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Jürgen Rockstroh Medizinische Klinik I Universitätsklinikum Bonn 3rd. Paris Hepatitis Conference, Paris, 19. January 2009 Management of HIV-HCV coinfected.

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Presentation on theme: "Jürgen Rockstroh Medizinische Klinik I Universitätsklinikum Bonn 3rd. Paris Hepatitis Conference, Paris, 19. January 2009 Management of HIV-HCV coinfected."— Presentation transcript:

1 Jürgen Rockstroh Medizinische Klinik I Universitätsklinikum Bonn 3rd. Paris Hepatitis Conference, Paris, 19. January 2009 Management of HIV-HCV coinfected patients Stanislas Pol, MD, PhD Unité d’Hépatologie & Inserm U-567 Hôpital Cochin, Paris, France

2 Prevalence of Hepatitis C (1960/5957 patients = 33%) Regions: south central north east South: 695 = 41,4 % North: 359 = 23,2 % Central: 293 = 19,6 % East: 613 = 46,9 % Rockstroh J et al., J Inf Dis 2005

3 Prevalence of Hepatitis Coinfection in Germany  Patients from the German Competence Network HIV/AIDS with complete hepatitis serology, HAART treatment information and still under observation and accesible in the cohort after the were included  Overall 2692 patients were evaluated a chronic hepatitis B infection (persistent HBs- Ag+) was present in 157 patients (5.8%) a chronic hepatitis C infection was determined in 351 Patienten (13.0%) Rockstroh J et al. DÖAK 2007;C19

4 Acute Hepatitis C cases reported in Germany  Berlin 110  Hamburg 25  NRW 12  Hessen 6  Bayern / BW 3

5 Risk factors in the transmission of acute HCV in HIV+ Schmidt et al. IAS 2007 MOPEB037

6 Question If an HIV patient gets infected with hepatitis C how high is his probability of spontaneously clearing HCV? 1.> 50% (yellow) 2.40% (green) 3.< 25% (red)

7 Hepatitis coinfection in EuroSIDA HCV genotype distribution and percentage of naturally cleared HCV infection within EuroSIDA Studied relationship between HCV genotype and/or HCV RNA level and risk for developing liver disease related death, or all cause mortality Results Of 2263 HCVAb+ patients, 1677 (74.1%) were serum HCV RNA+ (95% CI: 71– 78%) Soriano V, et al. 11 th EACS, Madrid 2007; PS8/1, Soriano V et al. Clin Infect Dis 2008 Northern Europe 0% 20% 40% 60% 1234 Southern EuropeCentral EuropeEastern Europe Distribution of HCV by genotype (1–4) in European regions

8 5 1a (other) 1b Genotypes VHC, France, aY aFrSSD25 4d FRSSD50 4d FRSSD171 4d FRSSD65 4d MRS95 4d P9 RCP 4d FRSSD58 4d FRSSD37 PAT PAT PAT PAT PAT PAT PAT PAT PAT PAT Phylogénie NS5b : 10/12 patients avec génotype 4d au CHU Necker La comparaison des séquences NS5b confirme l’homogéneité des souches (variabilité moyenne : 0,01 %) J Serpaggi, AIDS 2006 Clusters of sexual transmission

9 Treatment of acute hepatitis C Acute hepatitisC Jaundice HCV RNA at W12PEG-IFN and ribavirin 24 weeks NoYes + No treatment - HIV + Yes

10 Natural history of acute HCV in HIV- infected patients Week HCV PCR + 25 declined treatment Week 48 5 PCR– 20 PCR + 14 remained untreated Week 48 6 PCR– 8 PCR + Week HCV PCR- 150 patients S PCR + 25 refused treatment S 48 5 PCR– 20 PCR + Spontaneous HCV Clearance at W48 =11/150 overall (7%) =11/39 untreated (28%) 14 not treated S 48 6 PCR– 8 PCR + S PCR patients Azwa et al, EACS Madrid 2007

11 PegIFN + ribavirin combination in acute hepatitis Vogel et al, EACS Madrid 2007 Vogel et al, EACS Madrid 2007 Collaborative european study: 44 treated patients with SVR in 25/44 (57%)

