reciente Guia publicada por la OMS en Abril de 2014 ya incluye en sus recomendaciones los dos farmacos aprobados por la FDA (sofosbuvir, simeprevir), recientemente incorporados en Espana al Sistema Nacional de Salud y preve una actualizacion periodica en funcion de la aparicion de nuevas licencias (World Health Organization, 2014). Si bien los ensayos clinicos de los nuevos farmacos no se han realizado en pacientes consumidores de drogas por via parenteral, la Guia de la OMS recomienda no excluir a esta poblacion del tratamiento (maxima recomendacion); asimismo, la OMS recomienda detectar consumos de alcohol elevados y ofrecer a los pacientes una intervencion para reducir dicho consumo.

Cabe senalar que son necesarios estudios para analizar las posibles interacciones farmacologicas entre los AAD y los farmacos mas utilizados en el tratamiento del abuso de sustancias. Simeprevir y faldaprevir se metabolizan por el sistema citocromo P450 y es posible que muestre interacciones farmacocineticas con farmacos como metadona y buprenorfina (Mauss y Klinker, 2013).

En todo caso, las mejoras en el tratamiento farmacologico de la hepatitis C posiblemente se deban acompanar de cambios en la atencion clinica a los pacientes con abuso de sustancias; diagnostico de la infeccion y evaluacion clinica seran importantes para priorizar el tratamiento de los mas necesitados; en ese sentido, profesionales de atencion primaria y del tratamiento del abuso de sustancias deberan jugar un papel clave para que estos pacientes se evaluen clinicamente, se traten de la enfermedad y obtengan resultados terapeuticos similares a los que se esperan obtener en pacientes sin abuso de sustancias. Establecer un modelo mas inclusivo de atencion al paciente con hepatitis C asociada al abuso de sustancias se hara necesario ante el cambio que se avecina.

Conclusion

La importante carga de enfermedad hepatica y la elevada incidencia de infeccion por VHC en pacientes con abuso de sustancias hacen necesario mejorar el diagnostico y tratamiento de esta poblacion. Aparecen farmacos innovadores que atacan directamente proteinas responsables de formar el complejo de replicacion viral del VHC; la combinacion de dos o mas de estos farmacos puede resultar muy eficaz contra la mayoria de genotipos del VHC y en la mayoria de situaciones clinicas, incluyendo la cirrosis hepatica. Con la aparicion de farmacos tan eficaces y tolerables es probable que debamos revisar el modelo asistencial actual y orientarlo hacia uno mas agil e integrador que trate al mayor numero posible de pacientes infectados por el VHC. En la Figura 1 se muestra una aproximacion a un modelo asistencial multidisciplinar. En este mismo sentido, optimizar la prevencion, diagnostico, evaluacion y acceso a tratamiento de la hepatitis cronica C es prioritario. Para ello son diversos los abordajes que pueden plantearse, como por ejemplo:

--Identificar barreras y necesidades percibidas en la atencion primaria y centros de atencion a las drogodependencias y desarrollar tareas educativas para ampliar el conocimiento de la hepatitis cronica C,

--Revisar el proceso de evaluacion clinica de pacientes con hepatitis C asociada al abuso de sustancias,

--Categorizar la situacion clinica de los pacientes: nuevo diagnostico, previamente tratados, grado de enfermedad hepatica,

--Identificar pacientes a riesgo de infeccion por VHC y prevenir la infeccion mediante una intervencion breve y cribado de hepatitis viricas.

--Ofrecer tratamiento del abuso de alcohol o de drogas a los pacientes con hepatitis cronica C.

Financiacion

Trabajo parcialmente financiado por el Ministerio de Ciencia e Innovacion (RETICS RD12/0028 y RD12/0028/0006), Ministerio de Sanidad (EC11-042 y PNSD 2014|042); con la colaboracion del Programa Fellowship de Gilead Espana.

Recibido: Abril 2014; Aceptado: Noviembre 2014

Enviar correspondencia a:

Dr. Roberto Muga. Servicio de Medicina Interna. Hospital Universitari Germans Trias i Pujol. 08916 Badalona.

