Hépatites Virales C et B et Infection par le
                   VIH
Causes de décès d’origine infectieuse
       dans le monde (2000)
     HIV – HBV – HCV : TOP 10
  Maladies                ...
Viral hepatitis in HIV-infected
                  patients
                     HCV                    HBV

Prevalence    ...
Hépatite Chronique C
  Chez les Patients
Co-infectés par le VIH
Influence of HIV on HCV


• Major cause of mortality

• More severe liver lesions vs HCV
mono-infected

• Higher HCV RNA
No influence of HCV/HBV on response to
              HAART : EuroSIDA cohort
                HIV RNA <400 copies/ml       ...
Influence du VIH sur le VHC
          Mortalité liée à l’atteinte hépatique
                Mortalité chez les patients VI...
Impact of HAART on liver related
                       mortality

           1.1           Global Mortality
             ...
Progression to cirrhosis
influence of alcohol and immune
              status
                                     CD4 <20...
Timing for Anti-HCV and ARV
                     initiation
                                           HIV mono-infected  ...
Treatment of chronic hepatitis C
Genotype 2/3                   Genotype 1/4

                                   HCV RNA

...
w

                    R
                        x
                            48           PEG IFN/RBV
                ,
...
PRESCO                          APRICOT
                    (overall SVR 50%)               (overall SVR 40%)

           ...
r
                                    fo A
                             a
                                  n
            ...
APRICOT
                                    SVR according to Rx exposure

                                 GT1            ...
APRICOT
                    VR n (%)          PPV (%)                    NPV (%)

Week 4            G1       G2/3      G1 ...
PEG IFN2 (a:180 /b:1.5 µg) - RBV 1000 - 1200 mg
PEG IFN/RBV : Specific AE
• Liver decompensation : 10% of cirrhotic pts
     • Pl., Bilirubin, P alc, Hb and ddI
     • Co...
CONCLUSION

• HCV coinfection: X30 in HIV vs general population
• HCV coinfection major cause of mortality and
  morbidity...
Hépatite Chronique B
  Chez les Patients
Co-infectés par le VIH
Prevalence of HBsAg+ in HIV Infected
              Patients

• EuroSIDA Cohort (n= 9802) :
   Patients screened for HBsAg:...
Influence of HIV on CHB
In the Pre HAART era, HIV in HBsAg positive patients (compared to
HBV mono-infected):

       • In...
Mortality
    Liver-related mortality in 5293 patients (MACS), 1984 /1987–2000

            Viral status
                 ...
Impact of HIV Infection on Progression
           to HBV-Related Cirrhosis

                 100
                 90

    ...
Influence of HAART

• Increases duration of HBV
  by improving survival
                                                  ...
HIV/HBV Co-infection Mortality
     Liver-related mortality (1995-2003 - GERMIVIC Cohort)

ESLD related death % of total d...
Impact of Anti-HBV Therapy on Liver Fibrosis

                        ADV                                                 ...
Treatment of HBV in HIV Co-infected Patients

                                        Licensed for

                      ...
Interferon
                                                      Months of                           HBV DNA HBeAg
       ...
HIV/HBeAg+ LAM-R
                                                 PEG-IFN α2a + ADV
                                      ...
Lamivudine
                                  Median change in serum HBV DNA
                                              ...
Entecavir
   ETV 1mg qd 48w = 4.3 log DNA decline in HIV/HBeAg+ LAM-R patients
                                           ...
Telbivudine
• No in vitro anti HIV activity of LdT


                                                       HIV Isolate
  ...
Tenofovir Disoproxil Fumarate

                TDF vs. TDF+LAM (48 weeks)                                                 ...
Tenofovir Disoproxil Fumarate

TDF- vs LAM- containing HAART in ARV-naïve HIV/HBeAg+ Co-infected Patients (TICO Study):

R...
Treatment Algorithm
           Patients with Compensated Liver Disease and
         No Indication for HIV Therapy (CD4 cou...
Treatment Algorithm
              Patients with Compensated Liver Disease and
             Indication for HIV Therapy (CD4...
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Benhamou Hcv Hiv Du 2010

