![[object Object],Sergio Lupo](https://image.slidesharecdn.com/coinfeccinvih-vhc-110715185659-phpapp02/85/Coinfeccion-VIH-VHC-VHB-1-320.jpg)
Recomendados
Mais conteúdo relacionado
Mais procurados
Mais procurados (20)
Destaque
Destaque (20)
Semelhante a Coinfección VIH -VHC-VHB
Semelhante a Coinfección VIH -VHC-VHB (20)
Mais de cursobianualMI
Mais de cursobianualMI (20)
Último
Último (20)
Coinfección VIH -VHC-VHB
- 2. Causas de enfermedad hepática en el paciente con VIH
- 3. Hepatopatías en el paciente VIH positivo Común Poco común Hepatitis C Hepatitis autoinmune Hepatitis B Cirrosis biliar primaria Hepatitis alcohólica Colangitis biliar primaria Cirrosis alcohólica Hemocromatosis Hígado graso no alcohólico Enfermedad de Wilson Hepatotoxicidad por drogas Déficit alfa 1 antitripsina
- 4. Baruch Blumberg Luc montagnier-Barre Sinussy Michael Houghton Agentes virales Hepatitis aguda (42) Virus B (64) Virus A (73) VIH (83) Virus E (91) 1940 1950 1960 1970 1980 1990 2000 (87) B.Molecular Virus C
- 5. Virus Hepatitis Genoma Contagio Periodo Incubación (días) Hepatitis fulminante Cronicidad Ac A ARN Fecal-oral 15-45 1% No Anti HAV B ADN Parenteral Sexual 30-180 1% 2-7% Anti HBs HBc HBe C ARN Parenteral Sexual 15-150 <0.1% 70-85% Anti HCV (IgG) D ARN Parenteral Sexual 30-150 2-10% 2-7% 50% Anti HDV E ARN Fecal-oral 30-60 1% No Anti HEV
- 6. Coinfección VIH y hepatitis C
- 8. Prevalencia de Anti-HCV (+) y HCV-RNA (+) en coinfectados (Argentina) El 64,4% de los Anti-HCV (+), eran HCV-RNA (+)
- 12. Virus hepatitis C : complejidad 6 genotipos y 30 subtipos Genotipo 1: 67%
- 13. Infección por HCV: Distribución mundial por genotipo 1a, 1b 2a, 2b, 3a 1b 2a, 2b, 2c, 3a 4 5a 1b 1b, 6 1b, 3a 1b, 3a 3b 2a 4 ¿
- 14. 1a/1b genotipo Grupo 1 n (%) 1 1a/1b ng 4c/4d 1a/3a 1/4a 1/3a 3a 1b 1a genotipo n (%) 2 (2.4) 2(2.4) 10(11.7) 1(1.2) 1(1.2) 1(1.2) 17(20.5) 13(15.2) Grupo 2 Distribución genotipos HCV Argentina 3(3.5) 1 ng 3a 2b 2a/2c 2a 2 2(1.4) 2(1.4) 1(0.7) 18(12.5) 3(2.1) 5(3.5) 14(9.7) 13(9.0) n=85 n=144 1b/3 1(1.2) 1a 34(40) 1a 1b 29(20.1) 57(39.6) * * * *
- 15. Coinfección Virus C y VIH: Complicaciones a largo plazo Hepatitis crónica: 85% Cirrosis: 20-50%
- 16. Coinfección Virus C y VIH: Complicaciones a largo plazo Hepatocarcinoma:2 al 5%
- 17. Coinfección hepatitis C y VIH Evidencias a favor de una enfermedad hepática más agresiva Telfer P. et al Br J Hematol 1994 Eyster M. et al J. AIDS 1993 Darby S. Lancet 1997 116 pacientes 32 pacientes El tiempo entre el contagio del HCV y la cirrosis fue más corto en los pacientes con doble infección La mortalidad por causa hepática ocurrió 10 años antes en HCV + HIV (+)
- 19. Coinfección hepatitis C y VIH Evidencias a favor de una enfermedad hepática más agresiva Darby S. Lancet 1997 La mortalidad por causa hepática ocurrió 10 años antes en HCV + HIV (+) Pineda Hepatol. 2007 Sobre 1001 pacientes, 6% sufrieron descompenzación y 3 % murieron en 5 años