12 Liver-related mortality in HIV: Mortavic patients in 2004, 19.4 % HCV co-infected, 313 deaths AASLD 2007 – Rosenthal E, France, Abstract 135 HAART 8 91,6 1,5 6,9 2 84,5 6,6 8,8 1 48,7 36, ,5 48,5 34,8 1,2 Overall Mortality AIDS-related Mortality Liver-related Mortality Other ,6 16,7 14,3

13 To diagnose To evaluate liver disease Adaptation of ARV HCV antiviral treatement To improve efficacy Optimization of HCV treatment

14 HIV/HCV co-infection Evaluation of liver fibrosis LB Fibrotes t Liver stiffness H. Fontaine et al (HAS). GCB 2007 FIB-4/Shasta/Fibrometre/Hepascore …

15 Dynamics of liver fibrosis Unfair evaluation in F1 + -F3 - Aire de fibrose (%) F0 F1 F2 F3 F4

16   A2-A3 F2-F4 A0-A1 F0-F1 Biopsy /3 y NIM/y Antiviral treatment Biopsy and/or non invasive markers (NIM) Evaluation

17 180 HIV-HCV 701 Alcohol 812 HBV 382 Hemochromatosis 2313 HCV 93 Steatosis BMI> PBC Hazard function 4682 patients Poynard et al J Hepatol 2003;38: Age in years Progression to cirrhosis

18 Main reasons to treat chronic HCV in HIV-infected patients  HIV patients live longer  Faster progression to liver cirrhosis  Increased mortality due to ESLD (end stage liver disease)  Higher risk of hepatotoxicity following treatment with ART drugs

19 19 SVR to IFN-RBV reduces liver-related complications in HIV/HCV coinfection GESIDA 3603 study cohort Determine effect of achieving SVR on mortality, liver-related morbidity, HIV progression 711 HIV/HCV+ pts from Spain, started IFN-RBV between Jan 2000 and Dec 2005 SVR defined as undetectable serum HCV-RNA level 24 wks after discontinuation of therapy (achieved by 31% of pts) Analyses were adjusted for baseline liver fibrosis and benefit was highest in that group Kaplan-Meier estimate of liver-related events stratified according to response to IFN-RBV Berenguer J, et al. 15 th CROI, Boston 2008, #60 p<0.001 by log-rank test Follow-up (months) SVR No SVR Percentage

20 Case # 1  49-y-old patient with HIV/HCV coinfection IVDU transmission risk factor for HIV and HCV, no drug abuse more for >15 years HAART since 2002 (lopinavir/r/[AZT/3TC]) HIV-RNA 3 years CD4-count 535 /µl, 26% ALT 2-3 x ULN HCV-RNA IU, HCV GT 1a Liver Fibroscan 60 KPa (F4-Fibrosis) No clinical signs of advanced liver disease, but decreased platelets of /µl

21 Question How would you manage hepatitis C in this patient? 1.Cirrhosis and low platelets are contraindications for interferon therapy; therefore no HCV therapy (yellow) 2.Start with PEG-IFN/RBV (green) 3.First optimize HAART and switch [AZT/3TC] to different NUC-backbone (blue) 4.Prepare patient for liver transplantation (red)

22 Zidovudine: impact on HCV treatment Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005

23 PRESCO trial: design Wochen PEGASYS ® 180 µg plus COPEGUS ® 1000–1200 mg Follow-up G2,3 G1,4 G2,3 Follow-up Patients achieving an EVR (>2 log 10 decrease in HCV RNA at week 12) continue their treatment n=398 n=192 n=45 n=96 n=56

24 Ribavirin-Dosis in Genotype 1 - EVR: APRICOT (800 mg) vs PRESCO (1000 –1200 mg) Ramos B, et al. J Viral Hepatitis 2007 HCV RNA Abfall (% Patienten) PRESCO (n=94) APRICOT (n=176) >2 log >1 log Week 12 On-treatment Analysis Negative (<50 IU/mL) 34% 63% 84% 60% 78% 83%

