(CRITICAL APPRAISAL SKILLS PROGRAMME) PROGRAMA DE HABILIDADES EN LECTURA CRITICA

Entendiendo la evidencia sobre la eficacia clínica

Taller CASPin Habilidades en Lectura Crítica

Ensayo Clínico

(Lima, 23 de Mayo de 2012)

MATERIAL DEL TALLER

Artículo de trabajo:

Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection. N Engl J Med 2011; 364: 1207-17.

© CASPe

"LECTURA CRÍTICA DE LA LITERATURA"1

¡Bienvenido!

Este material está diseñado para ayudarte a participar en el taller CASPe de lectura crítica de la literatura que se celebrará el día 23 de Mayo 2012 en Lima. Contiene: • Una introducción a la lectura crítica y los objetivos del taller • El horario (página verde) • El "escenario" para el taller (página amarilla) • El artículo que se criticará en el taller "Boceprevir for

Previously Treated Chronic HCV Genotype 1 Infection". (Páginas blancas).

• Un glosario general (en la página azul) • Algunas direcciones de interés. Actividades esenciales antes del taller: • Por favor, lee el material antes del taller y ponte en la situación

del "escenario". Esto te llevará menos de una hora y sacarás más provecho del taller si lo haces. Si hay algo que no entiendas, búscalo en el glosario, si no aparece en él ¡no te preocupes! Probablemente no es muy importante, pero se podría discutir en el taller.

Si necesitas más información, puedes llamar a:

• Juan B. Cabello. Coordinación General del programa CASPe. E-mail: jbcabello@redcaspe.org

• WEB CASP España: www.redcaspe.org.

1 Este material ha sido desarrollado por el equipo de CASP en Oxford y traducido por el equipo CASP español (de modo particular por el grupo de la Unidad de Bioestadística Clínica del Hospital Ramón y Cajal)

© CASPe

¿Qué es el CASP?

CASP (Critical Appraisal Skills Programme) (Programa de habilidades en lectura crítica) es un programa para ayudar a los "decisores" del Servicio de Salud Inglés a adquirir habilidades para hacer lectura crítica y obtener así la evidencia científica necesaria para las decisiones. Trabaja con programas locales de promoción de cuidados de salud basados en la evidencia y colabora con el Centre for Evidence-Based Medicine (Centro de la Medicina Basada en la Evidencia) de la Universidad de Oxford, que enseña a los clínicos cómo tomar decisiones basadas en la evidencia. En España existe un grupo CASP (CASP España - CASPe) radicado en Alicante, que usa la aproximación CASP a la lectura crítica y que forma parte de una organización internacional llamada CASP Internacional (CASPi), que difunde este programa por todo el mundo.

¿Por qué la lectura crítica?

Hay un interés generalizado en hacer más eficaces a los servicios de salud, para maximizar la mejoría de salud que ofrecen. Pero ¿Cómo sabemos qué servicios son verdaderamente eficaces? ¿Cómo saben los financiadores qué tratamientos y cuidados de salud deben financiar? ¿Cómo deciden los clínicos que un tratamiento concreto es útil? Si queremos hacer lo mejor para nuestros pacientes, y para la colectividad necesitamos basar nuestras decisiones en evidencias2. Pero ¿Cómo conseguirlo ante la proliferación de literatura? Una solución es seleccionar el tipo de artículo adecuado, y en ese sentido los ensayos clínicos aleatorizados pueden ser una excelente fuente de evidencia. Sin embargo, ¿Cómo saber que el ensayo clínico aleatorizado que hemos conseguido es válido, y aplicable en nuestro medio? Aquí es donde la lectura crítica puede ayudar. Las habilidades en lectura crítica te permiten evaluar sistemáticamente los resultados de los trabajos publicados, su validez su relevancia y su aplicabilidad. durante el taller aprenderás cómo hacer lectura crítica de un ensayo clínico.

2 N.T Se ha preferido traducir en todo el texto evidence por evidencia debido a que es ya un término ampliamente aceptado. Queremos, sin embargo, resaltar que, el sentido en que se usa es cosa científicamente probada.

© CASPe

Objetivos del taller

Al final del taller serás capaz de:

1. Comprender la necesidad de la lectura crítica.

2. Entender los términos claves de un ensayo clínico.

3. Explicar porqué estos estudios son tan importantes para

fundamentar las decisiones que tomamos.

4. Aumentar la confianza acerca de la propia capacidad para

hacer lectura crítica.

5. Decidir sobre la utilidad e interés de la aproximación

pedagógica de "CASP".

© CASPe

Horario 15:30 - 15:45 Presentación del Programa Juan Cabello Equipo CASPe País Vasco 15:45 - 17:00 Introducción a la lectura crítica Juan Cabello Equipo CASPe País Vasco 17:00 - 18:15 Lectura crítica en pequeños grupos 18:15 - 18:45 Descanso 18:45 - 20:00 Plenario - Síntesis y Reflexión sobre la lectura

crítica

Carlos Cuello Equipo CASPe País Vasco

20:00 – 20:15 Evaluación del taller, resultados del voto etc. Comentarios, conclusiones. Nota: Éste es un taller interactivo y es muy

importante la puntualidad. Por favor, ayúdanos a mantener el horario.

© CASPe

ESCENARIO CLÍNICO

Eres un médico especialista en Digestivo que estás atendiendo una consulta general de la especialidad en el ambulatorio. Recibes en tu consulta a Julio que es un paciente de 47 años al que se le sigue desde hace tiempo por una hepatopatía crónica por virus C, que como es habitual en España tiene un genotipo 1. Previamente había sido tratado en la consulta monográfica con interferón y ribavirina sin respuesta, por lo que fue dado de alta de esa consulta y pasó a seguimiento rutinario. Julio ha solicitado anticipar su revisión porque ha recibido información de otros pacientes y ha leído en noticiarios de internet que hay disponibles nuevas medicaciones capaces de ofrecer resultados mejores que los tratamientos previos, e incluso son útiles en pacientes en los que han fracasado otros regímenes terapéuticos.

Le informas de que en efecto se anuncian cambios, pero le dices que la evidencia es muy reciente y que el tratamiento tardará un tiempo en estar disponible. Solicitas la analítica y ecografía de revisión y le dices que te gustaría revisar con detalle esa nueva evidencia y comentarlo posteriormente con él, al recoger los resultados.

Como sabes que la publicación es muy reciente (lo habéis comentado brevemente en el servicio) eludes buscar en los sumarios y en las síntesis de evidencias y buscas directamente en bases de datos de artículos originales. Encuentras el artículo: Bacon BR , Gordon SC, Lawitz E, Marcellin P, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-17.