- 26. Importancia del TAR en el paciente con hepatitis ↑ carga viral y transmisión HCV ↑ progresión a cirrosis VIH HCV Menor fibrosis Mayor sobrevida Sin TAAE ConTAAE Insuficiencia Hepática Reconstitución inmune
- 29. Toxicidad hepática: el EA más frecuente en la era del TAAE Reisler RB, et al . J Acquir Immune Defic Syndr 2003;34:379 – 86 Incidencia/ 100 personas
- 37. Rilpivirina
- 47. Peg interferon alfa -2a Tamaño: 40 kDa Eliminación hepática Dosis fija: 180 microGr/S Peg interferon alfa -2b Tamaño: 12 kDa Eliminación renal Dosis: 1,5 micro Gr/k/S
- 51. Ramos B et al; Critical role of ribavirin for the achievement of early virological response to HCV therapy in HCV/HIV-coinfected patients. J Viral Hepat. 2007 Jun;14(6):387-91 TAR en coinfección por virus C: interacciones ribavirina
- 52. Posible competencia intracelular entre abacavir y ribavirina Bani-Sadr et al. J Acq.Immune Def. Synd. 2007;45:123-125
- 56. Drogas antirretrovirales y toxicidad hepática Año 2011 RILPIVIRINA INTR INNTR IP IF II IR5 AZT ddI ddC 3TC d4T ABV FTC INTR TFV NEVIRAPINA DELAVIRDINA EFAVIRENZ ETRAVIRINA SAQUINAVIR/r RITONAVIR INDINAVIR/r NELFINAVIR AMPRENAVIR LOPINAVIR/r ATAZANAVIR/r FOSAMP/r DARUNAVIR/r TIPRANAVIR/r T 20 RALTEGRAVIR MARAVIROC
- 58. ¿Que dosis se debe utilizar? IFN PEG (una dosis semanal) + RBV (1000/1200 mg según < 75 Kg > de peso
- 60. Tratamiento del HCV en paciente HIV ACTG 5071 IFN Peg 2a + RBV 600 mg-1 g/d RIBAVIC IFN Peg 2b + RBV 800 mg/d APRICOT IFN Peg 2a +RBV 800 mg/d Chung et al. Carrat F Torriani et al. NEJM 2004 JAMA 2004 NEJM 2004
- 61. Coinfección hepatitis C y VIH Tratamiento Estudios Genotipo 1:RVS Genotipo 2/3:RVS Discontinuaciones ACTG 5071 14% 73% 12% APRICOT 29% 62% 15% RIBAVIC 15% 44% 31%
- 64. Algorritmo para el manejo de la coinfección VIH/HCV
- 65. Elastografia de transicion (fibroscan hepático)
- 66. Elastografia de transición (fibroscan hepático) La figura muestra la posición correcta de la sonda emisora-receptora. La onda mecánica se propaga dentro del hígado evaluando un volumen de parénquima 100 veces superior al de la biopsia. El valor de rigidez hepática expresado en kPas es proporcional al grado de fibrosis hepática. La rigidez hepática en sujetos sanos es de aproximadamente 5.5 ± 1.6 kPa
- 67. Ciclo de vida del HCV
- 68. Ciclo de vida del HCV
- 69. NS3 Protease Targets Serine proteinase catalytic site (Pawlotsky JM, et al Gastroenterology 2007;132:1979-98)
- 70. RESPUESTA AL TRATAMIENTO DEL PACIENTE CON HCV SVR % IFN + Riba 35 Peg IFN + Riba 48 Peg IFN + Riba +IP 70 Peg IFN + Riba + IP/polimerasa ? IFN 15
- 75. ADVANCE: Overall SVR and Relapse Rates 0 20 40 60 80 100 Patients (%) 69 SVR 75 44 P < .0001 for both treatment arms vs control 12-wk TVR + PR + 12/36-wk PR (n = 363) 48-wk PR (n = 361) 8-wk TVR + PR + 16/40-wk PR (n = 364) n = 250 271 158 Relapse 9 9 28 n = 28 27 64 Jacobson IM, et al. AASLD 2010. Abstract 211.
