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
~2.6 million
HBV m
Kourtis AP et al. N Engl J Med 2012;366:

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
CD4< 500
CD4 >500
DHSS (US) 
WHO
Evidence of severe chronic
liver disease
EACS (Europe)
If HBV DNA > 2000 IU/ml
or ALT elevated
BHIVA (UK)
HBV DNA > 2000 IU/ml
OR F=>2 by TE or biopsy

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
Testing accessible to >50%
Testing anonymous
Free to all
Free to some
Africa
20%
40%
10%
27%
SE Asia
29%
14%
Europe
86%
55%
Easterbrook et al Sem Liv 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 LMIC is 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 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
WHO expanded program of immunisation

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

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. 8-10% remain viraemic on tenofovir
Efficacy is never 100%
8-10% remain viraemic on tenofovir ?
78% optimal suppression over 7 years
Boyd et al
Hepatology 2014
De Vries Slujis 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 OR
95% CI
p-value
Age (per 10 yrs)
0.90
0.48, 1.69
0.74
HBeAg positive
12.06
3.73, 38.98
<0.0001
<95% adherent
2.52
1.16, 5.48
0.02
HAART <2 yrs
2.64
1.06, 6.54
0.04
CD4 < 200 cells/mm3
2.47
1.06, 5.73
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
17 eligible studies, including 10,889 participants, and found that TDF-containing ART regimens were associated with a significantly greater loss of kidney function than were ART regimens not containing TDF. We also found a significantly higher risk of acute renal injury associated with TDF use.
Change in glomerular filtration rate (in mL/min) calculated using the Cockcroft-Gault formulation (CG-GFR), for tenofovir disoproxil fumarate (TDF) therapy versus no treatment. BICOMBO 2009 refers to the study by Martinez et al [41], HEAT 2009 refers to the study by Smith et al [44], and HOPS 2007 refers to the HIV Outpatient Study by Young et al [20]. The other studies are indicated by first author and date of publication [16–19, 34, 37, 38, 40]. ART, antiretroviral treatment; CI, confidence interval; MD, mean difference; NNRTI, nonnucleoside reverse-transcriptase inhibitor; RCT, randomized controlled trial; RPI, ritonavir-boosted protease inhibitor.
A small but significantly increased risk of acute renal injury associated with TDF-containing regimens (risk difference, 0.7%; 95% CI, 0.2–1.2; statistical heterogeneity absent: I2=0%).
There was a significantly greater loss of kidney function over the course of treatment among those receiving TDF-containing ART, compared with control subjects (mean difference [MD] in CG-GFR, 3.92 mL/min; 95% confidence interval [CI], mL/min)
Cooper R D et al. Clin Infect Dis. 2010;51: , Bedimo AIDS (7)

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)
? Tenfovir Alafenamide (TAF)

29. Challenges in resource rich settings
Suboptimal efficacy
Toxicity
Eradication

30. The final challenge
Science 2014, 343,

31. Challenges at many levels
Implications of persistent viraemia
Management and incidence of flare
Options for switch
Cure strategies
Virological
Immunological
New agents for cure
Burden of disease
Understanding natural history
Role of GT
Occult HBV
HCC
Access to drug
National testing policies
Universal and birth dose vaccination
Policy/
advocacy
Epidemiology
Basic science
Clinical research