Lee el artículo y contesta a las siguientes preguntas:

1. ¿Es útil boceprevir más peginterferón y ribavirina para conseguir carga viral indetectable?

2. ¿Le darías a Julio boceprevir más peginterferón y ribavirina en el momento en que estuviera disponible?

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n engl j med 364;13 nejm.org march 31, 2011 1207

original article

Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection

Bruce R. Bacon, M.D., Stuart C. Gordon, M.D., Eric Lawitz, M.D., Patrick Marcellin, M.D., John M. Vierling, M.D., Stefan Zeuzem, M.D.,

Fred Poordad, M.D., Zachary D. Goodman, M.D., Ph.D., Heather L. Sings, Ph.D., Navdeep Boparai, M.S., Margaret Burroughs, M.D., Clifford A. Brass, M.D., Ph.D.,

Janice K. Albrecht, Ph.D., and Rafael Esteban, M.D., for the HCV RESPOND-2 Investigators*

From Saint Louis University School of Medicine, St. Louis (B.R.B.); Henry Ford Hospital, Detroit (S.C.G.); Alamo Medi-cal Research, San Antonio, TX (E.L.); Uni-versity Paris–Diderot, Hôpital Beaujon, Clichy, France (P.M.); Baylor College of Medicine, Houston (J.M.V.); the Depart-ment of Medicine, J.W. Goethe University Hospital, Frankfurt, Germany (S.Z.); Ce-dars–Sinai Medical Center, Los Angeles (F.P.); Inova Fairfax Hospital and the Betty and Guy Beatty Center for Integrat-ed Research, Falls Church, VA (Z.D.G.); Merck, Sharp & Dohme, Whitehouse Station, NJ (H.L.S., N.B., M.B., C.A.B., J.K.A.); and Hospital General Universita-rio Vall d’Hebron and Centro de Investig-ación Biomédica en Red de Enferme-dades Hepáticas y Digestivas del Instituto Carlos III, Barcelona (R.E.). Ad-dress reprint requests to Dr. Bacon at the Saint Louis University School of Medi-cine, 3635 Vista Ave. at Grand Blvd., St. Louis, MO 63110-0250, or at baconbr@slu.edu.

* The Hepatitis C Virus (HCV) RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebe-tol 2) Investigators are listed in the Supple-mentary Appendix, available at NEJM.org.

N Engl J Med 2011;364:1207-17.Copyright © 2011 Massachusetts Medical Society.

A BS TR AC T

Background

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon–ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.

Methods

To assess the effect of the combination of boceprevir and peginterferon–ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peg­interferon alfa­2b and ribavirin were administered for 4 weeks (the lead­in period). Subsequently, group 1 (control group) received placebo plus peginterferon–ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon–ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peg­interferon–ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks.

Results

A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was adminis­tered in 41 to 46% of boceprevir­treated patients and 21% of controls.

Conclusions

The addition of boceprevir to peginterferon–ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon–ribavirin alone. (Funded by Scher­ing­Plough [now Merck]; HCV RESPOND­2 ClinicalTrials.gov number, NCT00708500.)

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More than 170 million people are chronically infected with hepatitis C virus (HCV) worldwide.1 The standard

treatment is combination therapy with peginter­feron and ribavirin.2-4 Of the six HCV genotypes, genotype 1 is the least responsive to currently approved therapies, with rates of sustained viro­logic response of less than 50%.2,5-7 Thus, there is a large population of patients with few thera­peutic options, and direct­acting antiviral thera­py has become the focus of investigations re­garding treatment for HCV infection.8-11

Boceprevir is a structurally novel peptidomi­metic ketoamide protease inhibitor that binds reversibly to the HCV nonstructural 3 (NS3) ac­tive site.8 Boceprevir has demonstrated antiviral activity in phase 2 studies of both patients in­fected with HCV genotype 1 who have not received prior treatment and those who have received prior treatment.8 The primary objective of this phase 3 study of patients with previously treated HCV genotype 1 infection was to compare the safety and efficacy of two therapeutic regimens of bo­ceprevir in combination with peginterferon and ribavirin to therapy with peginterferon and riba­virin alone. The safety and efficacy of boceprevir in previously untreated patients are described in the article by Poordad and colleagues in this is­sue of the Journal.12

Me thods

Study Oversight

The study protocol is available with the full text of this article at NEJM.org. The trial (HCV RESPOND­2 [Retreatment with HCV Serine Pro­tease Inhibitor Boceprevir and PegIntron/Rebetol 2]) was funded by Schering­Plough (now part of Merck) and was designed, managed, and analyzed by Merck in conjunction with the external aca­demic investigators and members of the external data and safety monitoring board. The academic authors had agreements with the sponsor con­cerning the confidentiality of the data. The aca­demic authors collected the data, which was then analyzed by the sponsor. The sponsor held the data and made them available to the academic authors. The first draft of the manuscript was written by one academic author and three industry authors. All authors were involved in the collec­tion, analysis, or interpretation of the data; revi­sion of the manuscript; and the decision to submit

the manuscript for publication. All authors vouch for the completeness and accuracy of the data and analyses as well as the fidelity of the study to the protocol.

Study Patients

From August through November 2008, we screened 640 patients with HCV genotype 1 infection at 80 sites in North America and Europe. Eligibil­ity criteria included demonstrated responsive­ness to interferon (minimum duration of therapy, 12 weeks). We defined patients as having either nonresponse (i.e., a decrease in the HCV RNA level of at least 2 log10 IU per milliliter by week 12 but with a detectable HCV RNA level during the therapy period) or relapse (i.e., an undetectable HCV RNA level at the end of treatment, without subsequent attainment of a sustained virologic response [i.e., with a detectable HCV RNA level during the follow­up period]).

Exclusion criteria included hepatitis B or infec­tion with the human immunodeficiency virus, any other cause of clinically significant liver disease, decompensated liver disease, uncontrolled dia­betes mellitus, a severe psychiatric disorder, and active substance abuse. Liver­biopsy specimens were assessed for Metavir fibrosis scores and ste­atosis scores by a single academic author who is a pathologist and was unaware of the assignment of boceprevir or placebo. Possible Metavir fibro­sis scores are as follows: a score of 0 indicates no fibrosis, 1 indicates portal fibrosis without septa, 2 indicates portal fibrosis with few septa, 3 indi­cates numerous septa without cirrhosis, and 4 in­dicates cirrhosis.

Study Design

The primary objective was to compare two treat­ment regimens containing boceprevir in combi­nation with open­label peginterferon alfa­2b and ribavirin (PegIntron and Rebetol, respectively; Merck) to treatment with peginterferon–ribavi­rin plus placebo in previously treated adults with chronic HCV genotype 1 infection. Our study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. All patients provided writ­ten informed consent before randomization.