- 78. Study 110: Interim Data on Telaprevir in HIV/HCV Genotype 1-Coinfected Patients PR † (n = 16) Part B: Stable ART HIV/HCV-coinfected patients on stable ART, TDF/FTC/EFV or TDF + (FTC or 3TC) + ATV/RTV; CD4+ ≥ 300 cells/mm³; HIV-1 RNA ≤ 50 c/mL (N = 46) Follow-up Part A: No current ART HIV/HCV-coinfected patients; CD4+ ≥ 500 cells/mm³; HIV-1 RNA ≤ 100,000 c/mL (N = 13) Follow-up Placebo + PR (n = 16) PR † (n = 6) Placebo + PR (n = 6) PR † (n = 7) Telaprevir 750 mg q8h + PR † (n = 7) PR † (n = 30) Telaprevir * 750 mg q8h + PR (n = 30) Wk 12 Wk 48 Wk 72 *Telaprevir dose increased to 1125 mg q8h with efavirenz. † Peginterferon alfa-2a 180 μ g/wk; ribavirin 800 mg/day or weight based in France and Germany (1000 mg/day if weight < 75 kg; 1200 mg/day if weight ≥ 75 kg). Sulkowski M, et al. CROI 2011. Abstract 146LB.
- 84. SPRINT-2: Response Rates According to Race 0 20 40 60 80 100 Patients (%) SVR Relapse 4-wk PR + 44 weeks BOC + PR 4-wk PR + response-guided BOC + PR 48-wk PR 67 68 40 8 23 9 0 20 40 60 80 100 Patients (%) SVR Relapse 42 53 23 17 14 12 Nonblack Patients Black Patients P < .0001 P = .044 P = .004 Poordad F, et al. AASLD 2010. Abstract LB-4. n = 211 213 125 21 18 37 22 29 12 3 6 2
- 85. Phase III RESPOND-2: Boceprevir in GT1 Prior Non responders to PegIFN/RBV PR* (n = 80) PR* (n = 161) BOC + PR* BOC + PR* PR* (n = 162) BOC + PR* If detectable at Wk 8 PR* Bacon BR, et al. AASLD 2010. Abstract 216. Treatment-experienced patients with GT1 HCV monoinfection (N = 403) Wk 48 Wk 8 Wk 36 Follow-up † Follow-up † Follow-up † Follow-up † *Dosages: BOC 800 mg TID; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. † Follow-up for 24 wks after completion of therapy.
- 86. RESPOND-2: SVR Rates According to Treatment Arm and Previous Response 0 20 40 60 80 100 Overall SVR (%) 4-wk PR + 44-wk BOC + PR (n = 161) 59* Previous Nonresponders Previous Relapsers 48-wk PR (n = 80) 4-wk PR + response-guided BOC + PR (n = 162) 66 21 40 52 7 75 29 69 P < .0001 vs control (both arms) Bacon BR, et al. AASLD 2010. Abstract 216.
- 91. Un escenario probable del futuro tratamiento de la hepatitis C Genotipo 1 PEG-IFN + Pol Inhibitor +/- ribavirin + + or Prot Inhibitor + Pol Inhibitor + Prot Inhibitor All Oral Therapy 1989-1998 1998-2001 2001- present 2008-2009 2011-2014 2017 Oral immune modulators Other direct antivirals 10% 35% 42-50% Estimated 65-70% Estimated 85-90% 0 10 20 30 40 50 60 70 80 90 100 1st Stage 2nd Stage 3rd Stage 4th Stage 5th Stage 6th Stage Sustained Virologic Response in G1 (SVR)
- 92. Coinfección VIH y hepatitis B
- 93. Prevalencia de Anti-HBc (+) en Argentina
- 94. Prevalencia de HBsAg (+) en Argentina
- 100. Coinfección HIV/HBV : mortalidad aumentada Thio CL, Seaberg E, Skolasky RL, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360:1921-1926 .
