Challenges in HIV-HBV co-infection

1. Challenges in HIV-HBV co-infection Dr Gail Matthews MBChB MRCP FRACP PhD Clinical Academic And Senior Lecturer, Kirby Institute, UNSW Australia & St Vincent’s Hospital, Sydney Australia

2. Disclosures • Gilead: Advisory Board, Honoraria, Research Grants, Travel Sponsorship • BMS:Speaker fee, Travel Sponsorship • Abbvie: Advisory Board, Honoraia • Merck: Speaker fee, Research Grants, Travel Sponsorship • Roche: Travel Sponsorship, Speaker fee

3. HIV-HBV: a huge global burden HIV 35 m HIV-HBV ~2.6million HBV 250-350 m Kourtis AP et al. N Engl J Med 2012;366:1749-1752.

4. 13 years of tenofovir (TDF) Meta-analysis 23 studies 550 HIV-HBV patients on TDF Increasing suppression over follow-up in majority Little evidence of resistance Price et al, PLOs One 2013

5. All guidelines recommend TDF-containing ART as preferred regimen WHO ARV guidelines 2013

6. General agreement on when to start

7. If the majority of HIV-HBV infected individuals can be treated with a highly potent drug with no resistance what are the challenges remaining?

8. Challenges remain …in resource limited settings …in resource rich settings

9. Challenges in resource limited settings • Diagnosis and monitoring • Access • Mother-child transmission

10. Challenges in resource limited settings • Diagnosis and monitoring • Access • Mother-child transmission

11. Lack of access to routine testing and monitoring World Hepatitis Alliance/WHO global survey 2009: Testing for HBV and/or HCV • >50% people live in countries with no free testing • Only 4% low-income countries have ready access to testing Easterbrook et al SemLiv Dis 2012

12. Lack of access to routine testing and monitoring • Limited access to HBsAg testing means many co-infected individuals not identified pre-ART • Little understanding of natural history of co-infection in RLS • Liver disease fibrosis assessment not readily available • Widespread absence of virological monitoring by HBV DNA testing

13. Challenges in resource limited settings • Diagnosis and monitoring • Access • Mother-child transmission

14. Access to TDF in LMICis restricted First line ART in low and middle income countries 2008 Towards universal access. WHO progress report 2009

15. Although use is improving Trends in d4T, AZT and TDF use in first-line antiretroviral therapy regimens for adults in low- and middle-income countries, 2006–2011 Global update on HIV treatment 2013. WHO Tanzania: 3% HIV and 17% HIV/HBV on TDF regimen Hawkins IAC 2012

16. Challenges in resource limited settings • Diagnosis and monitoring • Access • Mother-child transmission

17. Preventing mother-child transmission • Screening of pregnant women for HBV is not routine in many countries • Despite WHO Expanded Program of Immunisation universal infant vaccination is not ‘universal’ • 56% in SE Asia • 47% in India • 57% Nigeria

18. Global and regional infant vaccination rates WHO/UNICEF estimates of third dose of HBV vaccine coverage 1989-2010 Thurz et al Nature Gastro 2012 ; 9; 492-494

19. Preventing mother-child transmission • Screening of pregnant women for HBV is not routine in many countries • Universal infant vaccination is not ‘universal’ • 56% in SE Asia • 47% in India • 57% Nigeria • High HBV viral loads in HIV infected women increase the likelihood of perinatal transmission even in the setting of immunisation – TDF-containing ART should be prioritised

20. Challenges in resource rich settings • Suboptimal efficacy • Toxicity • Eradication

21. Challenges in resource rich settings • Suboptimal efficacy • Toxicity • Eradication

22. Efficacy is never 100% 8-10% remain viraemic on tenofovir ? 78% optimal suppression over 7 years Boyd et al Hepatology 2014 De VriesSlujis Gastroenterology 2010

23. Patterns of suboptimal response to TDF based therapy in HIV-HBV • 165 HIV -HBV coinfected individuals followed for median of 4 years • HBV DNA detectable in 20% study visits Persistent viraemia (n=25) Viral rebound (n=13) Blipper (n=24) Matthews CID 2012

24. Factors associated with detectable HBV DNA On truvada based therapy at least 6 months Undetectable HIV RNA < 400 c/ml Long term adherence is always a challenge Matthews CID 2012

25. Drivers of HBV viraemia on TDF? • Neither genotypic or phenotypic resistance have been definitively described • Replication or reservoir release? • Virological (UDPS, SGA) and immunological studies may give insight

26. Challenges in resource rich settings • Suboptimal efficacy • Toxicity • Eradication

27. TDF associated with bone and kidney toxicity Cooper R D et al. Clin Infect Dis. 2010;51:496-505, Bedimo AIDS 2012 26(7) 825-831

28. Strategies when TDF is contra-indicated? • Reduce dose TDF • Switch to entecavir (caution if LAM-R) • Adefovir plus entecavir (?kidney disease) • Peg-interferon (?advanced liver disease) • ? TenfovirAlafenamide (TAF)

29. Challenges in resource rich settings • Suboptimal efficacy • Toxicity • Eradication

30. The final challenge Science 2014, 343, 1212-1213

31. Challenges at many levels Policy/ advocacy Epidemiology Basic science Clinical research