Patients were randomly assigned, in a 1:2:2 ratio with the use of an interactive voice­response system, to one of three treatment groups, with

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n engl j med 364;13 nejm.org march 31, 2011 1209

stratification according to previous response to therapy (nonresponse or relapse) and HCV sub­genotype (1a or 1b) as determined by means of sequencing of the HCV 5′ noncoding region (Tru­gene).13 Patients with HCV genotype 1 infection whose HCV subtype could not be classified were randomly assigned to one of the treatment groups. The HCV genotype 1 subtype was also determined by means of sequencing of the nonstructural 5B (NS5B) region (Virco).

The study design is illustrated in Figure 1. For purposes of the study doses, peginterferon alfa­2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly, and ribavirin was administered at a divided daily dose of 600 to 1400 mg per day on the basis of body weight. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and with an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir. The study was double­blinded regard­ing the administration of boceprevir.

During the 4­week lead­in period, all patients

received peginterferon plus ribavirin. Subsequent treatment varied according to group. Group 1 (the control group) received peginterferon–riba­virin plus boceprevir­matched placebo for 44 weeks. Group 2 received a response­guided ther­apy regimen consisting of boceprevir plus pegin­terferon–ribavirin, for 32 weeks; according to the week 12 stopping rule, patients with an unde­tectable HCV RNA level at weeks 8 and 12 com­pleted therapy at week 36, whereas those with a detectable HCV RNA level at week 8 (but an un­detectable level at week 12) received peginter­feron–ribavirin plus placebo for an additional 12 weeks. Group 3 received boceprevir and pegin­terferon–ribavirin for 44 weeks.

The stopping rule applied in all groups was that failure to achieve an undetectable HCV RNA level at week 12 resulted in discontinuation of all treatment and advancement to follow­up.

Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diag­nostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, re­spectively; the lower limit of detection was used

40 24 36128 48 72

Week

Control

Experimental

Group 1

Group 2

Group 3

Lead-in period HCV RNA levels assessedfor stopping rule

Follow-upPlacebo and peginterferon–ribavirinPeginterferon–

ribavirin

Boceprevir and peginterferon–ribavirin

Boceprevir and peginterferon–ribavirin

Undetectable HCV RNA levels at wk 8 and 12

Detectable HCV RNA levels at wk 8(but undetectable at wk 12)

Placebo and peginterferon–

ribavirinFollow-up

Follow-up

Follow-up

Peginterferon–ribavirin

Peginterferon–ribavirin

Figure 1. Study Design.

For 13 patients for whom the HCV RNA measurement at the end of the follow-up period was missing, the measure-ment obtained at 12 weeks of follow-up was carried forward; of these patients, a sustained virologic response was achieved in 2 (1 in group 2 and 1 in group 3). Patients with a detectable HCV RNA level at week 12 were considered to have had treatment failure (according to the stopping rule). Patients in group 1 were offered the opportunity to receive treatment with boceprevir plus peginterferon–ribavirin by means of an access study or to proceed to the follow-up phase of this study. Patients in groups 2 and 3 proceeded to the follow-up phase of this study. The primary efficacy end point was assessed at the end of the follow-up phase. The x-axis numbers are not to scale.

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for decision making at various points through­out the study.13 Measurement was performed at the screening visit, at baseline, every 2 weeks through week 12, and then at weeks 16, 20, 24, 30, 36, 42, and 48, as well as at weeks 4, 12, and 24 of the follow­up period.

Safety

Adverse events were graded by investigators ac­cording to a modified World Health Organiza­tion grading system. Non–life­threatening ad­verse events were managed by means of dose reduction. The recommended guidelines for a two­step dose reduction of peginterferon and for a three­step dose reduction of ribavirin were sim­ilar to those previously described (as is summa­rized in the Supplementary Appendix, available at NEJM.org).7,14-16

Viral breakthrough was defined as achieve­ment of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two sam­ples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete viro­logic response and rebound while receiving ther­apy, boceprevir treatment could be discontinued, but peginterferon–ribavirin could be continued for up to 48 weeks with appropriate clinical follow­up.

Statistical Analysis

Analyses regarding the primary objective includ­ed data from all patients who received at least one dose of any study medication. The key second­ary objective was to compare the two boceprevir regimens with the peginterferon–ribavirin regi­men in patients who completed the lead­in period and received at least one dose of placebo or bo­ceprevir. Specifically, comparisons for the pri­mary and key secondary objectives were made between group 3 and group 1 and between group 2 and group 1.

The primary efficacy end point was a sus­tained virologic response, defined as an undetect­able plasma HCV RNA level at week 24 of the follow­up period. Secondary and other efficacy analyses were performed to calculate the propor­tion of patients with an early response (i.e., an undetectable HCV RNA level at week 8) in whom a sustained virologic response was achieved, as well as the proportion of patients with a relapse.

The primary statistical comparison was car­ried out with the use of a two­sided Cochran–Mantel–Haenszel chi­square test with adjustment for the baseline stratification factors. The study had a statistical power of 90% to detect an ab­solute improvement in the rate of sustained viro­logic response by 21 percentage points over the rate in group 1 (assuming response rates of 22% in the control group and 43% in the boceprevir groups) with the use of a two­sided chi­square test and an alpha value of 0.05.

To control for type I error in the primary analysis, a step­down approach was used. Group 3 was first compared against group 1. If the P value for the comparison was less than 0.05, the next comparison — of group 2 and group 1 — was carried out. A similar step­down approach was prespecified to control for the type I error re­garding the key secondary objective. To account for multiplicity between the primary and key secondary analyses, the key secondary analyses were conducted only if the significance of the primary comparisons was established. P values calculated for sustained virologic response are provided for only the two prespecified primary and key secondary comparisons.

Summary statistics are reported for each of the three treatment regimens for subgroups of patients defined according to prespecified base­line characteristics. Multivariable logistic­regres­sion analyses involving treatment regimen and prespecified baseline characteristics were per­formed to evaluate sustained virologic respons­es. A stepwise procedure was used to identify independent predictors of sustained virologic response (with P = 0.05 as the threshold level for variables to be entered into the model and re­tained in the final model). In addition, we fit a stepwise logistic­regression model of the re­sponse (decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at treatment week 4 and base­line characteristics.