25 EOT and SVR Rate in PRESCO 90 % 50 % 67 % 41 % 72 % 33 % 55 % 36 % n= n= n= n=46 Nunez M et al., AIDS Res Hum Retroviruses 2007

26 Case # 1  Patient is switched from [AZT/3TC] + lopinavir/r to tenofovir/FTC + lopinavir/r; after 3 months of therapy and continued successful therapy with HIV-RNA < 50 copies/ml, HCV-therapy is initiated with PEG-IFN and ribavirin 1200mg weight adapted  After 12 weeks of HCV-therapy HCV viral load has dropped to 2000 IU; In parallel CD4-count has decreased to 160/µl (27%)

27 Question How would you continue to manage this patient? 1.Stop HCV therapy (yellow) 2.Continue therapy (red) 3.Consider PEG-IFN dose reduction (blue)

28 4/17/2015 Median Change from Baseline in CD4 + Counts* Median Change from Baseline in CD4 + Count (cells/  L) Time (Weeks) * Patients receiving 48 weeks of treatment BL Torriani F et al., N Eng J Med 2004

29 Mean Change from Baseline in HIV RNA: Patients with Detectable HIV RNA at Baseline* Change in Log 10 HIV RNA Time (Weeks) BL * Patients receiving 48 weeks of treatment Torriani F et al., N Eng J Med 2004

30 SVR-Raten in the PRESCO-trial 31% 53% 67% 82% 59/192 24/4564/9646/56 HCV GT 1/4 (n=237)HCV GT 2/3 (n=152) % SVR Nunez M et al., ICAAC 2006 Discontinuations due to Patient wish :15 (8%)36 (80%)4 (4%) 9 (16%)

31 APRICOT Study: SVR Rates in relation to virological response Genotype 1 RVR 13 % complete EVR 22 % partial EVR 26 % no EVR 40 % Genotype 2/3 RVR 37 % complete EVR 35 % partial EVR 12 % no EVR 17 % Rodriguez-Torres M et al., CROI (2008), Poster 1073 SVR = 1 % SVR = 17 % SVR = 63 % SVR = 82 % SVR = 6 % SVR = 18 % SVR = 70 % SVR = 94 %

32 HIV Medicine 2008

33 Proposed optimal duration of HCV therapy in HCV/HIV-coinfected patients. W4 W12 W24 W48W72 HCV-RNA neg HCV-RNA pos > 2 log drop in HCV-RNA < 2 log drop in HCV-RNA HCV-RNA neg HCV-RNA pos G2/3 G1/4 Stop G2/3 G1/4 24 weeks therapy * 48 weeks therapy 72 weeks therapy * In patients with baseline low viral load and minimal liver fibrosis. HIV Medicine 2008

34 Case 2 42-y-old hemophiliac with HIV/HCV coinfection –HIV first diagnosed 01/95, CDC C3 –CMV-Retinitis 2003 –08/07 HAART for 4 years with Abacavir/3TC/lopinavir/r –HIV-RNA <50 copies/ml –CD4 430/µl (27%) Patient is referred to our HIV-Hepatitis Clinic for further workup HCV-RNA IU/ml; GT 3 infection Fibroscan 10.2 KPa F2-F3 Fibrosis

35 Question How would you manage this patient? 1. Start PEG-IFN/RBV therapy for 48 weeks (yellow) 2. Switch Abacavir/3TC to Tenofovir/FTC and then start HCV-therapy (green) 3. Start PEG-IFN/RBV therapy for 24 weeks (blue) 4. Would not treat this patient for HCV at all (red)

36 Ribavirin in HIV/HCV Co-infection  Dose-dependent hemolytic anemia :  mean g/dL Hb < 4 wks  Drug-drug interactions Anti-HIV antagonism with pyrimidine nucleoside analogs - AZT, D4T, DDC (in vitro) 1 Inhibits intracellular phosphorylation Increased intracellular levels of DDI metabolites (in vitro); increased risk for lactic acidosis Recent data suggests decreased SVR under abacavir treatment; caveat abacavir treated patients had more fibrosis upon baseline and were more HAART experienced 2,3,4 1) Vogt MW. Science 1987;235:1376, Baba AAC 1987;31:1613 2) Margt NA and Miller MD, 2nd IAS Conference on HIV Pathogenesis and Treatment, Paris 2003; P980 3) RIBAVIC Subanalyses CROI 2007; 4) CROI 2008

