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Hepatitis-C and HIV Michael T. Wong, MD Assistant Professor of Medicine, Harvard Medical School Division of Infectious Diseases, Beth Israel Deaconess.

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Presentation on theme: "Hepatitis-C and HIV Michael T. Wong, MD Assistant Professor of Medicine, Harvard Medical School Division of Infectious Diseases, Beth Israel Deaconess."— Presentation transcript:

1 Hepatitis-C and HIV Michael T. Wong, MD Assistant Professor of Medicine, Harvard Medical School Division of Infectious Diseases, Beth Israel Deaconess Medical Center Michael T. Wong, MD Assistant Professor of Medicine, Harvard Medical School Division of Infectious Diseases, Beth Israel Deaconess Medical Center

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3 Modes of Transmission HCV HCV  Primarily through blood and blood products, IDU  Historical data now supports sexual risk of ~10-12% over lifetime in discordant couple studies  Perinatal transmission ~7% but increases to 28% in HIV coinfected mothers  Association with intranasal recreational agents like cocaine. HIV  Sexually through body fluids (semen, vaginal secretions, blood)  Blood (percutaneous exposures, IDU, blood products)  Perinatally (risk decreased to almost 0 with perinatal prophylaxis and elective C- sections in right settings, restriction on breast feeding

4 HCV HCV  Infect primarily hepatocytes without becoming integrated into the host genome, but more recently found in T- lymphocytes which represent a secondary reservoir HIV-  Infect primarily CD4 bearing T- lymphocytes via secondary binding site, CCR5 or CXCR4  Also found in variety of other cells including neural dendritic cells, GI epithelium, gonadal tissues

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7 Genotype 1: most common in the US and Western Europe (up to 75% of all infections in US); generally associated with IDU as well as contaminated blood products; most difficult to treat and resistant to therapy. Genotype 1: most common in the US and Western Europe (up to 75% of all infections in US); generally associated with IDU as well as contaminated blood products; most difficult to treat and resistant to therapy. Genotype 2 and 3: more responsive to therapy Genotype 2 and 3: more responsive to therapy Genotype 3: associated with insulin resistance and steatosis (fatty liver disease). Genotype 3: associated with insulin resistance and steatosis (fatty liver disease).

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9 Extrahepatic ManifestationsCondition Relative Frequency Mixed Cryoglobulinemia 36-45% 1 Porphyria Cutanea Tarda 62-82% 2 Renal Failure (MPGN, membranous GN, GN associated with mixed cryoglobulinemia) Uncertain; suggestion of up to 27% 3 Cognitive Dysfunction 9-38% 4 1. Ferri et al. Blood 1993;81: DeCastro et al. Hepatology 1993;17: Johnson et al. N Engl J Med 1993;328: Hilsabeck et al. J Int Neuropsychol Soc. 2003;9:847. Other conditions reported in HCV include: hyper/hypothyroidism, idiopathic pulmonary fibrosis; ITP, non Hodgkins lymphoma,

10 Psychosocial characterizations VA population 1 : VA population 1 :  580 patients referred for treatment for HCV.  Mean age: 51  Gender: 99% male  406 (70%) had psychosocial contraindications to therapy 1) active alcohol abuse (124, 21%)1) active alcohol abuse (124, 21%) 2) active non-alcohol substance abuse (21, 3.6%)2) active non-alcohol substance abuse (21, 3.6%) 3) active untreated clinical depression (93, 16%)3) active untreated clinical depression (93, 16%)  54 (10%) had medical contraindications 1) end-stage liver disease (34, 5.9%)1) end-stage liver disease (34, 5.9%) 2) poorly or uncontrolled diabetes (20, 3.4%)2) poorly or uncontrolled diabetes (20, 3.4%) VA Population 2 : VA Population 2 :  33 individuals treated; 68% had active mental health issues  13 or 19 developed psychiatric exacerbations on therapy  Those with history of SA 3 times more likely to discontinue therapy (20 vs 7 individuals) 1. Rowan et al. J Clin Gastroenterol. 2004;38: Ho et al. Am J Gastroenterol, 2001: 3.

