Post on 21-Sep-2020
4/16/2020
1
Participating in the Webinar
Listen using your computer audio. A headset is recommended but not required.
All attendees will be muted and will remain in Listen Only Mode.
Type your questions here so that the moderator can see them. Not all questions will be answered but we will get to as many as possible.
How to Receive CME and ABIM MOC Points
LIVE VIRTUAL GRAND ROUNDS WEBINAR
ACG will send a link to a CME & ABIM MOC evaluation to all attendees on the live webinar.
ABIM Board Certified physicians need to complete their MOC activities by December 31, 2020 in order for the MOC points to count toward any MOC requirements that are due by the end of the year. No MOC credit may be awarded after March 1, 2021 for this activity.
ACG will submit MOC points on the first of each month. Please allow 3-5 business days for your MOC credit to appear on your ABIM account.
1
2
American College of Gastroenterology
4/16/2020
2
MOC QUESTION
If you plan to claim ABIM MOC Points for this activity, you will be asked to: Please list specific changes you will make in your practice as a result of the information you received from
this activity.
Include specific strategies or changes that you plan to implement.THESE ANSWERS WILL BE REVIEWED.
ACG Virtual Grand Rounds
Join us for upcoming Virtual Grand Rounds!
Week 5: Refractory GERD: New Options for Treatment 2020Philip O. Katz, MD, MACGApril 23, 2020 at Noon EDT
Week 6: Celiac Disease: 10 Things Every Clinician Should Know Amy S. Oxentenko, MD, FACGApril 30, 2020 at Noon EDT
Visit gi.org/ACGVGR to Register
3
4
American College of Gastroenterology
4/16/2020
3
Register Now at gi.org/ACGVGR
Presenter: Nancy S. Reau, MD, FACG Research Support: Genfit, Intercept, ShireConsultant: Abbott, AbbVie, Gilead, Merck
Moderator: Mitchell L. Shiffman, MD, FACGAdvisory Board: AbbVie, Gilead, Intercept, Mallinckrodt, ShionogiResearch Grant: Conatus, CymaBay, Dova, Enanta, Gilead, InterceptRoyalties: SlackSpeakers Bureau: AbbVie, Daiichi Sankyo, Eisai, Gilead, Intercept, Shionogi
Disclosures:
5
6
American College of Gastroenterology
4/16/2020
4
Hepatitis B Update
Nancy S. Reau, MD, FACG
Chief, Section of Hepatology
Richard B. Capps Chair of HepatologyRush University Medical Center
Agenda
• General overview of HBV Treatment Guidelines
• Highlight treatment conundrums in hepatitis B infection
• Introduce future directions in HBV management
7
8
American College of Gastroenterology
4/16/2020
5
Epidemiology and Public Health Burden
1. EASL CPG HBV. J Hepatol 2017;67:370–98; 2. Schweitzer A, et al. Lancet 2015;386:1546–55; 3. Ott JJ, et al. Vaccine 2012;30:2212–9; 4. GBD 2013 Mortality and Causes of Death Collaborators. Lancet 2015;385:117–71; 5. Coppola N, et al. Euro Surveill 2015;20:30009; 6. Hampel A, et al. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz2016;59:578–83; 7. Chen C‐L, et al. J Hepatol 2015;63:354–63.
• Worldwide ≈250 million chronic HBsAg carriers2,3
• 686,000 deaths from HBV‐related liver disease and HCC in 20134
Increasing prevalence in some European countries:5,6
• Migration from high endemic countries
HBsAg prevalence, adults (1949 years), 20053
<2%24%57%≥8%Not applicable
Decreasing prevalence in some endemic countries, e.g. Taiwan7
Possible reasons:• Improved
socioeconomic status
• Vaccination • Effective treatments
Despite the risk, access to timely diagnosis and treatment is limited globally…
WHO. Global Hepatitis Report 2017. Available at: https://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/ (accessed May 2019)
257
221.7
0
50
100
150
200
250
300
Infected Diagnosed Started treatment
Only 9% of infected individuals globally are diagnosed and only 8% of those start treatment
Per
son
s (m
illio
n)
9% 8%
9
10
American College of Gastroenterology
4/16/2020
6
Current Standard of Care
1. Screening for HBV
2. Goals of therapy
3. Indications for treatment
4. Treatment strategies
5. Endpoints of therapy
Current Standard of Care
1. Screening for HBV
2. Goals of therapy
3. Indications for treatment
4. Treatment strategies
5. Endpoints of therapy
Screening: 1. HBsAg + anti‐HBs2. Anti‐HBs‐ Negative should be vaccinated3. Anti‐HBc not routine but has a role with HIV, HD, Donation and
Immune suppression4. Counsel HBsAg positive on transmission
11
12
American College of Gastroenterology
4/16/2020
7
*Including needle‐sharing contacts of HBsAg‐positive persons;†Those who are seronegative should receive hep B vaccine.