Email: rmuga.germanstrias@gencat.cat

Conflicto de intereses

No existen conflictos de intereses.

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ROBERTO MUGA *, PAOLA ZULUAGA *, ARANTZA SANVISENS *, INMACULADA RIVAS **, DANIEL FUSTER *, FERRAN BOLAO ***, JORDI TOR *, RED DE TRASTORNOS ADICTIVOS-RTA

* Servei de Medicina Interna. Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona.

** Centro de Atencion y Seguimiento de las drogodependencias (CAS DELTA) y Bus Intermunicipal de Metadona (BIM). Institut Municipal de Serveis Personals, Badalona. *** Servei de Medicina Interna. Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat.

Tabla 1.
Principales dificultades en el acceso ai tratamiento de la
hepatitis cronica C en pacientes con abuso de sustancias

Del sistema sanitario               De los pacientes

Conocimiento insuficiente           Conocimiento inadecuado
    de la hepatitis C:                  de la hepatitis C:
  --Formacion limitada                --Educacion limitada
  --Inexperiencia en la                 en relacion al VHC
    evaluacion del dano hepatico
  --Baja percepcion de la           Baja percepcion de la
      necesidad de tratamiento:         necesidad de tratamiento:
    * Enfermedad asintomatica         --Enfermedad asintomatica
    * Desconocimiento del             --Desconocimiento del
      estadio de la fibrosis            estadio de la fibrosis
    * Otras co-morbilidades           --Otras co-morbilidades
      prioritarias                      prioritarias

Percepciones erroneas acerca        Percepciones erroneas
    del tratamiento:                    acerca del tratamiento:
  --Alto riesgo/beneficio             --Alto riesgo/beneficio
  --Pacientes con abuso de            --Temor a la complejidad
      sustancias son malos              del tratamiento y efectos
      candidatos:                       secundarios
    * Adiccion/Enfermedad
      psiquiatrica                  Poca retencion en los
    * Mala adherencia                   circuitos asistenciales:
                                      --Adiccion/Enfermedad
Perdidas de entrada o entradas        --Acceso inadecuado a los
retardadas en el circuito               circuitos asistenciales
asistencial para la hepatitis C       --Estigmas/peores
                                        condiciones sociales


Hepatitis C associated with substance abuse: ever closer to a treatment without Interferon

Treatment of chronic hepatitis C will change in the coming years. This change will occur due to the introduction of medication that is more efficacious, better tolerated, that scarcely generates any pharmacological resistance, and that is administered during shorter periods of time. Studies published since 2012 have revealed the efficacy of some of these drugs, and if this is indeed the case, it indicates the need to expand such treatment to a larger numbers of patients; detection of the infection and assessment of liver disease will be relevant if it is confirmed that infection cure can reach levels greater than 90%, regardless of viral genotype or of previous treatment failure. When the efficacy of the new therapies is confirmed in clinical trials, treatment of the illness will be generalized, and subsequently the population effectiveness of those therapies will be demonstrated. But clinical efficacy and population effectiveness are not the same thing; the latter is necessary to reduce the enormous burden of hepatitis C virus (HCV) on society. What has all this got to do with substance users? A great deal. In Western countries, two out of three new HCV infections occur in individuals who have injected or are injecting drugs, but this population--not by coincidence - receives the least treatment for HCV. The reasons why people with a history of substance abuse do not receive HCV treatment are quite diverse, and are described in this review, but one of the most widely cited is their poor tolerance to Interferon, an immunomodulatory drug that has formed part of the core of HCV treatment for some two decades. But if the advantages of the new medications are confirmed, patients with substance-use-related HCV will be more likely to seek treatment, as occurred after the irruption of the highly effective antiretroviral drugs for the treatment of human immunodeficiency virus (HIV).

Epidemiology of hepatitis C

HCV infection is one of the principal causes of liver disease worldwide (Shepard, Finelli, & Alter, 2005). Prevalence of the infection in the world population, disregarding marked regional differences, is close to 3%--equivalent to some 185 million people. It is estimated that 10 million individuals infected by HCV are, or have been, injection drug users (IDUs) (Nelson et al., 2011; Mohd Hanafiah, Groeger, Flaxman, & Wiersma, 2013).