- 102. 1) Suprimir la replicación del HBV (negativizacion del DNA-HBV sérico) Se consigue mejoría del cuadro histológico 2) Obtener la seroconversión de HBeAg a anti-HBe Se consigue una supresión de la replicación más duradera 3) Conseguir la desaparición de la portación crónica ( negativización del HBsAg y la seroconversión a anti-HBs) Objetivo de máxima, poco posible Tratamiento de la hepatitis en la coinfección: objetivos
- 104. Alfa-Interferon: Fue la primer droga aprobada para el tratamiento de la hepatitis crónica HBV. Su eficacia es mayor en pacientes HBeAg +. En la coinfección HBV-HIV la mayor parte de los estudios fueron realizados en la época previa al TAAE. (respuesra < al 10%) IFN pegilado: parece ser más eficaz que el estándar de interferón alfa-2b para el tratamiento de VHB monoinfectados. Tienen mayores posibilidades de respuesta, los pacientes jóvenes, con HBeAg+, niveles bajos de ADN-VHB, transaminasas elevadas, genotipos A y B y probablemente mayores recuentos de CD4 Utilidad probable: en pacientes que no tengan indicaciones de TAR Tratamiento de la hepatitis en la coinfección: Drogas
- 105. Lamivudina: su eficacia se demostró en pacientes coinfectados, pero el éxito a largo plazo se ve limitado por la selección de mutaciones que producen resistencia (2 a 17% de coinfectados en pacientes no suprimidos). Emtricitabina (FTC): Tiene un perfil de actividad y resistencia similar a la lamivudina (13% de resistencia a las 48 semanas). Tratamiento de la hepatitis en la coinfección: Drogas
- 106. Adefovir: Fue el primer análogo nucleótido para el tratamiento del virus B. Tiene acción contra las cepas resistentes a la lamivudina y en población HIV-HBV demostró reducción de CV prolongadas, con menor resistencia que la lamivudina. Tras 5 años de tratamiento, el 20% presenta las mutaciones rtA181V y rtN236T Tenofovir: Es efectivo contra el HIV y contra el HBV tanto en cepas salvajes como en resistentes a la lamivudina. Las resistencias del HBV al TDF en pacientes coinfectados son infrecuentes , pero debemos remarcar que casi todos los estudios evaluados fueron realizados en combinación con lamivudina. Tratamiento de la hepatitis en la coinfección: Drogas
- 107. Entecavir: nucleósido análogo de la guanosina, disminuye la carga viral en 5-6,9 logaritmos. Tiene una acción moderada frente al VIH y puede seleccionar la mutación M184V en pacientes en monoterapia con entecavir, con y sin tratamiento previo con lamivudina. Tres pacientes en tratamiento con entecavir, sin TAR concomitante disminuyeron un log la CV para VIH y uno de los pacientes presentó una mutación en la 184V. ( McMahon M, al. 14th CROI 2007) y reconfirmado en una presentación del 15th CROI ( Audsley J, The anti-HIV activity of entecavir: Serum HIV RNA decreases and selection of the M184V mutation occurs in both ART-naive and -experienced HIV/HBV-co-infected individuals). Tratamiento de la hepatitis en la coinfección: Drogas
- 108. Telbivudina : Telbivudina es un análogo de la timidita que disminuye la carga viral 5-6,4 logaritmos. A los dos años desarrollan resistencias un 25% de los pacientes con HbeAg positivo y un 11% de los negativos. Durante el tratamiento se pueden elevar los enzimas musculares. Tiene resistencia cruzada con lamivudina . Tratamiento de la hepatitis en la coinfección: Drogas
- 109. Tratamiento de la hepatitis B en coinfectados HbsAg+ DNA+ > 2000 copias < 2000 copias ALT elevada ALT normal Tratamiento biopsia Biopsia si: a) Delta+ b) Ag E+ Con ALT alta Tratar si Metavir A2 O F2 Monitoreo Cada 6 a 12 meses Nivel DNA European AIDS Clinical Society
- 110. Tratamiento de la hepatitis B en coinfectados VIH/HBV coinfección Con indicación TAR Sin indicación TAR 3TC naive 3TC previo TAAE incluyendo TNF/3TC o FTC Agregar/sustituir con TNF Tto HBV no Indicado Tto HBV Indicado Monitoreo a) TAR con truvada b) Peg Int si: Genotipo A ALT Elevada CV baja European AIDS Clinical Society
- 111. Manejo del paciente VIH + Coinfecciones hepatitis SIRI Complicaciones oportunistas Comlicaciones neoplásicas TAR y efectos adversos Adherencia al TAR Osteopenia y Vit. D Trastornos cognitivos Eventos serios no relacionados Trastornos CV y metabólicos Investigación clínica Prevención y promoción salud
- 112. ¡GRACIAS!
