Hepatitis B Prevention and Treatment in People with HIV Darcy Wooten 02/22/2019 UCSD HIV & Global Health Rounds

2. Hepatitis B Prevention and
Treatment in People with HIV
Darcy Wooten, MD, MS
Pronouns: She/Her/Hers
Assistant Professor of Medicine
Infectious Diseases and Global Public Health

3. Disclosures
■ None
Acknowledgements
■ Dr. Kenneth Sherman
■ Dr. Chloe Thio
■ Dr. Davey Smith

4. Roadmap
■ Burden of disease
■ Current prevention strategies
■ Novel treatment and cure strategies

5. Burden of disease

6. Burden of disease
■ 248 million HBV mono-infection
■ 3.6 million co-infected HBV/HIV
worldwide (10% of HIV+ individuals)
■ ~100,000 co-infected HBV/HIV in the US
(8% of HIV+ individuals)
Puoti et al, AIDS, 2002; Kellerman et al, JID, 2003; Zhou et al, Best Pract Res Clin Gastroenterol, 2017

7. Patients with co-infection do worse
vs. patients with HBV mono-infection
■ Risk of developing chronic infection (21% vs. 7%)
■ Higher HBV DNA levels
■ Higher rates of reactivation (esp. w/ low CD4 cell
counts)
■ Lower rates of HBeAg clearance
Hadler et al, JID, 1991; McGovern et al, ANTIVIR THER, 2007;

8. Patients with co-infection do worse
vs. patients with HBV mono-infection
■ Faster rates of fibrosis progression
■ Increased risk of cirrhosis and ESLD
■ Increased risk of HCC
Konopnicki et al, AIDS, 2005; Thio et al, LANCET, 2002; Colin et al, HEPATOLOGY, 1999.

9. Patients with co-infection do worse
vs. patients with HIV mono-infection
■ Higher liver-related mortality (14.2/1000 vs.
0.8/1000)
■ Higher all-cause mortality (RR 1.36, 95% CI 1.12-
1.64)
– Even among patients on suppressive ART
■ Increased risk of drug induced hepatoxicity
Thio et al, LANCET, 2002; Nikilopoulos et al, CID, 2009; Sulkowski, AIDS, 2004.

10. What about ART (F/TAF) as PrEP for HBV?
■ ART is good but not perfect for HBV PrEP
■ 89% relative risk reduction of acquiring
HBV with tenofovir as PrEP for HBV
infection
■ Patients on NRTI-sparing regimens are not
protected
Heuft et al, AIDS, 2014

11. Why does HBV prevention and cure
matter for patients with HIV?
■ Disease burden
■ Increased risk of worse outcomes
■ ART (F/TAF) as PrEP is great but not perfect

12. Current Prevention (Vaccination)
Strategies

13. Available Vaccines in the US
■ Recombivax HB
– 10 mcg antigen dose
– 40 mcg antigen dose (dialysis)
■ Energix-B
– 20 mcg antigen dose
– No 40 mcg dose but double dose approved for dialysis
■ Twinrix
– 20 mcg HBsAg dose (+ inactivated hepatitis A vaccine)
■ HEPLISAV-B
– 20 mcg HBsAg + TLR9 Agonist

14. Current DHHS Guideline
Recommendations: Immune-Naive
■ Vaccinate all individuals who are non-immune (sAb <10 mIU/mL)
■ Isolated core Ab +:
– Single dose of standard HBV vax à check titer 4 weeks later
– à if >100 IU/mL, immune and no vaccination needed
– à if <100 IU/mL, non-immune and give complete vaccine series
■ Ideal to vaccinate if CD4 >350 (although don’t necessarily wait)
DHHS Guidelines. Accessed January 14, 2019. https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-opportunistic-infection/344/hbv

15. Current DHHS Guideline Recommendations:
Vaccine Non-responders
■ Check HBsAb 1 month after vaccination series (goal >10 mIU/mL)
■ Standard 3-dose revaccination
■ Double 3-dose revaccination
■ Standard 4-dose revaccination (0, 1, 2, and 6 mo)
■ Double 4-dose revaccination (0, 1, 2, and 6 mo)
DHHS Guidelines. Accessed January 14, 2019. https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-opportunistic-infection/344/hbv

16. HBV Primary Vaccination Efficacy in HIV
0
10
20
30
40
50
60
70
80
90
100
Rey et al Tedaldi et al Overton
et al
Ungalkraiwit
et al
Paitoonpong
et al
Kim et al
96% in HIV
uninfected
Adapted from Sun et al, WORLD J GASTRO, 2014

