Traitements d’activité duale anti-VIH et anti-VHB Stanislas Pol Pôle d’Hépato-Gastro-Entérologie médico-chirurgical Unité d’Hépatologie & Inserm U-567 Hôpital Cochin, Paris, France

Réplication du VHB uncoating CCC DNA transcription ccc DNA amplification mRNA AAA protein translation encapsidation ADN polymerase reverse transcription ADN (-) ARN (+)

Réplication du VHB uncoating CCC DNA transcription ccc DNA amplification mRNA AAA protein translation encapsidation ADN polymerase reverse transcription ADN (-) ARN (+)

Réplication du VHB nucleoside analogues uncoating CCC DNA transcription ccc DNA amplification mRNA AAA protein translation encapsidation ADN polymerase reverse transcription ADN (-) ARN (+) nucleoside analogues

Possibilités thérapeutiques cytokines antisense ribozyme uncoating CCC DNA transcription ccc DNA amplification mRNA AAA vaccins protein translation encapsidation ADN polymerase reverse transcription reverse transcription ADN (-) ARN (+) cytokines antisense nucleoside analogues antisense

Traitement Anti VHB Interferon alfa-2b HBV e+/e- Lamivudine HBV/HIV Adefovir dipivoxil e+/e-/lam-R Entecavir HBV (HIV?) Peg IFN alfa-2a Telbivudine Tenofovir HIV/HBV Emtricitabine

Co-infection VIH-VHB: traitements IFN LMV ETV* FTC TDF* ADV* Nb. de patients 87 215 51 33 200 35 Durée (semaines) 12-24 48 24 24-48 48-144 Activité Anti-VHB wt, preC wt, preC, LMV-R wt, preC LMV-R  ADN VHB (log cp/ml) 26 %** 2.7 3.6 3 4.4 4 - 5.4 Seroconv. HBe 9% 11% ? 4% 7% Réponse ALAT 12-20 % 30-50 % 49 % 35-66 % Amélioration Histologique 33-50 % * Ajouté à LMV dans la majorité des cas. ** < 6 log copies/ml Wong DK et al. Gastroenterology 1995. Di Martino V et al. Gastroenterology 2002. Dore GJ et al. J Infect Dis 1999. Benhamou Y et al. Hepatology 1996. Pessoa W et al. CROI 2005. Raffi F et al. 2003 IAS. Peter M et al. CROI 2005. Ristig MB et al. J Infect Dis. 2002. Benhamou Y et al. N Engl J Med. 2003. Benhamou Y et al. Lancet 2001 and AASLD, 2003

HBV DNA (log10 copies/mL) Tenofovir Mean changes from baseline (8.64±0.08 log10 copies/mL) in serum HBV DNA measured by PCR during tenofovir (300 mg.d) therapy in 10 HIV patients with HBV resistance to lamivudine P<0.0001 -1 HBV DNA (log10 copies/mL) -3 -4 Incl. 4 8 12 Weeks of Tenofovir Y Benhamou et al. N Engl J Med 2003

Temps pour atteindre l’indétectabilité ADN VHB mois) Ténofovir est plus efficace qu’adefovir chez les sujets co-infectés VIH-VHB 85 patients inclus (56 sous ténofovir TDF, 29 sous adéfovir ADV), comparables (excepté génotype G présent dans 41,7 % des patients sous adéfovir versus 5,4 % sous ténofovir) 1,00 0,75 0,50 0,25 0,00 10 20 30 40 Temps pour atteindre l’indétectabilité ADN VHB mois) ADV TDF Proportion avec < 200 copies/ml Conclusion : indétectabilité anti-VHB plus souvent atteinte avec ténofovir (HR = 2,8 ; IC95% 1,1-6,8 ; p = 0,025) CROI 2007, Lacombe K, abst 945