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R esult s

Baseline Characteristics

A total of 640 patients were evaluated for enroll­ment in the study; 403 were enrolled and under­went randomization and treatment (Fig. S1 in the Supplementary Appendix). The baseline demo­graphic characteristics were balanced among the three treatment groups (Table 1), with the excep­tion of high viral load (group 2 vs. group 1, P = 0.04). The mean age was 52.7 years, 12% of patients were black, and the mean body weight was 84.9 kg. Approximately 88% of patients had a high viral load (an HCV RNA level >800,000 IU per milliliter) at baseline. The prevalence of in­fection with HCV genotypes 1a and 1b was simi­lar (47% and 44%, respectively). A total of 19% of patients had a Metavir fibrosis score of 3 or 4. The majority of patients (64%) had had a relapse after previous HCV therapy.

Efficacy

In the primary­analysis population, rates of sus­tained virologic response were significantly high­er among patients receiving boceprevir than among those treated with peginterferon–ribavirin alone (Fig. 2), with overall rates of sustained virologic response of 21%, 59%, and 66% in groups 1, 2, and 3, respectively (P<0.001). This increase seen with boceprevir was due largely to end­of­treat­ment rates of response (i.e., an undetectable HCV RNA level) that were greater in group 2 (70%) and group 3 (77%) than in group 1 (31%), as well as a decreased rate of relapse in group 2 (in 17 of 111 patients [15%]) and group 3 (in 14 of 121 pa­tients [12%]) as compared with group 1 (in 8 of 25 patients [32%]). Viral breakthrough and incom­plete virologic response were infrequent during the treatment period (with either occurring in 1 of 80 patients [1%] in group 1, in 9 of 162 patients [6%] in group 2, and in 7 of 161 patients [4%] in group 3).

The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonre­sponse, the corresponding rates were 7% versus 40% and 52%. A total of 102 patients (15%, 28%, and 27% in groups 1, 2, and 3, respectively) had a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter after the 4­week lead­in period (Fig. 2).

In this subgroup, a sustained virologic response was achieved in none of the patients in group 1 and in 33% and 34% in groups 2 and 3, respec­tively. Among patients who had a good response to interferon (a decrease in HCV RNA level of 1 log10 IU per milliliter or more at treatment week 4), the rates of sustained virologic response were 25%, 73%, and 79% in group 1, group 2, and group 3, respectively.

An assessment for amino acid variants associ­ated with reduced susceptibility to boceprevir was performed for 114 patients in group 2 or group 3 in whom a sustained virologic response did not occur. Postbaseline data were available for 98 of the 114 patients (86%), with variants detected in 43 of these 98 patients (44%). The rate of amino acid variants associated with reduced susceptibil­ity to boceprevir was higher among patients with a poor response to interferon (13 of 46 [28%] in group 2 and 15 of 44 [34%] in group 3) than among patients with a good response to inter­feron (10 of 110 [9%] in group 2 and 7 of 112 [6%] in group 3).

In group 2, the duration of total therapy was based on a prespecified decision at treatment week 8, at which time patients with an undetect­able HCV RNA level were eligible for a shorter period of therapy. The proportion of patients with an undetectable HCV RNA level at week 8 in the boceprevir groups (74 of 162 patients [46%] in group 2 and 84 of 161 patients [52%] in group 3) was approximately six times the proportion in group 1 (7 of 80 [9%]). Early response (i.e., an undetectable HCV RNA level at week 8) was as­sociated with high rate of sustained virologic response in all three groups (7 of 7 patients [100%] in group 1; 64 of 74 patients [86%] in group 2; and 74 of 84 patients [88%] in group 3).

An evaluation of treatment effect according to subgroups of baseline characteristics showed that the numerical odds of a sustained virologic response was greater, across all subgroups, with either response­guided triple therapy (group 2) or 44­week triple therapy (group 3) than with the standard of care (group 1) (Fig. 3).

Although there was a sustained virologic re­sponse in 12 more patients in group 3 than in group 2, the rates in each group did not differ significantly (odds ratio of a sustained virologic response in group 3 vs. group 2, 1.4; 95% confi­dence interval, 0.9 to 2.2). A similarly small dif­ference was seen between these two groups dur­

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Table 1. Baseline Characteristics of the Patients, According to Treatment Group.*

Characteristic Group 1 (N = 80) Group 2 (N = 162) Group 3 (N = 161)

Mean age — yr 52.9 52.9 52.3

Male sex — no. (%) 58 (72) 98 (60) 112 (70)

Race — no. (%)†

White 67 (84) 142 (88) 135 (84)

Black 12 (15) 18 (11) 19 (12)

Other 1 (1) 2 (1) 7 (4)

Region — no. (%)

North America 51 (64) 115 (71) 119 (74)

European Union 29 (36) 46 (28) 42 (26)

Latin America 0 1 (1) 0

Body-mass index‡ 28.2±4.3 28.8±4.6 28.2±4.6

HCV subtype — no. (%)§

1a 46 (58) 94 (58) 96 (60)

1b 34 (42) 66 (41) 61 (38)

Missing data 0 2 (1) 4 (2)

ALT > upper limit of the normal range — no. (%) 55 (69) 109 (67) 115 (71)

Platelet count — no. (%)¶

≥100,000 to <150,000/μl 10 (12) 21 (13) 19 (12)

≥150,000/μl 70 (88) 141 (87) 142 (88)

High viral load (>800,000 IU/ml) — no. (%)‖ 65 (81) 147 (91) 141 (88)

Metavir fibrosis score — no. (%)**

0, 1, or 2 61 (76) 117 (72) 119 (74)

3 or 4 15 (19) 32 (20) 31 (19)

Cirrhosis — no. (%)** 10 (12) 17 (10) 22 (14)

Steatosis — no. (%)**

0% 23 (29) 36 (22) 45 (28)

>0–4% 53 (66) 113 (70) 105 (65)

Previous therapy — no. (%)

Peginterferon alfa-2a 42 (53) 79 (49) 68 (42)

Peginterferon alfa-2b 38 (48) 83 (51) 93 (58)

Prior nonresponse — no. (%)†† 29 (36) 57 (35) 58 (36)

Prior relapse — no. (%)†† 51 (64) 105 (65) 103 (64)

* ALT denotes alanine aminotransferase, and HCV hepatitis C virus.† Race was self-reported.‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.§ The HCV subtype was ascertained by means of sequencing of the nonstructural 5B (NS5B) region.¶ Eligibility criteria included an absolute neutrophil count of 1500 per cubic millimeter or higher for nonblacks and 1200

per cubic millimeter or higher for blacks, a platelet count of 100,000 per cubic millimeter or higher, and a hemoglobin level of 12 g per deciliter or more for women and 13 g per deciliter or more for men.