AST: aspartate aminotransferase; CDC: Centers for Disease Control; USPSTF: US Preventative Service Task Force; MSM: men who have sex with men; ESRD: persons with end‐stage renal disease; PEP: postexposure prophylaxis
Risk factorsUSPSTF 2014
CDC 2008
AASLD 2018
Persons born in region with ≥2% prevalence
US‐born persons not vaccinated as infants whose parents were born in regions with ≥8% prevalence
†
MSM †
PWID †
HIV‐positive †
Household and sexual contacts of HBV‐infected persons *†
Requiring immunosuppressive therapy
ESRD, including haemodialysis patients †
Persons with elevated ALT or AST †
Persons who are the source of blood or body fluid exposure that might require PEP †
Pregnant women †
Infants born to HBV‐infected mothers †
Groups Recommended for HBV Screening
Terraut NA, et al. Hepatology 2018;67:1560–99; Terrault NA, et al. Hepatology 2016;63:261–83; Abara WE, et al. Ann Intern Med 2017;167:794–805; Lefevre ML. Ann Intern Med 2014;161:58–66; Weinbaum CM, et al. Hepatology 2009;49(5 Suppl):S35–S44
Risk factorsUSPSTF 2014
CDC 2008 AASLD 2018
Blood and tissue donors
Persons with chronic liver disease, e.g. HCV *
Persons who are not in a long‐term, mutually monogamous relationship *
Persons seeking evaluation or treatment for a STD *
At‐risk health care and public safety workers *
Residents and staff of facilities for developmentally disabled persons *
Travelers to countries with intermediate or high prevalence of HBV infection *
Inmates of correctional facilities *
Unvaccinated persons with diabetes who are aged 19–59 years *
Groups Recommended for HBV Screening (cont’d)
*Those who are seronegative should receive Hep B vaccine.STD: sexually transmitted disease
Terraut NA, et al. Hepatology 2018;67:1560–99; Terrault NA, et al. Hepatology 2016;63:261–83; Abara WE, et al. Ann Intern Med 2017;167:794–805; Lefevre ML. Ann Intern Med 2014;161:58–66; Weinbaum CM, et al. Hepatology 2009;49(5 Suppl):S35–S44.
13
14
American College of Gastroenterology
4/16/2020
8
HBV Serology Interpretation and Management
Screening test resultsInterpretation Management
HBsAg Total/IgG anti‐HBc Anti‐HBs
+ + ‐/+ Current infectionCounselling, evaluation, management, treatment, and HCC risk assessment and surveillance; refer household and sexual contacts for HBV screening and vaccination
‐ + + Prior infection with immune controlNo transmission risk; HBV dormant in the liver; reactivation risk on immunosuppressive medications
‐ + ‐Prior infection, occult* infection, or false‐positive anti‐HBc (< 0.2%)
If immunocompetent†, counsel as prior infection above; if immunocompromised, check HBV DNA for occult infection
‐ ‐ + Immune from prior vaccination Protected for life. No need for booster vaccine
‐ ‐ ‐ Susceptible Vaccinate‡
*Occult HBV infection is defined by the presence or detectable HBV DNA in persons who are HBsAg-negative. Patients with occult HBV infection should be managed similarly to those with current infection.†Consider HBV vaccination for persons not from an area of intermediate or high endemicity, as this may represent a false-positive anti-HBc result. The false-positive anti-HBc is <2/1000, using current assays.‡Groups at high risk for HBV transmission and immunocompromised persons should be assessed for response to vaccination with a PVST of anti-HBs between 1–2 months after the final dose of the vaccine. A challenge vaccine dose or full vaccine series followed by PVST may be given to persons from high-risk groups with documentation of complete vaccination but not PVST.
Slide Courtesy of Amy S Tang, MD, National Hepatitis B Task Force PVST: post‐vaccination serology test.