Notas do Editor
- Global prevalence of HIV –HCV co-infection This slide illustrates the proportion of HIV and HCV patients that are co-infected with HCV and HIV, respectively. Approximately a third of patients with HIV are also infected with HCV while 5-10% of HCV infected patients are co-infected with HIV. Slide updated in March 2005. Further information available at: http://www.roche-hiv.com/home/home.cfm
- HIV infection: introduction These are both viruses that end up in Infectious Diseases Society of America (IDSA) territory, but they're very different. Hepatitis C is a very dynamic infection, more dynamic probably than human immunodeficiency virus (HIV), and a very diverse and complex virus. It's infecting the liver and not the lymphoid tissue, there are different receptors involved, and it's attacking the cells. The infections often do go together. Mientras que el material genético del virus VIH está integrado al genoma de la célula del huésped, estableciendo así una infección continua imposible de erradicar con la terapia antirretroviral actual, el HCV no requiere integración, su replicación es hepatocitaria y puede ser erradicado con tratamiento especifico aún pasados varios años desde que se ha establecido la enfermedad.
- En el HIV el promedio de recambio de partículas nuevas liberadas es de 10 billones, para el HCV es de aproximadamente 10 trillones La tasa de cronicidad para los pacientes VIH (+) se estima que es casi del 100%, mientras que en el enfermo HCV(+) es de aproximadamente 85%.
- Evaluación de emergencia de cuasiespecies en estudio de cohorte longitudinal en pacientes hemofílicos coinfectados y no coinfectados. Se secuenciaron y subclonaron la primer región hipervariable (HVR1) y la región core con un seguimiento de 9,3 años. El patrón de evolución de los no progresores a fibrosis difirió al de los progresores en cuanto a la formación de cuasiespecies
- Objective: To estimate incidence and predictors of serious or life-threatening events that are not AIDS defining, AIDS events, and death among patients treated with highly active antiretroviral therapy (HAART) in the setting of 5 large multicenter randomized treatment trials conducted in the United States. Methods : Data were analyzed from 2947 patients enrolled from December 1996 through December 2001. All patients were to receive antiretrovirals throughout follow-up. Data collection was uniform for all main outcome measures: serious or life-threatening (grade 4) events, AIDS, and death. Results : During follow-up, 675 patients experienced a grade 4 event (11.4 per 100 person-years); 332 developed an AIDS event (5.6 per 100 person-years); and 272 died (4.6 per 100 person-years). The most common grade 4 events were liver related (148 patients, 2.6 per 100 person-years). Cardiovascular events were associated with the greatest risk of death (hazard ratio = 8.64; 95% CI: 5.1 to 14.5). The first grade 4 event and the first AIDS event were associated with similar risks of death, 5.68 and 6.95, respectively. Conclusions: Grade 4 events are as important as AIDS events in the era of HAART. To adequately evaluate the impact of HAART on morbidity, comorbidities and other key factors must be carefully assessed.
- Objective: To estimate incidence and predictors of serious or life-threatening events that are not AIDS defining, AIDS events, and death among patients treated with highly active antiretroviral therapy (HAART) in the setting of 5 large multicenter randomized treatment trials conducted in the United States. Methods : Data were analyzed from 2947 patients enrolled from December 1996 through December 2001. All patients were to receive antiretrovirals throughout follow-up. Data collection was uniform for all main outcome measures: serious or life-threatening (grade 4) events, AIDS, and death. Results : During follow-up, 675 patients experienced a grade 4 event (11.4 per 100 person-years); 332 developed an AIDS event (5.6 per 100 person-years); and 272 died (4.6 per 100 person-years). The most common grade 4 events were liver related (148 patients, 2.6 per 100 person-years). Cardiovascular events were associated with the greatest risk of death (hazard ratio = 8.64; 95% CI: 5.1 to 14.5). The first grade 4 event and the first AIDS event were associated with similar risks of death, 5.68 and 6.95, respectively. Conclusions: Grade 4 events are as important as AIDS events in the era of HAART. To adequately evaluate the impact of HAART on morbidity, comorbidities and other key factors must be carefully assessed.