Globally, prevalence of the infection is higher in men, in people aged 30 to 49, and in those with low socio-economic status (Alter, 2007). Risk factors for infection vary, but transfusions (blood and/or blood derivatives) carried out before 1992, the use of re-usable healthcare materials and injection drug use are still the most important ones (Des Jarlais et al., 2003; Memon & Memon, 2002). In the USA there are over 2 million injection drug users, and the incidence of HCV infection is estimated at between 8% and 25% annually among the youngest of these. Data from the US also indicate that 30,000 new cases of infection are diagnosed each year, and that the incidence of infection is greater in new drug users and during the first year of drug use (Nelson et al., 2011; Page et al., 2009). It has been demonstrated that the transmission of HCV is 10 to 15 times higher than that of HIV (Page et al., 2009; Page, Morris, Hahn, Maher, & Prins, 2013), which reveals just how easily it can be transmitted in this population.

Also, people with alcohol use disorder present higher prevalence of HCV infection than the general population. Up to 20% of a series of 700 patients who sought treatment for alcoholism in the Barcelona were infected with HCV, according to a recent study (Rivas et al., 2013).

HCV is the principal cause of liver transplant and of hepatocellular carcinoma (HCC) in Western countries (Freeman et al., 2008; Yang et al., 2011). In fact, HCC and cirrhosis of the liver have increased in recent years among people infected with HCV, and it is forecasted that incidence of the two diseases will increase significantly in the coming decades (Mehta et al., 2010; Rein et al., 2011). A study in the US highlighted the growing number of deaths among those infected with HCV, which is now higher than that for deaths attributed to HIV/AIDS (Ly et al., 2012); the same study indicated that deaths related to HCV occur mainly in the age group 45 to 64 (Ly et al., 2012), and this has led health authorities in the US to recommend that the general population in this age group should be screened for HCV. It has been estimated, moreover, that a million people with HCV infection in the US will die as a result of complications related to the illness if they go untreated (Rein et al., 2011, 2012).

In Spain, estimates reveal that the number of people with HCV infection is around 430,000, with people older than 50 showing the highest prevalence of infection. The explanation for this can probably be found in the explosion of intravenous heroin use that occurred among young people in this country from the early 1980s onwards (Cornberg et al., 2011).

Natural history of hepatitis C

HCV causes an acute infection that remains asymptomatic in the majority of cases. Around 20-25% of substance-abusing patients will eliminate the viremia spontaneously in the 6 months following infection (Grebely et al., 2012; Page et al., 2009). Among the factors associated with spontaneous cure of the infection are being a woman, infection through genotype 1 (the most common in our context), and being a homozygote for the Interleukin-28 (IL-28B) gene, a gene that codes the Interleukin-23 protein, involved in the replication of HCV (Liu, Fisher, Thomas, Cox, & Ray, 2012; Page et al., 2009). On the other hand, 75-80% of those infected will develop a chronic infection, and the risk of developing cirrhosis, HCC, or other extra-hepatic complications may be relatively high in the medium and long term (Grebely, deVlaming, Duncan, Viljoen, & Conway, 2008), especially if we take into account that the majority of patients with a history of substance abuse become infected at a very early age.

In chronic HCV infection, hepatic histological alteration is characterized by portal and lobular necro-inflammation. In a third of patients, the infection will follow an indolent course, but in the rest there will be a progressive increase of hepatic fibrosis, which will manifest clinically on the long term (Afdhal, 2004). The progression of hepatic fibrosis is not a linear process, since factors such as HIV infection, HBV, alcohol use and others can accelerate it (Muga et al., 2012; Carton et al., 2011); age at the time of infection, male sex, obesity, diabetes mellitus and hepatic steatosis have also been associated with greater risk of fibrosis progression (Afdhal, 2004; Poynard, Bedossa, & Opolon, 1997). Once established the final phase of the disease, or liver cirrhosis, the probability of presenting a decompensation is 5% the first year and 30% ten years after diagnosis, whilst the risk of occurrence of HCC is 1-4% per year (Dore, Freeman, Law, & Kaldor, 2003; Raimondi, Bruno, Mondelli, & Maisonneuve, 2009). In general, it is accepted that median survival of patients presenting a first decompensation of liver cirrhosis is 5 years (Dore et al., 2003).