Current Standard of Care
1. Screening for HBV
2. Goals of therapy
3. Indications for treatment
4. Treatment strategies
5. Endpoints of therapy
15
16
American College of Gastroenterology
4/16/2020
9
Goals of Therapy
• Improve survival and quality of life by preventing disease progression and HCC
• Prevent mother‐to‐child transmission, reactivation, and extrahepatic manifestations
Recommendations
Main endpoint• Induction of long-term suppression of HBV DNA
I 1
Valuable endpoint• Induction of HBeAg loss (± anti-HBe seroconversion)
in HBeAg-positive patients with chronic hepatitis B*II-1 1
Additional endpoint • ALT normalization (biochemical response)†
II-1 1
Optimal endpoint • HBsAg loss (± anti-HBs seroconversion)‡
II-1 1
Grade of evidence Grade of recommendation
*Often represents a partial immune control of the chronic HBV infection;†Achieved in most patients with long-term suppression of HBV replication;‡Indicates profound suppression of HBV replication and viral protein expression.EASL CPG HBV. J Hepatol. 2017;67:370–98.
Current Standard of Care
1. Screening for HBV
2. Goals of therapy
3. Indications for treatment
4. Treatment strategies
5. Endpoints of therapy
17
18
American College of Gastroenterology
4/16/2020
10
HBeAg positive HBeAg negative
Phase 1 Phase 2 Phase 3 Phase 4 Phase 5
Chronic HBV infection
Chronichepatitis B
Chronic HBV infection
Chronichepatitis B
Resolved HBV infection
HBsAg HighHigh/
intermediateLow Intermediate Negative
HBeAg Positive Positive Negative Negative Negative
HBV DNA >107 IU/mL 104–107 IU/mL <2,000 IU/mL* >2,000 IU/mL <10 IU/mL‡
ALT Normal Elevated Normal Elevated† Normal
Liverdisease
None/minimalModerate/
severeNone
Moderate/severe
None§
Immune tolerant
Immune ActiveHBeAg positive
CHBInactive CHB
Immune ActiveHBeAg negative
CHBResolved
Nomenclature Differs by Guideline
*HBV DNA levels can be between 2,000 and 20,000 IU/mL in some patients without signs of chronic hepatitis;†Persisitently or intermittently, based on traditional ULN (~40 IU/L). ‡cccDNA can frequently be detected in the liver;§Residual HCC risk only if cirrhosis has developed before HBsAg loss. EASL CPG HBV. J Hepatol 2017;67:370–98 Terrault NA, et al. Hepatology 2018;67:1560–99;
Chronic HBVinfection
Chronic hepatitis B
EASL
AASLD
qHBsAg<1000 IU/mL
Management of CHB in Patients Without Cirrhosis
Threshold for treatment5
APASL (2015)1 EASL (2017)2US algorithm
(2015)3AASLD (2018)4
HBV DNA, IU/mLHBeAg positiveHBeAg negative
>20,000>2000
>2000>2000
≥2000≥2000
>20,000≥2000
ALTULN for malesULN for females
>2 x ULN40 IU/mL40 IU/mL
>ULN40 IU/L40 IU/L
>ULN30 IU/L19 IU/L
≥2 x ULN35 U/L25 U/L
1. Sarin APASL HBV guidelines. Hepatol Int 2016;10:1; 2. EASL. J Hepatol 2017;67:370; 3. Martin. Clin Gastroenterol Hepatol 2015;13:2071; 4. Terrault. Hepatology 2018;67:1560; 5. Clinical options. Available at clinicaloptions.com (accessed June 2019)
May be treated
• Patients with HBeAg-positive chronic HBV infection† >30 years old, regardless of severity of liver histological lesions
19
20
American College of Gastroenterology
4/16/2020
11
ELEVATED ALT >ULN SIGNIFICANTLY INCREASES RISK OF LIVER‐RELATED COMPLICATIONS
≥45
>30
>20
ALT level (U/L)
Significantly increases risk of developing cirrhosis and HCC1,2
Significantly increases risk of significant liver disease (presence of inflammation and fibrosis) and mortality3
Significantly increases risk of liver disease mortality (20 for women and 30 for men)4
Risk of liver-related complications
1. Iloeje UH, et al. Gastroenterology. 2006;130:678-686; 2. Chen CJ, et al. JAMA. 2006;295:65-73; 3. Wang H, et al. PLoSONE. 2013;8:e80585; 4. Shim JJ, et al. Liver Int. 2018 Jan 27. [epub ahead of print]; 5. Martin P, et al. Clin Gastroenterol Hepatol. 2015;13:2071-2087; 6. Terrault NA, et al. Hepatology. 2018 February 5. Epubahead of print.
AASLD=American Association for the Study of Liver Diseases; ULN=upper limit of normal; USTA=US Treatment Algorithm.
