Benhamou co infection

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  • Zahlen untermauern eindrucksvoll die weltweite Bedeutung der Hepatitis- und HIV-Infektion Hepatitis- und HIV-Infektionen zählen zu den weltweit häufigsten Infektionskrankheiten Literatur: HBV: http://www.who.int/mediacentre/factsheets/fs204/en/ HCV: http://www.who.int/mediacentre/factsheets/fs164/en/ HIV: http://www.who.int/hiv/data/2008_global_summary_AIDS_ep.png Koinfektionen: Alter MJ. J Hepatol 2006; 44(Suppl.1): S6-S9.
  • This slide shows the results of a study that investigated the frequency of liver-related deaths in the DAD cohort. This study evaluated more than 76.000 person-years of follow-up in more than 23.000 HIV-infected persons. There were 1.246 deaths 14.5% were from liver-related causes. HBV caused 3% of all deaths
  • Fibrosis progression to cirrhosis varies by cause and population. This large retrospective analysis shows that in this cohort of over4500 patients progression to cirrhosis was fastest in HIV/HCV co-infected patients. Not only did progression vary by disease, but also there was acceleration of fibrosis progression by aging. Therefore, staging helps identify level of fibrosis and helps in prognosis and individual treatment decision-making in patients with HIV/HCV.
  • - Die PRESCO-Studie ist eine prospektive, multizentrische Studie, die in Spanien zwischen Februar 2003 und Januar 2006 durchgeführt wurde. Die Studie war ursprünglich darauf ausgelegt, die Wirksamkeit von hohen RBV-Dosierungen (< 75 kg 1.000 mg/Tag bzw. > 75 kg 1.200 mg/Tag) zu untersuchen. - 389 HIV/HCV-koinfizierte Patienten erhielten PEG-IFN-  2a 180µg/Woche plus Ribavirin 1.000-1.200 mg/Tag. - Patienten mit Genotyp 2 und 3 wurden 24 oder 48 Wochen lang behandelt, Patienten mit Genotyp 1 und 4 wurden 48 oder 72 Wochen lang behandelt mit einer Nachbeobachtungszeit von jeweils 24 Wochen. - Der primäre Endpunkt war die SVR ( sustained virologic response ) , definiert als Viruslast unter der Nachweisgrenze 24 Wochen nach Therapieende. - In der Abbildung ist das virologische Ansprechen abhängig vom HCV Genotyp gezeigt: Eine SVR war mit 72,4% bei einem größeren Anteil der Patienten erreicht, die mit Genotyp 2/3 infiziert waren im Vergleich zu 35% mit Genotyp 1/4. PRESCO – Peginterferon Ribavirin España Coinfection SVR - anhaltendes virologisches Ansprechen, sustained virologic response Literatur: Nunez et al. AIDS Res Hum Retroviruses 2007; 23(8): 972-982.
  • Notes for speaker: For Part A, no ART the requirements were CD4 >=300 cells/mm3 and HIV RNA <+ 100,000 copies/mL
  • About one half of HBeAg-negative patients have serum HBV DNA levels persistently <10 5 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 ≥10 4 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).

Transcript

  • 1. Hépatites Virales C et B et Infection par le VIH
  • 2. HIV, Hepatitis B and C: global prevalence 350.000.000 170.000.000 33.000.000 2-4.000.000 4-5.000.000 1. WHO Factsheets HBV, HCV, HIV; 2. Alter MJ. J Hepatol 2006; 44(Suppl.1): S6-S9.