Impact de l’entécavir sur la réplication et la sélection de résistances du VIH-1 Entécavir : sans activité antirétrovirale jugée cliniquement pertinente (RCP) 3 observations cliniques de baisse de la charge virale VIH de 1 log sous entécavir Étude des populations clonales VIH d’un des 3 patients VIH-VHB sous entécavir monothérapie : 0 % de mutations M184V à J0 vs 61 % et 96 % à M4 et M6 Commentaires : Capacité supposée de sélection de la mutation M184V avec résistance croisée 3TC établie à partir d’un patient, non démontrée in vitro par exposition répétée d’un VIH sauvage à l’entécavir Pas de données issues des 2 autres patients (car entécavir suivi d’une HAART ayant conduit à une indétectabilité VIH) Pas de données pharmacologiques Mais recommandation « principe de précaution » par le laboratoire BMS, à suivre CROI 2007, McMahon M, abst 136LB

La physiopathologie de l’hépatite B est immuno-médiée Cellule T cytotoxique

Les risques des traitements anti-VIH et anti-VHB Immunorestauration Résistance

Immuno-restauration induite par HAART Hépatite fulminante Aggravation d’une hépatopathie sous-jacente Cellule T cytotoxique

Immuno-restauration induite par HAART Seronconversion Anti HBe et Anti HBs avec/sans rebond de transaminases Cas rapportés : 4 études avec 9 cas Incidence : 1 sur 24 dans une étude prospective Rebond de l’activité nécrotico-inflammatoire sans séroconversion Cas rapportés : 4 études avec 7 cas Carr, Lancet 1997 ; Velasco, NEJM 1999 ; Rouanet, Eur J Gastro 2003 ; Lascar, JID 2003 ; Piroth, J Hepatol 2000 ; Mastroianni, AIDS 1998 Proia, Am J Med 2000 ; Manegold, JID 2001 ; Drake, CID 2004

Résistances aux antiviraux

Résistance VHB (Ag HBe+) 65 71 55 Patients (%) 46 0,7 21 3 0,7 23 <1 13 années 3 LAM1 ADV2 LdT3 ETV4 FTC5 CLV6 1. Lok A. Gastroenterology 2003. 2. Marcellin P, et al. J Hepatol 2005;42 (suppl2):31-32. 3. Lai CL, et al. Hepatology. 2006;44(suppl):222A . 4. Colonno R et al. Hepatology 2006; 44 (suppl): 229A.EASL 2007 5. Shiffman ML et al. Hepatology 2004; 40(suppl):172A. 6. Chung YH. Hepatology 2006; 44 (suppl):698A.

Lamivudine et co-infection VHB-VIH Risque cumulé de développer une résistance du VHB à la lamivudine chez 57 patients HIV-HBV traités par 300 mg/j 0,00 0,25 0,50 0,75 1,00 368 735 1103 1470 Days of Lamivudine Therapy* Proportion of Patients with sustained HBV DNA suppression Y Benhamou et al. Hepatology 2000

Relation résistance et cinétique virale B Lamivudine[1] Resistance at Median 29 months vs Week 24 HBV DNA Adefovir[2] Resistance at Week 144 vs Week 48 HBV DNA 64% 67 % % Resistance 32% 26 % 13% 8% 4 % < ND < 3 < 4 > 4 < ND 3-6 > 6 Week 48 HBV DNA (log10 copies/mL) N = 114 primarily HBeAg- patients Week 24 HBV DNA (log10 copies/mL) N = 159 HBeAg+ patients 1Yuen MF, et al. Hepatology. 2001;34:785-791. 2Locarnini S, et al. J Hepatol 2005;42(suppl 2):17.

Spectre de réponse Primary NR Partial VR

Spectre de réponse Change Rx High risk of resistance And disease progression Change Rx (add on prefered) Primary NR Risk of resistance Consider change Rx Partial VR

Adaptation du traitement anti-VHB selon la réponse virologique Primary NR and Inadequate VR ADV* Add LdT or ETV LdT* Add ADV ADV+LdT* Switch LdT for ETV? Consider initiation of HAART (including TDF) TDF Add LAM or FTC TDF+LAM/FTC Add LdT or ETV switch LAM/FTC for another NRTI * Patients with no indication for anti-HIV therapy

