1. Epidémiologie génétique du VHB
Anders Boyd, MPH, PhD
Inserm U707
Hôpital Saint-Antoine
Service des maladies infectieuses et tropicales
Paris, France

2. Summary Epidemiology and clinical course Genetic variability
Therapeutic considerations
Virological response, failure, and suboptimal response
Therapeutic options
Perspectives
Conclusion

3. Epidemiology Top 3 most common routes of transmission HBV HIV
Heterosexual/ Homosexual contact
IDU
Mother-to-child transmission

4. Epidemiology Global prevalence
HIV prevalence, 2008
90% of HIV-infected patients with markers of prior HBV infection % w/ chronic infection1
HIV (33M), HBV (400M) making 2-4M HIV-HBV2
1Alter M. J Hepatol WHO Report, 2008.

5. Clinical course of co-infection

6. Clinical course of co-infection
Impact on morbidity/mortality ↓
Incidence/Mortality AIDS-related events1 ↑
Liver disease
morbidity/mortality2,3
cART
era
Ex: patients living in Europe 36% excess risk / HBV4
Adults: 25% chronic ↑
ESLD & HCC5,6
Acute HBV infection
Children: 50-90% chronic
1Palella FJ, JAIDS Konopnicki D, AIDS Lewden C, JAIDS Nikolopoulos G, CID Thio CL, Lancet Salmon-Ceron D, J Hepatol 2009

7. Genetic variability Genotypic distributions worldwide
Datta et al. Virology Journal, 2008

8. Genetic variability and public health impact
Risk of Hepatocellular Carcinoma
aHR (95%CI) p
Group of long-term HBV DNA change
Control group: HBV DNA level <104
1.00 (referent)
Group A-B-C: →↑ ↓ to <104
2.25 (0.68–7.37)
0.18
Group D: ↔ at 104 to 105
3.12 (1.09–8.89)
0.03
Group E-F: ↓/↔ at 105 to 106
8.85 (3.85–20.35)
<0.001
Group G-H: ↓/↔ at 106 to 107
16.78 (7.33–38.39)
Group I: ↔ at >107
3.61 (1.15–11.38)
HBV genotype
B or mixed genotype C
2.05 (1.20–3.51)
.009
I will now point out some challenges that we, as clinicians, need to be aware of.
First of all, the genetic variability of HBV in the context of HIV.
You know that mutations on the polymerase gene are selected by long term exposure to antiHBV NRTI. They provide cross resistance to NRTIs and lead to treatment failure.
Because of overlapping pol and S genes, pol mutations might induce mutations on the S gene, which are also selected by selective pressure exherted by the host immune system.
Those S mutations have many consequences:
They have been shown to be associated with a decrease in HBs antigenicity and imunogenicity
they also lead to the emergence of HBV vaccine escape mutants
and they can finally be responsible for false negative results with ELISA test.
In the context of HIV should we fear the emergence of vaccine escape mutants (because of treatment history with lamivudine) and drugresistant strains (because of long term exposure to NRTIs)? The last issue will extensively addressed by Christina Valente and I would like to share with you some data on vaccine escape mutants that our team has recently reported at the AASLD and CROI meetings.
Adjusted for age, sex, cigarette smoking, alcohol drinking, total number of repeated measurements of ALT, long-term pattern of ALT, and the other factors listed in the table.
Chen C-F, Gastroenterology, 2011. 8

