Tratamento atual dos Genótipos 2 e 3: Clube do Fígado do DF
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O documento discute as opções de tratamento para os genótipos 2 e 3 do vírus da hepatite C. Para pacientes genótipo 2 sem cirrose, a combinação de sofosbuvir e ribavirina por 12 semanas tem alta taxa de sucesso. Para pacientes genótipo 3 sem cirrose, sofosbuvir combinado com outros antivirais como daclatasvir ou velpatasvir por 12 semanas também apresenta bons resultados. O tratamento de pacientes cirróticos requer esquemas mais longos ou a adição de ribavirina.
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Tratamento atual dos Genótipos 2 e 3: Clube do Fígado do DF
- 1. 1 Liliana Mendes Hospital de Base do Distrito Federal Brasília DF Tratamento atual dos Genótipos 2 e 3: Clube do Fígado do DF 08 de junho de 2017
- 2. 2 Declaração de conflito de interesse Resolução RDC 96/2008 da ANVISA • Realizo palestras técnico-científicas para as indústrias Janssen Cilag • Participação em pesquisas aprovadas no CEP – Plataforma Brasil em hepatite C
- 3. Genótipos 2 e 3 têm distribuição global 3 http://www.medscape.org/viewarticle/561043_4 Prevalência Genótipo 1 Genótipo 2 Genótipo 3 EUA 75% 15% 7% França 57% 9% 21% Alemanha 62% 7% 28% Itália 62% 27% 7% Espanha 65% 3% 20% Reino Unido 45% 10% 40% Brasil 70% 5% 25% • Alter MJ, et al. New England J Med. 1999;341:556-62.; • Cornberg M, et al. Liver Int. 2011;31(s2):30-60. SUL DO BRASIL > 40%
- 4. GT2 ≠ GT3 RESPOSTA aos esquemas com DAAs
- 5. Nkontchou G, et al. J Viral Hepat. 2011Bochoud PY, et al. J Viral Hepat. 2009 G3 G1 G2 P<0,001 História natural da infecção pelo GT2 e GT3 Evolução mais rápida para cirrose Menor sobrevida livre de HCC P=0,002 Anos GT3: RISCO que outros genótipos de esteatose hepática cura quando comparado a outros genótipos (especialmente em cirróticos)
- 6. 6 Tratamento do paciente VHC – GT 2 NÃO CIRRÓTICO Cube do Fígado do DF 08 de junho de 2017 Clube do Fígado do DF 08 de junho de 2017
- 7. 7 RVS24(%) 91 34 0 20 40 60 80 100 GT 2 GT 3 RVS24(%) 98 61 0 20 40 60 80 100 GT 2 GT 3 SEM CIRROSE COM CIRROSE 58/59 89/145 10/11 13/38 Lawitz E, et al. N Engl J Med. 2013 GT2 n=70 GT3 n=183 Estudo FISSION: SOF + RBV 12s em GT 2/3 naives n 183 GT3: 145 pacientes SEM cirrose
- 8. 97 78 98 82 91 62 0 20 40 60 80 100 RVS-12(%) 58/59 44/54 10/11 8/1368/70 52/67 SOF + RBV 12s PEG + RBV 24s Sem cirrose Com CirroseGlobal ESTUDO FISSION (SOF/RBV 12s versus PEG/RBV 24s) Naïves Em pacientes Genótipo 2, é melhor que PEG/RBV 24 sem Lawitz E, et al. N Engl J Med. 2013
- 9. 9 Mesmos genótipos do VHC em realidades diferentes… O que é bom perto do ótimo?
- 10. 10 99 94 12 sem 12 sem
- 11. DCV + SOF 12 sem GT2 Guideline AASLD 2017 Esquema aprovado pelo FDA para HCV GT3 o DCV mantém atividade adequada contra o GT 2 do HCV Taxas elevadas de RVS em GT 2 naives com 12 sem e 24 sem de tratamento Não está claro um subgrupo de HCV GT2 se beneficiaria com 24 sem tratamento.