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13 Activated, HIV- cells t1/2 = 1.5 d Productive HIV+ cells, t1/2=1/2-1 d Free HIV t1/2= 30 min Macrophage t1/2= 14 d Latent Memory CD4+ HIV+ cell, T1/2>>>6 mo Latent, CD4+ HIV+ cell, t1/2= 8.5 d Long-lived CD4+ HIV+ cells, t1/2= 6 mo 93-99% 1% 1-7%

14 In situ HIV-associated CD3+CD4+ syncytia, CXCR4 variant Splenic tissue from HIV+ patient, p24+, CD3+CD4+ by immunofluorescent staining indicating in situ syncytia. Wong, MT, unpublished

15 HIV natural history Acute infection- extraordinarily high HIV viral load, no antibodies, fever, adenopathy, thrush, nonpruritic rash Acute infection- extraordinarily high HIV viral load, no antibodies, fever, adenopathy, thrush, nonpruritic rash Viral control- “viral set point” averages ~50,000 copies/mL and results in a loss of total CD4 count by 60 cells/year Viral control- “viral set point” averages ~50,000 copies/mL and results in a loss of total CD4 count by 60 cells/year  Viral generation time ~24 hours  T cell generation time 5-7 days Asymptomatic period ~8-12 years Asymptomatic period ~8-12 years Death from HIV ~12-15 years after primary infection Death from HIV ~12-15 years after primary infection

16 HIV and HCV, US Est 800,000 – 1,000,000 persons HIV+ Est 800,000 – 1,000,000 persons HIV+ Est 4,000,000 persons HCV+ Est 4,000,000 persons HCV+  Of those HIV+, 30-35% are coinfected with HCV  IDU >90% coinfection rates  Hemophilia >90% coinfection rates  MSM ~15% coinfection rates  Of those HCV+, 8-12% are coinfected with HIV

17 Over 90% of HAART Regimens PI Based HOPS: Mortality and Frequency of HAART Use Deaths per 100 person-years Deaths Use of HAART HAART, % patient-days Palella. N Engl J Med 1998;338:853. Update: Palella. Personal Communication, 1999.

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19 Causes of Death in HIV-HCV Co-infection 240 HIV/HCV co-infected patients in France who died in HIV/HCV co-infected patients in France who died in 2000 At death: At death:  38% had CD4 count >200 cells/mm 3  37% had a viral load <500 c/mL Dominique S et al. 42 nd ICAAC; San Diego, 2002: Abstract #1719.

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22 Impact of HIV Coinfection on the Long- Term Outcome of HCV Cirrhosis Variable Hazards Risk, Death overall (P) Hazards Risk, Cirrhotic Death (P) HIV 2.7 (0.04) 3.8 (0.2) ETOH use 1.2 (NS) 1.7 (NS) Age > (0.01) 2.6 (0.001) AntiHCV therapy 0.6 (0.01) 0.4 (<0.001) DiMartino, V, et al. 8 th CROI, Chicago, 2001, #567

23 Determinants of HCV Clearance in coinfection 207 HIV+HCV+ and 121 HIV- HCV+ hemophiliacs, enrolled prospectively Daar, et al. #35

24 Determinants of HCV Clearance in coinfection

25 ACTG 5071 Study Design IFN  -2a 6 MIU tiw x12 WK then 3 MIU TIW + RBV 600  1 gm/day PEG IFN  -2a 180  g QW + RBV 600 mg  1 gm/day 133 subjects randomized BaselineBaseline % ETVR 12% ETVR 48 27% SVR Virologic response at week 72 (SVR) Virologic response at week 72 (SVR) 12% SVR 72 Weeks 10/67 responders (15%) 29/66 responders (44%) Primary endpoint: Primary endpoint: Virologic response at week 24 Biopsy for NR: HR continue Primary endpoint: Primary endpoint: Virologic response at week 24 Biopsy for NR: HR continue Chung, NEJM 2004

26 InterferonPegIFN Overall Response (SVR) 15%44% Genotype 1 7%33% Non Type 1 40%82% Bx Results (non responders) 40%26% VR+BR37%53% Absolute CD CD4 %

27 SVR in ACTG 5071 by Genotype Genotype 1 N = 103 Genotype 2/3 N = 30 IFN/RBV PEG/RBV Chung, NEJM 2004

28 Predictors of SVR in 5071 Variable Odds Ratio (95% CI) PEG/RBV 4.76 (1.49 – 15.2) Genotype non (4.94 – 50.5) Previous IDU 0.48 (0.27 – 0.83) Base HIV VL > (1.19 – 10.6) Chung, NEJM 2004

29 APRICOT 868 patients with HIV/HCV enrolled at 95 centers in 19 countries 868 patients with HIV/HCV enrolled at 95 centers in 19 countries Randomized to one of three arms for 48 weeks: Randomized to one of three arms for 48 weeks:  IFN alfa-2a (3 MIU TIW) + RBV 800 mg  PEG-IFN alfa 2a 180  g QW + placebo  PEG-IFN alfa 2a 180  g QW + RBV 800 mg 5 –7 % had CD4 <200 5 –7 % had CD4 <200 25% (PEG/RBV) to 39% (IFN/RBV) discontinuation rate and 20% dose reduction rate 25% (PEG/RBV) to 39% (IFN/RBV) discontinuation rate and 20% dose reduction rate Torriani, NEJM 2004