Les avantages des traitements doubles Anti-VHB et anti-VIH Eviter (ou réduire) les risques de l’immunorestauration Cumuler les bénéfices de la virosuppression VIH et VHB

HBeAg(-), normal ALT (n=2,923) Adjusted relative risk of La viro-suppression optimale est le but du traitement antiviral: pourquoi? REVEAL: la virémie B est associée au risque de cirrhose 18 All participants (n=3,582) 18 HBeAg(-), normal ALT (n=2,923) 16 *p<0.001 16 *p<0.001 14 14 * 12 * 12 * Adjusted relative risk of cirrhosis (95% CI)* * 10 10 8 8 6.5 6.6 5.6 * 6 6 5.6 * KEY TAKEAWAY High baseline HBV viral load is an independent risk factor for the development of cirrhosis. Independent of - ALT levels - e-antigen serostatus - age - gender - cigarette smoking - alcohol consumption. A multivariate-adjusted relative risk analysis was also performed for various subsets of the cohort.1 After adjusting for age, sex, cigarette smoking, alcohol consumption, HBeAg status and ALT level, the multivariate-adjusted relative risk increased with increasing HBV DNA level, as previously observed. A similar trend was noted when the analysis was restricted to HBeAg-negative patients with normal ALT levels. References Iloeje UH, et al. Gastroenterology. 2006;130:678–86. 4 4 2.5 2.5 2 1.4 2 1.4 300–<104 104–105 105–106 >106 300–<104 104–105 105–106 >106 HBV DNA copies/mL HBV DNA copies/mL *Cox proportional hazards regression analysis. Relative to HBV DNA <300 copies/mL Relative risk adjusted for age, gender, cigarette smoking, alcohol consumption , HBeAg status and ALT Iloeje UH, et al. Gastroenterology. 2006;130:678–86 Why Treat Hepatitis B? Date of preparation: August 2007 BAR-08/07/246 23 23

24 La viro-suppression optimale est le but du traitement antiviral: pourquoi? REVEAL: la virémie B est associée au risque de carcinome hépatocellulaire 16 Baseline HBV DNA level (copies/mL) 14.89% 14 ≥106 105–<106 104–<105 300–<104 <300 12.17% 12 10 Cumulative Incidence of HCC (%) 8 6 KEY TAKEAWAY High baseline HBV viral load is an independent risk factor for the development of cirrhosis.1 The cumulative incidence of HCC was 1.3%, 1.4%, 3.6%, 12.2% and 14.9% for patients with baseline serum HBV DNA serum levels of <300, 300–9.9 x 103, 1.0–9.9 x 104, 1.0–9.9 x 105, and ≥106 copies/mL, respectively.1 Reference Chen CJ, et al. JAMA. 2006;295:65–73. 4 3.57% 2 1.37% 1.30% 1 2 3 4 5 6 7 8 9 10 11 12 13 All participants (n=3,653) Year of follow-up Adapted from Chen CJ, et al. JAMA. 2006;295:65-73 Why Treat Hepatitis B? Date of preparation: August 2007 BAR-08/07/246 24 24

Résultats à 1, 2, 3 ans ADN VHB indétectable chez patients Ag HBe positifs LIN† technique (copies/ml) ETV 300 Cobas Amplicor® HBV PCR LdT 300 Cobas Amplicor® HBV PCR LVD 300 Cobas Amplicor® HBV PCR Peg IFN 400 Cobas Amplicor® HBV PCR ADV 400 Amplicor® HBV DNA PCR CLV 300 Cobas Amplicor® HBV PCR †limite de détection 82% 80% 56% 68% 39% 48% 68% 67% 60% 40% Patients (%) 14% 36% 40% 25% 21% années ETV1 LdT2 LAM1,2 PEG IFN3 ADV4 CLV5 Chang TT, et al. N Engl J Med. 2006;354(10):1001-10. 2. Lai CL, et al. Hepatology. 2005;42(suppl):748A (Abstract LB01) 3. Lau GK, et al. N Engl J Med. 2005;352(26):2682-95. 4. Marcellin P, et al. N Engl J Med. 2003;348(9):808-16 5.Chung YH. Hepatology 2006; 44 (suppl):698A. 25