- 12. 12 Easl 2016 e AASLD 2017 – GT 2 SEM Cirrose : Naïve ou experimentado a PR
- 13. Melhores evidências apontam para: SOF/RBV 12 sem – Ensaios clínicos (VALENCE, POSITRON, FUSION E FISSION): 60-94% (84%) – Vida real (VALOR): 79% • PCDT Brasil disponibiliza: PCDT Hepatite C - Genótipo 2
- 14. Proposta de atualização do PCDT Consulta Pública Início: 08/04/2017 Término: 27/04/2017
- 15. • Tratamento do paciente VHC – GT 3 não cirrótico Clube do Fígado do DF 08 de junho de 2017
- 16. Zeuzem S, et al. N Engl J Med 2014;370:1993–2001 16 212/250 12/13 95 87/92 87 85/98 62 29/47 0 20 40 60 80 100 85 213/250 Global Naïve, Sem cirrose Experimentado Sem cirrose Naïve, Com cirrose Experimentado Com cirrose SVR12(%) 92 Interrupção por EAs: 1% ESTUDO VALENCE em GT3 (SOF + RBV por 24 semanas) RVS em GT3 “difíceis” (CIRRÓTICOS/EXPERIMENTADOS)RVS-12(%)
- 17. RVS-12(%) 65/ 72 68/ 71 18/ 22 21/ 23 44/ 54 49/ 52 26/ 34 30/ 35 Estudo BOSON: GT3 SOF+RBV 24s vs. SOF+PEG/R 12s Naïves 90 82 96 91 Não Cirróticos Cirróticos Experimentados 82 77 94 86 Não Cirróticos Cirróticos
- 18. Nelson DR, et al. Hepatology. 2015 Estudo ALLY-3: SOF + DCV por 12 semanas (n =141 pacientes GT3) Sem Cirrose Com cirrose Interrupção por EAs: 0% 96 97 94 0 20 40 60 80 100 RVS-12,% 73 75 105 109 32 34 63 58 69 0 20 40 60 80 100 20 32 9 13 11 19 Global Naïve Experimentado
- 19. Tratamentos do HCV GT 3 com SOF SEM CIRROSE 19 Resumo de RVS dos estudos VALENCE, ALLY-3 E BOSON Esquema baseados em SOF resultam em RVS similares em pacientes GT 3 naïve ou experimentados RVS12,% 95 92 87 62 98 58 92 69 96 91 94 86 0 20 40 60 80 100 Naïve não cirrótico Naïve cirrótico Experimentado não cirrótico Experimentado cirrótico SOF+RBV x 24 sem (VALENCE) SOF+DCV x 12 sem (ALLY-3) SOF+PegIFN+RBV x 12 sem (BOSON) Zeuzem S, et al. NEJM. 2014. Gane, et al. Gastroenterology 2015. Accepted Article. Foster, et al. Gastroenterology 2015. Accepted Article. Daklinza™ US PI July 2015 Lawitz E, DDW 2015, Poster Tu1018
- 20. 20 TRATAMENTO DE VHC SEM CIRROSE - ASTRAL 3 SOF VELPA
- 21. 21 EASL 2016 – SEM Cirrose hepatica: Naïve ou experimentado a PR
- 22. 22 EASL E AASLD – Opções IFN Free para G3 SEM CIRROSE SOF+VELPA NAIVE EXP PEG + RIBA 12 wk sem riba 12 wk sem riba 12 wk com riba ou 24 wk sem riba 12 wk com riba ou 24 wk sem riba AASLD GUIDANCE => ABRIL 2017: NAÏVE EXP PEG + RIBA SOF+VELPA 12 wk sem riba SOF+DCV 12 wk sem riba SOF+VELPA 12 wk sem riba SOF+DCV 12 wk sem riba http://www.hcvguidelines.org Changes made April 12, 2017. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol (2016)
- 23. PCDT Brasil: GT3 sem cirrose – SOFOSBUVIR+PEG+RBV 12 semanas – SOFOSBUVIR+DACLATASVIR 12 semanas