‖ For a viral load >800,000 IU per milliliter, P = 0.04 for the comparison of group 2 versus group 1.** Metavir scores and percent steatosis were determined on the basis of assessment of liver-biopsy specimens by a sin-

gle pathologist who was unaware of the assignment to boceprevir or placebo. A total of 28 patients (4 in group 1, 13 in group 2, and 11 in group 3) had missing data regarding these characteristics. Possible fibrosis scores are as fol-lows: 0 (indicating no fibrosis), 1 (indicating portal fibrosis without septa), 2 (indicating portal fibrosis with few sep-ta), 3 (indicating numerous septa without cirrhosis), and 4 (indicating cirrhosis).

†† Prior nonresponse was defined as a decrease in the HCV RNA level of at least 2 log10 IU per milliliter by week 12 of prior therapy but a detectable HCV RNA level throughout the course of prior therapy, without subsequent attainment of a sustained virologic response. Prior relapse was defined as an undetectable HCV RNA level at the end of prior therapy, without subsequent attainment of a sustained virologic response.

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n engl j med 364;13 nejm.org march 31, 2011 1213

ing the period in which the therapy was identical (week 0 through treatment week 36), with 9 to 14 more patients having an undetectable HCV RNA level during treatment weeks 8 to 36 in group 3 than in group 2 (Fig. S2 in the Supple­mentary Appendix). In post hoc exploratory analyses, we observed that this difference ap­peared to be driven by patients with cirrhosis at baseline: the percentage of patients with cirrho­sis who had an undetectable HCV RNA level at week 8 was 18% (3 of 17 patients) in group 2, versus 73% (16 of 22 patients) in group 3, despite identical treatment through this time point (Fig. S2 in the Supplementary Appendix). This suggests an underlying difference in responsiveness that is not fully accounted for by treatment­group randomization. In contrast, among patients with­out cirrhosis at baseline, the percentage with an

undetectable HCV RNA level at week 8 was 50% (66 of 132 patients) in group 2 and 49% (63 of 128) in group 3. The odds of a sustained viro­logic response were similar between group 3 and group 2 for most baseline factors except for body weight under 75 kg, elevated alanine amino­transferase level, and cirrhosis, for which there was a greater odds of a sustained virologic re­sponse in group 3 (Fig. S3 in the Supplementary Appendix). In contrast, the odds of a sustained virologic response were not different for those with advanced fibrosis (a Metavir fibrosis score of 3 or 4), which is often preferentially used ow­ing to the variability of biopsy readings.

Multivariable stepwise logistic­regression analy­sis served to identify five baseline factors that were significantly associated with achievement of a sustained virologic response: assignment to

59

21

66

22

61

67

29

69

75

7

40

52

33

0

34

25

73

79Su

stai

ned

Vir

olog

ic R

espo

nse

(%)

100

80

90

70

60

40

30

10

50

20

0Prespecified

PrimaryAnalysis

PrespecifiedSecondaryAnalysis

PriorRelapse

PriorNonresponse

Poor Responseto Interferon

Good Responseto Interferon

No. with SVRNo. of Patients

1780

95162

107161

1778

95156

107160

1551

72105

77103

229

2357

3058

012

1546

1544

1767

80110

90114

Group 1 Group 3Group 2

Figure 2. Patients with a Sustained Virologic Response, According to Treatment Group and Analysis.

The percentages of patients with a sustained virologic response are shown. The prespecified primary analysis involved all patients who were randomly assigned to a treatment group and received at least one dose of any study medication. The prespecified secondary analy-sis involved all patients who were randomly assigned to a treatment group and received at least one dose of boceprevir or placebo. Prior relapse was defined as an undetectable HCV RNA level at the end of prior therapy without subsequent attainment of a sustained viro-logic response. Prior nonresponse was defined as a decrease in the HCV RNA level of at least 2 log10 IU per milliliter by week 12 of prior therapy but a detectable HCV RNA level throughout the course of prior therapy, without subsequent attainment of a sustained virologic response. Poor response to interferon was defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter after the 4-week lead-in period (treatment week 4). Good response to interferon was defined as a decrease in HCV RNA level of 1 log10 IU per milliliter or more after the lead-in period. For the primary analysis, the absolute difference between group 2 and group 1 was 37.4 per-centage points (95% confidence interval [CI], 25.7 to 49.1; P<0.001), and between group 3 and group 1, 45.2 percentage points (95% CI, 33.7 to 56.8; P<0.001). For the secondary analysis, the absolute difference between group 2 and group 1 was 39.1 percentage points (95% CI, 27.2 to 51.0; P<0.001), and between group 3 and group 1, 45.1 percentage points (95% CI, 33.4 to 56.8; P<0.001). The P values were calculated with the use of the Cochran–Mantel–Haenszel chi-square test after adjustment for baseline stratification factors. I bars are 95% confidence intervals.

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n engl j med 364;13 nejm.org march 31, 20111214

1.0 10.0 100.0 1000.0

Boceprevir BetterControl Better

All patients

Race

Black

Nonblack

Viral load

Low (≤800,000 IU/ml)

High (>800,000 IU/ml)

Sex

Male

Female

Age

≤53 yr

>53 yr

Weight

<75 kg

≥75 kg

BMI

≤25

>25–30

>30

Platelet count

≤150,000/µl

>150,000–200,000/µl

>200,000/µl

Metavir fibrosis score

0 , 1, or 2

3 or 4

Steatosis

0%

>0%

Cirrhosis

Yes

No

Genotype 1

Subtype unknown

1a

1b

Previous peginterferon treatment

Alfa-2a

Alfa-2b

Treatment history

Prior nonresponse

Prior relapse

ALT

Elevated

Normal

Statin use

Yes

No

Odds Ratio (95% CI)Group 2Subgroup

95/162 (59)

11/18 (61)

84/144 (58)

12/15 (80)

83/147 (56)

59/98 (60)

36/64 (56)

53/89 (60)

42/73 (58)

20/42 (48)

75/120 (62)

21/35 (60)

41/68 (60)

33/59 (56)

8/21 (38)

20/37 (54)

67/104 (64)

77/117 (66)

14/32 (44)

24/36 (67)

67/113 (59)

6/17 (35)

85/132 (64)

9/13 (69)

37/74 (50)

49/75 (65)

44/79 (56)

51/83 (61)

23/57 (40)

72/105 (69)

58/109 (53)

37/53 (70)

7/8 (88)

88/154 (57)

107/161 (66)

10/19 (53)

97/142 (68)

16/20 (80)

91/141 (65)

75/112 (67)

32/49 (65)

52/82 (63)

55/79 (70)

34/44 (77)

73/117 (62)

30/44 (68)

44/66 (67)

33/51 (65)

13/19 (68)

27/45 (60)

67/97 (69)

81/119 (68)

21/31 (68)