Séroconversion HBe chez patients Ag HBe positifs 46% 39% 28% 23% 33% 31% 30% Patients (%) 25% 26% 32% 22% 22% 20% 21% 16% 14% années ETV1 LdT2 LAM1,2 PEG IFN3 ADV4 CLV5 1. Chang TT, et al. Hepatology. 2006;44(suppl)229A. 2. Lai CL, et al. Hepatology. 2006;44(suppl):222A 3. Lau GK, et al. N Engl J Med. 2005;352(26):2682-95. 4. Marcellin P, et al. J Hepatol 2005;42 (suppl2):31-32 5.Chung YH. Hepatology 2006; 44 (suppl):698A. 26

Diagnosis of HCC (% of patients) 27 Bénéfices cliniques associés à la virosuppression: réduction de la survenue du CHC 25 HCC occurred in: 7.4% in placebo arm 3.9% in LVD arm Hazard ratio 0.49 (p=0.047) 20 15 Diagnosis of HCC (% of patients) Placebo 10 Treatment with LVD reduced the incidence of HCC in these patients with advanced liver disease.1 This slide shows the Kaplan–Meier estimates of time to diagnosis of HCC amongst patients within the placebo and LVD arms of the study. Patients in the placebo group were more than twice as likely to develop HCC in the 3-year period compared with patient who received LVD treatment. HCC occurred in 16 patients (7.4%) who received placebo versus 17 patients (3.9%) who received LVD (p=0.047). HCC developed in five patients during the first year of the trial; two in the placebo group and three in the LVD group. However, even if these tumours had existed before study entry and had been missed during screening, the exclusion of these patients would not have affected the result of the primary analysis of time to disease progression. Exclusion of the patients changes the hazard ratio for time to diagnosis of HCC from 0.49 (p=0.047) to 0.47 (p=0.052). Reference Liaw YF, et al. N Engl J Med. 2004;351:1521–31. 5 LVD 6 12 18 24 30 36 No. at risk Months Placebo 215 209 198 184 173 153 43 LVD 436 429 417 400 385 347 122 Liaw YF, et al. N Engl J Med. 2004;351:1521-31 Why Treat Hepatitis B? Date of preparation: August 2007 BAR-08/07/246 27 27

On-treatment with LVD (100 mg OD)† Bénéfices cliniques associés à la virosuppression On-treatment with LVD (100 mg OD)† HCC Survival‡ 1.0 1.0 (n=116) HBV DNA >105 copies/mL HBV DNA <105 copies/mL 0.8 0.8 p=0.027 (n=69) 0.6 0.6 Incidence of HCC Cumulative survival‡ 0.4 (n=87) 0.4 KEY TAKEAWAY HBeAg-negative patients with cirrhosis who maintained a virologic response (HBV DNA <105 copies/mL) on antiviral therapy had a greater probability of survival compared with those who had virologic breakthrough (reappearance of serum HBV DNA using non-PCR methods or HBV DNA >105 copies/mL using PCR). In HBeAg-negative patients with cirrhosis, the likelihood of developing HCC was significantly lower for patients with maintained virologic response compared with those with virological breakthrough. Similarly, in patients with Child-Turcotte-Pugh A cirrhosis, the probability of survival was higher if a virological response was maintained (p<0.01). Reference Di Marco V, et al. Hepatology. 2004;40:883–9. p<0.001 0.2 (n=192) 0.2 0.0 0.0 12 24 36 48 60 72 12 24 36 48 60 72 Months Months *Virologic response = HBV DNA <105 copies/mL; †Minority of patients received LVD 150 mg OD; ‡Patients with Child-Turcotte-Pugh A cirrhosis Adapted from Di Marco V, et al. Hepatology. 2004;40:883-9 Why Treat Hepatitis B? Date of preparation: August 2007 BAR-08/07/246 28 28

Etude 438 (AgHBe-): réponses histologiques à 5 ans Bénéfices cliniques associés à la virosuppression Etude 438 (AgHBe-): réponses histologiques à 5 ans Hadziyannis S. et al, Gastroenterology 2006