- 24. 24 Proposta de atualização do PCDT Consulta Pública Início: 08/04/2017 Término: 27/04/2017 + RIBA
- 25. Tratamento do paciente HCV GT2 CIRRÓTICO COMPENSADO 25 Clube do Fígado do DF 08 de junho de 2017
- 26. 93 68/73 212/250 Global 97 100 94 78 Naïve sem cirrose Experimentado sem cirrose 29/30 2/2 7/930/32 Naïve com cirrose Experimentado com cirrose 0 20 40 60 80 100 Interrupção por EAs: 1% ESTUDO VALENCE: 73 pacientes GT2 tratados com SOF/RBV 12s RVS-12(%) SOF/RBV 12 semanas é suficiente para a maior parte dos pacientes com GT2… Zeuzem S, et al. N Engl J Med 2014;370:1993–2001 Cirróticos experimentados parecem ter menor RVS
- 27. SOF/RBV 12sem em GT2 naïves e experimentados Dieterich D, et al. AASLD 2014 Análise ITT Estudo TRIO: vida real EUA n=179
- 28. 28 EASL 2016 – COM Cirrose hepatica GT2:Naïve ou exp a PR
- 30. • PCDT Brasil disponibiliza: PCDT Hepatite C - Genótipo 2
- 31. Proposta de atualização do PCDT Consulta Pública Início: 08/04/2017 Término: 27/04/2017
- 32. Tratamento do paciente HCV GT3 CIRRÓTICO COMPENSADO 32 Clube do Fígado do DF 08 de junho de 2017
- 33. 82 77 91 86 Naïves Experimentados SOF + RBV 24 sem. SOF + PEG/R 12 sem. RVS-12(%) 18 22 21 23 26 34 30 35 Estudo BOSON: SOF+RBV 24s vs. SOF+PEG/R 12s – análise do subgrupo de cirróticos GT3 Foster GR, et al. EASL 2015 - Oral
- 34. Nelson DR, et al. Hepatology. 2015 Estudo ALLY-3: SOF + DCV por 12 semanas (n =141 pacientes GT3) Sem Cirrose Com cirrose Interrupção por EAs: 0% 96 97 94 0 20 40 60 80 100 RVS-12,% 63 58 69 0 20 40 60 80 100 20 32 9 13 11 19 Global Naïve Experimentado 73 75 105 109 32 34 RVS-12,%
- 35. ALLY-3 Plus: SOF+DCV+RBV 12 semanas vs 16 semanas Pacientes GT 3 com Cirrose Leroy V, et al. AASLD, 2015
- 36. Tratamentos do HCV GT 3 com SOF Sem response-guided therapy (RGT) VALENCE: Naïve e Experimentados 0 12 24 36Seman a RVS12SOF + RBV, n=250 ⸗ Sofosbuvir 85% BOSON: Naïve e Experimentados SOF + PegIFN + RBV, n=181 RVS12 84% 93% RVS12 LONESTAR-2: Experimentados RVS12SOF + PegIFN + RBV, n=24 83% RVS12SOF + RBV, n=182 ⸗ ⸗ SOF + DCV, n=51 RVS12 86% ALLY-3: Naïve e Experimentados RVS12SOF + DCV, n=101 90% Zeuzem S, et al. NEJM. 2014. Gane, et al. Gastroenterology 2015. Foster, et al. Gastroenterology 2015. Daklinza™ US PI July 2015 Lawitz E, DDW 2015, Poster Tu1018 Resumo de RVS dos estudos VALENCE, ALLY-3, BOSON e LONESTAR-2 Cirroticos n:60 (24%) Cirroticos n:56 (31%) Cirroticos n:58 (32%) Cirroticos n:12 (50%) Cirroticos n:19 (19%) Cirroticos n:13 (25%)
- 37. HEPATHER: GT3 vida real na França SOF/DCV ±RBV por 12 ou 24 semanas Uso compassivo em pacientes Genótipo 3 – 77% com cirrose – 12% com Child B/C – 73% experimentados SOF/DCV por 24 semanas (± RBV) parece melhorar RVS em pacientes GT3 com cirrose avançada. 22 29 52 59 11 12 5 6 Pol S, et al. EASL 2015