Diagnosis and assessment

Hepatic fibrosis is the principal marker of the course of liver disease (Thomas & Seeff, 2005). Liver biopsy has been considered the most reliable method for assessing the presence of fibrosis, and hence the most suitable tool for selecting candidates for treatment. However, recent years have seen the introduction of new methods for assessing fibrosis levels without the need for an invasive procedure, with elastography and biochemical markers playing an increasingly important role (de Ledinghen et al., 2006; Sanvisens et al., 2009; Sterling et al., 2006; Wai et al., 2003).

Among the biochemical markers, the APRI (AST-to-Platelet Ratio Index) or the FIB-4 (age, platelets, AST, ALT) are easy to use, since their calculation requires parameters that are employed in the routine clinical assessment of patients with liver disease. These two indexes are recommended by the World Health Organization (WHO) in the recently-published Guidelines for the screening, care and treatment of persons with HCV (World Health Organization, 2014); moreover, they have been validated in patients with HCV infection (Mallet et al., 2009; Vallet-Pichard et al., 2007; Wong et al., 2010), though their validity in chronic alcohol users might be limited.

Knowing the magnitude of hepatic damage in this group of patients with chronic hepatitis C is of crucial importance with the advent of new therapeutic regimens. In our experience, the prevalence of moderate and severe hepatic fibrosis is 40% and 17%, respectively, in this population (Sanvisens et al., 2011).

Current situation of hepatitis C treatment in substance-abusing patients

The prevalence of HCV infection in injection drug users is very high (50%-80%), and the most common genotypes are 1a, 1b and 3 (Robaeys et al., 2013). Despite the fact of being the population at greatest risk of infection, these patients tend not to receive treatment for chronic hepatitis C. According to European Union figures, the number of patients treated for hepatitis C does not reach 0.5% of the 700,000 people currently receiving methadone treatment (European Monitoring Centre for Drugs and Drug Addiction 2011).

In general, current standard treatment for hepatitis C is received over a period of 24 to 48 weeks, and the drugs employed are pegylated Interferon (PEG-IFN), Ribavirin (RBV) and Boceprevir or Telaprevir, these last two as first-generation protease inhibitors (World Health Organization, 2014). Treatment with PEG-IFN consists in the administration of weekly subcutaneous injections, and the side-effects are well-known and include flu-like symptoms, anxiety, depression, asthenia and cytopenias which, if they affect the erythrocyte series, may require treatment with erythropoietin (Chung, 2012). The ultimate goal of hepatitis C treatment is the eradication of the virus; the so-called sustained viral response (SVR) defined as undetectable HCV RNA 6 months after the end of treatment. Given its adverse effects, mainly on the Central Nervous System, a portion of patients receiving PEG-IFN should add antidepressants to their hepatitis C treatment.

In patients with a history of substance abuse, the healthcare reality of hepatitis C treatment is that only a minority are treated (Grebely et al., 2008; Mehta et al., 2008); the reasons for not receiving treatment are many, but three of them stand out: risk of poor therapeutic compliance, risk of reinfection and risk of exacerbation of psychiatric comorbidity (Edlin, 2002; Kramer et al., 2011).

At the care level there are still other barriers to access treatment for chronic hepatitis C, such as the lack of care contexts for the treatment of this population or the insufficient clinical training in the management of liver disease and substance abuse (Grebely & Tyndall, 2011; Litwin et al., 2007; Reimer & Haasen, 2009). Here in Spain, although the rate of diagnostic screening is high, the assessment of substance abuse and of medical and psychiatric comorbidity is somewhat heterogeneous, and involves various specialities; moreover, the care protocols for the assessment of drug dependence, psychopathology and liver disease are long-winded, and certainly do not favour the retention of these patients in the health system. Lack of knowledge about the illness by patients themselves and lack of social support have also been cited as barriers to acceding to treatment (Alavi et al., 2013). Table 1 includes a summary of the principal barriers to access to HCV treatment.