- Slide #62: Risk Factors for Severe, Life-Threatening, and Fatal Hepatotoxicity With Nevirapine Recent data have prompted the marketers of nevirapine to issue a clarification regarding the risk of severe hepatoxicity associated with nevirapine use. Women with CD4 cell counts >250 cells/mm 3 , including pregnant women receiving chronic treatment for HIV infection, are at 12-fold higher risk of severe hepatotoxicity while receiving nevirapine. Some of these events have been fatal. Greatest risk of severe and potentially fatal hepatic events often associated with rash, and occurs in first 6 weeks of nevirapine therapy. The risk continues after this time and it is advised to monitor patients closely for first 18 weeks of nevirapine exposure. In some cases, hepatic injury progresses despite discontinuation of treatment. If rash develops, all patients should have liver function tests performed. Nevirapine should not be used for chronic therapy among women with CD4 >250 cells/mm 3 when other options exist.
- Nevirapine hypersensitivity: any combination excluding isolated rash. HLA-DRB1*0101 carriage frequency: United Kingdom: 22% Australia: ≈ 18% US Caucasian: ≈ 18% Mediterranean: 15% to 18% Japan: 11% to 18% US Asian: ≈ 7% US Hispanic: ≈ 7% US African-American: ≈ 3% to 4% Thailand: 1% If there is class 2 MHC involvement, then CD4+ cell counts may influence the risk of nevirapine hypersensitivity reactions The MHC class ll are cell surface molecules which perform an essential function in immunological detection using T-helper cells. They are encoded by the genes HLA-DR, -DQ and -DP Class II molecules interact exclusively with CD4+ T cells (also known as helper T cell lymphocytes or HTLs). The helper T cells then help to trigger an appropriate immune response which may include localized inflammation and swelling due to recruitment of phagocytes or may lead to a full-force antibody immune response due to activation of B cells
- Hepatitis C Virus and Human Immunodeficiency Virus Coinfection Slide 1. General Overview of HIV/HCV Coinfection: Epidemiology of HIV and HCV Slide 2. I'm going to give brief introductory comments on the epidemiology of coinfection. These are both viruses that end up in Infectious Diseases Society of America (IDSA) territory, but they're very different. Hepatitis C is a very dynamic infection, more dynamic probably than human immunodeficiency virus (HIV), and a very diverse and complex virus. It's infecting the liver and not the lymphoid tissue, there are different receptors involved, and it's attacking the cells. The infections often do go together. Slide 3. Most of the patients infected with hepatitis C are monoinfected with hepatitis C, and a minority is coinfected with HIV. However, on the HIV side, it's more evenly split between those monoinfected and those coinfected. Slide 4. The type of person who is coinfected varies by the risk factor for their HIV, with a much higher prevalence rate in the intravenous drug using population compared with the other populations, with heterosexuals about 14%, and homosexuals about 10%. Slide 5. In terms of the risk of coinfection with hepatitis C, hepatitis B, and HIV in drug users, and this is from the Baltimore group, hepatitis C is the more common one, and it's dramatically higher than HIV. Impact of Human Immunodeficiency Virus on Hepatitis C Virus What about the interaction between these 2 viruses? HIV accelerates hepatitis C virus (HCV)-related liver disease. Prior to highly active antiretroviral therapy (HAART), I was signing between 50 and 100 death certificates a year because we have a very large HIV clinic next door. Then in 1999, I only signed 1 death certificate. And that was a patient who died of chronic liver disease from hepatitis C with good control of the HIV. The data support the fact that HIV-coinfected patients progress more to liver failure and also to death.