30 SVR in Genotype 1 by HCV VL HCV VL< 800,000 IU/mlHCV VL > 800,000 IU/ml IFN/RBV PEG-IFN PEG/RBV Torriani, NEJM 2004

31 APRICOT: SVR in Cirrhosis Cirrhotic IFN/RBV PEG/Pl PEG/RBV All Patients 3 deaths in cirrhotics: two decompensation, one suicide Sasadeusz, #372, AASLD 2004

32 Prediction of SVR with Weeks 4, 12 or 24 ERV in APRICOT EVR (%) at weeks Patients41224 SVR wk 72 PPV (%) wks 4;12;24 NPV (%) wks 4;12;24 All (289) 15 1 (52 ) 204 (71) 216 (75) 116 (40%) 66, 56, 53 88, 98,99 Geno 1 (176) 71 (40 ) 110 (63) 120 (68) 51 (29%) 58; 45; 43 90; 98; 100 Geno 2,3 (95) 76 (80 ) 84 (88) 85 (89) 59 (62%) 74; 70; 69 84; 100; 100 Positive predictive value = probability of SVR after an EVR Rodriguez-Torres, ICAAC 2004, H1751

33 Predictors of SVR for PEG-IFN/RBV Arm in APRICOT Variable Odds Ratio Genotype non ALT quotient (I unit incr)1.17 Age (per 10 year decr)1.28 No cirrhosis1.96 HCV VL <800,000 IU/ml3.56 Cooper, Bangkok IAC 2004 *Baseline CD4 count did not predict SVR

34 Histological Improvement with PEG/RBV in APRICOT Improvement = 2 or more decrease in HAI score Lissen, #174 AASLD 2004

35 Adverse events in APRICOT Adverse event PEG-IFN/PlaceboPEG-IFN + ribavirin Number Patients D/C for any reason 31%25% Serious Adverse events 21%17% Dose reduce - anemia 8%17% Dose reduce -  WBC 30%28% Influenza like symptoms Headache 38%39% Fatigue 41%44% Myalgias 33%36% Fever 43%44% GI symptoms Diarrhea 26% 28% Nausea 27%30% Psychiatric symptoms Depression 20%26% Insomnia 21%26% Asthenia 22%28% Torriani, NEJM 2004

36 APRICOT: Quality of Life Improves in SVR on PEG-IFN with RBV Dieterich ICAAC 2004

37 APRICOT Summary PEG-IFN + RBV was the most effective regimen for clearance of HCV PEG-IFN + RBV was the most effective regimen for clearance of HCV Relapse rate was lower than 5071: Relapse rate was lower than 5071:  Genotype 1: ETR 38% and SVR 29%  Genotype 2/3: ETR 64% and SVR 62% APRICOT had more Caucasian patients than 5071 – in HCV alone, African-Americans have a lower response rate APRICOT had more Caucasian patients than 5071 – in HCV alone, African-Americans have a lower response rate Torriani, NEJM 2004

38 Interaction between Ribavirin and NRTIs FDA Adverse Event Reporting System FDA Adverse Event Reporting System 85 cases of ribavirin/NRTI events; 31 cases consistent with mitochondrial toxicity 85 cases of ribavirin/NRTI events; 31 cases consistent with mitochondrial toxicity ddI OR 12.4 (3.8, 40.8) ddI OR 12.4 (3.8, 40.8) d4T OR 3.3 (1.3, 8.5) d4T OR 3.3 (1.3, 8.5) AZT OR ( 0.007, 0.448) AZT OR ( 0.007, 0.448) 5/31 died from lactic acidosis, all on ddI 5/31 died from lactic acidosis, all on ddI Don’t combine ddI and ribavirin Don’t combine ddI and ribavirin Fleisher, 10 th CROI, #763

