Bible Class: HBV Infection - Nasser Semmo

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Bible Class: HBV Infection - Nasser Semmo
Bible Class:
               HBV Infection

Nasser Semmo          UVCM, Hepatology
Bible Class: HBV Infection - Nasser Semmo
What is the HBV prevalence?

                              2
Hepatitis B
• Worldwide approx. 350 Mio. chronically infected with HBV

• Approx. 40% of the world population: anti-HBc-Antibodies
  positive

• Approx. 15 Mio. chronically HBV infected in Europe

• Switzerland 0,3% (24000)

• Worldwide annually, 0,6 -1 Mio. people die from
  complications of chronic HBV-Infection (WHO, 2002)

• HBV responsible for 60% of all HCC cases worldwide
                                                             3
Worldwide distribution of HBV infection

                                          4
What are Hepatitis B Risk Factors?

                                     5
Hepatitis B Risk Factors

• Blood contamination
   – IV-Drug Abuse
   – Injured mucus membranes

• Sexual Transmission

• Perinatal Transmission

                               6
Natural course of HBV Infection?

                                   7
Natural Course of Hepatitis B Infection

                  Acute Hepatitis B
          90%

 Resolution               10%   Fulminant Hepatitis (0.5-1%)
                 Chronic Hepatitis B
           70%

Asymptomatic              30%              ?
   carriers
                  Liver cirrhosis
                                       3-5%/year

 Liver failure                             HCC

                                                        8
Who to screen for HBV ?

                          9
Hepatitis B
Whom to screen?

• Elevated Liver enzymes and/or signs of hepatitis or chronic
  liver disease of unknown origin
• Liver cirrhosis/-fibrosis
• New diagnosis of HCC
• Pat. with migration background and from regions with high
  HBsAg prevalence (East Europe, Mediterranean)
• Family member or sexual partner from HBV infected
  patients

DGVS-Leitlinie Hepatitis B 2007/ EASL 2012

                                                            10
Hepatitis B
Whom to screen?

• Medical staff
• Homosexuals a/o persons with frequent changing sexual
  partners
• Active o. previous i.v.-drug abuse
• Dialysis patients

DGVS-Leitlinie Hepatitis B 2007/ EASL 2012

                                                          11
Hepatitis B
Whom to screen?

• HIV- a/o HCV-infected Pat.
• Recipients of organs before transplantation
• Blood- and Organ donors
• Patients before or during immunsuppressive therapy or
  Chemotherapy
• Pregnant women (HBsAg)

DGVS-Leitlinie Hepatitis B 2007/ EASL 2012

                                                          12
Prevention of HBV Reactivation
         Algorithm??

                                 13
Prevention of HBV Reactivation

     HBsAg +                      HBsAg -                    HBsAg -
                                  Anti-HBc +                 Anti-HBc -
                                  Anti-HBs +/-               Anti-HBs -

  HBV-DNA +/-                     HBV-DNA &                   Impfung
                                  ALT alle 1-3 m             Vor Start immun-
                                                             suppressiver Tx

                                  HBV DNA –    HBV DNA –
                      HBV DNA +
                                  ALT < ULN    ALT > ULN

Preemptive antivirale Tx                      Suche nach anderen
(NAs) bis zu 12 M nach                        Ursachen einer Erhöhung
Ende immunsuppr. Tx                           der Leberenzyme
                                                                                14
When to treat pregnant HBV pos. women?

                                         15
Vertical transmission despite active and
              passive vaccination
   • N=1068 Kinder von HBeAg positiven Müttern

   • 3% vertikale Transmission bei HBV DNA >106 cop/ml

   • 5,5 % vertikale Transmission bei HBV DNA >107 cop/ml

   • 9,6% vertikale Transmission bei HBV DNA >108 cop/ml

   à Antivirale Therapie im 2./3. Trimester ab 200.000 IU/ml

Han et al., J Hepatology 2011, Petersen Hepatology 2011
                                                            16
Prävention einer HBV Reaktivierung

 • Screening aller Patienten auf HBsAg und anti-HBc
   vor Einleitung einer immunsuppressiven Therapie
   und/oder einer Chemotherapie!
 • HBV Impfung, wenn HBV Serologie komplett negativ
 • HBsAg + Pat.: Preemptive Therapie mit NA bis zu 12
   Monate nach Ende einer immunsuppressiven Tx/
   Chemotherapie, unabhängig von HBV Viruslast
 • Behandlung mit Lamivudine, wenn HBV Viruslast <
   2000 IU/mL
 • Behandlung mit Entecavir oder Tenofovir wenn HBV
   Viruslast > 2000 IU/mL
                                 EASL CPG, J Hepatol 2012
                                                            17
Prävention einer HBV Reaktivierung

 • HBsAg -/ Anti-HBc + pat.: HBV Viruslast-Bestimmung,
   wenn pos. = „Okkulte“ HBV Infektion
 • „Okkulte“ HBV Infektion: Preemptive Therapie mit NA
 • HBsAg -/ Anti-HBc + / HBV DNA - pat.: Regelmässige
   Kontrollen von ALT und HBV DNA, und Tx mit NA
   sobald HBV-Reaktivierung, vor Erhöhung der ALT
 • Kontrollintervalle zwischen 1-3 Monate, abhänging von
   der Art der immunosuppressiven Therapie und
   Komorbiditäten

                                   EASL CPG, J Hepatol 2012
                                                              18
Prävention einer HBV Reaktivierung

 • Empfehlung einiger Experten: Prophylaxe mit Lamivudin
   bei allen HBsAg-negativen, anti-HBc positiven
   Patienten, die Rituximab und/oder kombinierte
   Therapien für hämatologische Tumorerkrankungen
   erhalten, wenn sie anti-HBs negative und/oder eine
   engmaschiges Monitoring der HBV DNA nicht garantiert
   ist
 • Die optimale Prophylaxedauer für diese Indikation ist
   nicht klar
 • HBsAg-negative Empfänger von Lebertransplantaten
   von anti-HBc positiven Spendern sollten eine
   dauerhafte Prophylaxe mit Lamivudin erhalten
                                  EASL CPG, J Hepatol 2012
                                                             19
When to treat HBV ?