31/45 (69)

71/105 (68)

17/22 (77)

85/128 (66)

11/17 (65)

47/77 (61)

49/67 (73)

42/68 (62)

65/93 (70)

30/58 (52)

77/103 (75)

77/115 (67)

30/46 (65)

2/2 (100)

105/159 (66)

Group 1

17/80 (21)

1/12 (8)

16/68 (24)

6/15 (40)

11/65 (17)

13/58 (22)

4/22 (18)

8/40 (20)

9/40 (22)

4/17 (24)

13/63 (21)

4/20 (20)

11/42 (26)

2/18 (11)

2/10 (20)

4/16 (25)

11/54 (20)

14/61 (23)

2/15 (13)

5/23 (22)

11/53 (21)

0/10 (0)

16/66 (24)

0/6 (0)

9/38 (24)

8/36 (22)

10/42 (24)

7/38 (18)

2/29 (7)

15/51 (29)

9/55 (16)

8/25 (32)

1/4 (25)

16/76 (21)

Group 3

no. with sustained virologic response/total no. (%)

Group 3 vs. Group 1

Group 2 vs. Group 1

Boceprevir for previously treated HCV

n engl j med 364;13 nejm.org march 31, 2011 1215

either boceprevir group rather than the control group (odds ratios for group 2 and group 3 vs. group 1, 7.3 and 10.7, respectively; P<0.001 for both comparisons), previous relapse (odds ratio vs. previous nonresponse, 3.1; P<0.001), low vi­ral load at baseline (odds ratio vs. high load, 2.5; P = 0.02), and absence of cirrhosis (odds ratio vs. presence, 2.1; P = 0.04) (Table S1 in the Supple­mentary Appendix). When the decline in viral load (i.e., decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at week 4 (was added to the model, the week 4 response was a stronger predictor of sustained virologic response than historical re­sponse (odds ratio, 5.2; P<0.001).

Safety

The study included a stopping rule whereby pa­tients in whom an undetectable HCV RNA level was not achieved by treatment week 12 discon­tinued all therapy. The low rate of an undetect­able HCV RNA level by treatment week 12 in group 1 resulted in 61% of patients discontinu­ing treatment for this reason, as compared with 22% and 18% of patients in group 2 and group 3, respectively (Fig. S1 in the Supplementary Appen­dix). Thus, the median duration of treatment was 2.4 to 3.2 times longer in the boceprevir groups than in the control group (Table 2).

In the boceprevir groups as compared with the control group, a greater proportion of pa­

tients reported serious adverse events and there were more discontinuations and dose modifica­tions owing to adverse events. There was a higher incidence of anemia in the groups receiving boceprevir (43 to 46%) than in the control group (20%). Consistent with the increased incidence of anemia, the proportion of patients with hemo­globin levels of 6.5 to less than 9.5 g per deciliter was higher in groups 2 and 3 than in group 1; however, discontinuation owing to anemia was infrequent (occurring in 0% of patients group 1 and group 2 and in 3% [5 of 161 patients] in group 3). Erythropoietin was administered to 21%, 41%, and 46% of patients in groups 1, 2, and 3, respectively. Of the 403 patients, 17 received a transfusion for the management of anemia; 16 of these patients also received erythropoietin. Ad­verse events, dose modifications, and study­drug discontinuation in the 49 patients with cirrhosis are summarized in Table S3 in the Supplemen­tary Appendix.

The most common adverse events observed in all treatment groups were flulike symptoms that are typically reported in association with pegin­terferon–ribavirin therapy (Table S5 in the Sup­plementary Appendix). Dysgeusia, rash, and dry skin were reported more commonly in the boce­previr groups than in the control group.

Discussion

Our data show that the addition of boceprevir to peginterferon–ribavirin therapy leads to high rates of sustained virologic response among pa­tients in whom prior treatment had failed. Fur­thermore, patients who had previously had a re­lapse after receiving the standard of care had rates of sustained virologic response of up to 75%, with rates of 40 to 52% in the subgroup of pa­tients with a previous nonresponse. Patients with undetectable HCV RNA levels at treatment week 8 were shown to have a rate of sustained viro­logic response that was similar whether bocepre­vir was taken for 32 weeks or 44 weeks; thus, an early response identified patients who could ben­efit from shorter treatment. There were no iden­tified groups of patients with a previous treat­ment failure for whom the standard of care was more efficacious than was triple therapy. We ob­served high rates of a sustained virologic response among black patients and patients with advanced liver disease, who usually have a poor response,17,18

Figure 3 (facing page). Odds Ratios for a Sustained Virologic Response in Group 2 versus Group 1 and Group 3 versus Group 1, According to Subgroup.

Odds ratios are shown for group 3 versus group 1 (solid circles) and group 2 versus group 1 (open circles) on a log10 scale. The dashed vertical line at unity indicates no difference between the two groups (odds ratio of 1). The dashed horizontal arrows indicate odds ratios and confidence intervals that exceed the x-axis scale. Race was self-reported. The body-mass index (BMI) is the weight in kilograms divided by the square of the height in meters. For the Metavir fibrosis score, presence or absence of cirrhosis, and percent steatosis, a total of 28 patients (4 in group 1, 13 in group 2, and 11 in group 3) had missing data. Data on sustained virologic response for other subgroups are listed in Table S2 of the Supplementary Appendix. P values for the interac-tion between treatment group and baseline character-istic are given in Table 6 of the Supplementary Appen-dix. The HCV genotype 1 subtype was determined with the use of the Trugene assay (Bayer Diagnostics). ALT denotes alanine aminotransferase.

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 364;13 nejm.org march 31, 20111216

representing a clinically significant improvement over the standard of care.19

Rates of anemia were higher among patients receiving boceprevir­containing regimens than among those receiving control therapy, and many patients required erythropoietin treatment. Dis­continuation for anemia was infrequent (affect­

ing 3% of patients in group 3 only). Consistent with the increased incidence of anemia, a higher proportion of boceprevir recipients, as compared with controls, had a neutrophil count of 500 to less than 750 per cubic millimeter or underwent a red­cell transfusion.