37 37 Effect of ABC on SVR rates in HCV patients treated with RBV Proposed intracellular competition between ABC and RBC (guanosine analogs) Retrospective study of 256 HIV/HCV pts on HAART starting peg-IFN + RBV 1 – Differences between NRTI combinations mainly observed in subjects receiving lower RBV doses and in those needing higher RBV doses (GT 1 pts) – Use of TDF/3TC was associated with improved SVR No difference in SVR with regard to NRTI choice (TDF vs ABC) 2 1 Mira J, et al. 15 th CROI, Boston 2008, #1074; 2 Moreno A, et al. ibid, #1075 p=0.02 p= ITT analysisPer-protocol analysis ABC+ 3TC TDF+ 3TC or FTC n = n = SVR (%) Response by NRTI group

38 38 Negative impact of abacavir at W4, W12, W48 & W72 is significant only when ribavirine levels are < 2.2 μg/ml, suggesting a putative interaction between ribavirin and abacavir Relapsers (%) RBV > 2.2 μg/ml p = 0.44p = 0.08 RBV < 2.2 μg/ml Relapse rate according to abacavir and ribavirin levels AASLD 2007 – Barreiro P et al.Abstract 342 Number of patients 5527 with ABC without ABC Negative impact of abacavir on SVR (2)

39 Ribavirin monitoring (1) 22 HIV/HCV co-infected patients treated by PEG-IFN  2a 180 ug/sem + ribavirin mg/d –Genotype 1 : n = 10 ; 3 : n = 8 –50 % with F > 2 –HCV RNA = 6 log 10 copies/ml Measure of plasmatic (Cp) and erythrocyte (Ce) ribavirin levels (= 12 h after) at W4 and W12 : –Significant correlation between Cp and Ce –Correlation between Cp, Ce and hemoglobin decline CROI 2007, Dominguez S et al. abst 893

40 Correlation between Cp, Ce at W4 and EVR – Cut off Cp = 1,6 mg/l (génotypes 1,4) – Cut off Ce = 140 mg/l Non respondersResponders 1 1,4 1,2 1,6 1,8 2 2,2 2,4 RBV-P C min (mg.l -1 ) Non respondersResponders RBV-E C min (mg.l -1 ) CROI 2007, Dominguez S et al. abst 893 Ribavirin monitoring (2)

41 41 Case 3 35-y-old female patient with HIV/HCV coinfection – HIV first diagnosed 01/08, CDC B2 – HIV-RNA copies/ml – CD4 311/µl (23%) – No HAART Patient is referred to our HIV-Hepatitis Clinic for further workup Liver enzymes are slightly elevated (Grade 1) HCV-RNA IU/ml; GT 3 infection Fibroscan 8.2 KPa F2 Fibrosis

42 42 Question How would you manage this patient? 1. Start PEG-IFN/RBV therapy for 48 weeks (yellow) 2. Start HAART first and then treat HCV-infection (green) 3. Would not treat this patient for HCV at all (blue) 4. Something different (red)

43 Rate of SVR increases with higher CD4 %: APRICOT Opravil et al. J AIDS All patients (n=242) HCV genotype 1 (n=150) HCV genotypes 2-3 (n=78) CD4% Min – Q1 Q1 – Med Med – Q3 Q3 – Max SVR rates

44 Use of ARV in co-infected patients treated for HCV (1) Use of ARV : –Cautious use of nevirapine (AII) – Same recommendations for initiation of ARV in co- infected patients than in HIV mono-infected (BII) –If CD4 count at the limit of the recommended level  ARV are prioritary (BIII) –Avoid severe immune status (CD4 < 200/mm 3 ) in co- infected patients (BII) Alberti et al. ECC. J Hepatol 2006