17. Lower Rates of Seroconversion
■ Low CD4 cell count
■ Detectable HIV viral load
■ Occult HBV infection
■ HCV coinfection

18. ANRS HBV-03
■ N = 437
■ HIV+, CD4 >200, no HBV serologic marker, on ART if
CD4<350
■ 3 Study Arms (1:1:1)
– 3 doses 20 mcg IM (0, 4, 24 mo)
– 4 doses 40 mcg IM (0, 4, 8, 24 mo)
– 4 doses 40 mcg ID (0, 4, 8, 24 mo)
■ Primary Outcome
– % > 10 mIU/mL at week 28
Launay et al, JAMA, 2011

19. Launay et al, JAMA, 2011

20. Launay et al, JAMA, 2011

21. Thai Study
■ N = 132
■ HIV+, CD4 >200, VL UD, no HBV serologic marker
■ 3 Study Arms
– 3 doses 20 mcg IM (0, 1, 6 mo)
– 4 doses 20 mcg IM (0, 1, 2, 6 mo)
– 4 doses 40 mcg IM (0, 1, 2, 6 mo)
■ Primary Outcome
– % > 10 mIU/mL at week 28
Chaiklang et al, PLOS One, 2013

22. Chaiklang et al, PLOS One, 2013

23. HBV Re-Vaccination Efficacy in HIV

24. ANRS HB04 B-BOOST
■ N = 178
■ HIV+, CD4 >200, no HBV serologic marker, on ART of CD4<350
■ Previous vaccination with 2-4 injections of 20 mcg vaccine
■ Repeat vaccination with either
– 3 doses 20 mcg IM
– 3 doses 40 mcg IM
■ Primary Outcome
– % > 10 mIU/mL
Rey et al, LANCET INF DIS, 2015

25. ANRS HB04 B-BOOST
Rey et al, LANCET INF DIS, 2015
0
10
20
30
40
50
60
70
80
90
100
20 mcg x3 40 mcg x3

26. HBV Vaccine Adjuvants: TLR agonists

27. Recombinant sAg + TLR-9 agonist
■ N = 38 HIV+ patients
■ Energix-B 40 mcg vs Energix-B 40 mcg + CPG 7909
■ Doses at 0, 1, and 2 months
■ Stratified by vaccine-naïve or failure of standard HBV
vaccine series
Cooper et al et al, AIDS, 2005; Cooper et al, CID, 2008

28. Recombinant sAg + TLR-9 agonist
Cooper et al et al, AIDS, 2005; Cooper et al, CID, 2008

29. HEPLISAV-B
■ FDA approved in 2017
■ CpG + recombinant HBsAg (20 mcg)
– CpG: TLR-9 agonist
– Leads to enhanced T and B memory for HBsAg
■ 3 trials showed superiority to Energix-B at standard doses in
HIV uninfected patients (DM, ESRD on dialysis): 95% vs 70%
– Signal of increased CV events unlikely to be true
Heyward et al, VACCINE, 2013; Jackson et al, VACCINE, 2018; Hyer et al, VACCINE, 2018

30. A5379: BEe-HIVe
■ RCT
■ HIV+
■ Heplisav-B 0 and 4 mo
■ Heplisav-B 0, 4, and 24 mo
■ Energix-B 0, 4, and 24 mo
■ Primary outcome: Seroprotection 4 weeks post-vaccination
■ Predicted to open July, 2019

31. Novel treatment and cure strategies

32. Why is it difficult to cure HBV?

33. Different definitions of cure
■ Functional Cure
– Loss of HBsAg, +HBsAb
– cccDNA present but low/no transcription
■ Eradication
– Loss of HBsAg, +HBsAb
– Elimination of cccDNA

34. Surrogate markers of cure
■ Quantitative HBsAg
– <100 IU/mL predicts functional cure
■ HBCrAg: Hepatitis B core-related antigen
– Levels correlate with cccDNA activity
– Low levels predict HBeAg seroconversion
■ HBV RNA
– Declines 3-6 months after initiation of treatment
– Low levels predict HBeAg seroconversion
– Risk of relapse 3-fold lower if UD when stopping therapy (vs detectable RNA)
Lazarus et al. NATURE REVIEWS GASTROENTEROLOGY, 2018.

35. Novel treatment and cure strategies
■ Virologic approaches
■ Immunologic approaches

39. Entry Inhibitors
■ Compete with HBV for NTCP binding
■ Inhibits HBV entry into new hepatocytes and subsequent cccDNA
amplification
■ Does not have an effect on hepatocytes already infected
■ Example
– Myrcludex-B: HBV-derived peptides that acts as an entry inhibitor at
NTCP
– Decreases HBV DNA levels but no effect on qHBsAg
Lazarus et al. NATURE REVIEWS GASTROENTEROLOGY, 2018.