This study included a 4­week lead­in period

Table 2. Adverse Events, According to Treatment Group.*

EventGroup 1 (N = 80)

Group 2 (N = 162)

Group 3 (N = 161) P Value

Group 2 vs. Group 1

Group 3 vs. Group 1

Median duration of study-drug exposure — days 104 252 336

Death — no. (%) 0 1 (<1)† 0 0.99 0.99

Any adverse event — no. (%) 77 (96) 160 (99) 161 (100) 0.34 0.04

Discontinuation owing to adverse event — no. (%) 2 (2) 13 (8) 20 (12) 0.15 0.02

Dose modification owing to adverse event — no. (%) 11 (14) 47 (29) 53 (33) 0.01 0.002

Any life-threatening adverse event — no. (%) 0 4 (2) 5 (3) 0.31 0.17

Any serious adverse event — no. (%) 4 (5) 16 (10) 23 (14) 0.23 0.03

Hematologic event

Reduced neutrophil count — no. (%)

Grade 3: 500 to <750 per mm3 7 (9) 30 (19) 32 (20) 0.06 0.03

Grade 4: <500 per mm3 3 (4) 10 (6) 11 (7) 0.55 0.40

Mean change in hemoglobin from baseline — g/dl

At wk 12 –2.89 –4.02 –3.96 <0.001 <0.001

At wk 24 –2.69 –4.36 –4.31 <0.001 <0.001

At wk 48 –3.45 –4.16 –4.49 0.09 0.005

Hemoglobin level — no. (%)

Grade 2: 8.0 to <9.5 g/dl 9 (11) 42 (26) 41 (25) 0.01 0.01

Grade 3: 6.5 to <8.0 g/dl 1 (1) 5 (3) 12 (7) 0.67 0.07

Grade 4: <6.5 g/dl 0 0 1 (<1) 0.99 0.99

Erythropoietin use 17 (21) 66 (41) 74 (46) 0.003 <0.001

Transfusion 0 3 (2) 14 (9) 0.55 0.006

Common adverse event — no. (%)‡

Anemia 16 (20) 70 (43) 74 (46) <0.001 <0.001

Dry skin 6 (8) 34 (21) 36 (22) 0.009 0.004

Dysgeusia 9 (11) 69 (43) 72 (45) <0.001 <0.001

Rash 4 (5) 27 (17) 22 (14) 0.01 0.05

* A listing of all life-threatening and serious adverse events can be found in Table S4 in the Supplementary Appendix. The P values presented are nominal, have not been adjusted for multiple comparisons, and are based on Fisher’s exact test for categorical variables and Student’s t-test for continuous variables.

† There was one death by suicide in group 2, which occurred 18 weeks after the end of the study treatment and was con-sidered to be unrelated to the study treatment.

‡ Common adverse events were those classified as being related to a study treatment and occurring with an incidence of 15% or more in any group. Only common adverse events for which P<0.05 for a pairwise comparison with group 1 (group 3 vs. group 1 or group 2 vs. group 1) are shown. All other common adverse events (for which the treatment- related incidence was 15% or more in any group) can be found in Table S5 in the Supplementary Appendix.

Boceprevir for previously treated HCV

n engl j med 364;13 nejm.org march 31, 2011 1217

during which peginterferon–ribavirin was admin­istered, which allowed for the assessment of the patient’s interferon responsiveness immediately before the addition of boceprevir. We have previ­ously shown that a decline in viral load of less than 1 log10 IU per milliliter after 4 weeks of peginterferon–ribavirin therapy is significantly correlated to a decline of less than 2 log10 IU per milliliter after 12 weeks of treatment.20 We iden­tified 102 patients with a poor response to inter­feron, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at week 4. This is an important recognition of the changes that can evolve over time in patients who had previously been treated and are awaiting retreat­ment. Possible explanations for such changes include an increase in body weight, development of glucose intolerance, an increase in hepatic steatosis, and progression of fibrosis, all of which could have resulted in diminished responsiveness

to peginterferon–ribavirin. Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33 to 34% of the patients with a poor response to inter­feron, as compared with 0% in the patients re­treated with peginterferon–ribavirin alone.

In summary, the results of our phase 3 trial show that boceprevir, when added to peginter­feron alfa­2b and ribavirin, leads to high rates of sustained virologic response in difficult­to­treat patients.

The opinions expressed in this report represent the consensus of the authors and do not necessarily reflect the formal position of Merck or other institutions listed as authors’ affiliations.

Sponsored by Schering­Plough (now part of Merck).Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.We thank all the patients, health care providers, and investi­

gators involved in the study, Dr. Lisa Pedicone of Merck for her helpful advice and invaluable support, and Karyn Davis of Merck for technical assistance.

References

1. Hepatitis C fact sheet. Geneva: World Health Organization. (http://www.who.int/ mediacentre/factsheets/fs164/en.)2. Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 2006;355:2444­51.3. Feld JJ, Hoofnagle JH. Mechanism of action of interferon and ribavirin in treat­ment of hepatitis C. Nature 2005;436:967­72.4. Hofmann WP, Herrmann E, Sarrazin C, Zeuzem S. Ribavirin mode of action in chronic hepatitis C: from clinical use back to molecular mechanisms. Liver Int 2008; 28:1332­43.5. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon­alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment dura­tion and ribavirin dose. Ann Intern Med 2004;140:346­55.6. Zeuzem S. Heterogeneous virologic response rates to interferon­based therapy in patients with chronic hepatitis C: who responds less well? Ann Intern Med 2004; 140:370­81.7. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa­2b or alfa­2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361:580­93.8. Berman K, Kwo PY. Boceprevir, an

NS3 protease inhibitor of HCV. Clin Liver Dis 2009;13:429­39.9. Mederacke I, Wedemeyer H, Manns MP. Boceprevir, an NS3 serine protease inhibitor of hepatitis C virus, for the treatment of HCV infection. Curr Opin Investig Drugs 2009;10:181­9.10. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827­38. [Erratum, N Engl J Med 2009;361:1516.]11. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362:1292­303. [Erratum, N Engl J Med 2010;362:1647.]12. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195­206.13. Germer JJ, Majewski DW, Rosser M, et al. Evaluation of the TRUGENE HCV 5′NC genotyping kit with the new GeneLibrarian module 3.1.2 for genotyping of hepatitis C virus from clinical specimens. J Clin Microbiol 2003;41:4855­7. [Erratum, J Clin Microbiol 2004;42:3911.]14. Jacobson IM, Brown RS Jr, Freilich B, et al. Peginterferon alfa­2b and weight­based or flat­dose ribavirin in chronic

hepatitis C patients: a randomized trial. Hepatology 2007;46:971­81.15. PegIntron (Peginterferon alfa­2b) prod­uct information. (http://www.spfiles.com/pipeg­intron.pdf.)16. Rebetol (ribavirin USP) prescribing information. (http://www.spfiles.com/pirebetol.pdf.)17. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa­2b and ribavirin for the treatment of chronic hepatitis C in blacks and non­Hispanic whites. N Engl J Med 2004;350:2265­71. [Erratum, N Engl J Med 2004;351:1268.]18. Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon alfa­2a in pa­tients with chronic hepatitis C and cirrho­sis. N Engl J Med 2000;343:1673­80.19. Negro F. Adverse effects of drugs in the treatment of viral hepatitis. Best Pract Res Clin Gastroenterol 2010;24:183­92.20. Poordad F, Sulkowski M, McHutchi­son J, et al. High correlation between week 4 and week 12 as the definition for null response to peginterferon alfa (PEG) plus ribavirin (R) therapy: results from the IDEAL trial. Presented at the 61st an­nual meeting of the American Associa­tion for the Study of Liver Diseases, Bos­ton, October 29–November 2, 2010.Copyright © 2011 Massachusetts Medical Society.