  • 3. Liver-related (LR) deaths in 23 441 HIV+ from developed countries• 76 893 person-years of follow-up in 23 441 HIV+• 1246 deaths (5.3%; 1.6 per 100 person- years);• 14.5% were from liver-related causes: – 10% HCV 10% HCV – 2% HBV 86% 14% 1% – 1% HBV-HCV Non Liver 2% – LR 1% other causes Related (LR) 1% HBV otherThe D:A:D study Arch Intern Med 2006;166:1632-1641
  • 4. Hépatite Chronique C Chez les PatientsCo-infectés par le VIH
  • 5. Fibrosis progression
  • 6. Progression to cirrhosis 1.00 4,682 patientsHazard function 180 HIV-HCV 701 Alcohol 812 HBV 382 Hemochromatosis 2,313 HCV 93 Steatosis BMI>25 200 PBC 0 20 40 60 80 Age in years Poynard, T. et al. J Hepatol 2003;38:257-265
  • 7. SVR = regression, NR = progression ? Ingiliz, Benhamou et al., J Hepatol, submitted, under review
  • 8. Current treatment for HCV
  • 9. Drug-Drug-Interactions (DDIs)Known and anticipated DDIs between antiretrovirals and anti-HCV drugs in current use and theHCV protease inhibitors in Phase III development No clinically significant interaction, or interaction unlikely based Hepatitis C Therapies on knowledge of drug metabolism Protease Inhibitors Potential interaction that may require close dose monitoring, Current Agents (Phase III trials) alteration of dosage or timing of administration PEG-IFN Ribavirin Telaprevir Boceprevir Interaction likely, do not use or use with caution PIs 1 1 1 = atazanavir/ritonavir 1 NNRTIs 2 = didanosine, zidovudine 2 NRTIs 2 2 3 3 4 4 4 4 3 = emtricitabine, lamivudine, tenofovir 3 4 = zidovudine 4 Entry 5 5 5 5 5 = maraviroc 5InhibitorsIntegrase 6 6 6 = raltegravir 6Inhibitors Adapted from Seden K, et al. J Antimicrob Chemother 2010; 65:1079-85; Ashby J, et al. HIV 10; Glasgow; November 7-11, 2010; Abst. O315.
  • 10. PRESCO (ITT analysis): virological response, genotype End of treatment (EOT) SVR (%) Sustained virological response (SVR) 100 90,1% 90,1% 80 72,4% 72,4% 67,3% 67,3% 60 55% 55% 49,6% 49,6% 40 41% 41% 35,6% 35,6% 32,6% 32,6% 20 n= 262 193 106 68 137 110 19 15 0HCV genotype Total GT1 GT2/3 GT4 patients n= 389 191 152 152 SVR defined as undetectable HCV RNA 24 weeks after end of treatment Nunez et al. AIDS Res Hum Retroviruses 2007; 23(8): 972-982.
  • 11. European guidelines for the treatment of HIV-HCV coinfection GT 2, 3 and 4 EACS guidelines, version 5-2
  • 12. IL-28B genotype and treatment response - Influence of HCV genotype - Pineda et al., abstract #656, CROI 2010
  • 13. 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 GCSFAlberti 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
  • 14. Study Design Weeks 12 24 28 48 72 PEG2b Placebo + PEG2b + RBV Follow-up Arm 1 +RBV 44 wk SVR-24 wk 4 wk PEG2b Boceprevir + PEG2b + RBV Follow-up Arm 2 +RBV 44 wk SVR-24 wk 4 wk Futility Rules• Two-arm study, double-blinded for BOC, open-label for PEG2b/RBV • 2:1 randomization (experimental: control) • Boceprevir dose 800 mg TID• 4-week lead-in with PEG2b/RBV for all patients • PEG-2b 1.5 µg/kg QW; RBV 600-1400 mg/day divided BID• Control arm patients with HCV-RNA ≥ LLOQ at TW 24 were offered open-label PEG2b/RBV+BOC via a crossover arm 15
  • 15. Virologic Response Over Time† 100 PR B/PR% HCV RNA Undetectable 80 73.4 65.6 59.4 60.7 60 42.2 40 32.4 29.4 26.5 23.5 20 14.7 8.8 4.7 3/34 3/64 5/34 27/64 8/34 38/64 11/34 47/64 10/34 42/64 9/34 37/61 0 4 8 12 24 EOT SVR12 Treatment Week † Three patients undetectable at FW4 have not yet reached FW12 and were not included in SVR12 analysis. 16
  • 16. SVR-12 by PI Regimen on Day 1 PR B/PR Atazanavir/r 8/13 (62%) 12/18† (67%) Lopinavir/r 0/10 (0%) 10/15†† (67%) Darunavir/r 0/5 (0%) 8/12 (67%) Other PI/r* 0/3 (0%) 4/7 (57%) † Excludes 2 patients not yet at FW12 but undetectable at FW4. †† Excludes 1 patient not yet at FW12 but undetectable at FW4. *Includes saquinavir, fosamprenavir and tipranavir 17