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Benhamou Hcv Hiv Du 2010

  1. 1. Hépatites Virales C et B et Infection par le VIH
  2. 2. Causes de décès d’origine infectieuse dans le monde (2000) HIV – HBV – HCV : TOP 10 Maladies Décès par an Infections respiratoires ~3,5 million VIH ~3,0 million Diarrhées ~2,2 million Tuberculose ~2,0 million Malaria ~1-3 million Rougeole ~888,000 Hépatite B ~750,000 Pertussis ~355,000 Tétanos néonatal ~300,000 Hépatite C ~ 250,000 Source : CDC, WHO, UNICEF, UNAIDS
  3. 3. Viral hepatitis in HIV-infected patients HCV HBV Prevalence 20%-35% 7%-10% Mortality Major cause of death Higher compare to HBV mono-infected Progression to Accelerated ? Cirrhosis Hepatotoxicity Controversies ? of anti-retroviral therapies Active consideration for treatment of hepatitis
  4. 4. Hépatite Chronique C Chez les Patients Co-infectés par le VIH
  5. 5. Influence of HIV on HCV • Major cause of mortality • More severe liver lesions vs HCV mono-infected • Higher HCV RNA
  6. 6. No influence of HCV/HBV on response to HAART : EuroSIDA cohort HIV RNA <400 copies/ml 50% rise in CD4 70 70 50 50 HCV 30 30 10 10 0 3 6 9 12 Konopnicki D et al. AIDS. 2005;19:593-601.
  7. 7. Influence du VIH sur le VHC Mortalité liée à l’atteinte hépatique Mortalité chez les patients VIH en France Étude du groupe GERMIVIC 100 91,6 90 84,5 80 70 60 50 48,7 47 % 40,4 40 36,7 30 20 14,3 12,6 10 8 6,9 2 6,6 8,8 1,5 1 1 0 1995 1997 2001 2003 Mortalité Globale Mortalité liée au Sida Mortalité liée au foie CHC Caboub et al, CID 2001; Rosenthal et al, AIDS 2003.
  8. 8. Impact of HAART on liver related mortality 1.1 Global Mortality Global Mortality 1.1 Liver Mortality Liver Mortality HAART 0.9 HAART 0.9 Survival ARV Survival p < 0,0001 Untreated 0.7 0.7 0.5 ARV 0.5 p < 0,018 Untreated 0.3 0.3 0 1000 2000 3000 4000 5000 6000 0 1000 2000 3000 4000 5000 6000 Days of observation Days of observation Qurishi N et al, Lancet 2003
  9. 9. Progression to cirrhosis influence of alcohol and immune status CD4 <200/µL CD4 >200/ L OH <50 g/j OH<50 g/j 4 CD4<200/ L OH>50 g/j HIV- OH<50 g/j Fibrosis 3 (METAVIR) 2 1 0 5 10 15 20 25 30 35 40 Estimated duration of HCV infection Benhamou et al. Hepatology 1999;30:1054-1058
  10. 10. Timing for Anti-HCV and ARV initiation HIV mono-infected HIV/HCV < 200 CD4 cells/µL ARV recommended > 200 CD4 cells/µL and ARV possible : - ARV recommended < 350 CD4 cells/µL - High HIV RNA and - ARV before anti-HCV - Rapid CD4 decline > 350 CD4 cells/µL and Monitor - Monitor HIV < 500 CD4 cells/µL - Anti-HCV recommended (if indicated) CD4>350 : • Fibrosis progression rate is reduced • CD4 decline to « dangerous » level if anti-VHC is initiated Alberti et al. 1st ECCC. J Hepatol. 2005 Adapted from IAS–USA panel guidelines. Yeni P. at al. JAMA, 2004
  11. 11. Treatment of chronic hepatitis C Genotype 2/3 Genotype 1/4 HCV RNA < 800 000 UI/mL > 800 000 UI/ml Fibrosis: 0/1 Fibrosis: >2 TREAT Rx differed TREAT Alberti et al. 1st ECCC. J Hepatol. 2005
  12. 12. w R x 48 PEG IFN/RBV , /3 G T2 Virological response GT 1/4 GT 2/3 90% 90% 80% 80% 80% 73% 70% 68% 70% 64%62% 60% 60% 53% 50% 50% 38% 40% GT 4 40% 29% 29% 31% 30% GT 1 21% 30% 20% 14% 15% 20% 10% 10% 0% 0% ACTG APRICOT RIBAVIC ACTG APRICOT Laguno RIBAVIC EOT SVR EOT SVR RBV 800 mg 24 weeks Torriani F et al. NEJM 2004. Carrat F et al. JAMA 2004. Laguno C ett al. AIDS 2004. Chung R. NEJM. 2004