>40
Recommended ALT ULN
men
USTA 20155
30 U/Lwomen19 U/L
men
AASLD 20186
35 U/L 25 U/Lwomen!
Current Standard of Care
1. Screening for HBV
2. Goals of therapy
3. Indications for treatment
4. Treatment strategies
5. Endpoints of therapy
21
22
American College of Gastroenterology
4/16/2020
12
“In most people... treatment does not cure hepatitis B infection, but only suppresses the replication of the virus. Therefore, most people who start
hepatitis B treatment must continue it for life.”
– World Health Organization2
19984
LAM
20025
ADV
20056,7
ETV, PEG‐IFN
20068
LdT
20089
TdF
201610
TAF
Because CHB endures, management must account for the changing needs of patients1-3
CHB Therapy Has Changed Over the Years
adefovir dipivoxil; ETV, entecavir; LAM, lamivudine; LdT, telbivudine; PEG-IFN, peginterferon alfa-2a.1. Terrault NA, et al. Hepatology. 2016;63(1):261-283; 2. WHO Hepatitis B Fact Sheet. Updated July 2016; 3. EASL HBV Clinical Practice Guidelines.J Hepatol. 2012;57(1):167-185; 4. Epivir-HBV® FDA approval letter. December 8, 1998; 5. Hepsera® FDA approval letter. September 20, 2002; 6. Baraclude® FDA approval letter. May 13, 2005; 7. Pegasys® FDA biologics license approval letter. May 13, 2005; 8. Tyzeka® FDA approval letter. October 25, 2006; 9. Viread FDA approval letter. August 11, 2008; 10. VEMLIDY [package insert]. Foster City, CA: Gilead Sciences, Inc; November 2016.
*Evidence level I, grade of recommendation 1; †Collation of currently available data – not from head-to-head studies;‡No evidence of resistance has been shown after 8 years of TDF treatmentEASL CPG HBV. J Hepatol 2017;67:370–98
Cumulative incidence of HBV resistance to NAs in pivotal trials in NA-naïve patients with CHB†
24
38
49
6770
03
11
18
29
4
17
0.50.21.2
0 0 0 0 0 0 00
10
LAM
20
30
40
50
ADV TBV ETV TDF† TAF
60
70
801 year2 years3 years4 years5 years
3 first line oral therapies
Prevention of resistance should rely on the use of first‐line NAs with a high barrier to resistance*
Preferred regimens : PEG, ETV, TDF and TAF
NOT recommended: LAM, ADV and TBV
23
24
American College of Gastroenterology
4/16/2020
13
Indications for selecting ETV or TAF over TDF*
*TAF should be preferred to ETV in patients with previous exposure to NAs; †ETV dose needs to be adjusted ifeGFR <50 ml/min; no dose adjustment of TAF is required in adults or adolescents (aged ≥12 years and ≥35 kg body weight) with estimated CrCl ≥15 ml/min or in patients with CrCl <15 ml/min who are receiving haemodialysisEASL CPG HBV. J Hepatol 2017;67:370–98
Age • >60 years
Bone disease
• Chronic steroid use or use of other medications that worsen bone density
• History of fragility fracture• Osteoporosis
Renal alteration†
• eGFR <60 ml/min/1.73 m2
• Albuminuria >30 mg/24 h or moderate dipstick proteinuria• Low phosphate (<2.5 mg/dl)• Haemodialysis
TAF vs. TDF for HBV: Change in eGFR
Agarwal K, et al. J Hepatol 2018;68:67281
Median change from baseline in eGFR over 96 weeks TAF 25 mg (n=866) vs. TDF 300 mg (n=432)
TAFTDF
TAF: -1.2
TDF: -4.8p<0.001
25
26
American College of Gastroenterology
4/16/2020
14
TAF vs. TDF for HBV: change in BMD
Agarwal K, et al. J Hepatol 2018;68:67281
Median change from baseline in BMD over 96 week TAF 25 mg (n=866) vs. TDF 300 mg (n=432)
TAF
TDF
Hip SpineTAF
TDFp<0.001 p=0.80
Monitoring Patients Treated with ETV, TDF or TAFRecommendations (monitoring)ALT and serum HBV DNA*• All patients treated with NAs q3–4 months for first year then q6 months
Renal monitoring†
• Patients at risk of renal disease treated with any NA • All patients treated with TDF, regardless of renal risk
Switch to ETV or TAF‡
• Should be considered in patients on TDF at risk of development of and/or with underlying renal or bone disease
Recommendations (long‐term surveillance)HCC surveillance recommended• All patients under effective long‐term NA therapy
HCC surveillance mandatory• All patients with cirrhosis or with moderate or high HCC risk scores at the onset of NA therapy