  • 17. Summary of Safety PR B/PR (N=34) (N=64)Any AE 34 (100) 63 (98)Serious AEs 7 (21) 11 (17)Death 0 0Treatment-related treatment-emergent 34 (100) 61 (95)AEsStudy discontinuation due to an AE 3 (9) 13 (20)Any drug modification due to an AE 8 (24) 18 (28)All data shown as number (%) of patients. 18
  • 18. Most Common Adverse Events With aDifference of ≥10% Between Groups PR B/PR (N=34) (N=64)Anemia 26% 41%Pyrexia 21% 36%Asthenia 24% 34%Decreased appetite 18% 34%Diarrhea 18% 28%Dysgeusia 15% 28%Vomiting 15% 28%Flu-like illness 38% 25%Neutropenia 6% 19% 19
  • 19. Study Design: Randomized, Double-blind, Placebo-controlled Trial Part A: no ART SVR24 T/PR TVR + PR PR SVR12 1:1 PR48 SVR24 Pbo + PR PR SVR12(control) Part B: ART (EFV/TDF/FTC or ATV/r + TDF + FTC or 3TC) SVR24 T/PR TVR + PR PR SVR12 2:1 PR48 SVR24 Pbo + PR PR SVR12(control) Weeks 0 12 24 36 48 60 72 EFV = efavirenz; TDF = tenofovir; FTC = emtricitabine; ATV/r = ritonavir-boosted atazanavir; 3TC = lamivudine; T/TVR = telaprevir 750 mg q8h or 1125 mg q8h (with EFV); Pbo=Placebo; P/Peg-IFN = pegylated interferon alfa-2a (40 kD) 180 µg/wk); SVR = sustained virologic response
  • 20. SVR at post-treatment week 24 (SVR24) No ART EFV/TDF/FTC ATV/r/TDF/FTC Total Patients with SVR (%) n/N = 5/7 11/16 12/15* 28/38 2/6 4/8* 4/8 10/22 T/PR PR*Prior to Week 24 visit, 1 patient in this cohort was lost to follow up. SVR24 was imputed based on SVR12 for this patient.
  • 21. Most Common Adverse Events: TVR treatmentphase (Weeks 1-12)* N (%) T/PR, N=38 (%) PR, N=22 (%) Fatigue 15 (39) 9 (41) Pruritus 13 (34) 1 (5) Headache 13 (34) 5 (23) Nausea 12 (32) 4 (18) Rash‡ 11 (29) 4 (18) Diarrhea 8 (21) 3 (14) Dizziness 8 (21) 2 (9) Pyrexia 7 (18) 2 (9) Depression 6 (16) 2 (9) Neutropenia 3 (8) 1 (5) Anemia‡ 5 (13) 4 (18) Vomiting 6 (16) 2 (9) Myalgia 5 (13) 5 (23) Chills 5 (13) 4 (18) Insomnia 5 (13) 4 (18) Decreased appetite 4 (11) 3 (14) Weight decreased 2 (5) 2 (9)*Reported in >15% of patients regardless of severity in total T/PR or PR in overall treatment phase, in bold event occurring at >10% points differencebetween T/PR group vs PR. ‡ Rash and anemia were defined using a group of related search terms in which the event of highest severity was scored.
  • 22. Events of Special Interest: Overall Treatment Phase T/PR PR n (%) N=38 N=22 Severe rash 0 (0) 0 (0) Mild and moderate rash 13 (34) 5 (23) Any anemia (hemoglobin <10g/dL) 7 (18) 4 (18) Severe anemia (hemoglobin 7.0-8.9 g/dL 11 (29) 5 (23) or decrease from baseline ≥4.5 g/dL) Use of erythropoietin stimulating agent 3 (8) 1 (5) Blood transfusions 4 (11) 1 (5) Discontinuation due to AE 3 (8) 0 (0) • No HIV breakthrough; CD4 counts declined in T/PR and PR groups; CD4% unchanged• 3 T/PR patients discontinued due to adverse event (3 T/PR)
  • 23. Acute hepatitis C
  • 24. Acute HCV among HIV+ MSM USA1,2: 54 cases Europe: 951 cases Prevalence chronic HCV/HIV14,15 Prevalence chronic HCV/HIV12-14 25%: 185.500 15 – 30%: 180.000 – 360.000 -UK3,4 552 -Germany5 157 -France6,7 117 -Netherlands8 81 -Swiss9 23 -Italy10 21 Australia11: 28 cases Prevalence chronic HCV/HIV16 < 1%: 1.0001.Luetkemeyer JAIDS 2006; 2.Fierer 5th Works. HIV & Hep. Coinf. 2009; 3.Giraudon Sex Transm Infect 2008; 4.Ruf Eurosurveill 2008; 5. Vogel CID 2009;6.Gambotti Euro Surveill 2005; 7.Larsen AASLD 2007; 8.Urbanus AIDS 2009; 9.Rauch CID 2005; 10.Gallotta 4th Works. HIV & Hep. Coinf. 2008;11.Matthews CID 2009; 12. Sherman CID 2002; 13: Backus JAIDS 2005; 14: UNAIDS Report 2008; 15: Soriano JID 2008; 16: NCHECR Report 2008.
