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Epidémiologie génétique du VHB

Epidémiologie génétique du VHB. Anders Boyd, MPH, PhD Inserm U707 Hôpital Saint-Antoine Service des maladies infectieuses et tropicales Paris, France. Summary. Epidemiology and clinical course Genetic variability Therapeutic considerations

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Epidémiologie génétique du VHB

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  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. Top 3 most common routes of transmission Epidemiology

  4. Epidemiology • Global prevalence HIV prevalence, 2008 • 90% of HIV-infected patients with markers of prior HBV infection + 5-15% w/ chronic infection1 • HIV (33M), HBV (400M) making 2-4M HIV-HBV2 1Alter M. J Hepatol 2006. 2WHO Report, 2008.

  5. Clinical course of co-infection http://ocw.tufts.edu/Content/48/lecturenotes/595117/595146

  6. Clinical course of co-infection • Impact on morbidity/mortality ↓ Incidence/Mortality AIDS-related events1 ↑ Liver disease morbidity/mortality2,3 cART era • Ex: 12 382 patients living in Europe 36% excess risk / HBV4 Adults: 25% chronic ↑ ESLD & HCC5,6 Acute HBV infection 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

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

  8. Genetic variability and public health impact 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.

  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 Lee WM.N Engl J Med. 1997 1Torresi J, J Clinc Virol 2002. 2Kamili S, Hepatol 2009.

  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 Gish R et al., Lancet Inf Dis, 2012

  12. 1.00 0.80 0.60 Cumulative probability 0.40 0.20 0.00 0 12 24 36 48 60 72 84 Time from TDF-initiation (months) Suboptimal response Cumulative probability in achieving undetectable HBV in HIV-HBV co-infected patients treated with TDF 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) Primary non response (n=14) 6 MO 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: 0.5-1.4 days) Median infected cell half-life: 7.9 days (6.3-11.0 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 2.0-6.3 vs >6.3 log10 IU/mL) 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. Therapeutic options • Effect of multiple switching on genetic variability in LAM-experienced, HIV-HBV co-infected patients Lacombe et al., Hepatology, 2012 [accepted]

  19. Perspectives • Supériorité entre les traitements anti-VHB chez les patients co-infectés par le VIH et VHB ? Dans le contexte africain ? TDF > 3TC ?? ?? ?? TDF > 3TC

  20. Perspectives • VarBVa : étude de cohorte, nichée, prospective TRIVACAN TEMPRANO OMS OMS+INH ARV précoce ARV précoce+INH ARV continue Sans ARV ARV ITP fixe ARV ITP adapté 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. Gilead Sciences, Inc.

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