- 38. French CUP RVS 12 de acordo com Child-Pugh em GT3 . DCV + SOF ± RBV 12 semanas DCV + SOF 24 semanas Child-Pugh A Child-Pugh B or C SVR12(%) DCV + SOF + RBV 24 semanas 100 80 60 40 20 0 80 33 90 71 85 70 28/ 33 7/ 10 90/ 100 12/ 17 24/ 30 2/ 6 Hezode C, et al. AASLD 2015. Abstract 206. Geral 87% 142/163 Geral 64% 21/33
- 39. 39 TRATAMENTO DE VHC GT3 COM CIRROSE - ASTRAL 3 24 SEM12 SEM
- 40. 40
- 41. 41 GUIDELINE EASL 2016 NS5A RAS Y93H Sem cirrose experimentados Cirroticos NAIVES OU EXPERIMENTADOS ACRESCENTAR RIBAVIRINA !!!
- 42. DCV or VEL in Treatment- Experienced GT3 HCV Infection Vermehren J, et al. EASL 2017. Abstract PS-155. Reproduced with permission. • Real-world cohort of patients with GT3 HCV infection treated according to baseline NS5A RASs, previous treatment failure, and cirrhosis status (N = 167) DCV + SOF VEL/SOF 12 wks, no RBV 12-24 wks, with RBV 24 wks, with RBV No Cirrhosis Cirrhosis No Cirrhosis BLY93H Cirrhosis No BL A30K BL A30K SVR12(%) n/N = 100 80 60 40 20 0 All NaiveTx Exp All NaiveTx Exp All Naive Tx Exp 45/ 47 30/ 32 15/ 15 3/ 3 2/ 2 1/ 1 33/ 36 10/ 10 23/ 26 17/ 17 12/ 12 5/ 5 3/ 3 2/ 2 1/ 1 12/ 12 8/ 8 4/ 4 96 94 100 100 100 100 100 100100100100100 100100100100 92 88 All NaiveTx Exp All NaiveTx Exp All Naive Tx Exp
- 43. 43 Easl 2016 - Cirrose hepatica: Naive ou experimentado a PR EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol (2016) EASL e AASLD GUIDELINES : 2016-2017 CIRROSE HEPÁTICA CHILD-PUGH A: GT3 naives e exp PEG RIBA EASL: SOF + DACL + RIBA 24 SEMANAS AASLD+RIBA naives e + RIBA exp EASL: SOF + velpa + RIBA 12 SEMANAS - RIBA 24 SEMANAS AASLD => SOF + velpa 12 sem: naives SOF + velpa + riba 12 sem: Exp PR elbasvir/grazoprevir + SOF 12 sem
- 44. ??? PCDT Brasil: GT3 sem cirrose – SOFOSBUVIR+PEG+RBV 12 semanas – SOFOSBUVIR+DACLATASVIR± RBV 12 semanas COM * Ribavirina opcional RVS no CH exp 70% - 83%
- 45. 45 SOF + DCV + RIBA 24s : 85 – 90 % CHILD A 70% CHILD C SOF + PEG + RIBA 12s = 90 - 95 % SOF + DCV 12s = 96 % TRATAMENTO DA HEPATITE C GENÓTIPO 3 Drogas aprovadas no Brasil - RVS SEM CIRROSE SOF + PEG + RIBA 12s:86% COM CIRROSE SOF + DCV + RIBA 12s:83-88%? ALLY 3 PLUS 71% descompensados SOF + RIBA 24s = 68% SOF + RIBA 24s = 87 – 95 %
- 47. Proposta de atualização do PCDT Consulta Pública Início: 08/04/2017 Término: 27/04/2017 + RIBA
- 48. Para guardar... Não cirrótico Cirrótico SOF + PEG/RBV 12s Tolerantes a PEG/RBV Intolerantes a PEG/RBV SOF/DCV 12s SOF/DCV 24s (com RBV) Intolerantes a PEG/RBV HEPATITE C GENÓTIPO 3 no Brasil