- For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202010/Tracks/HCV%20Treatment/Capsules/211.aspx
- For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202010/Tracks/HCV%20Treatment/Capsules/211.aspx
- Telaprevir is an investigational serine HCV protease inhibitor. In the ADVANCE trial, conducted in patients with genotype 1 HCV monoinfection, the coadministration of telaprevir with peginterferon/ribavirin was shown to substantially increase sustained virologic response (SVR) rates vs peginterferon/ribavirin alone in HCV treatment–naive patients (Capsule Summary).[35] At CROI 2011, Sulkowski and colleagues[36] reported interim results of the first treatment trial of triple combination therapy for HCV infection in HIV/HCV-coinfected patients receiving or not receiving concomitant antiretroviral therapy. (Capsule Summary). Study 110 is a randomized, placebo-controlled clinical trial designed to evaluate the safety and efficacy of telaprevir plus peginterferon alfa-2a/ribavirin in HIV/genotype 1 HCV–coinfected patients who were naive to HCV treatment at entry. Part A recruited 13 patients with CD4+ cell counts > 500 cells/mm3 and HIV-1 RNA < 10,000 copies/mL, who were not currently receiving HIV therapy. These individuals were randomized to telaprevir or placebo, each combined with peginterferon/ribavirin. In Part B, 46 patients with CD4+ cell counts > 300 cells/mm3 and HIV-1 RNA < 50 copies/mL on stable antiretroviral therapy comprising tenofovir/emtricitabine/efavirenz or tenofovir with either emtricitabine or lamivudine plus atazanavir/ritonavir were similarly randomized to peginterferon/ribavirin with telaprevir or placebo. In both parts of the study, telaprevir or placebo was administered in combination with peginterferon/ribavirin for 12 weeks, followed by peginterferon/ribavirin alone to Week 48, and patients were evaluated for SVR 24 weeks later, at Week 78. The data presented at this interim analysis included results to Week 12. Telaprevir was dosed 750 mg every 8 hours, except in patients receiving efavirenz, who received an increased telaprevir dose of 1125 mg every 8 hours to manage an observed drug-drug interaction between these 2 agents. At Week 12, use of telaprevir increased rates of undetectable HCV RNA vs placebo in the overall study group and in all treatment subgroups. In the combined study population, the response rate in the telaprevir group was 68% vs 14% for placebo. Among those who received HAART and telaprevir, response rates were 75% for the efavirenz group and 57% for the atazanavir/ritonavir group, compared with 12% for the comparator placebo arm in each case. In the no-HAART group, 71% of patients receiving telaprevir achieved undetectable HCV RNA vs 17% of those on placebo. Nausea, pruritus, dizziness, and fever were more common among telaprevir recipients compared to those allocated placebo, with serious adverse events reported in 3 patients in the active treatment arms, 1 of whom received no HAART, whereas the other 2 received atazanavir/ritonavir. The safety profile was also somewhat reassuring. A greater risk of moderate rash events was observed in the telaprevir group (11% vs < 1% for placebo), although it was not clear if this led to discontinuations. Overall, it is encouraging to see data on telaprevir in HIV/HCV-coinfected patients, but I fear that the need to increase the telaprevir dose when it is used with efavirenz may prove confusing. Es alentador observar que no hubo pérdida de la eficacia antirretroviral con la adiciónde la terapia de la hepatitis, aunque las concentraciones de efavirenz y atazanavirdisminuyeron aproximadamente un 20%. Estas impresionantes tasas de respuesta del VHC son los primeros datos, lo que refleja la respuesta en la semana 12 sólo, aunque se sabe que las respuestas iniciales son altamente predictivos de RVS. Sin embargo, será importante ver los datos decriterio de valoración principal en las tasas de RVS antes de sacar conclusiones firmesse pueden extraer.
- A separate report on drug-drug interaction studies with telaprevir and antiretrovirals demonstrated negative interactions between telaprevir and most boosted PIs, that is, lopinavir/ritonavir, darunavir/ritonavir, and fosamprenavir/ritonavir, which really only leaves atazanavir/ritonavir (Capsule Summary).[37] When telaprevir is given with an efavirenz-based regimen, increasing the telaprevir dose from 900 mg to 1125 mg 3 times daily will result in a substantial pill burden, albeit only for the 12 weeks of telaprevir administration.
