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Jürgen Rockstroh Medizinische Klinik I Universitätsklinikum Bonn

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

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

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

6 Question > 50% (yellow) 40% (green) < 25% (red)
If an HIV patient gets infected with hepatitis C how high is his probability of spontaneously clearing HCV? > 50% (yellow) 40% (green) < 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%) 60% Distribution of HCV by genotype (1–4) in European regions Soriano V, et al. PS8/1 Background It is unknown which determine the rate of spontaneous clearance of HCV in HIV + patients Goal: To characterize anti-HCV Ab+ HIV-infected patients within the EuroSIDA cohort with regard to level of serum HCV-RNA and genotype distribution Methods All anti-HCV Ab+, interferon-naive patients were examined for serum HCV-RNA (lower limit of detection: 615 IU/ml) and HCV genotype. Logistic regression was used to identify which variables were associated with HCV-genotype 1 (HCV-1) infection and spontaneous HCV clearance, after adjustment for demographic, clinical and therapeutic factors. Results Injecting drug users were less likely to have cleared spontaneously HCV infection compared to men-having-sex-with-men (22% vs 34%, adjusted odds ratio(aOD)=0.43(95%CI: ), whereas persons infected with HBV (HBsAg+) were more likely to have cleared HCV infection (46% in HBsAg+ vs 25% in HBsAg-, aOD=2.48 (95%CI: ). Being female (aOD=0.72( ) and older age [aOD=0.78/10 years older, ( )] were also independently associated with a lower odds of being infected with HCV-1, whereas having a higher HCV-RNA level was associated with increased odds of HCV-1 [1.29/log10 HCV-RNA ( )]. Conclusions 3/4 of HIV patients with detectable anti-HCV Ab in EuroSIDA show active HCV replication. Viremia was more likely in injecting drug-users and in persons not chronically infected with HBV. Of patients with active HCV replication, 53% were infected by HCV-1. HCV-1 infection was associated with higher HCV-RNA-load and male gender, and less prevalent in Eastern Europe. 40% 20% 0% 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 Southern Europe Northern Europe Central Europe Eastern Europe Soriano V, et al. 11th EACS, Madrid 2007; PS8/1, Soriano V et al. Clin Infect Dis 2008

8 Clusters of sexual transmission
5 Phylogénie NS5b : 10/12 patients avec génotype 4d au CHU Necker 4 6 2 1b 4aY11604 4aFrSSD25 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 900 1000 999 3 1a 1 (other) Genotypes VHC, France, 2003 La comparaison des séquences NS5b confirme l’homogéneité des souches (variabilité moyenne : 0,01 %) J Serpaggi, AIDS 2006

9 Treatment of acute hepatitis C
Jaundice No Yes Yes HIV + PEG-IFN and ribavirin 24 weeks HCV RNA at W12 + - No treatment Lecture Notes Treatment of HCV infection should be a priority. The goal of treatment is defined by the patient’s immunologic status. If CD4 cell count is greater than 200, the treatment goal is to eradicate the virus. But if the CD4 cell count is less than 200, the goal of treatment is to improve the immune status with antiretroviral medications while reducing the progression of liver disease and improving the patient’s quality of life. 9

10 Natural history of acute HCV in HIV-infected patients
Week 12 S 12 Week 12 S 12 23 HCV PCR 23 PCR - - 127 HCV PCR + 127 PCR + 14 remained untreated 14 not treated 25 declined treatment 25 refused treatment Week 48 S 48 Week 48 S 48 5 PCR 5 PCR 6 PCR 6 PCR 20 PCR + 20 PCR + 8 PCR + 8 PCR + Spontaneous HCV Clearance at W48 =11/150 overall (7%) Azwa et al, EACS Madrid 2007 =11/39 untreated (28%)

