HIVHBV coinfection: current strategies and new challenges

1
HIV-HBV co-infection current strategies and new
challenges
7th Advanced HIV Course Montpellier 2009

• Dr Karine Lacombe, M.D., PhD
• UPMC, Paris VI
• Inserm UMR-S707
• Hôpital Saint-Antoine, AP-HP, France.

2
Summary

• Recent trends in epidemiology
• Impact of HIV and ARV on liver injury
• Diagnostic and follow-up tools
• Advances in therapeutic management
• New challenges
• Conclusion

3
Recent trends in Epidemiology (1)

• Global prevalence

• Same routes of transmission
• 90 of HIV-infected patients with markers of
  prior HBV infection 5-15 w/ chronic infection1
• HIV (33M) HBV (400M) 2-4M HIV-HBV2
• Routes of transmission and age at transmission
  differ
• Zones with low HBV endemicity (lt2)
• Europe, North America
• IDU, sex
• P(HIV-HBV) 5 10
• Zones with high HBV prevalence (gt8)
• Africa, Asia
• perinatal, young age (injections, scarification)
• p(HIV-HBV) 15

HIV prevalence, 2008
1Alter M. J Hepatol 2006. 2WHO Report, 2008.
4
Recent trends in Epidemiology (2)

• Impact on morbi-mortality

cART era

• Incidence / Mortality
• AIDS-related events1

• Liver disease
• Morbidity / mortality2,3

• Ex 12 382 patients living in Europe ? 36
  excess risk / HBV (OR1.36 1.12 1.644

If HBV when adults 25 chronic
? ESLD / HCC5,6
Acute infection
If HBV when children 50-90 chronic
1Palella FJ, JAIDS 2006. 2Konopnicki D, AIDS
2005. 3Lewden C, JAIDS 2008. 4Nikolopoulos G, CID
2009. 5Thio CL, Lancet 2002. 6Salmon-Ceron D, J
Hepatol 2009
5
Recent trends in Epidemiology (3)

• Multiple hepatic virus co-infection
• Routes of transmission common to HCV and HDV
• 29.9 of HIV-HBV-HCV in Eurosida1
• 7.8 of HIV-HBV-HDV and HIV-HBV-HCV-HDV in French
  HIV-HBV Cohort2
• ? HCV and HDV viral replication3
• ? progression to cirrhosis and ESLD4,5

1Konopnicki D, AIDS 2005. 2Lacombe K, AIDS 2005.
3Boyd A, J Viral Hepat 2009. 4lacombe K, AIDS
2007. 5Sheng WH, CID 2007.
6
Impact of HIV and ARVs on liver injury (1)
profibrogenic effect of HIV

• HIV tropism for HSC and hepatocytes
• direct cytopathic effect of HIV on liver tissue
  through CCR5 or CXCR4 coreceptors expressed on
  hepatocytes and HSC surface, enhancing cell
  apoptosis1
• Infection of HSC through CCR5 and promotion of
  myofibroblastic differenciation, leading to
  accelerated fibrosis2

1Babu CK, PLoS One 2009. 2Tuyama A. CROI 2008
7
Impact of HIV and ARVs on liver injury (2)
profibrogenic effect of HIV

• Altered innate and adaptive immune response
• Immune response suboptimal in HIV context (?
  frequency of HBs and HBe seroconversion)
• Multifactorial
• Modification of TLRs ( pathogen-recognition
  receptors) course of expression by HIV1 and HBV2
  ? pro-inflammatory signalling cascade ? ?
  fibrosis
• Impairment of HBV-specific CD8 T cells? chronic
  evolution3

1Thibault S, Rettrovirology 2009. 2Jun W,
Hepatology 2009. 3Chang JJ, J Virol 2009
8
Impact of HIV and ARVs on liver injury (3) HBV
immune restoration and reactivation

• Frequent hepatic flares (gt2N 13.4/100py1)
• 2 frequent etiologies
• HBV immune restoration restoration of antiHBV
  immune response under ARV, with production of
  chemokines, of which CXCL-10,  profibrogenic 
  factor 2
• HBV reactivation when unplanned HIV/HBV drug
  interruption or drug escape HBV mutants, possibly
  leading to hepatic failure3

1Chauvel O, Antivir Ther 2007. 2Roe B, JID 2007.
3Bellini C, HIV Medicine 2009.
9
Impact of HIV and ARVs on liver injury (3)
hepatotoxicity and metabolic syndrome

• Other frequent etiologies of hepatic flares, not
  directly linked to HBV, but co-factors
• Hepatotoxicy1,2 mitochondrial toxicity (NRTIs),
  idiosyndratic hypersensitivity (NVP, ABC),
  alteration of metabolism (TPV, RTV)
• NAFLD3,4 lipodystrophy, insulinresistance with
  dyslipidemia induced by ARVs major co-factors
  of fibrosis progression
• ? Direct role of HIV through suppression of PPAR?
  (major transcription factor involved in lipid
  metabolism, insulin sensitivity, inflammation
  process and fibrogenesis5