  13. 13. PRESCO APRICOT (overall SVR 50%) (overall SVR 40%) 72% 62% 50 Patients (%) 40 36% 30 29% 20 10 0 Geno 1 Geno 3 Geno 1 Geno 3 n=191 n=152 n=176 n=95 24, 48 or 72 weeks therapy all 48 weeks therapy HIV-pos; weight-based RBV HIV-pos; low RBV dose Ramos et al. J Viral Hepat (in press)
  14. 14. r fo A a n tio RN l u CV Impact of HCV RNA on a ev h H r ve , hi i 1 L T g SVR G HCV RNA 100 N SVR CD4 80 GT 1 GT 2/3 < 200/µL 17 8 (47 %) P ro p o rtio n o f p a tie n ts 61 61 63 60 < 350 /µL 72 26 (36 %) ≥ 350 /µL 216 90 (47 %) 40 18 HIV RNA 20 < 50 cp/mL 173 72 (42 %) 50-5000 cp/mL 66 23 (35 %) 0 > 5000 cp/mL 49 21 (43 %) ≤800,000 >800,000 ≤800,000 >800,000 n=46 n=130 n=28 n=67 Torriani F et al. NEJM. 2004. Cooper D. et al, XV AIDS Conference
  15. 15. APRICOT SVR according to Rx exposure GT1 GT2/3 50 100 39% 40 SVR rate (%) SVR rate (%) 80 69% 29% 30 59% 60 20 40 11% 26% 10 20 n= 176 62 114 n= 111 27 84 0 0 All <80/80/80 ≥80/80/80 All <70/70/70 ≥70/70/70 patients exposure* exposure patients exposure* exposure *Patients violated the rule if ≥1 of the three targets were not achieved Opravil M. et al. 45th ICAAC 2005; Abstract 2038
  16. 16. APRICOT VR n (%) PPV (%) NPV (%) Week 4 G1 G2/3 G1 G2/3 G1 G2/3 ≥1 log10 drop 119 (68) 83 (87) 39 70 93 92 ≥2 log10 drop 71 (40) 76 (80) 58 74 90 84 HCV RNA -ve 22 (13) 35 (37) 82 94 79 57 Week 12 ≥1 log10 drop 148 (84) 89 (94) 34 66 96 100 ≥2 log10 drop 110 (63) 84 (88) 45 70 98 100 HCV RNA -ve 60 (34) 68 (72) 70 82 92 89 Torriani F, et al. 45th ICAAC 2005; Abstract 1024
  17. 17. PEG IFN2 (a:180 /b:1.5 µg) - RBV 1000 - 1200 mg
  18. 18. PEG IFN/RBV : Specific AE • Liver decompensation : 10% of cirrhotic pts • Pl., Bilirubin, P alc, Hb and ddI • Compensated cirrhosis: No ddI, Monitoring +++ • Mitochondiral toxicity (1%-3%) • ddI (d4T) (RR x23) • No ddI – (d4T ?) • Monitor : Amylase, lipase, lactic acid • Anemia : Hb <8 g/dL : 3.8% • AZT (RR x2) • Use EPO • Neutropenia : Neutrophils <750: 2-11% • Use GCSF Alberti A et al. 1st ECCC. J Hepatol. 2005 .Torriani F et al. NEJM 2004. Carrat F et al. JAMA 2004. Chung R et al. NEJM. 2004
  19. 19. CONCLUSION • HCV coinfection: X30 in HIV vs general population • HCV coinfection major cause of mortality and morbidity in HIV population • Less than 20% of the Patients have received anti- HCV therapy in Europe • Coinfected patients should be actively considered for HCV therapy
  20. 20. Hépatite Chronique B Chez les Patients Co-infectés par le VIH
  21. 21. Prevalence of HBsAg+ in HIV Infected Patients • EuroSIDA Cohort (n= 9802) : Patients screened for HBsAg: 5883 (60%) HBsAg+: 530 (9%) - South: 9.1% - Central: 9.2% - North: 9.7% - East: 6% Konopnicki D, et al. AIDS. 2005.
  22. 22. Influence of HIV on CHB In the Pre HAART era, HIV in HBsAg positive patients (compared to HBV mono-infected): • Increased the risk of chronic infection after contamination • Reduced the seroconversion rates to anti-HBe and anti- HBs • Increased HBV replication • Frequent reactivation related to CD4 decline • Accelerated fibrosis progression • Increased risk of liver decompensation, HCC and liver death Bodsworth, JID 1989 ; Hadler, JID 1991 ; Krogsgaard, Hepatology 1987 ; Bodsworth, JID 1989 ; Gilson, AIDS 1997. Piroth, J Hepatol 2002; Vogel Cancer Res 1991; Corallini Cncer Res 1993 ; Altavilla Am J Pathol 2000 ; Bodsworth, JID 1989 ; Mills, Gastroenterol 1990 ; Goldin, J Clin Pathol 1990 ; Gilson, AIDS 1997 ; Thio, Lancet 2002 ; Di Martino, Gastroenterol 2002; Colin Hepatol 1999; Perillo, Ann Int Med 1986 ; McDonald, J Hepatol 1987