Various studies indicate that alcohol or substance use does not usually affect adherence to hepatitis C treatment, and nor does such abuse imply poorer response rates, even if more difficulties for treatment completion have been observed (Anand et al., 2006; Grebely & Tyndall, 2011; Hellard, Sacks-Davis, & Gold, 2009). A recent systematic review on drug users eligible for HCV treatment with PEG-IFN and RBV yielded a global SVR of 56% (37% for genotypes 1/4 and 67% for 2/3) (Aspinall et al., 2013); these figures are somewhat lower than those reported in most clinical trials for these drugs, but are similar to those described in two studies on the effectiveness of the treatment (39%-46% for genotype 1 and 70%-84% for genotype 2/3) (Borroni et al., 2008; Innes et al., 2012). In that same systematic review (Aspinall et al., 2013) a high level of treatment adherence was observed, 83%, somewhat higher than that shown in patients not abusing substances (McHutchison et al., 2002; Ravi, Nasiri Toosi, Karimzadeh, Ahadi-Barzoki, & Khalili, 2013)--though it should be borne in mind that the differences observed would be explained by the way adherence is defined. Moreover, the HCV reinfection rate was moderate (2.4 per 100 person-years), suggesting that this has little effect on long-term treatment effectiveness (Aspinall et al., 2013).

Paradigm shift: new treatments for hepatitis C without IFN

The growing numbers of patients that will need hepatitis C treatment, the contraindications and side effects of current treatment with IFN, and improved knowledge of the HCV life cycle have led to the development of new drugs. The advent of treatment regimens without IFN will represent a fundamental step forward in increasing treatment access. Everything points to the fact that patients with a history of substance abuse and hepatitis C will be no exception.

This paradigm shift in the treatment of hepatitis C begins to become a reality after the approval in the USA of the second-generation protease inhibitors and of the first HCV polymerase inhibitor in 2013. The first step in the direction of new treatment came after 2011, with the introduction of first-generation HCV protease inhibitors (Telaprevir and Boceprevir).

Second-generation protease inhibitors provide a better barrier with regard to pharmacological resistance, have fewer adverse effects, and show enhanced pharmacological activity against other HCV genotypes (Wendt et al., 2014). Protease and polymerase are key proteins in the HCV life cycle, only understood in detail in the last few years. Various pharmaceutical companies have analyzed therapeutic targets in key areas of the virus. The identification of these new therapeutic targets, based on attacking non-structural proteins of the virus, has led to the recognition of more than 10 Direct Antiviral Agents (DAAs). These agents include inhibitors of the protease NS3/4A, inhibitors of the polymerase NS5B, inhibitors of the NS5A complex, inhibitors of cyclophilin and direct inhibitors of RNA viral polymerase. Antivirals against HCV and Sofosbuvir (Lawitz & Gane, 2013) or Simeprevir (Asselah & Marcellin, 2014) approved by the FDA at the end of 2013, and others such as Daclatasvir (Gentile et al., 2013), Asunaprevir (Suzuki et al., 2013), Faldaprevir, Deleobuvir (Zeuzem et al., 2013) or Ledipasvir (Link et al., 2014), are highly efficacious, and set out to eradicate the virus through oral therapeutic regimens of 12 weeks in some genotypes, and with few adverse effects (Gane et al., 2014; Sulkowski et al., 2014). In this regard, the recent Guide published by the WHO in April 2014 already includes in its recommendations the two drugs approved by the FDA (sofosbuvir, simeprevir) and recently incorporated into the Spanish National Health System, and anticipates regular updates as new licences are granted (World Health Organization, 2014). Even though clinical trials on the new drugs have not been carried out on substance-injecting patients, the WHO Guide recommends not excluding this population from treatment (priority recommendation); likewise, the WHO recommends detecting heavy drinkers and offering such patients interventions for reducing their intake.

We should point out the need for studies that analyze potential pharmacological interactions between DAAs and the drugs most widely used in the treatment of substance abuse. Simeprevir and faldaprevir are metabolized by the cytochrome P450 system, and it is possible that they show pharmacokinetic interactions with drugs such as methadone and buprenorphine (Mauss & Klinker, 2013).