1Vogel M, Curr Opin HIV AIDS 2007. 2Sulkowski M,
JID 2008. 3Lemoine M, AIDS 2006. 4Ingiliz P,
Hepatol 2009. 5Shrivastav S, Mol Endocrinol 2008.
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Diagnostic and follow-up tools (1)

• Frequency of periodic screening
• When HIV diagnosed and every year if
  antiHBcAb-antiHBsAb negative1
• Test for HCV ab, HDV Ab and HAV Ab
• If HAV neg, immunization
• If antiHBcAb neg antiHbsAb neg
• immunization
• If isolated antiHBcAb
• Fear of occult HBV infection3,4
• Screen for HBV-DNA
• If suspicion of acute HBV
• Screen for antiHBc immunoglobulin M

1Rockstroh J, HIV Med 2008. 3Piroth L, JHepatol
2002. 4Perez-Rodriguez MK, World J Gastroenterol
2009
11
Diagnostic and follow-up tools (2)

• Initial liver assessment
• Clinical comorbidities (metabolic syndrome,
  alcohol, drugs, multiple viral hepatitis)
• Biological standard lab tests, viral hepatitis
  serologies (HCV, HDV, HAV, HEV), other causes of
  hepatitis
• HBV full serology, HBV-DNA
• Liver grading and staging
• Liver biopsy still important1
• Biochemical tests interesting2
• Elastometry not evaluated in HIV-HBV
  co-infection3

1Don CR, Hepatol 2009. 2Bottero J, JHepatol 2009.
3Marcellin P, Liver Int 2009.
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Diagnostic and follow-up tools (3)

• Follow-up and prevention of ESLD1
• Physical exam doppler US ?FP
• Cirrhotic every 3 months
• Pre-cirrhotic every 6 months
• Others every year
• Risk of HCC without cirrhosis when HBV
• Doppler US / Sonoview / MRI2?

1AASLD guidelines 2009. 2ZechCJ, Dig Dis 2009.
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Advances in therapeutic management (1)
IFN 1983
Adefovir 2003
Entecavir 2006
Tenofovir 2002
Telbivudine 2007
Peg IFN 2005
Lamivudine 1999
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Take home message 1 IFN and PegIFN
Advances in therapeutic management (1)

• Peg-IFN ADV2 17 patients treated w/ ADV
  PegIFN?2a for 48ws (pilot)
• ? no HBe or HBs seroconversion
• ? 100 HBV-dNA rebound after end of treatment
• ? effect on ALT/AST on treatment only
• PegIFN TDF3 10 patients treated w/ TDF alone
  or PegIFN?2a for 24ws then TDF (randomized trial)
• ? Non difference in seroconversion rates or
  HBV-DNA levels at 48ws

1
HIV-/IFN
HIV/IFN-
HIV/IFN
HIV-/IFN-
A-B, A-C, A-D plt0,05 B-C, B-D, C-D NS
? Still any room for PegIFN in HIV-HBV context?
1Di Martino V, Gastroenterol 2002. 2Ingiliz M,
Antivir Ther 2008. 3Johnson M, HIV Clin Trials
2007.
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Take home message 2 Lamivudine
Advances in therapeutic management (1)
? gt 90 of HIV-HBV patients treated w/ Lamivudine
experiencing viral breakthrough at year 4
HOWEVER LAM efficient in preventing HBV
reactivation in antiHBc only on immunosuppressive
therapy or HBV-MTCT
1Benhamou Y, Hepatol 1999.
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Take home message 3 Adefovir
Advances in therapeutic management (1)
1
HBV DNA (lt 2.6 log10 copies/ml) 8/35 HBeAg
negative 3/33 HBe seroconversion 2/33
2

• Slow decline of HBV-DNA with emergence of ADV-R
  strains
• New ADV-R strains selected in HIV-infected
  patients3

1Benhamou Y, J Hepatol 2006. 2Peters M, Hepatol
2006. 3Lacombe K, AIDS 2006
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Take home message 4 Entecavir
Advances in therapeutic management (1)
Selection of M184V following ETV tx1,2
70
ART naïve
with M184V
3/5
60
ART experienced
6/12
Univariate analysis for selection of M184V
Total
50
3/7
40
30
20
10
0
Median time to M184V 148 days 98 days
1Sasdeusz J, AIDS 2008. 2McMahon MA, NEJM 2007
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Take home message 5 Telbivudine
Advances in therapeutic management (1)
No HIV resistance found
? Mild suppression of HIV replication during LdT
course
1Low E, AIDS 2009
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Take home message 6 Tenofovir
Advances in therapeutic management (1)

