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Quando suspender análogos nucleotídeos na hepatite B
- 1. Quando suspender os análogos núcleos(t)ídeos ? Liliana Sampaio Costa Mendes Brasília – DF HOSPITAL DE BASE DO DISTRITO FEDERAL
- 2. Declaração de conflito de interesse Resolução RDC 96/2008 da ANVISA sem conflito de interesse na apresentação dessa palestra
- 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
- 5. Fatores a considerar Perfil Hbe (positivo vs negativo) Perda do HBsAg Cirrose Monitorização APÓS suspensão do AN
- 6. 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 2016 Soroconversão do sistema “e” consolidada em não cirróticos Perda do HBsAg
- 7. Soroconversão do sistema “s” HBsAg + HBsAg –
- 8. Taxa de perda anual do HBsAg 1% LAMIVUDINA 2% ENTECAVIR 3% TENOFOVIR 0% TELBIVUDINA
- 9. 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
- 10. 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 (2 anos de seguimento)
- 11. 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)
- 12. Soroconversão do sistema “e” HBeAg + HBeAg – (20% COM AN )
- 13. Pacientes HBeAg(+) com soroconversão ‘‘e’’ não cirrótico AASLD 2016: “paciente não cirrótico que faz soroconversão HBe em uso de análogos deve interromper o seu uso após um período de consolidação evidência muito baixa força da recomendação condicional
- 14. HbeAg (+) com soroconversão “e” não cirróticos 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 EASL 2017
- 15. CONSOLIDAÇÃO Período de consolidação: 12 meses ALT normal + HBV-DNA indetectável Tratar por períodos mais longos ( ex 24 meses) diminui a chance de recorrência virológica? Monitorar a cada 3 meses HBV-DNA durante 1 ano AASLD 2016
- 16. Metas após suspensão dos analogos de nucleos(t)ideos nos HBeAg + HBeAg - Manutenção da soroconversão ‘‘e’’ ocorre em > 90% (3 anos após) Remissão virologica (DNA 2000-20000UI) ocorre em > 50% (3 anos após) EASL 2017
- 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) Neste grupo seguir mensalmente com carga viral e ALT nos 1os seis meses e após a cada três meses AASLD 2016
- 19. HBeAg negativo suspensão do AN? “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) AASLD 2016
- 20. HBeAg (-) não cirrótico Interrupção dos AN em não cirróticos HBeAg negativos que tenham conseguido a supressão virológica de longo prazo (3 anos) pode ser considerada se um monitoramento pós-AN próximo pode ser garantido EASL 2017
- 21. HBeAg negativo com cirrose Dados limitados mas não se recomenda a suspensão no paciente cirrótico Indicação no paciente que negativa o HBsAg? Evidência limitadas
- 22. Critério da APASL para suspensão: - HBV-DNA indetectável 3 ocasiões por 6 meses consecutivos Estudo retrospectivo 586 cirróticos em uso de Entecavir (China) 381 continuaram 205 suspenderam Não houve aumento na incidência de CHC no grupo que suspendeu entecavir Aliment Pharmacol Ther. 2015 Nov;42(10):1182-91 mean follow-up duration of 54.6 + 20.6 months
- 23. HBeAg negativo – duração do tratamento “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 .’’ AASLD guideline, 2016
- 24. Quando suspender os analogos de nucleos(t)ideos na Profilaxia da hepatite B para imunossupressão Faltam evidências do tempo ideal da duração da profilaxia antiviral. A maioria dos estudos avaliou uso adicional de 3-6 meses de antiviral após completada imunossupressão. -> guideline EASL suspender 12 m apos QT Sem comparações diretas entre estudos limitando fortes recomendações Reativações tardias com Rituximab após suspensão do antiviral -> guideline EASL suspender 18m apos QT Feld J. J, Dig Dis, 2017ç 35: 351-358
- 25. Quando suspender os analogos de nucleos(t)ideos na prevenção de hepatite B vertical Inicio do AN: DNA VHB >200,000 IU/mL (1 milhão copias/mL) Antiviral foi descontinuado do nascimento até 3 meses após o parto na maioria dos estudos. (monitorar ALT a cada 3 meses por 6 meses) AASLD 2016
- 26. Quando suspender os analogos de nucleos(t)ideos após o transplante hepático Nunca!
