Aula sbad 2017 2
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1) O documento discute os critérios para suspensão do tratamento com análogos de nucleotídeos para hepatite B crônica. 2) Fatores como perfil HBe, perda do HBsAg, cirrose e nível de detecção do HBV-DNA devem ser considerados na decisão. 3) Recomenda-se não suspender o tratamento em pacientes cirróticos ou na profilaxia de hepatite B para imunossuprimidos ou após transplante hepático.
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Aula sbad 2017 2
- 1. Quando suspender os análogos núcleos(t)ídeos ? Liliana Sampaio Costa Mendes Brasília – DF HOSPITAL DE BASE DO DISTRITO FEDERAL
- 2. sem conflito de interesse na apresentação dessa palestra Declaração de conflito de interesse Resolução RDC 96/2008 da ANVISA
- 3. Motivo de início do análogo de nucleot(s)ídeo Tratamento da hepatite crônica B Profilaxia na imunossu- pressão Prevenção de hepatite B vertical Após transplante hepático
- 4. Dúvidas na descontinuação do tratamento para hepatite B Quais os preditores de RVS?
- 5. Referências: AASLD guidelines EASL guidelines Revisões sistemáticas (2016) avaliando dados e fatores preditivos de remissão Estudos: descontinuação dos análogos e seguimento por um mínimo de 12 meses.
- 6. Fatores a considerar Perfil Hbe (positivo vs negativo) Perda do HBsAg Cirrose Limite de detecção do HBV- DNA Monitorização APÓS suspensão do AN
- 7. Critérios de suspensão de análogos de nucleos(t)ideos na Hepatite B Crônica HBeAg+ HBeAg -- APASL update 2015 Publicado 2016 Soroconversão consolidada 1-3 anos do HBeAg seroconversion e ALT normal Obs: Pode ser considerada em cirróticos com plano de motitorizacção eficiente (A1). Perda do HBsAg Consolidada > 1ano em não cirróticos Ou tratamentos de > 2 anos com HBV DNA neg 3 vezes com intervalos de 6 meses EASL 2017 Perda do HBsAg Soroconversão do sistema “e” Consolidada em não cirróticos Perda do HBsAg Supressão virologica > 3 anos em não cirróticos AASLD 2015 Soroconversão do sistema “e” consolidada em não Perda do HBsAg
- 8. Soroconversão do sistema “s” HBsAg + HBsAg – Cirróticos x não cirróticos
- 9. Taxa de perda anual do HBsAg 1% LAMIVUDINA 2% ENTECAVIR 3% TENOFOVIR 0% TELBIVUDIN A
- 10. Preditores de perda do HBsAg nos HBeAg (+) em uso de AN controvérsias!!! Idade mais elevada Elevada ALT Perda de HBeAg Tempo para perda de HBsAg com AN: após 36 anos de AN nos HBeAg+ após 39 anos de AN nos HBeAg – Zoutendijknet, R. al, 2011 > 50 anos de AN!!! Chevaliez, S et al, 2013
- 11. Acrescentar Peg IFN aos análogos de nucleos(t)ideos colabora com a perda do HBsAg? N: 48 HBV com HBeAg + ou - com TNF > 6 meses N: 23 TENOFOVIR +Peg IFN 180mcg sem 12 meses TENOFOVIR 12 meses PERDA HBsAg: 4,3% 2 interrupções por efeitos colaterais N:25 TENOFOVIR ISOLADO 24 meses PERDA HBsAg 0% 2013-2016 Unicêntrico Arabia Saudita, Riyhiad
- 12. Guideline EASL 2017 NAs devem ser descontinuados após a perda confirmada do HBsAg, com ou sem seroconversão anti-HBs (nível de evidência II-2, grau de recomendação 1)
- 13. Soroconversão do sistema “e” HBeAg + HBeAg – (20% COM AN )
- 14. Pacientes HBeAg(+) com soroconversão HBe AASLD 2015: “paciente não cirrótico que faz seroconversão HBe em uso de análogos deve interromper o seu uso após um período de consolidação” evidência muito baixa força da recomendação condicional
- 15. Guideline EASL 2017 HbeAg (+) com soroconversão HBe ANs podem ser descontinuados em pacientes não cirróticos com soroconversão HBeAg estável: HBV- DNA indetectável e que completaram pelo menos 12 meses de terapia de consolidação. O acompanhamento imediato pós-NA é garantido (nível de evidência II-2, grau de recomendação 2).