41. Targeting cccDNA
■ In vitro studies using CRISPER-Cas9 technologies to destroy cccDNA
■ Disruption of histones that stabilize cccDNA
■ siRNA
– Silence mRNA from cccDNA
– Pre-clinical and early clinical studies have shown a single dose can
decreased qHBsAg levels for long periods of time
■ Current issues: stable delivery systems, entry into target cells
Kim et al. ADVANCES IN HEPATOLOGY. 2017

43. Encaspidation Inhibitors
■ Disrupt capsid assembly/disassembly
■ CAM JNJ-56136379 (Phase 2 study)
– Decrease in HBV DNA and HBV RNA following dose
– No change in HBsAg
– HBV DNA levels rebounded 8 weeks after stopping therapy
– Ongoing studies in treatment naïve and suppressed patients
Lazarus et al. NATURE REVIEWS GASTROENTEROLOGY, 2018.

46. Decreased HBsAg secretion
■ Rationale: High level of HBsAg secreted from hepatocytes à T cell
exhaustion
■ siRNA to decrease HBsAg production
– Mouse model showed a dose dependent response
■ Nucleic acid polymers to block subparticle secretion of HBsAg
Lazarus et al. NATURE REVIEWS GASTROENTEROLOGY, 2018.

47. REP 401
■ 40 pts
■ REP 2139: nucleic acid polymer that blocks secretion of HBsAg
■ Patients received:
– TDF alone
– TDF + PEG-IFN
– REP 2139 (nucleic acid polymer) + TDF + PEG-IFN
■ Prelim results
– 24/40 HBsAg loss at 48 weeks
Lazarus et al. NATURE REVIEWS GASTROENTEROLOGY, 2018.

49. Immunologic Approaches

50. Immunologic Approaches
■ Innate immune response
– TLR7 and TLR8 agonists: Data in chimps showed HBV DNA and HBsAg. In humans on
TDF, immune response markers were improved but no change in HBsAg
Lazarus et al. NATURE REVIEWS GASTROENTEROLOGY, 2018.

51. Immunologic Approaches
■ Innate immune response
– TLR7 and TLR8 agonists: Data in chimps showed HBV DNA and HBsAg. In humans on
TDF, immune response markers were improved but no change in HBsAg
– RIG-I: 30 pts showed a decrease in HBV DNA and RNA compared to placebo but this was not
statistically significant; no difference in HBsAg
Lazarus et al. NATURE REVIEWS GASTROENTEROLOGY, 2018.

52. Immunologic Approaches
■ Innate immune response
– TLR7 and TLR8 agonists: Data in chimps showed HBV DNA and HBsAg. In humans on
TDF, immune response markers were improved but no change in HBsAg
– RIG-I: 30 pts showed a decrease in HBV DNA and RNA compared to placebo but this was not
statistically significant; no difference in HBsAg.
■ Adaptive immune response
– Blockade of PD-1 to reverse T cell exhaustion: Anti PD-1 synergizes with entecavir
in a woodchuck hepatitis B model
Lazarus et al. NATURE REVIEWS GASTROENTEROLOGY, 2018.

53. Immunologic Approaches
■ Innate immune response
– TLR7 and TLR8 agonists: Data in chimps showed HBV DNA and HBsAg. In humans on
TDF, immune response markers were improved but no change in HBsAg
– RIG-I: 30 pts showed a decrease in HBV DNA and RNA compared to placebo but this was not
statistically significant; no difference in HBsAg.
■ Adaptive immune response
– Blockade of PD-1 to reverse T cell exhaustion: Anti PDL1 synergizes with entecavir
in a woodchuck hepatitis B model
■ Therapeutic vaccine
– GS-4774: Did not have any effect on HBsAg
Lazarus et al. NATURE REVIEWS GASTROENTEROLOGY, 2018.

54. Summary: Novel treatment and cure
strategies
■ Cure research is in its infancy
■ No ONE virologic or immunologic approach is likely to be effective by
itself
■ Will probably need a combination approach with strategies that
target different steps in the viral life cycle as well as strategies that
focus on the immune response

55. Closing Thoughts
■ HBV prevention and treatment IS important given the burden of
disease
■ Current HBV vaccination strategies remain suboptimal but vaccine
adjuvants like TLR agonists hold promise
■ Curative treatments will be challenging and will likely require a
combination of both virologic and immunologic therapies

56. Thank you
Questions?