  23. 23. Mortality Liver-related mortality in 5293 patients (MACS), 1984 /1987–2000 Viral status Liver-related Liver death N HIV HBsAg mortality (n) (1000 pers/yr) P 3093 – – 0 0.0 139 – + 1 0.8 0.04 2346 + – 35 1.7 <0.0001 213 + + 26 14.2 <0.0001 5293 62 1.1 Liver related mortality X 19 HBV/HIV vs HBV (RR:18; 73,1-766,1; P<0,001) Thio CL, et al. Lancet. 2002;360:1921-1926.
  24. 24. Impact of HIV Infection on Progression to HBV-Related Cirrhosis 100 90 80 % of cirrhosis 70 HIV positive 60 50 40 p=0.005 30 20 HIV negative 10 0 0 1 2 3 4 5 6 7 8 9 10 Follow-up (years) Di Martino V et al. Gastroenterology. 2002.
  25. 25. Influence of HAART • Increases duration of HBV by improving survival • Inhibition of HBV replication • Increases the risk of ALT (LAM – FTC – ADV) flares related to – Histological improvement – Immune restoration ? – Hepatotoxicity – Reactivation • ARV discontinuation • HBV resistance Proia et al. Am J Med 2000. Wit et al. JID 2002. Benhamou et al. J Hepatol 2005. Bruno et al. Gastroenerol 2002. Bonacini et al. Gastroenterol 2002. Puoti et al. Antiviral Ther 2004. Gouskos AIDS 2004
  26. 26. HIV/HBV Co-infection Mortality Liver-related mortality (1995-2003 - GERMIVIC Cohort) ESLD related death % of total death ESLD related death: % of HBsAg+ 16 45 42 14.3 38 40 14 12.6 35 12 30 10 25 21 8 6.6 20 6 15 7 4 10 1.5 5 2 0 0 1995 1997 2001 2003 1995 1997 2001 2003 Rosenthal E, et al. J Viral Hep. 2007.
  27. 27. Impact of Anti-HBV Therapy on Liver Fibrosis ADV TDF Median METAVIR F at Baseline = 2 Median time F. up : 29.5 months 70% Week 48 Week 192 50% F0-F1 F2 F3-F4 30% 50% Improved * F0-F1 8 0 0 33% (n=8) 10% 8% F2 7 6 4 -10% 20% (n=17) Worsened ** -30% N= 15 12 F3-F4 1 1 11 * Improvement defined as ≥1 point reduction (n=13) ** Worsening defined as ≥ 1 point increase Benhamou Y et al. J Hepatol 2005. Lacombe, et al. CROI 2009, Abstract 815.
  28. 28. Treatment of HBV in HIV Co-infected Patients Licensed for HIV HBV Interferon (IFN) Lamivudine (LAM) Emtricitabine (FTC) Entecavir (ETV) Telbivudine (LDT) Adefovir dipivoxil (ADV) Tenofovir disoproxil fumarate (TDF)
  29. 29. Interferon Months of HBV DNA HBeAg Pts α-IFN therapy CD4 <6 log clearance McDonald 87 14 2.5-10 6 – – 0 Marcellin 93 10 3-5 4-6 20-858 2 2 Wong 95 12 10 6 No AIDS 1 1 Zylberberg 96 25 6 6 480 ± 234 9 2 Di Martino 02 26 5 6 331 ± 207 7 3 Total 87 19 (26%) 8 (9%) McDonald. Hepatology. 1987; Marcellin. Gut. 1993; Wong. Gastroenterology. 1995; Zylberberg. Gastroenterol Clin Biol. 1996; Di Martino. Gastroenterology. 2002.
  30. 30. HIV/HBeAg+ LAM-R PEG-IFN α2a + ADV HBV DNA ALT N=17 PEG-IFN2a + ADV PEG-IFN2a + ADV 9 S e ru m H B V D N A (lo g 8 100 7 S e r u m A L T (IU /L ) 80 c o p ie s /m L ) 6 5 60 4 3 40 2 20 1 0 0 Baseline 12 24 48 72 4 8 12 24 36 40 48 60 72 e lin Weeks se Ba Weeks Ingliz P. et al, Antiviral Therapy 2008