- 49. Proposta de atualização do PCDT Consulta Pública Início: 08/04/2017 Término: 27/04/2017
- 50. Para guardar... Não cirrótico Cirrótico SOF + RBV 12s Tolerantes a RBV Intolerantes A RBV SOF/DCV 12s SOF/DCV 12s (com RBV) HEPATITE C GENÓTIPO 2 no Brasil
- 51. 51 OBRIGADO!!! mendesliliana2@gmail.com Telefone (061) 984013142 Todos juntos para erradicação da hepatite C Antes de 2030…
Notas do Editor
- SOF VELPA 12 X SOF RIBA 12 SEM
- A cirrose é o principal preditor de resposta no G 3 –pegar Manga et al AASLD 2013 poster 1115
- Qd comparamos SOF e Riba 24 com Sof;P e riba 12 para não CH observamos uma excelente resposta ao Sofo-Peg-Riba 12 semanas que se mantem no subgrupo de experimentados. Há uma queda de resposta ao Sof e Riba 24 sem naqueles experimentados em relaçcão aos naives
- Transition: Here is a summary of SVR12 rates in GT 3 patients treated with SOF-based regimens in the VALENCE, ELECTRON-2, ALLY-3, and BOSON studies Main Message: SOF-based regimens resulted in similar SVR rates in TN and TE HCV GT 3 patients
- pa- tients were enrolled at 76 sites in the United States, Canada, Europe (France, Germany, Italy, and the United Kingdom), Australia, and New Zealand from July 30, 2014, through December 17, 2014.
- ALLY 3 CIRROSE COMPENSADA
- EMBORA PAREÇCA QUE 16 SEM TEM SEU PAPEL FICA DIFICIL POSICIONAR COM N PEQ Main message 12 semanas não foi pior que 16 semanas qd usado SOF DACL e RIBA, então 12 semans seriam suficientes 86% overall SVR12 in cirrhotics, 88% in treatment experienced cirrhotics on 12 weeks and 86% in treatment experienced on 16 weeks 100% SVR was seen in the advanced fibrosis group 4 patients relapsed on therapy 1 relapser had baseline NS5A RAVs 38/41 pts without baseline NS5A RAVs achieved SVR (93%) 7/8 pts with baseline NS5A RAVs achieved SVR (88%) Background This data should be viewed in context of the ASTRAL-3 SOF/VEL x 12 weeks data, SVR rates of 93% in TN cirrhotics (40/43) and 89% in TE cirrhotics (33/37), without the use of ribavirin Many strategies have been employed to achieve higher SVR rates in genotype 3 patients, historical references specifically for cirrhotic patients are below: ALLY-3 results (DCV+SOF x 12 wks) 63% cirrhotics, 58% in TN cirrhotics, 69% in TE cirrhotics ELECTRON-2 results (LDV/SOF+RBV x 12 wks 100% in TN cirrhotics (5/5), 73% in TE cirrhotics (16/22) BOSON results (SOF+P/R x 12 wks) 91% in TN cirrhotics (21/23), 86% in TE cirrhotics (30/35) Details on 4 relapsers: 1 TN, 3 TE (2 prior SOF+RBV relapse, 1 IFN based viral breakthrough), 3 IL28B CT, 1 IL28B CC, all patients with cirrhosis, by either biopsy or FibroScan. No relapsers had ribavirin dose reduction.