©CASPe

GLOSARIO DE TRATAMIENTO (Ensayo y Revisión)

La Colaboración Cochrane (The Cochrane Collaboration) es un empeño internacional en el que gente de muy distintos países busca sistemáticamente, critica y revisa la evidencia disponible a partir de los ECC's. Los objetivos de la Cochrane son el desarrollo y mantenimiento de revisiones sistemáticas, la puesta al día de los ECC's en todas las formas de cuidados de salud y hacer que esta información esté realmente accesible para los clínicos y otros "decisores" en todos los niveles de los sistemas de salud. El Centro Coordinador de la Colaboración Cochrane española está en el Hospital de la Santa Cruz y San Pablo de, Sabadell. Controles (Controls) en un ECC son los individuos que forman el grupo de comparación. Reciben el tratamiento convencional (o placebo) mientras que el grupo experimental recibe el tratamiento que se está probando. Ensayo clínico controlado (ECC) (Randomised Controlled Trial (RCT)) es un diseño de estudio en el que los sujetos son aleatoriamente asignados a dos grupos: uno (grupo experimental) recibe el tratamiento que se está probando y el otro (grupo de comparación o control) recibe un tratamiento alternativo. Los dos grupos son seguidos para observar cualquier diferencia en los resultados. Así se evalúa la eficacia del tratamiento. Efectividad clínica (Clinical effectiveness) es la magnitud en la que una intervención (tratamiento, procedimiento o servicio) mejora los resultados para los pacientes en la práctica. También se le denomina simplemente 'efectividad'. Eficacia (Efficacy) es la magnitud en la que una intervención (tratamiento, procedimiento o servicio) mejora los resultados para los pacientes en condiciones ideales (típicamente un ECC) . Homogeneidad (Homogeneity) significa "similaridad". Se dice que unos estudios son homogéneos si sus resultados no varían entre sí más de lo que puede esperarse por azar. Lo opuesto a homogeneidad es heterogeneidad. Intervalo de confianza (IC) (Confidence Interval (CI)) es el intervalo dentro del que se encuentra la verdadera magnitud del efecto (nunca conocida exactamente) con un grado prefijado de seguridad. A menudo se habla de “intervalo de confianza al 95%" (o "límites de confianza al 95%”). Quiere decir que dentro de ese intervalo se encontraría el verdadero valor en el 95% los casos. Lectura crítica (Critical Appraisal) es el proceso de evaluar e interpretar la evidencia aportada por la literatura científica, considerando sistemáticamente los resultados que se presentan, su validez y su relevancia para el trabajo propio. MEDLINE es una base de datos informatizada que resume miles de artículos de investigación biomédica publicados en revistas seleccionadas. Está disponible en la mayoría de las bibliotecas sanitarias y es accesible mediante CD-ROM y por otros medios. Meta-análisis (Meta-analysis) es una técnica estadística que permite integrar los resultados de distintos estudios en un único estimador, dando más peso a los resultados de los estudios más grandes. Número necesario a tratar (NNT) (Number Needed to Treat) es una medida de la eficacia de un tratamiento. Es el número de personas que se necesitaría tratar con un tratamiento específico (vgr. aspirina a quienes han sufrido un ataque cardíaco) para producir, o evitar, una ocurrencia adicional de un evento determinado (vgr. prevención de muerte). Del mismo modo se define número necesario para perjudicar (NNP) (number needed to harm (NNH)) para evaluar efectos indeseables. Odds es un término poco usado fuera del juego (en Inglaterra) y la estadística. Se define como el cociente entre la probabilidad de que un evento ocurra y la de que no ocurra. Piensa en él como una medida del "riesgo". Odds ratio (OR) es una medida de la eficacia de un tratamiento. Si es igual a 1, el efecto del tratamiento no es distinto del efecto del control. Si el OR es mayor (o menor) que 1, el efecto del tratamiento es mayor (o menor) que el del control. Nótese que el efecto que se está midiendo puede ser adverso (vgr. muerte, discapacidad) o deseable (vgr. dejar de fumar). Placebo es un tratamiento inactivo dado a menudo como control en los ECC. El placebo se suministra en una forma que es aparentemente idéntica a la del tratamiento activo que se está probando, para eliminar los efectos psicológicos. Revisión (Review) es cualquier resumen de la literatura. Revisión sistemática (Systematic review) es una revisión en la que la evidencia sobre un tema ha sido sistemáticamente identificada, criticada y resumida de acuerdo a unos criterios predeterminados. Sesgo (Bias) es la desviación sistemática entre el resultado obtenido y el verdadero valor, debido a la forma en que se hizo el estudio. Sesgo de publicación (Publication bias) refleja la tendencia reconocida a publicar sólo estudios con resultados "positivos". Validez (Validity) se refiere a la solidez o rigor de un estudio en relación con el grado de aproximación a la 'verdad' de sus resultados. Un estudio es válido si el modo en que ha sido diseñado y realizado hace que los resultados no estén sesgados, es decir, nos da una 'verdadera' estimación de la efectividad clínica.

EL LOGOTIPO DEL CASP

¿Qué significa? El logotipo del CASP son tres flechas que se solapan. Éstas representan los tres pasos necesarios a seguir para usar la evidencia en tu trabajo.

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EQUATOR NETWORK

Con frecuencia una buena evidencia de la investigación se ve socavada por la presentación de informes de mala calidad. La Red Equator es una iniciativa internacional que busca mejorar la fiabilidad y el valor de la literatura de investigación médica mediante la promoción de una información transparente y precisa de los estudios de investigación.

Este objetivo se logrará a través de: 1. La sensibilización de la importancia de una información de calidad de la

investigación. 2. Convertirse en un centro global y reconocido para la provisión de recursos,

educación y formación en la presentación de informes de la investigación en salud y para el uso de las directrices de presentación de informes.

3. Ayudar en el desarrollo, difusión y aplicación de las recomendación sobre presentación de informes.

4. Seguimiento de la situación de la calidad de la información a través de la literatura de investigación en salud.

5. La investigación sobre la calidad de la información.