Impact de la virosuppression et de la réversibilité de la cirrhose Impact sur la morbidité AASLD 2007 Mallet V et al, Abstract 754, 572A

Impact de la virosuppression et de la réversibilité de la cirrhose Impact sur la mortalité Réponse virologique Réponse histologique AASLD 2007 Mallet V et al, Abstract 754, 572A

Progressions cliniques comparées des co-infections VIH-VHB et VIH-VHC 1 129 patients co-infectés VIH-VHC et 815 co-infectés VIH-VHB de la cohorte ATHENA, 85 % sous HAART, suivis entre 2001 et 2006 Co-infection VHB 30 Co-infection VHC Pas de coinfection VHB ou VHC Co-infection VHB et VHC 25 20 14 % Probabilité de décès 15 10 7 % 5 1 2 3 4 5 6 7 8 Années sous traitement antirétroviral hautement actif www/Hepatonews CROI 2007, Smit C, abst 932

Evolution sérologique du VHB et impact clinique sous HAART (2) 633 patients suivis prospectif (moyenne 5,1 ans) de l’évolution ou de l’apparition des marqueurs du VHB (Ag HBs, anti HBs, ant HBc) Survie en fonction du statut sérologique de départ 1,0 Proportion survie 1 2 3 4 5 6 7 8 9 10 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 Années Patients avec Ag HBs (n = 119) Patients avec Ac anti-HBs (n = 270) Patients avec Ac anti-HBc isolés (n = 179) Patients sans marqueurs VHB (n = 65) www/Hepatonews CROI 2007, Sheng WH, abst 941

Les avantages des combinaisons Anti-VHB Renforcer les bénéfices de la virosuppression Limiter les risques de résistance

Résistance chez les patients LAM-R resistance mutations % of patients with Lampertico et al AASLD 2006; Colonno et al AASLD 2006, EASL2007

Mean changes from baseline in HBV DNA (log10 copies/mL) Adéfovir: ADN du VHB Mean changes from baseline (8.64±0.08 log10 copies/mL) in serum HBV DNA measured by PCR during adefovir dipivoxil therapy -5.5 -3.7 -1.8 0.0 Weeks of adefovir dipivoxil Mean changes from baseline in HBV DNA (log10 copies/mL) Incl. 2 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 P<0.0001 Aucun rebond de la réplication VHB - 4.77 log copies/mL Y Benhamou et al. Lancet 2001

Incidence de la résistance sous traitement combiné antiVHB de novo Combination Therapy in HBV Mono-Infected Patients HIV Coinfected Patients 1 Sung et al. J Hepatol 2003 ;38 (suppl 2):25-26 . 2 Marcellin et al. N Engl J Med 2004; 351: 1206-17 . 3 Lau et al. Hepatology 2004;40:171A 4 Lai et al. Hepatology 2003;38:262A

Recommandations pour le traitement de la co-infection VIH-VHB No immediate indication for anti-HIV therapy HBV DNA HBeAg+ : >20,000 IU/mL HBeAg-: >2000 IU/mL HBeAg, HBV DNA ALT Normal ALT Active disease Low HBV DNA Abnormal ALT High HBV DNA* MONITOR Liver disease status required No evidence Evidence of active disease of active disease METAVIR A≤1 F≤1 METAVIR A≥2 F≥2 MONITOR CD4 >500 CD4 <500 Treat HBV only ADV/ ETV / PEG IFN Start ART with anti-HBV drugs TDF + LAM/FTC (LdT) Alberti A et al. J Hepatol. 2005

Recommandations pour le traitement de la co-infection VIH-VHB avec indication au traitement VIH HBV DNA HBeAg+ : >20,000 IU/mL HBeAg-: >2000 IU/mL Alberti A et al. J Hepatol. 2005