*Liver function tests should be performed every 3–4 months during the first year and every 6 months thereafter. Serum HBV DNA should be determined every 3–4 months during the first year and every 6–12 months thereafter; †Including at least eGFR and serum phosphate levels. Frequency of renal monitoring can be every 3 months during the first year and every 6 months thereafter, if no
deterioration. Closer renal monitoring is required in patients who develop CrCl <60 ml/min or serum phosphate levels <2 mg/dl; ‡Depending on previous LAM exposureEASL. J Hepatol 2017;67:370–398
AASLD: HBsAg-positive adults at high risk for HCCAsian or black men > 40 yrs of age; Asian women > 50 yrs of ageFirst-degree relative with history of HCC Coinfection with HDV
27
28
American College of Gastroenterology
4/16/2020
15
Current Standard of Care
1. Screening for HBV
2. Goals of therapy
3. Indications for treatment
4. Treatment strategies
5. Endpoints of therapy
Discontinuation of NA Treatment
EASL CPG HBV. J Hepatol 2017;67:370–98
Long‐term therapy with NAs is usually required: HBV eradication is not usually achieved
Recommendations
NAs should be discontinued • After confirmed HBsAg loss (± anti-HBs seroconversion)
II-2 1
NAs can be discontinued• In HBeAg-positive patients, without cirrhosis, who achieve stable HBeAg
seroconversion and undetectable HBV DNA and complete ≥12 months of consolidation therapyClose post-NA monitoring is warranted
II-2 2
NAs may be discontinued • In selected HBeAg-negative patients, without cirrhosis, who achieve long-term (≥3
years) virological suppression, if close post-NA monitoring can be guaranteedII-2 2
Grade of evidence Grade of recommendation
29
30
American College of Gastroenterology
4/16/2020
16
References (6-16)*Assessed 6 months after completion of 12 months of therapy.†Assessed after 3 years of continuous therapy.‡Assessed after 2 years of continuous therapy.§HBV DNA <2,000-40,000 IU/mL for peg-IFN; <60 IU/mL for entecavir and tenofovir disoproxil fumarate; <29 IU/mL for tenofovir alafenamide.llHBV DNA <20,000 IU/mL for peg-IFN; <60 IU/mL for entecavir and tenofovir disoproxil fumarate; <29 IU/mL for tenofovir alafenamide.¶ALT normalization defined by laboratory normal rather than ≤35 and ≤25 U/L for males and females. Terrault, et al. Hepatology. Vol. 67, No.4. 2018.
HBeAg Positive Peg-IFN* Entecavir†Tenofovir
Disoproxil Fumarate†
Tenofovir Disoproxil Fumarate†
Tenofovir Alafenamide‡
Tenofovir Alafenamide‡Entecavir
90-91 (<50-60 IU/mL) 93 (<60 U/mL) 90 (<29 IU/mL)
61 (<50-60 IU/mL) 76 (<60 IU/mL) 73 (<29 IU/mL)
Peg-IFN
32-36 22-25
21-22 21 18
81
<1
1
22
68
76
8
68-81
4-5
78-88
0-1 0
59
29-3634-52
2-711 (at 3 years posttreatment)
46 (at 3 years posttreatment)
30-42 (<2,000-40,000 IU/mL)8-14 (<80 IU/mL)
43 (<4,000 IU/mL)19 (<80 IU/mL)
% HBeAg loss
% HBsAg loss
% HBsAg loss
Table 2. Efficacy of Approved First-Line Antiviral Therapies in Adults with Treatment-Naïve Chronic Hepatitis B and Immune-Active Disease (Not Head-to-Head Comparisons)
HBeAg Negative
% HBeAg seroconversion
% HBV-DNA suppression(cutoff to define HBV-DNA suppression)§
% HBV-DNA suppression(cutoff to define HBV-DNA suppression)ll
% Normalization ALT
% Normalization ALT¶
Discontinuation of NA Treatment
EASL CPG HBV. J Hepatol 2017;67:370–98
Long‐term therapy with NAs is usually required: HBV eradication is not usually achieved
Recommendations
NAs should be discontinued • After confirmed HBsAg loss (± anti-HBs seroconversion)
II-2 1
NAs can be discontinued• In HBeAg-positive patients, without cirrhosis, who achieve stable HBeAg
seroconversion and undetectable HBV DNA and complete ≥12 months of consolidation therapyClose post-NA monitoring is warranted
II-2 2
NAs may be discontinued • In selected HBeAg-negative patients, without cirrhosis, who achieve long-term (≥3
years) virological suppression, if close post-NA monitoring can be guaranteedII-2 2
Grade of evidence Grade of recommendation
AASLD: HBeAg negative: indefinite therapy; if considering discontinuation in patients with mild disease, discuss risks and defer to center with expertise