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

12 Liver-related mortality in HIV: Mortavic 2005
patients in 2004, 19.4 % HCV co-infected, 313 deaths HAART 100 91,6 84,5 80 60 48,7 47 48,5 36,7 40,5 40 34,8 L’enquête MORTAVIC 2005 a pour objectif de déterminer la mortalité hépatique chez les patients infectés par le VIH à travers un observatoire trimestriel réalisé dans les service d’infectieux et de médecine interne du réseau GERMIVIC. Cette enquête a été comparée à celle réalisée les années précédentes par le même réseau. En 2004, patients VIH ont été vus dans ces services dont 19,4 % étaient co-infectés par le VHC. 313 décès ont été notifiés dont 287 documentés. Depuis l’introduction des multithérapies antirétrovirales (MTAV) l’incidence annuelle de la mortalité globale a chuté passant de 8 % à 1,2 % en 2005 (p < 0,01), de même que l’incidence annuelle de la mortalité liée au VIH. Par contre, la mortalité hépatique est la deuxième cause de mortalité principalement en rapport avec la co-infection par le VHC et la consommation d’alcool. La majorité des patients qui décèdent de maladie hépatique ont, en 2005, une multithérapie antirétrovirale et un taux de CD4 moyen à 237, témoignant d’un bon contrôle de l’immunodépression. 20 16,7 8,8 14,3 8 12,6 6,9 6,6 1,5 2 1 1 1,2 1995 1997 2001 2003 2005 Overall Mortality AIDS-related Mortality Liver-related Mortality Other AASLD 2007 – Rosenthal E, France, Abstract 135 12 12

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

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

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

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

17 Progression to cirrhosis
1.00 4682 patients 0.83 180 HIV-HCV 701 Alcohol 812 HBV 382 Hemochromatosis 2313 HCV 93 Steatosis BMI>25 200 PBC 0.67 0.50 Hazard function 0.33 0.17 0.00 20 40 60 80 Age in years Poynard et al J Hepatol 2003;38:

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 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 p<0.001 by log-rank test 100 80 60 40 20 48 42 36 30 24 18 12 6 Follow-up (months) SVR No SVR Percentage Berenguer J, et al. (#60) Background Little is known regarding the long-term clinical consequences of achieving SVR following interferon + ribavirin therapy in HIV/HCV co-infected patients. Methods Analysis of patients in the GESIDA 3603 Study Cohort who received interferon (IFN)-based + RBV therapy between Jan 2000 and Dec 2005 and with active follow-up every 6 months. Cox regression analysis was performed adjusting for CDC clinical category (A-B vs. C), HCV genotype (1/4 vs. 2/3) and stage of liver fibrosis. Results 69% of patients had genotype 1 or 4. 82% of patients received a pegylated interferon product. 84% of patients were receiving ART for their HIV-infection 35% of patients received NNRTI-based therapy 25% of patients received PI-based therapy; 17% of patients received triple NRTI 7% of patients were on other therapies. SVR was 31% (14% for genotype 1/4; 46% for genotypes 2/3). Independent factors associated with SVR were nadir CD4 cells, genotype 2/3, and HCV RNA <500k IU/mL at baseline. Failure to achieve SVR was independently associated with a higher hazard ratio of developing a liver-related event (liver-related mortality, liver decompensation, hepatocellular carcinoma). Conclusions Achievement of SVR after interferon + RBV therapy in HIV/HCV co-infected patients reduces liver-related complications and mortality. Berenguer J, et al. 15th CROI, Boston 2008, #60 19

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 < 50 copies/ml for > 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?
Cirrhosis and low platelets are contraindications for interferon therapy; therefore no HCV therapy (yellow) Start with PEG-IFN/RBV (green) First optimize HAART and switch [AZT/3TC] to different NUC-backbone (blue) 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 PEGASYS® 180 µg plus COPEGUS® 1000–1200 mg
PRESCO trial: design G1,4 Follow-up n=192 G1,4 Follow-up PEGASYS® 180 µg plus COPEGUS® 1000–1200 mg n=45 n=398 G2,3 n=96 Follow-up G2,3 Follow-up n=56 12 24 36 48 60 72 84 96 Wochen Patients achieving an EVR (>2 log10 decrease in HCV RNA at week 12) continue their treatment

24 HCV RNA Abfall (% Patienten)
Ribavirin-Dosis in Genotype 1 - EVR: APRICOT (800 mg) vs PRESCO (1000 –1200 mg) 90 84% 83% APRICOT (n=176) 78% 80 PRESCO (n=94) 70 63% 60% 60 HCV RNA Abfall (% Patienten) 50 40 34% 30 20 10 >1 log >2 log Negative (<50 IU/mL) Week 12 On-treatment Analysis Ramos B, et al. J Viral Hepatitis 2007