Algorithme pour le traitement de la co-infection VIH-VHB avec hépatopathie non cirrhotique sans indication au traitement VIH HIV/HBV HBV DNA <2,000 IU/mL HBV DNA ≥2,000 IU/mL ALT Normal ALT Elevated About one half of HBeAg-negative patients have serum HBV DNA levels persistently <105 copies/mL at the time of presentation.1 Because these patients have lower HBV DNA values but may still have disease, it was recommended that patients with HBV DNA ≥104 be considered for treatment. The remainder of the recommendations of the panel are similar to those recommended for patients with HBeAg-positive chronic hepatitis B. Once again, interferon/peginterferon, lamivudine, adefovir, and entecavir are all first-line options. Unless HBsAg seroconversion occurs, long-term treatment is generally required, and adefovir is preferred to lamivudine as an oral agent because of a lower risk of resistance. Long-term data are not yet available for entecavir. 1. Adapted from Keeffe EB. Clin Gastroenterol Hepatol. 2004;2:87-106. 2. Chu CJ et al. Hepatology. 2002;36:1408-15. 3. Shouval D et al. Hepatology. 2004;40(suppl 1):728A(LB07). No treatment Monitor every 6–12 months Monitor ALT every 3-12 months Consider biopsy and treat if disease Treat PEG IFN: e+ - GT A - ALT ADV- LdT?-(ETV?) mono Rx? Combination +++

Algorithme pour le traitement de la co-infection VIH-VHB avec hépatopathie non cirrhotique avec indication au traitement VIH HIV/HBV HBV DNA <2,000 IU/mL HBV DNA ≥2,000 IU/mL About one half of HBeAg-negative patients have serum HBV DNA levels persistently <105 copies/mL at the time of presentation.1 Because these patients have lower HBV DNA values but may still have disease, it was recommended that patients with HBV DNA ≥104 be considered for treatment. The remainder of the recommendations of the panel are similar to those recommended for patients with HBeAg-positive chronic hepatitis B. Once again, interferon/peginterferon, lamivudine, adefovir, and entecavir are all first-line options. Unless HBsAg seroconversion occurs, long-term treatment is generally required, and adefovir is preferred to lamivudine as an oral agent because of a lower risk of resistance. Long-term data are not yet available for entecavir. 1. Adapted from Keeffe EB. Clin Gastroenterol Hepatol. 2004;2:87-106. 2. Chu CJ et al. Hepatology. 2002;36:1408-15. 3. Shouval D et al. Hepatology. 2004;40(suppl 1):728A(LB07). No drug with dual antiviral activity acceptable Monitor every 6–12 months Treat TDF + LAM/FTC TDF TDF+ LdT/ETV?

Algorithme pour le traitement de la co-infection VIH-VHB chez le cirrhotique HIV/HBV Indication for anti HIV No indication for anti HIV About one half of HBeAg-negative patients have serum HBV DNA levels persistently <105 copies/mL at the time of presentation.1 Because these patients have lower HBV DNA values but may still have disease, it was recommended that patients with HBV DNA ≥104 be considered for treatment. The remainder of the recommendations of the panel are similar to those recommended for patients with HBeAg-positive chronic hepatitis B. Once again, interferon/peginterferon, lamivudine, adefovir, and entecavir are all first-line options. Unless HBsAg seroconversion occurs, long-term treatment is generally required, and adefovir is preferred to lamivudine as an oral agent because of a lower risk of resistance. Long-term data are not yet available for entecavir. 1. Adapted from Keeffe EB. Clin Gastroenterol Hepatol. 2004;2:87-106. 2. Chu CJ et al. Hepatology. 2002;36:1408-15. 3. Shouval D et al. Hepatology. 2004;40(suppl 1):728A(LB07). Treat ADV + LdT/(ETV?) Treat TDF + LAM/FTC TDF+ LdT/ETV ? Refer patient for LT if decompensated cirrhosis

Conclusions Treatment guidelines in co-infected patients ~ HBV mono-infected Both HIV and HBV must be considered Short term objectives: VR Disease progression: HBV DNA <2,000 IU/mL(4 logs) Resistance: <60 IU/mL (2.3 logs) Indefinite duration of anti-HBV Long term tolerability Long term resistance