- For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202010/Tracks/HCV%20Treatment/Capsules/LB4.aspx
- For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202010/Tracks/HCV%20Treatment/Capsules/LB4.aspx
- For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202010/Tracks/HCV%20Treatment/Capsules/216.aspx
- BOC, boceprevir; PR, peginterferon/ribavirin; SVR, sustained virological response. The results of RESPOND-2 are shown on this graph. The overall SVR rates in the response-guided therapy and standard-duration therapy arms were 59% and 66%, respectively; both of these SVR rates were significantly higher than in the control arm, at 21% ( P < .0001). When analyzed by type of previous nonresponse, relapsers achieved higher SVR rates of 69% to 75% vs 29% in the control arm. Previous nonresponders also achieved higher SVR rates of 40% to 52% vs 7% in the control arm. In the response-guided arm, 46% of patients were eligible for a shorter duration of therapy; those individuals achieved a very high SVR rate of 86%. For more information, go online to: http://clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202010/Tracks/HCV%20Treatment/Capsules/216.aspx
- Boceprevir is a second orally administered investigational HCV serine protease inhibitor that is active against genotype 1 HCV. Phase III trials of boceprevir plus peginterferon/ribavirin have been completed in genotype 1 HCV–monoinfected patients in both the treatment-naive (Capsule Summary)[38] and treatment-experienced setting (Capsule Summary),[39] and this agent is currently being considered for approval by regulatory authorities around the same time as telaprevir. Boceprevir is a substrate and selective inhibitor of cytochrome P (CYP) 3A4/5, as well as being a substrate and inhibitor of P-glycoprotein. Studies of the use of boceprevir in HIV/HCV-coinfected patients are ongoing but no data are available yet. However, at CROI 2011, Kasserra and colleagues[40] presented a study that evaluated the clinical pharmacology of boceprevir and interactions with common drug probes and HIV medications (Capsule Summary). All elements of this phase I study were conducted in healthy volunteers, except for the peginterferon-boceprevir interaction study, which was conducted in patients with chronic genotype 1 HCV monoinfection and nonresponse to previous peginterferon (with/without ribavirin). Boceprevir pharmacokinetics were not markedly altered by coadministration with most metabolic inhibitors, including diflunisal, ritonavir, and clarithromycin, or with tenofovir or peginterferon. Coadministration with efavirenz reduced mean trough boceprevir concentration, but further study will be required to determine any clinical implications. The investigators showed that boceprevir pharmacokinetics were not altered by ritonavir, clarithromycin, tenofovir, or pegylated interferon, but boceprevir levels were increased by ketoconazole, which is a well known CYP3A4 inhibitor, albeit a less potent inhibitor than ritonavir. The investigators proposed that the increase in boceprevir levels with ketoconazole suggests that another non–CYP3A4-mediated metabolic pathway is also involved, so there appear to be some questions still to be answered about the pharmacology of boceprevir. It was disappointing that there were no data on interactions between boceprevir and boosted PIs (other than the low-dose ritonavir component) and no data on raltegravir. Overall, I came away from this presentation feeling that I still need to know more about how to use boceprevir with antiretroviral agents. P reocupa el posible uso fuera de etiqueta de estos agentes en pacientes coinfectados, en caso de ser licenciado en monoinfección por VHC,como se espera. Existe un potencial de toxicidad, el fracaso antirretroviral y / o hepatitis C y el fracaso del tratamiento resistencia si estos fármacos se utilizan de forma inadecuada en los pacientes coinfectados antes de que tengamos un conocimiento adecuado de las posibles interacciones.
- Global prevalence of HIV –HCV co-infection This slide illustrates the proportion of HIV and HCV patients that are co-infected with HCV and HIV, respectively. Approximately a third of patients with HIV are also infected with HCV while 5-10% of HCV infected patients are co-infected with HIV. Slide updated in March 2005. Further information available at: http://www.roche-hiv.com/home/home.cfm
- Data on 9802 patients in 72 European HIV center were analyzed. Incidence rates of AIDS, global mortality and liver-related mortality, time to 25% CD4 cell count increase and time to HIV viral load <400 copies/ml after starting anti-HIV were calculated and compared between HBsAg(+) and HBsAg(-) patients. The incidences of all-cause and liver-related mortalities were significantly higher in HBsAg-positive subjects compared with HBsAg-negative subjects. HBsAg status did not influence viral or immunological responses among the 1679 patients starting potent anti-HIV therapy. Reference: 1. Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS . 2005;19(6):593-601.
- Data on 9802 patients in 72 European HIV center were analyzed. Incidence rates of AIDS, global mortality and liver-related mortality, time to 25% CD4 cell count increase and time to HIV viral load <400 copies/ml after starting anti-HIV were calculated and compared between HBsAg(+) and HBsAg(-) patients. The incidences of all-cause and liver-related mortalities were significantly higher in HBsAg-positive subjects compared with HBsAg-negative subjects. HBsAg status did not influence viral or immunological responses among the 1679 patients starting potent anti-HIV therapy. Reference: 1. Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS . 2005;19(6):593-601.