- Transition: The study designs for the sofosbuvir-based studies with GT 3 patients are presented in this slide Background: Objective: to evaluate the safety and efficacy of the following SOF-based therapies for patients infected with HCV GT 3 infection: Treatment Naïve (TN) SOF + RBV for 24 weeks SOF + PegIFN + RBV for 12 weeks LDV/SOF for 12 weeks LDV/SOF + RBV for 12 weeks Treatment Experienced (TE) SOF + RBV for 24 weeks SOF + PegIFN + RBV for 12 weeks LDV/SOF + RBV for 12 weeks Inclusion criteria had no upper limit to age or body mass index Minimum platelet count at screening VALENCE: ≥50,000 cells/mL BOSON: ≥60,000 cells/mL LONESTAR-2: ≥90,000 cells/mL (or ≥ 75,000/μL for patients with cirrhosis) ELECTRON-2: ≥50,000 cells/mL Primary efficacy endpoint - HCV RNA <LLOQ at post-treatment Week 12 VALENCE, LONESTAR-2, ELECTRON-2: analyzed by COBAS® TaqMan® HCV Test v2.0 HPS (LLOQ of <25 IU/mL) BOSON: analyzed by Ampliprep TaqMan® HCV Test v2.0 (LLOQ <15 IU/mL) Primary safety endpoints - adverse events, discontinuations, and laboratory abnormalities
- Qto mais avança o CHILD pior a resposta sobretudos em esquemas com 12 semanas, há sinais de que mesmo qd riba é adicionada nas fases mais avançadas ela não agrega mais resposta
- pa- tients were enrolled at 76 sites in the United States, Canada, Europe (France, Germany, Italy, and the United Kingdom), Australia, and New Zealand from July 30, 2014, through December 17, 2014.
- DCV, daclatasvir; GT, genotype; RAS, resistance associated substitution; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response as 12 weeks post treatment; Tx, treatment; VEL, velpatasvir; BL, baseline.
- Aasld 2017 Daclatasvir with sofosbuvir for 12 weeks was approved by the FDA for treatment of HCV genotype 3 infection. The recommendation is based on ALLY-3, a phase III study of the once-daily NS5A inhibitor daclatasvir plus sofosbuvir for 12 weeks; the study included 101 treatment-naïve patients and demonstrated an SVR12 rate of 90%. In treatment-naïve patients without cirrhosis (Metavir F0-F3), 97% achieved SVR12, and in treatment-naïve patients with cirrhosis (Metavir F4), 58% achieved SVR12 (Nelson, 2015). This suggests that patients with genotype 3 infection and cirrhosis are likely to benefit from an extension of therapy. This has been confirmed in cohort studies, including the European compassionate-use program, which reported SVR12 rates of 70% versus 86% when daclatasvir and sofosbuvir were used for 12 weeks and 24 weeks in HCV genotype 3-infected patients with cirrhosis, respectively. The role of ribavirin could not be clarified, as only 4 patients received daclatasvir plus sofosbuvir and ribavirin for 12 weeks, all or which achieved SVR12. SVR12 was comparable between the 24-week arms irrespective of the addition of ribavirin (85.9% [116/135] without compared to 81.3% [39/48] with ribavirin). SVR12 rates were also higher in those with compensated Child-Pugh A cirrhosis (85%-90% compared to 70.6% in Child B/C). Again the addition of ribavirin did not increase SVR12 rates in the 24-week arms (Hezode, 2017). 