9. Genetic variability and public health impact
pol mutations selected by exposure to nucleos(t)ides (3TC, FTC, ADV, ETV, LdT)
Double stranded DNA with overlapping reading frames: pol mutations → S mutations
S mutations selected as consequence of pol mutations + selective pressure of host origin
associated with decrease of HBs antigenicity1 and vaccine escape2
false negative with ELISA test
I will now point out some challenges that we, as clinicians, need to be aware of.
First of all, the genetic variability of HBV in the context of HIV.
You know that mutations on the polymerase gene are selected by long term exposure to antiHBV NRTI. They provide cross resistance to NRTIs and lead to treatment failure.
Because of overlapping pol and S genes, pol mutations might induce mutations on the S gene, which are also selected by selective pressure exherted by the host immune system.
Those S mutations have many consequences:
They have been shown to be associated with a decrease in HBs antigenicity and imunogenicity
they also lead to the emergence of HBV vaccine escape mutants
and they can finally be responsible for false negative results with ELISA test.
In the context of HIV should we fear the emergence of vaccine escape mutants (because of treatment history with lamivudine) and drugresistant strains (because of long term exposure to NRTIs)? The last issue will extensively addressed by Christina Valente and I would like to share with you some data on vaccine escape mutants that our team has recently reported at the AASLD and CROI meetings.
Lee WM.N Engl J Med. 1997
1Torresi J, J Clinc Virol Kamili S, Hepatol 2009. 9

10. Virological response
Definition of virological response on nucleoside analogue (NA) therapy:
"Virological response is defined as undetectable HBV DNA by a sensitive PCR assay [usually at W48].”
“It is usually evaluated every 3-6 months during therapy depending on the severity of liver disease and the type of NA.”
EASL Clinical Practice Guidelines, April 2012

11. Virological failure
Primary antiviral resistance mutations in the polymerase gene
Treatment
Domain
Number of mutations B C D E
LAM/TdV
rtV173L
rtL180M
rtA181T/V
rtM204V/I 1
ADV
rtN236T
TDF
(rtA194T) ?
ETV
rtL180M rtT184
rtM204I/V
rtS202
rtM250I/V 3
Gish R et al., Lancet Inf Dis, 2012

12. Suboptimal response
Cumulative probability in achieving undetectable HBV in HIV-HBV co-infected patients treated with TDF
0.00
0.20
0.40
0.60
0.80
1.00
Cumulative probability 12 24 36 48 60 72 84
Time from TDF-initiation (months)
23.5%
4.3%
Delayed response is commonplace in HIV-HBV co-infected patients
Lacombe et al., CROI 2009; Unpublished data, French HIV-HBV and BI-LIVER cohorts

13. Determinants of suboptimal response
Virological determinants in delayed response
LAM→TDF+FTC
In the DR vs EVR group:
- Higher % of HBV genotype G
- Longer duration of LAM
- Higher % of mutated HBV clones (quasispecies variability)
Early virological response (<2.3 log10 IU/mL)
(n=32)
6 MO
Primary non response
(n=14)
Delayed response
(n=7)
END FU
Non-adherent
(n=7)
Lada O et al., Liver Int, 2012; Lada O et al. Antiviral Ther, 2012.

14. Therapeutic options
Suboptimal response
Intensification
No modification
Switch
What is the effect of these treatment options on genetic variability?
EASL Clinical Practice Guidelines, April 2012

15. Therapeutic options
Intensification: evidence that anti-HBV drugs with lower potency may not work
Treatment effectiveness:
LAM 97%, TDF 98%, LAM+TDF 97%
Median HBV virion half-life: 1.2 days (IQR: days)
Median infected cell half-life: 7.9 days ( days)
Matthews Avihingsanon et al. Hepatol 2008; Lewin et al. Hepatol, 2009

16. Therapeutic options
Intensification: evidence that anti-HBV drugs with lower potency may work
Ordinal regression (<2.0 vs vs >6.3 log10 IU/mL) OR
95% CI
HBV active therapy
TDF+FTC/LAM
1.00
No TDF/LAM/FTC
16.8
( )
LAM/FTC only
36.6
( )
TDF only
8.4
( )
Detectable HIV virus
7.4
( )
HBeAg+
85.2
( )
Matthews et al. AIDS 2009

17. Therapeutic options
Switching to less potent therapies: evidence of its effect on HBV parameters
Unpublished data, French HIV-HBV and BI-LIVER Cohorts