- 16. O Que é Consolidação soroconversão HbeAg : Período de consolidação: 12 meses estabilidade da soroconversão ‘’e’’ + HBV-DNA indetectável (ALT normal) Consolidações mais longas reduzem a recorrência virológica? Monitorar a cada 3 meses HBV-DNA durante > 1 ano
- 17. Suspensão na soroconversão HbeAg :CIRROSE “Pacientes cirróticos que fazem soroconversão Hbe devem permanecer em uso de análogos indefinidamente” Considerar a suspensão naqueles que perdem o HBsAg (sem evidência suficiente) (seguir mensalmente com carga viral e ALT nos 1os seis meses e após a cada três meses) AASLD 2015
- 18. NÃO SUSPENDER O ANALOGO DE NUCLEOS(T)IDEO !!! Guideline EASL 2017 Cirrose e soroconversão ‘‘e’’
- 19. Metas após suspensão dos AN na soroconversão “e” MANTER Anti-Hbe positivo e HBeAg negativo DNA VHB < 2000-20.000UI EASL 2017
- 20. Suspensão dos Análogos nos HBeAg – Cirróticos x não cirróticos
- 21. Critério da APASL para suspensão: HBV-DNA indetectável 3 ocasiões por um período de 6 meses consecutivos) Estudo retrospectivo - 581 cirróticos 381 continuaram Entecavir 205 suspenderam Não houve aumento na incidência de CHC no grupo que suspendeu entecavir
- 22. Considerar descontinuação em não cirroticos selecionados se supressão viral (DNA negativo > 3anos) sob uso de analogos Se monitorização de perto (nível de evidência II-2, grau de recomendação 1) Guideline EASL 2017 Sem Cirrose e Hbe negativo
- 23. AASLD 2015 HBeAg negativo – duração do tratamento “Pacientes com hepatite B HBeAg negativo devem manter a terapia indefinidamente a menos que haja um racional para suspensão da mesma” (evidência baixa e recomendação condicional)
- 24. AASLD 2015 HBeAg negativo – CIRROSE Dados limitados mas não se recomenda a suspensão no paciente cirrótico Indicação no paciente que negativa o HBsAg? Evidência limitadas
- 25. HBeAg negativo – duração do tratamento O “Dada a lacuna de conhecimento em relação aos desfechos a longo prazo com e sem terapia com antivirais, são necessários mais RCT com maior tempo de acompanhamento para determinar se a terapia antiviral pode ser interrompida de forma segura em pessoas HBeAg- negativo, infectadas com HBV com e sem cirrose . O AASLD guidelines, 2015
- 26. Perfil HBe Papatheodoridis et al, Hepatology 2016
- 27. HBeAg (+) Pacientes HBeAg (+) que soroconverteram. Suspensão após pelo menos seis meses de consolidação
- 28. Quando suspender os analogos de nucleos(t)ideos na Profilaxia da hepatite B para imunossupressão
- 29. Quando suspender os analogos de nucleos(t)ideos na prevenção de hepatite B vertical
- 30. Quando suspender os analogos de nucleos(t)ideos após o transplante hepático Nunca!
Notas do Editor
- Por a referencia
- Easl 2017 NAs should be discontinued after confirmed HBsAg loss, with or without anti-HBs seroconversion (Evidence level II-2, grade of recommendation 1). NAs can be discontinued in non-cirrhotic HBeAg- positive CHB patients who achieve stable HBeAg sero- conversion and undetectable HBV DNA and who com- plete at least 12months of consolidation therapy. Close post-NA monitoring is warranted (Evidence level II-2, grade of recommendation 2). Discontinuation of NAs in selected non-cirrhotic HBeAg-negative patients who have achieved long- term (P3years) virological suppression under NA(s) may be considered if close post-NA monitoring can be guaranteed (Evidence level II-2, grade of recom- mendation 2). Apasl 2016 For HBeAg-positive patients without liver cirrhosis, the optimal duration of NA therapy is unknown, and the therapy can be stopped after at least 1 year (A1), but preferably after 3 years (C1) of additional therapy after HBeAg seroconversion with undetectable HBV DNA by PCR and persistently normal ALT levels. The optimal duration of NA therapy is unknown in patients with HBeAg-negative CHB. In patients without liver cirrhosis, the treatment can be withdrawn (1) after HBsAg loss following either anti-HBs seroconversion or at least 12 months of a post-HBsAg clearance consolidation per- iod (B1), or (2) after treatment for at least 2 years with undetectable HBV DNA documented on three separate occasions, 6 months apart (B1). After stopping of NAs, patients should be monitored monthly for the initial 3 months and then every 3–6 months thereafter for relapse (A2). The stopping of NA therapy may also be considered in cirrhotic patients with a careful off-therapy monitoring plan (A1).