73% of patients were treatment-experienced, however earlier data suggested that SVR12 rates were higher in treatment-naïve patients (91%-100%) compared to experienced (81%-82%). SVR12 rates were similar in those that received ribavirin (88%, 29/33) and those that did not (86%, 42/49) (Hezode, 2015b). The exact duration of therapy for a treatment-naïve genotype 3 patient with compensated cirrhosis is not known. The phase III study, ALLY3-+, investigated the combination of daclatasvir plus sofosbuvir and ribavirin for 12 weeks or 16 weeks in treatment-naïve and -experienced genotype 3 patients with both stage 3 and compensated cirrhosis. Overall SVR12 rates were 86% with cirrhosis, the majority of which were treatment experienced. Extending the duration to 16 weeks did not have a strong impact with 88% (15/17) achieving SVR12 with 12 weeks and 89% (16/18) achieving SVR12 with 16 weeks. All 14 patients with stage 3 disease achieved SVR12 irrespective of treatment duration (Leroy, 2016). Presence of baseline NS5A RASs significantly reduces rates of SVR12 with a 12-week course of daclatasvir plus sofosbuvir in genotype 3-infected patients. In analysis of 175 subjects infected with HCV genotype 3 and nucleotide sequence data in the ALLY-3 trial, the presence of a NS5A Y93H substitution was associated with a reduced SVR12 rate; 54% (7/13) compared to 92% (149/162). Although the small numbers make interpretation difficult, only 7% (13/175) had NS5A Y93H substitution, all of which were subgenotype 3a. SVR rates were numerically lower in those with both cirrhosis and Y93H. In non-cirrhotic subjects with Y93H, 67% (6/9) achieved SVR12 compared to 98% (125/128) of those non-cirrhotic without Y93H. In those with both cirrhosis and Y93H, 25% (1/4) achieved SVR12 compared to 71% (24/34) in those with cirrhosis but without the substitution (Daklinza PI). Substitutions at A30K, L31F, L31I in genotype 3a replicon are associated with reduced daclatasvir susceptibility (Daklinza PI). In the ALLY-3 trial, subjects with A30K and without cirrhosis achieved 100% SVR12 (9/9), however those with cirrhosis had lower SVR12 rates (1/5) (Nelson, 2015). The impact of this single substitution is difficult to discern as 2/5 had compound substitutions with Y93H. Pending further data on optimal therapy in the setting of baseline Y93 substitution, the addition of ribavirin for patients with cirrhosis is recommended. Additional real-world studies support the use of this regimen for treatment-naïve, genotype-3 infected patients with advanced liver disease (Welzel, 2016). Sofosbuvir/velpatasvir Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks was approved by the FDA for the treatment of HCV genotype 3 infection in patients with and without cirrhosis. ASTRAL-3 demonstrated superiority of 12 weeks of sofosbuvir/velpatasvir to 24 weeks sofosbuvir plus ribavirin in 552 treatment- naïve and -experienced subjects with and without cirrhosis (Foster, 2015a). In treatment-naïve, non-cirrhotic subjects, SVR12 rates were 98% (160/163) compared to 90% (141/156), respectively. In those with cirrhosis SVR12 was 93% (40/43) compared to 73% (33/45), respectively. Of the 250 subjects that received sofosbuvir/velpatasvir 43 (16%) had baseline NS5A RASs; of which 88% achieved SVR12 compared to 97% without baseline substitutions. 84% (21/25) with Y93H achieved SVR12. Pending further data on optimal therapy in the setting of baseline Y93 substitution, the addition of ribavirin for patients with cirrhosis is recommended. Elbasvir/grazoprevir + sofosbuvir C-SWIFT investigated the efficacy of triple therapy with the daily fixed-dose combination of elbasvir/grazoprevir and sofosbuvir (400 mg) for 8 weeks to 12 weeks in genotype 3 treatment-naïve patients with and without compensated cirrhosis. 93% (14/15) of non-cirrhotic patients achieved SVR12 with 8 weeks and 100% (14/14) with 12 weeks of this combination. 91% (10/11) compensated cirrhotic subjects achieved SVR12 with 12 weeks of therapy (Poordad, 2016).