  • 25. Monitoring and initiation antiviral therapy Initial presentation Initial presentation acute HCV acute HCV < 2 log10Week 4Week 4 Decay HCV-RNA Decay HCV-RNA Treatment Treatment ≥ 2 log10 positiveWeek 12Week 12 HCV-RNA HCV-RNA Treatment Treatment negative wait: cont´d controls wait: cont´d controls throughout week 48 throughout week 48 Courtesy: Martin Vogel, Germany
  • 26. Antiviral therapy of AHC Week 4 Week 4 Week 12 Week 12 HCV-RNA HCV-RNA 24 weeks 24 weeks negative* negative*peg-IFN +peg-IFN +RBV (AII)RBV (AII) HCV-RNA HCV-RNA Drop HCV-RNA Drop HCV-RNA 48 weeks 48 weeks positive* positive* ≥ 2 log10 ≥ 2 log10 < 2 log10 Stop Therapy Stop Therapy *evidence based on using a 615 IU/ml cutoff to define negative HCV-RNA Courtesy: Martin Vogel, Germany
  • 27. Hépatite Chronique B Chez les PatientsCo-infectés par le VIH
  • 28. 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.
  • 29. 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 progressionBodsworth, 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, • Increased risk of liver decompensation, HCC and liverGastroenterol 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 death
  • 30. Mortality Liver-related mortality in 5293 patients (MACS), 1984 /1987–2000 Viral status Liver-related Liver deathN HIV HBsAg mortality (n) (1000 pers/yr) P3093 – – 0 0.0139 – + 1 0.8 0.042346 + – 35 1.7 <0.0001213 + + 26 14.2 <0.00015293 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.
  • 31. 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.
  • 32. 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
  • 33. Impact of Anti-HBV Therapy on Liver Fibrosis ADV TDF Median METAVIR F at Baseline = 2 Median time F. up : 29.5 months70% Week 48 Week 19250% F0-F1 F2 F3-F430% Improved * F0-F1 8 0 0 50% 33% (n=8)10% F2 7 6 4 8%-10% 20% (n=17) Worsened **-30% N= 15 12 F3-F4 1 1 11 (n=13) * Improvement defined as ≥1 point reduction ** Worsening defined as ≥ 1 point increase Benhamou Y et al. J Hepatol 2005. Lacombe, et al. CROI 2009, Abstract 815.
  • 34. 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)  
  • 35. Lamivudine Median change in serum HBV DNA HBV resistance to LAM HIV/HBeAg+ Naïve Pts 1 Proportion of patients LAM-R 0.75 N= 57 0.50 0.25 0 350 700 1050 1400 Days of lamivudine therapy 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
  • 36. Tenofovir Disoproxil Fumarate TDF vs. TDF+LAM (48 weeks) TDF + LAM (48 weeks) TDF TDF+LAM 100 42/50 80 19 / 2 5 LAM LAM 29/50 14 / 2 5 Naive ExperiencePatients (%) 60 d (n=9) 40 9/25 (n=47) 12 / 5 0 20 3 / 5 0 1/ 2 5 0 HBV DNA <15 9 41 DNA<3 AST<45 HBeAg HBsAg UI/mL log U/L loss loss Mean time to 49 67 DNA < LOD (weeks) Schmutz G, et al. AIDS. 2006. Tuma R, et al. AASLD 2008, Abstract 967.
  • 37. Tenofovir Disoproxil FumarateTDF- 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
  • 38. 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.
  • 39. 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 includingPatients without Patients with TDF+LAM/FTCHBV-associated HBV-associated HAART regimenLAM resistance LAM resistance of choice Refer patient for liverHAART including transplantation TDF+3T/FTC Substitute one NRTI by 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.