- Duration of Treatment in Persons With HBeAg-Negative Immune-Active CHB Recommendations 4. The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative immune-active CHB, unless there is a competing rationale for treatment discontinuation. Quality/Certainly of Evidence: Low Strength of Recommendation: Conditional Technical Remarks 1. A decision to discontinue therapy for HBeAg- negative adults without cirrhosis requires careful consideration of risks and benefits for health out- comes including: (i) risk for virological relapse, hepatic decompensation, liver cancer, and death; (ii) burden of continued antiviral therapy, finan- cial concerns associated with medication costs and long-term monitoring, adherence, and poten- tial for drug resistance with treatment interrup- tions; and (iii) patient and provider preferences. 2. Treatment discontinuation in persons with cir- rhosis is not recommended owing to the potential for decompensation and death, although data are limited. 3. Treatment discontinuation may be considered in persons who have demonstrated loss of HBsAg. However, there is currently insufficient evidence to definitively guide treatment decisions for such persons. 4. Persons who stop antiviral therapy should be monitored every 3 months for at least 1 year for recurrent viremia, ALT flares, and clinical decompensation. 5. Antiviral therapy is not recommended for persons without cirrhosis who are HBeAg negative with normal ALT activity and low-level viremia (<2,000 U/mL; “ inactive chronic hepatitis B” ). Background The available NAs are highly effective in suppressing HBV DNA replication. However, they do not eliminate cccDNA or viral DNA integrated into the host genome.58 Importantly, HBV viremia typically recurs upon treatment cessation despite successful virus sup- pression during therapy, in some with hepatitis flares and/or decompensation.59 In this context, long-term antiviral therapy is considered. A previous AASLD hepa- titis B practice guideline (2009)2 recommended antiviral therapy for HBeAg-negative persons until HBsAg clear- ance was achieved. Evidence and Rationale The evidence profile is summarized in Supporting Table 3. We found no high-quality evidence comparing clinically important long-term outcomes, such as HCC, 272 TERRAULT ET AL. HEPATOLOGY, January 2016 cirrhosis, decompensation, and death, among HBeAg- negative persons who stopped compared to those who continued antiviral therapy. There were also no data examining optimal duration of therapy before stopping antiviral therapy in HBeAg-negative adults. Although an RCT compared continuing versus stopping adefovir therapy,60 treatment duration and follow-up were short (only 1 year) with recurrence of viremia in most persons upon treatment discontinuation. Similarly, viremia recurred in most persons with 1 year or less of lamivu- dine therapy.61,62 Subsequently, four cohort studies examined the effect of treatment discontinuation in HBeAg-negative per- sons with longer duration of NA therapy (median 2 or more years) including 27 Chinese Canadians,63 61 Chi- nese,64 33 Greek,65 and 95 Taiwanese persons.66 These studies showed recurrent viremia to level 2,000 IU/ mL in almost half and ALT elevation in approximately one third to one half of the persons. HBsAg loss was observed in 8 of 61 (13%) persons who stopped therapy after at least 24 months (median, 27; range, 24-66 months) of lamivudine therapy in one study64 and in 13 of 33 (39%) after 4-5 years of adefovir therapy in another study.65 Although there was no significant dif- ference in clinical decompensation between adults with and without cirrhosis, decompensation occurred in 1 of 39 (2.6%) with cirrhosis in one study.66 In a separate study from Taiwan67 of 263 persons with CHB (includ- ing 147 HBeAg negative) who discontinued lamivudine therapy after recovery from a hepatitis B flare with hepatic decompensation, the cumulative incidence of hepatic decompensation at 1, 2, and 5 years was 8.2%, 12.5%, and 19.8%, respectively. Though there was no difference in the incidence of hepatic decompensation between persons with and without cirrhosis, 3 persons with cirrhosis died of hepatic decompensation. Collectively, these foregoing studies suggest that virus suppression (<2,000 IU/mL) and ALT normalization may be sustained in almost half of the HBeAg-negative persons with treatment duration longer than 2 or more years. However, the effect of treatment discontinuation on long-term morbidity and mortality remains unclear, with persistent concern for hepatic decompensation and death (particularly in persons with cirrhosis). Thus, con- sideration for treatment discontinuation requires careful weighing of potential for harm and benefit. Future Research Given the knowledge gap regarding long-term health outcomes with and without antiviral therapy, more RCTs with longer duration of follow-up are needed to determine whether antiviral therapy can safely be stopped in HBeAg-negative, HBV-infected persons with and without cirrhosis. Alternative treatment strategies for patients on long-term NA therapy, such as adding or switching to Peg-IFN therapy, warrant further study. Additional studies are needed to identify potential pre- dictors for safe treatment discontinuation, including HBsAg levels (not available in the United States) and cccDNA.