25 EOT and SVR Rate in PRESCO
90 % 72 % 67 % 55 % 50 % 41 % 36 % 33 % n=389 n=191 n=152 19 15 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?
Stop HCV therapy (yellow) Continue therapy (red) Consider PEG-IFN dose reduction (blue)

28 Median Change from Baseline in CD4+ Counts*
in CD4+ Count (cells/L) BL 4/11/2017 Time (Weeks) * Patients receiving 48 weeks of treatment 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 Log10 HIV RNA BL Time (Weeks) * Patients receiving 48 weeks of treatment Torriani F et al., N Eng J Med 2004

30 SVR-Raten in the PRESCO-trial
82% 67% 53% % SVR 31% 59/192 24/45 64/96 46/56 HCV GT 1/4 (n=237) HCV GT 2/3 (n=152) Discontinuations due to Patient wish: 15 (8%) 36 (80%) 4 (4%) (16%) Nunez M et al., ICAAC 2006

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

32 HIV Medicine 2008

33 Proposed optimal duration of HCV therapy in HCV/HIV-coinfected patients.
W4 W12 W24 W48 W72 G2/3 24 weeks therapy * HCV-RNA neg G1/4 48 weeks therapy G2/3 HCV-RNA neg > 2 log drop in HCV-RNA G1/4 72 weeks therapy HCV-RNA pos HCV-RNA pos Stop < 2 log drop in HCV-RNA Stop * In patients with baseline low viral load and minimal liver fibrosis. HIV Medicine 2008

34 Case 2 HIV first diagnosed 01/95, CDC C3 CMV-Retinitis 2003
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?
Start PEG-IFN/RBV therapy for 48 weeks (yellow) Switch Abacavir/3TC to Tenofovir/FTC and then start HCV-therapy (green) Start PEG-IFN/RBV therapy for 24 weeks (blue) 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 experienced2,3,4 Slide Ribavirin in HIV/HCV Co-infection Ribavirin causes anemia particularly in patients receiving AZT aNR other pyrimidine nucleoside analogs. The hemolytic anemia appears to be dose depeNRent aNR respoNRs to dose reduction or treatment with erythropoietin. 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 2

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 + RBV1 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 p=0.02 p=0.01 10 20 30 40 50 60 ITT analysis Per-protocol analysis ABC+ 3TC TDF+ 3TC or FTC n = n = SVR (%) Response by NRTI group1 29 45 33 52 Mira J, et al. (#1074) Background Abacavir (ABC)use when given concomitantly with pegylated interferon (peg-IFN)/ribavirin (RBV) is associated with lower response rates for HCV. ABC was co-administrated with ZDV in many of these patients which could be a confounder due to ZDV’s hemotologic side effect profile. Methods Retrospective, multicenter study identified HIV/HCV coinfected patients naïve to HCV therapy with detectable HCV-RNA levels. Patients were treated with peg-IFN/RBV and triple ARV therapy; ARV therapy needed to include ABC and 3TC or TDF and 3TC/FTC. Anti-HCV therapy was 48 weeks for genotype 1 or 4 and 24 to 48 weeks for genotypes 2 or 3. The main outcome was SVR, defined as an undetectable serum HCV-RNA 24 weeks after completion of anti-HCV therapy. Results There was no difference in patient demographics between those receiving ABC and 3TC or TDF and FTC/3TC. There was no difference in early virologic response between ABC and TDF (67% vs. 73% [p=0.3]). ABC-containing regimens had a lower response rate when compared to TDF-containing regimens in patients with genotypes 1 of 4 (p=0.07), HCV RNA ≥ 600,000 IU/mL (p=0.02) and patients receiving <13.2 mg/kg of RBV (p=0.03). Conclusions HIV/HCV co-infected patients had a lower SVR when receiving ABC and 3TC when compared to those receiving TDF and FTC/3TC. The lower SVR in patients receiving ABC was particularly remarkable among patients who received lower doses of RBV. Moreno A, et al. (#1075) Controversy exists regarding the role of NRTIs, specifically guanosine analogs, on the efficacy of pegylated interferon (peg-IFN)/ribavirin (RBV) therapy in HIV/HCV coinfected patients, possibly due to intracellular interactions that lower RBV concentrations. A prospective, non-randomized study was conducted to evaluate the effect of ABC or TDF-containing HAART or the use of triple NRTI on the rate of SVR and to assess baseline predictors in SVR. HIV/HCV chronically infected patients who were HBVsAg(-) and HCV-treatment naïve patients who received their first cycle of peg-IFN/RBV therapy between Jan 2001 to March 2006 were eligible for the study. 174 patients were included in the study. Patients receiving TDF (n = 65) had lower baseline CD4 counts (p=0.03) and HIV RNA (p=0.002) when compared to the non-TDF based regimens; there was no difference in SVR in patients receiving TDF or non-TDF containing regimens. There was no difference in SVR in patients receiving ABC (n = 56) or non-ABC regimens (n = 118). Baseline HCV RNA, genotype, fibrosis scoring, baseline CD4 count and GGT but not ABC or TDF use were factors associated with SVR failure in a univariate analysis. HCV genotype 1 or 4, HCV-RNA and fibrosis scoring continued to be factors associated with SVR failure in a multivariate analysis. Neither ABC or TDF nor the use of three NRTIs significantly influenced the SVR rate. In a multivariate analysis, genotypes 1 or 4, higher HCV RNA and higher fibrosis scoring were independently associated with treatment failure. 1 Mira J, et al. 15th CROI, Boston 2008, #1074; 2 Moreno A, et al. ibid, #1075 37 37