                      20
HBV Treatment Indication

                           21
How to treat HBV ?

                     22
HBV- Treatment: HOW?
High TA (>3-5 x)
Low viral titer
Short duration of infection
GT A or B
PEG-IFN 2a 180ug 48 weeks

                              23
Is there a stopping rule for PegIFN?

                                       24
Practical application of response-guided
 therapy using HBsAg levels (pegIFN-treated)

    Identify responders (PPV)              Identify non-responders (NPV)

Week 12:                                  Week 12:
- HBeAg-positive                    e+    - HBeAg-positive e+
           HBsAg 20,000 IU/mL
                                          - HBeAg-negative                  e-
- HBeAg-negative                     e-

                                                  No decline in HBsAg +
          ≥10% decline HBsAg
HBV Treatment: HOW?

                      26
Response-guided therapy (RGT) using HBsAg
 levels in Peg-IFN-treated patients: to identify
                good responders

           HBeAg positive                            HBeAg negative

 Week 12 - 24:                               Week 12 - 24 (geno D):
 - HBsAg
Response-guided therapy (RGT) using HBsAg levels in
    Peg-IFN-treated patients: to identify non responders

                HBeAg-positive             HBeAg-negative (geno D)

   Week 12:                               Week 12:
   - No decline of HBsAg (A,D)            - No decline in HBsAg +
   - HBsAg >20,000 IU/mL (B,C)              20,000 IU/ml (A,B,C,D)

                      97-100% Negative Predictive Values
Sonneveld et al. Hepatology 2010
Piratvisuth et al. APASL 2010
Liaw et al. Hepatology 2011                  Rijckborst et al. Hepatology 2010
Sonneveld et al., Hepatology 2013            Rijckborst / Lampertico et al. J Hepatol 2012
                                                                                         28
What are the NUC options?

                            29
HBV is suppressable
…in most cases with indefinite treatment duration...

                Lamivudin (Zeffix,                                   36-72%
                Epivir)
                Adefovir (Hepsera)                                   21-51
                                                                     %
                Entecavir (Baraclude)                                67-90%

                Telbivudin (Sebivo)                                  60-88%

                Tenofovir (Viread)                                   76-94%
                                                                                                         25.03.15
Lai CL, et al. Hepatology 2005; 42:748A (AASLD Abstract LB01); Lau G, et al. NEJM 2005; 352:2882–2695; Chang   T-T, et al.
NEJM 2006; 354:1000–1010; Marcellin P, et al. NEJM 2003;348:808–816; Marcellin et al., AASLD 2007, Heathcote et al., 30
Can NUCs be stopped?

                       31
When to stop NUC therapy ?
                                Treatment End points

                                        HBeAg+	
                                                         HBeAg-­‐	
  

       Seroconversion	
                                         No	
  
      HBeAg-­‐/anA-­‐HBe+	
                               seroconversion	
  

          End	
  of	
  therapy:	
  
  At	
  least	
  a6er	
  12	
  months	
                                                           Long-­‐term	
  therapy	
  
                                                        Long-­‐term	
  therapy	
  
   A6er	
  seroconversion	
                                                                                 	
  
  And	
  HBV-­‐DNA	
  negaAve	
  

                                        End	
  of	
  therapy:	
  AnA-­‐HBs-­‐Seroconversion	
  

                                                                                      EASL HBV Guidelines 2012
                                                                                                                               32
When to stop NUC therapy ?

 CHB Treatment
  Guidelines
                                           EASL 2012 guidelines

                       A) confirmed anti-HBe seroconversion (and undectable
                          HBV DNA) after at least 12 months of consolidation*
 HBeAg positive
                       B) confirmed HBsAg loss and anti-HBs seroconversion

 HBeAg negative            confirmed HBsAg loss and anti-HBs seroconversion

   Cirrhotics              confirmed HBsAg loss and anti-HBs seroconversion

  *A proportion of patients who discontinue NUC therapy after anti-HBe seroconversion may
   require retreatment, since they fail to sustain their serological and/or virological response

                                                  adapted from EASL HBV Guidelines, J Hepatol 2012
                                                                                                   33
Management of adverse events

When to reduce IFN, and when to stop it?

                                           34
Pegylated Interferon

- Reduce Peg IFN if

   - Absolute neutrophil count falls below 750/mm3
   - Platelet count falls below 50,000/mm3

- Stop Peg IFN if

   - Absolute neutrophil count falls below 500/mm3
   - Platelet count falls below 25,000/mm3
   - or if severe unmanageable depression develops

                                                     35
Leukopenia/Neutropenia
• In general, infection rate during HBV treatment is elevated

• However, neutropenia alone in patients with compensated HBV
  infection is not associated with elevated infection risk

• Patients with neutropenia do not have higher infection rate in
  comparison to those without neutropenia

• Dose reduction of IFN does not lead to reduction of susceptibility to
  infections

• Therefore dose reduction not necessary if no signs of infection present
 Thus: IFN-reduction in pat. with co-morbidities, older pat, liver
 cirrhosis a/o Diabetes if neutrophiles < 750,
 Filgrastim (Neupogen) if neutrophiles
Thrombopenia

• IFN Dose reduction if Tc
THANK YOU

            38
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