  31. 31. Lamivudine Median change in serum HBV DNA HBV resistance to LAM HIV/HBeAg+ Naïve Pts Week 52 Median Change in Log HBV DNA 1 0 Proportion of patients LAM-R 0.75 -1 N= 57 0.50 -2 0.25 -3 -2.7 -4 0 350 700 1050 1400 Days ofamivudine therapy l -5 Number of patients 57 32 13 6 3 under observation (LAM 150 mg bid) Dore GJ, et al. J Infect Dis. 1999;180:607-613. Benhamou Y, et al. Hepatology 1999; 30:1302-06
  32. 32. Entecavir ETV 1mg qd 48w = 4.3 log DNA decline in HIV/HBeAg+ LAM-R patients Pessoa et al. AIDS 2008 • 17 HIV/HBV Pts who received ETV for HBV • Switch from a TDF to ETV for HBV - Significant reduction in HIV RNA in the suppression majority of pts - 6 pts switched to ETV because of Selection of M184V (HIV RT) TDF renal tox following ETV treatment ART naïve - HBeAg+ and HBV DNA <LOD: 6 ART experienced - L180M and M204V: 5 70 3/5 Total 60 • Outcome results: % with M184V 6/12 50 3/7 - HBV rebound on ETV: 6 40 - Median time to rebound: 3 months 30 - All pts maintained HIV suppression 20 10 0 Median time M184V 148 days 98 days Hull M, et al. 9th Intl. Congress on Drug Therapy in HIV Audsley J, et al. 15th CROI, Boston 2008, #63. Infection. Glasgow 2008.
  33. 33. Telbivudine • No in vitro anti HIV activity of LdT HIV Isolate NNRTI Multi drug resistant ETV LdT Drug ETV LdT IC50 µM 11.67 >600 Fold change 0.93 >Max HIV Isolate Subtype A Drug ETV LdT IC50 µM 13.21 >600 Fold change 1.05 >Max • One doubtful case of LdT anti-HIV activity ? Low et al., CROI 2009. Abstract 813a Avila et al. CROI 2009, Abstract 1002.
  34. 34. Tenofovir Disoproxil Fumarate TDF vs. TDF+LAM (48 weeks) TDF + LAM (48 weeks) TDF TDF+LAM 100 LAM LAM 42/ 50 Naive Experienced 80 19 / 2 5 (n=9) (n=47) 29/ 50 14 / 2 5 Patients (%) 60 HBV DNA <15 9 41 40 9/ 25 UI/mL 12 / 5 0 20 Mean time to 49 67 3/ 50 1/ 2 5 DNA < LOD 0 (weeks) DNA<3 AST<45 HBeAg HBsAg log U/L loss loss Schmutz G, et al. AIDS. 2006. Tuma R, et al. AASLD 2008, Abstract 967.
  35. 35. Tenofovir Disoproxil Fumarate TDF- vs LAM- containing HAART in ARV-naïve HIV/HBeAg+ Co-infected Patients (TICO Study): Randomized Thai trial (1:1:1) of LAM vs TDF vs LAM/TDF within an EFV-based HAART regimen LAM TDF TDF+LAM W48 outcomes p N=12 N=12 N=12 Median DNA Reduction 4.07 4.57 4.73 .7 DNA <3 log 46% 92% 91% .01 HBeAg loss 3 1 3 Anti-HBe Seroconversion 1 1 3 HBsAg loss 1 1 1 Matthews G et al. Hepatology 2008
  36. 36. Treatment Algorithm Patients with Compensated Liver Disease and No Indication for HIV Therapy (CD4 count >350/µL) HBV DNA HBV DNA HBV DNA <2000 IU/mL ≥2000 IU/mL ALT Elevated ALT Normal • No treatment • Monitor ALT every • PEG IFN 3-12 months • LdT (if HBV DNA>LOD at w24 add ADV) • Monitor every 6–12 months • Consider biopsy • ADV+LdT and treat if disease present • Early HAART initiation –TDF+LAM/FTC ECC Statement. J Hepatol. 2005. Rockstroh et al. HIV Medicine 2008.
  37. 37. Treatment Algorithm Patients with Compensated Liver Disease and Indication for HIV Therapy (CD4 count <350/µL) HBV DNA Patients with cirrhosis HBV DNA HBV DNA ≥2000 IU/ml <2000 IU/ml HAART including TDF+LAM/FTC Patients without Patients with HBV-associated HBV-associated HAART regimen LAM resistance LAM resistance of choice Refer patient for liver HAART including transplantation Substitute one NRTI by TDF+3T/FTC evaluation if TDF or add TDF* decompensation *If feasible and appropriate from the perspective ECC Statement. J Hepatol. 2005. of maintaining HIV suppression. Rockstroh et al. HIV Medicine 2008.
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