38 Negative impact of abacavir on SVR (2)
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 Relapse rate according to abacavir and ribavirin levels p = 0.44 p = 0.08 100 80 with ABC 60 without ABC Relapsers (%) Cette étude rétrospective a inclus 426 patients entre 2002 et 2005 dans 3 hôpitaux espagnols. Elle retrouve l’impact négatif de l’Abacavir sur la réponse au traitement par PEG-IFN + RBV confirmant les données récentes issues de l’étude RIBAVIC. La disparition de cet effet négatif, ou son caractère moins marqué, chez les malades ayant des taux sériques élevés de RIBAVIC suggère aux auteurs l’existence d’une inhibition compétitive entre les deux molécules lors des étapes de la phosphorylation intra-cellulaire. Le caractère rétrospectif de l’étude et le nombre relativement faible de malades ayant bénéficié de dosage de Ribavirine invite néanmoins à la prudence quant à ces conclusions. Ces résultats et ceux de l’étude RIBAVIC conduisent bien sur à s’interroger sur le maintien d’un traitement par abacavir après celui de la ddI, de la d4T et de l’AZT lors d’un traitement anti-VHC. S’ils sont confirmés, ils réduisent de façon très importante la possibilité d’utiliser les analogues de nucléosides dans cette situation. 40 20 RBV > 2.2 μg/ml RBV < 2.2 μg/ml Number of patients 55 27 AASLD 2007 – Barreiro P et al.Abstract 342 38 38

39 Ribavirin monitoring (1)
22 HIV/HCV co-infected patients treated by PEG-IFN a2a 180 ug/sem + ribavirin mg/d Genotype 1 : n = 10 ; 3 : n = 8 50 % with F > 2 HCV RNA = 6 log10 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 39

40 Ribavirin monitoring (2)
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 responders Responders 1 1,4 1,2 1,6 1,8 2 2,2 2,4 RBV-P Cmin (mg.l-1) 20 60 100 140 180 220 Non responders Responders RBV-E Cmin (mg.l-1) Commentaires : Cmin plasmatique de ribavirine prédictive de la réponse virologique, et probablement suffisante par rapport aux dosages érythrocytaires Confirmation d’une marge thérapeutique étroite Intérêt clairement démontré pour génotypes 1-4 et probablement a minima pour génotypes 2-3 Valeur seuil proposée de 1,6 mg/l correspondant à la CE50, probablement plus bas que l’objectif à atteindre en pratique clinique (CE 90 de 2,5 à 3 mg/l, Rendon CROI 2006 abst 581, Gonzalez CROI 2006 abst 857) Conclusion : doser, adapter et répéter si besoin CROI 2007, Dominguez S et al. abst 893 40

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

43 Rate of SVR increases with higher CD4 %: APRICOT
33 36 41 47 16 29 34 27 62 73 69 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 Opravil et al. J AIDS 2008