31
32
American College of Gastroenterology
4/16/2020
17
Fewer Relapses With Longer Duration of Consolidation After HBeAg Seroconversion
1. Kuo. Scand J Gastroenterol. 2010;45:75. 2. Dai. J Antimicrob Chemother. 2013;68:2332.
< 12 mos(n = 39)
12‐18 mos(n = 41)
> 18 mos(n = 21)
Duration of ConsolidationMaintained Response
†6 M
os
After Therapy Cessation (%)[2]
< 6 mos(n = 47)
6‐12 mos(n = 46)
> 12 mos(n = 31)
Duration of Consolidation
26
39
71
*No HBeAg seroreversion or HBV DNA increase to > 105 copies/mL. †HBeAg seroconversion and undetectable serum HBV DNA.
Maintained Response* 2 Yrs
After Therapy Cessation (%)[1]
100
80
60
40
20
0
100
80
60
40
20
0
2923
48
Age at HBeAg Seroconversion Predicts Durability of Sustained Response
1. Pan. PLoS One. 2013;8:e68568. 2. Song. World J Gastroenterol. 2012;18:6277.
Group C: > 40 yrs AND < 15 mos consolidation
Group B: ≤ 40 yrs OR ≥ 15 mos consolidation
Group A: ≤ 40 yrs AND ≥ 15 mos consolidation
Mos After Treatment Cessation
Virologic Recurrence
[2]
Group A vs C: P = .014
≤ 37 yrs
> 37 yrs
P = .045
Follow‐up (Mos)
Cumulative Relapse Rate[1]
1.0
0.8
0.6
0.4
0.2
0
0 10 20 30 40 50 0 6 12 18 24 30 36
1.0
0.8
0.6
0.4
0.2
0
33
34
American College of Gastroenterology
4/16/2020
18
Current Conundrums in Standard of Care
1. Do I treat acute HBV?
Acute HBV• >95% immunocompetent adults recover spontaneously
– Do not routinely treat symptomatic acute HBV– Verify HBsAg loss after 6‐12 months
• Severe Acute Hepatitis B: consider therapy with ETV/TdF or TAF– Tbili >3 mg/dL, INR >1.5, HE or ascites
• LAM studies: improved HBV DNA but no difference in biochemical improvement or HBsAg loss– Hepatic encephalopathy– Serum bilirubin >10.0 mg/dL– INR >1.6
Terrault NA, et al. Hepatology. [online ahead of print February 5, 2018]. doi: 10.1002/hep.29800.
35
36
American College of Gastroenterology
4/16/2020
19
Current Conundrums in Standard of Care
1. Do I treat acute HBV?
2. How do I prevent MTCT
2017 TDFLAM, LdT
Second trimester of pregnancy
HBV DNA >2x105 IU/mL, HBsAg levels> 4 logs IU/mL
2018 TDFLAM, LdT
28-32 weeks of gestation
HBV DNA >2×105 IU/mL.
APASL 2015 TDF,LdT
28-32 weeks of gestation
HBV DNA>106–7 IU/mL
Recommendations from Association Guidelines forPreventing HBV MTCT
TDF Preferred
37
38
American College of Gastroenterology
4/16/2020
20
Algorithm for the Management of Chronic Hepatitis B During Pregnancy
Recommend all infants to receive HBIG and HBV vaccination series
(1st dose of vaccine and HBIG within 12 hours of birth)
Cirrhosis / stage IV fibrosis
or severe hepatitis flareNo
Monitoring without treatment. Test HBV DNA at end of the 2nd trimester
HBV DNA > 200,000 IU/mL, or threatened pre-term labor, or previous child has
immunoprophylaxis failure
Maternal HBV DNA < 200,000
IU/mL
TDF/LAM/LTD at beginning of the
3rd trimester
Monitoring without
treatment
Yes
TDF therapy throughout the entire pregnancy
Consultation: breastfeeding is recommended (Use TDF if
treatment is needed)
TDF, tenofovir-DF; LAM, lamivudine; LTD, telbivudine; HBIG, hepatitis B immunogloburin
No
Give TDF up to delivery (or 1‐3
mos postpartum); 3TC and
telbivudine are alternatives
Terrault. Hepatology. 2018;67:1560. Zhang. Hepatology. 2014;60:468.