- Duration of Treatment in Persons With HBeAg-Negative Immune-Active CHB Recommendations 4. The AASLD suggests indefinite antiviral therapy for adults with HBeAg-negative immune-active CHB, unless there is a competing rationale for treatment discontinuation. Quality/Certainly of Evidence: Low Strength of Recommendation: Conditional Technical Remarks 1. A decision to discontinue therapy for HBeAg- negative adults without cirrhosis requires careful consideration of risks and benefits for health out- comes including: (i) risk for virological relapse, hepatic decompensation, liver cancer, and death; (ii) burden of continued antiviral therapy, finan- cial concerns associated with medication costs and long-term monitoring, adherence, and poten- tial for drug resistance with treatment interrup- tions; and (iii) patient and provider preferences. 2. Treatment discontinuation in persons with cir- rhosis is not recommended owing to the potential for decompensation and death, although data are limited. 3. Treatment discontinuation may be considered in persons who have demonstrated loss of HBsAg. However, there is currently insufficient evidence to definitively guide treatment decisions for such persons. 4. Persons who stop antiviral therapy should be monitored every 3 months for at least 1 year for recurrent viremia, ALT flares, and clinical decompensation. 5. Antiviral therapy is not recommended for persons without cirrhosis who are HBeAg negative with normal ALT activity and low-level viremia (<2,000 U/mL; “ inactive chronic hepatitis B” ). Background The available NAs are highly effective in suppressing HBV DNA replication. However, they do not eliminate cccDNA or viral DNA integrated into the host genome.58 Importantly, HBV viremia typically recurs upon treatment cessation despite successful virus sup- pression during therapy, in some with hepatitis flares and/or decompensation.59 In this context, long-term antiviral therapy is considered. A previous AASLD hepa- titis B practice guideline (2009)2 recommended antiviral therapy for HBeAg-negative persons until HBsAg clear- ance was achieved. Evidence and Rationale The evidence profile is summarized in Supporting Table 3. We found no high-quality evidence comparing clinically important long-term outcomes, such as HCC, 272 TERRAULT ET AL. HEPATOLOGY, January 2016 cirrhosis, decompensation, and death, among HBeAg- negative persons who stopped compared to those who continued antiviral therapy. There were also no data examining optimal duration of therapy before stopping antiviral therapy in HBeAg-negative adults. Although an RCT compared continuing versus stopping adefovir therapy,60 treatment duration and follow-up were short (only 1 year) with recurrence of viremia in most persons upon treatment discontinuation. Similarly, viremia recurred in most persons with 1 year or less of lamivu- dine therapy.61,62 Subsequently, four cohort studies examined the effect of treatment discontinuation in HBeAg-negative per- sons with longer duration of NA therapy (median 2 or more years) including 27 Chinese Canadians,63 61 Chi- nese,64 33 Greek,65 and 95 Taiwanese persons.66 These studies showed recurrent viremia to level 2,000 IU/ mL in almost half and ALT elevation in approximately one third to one half of the persons. HBsAg loss was observed in 8 of 61 (13%) persons who stopped therapy after at least 24 months (median, 27; range, 24-66 months) of lamivudine therapy in one study64 and in 13 of 33 (39%) after 4-5 years of adefovir therapy in another study.65 Although there was no significant dif- ference in clinical decompensation between adults with and without cirrhosis, decompensation occurred in 1 of 39 (2.6%) with cirrhosis in one study.66 In a separate study from Taiwan67 of 263 persons with CHB (includ- ing 147 HBeAg negative) who discontinued lamivudine therapy after recovery from a hepatitis B flare with hepatic decompensation, the cumulative incidence of hepatic decompensation at 1, 2, and 5 years was 8.2%, 12.5%, and 19.8%, respectively. Though there was no difference in the incidence of hepatic decompensation between persons with and without cirrhosis, 3 persons with cirrhosis died of hepatic decompensation. Collectively, these foregoing studies suggest that virus suppression (<2,000 IU/mL) and ALT normalization may be sustained in almost half of the HBeAg-negative persons with treatment duration longer than 2 or more years. However, the effect of treatment discontinuation on long-term morbidity and mortality remains unclear, with persistent concern for hepatic decompensation and death (particularly in persons with cirrhosis). Thus, con- sideration for treatment discontinuation requires careful weighing of potential for harm and benefit. Future Research Given the knowledge gap regarding long-term health outcomes with and without antiviral therapy, more RCTs with longer duration of follow-up are needed to determine whether antiviral therapy can safely be stopped in HBeAg-negative, HBV-infected persons with and without cirrhosis. Alternative treatment strategies for patients on long-term NA therapy, such as adding or switching to Peg-IFN therapy, warrant further study. Additional studies are needed to identify potential pre- dictors for safe treatment discontinuation, including HBsAg levels (not available in the United States) and cccDNA.