44 Use of ARV in co-infected patients treated for HCV (1)
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/mm3) in co-infected patients (BII) Alberti et al. ECC. J Hepatol 2006 44

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 45

46 Kaplan Meier Analysis of Overall and Liver-related Mortality
A) Overall-Mortality A) Liver-related-Mortality 1,1 1,1 P<0.0001 P<0.018 Patients with HAART Patients with HAART ,9 ,9 Patients with ART Cumulative survival Cumulative survival untreated Patients ,7 ,7 ,5 Patients with ART ,5 untreated Patients ,3 ,3 1000 2000 3000 4000 5000 6000 1000 2000 3000 4000 5000 6000 Observation time[days] Observation time[days] Patients under observation: HAART-group: ART-group: Untreated-group: Patients under observation: HAART-group: ART-group: Untreated-group: Qurishi N et al., Lancet 2003:362:

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

48 Recommended intervention Category
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 intervention Category Soriano V, Puoti M, Sulkowski M, Cargnel, Benhamou Y, Peters M, Mauss S, Brau N, Hatzakis A, Pol S, Rockstroh J. AIDS 2007

49 Absolute change in Metavir Fibrosis Score
Sustained long-term antiviral maintenance with peg-IFN in HCV/HIV coinfected patients (SLAM-C) Absolute change in Metavir Fibrosis Score Treatment arm Study design: ACTG 5178 Fibrosis change: Paired sample analysis 6 5 4 3 2 1 -1 -2 -3 -4 -5 -6 peg-IFN Observation peg-IFN + Wt-based RBV peg-IFN maintenance Untreated controls 12 wks 6 wks Liver biopsy 72 wks NR* n=24 n=21 Sherman K, et al. (#59) Background Sustained Long-term Antiviral Maintenance with Pegylated Interferon in HCV/HIV Coinfected Patients (SLAM-C). Approved treatment regimens for HCV in HIV-infected patients yield Sustained Viral Response (SVR) in less than 40% of cases. It has been suggested that fibrotic progression is accelerated in HCV/HIV co-infection. Methods HCV/HIV co-infected patients who were naïve or refractory to HCV treatment received pegylated interferon α-2a 180 mcg/week + weight-based ribavirin 1000 to 1200 mg per day in divided doses for 12 to 18 weeks. Early virologic response was defined as an undetectable HCV VL (<600 IU) or 2-log decline at week 12. Non-early virologic responders underwent liver biopsy and were randomized (1:1) to an intervention group who continued pegylated interferon α-2a + ribavirin for 72 weeks or an observation group. Results 330 patients were enrolled; 329 patients received pegylated interferon α-2a + ribavirin. 32% were interferon-experienced. 74% had an HIV RNA VL <50 cells/mm3. STEP 1: Early virologic response was observed in 55.6% (95% CI 50 – 61%; ITT); 42% achieved undetectable HCV and this was more likely to occur in patients with genotype 2,3, those of white race and male gender. STEP 2: consisted of non-early virologic responders; paired liver biopsies comparing control (no treatment) vs. continued treatment was terminated due to lack of fibrosis in the observation arm. Conclusions Treatment with pegylated interferon and weight-based ribavirin resulted in enhanced EVR compared to other trials. Maintenance therapy did not prevent progression to fibrosis. *NR, non-response Lack of fibrotic progression in observation arm precludes ability to find efficacy in maintenance therapy Sherman K, et al. 15th CROI, Boston 2008, #59

50 Liver transplantation
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) 20 40 60 80 100 1 2 3 4 5 6 7 8 9 10 Années Survie (%) 73 % 61 % 34 % 20 40 60 80 100 1 2 3 4 5 6 7 8 9 10 Années Survie (%) 87 % 79 % 44 % 25 % Transplantation hépatique (n = 56) Décès avant TH (n = 16) Duclos-Vallée J.C , EASL 2007, A 154 50

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/mm3 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) Survie greffons VIH+ VIH- 1 an 82 % 78 % 2 ans 72 % 71 % 3 ans 61 % 65 % Survie patients VIH+ VIH- 1 an 88 % 81% 2 ans 75 % 74 % 3 ans 64 % 69 % Miro JM et al., ICAAC 2007, A H1732

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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