In any case, improvements in the pharmacological treatment of hepatitis C should perhaps be accompanied by changes in the clinical care model applied to substance-abusing patients; diagnosis of the infection and clinical assessment are of great importance in the prioritization of treatment for the most in need. Health care professionals involved in the treatment of substance abuse should play a key role in ensuring that these patients are clinically evaluated, are treated for their illness, and obtain therapeutic results similar to those we would expect to obtain in patients without substance abuse. Establishing a more inclusive care model for patients with substance-use-related hepatitis C will become necessary in the face of all the imminent changes.

Conclusion

The substantial burden of liver disease and the high incidence of HCV infection in substance-abusing patients make it necessary to improve diagnosis and treatment in this population. New, innovative drugs are appearing that directly attack proteins responsible for forming the viral replication complex of HCV; the combination of two or more of these drugs can be highly efficacious against the majority of HCV genotypes and in the majority of clinical situations, including liver cirrhosis. With the introduction of such efficacious and well-tolerated drugs, there is a need to review the current care model and replace it with a more flexible and integrated one that attempts to treat the highest possible number of HCV-infected patients. Figure 1 shows a first approach to a multidisciplinary care model. Likewise, optimizing the prevention, diagnosis, assessment and treatment access of chronic hepatitis C is high-priority. The approaches that can be proposed are diverse, and would include:

--Identifying perceived barriers and needs in primary care and drug-dependence clinics and developing educational activities for improving knowledge about chronic hepatitis C,

--Reviewing the process of clinical assessment of patients with hepatitis C associated with substance abuse,

--Categorizing patients' clinical situation: new diagnosis, previously treated, stage of liver disease, etc.

--Identifying patients at risk of HCV infection and preventing infection through a brief intervention and screening for viral hepatitis.

--Offering treatment for alcohol or drug abuse to patients with chronic hepatitis C.

Received: April 2014; Accepted: November 2014

Address for correspondence:

Dr. Roberto Muga. Servicio de Medicina Interna. Hospital Universitari Germans Trias i Pujol. 08916 Badalona, Spain. E-mail: rmuga.germanstrias@gencat.cat

Funding

Work partially funded by the Spanish Ministries of Science and Innovation (RETICS RD12/0028 and RD12/0028/0006) and Health (EC11-042), with the collaboration of the Gilead Espana Fellowship Programme.

Conflicts of interests

There are no conflicts of interests.

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Roberto Muga *, Paola Zuluaga *, Arantza Sanvisens *, Inmaculada Rivas **, Daniel Fuster *, Ferran Bolao ***, Jordi Tor *, Red de Trastornos Adictivos-RTA

* Servei de Medicina Interna. Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona.

** Centro de Atencion y Seguimiento de las Drogodependencias (CAS DELTA) y Bus Intermunicipal de Metadona (BIM). Institut Municipal de Serveis Personals, Badalona. *** Servei de Medicina Interna. Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat.

Table 1.
Major difficulties in access to treatment of chronic hepatitis C
in patients with substance abuse

In the health system                In patients

Insufficient knowledge              Inadequate knowledge
    of hepatitis C:                     of hepatitis C:
  --Limited training                  --Limited Education in
  --Inexperience in the                 relation to HCV
    evaluation of liver damage
  --Low awareness of the            Low perceived need for
      need for treatment:               treatment:
    * asymptomatic disease            --Asymptomatic disease
    * Ignorance of the stage          --Ignorance of the stage
      of fibrosis                       of fibrosis
    * Other priority co-              --Other priority co-
      morbidities                       morbidities
                                    Misperceptions about
Misperceptions about treatment:         treatment:
  --High risk/benefit                 --High risk/benefit
  --Patients with substance           --Fear of the complexity
      abuse are poor candidates:        of treatment and side effects
    * Addiction/psychiatric         Poor retention in care circuits:
      illness                         --Addiction/psychiatric illness
    * Poor adherence                  --Inadequate access to
                                        care circuits
Lost entries or delayed               --Stigma/poorer social
  entries in the care circuit           conditions
  for hepatitis C
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