- 27. Quando suspender os análogos núcleos(t)ídeos ? Conclusões Existe a possibilidade de suspender os AN na perda do HBsAg e soroconversão consolidada do sistema ‘‘e’’ Monitorização garantida de ALT e DNA após a suspensão do AN Menor evidência de segurança de suspensão do AN nos HBeAg negativos e cirróticos Não esta definido tempo de suspensão mas evidencias apontam para 3 m apos parto, 12 m apos QT E 18 m apos Rituximab Tratamento de hepatite crônica B Prevenção de reativação de hepatite crônica B e da transmissão vertical
- 28. R4 de Gastro Germania Ana Carolina Raphael Dantonio Ariana Cadurin R3 de Gastro R5 de EDA Felipe Bezerra R5 de Hepato Raquel
Notas do Editor
- Dna < 2000 1 a apos a retirada do an
- 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.
- Easl 2017 Long-term, perhaps indefinite, NA therapy is usually given in HBeAg-negative CHB patients, who are considered to be able to safely stop NAs only if they achieve HBsAg loss.1 Recent evidence, accumulating mainly from Asian countries, in which NAs can be discontinued in HBeAg-negative CHB patients who achieve serum HBV DNA undetectability on three separate occasions 6 months apart,97 suggests that the discontinuation of NAs might be also feasible in this setting. An important factor affecting the probabil- ity of off-NA virological remission appears to be the duration of on-therapy HBV DNA undetectability.41 According to the existing data, virological remission defined as HBV DNA \2,000– 20,000 IU/ml will be maintained in approximately 50% of such patients 3 years after NAs cessation if they have remained for more than two years on virological remission during therapy.41 Since such findings are based on studies with durations of on- therapy virological remission of [2 to 5 years,41 the optimal dura- tion of on NAs remission before discontinuation remains unclear. Since overt hepatitis flares and life-threatening episodes have been rarely reported in patients with pre-existing cirrhosis who discontinue NAs,98 treatment discontinuation is currently dis- couraged in patients with cirrhosis. Moreover, NAs may be discon- tinued only in patients who can be followed closely with ALT and HBV DNA determinations at least during the first year following NAs cessation. Unfortunately, no reliable predictor of post-NAs remission has been identified to date. Retreatment criteria are also important, but have yet to be determined.41 Based on reasonable clinical judgment, treatment indications for naïve CHB patients may be also applied in patients who discontinue NAs.
- Aliment Pharmacol Ther. 2015 Nov;42(10):1182-91. doi: 10.1111/apt.13409. Epub 2015 Sep 18. Clinical outcomes after interruption of entecavir therapy in HBeAg-negative chronic hepatitis B patients with compensated cirrhosis. Chen YC1, Peng CY2, Jeng WJ1, Chien RN3, Liaw YF1. Author information Abstract BACKGROUND: Long-term nucleos(t)ide analogues therapy may reduce hepatocellular carcinoma (HCC) in chronic hepatitis B patients with advanced fibrosis or cirrhosis. AIM: To investigate in a retrospective-prospective study whether this beneficial effect would be reduced in cirrhotic patients who discontinued a successful course of entecavir (ETV) therapy. METHODS: The study included 586 hepatitis B e antigen (HBeAg)-negative patients with compensated cirrhosis, mean age of 53.8 ± 10 years and 81% males, treated with ETV for at least 12 months. After ETV therapy for 46.5 ± 22.9 months, 205 patients who achieved hepatitis B virus (HBV) DNA suppression discontinued therapy. The clinical outcomes were assessed and HCC incidence was compared between propensity score (PS)-matched patients who continued and patients who discontinued ETV therapy by Asian Pacific Association for the Study of Liver stopping rule. RESULTS: During a mean duration of 59.3 ± 19 months after start of ETV therapy, nine and six HCC developed in an estimated annual incidence of 2.3% and 1.6% in 154 PS-matched patients who continued and who discontinued ETV therapy, respectively (P = 0.587). Multivariate Cox proportional hazards regression analyses showed that age (HR 1.065, P < 0.001) and HBV DNA (HR 1.216, P = 0.048) were the significant factors for HCC development. The rates of adverse clinical outcomes were comparable. CONCLUSIONS: The clinical outcomes, including HCC, after cessation of a successful course of entecavir therapy in patients with compensated cirrhosis were comparable to those who continued therapy. The results suggest that this strategy of finite therapy is safe and a feasible alternative to indefinite therapy, especially in a low resources setting.