45 Use of ARV in co-infected patients treated for HCV (2) ddI –Contra-indicated if cirrhosis (EI) –To avoid in patients with less severe liver disease (EII) Alberti et al. ECC. J Hepatol 2006

46 A) Overall-Mortality Observation time[days] Cumulative survival 1,1,9,7,5,3 P< Patients with HAART Patients with ART untreated Patients 6000 Patients under observation: HAART-group: ART-group: Untreated-group: ,1,9,7,5,3 A) Liver-related-Mortality P<0.018 Patients with HAART Patients with ART untreated Patients Kaplan Meier Analysis of Overall and Liver-related Mortality Qurishi N et al., Lancet 2003:362: Cumulative survival Observation time[days] Patients under observation: HAART-group: ART-group: Untreated-group:

47 Pineda JA et al., Hepatology 2007;46: Probability of remaining free of developing a hepatic decompensation

48 Interventions for HCV/HIV-coinfected non- responders/relapsers to prior interferon-based therapies Wait until new antivirals come to the market in the rest Virological failure Optimal support (psychiatric, pharmacists, use of hematopoietic growth factors) Limiting toxicities & poor adherence Re-treatment using combination therapy with peginterferon plus weight-based ribavirin doses Suboptimal prior treatment schedules: Interferon (monotherapy or with ribavirin) Low ribavirin doses Short length of therapy Recommended interventionCategory Soriano V, Puoti M, Sulkowski M, Cargnel, Benhamou Y, Peters M, Mauss S, Brau N, Hatzakis A, Pol S, Rockstroh J. AIDS 2007

49 49 Sustained long-term antiviral maintenance with peg-IFN in HCV/HIV coinfected patients (SLAM-C) Sherman K, et al. 15 th CROI, Boston 2008, #59 Study design: ACTG 5178 Lack of fibrotic progression in observation arm precludes ability to find efficacy in maintenance therapy *NR, non-response peg-IFN + Wt-based RBV peg-IFN maintenance Untreated controls 12 wks6 wks Liver biopsy 72 wks NR * Liver biopsy peg-IFNObservation Absolute change in Metavir Fibrosis Score Treatment arm n=24n=21 Fibrosis change: Paired sample analysis

50 Liver transplantation Duclos-Vallée J.C, EASL 2007, A 154 Suivi de 99 patients VIH-VHC et VIH-VHB après leur première consultation dans un centre de transplantation entre décembre 1999 et septembre 2006 –VIH-VHC (n = 75), VIH-VHB (n = 8), VIH-VHB-VHC (n = 8), hépatite fulminante (n = 3), HNR (n = 3), autre cirrhose (n = 2) Survie après la première consultation (n = 72) Années Survie (%) 73 % 61 % 34 % Années Survie (%) 87 % 79 % 44 % 25 % Transplantation hépatique (n = 56) Décès avant TH (n = 16)

51 Survival of co-infected after liver transplantation 51 patients co-infectés VIH-VHC suivis dans 14 centres et transplantés en (75 % d’hommes, 14 % AgHBs+, 16 % avec HCC) Comparés à patients mono-infectés VHC greffés dans la même période Critères sélection pour transplantation : –Pas d’antécédent d’affection classante SIDA –CD4 >100/mm 3 –ARN VIH indétectable ou possibilité d’indétectabilité Résultats/commentaires –Survie à 3 ans comparable entre patients VIH+ et VIH- (mais suivi médian 1,4 an) –Résultats meilleurs que dans les autres séries européennes (France, Royaume Uni) VIH+VIH- 1 an82 %78 % 2 ans72 %71 % 3 ans61 %65 % Miro JM et al., ICAAC 2007, A H1732 Survie greffons Survie patients VIH+VIH- 1 an88 %81% 2 ans75 %74 % 3 ans64 %69 %

52 Summary  Chronic hepatitis C can be found in 30% of all HIV-patients  HCV/HIV coinfected patients show a faster progression to cirrhosis and increased liver- related mortality  With availability of pegylated interferon Hepatitis C specific treatment options should be considered before onset of immunodeficiency in HIV- coinfected patients  HAART should not be withheld in coinfected patients

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