18. % of patients with incident mutations
Therapeutic options
Effect of multiple switching on genetic variability in LAM-experienced, HIV-HBV co-infected patients
% of patients with incident mutations
TDF±LAM/FTC
Multiple switches
Mutation class
% (n)
Alkyl phosphonate-associated pol-gene
(n=49)
(n=15)
6.1
6.7
Immune-associated S-gene
(n=73)
(n=18)
1.4
5.6
L-nucleoside-associated pol-gene/antiviral-associated S-gene
(n=64)
9.4
33.3
Lacombe et al., Hepatology, 2012 [accepted]

19. Perspectives Efficace Non efficace
Suppression de la réplication virale
Mutations de résistance
Perte (décroissance) de l’ag HBe/HBs
↑ morbidité/mortalité
↑ risque des mutations liées à l’antigène HBs
TDF > 3TC ?? ?? ??
TDF > 3TC
Supériorité entre les traitements anti-VHB chez les patients co-infectés par le VIH et VHB ? Dans le contexte africain ?

20. Perspectives VarBVa : étude de cohorte, nichée, prospective
TRIVACAN
TEMPRANO
ARV continue
ARV ITP fixe
ARV ITP adapté
Sans ARV
OMS
OMS+INH
ARV précoce
ARV précoce+INH
3TC
Sans tx
TDF+FTC
Critères d’inclusion
Sérologie VIH-1 positive ou VIH-1+VIH-2 positive
HBsAg+ (≥6 mois)
Naïf de traitement

21. Conclusion
Suboptimal response is common in HIV-HBV co-infected patients
Most patients can achieve undetectable HBV-DNA
Transient replication can occur
Many genetic determinants of treatment response are up for debate – especially in treatment-naïve patients and in the African context
Impact of suboptimal response in HIV-HBV co-infection on clinical outcomes is largely unknown

22. Hospital Saint-Antoine, Paris:
Hospital Tenon, Paris:
N. Algans
M. Atlou
C. Bessette
H. Bideault
D. Binet
D. Bollens
E. Bui
F. Cao
A. Charrois
N. Desplanque
G. Epinette
L. Fonquernie
J. Guéchot
N. Harchi
J. L. Lagneau
F. Lallemand
B. Lefebvre
C. Lupin
V. Massari
C. Masseguin
O. Massot
J. L. Meynard
M. C. Meyohas
R. Mouchotte
L. Morand-Joubert
H. Rougier
M. Sebire
L. Serfaty
P. Tran
P. Tangre
J. Tredup
D. Wendum
X. Amiot
A. Baakili
F. Bani-Sadr
P. Callard
B. Cardon
E. Chakvetadze
B. Fouqueray
S. Gharakhanian
J. D. Grange
J. B. Guiard-Schmid
B. Hadacek
M. G. Lebrette
Ph. Mariot
R. Missonnier
C. Le Pendeven
G. Pialoux
C. Poirot
W. Rozenbaum
L. Slama
M. P. Treilhou
J. P. Vincensini
F. Zatla
C. Zurita
Hospital Saint-Louis, Paris:
Hospital Hôtel-Dieu, Lyon:
Laboratoire du Chemin-Vert:
P. Bertheau
N. de Castro
N. C. de Verdière
J. Delgado
S. Ferret
S. Fournier
I. François
A. Furco
A. Janin
M. Lafaurie
M. Lagrange
S. Neuville
P. Palmer
J. Pavie
C. Pintado
D. Ponscarme
A. Raschline
C. Scieux
M. E. Schlageter
D. Séréni
O. Tauléra
M. Tourneur
F. Vincent
C. Augustin-Normand
F. Bailly
I. Bordes
C. Brochier
M. Chevallier
L. Cotte
V. Guéripel
B. Lebouche
M. Maynard-Muet
I. Schlienger
V. Thoirain
A. M. Trabaud
C. Trepo
A. Ollivet
C. Durrafour
F. Lavocat
F. Zoulim
G. Kreplak
R. Legouge
Inserm U707:
G. Pannetier
F. Carrat
Gilead Sciences, Inc.