Current Conundrums in Standard of Care
1. Do I treat acute HBV?
2. How do I prevent MTCT
3. Role of qHBsAg
39
40
American College of Gastroenterology
4/16/2020
21
Role of qHBsAg
• HBeAg‐negative patients:
– qHBsAg <1,000 IU/mL and HBV DNA <2,000 IU/mL suggest inactive CHB
– qHBsAg<1,000 IU/mL predicts spontaneous HBsAg clearance
• Predicts treatment response:
– Peg‐IFN: qHBs @ week 12
• HBeAg positive: qHBsAg<1,500 IU/mL 57% for HBeAg seroconversion and 18% for HBsAg loss (no decline high assoc w/ failure)
– NA: HBeAg negative
• >1 log decline in qHBsAg predicted increased loss of HBsAg,
• qHBsAg level<100 IU/mL sustainable off‐treatment response after 3+ years consolidation therapy
Terrault NA, et al. Hepatology. [online ahead of print February 5, 2018]. doi: 10.1002/hep.29800.
Role of qHBsAg
• HBeAg‐negative patients:
– qHBsAg <1,000 IU/mL and HBV DNA <2,000 IU/mL suggest inactive CHB
– qHBsAg<1,000 IU/mL predicts spontaneous HBsAg clearance
• Predicts treatment response:
– Peg‐IFN: qHBs @ week 12
• HBeAg positive: qHBsAg<1,500 IU/mL 57% for HBeAg seroconversion and 18% for HBsAg loss (no decline high assoc w/ failure)
– NA: HBeAg negative
• >1 log decline in qHBsAg predicted increased loss of HBsAg,
• qHBsAg level<100 IU/mL sustainable off‐treatment response after 3+ years consolidation therapy
Terrault NA, et al. Hepatology. [online ahead of print February 5, 2018]. doi: 10.1002/hep.29800.
• HBsAg quantitation can be useful in managing patients receiving peg‐INF therapy.
• HBsAg quantitation is not recommended for the routine testing or follow‐up of patients with CHB
41
42
American College of Gastroenterology
4/16/2020
22
Current Conundrums in Standard of Care
1. Do I treat acute HBV?
2. How do I prevent MTCT
3. Role of qHBsAg
4. How do I follow patients I don’t have on therapy
Warning:There are a lot of these patients
They get lost to follow‐up
Monitoring Patients Not on Therapy: HBeAg +
Terrault NA, et al. Hepatology. [online ahead of print February 5, 2018]. doi: 10.1002/hep.29800.
43
44
American College of Gastroenterology
4/16/2020
23
Monitoring Patients Not on Therapy: HBeAg (‐)
• Normal ALT + HBV DNA <2,000 IU/mL– Test ALT +/‐ HBV DNA q3 months for a
year then 6‐12 months
– Check HBsAg status at 6‐12 month intervals
• HBV DNA >2,000 IU/mL + ALT <2x ULN– Assess histology treat if F2
– Treat especially if >40 yo
Terrault NA, et al. Hepatology. [online ahead of print February 5, 2018]. doi: 10.1002/hep.29800.
Monitoring in Other Groups
Monitoring Patients Not on Therapy: HBsAg Loss
• ALT and HBV‐DNA monitoring no longer required
• HCC screening if cirrhosis, FMHx of HCC or long duration of infection (>40 years for men, >50 years for women if infected at young age)
HBV DNA <2,000 IU/mL with elevated ALT
• Evaluate for other liver diseases, especially HDV
Terrault NA, et al. Hepatology. [online ahead of print February 5, 2018]. doi: 10.1002/hep.29800.