• French HIV-HBV Cohort1 165 patients on TDF
  (3TC/FTC, 80 LAM-R)

0
BL
24 weeks
-1
-2
-3
-4
-5
P0.045 TDF/TDF3TC vs. 3TC
-6
TDF
3TC
TDF/3TC
N 10 11 6
- TDF/3TC gt 3TC alone but not TDF in HBV naïve
- No benefit continuing 3TC in experienced HBV
viraemic patients - No difference between adding
or switching TDF

• 98 lt2000 UI/ml
• 0 non responder, 2/165 mild rebounders
  (lt10000UI/mL)
• Resistance ?

1Lacombe K, CROI 2009. 2Lewin R, Hepatol 2009
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Advances in therapeutic management (2) timely
initiation of treatment
Indication for HIV treatment
EACS guidelines 2008
HBV-DNA 2000IU/mL
HBV-DNA lt 2000IU/mL
cirrhosis
cART including 3TC / FTC and TDF And refer to
transplantation if decompensation
Patient with HBV Associated 3TC resistance
Patient without HBV Associated 3TC resistance
cART including 3TC / FTC and TDF
Substitute on NRTI by TDF or add TDF or ETC
cART regimen of choice (include TDF 3TC/FTC ?)
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Advances in therapeutic management (2) timely
initiation of treatment
No Indication for HIV treatment
EACS guidelines 2008
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New challenges (1) genetic variability

• Genotype G increased liver fibrosis1
• Genotype C increased risk of HCC2
• Genotype A better response to IFN
• Genotype B mild hepatitis B, higher rate of
  seroconversion

Worldwide HBV genotype distribution (adapted
Baghani S.)
? Whether routine genotyping is useful remains to
be proved
1Lacombe K, AIDS 2006. 2Chan HL, J Clin Oncol
2008.
23
New challenges (1) genetic variability and
public health impact
Lee WM.N Engl J Med. 1997

• Double stranded DNA with overlapping reading
  frames
• Mutations on Pol gene can be associated with
  mutations on S gene
• Mutations on Pol gene selected by exposure to
  Nucleos(t)ides (3TC, FTC, ADV, ETV, LdT)
• S gene mutations known to be associated with
  decrease of HBs antigenicity1 and vaccine escape2

? Public health impact of emergence of vaccine
escape mutants due to heavily treated patients
such as those with HIV ?
1Torresi J, J clinc virol 2002. 2Kamili S,
Hepatol 2009
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New challenges (2) New markers of treatment
efficacy

• Rare HBe or HBs seroconversion on nucleos(t)ides
  despite undetectable HBV-DNA ? new markers
  predicting seroconversion?
• cccDNA highly correlated to HBs clearance on
  ADV, but measured into the liver
• HBsAg quantification strong marker of HBs
  clearance in HBV mono-infected patients treated
  w/ PegIFN (gt1log drop HBsAglt10UI/mL at W48
  predictive of HBs clearance at W72)

? Need to be evaluated with nucleos(t)ides and in
HIV context
25
New challenges (3) Access to OLT and innovative
procedures for HCC treatment

• HCC a harbinger of an emerging problem for
  persons living with hepatic co-infection in
  regions with access to potent ARV regimen dixit
  M. Sulkowski (J Hepatol 2009)
• Very reassuring outcome for transplanted HIV-HBV
  patients 100 survival at year 31
• Need for evaluation of innovative drugs such as
  sorafenib in HIV context when OLT not possible2

1Tatteo M, AIDS 2009. 2Deeken JF, Curr Opin Oncol
2009
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New challenges (4) resource-constraint settings

• Access to HBV screening ? part of WHO guidelines
  but implementation in everyday practice ???
  Because of high cost
• Access to immunization in non immune patients ?
  cost of vaccine and low efficacy in heavily
  immunosuppressed patients
• Access to potent drugs (i.e. TDF) ? part of WHO
  guidelines but TDF not available as 1st line in
  many countries
• Access to HBV-MTCT ?antiHBV-Ig too expensive,
  need to evaluate TDF 3TC (3TC proved to be
  efficient)
• Access to HCC treatment ? high risk because of
  long exposure to HBV infection aflatoxine, but
  no treatment prevent

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Conclusion

• Thanks to TDF, is HBV infection still a
  problem?...
• Many hepatologists think NO
• As infectious diseases specialist, I think YES
• Tolerance issue with TDF (renal, bone)
• Access issue of TDF in resource-limited countries
• Emergence of resistance on the long term (HIV
  context has proved to be favorable for that in
  the past)
• What to do with HBV vaccine escape mutants?

? We breathe better, but still need to be on our
guards