45
46
American College of Gastroenterology
4/16/2020
24
NA-Induced HBsAg Loss is Durable
Kim et al Abstract 0198Implications for clinical practice:: HBsAg loss is a durable and safe endpoint for stopping therapy
50
40
30
20
10
0
0 12 24 36 48 60 72 84
Cumulative Risk of HCC development (%
)
Follow-up duration (months)No. at risk
NUC‐continuation
NUC‐discontinuation
HR=0.53 (95% CI, 0.12–2.23), log‐rank p=0.3850
40
30
20
10
0
0 12 24 36 48 60 72 84
Cumulative
Risk of HBsA
g‐Reversion (%)
145
131
129
121
100
97
62
67
44
51
34
38
25
25
13
12
145
131
124
114
89
87
57
58
37
41
29
28
19
195
10
8
Follow-up duration (months)
HR=0.45 (95% CI, 0.12–1.76), log‐rank p=0.24
Retrospective analysis of patients who stopped or continued NA after HBsAg loss Evaluated incidence of HBsAg sero‐reversion and HCC
Stop
Continue
Stop
Continue
NA-Induced HBsAg Loss is Durable
Kim et al Abstract 0198Implications for clinical practice:: HBsAg loss is a durable and safe endpoint for stopping therapy
50
40
30
20
10
0
0 12 24 36 48 60 72 84
Cumulative Risk of HCC development (%
)
Follow-up duration (months)No. at risk
NUC‐continuation
NUC‐discontinuation
HR=0.53 (95% CI, 0.12–2.23), log‐rank p=0.3850
40
30
20
10
0
0 12 24 36 48 60 72 84
Cumulative Risk of HBsA
g‐Reversion (%)
145
131
129
121
100
97
62
67
44
51
34
38
25
25
13
12
145
131
124
114
89
87
57
58
37
41
29
28
19
195
10
8
Follow-up duration (months)
HR=0.45 (95% CI, 0.12–1.76), log‐rank p=0.24
Retrospective analysis of patients who stopped or continued NA after HBsAg loss Evaluated incidence of HBsAg sero‐reversion and HCC
Stop
Continue
Stop
Continue
Current Conundrums in Standard of Care
1. Do I treat acute HBV?
2. How do I prevent MTCT
3. Role of qHBsAg
4. How do I follow patients I don’t have on therapy
5. TDF vs ETV
47
48
American College of Gastroenterology
4/16/2020
25
Overview of TDF vs ETV on HCC incidence in CHB Patients: AASLD 2019
The Future of HBV
• Cure: Elimination of all forms of potentially replicating HBV
• Functional Cure: HBV DNA is not detectable after completion of a finite course of treatment with HBsAg loss and decreased risk of HCC
• Partial Cure: Detectable HBsAg but HBV DNA negative after completion of finite therapy
Liang, et al. Hepatology. 62(6) 2015.
49
50
American College of Gastroenterology
4/16/2020
26
Gastroenterology 2019 156, 311-324DOI: (10.1053/j.gastro.2018.07.057)
1. Entry and uncoating2. Nucleocapsid transported to nucleus3. Partially ds rcDNA repaired4. cccDNA bound to chromatin5. cccDNA transcribed into pgRNA6. pgRNA reverse transcribed into HBV
DNA and mRNA7. mRNA translated into proteins8. Nucleocapsid assembled in cytoplasm
(pgRNA+ core + polymerase)9. pgRNA reverse transcribed into DNA10. Enveloped and secreted
HBV Life Cycle
Conclusions
• Therapy is recommended for those with chronic hepatitis B (elevated ALT, HBV DNA >2,000 in HBeAg negative and >20,000 IU/mL in HBeAg positive)
• Treatment is also recommended in those at high risk for progression and cancer
• Medications with a high barrier for resistance are recommended as first line therapy
• Regular monitoring for response and adverse events is necessary
• We may start to use the word cure in the discussion of HBV management
51
52
American College of Gastroenterology
4/16/2020
27
How to Receive CME and ABIM MOC Points
LIVE VIRTUAL GRAND ROUNDS WEBINAR
ACG will send a link to a CME & ABIM MOC evaluation to all attendees on the live webinar.
ABIM Board Certified physicians need to complete their MOC activities by December 31, 2020 in order for the MOC points to count toward any MOC requirements that are due by the end of the year. No MOC credit may be awarded after March 1, 2021 for this activity.
ACG will submit MOC points on the first of each month. Please allow 3-5 business days for your MOC credit to appear on your ABIM account.
ABIM MOC QUESTION
If you plan to claim ABIM MOC Points for this activity, you will be asked to: Please list specific changes you will make in your practice as a result of the information you received from
this activity.
Include specific strategies or changes that you plan to implement.THESE ANSWERS WILL BE REVIEWED.
53
54
American College of Gastroenterology
4/16/2020
28
Register Now at gi.org/ACGVGR
ACG Virtual Grand Rounds
Join us for upcoming Virtual Grand Rounds!
Week 5: Refractory GERD: New Options for Treatment 2020Philip O. Katz, MD, MACGApril 23, 2020 at Noon EDT
Week 6: Celiac Disease: 10 Things Every Clinician Should Know Amy S. Oxentenko, MD, FACGApril 30, 2020 at Noon EDT
Visit gi.org/ACGVGR to Register
55
56
American College of Gastroenterology
4/16/2020
29
giondemand.com
57
58
American College of Gastroenterology
4/16/2020
30
gi.org/COVID19
60
59
60
American College of Gastroenterology
4/16/2020
31
61
American College of Gastroenterology