39 Effect of AZT on Anemia 107 subjects with HIV/HCV on IFN 3 mu TIW with RBV 800 mg/day or IFN + placebo for first 16 weeks, then RBV added if HCV VL detectable 107 subjects with HIV/HCV on IFN 3 mu TIW with RBV 800 mg/day or IFN + placebo for first 16 weeks, then RBV added if HCV VL detectable Hgb decreased –2.52 g/dl on IFN/RBV compared to –1.02 g/dl on IFN/Placebo Hgb decreased –2.52 g/dl on IFN/RBV compared to –1.02 g/dl on IFN/Placebo On IFN/RBV, those taking AZT had –3.64 g/dl decrease compared to no AZT –2.08 On IFN/RBV, those taking AZT had –3.64 g/dl decrease compared to no AZT –2.08  Nadir Hgb in AZT group 10.1 g/dl compared to 13.0 with no AZT 60% of subjects on AZT had anemia related dose reduction of RBV compared to 16% of those not on AZT 60% of subjects on AZT had anemia related dose reduction of RBV compared to 16% of those not on AZT Bräu, Hepatotolgy, 2004; 39:989

40 Drug-Drug Interactions: NRTI and HCV Therapy Ribavirin - inhibits the phosphorylation of AZT, d4T and ddC in vitro Ribavirin - inhibits the phosphorylation of AZT, d4T and ddC in vitro Ribavirin - enhances the anti-HIV activity of didanosine (ddI) by increasing intracellular conversion to its active metabolite and may also increase its toxicity Ribavirin - enhances the anti-HIV activity of didanosine (ddI) by increasing intracellular conversion to its active metabolite and may also increase its toxicity ddI/d4T and IFN increase mitochondrial toxicity ddI/d4T and IFN increase mitochondrial toxicity  77% of 47 patients lost weight and 65% had elevated lactate levels on d4T or ddI with IFN/RBV 1  16% of 416 patients with ddI and IFN developed MT over 48 weeks 2 Competition among AZT, d4T, and ribavirin in vitro for thymidine kinase phosphorylation is not clinically important Competition among AZT, d4T, and ribavirin in vitro for thymidine kinase phosphorylation is not clinically important 1 Gonzalez-Benayas et al. 42 nd ICAAC; San Diego, 2002: Abs #H Hor ICAAC 2002 Abs H1735.

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42 Incidence of Elevated ALT/AST with HAART: The TARGET Cohort NNRTIsNRTIsPls NVP EFV ZDV d4T Combivir 3TC ddl ABC NFV SQV RTV IDV APV Rate (per 100 person-years) Imperiale et al. 4th International Workshop on Adverse Events and Lipodystrophy in HIV; 2002: Abstract 89. Risk of ALT/AST >5 x ULN among 2198 patients who received antiretroviral therapy between 1997 and 2001

43 Incidence and Relative Risk of Grade 3-4 Hepato- toxicity* Associated With Antiretroviral Regimens ART Regimen NRTIPIs RTV (single PI) RTV + SQV SQVIDVNFVTotal No. of Subjects Cases Person-Time (100 Person-Month) Incidence (Cases/100 Person-Months) (95% CI) Relative Risk (95% CI) ( ) 4.8 ( ) 5.6 ( ) 1.0 ( ) 1.2 ( ) 1.0 (0.3)-4.1) NA *>5 x ULN AST or ALT levels; > 10 x ULN AST or ALT Sulkowski. JAMA 2000;283(1):74.

44 Hepatotoxicity associated with NNRTI 8.2 ( )897EFV 16.7 ( )34203NVP Incidence (95% CI)Cases (Grade 4) N* Sulkowski, M. et al. 8 th CROI, Chicago, 2001, #618 * 49% NVP recipients HCV+; 45% EFV recipients HCV+. In multivariate regression analysis, Grade 4 hepatotoxicity was determined only by CD4 increase of >50 cells/uL from baseline.

45 Impact of PI Containing regimens on HCV Benhamou Y et al, Hepatology 2001;34:283-7 PI Containing Non PI based Regimens P value Fibrosis Score 1.25+/ / Inflammation Score 1.69+/ / Multivariate factors associated with HCV progression: absence of PI based therapy; CD4 count 5g/d; age >20 at time of infection.

46 Summary Liver disease has emerged as a major cause of morbidity and mortality in HIV positive patients Liver disease has emerged as a major cause of morbidity and mortality in HIV positive patients Preservation of liver function is important in the co-infected population Preservation of liver function is important in the co-infected population Must balance HIV therapy with liver health Must balance HIV therapy with liver health Therapies for HCV are not easy, come with significant side effects and may interact with HIV therapies Therapies for HCV are not easy, come with significant side effects and may interact with HIV therapies Newer HCV regimens including serine protease inhibitors that act directly upon HCV are in phase 2 and 3 trials now Newer HCV regimens including serine protease inhibitors that act directly upon HCV are in phase 2 and 3 trials now Since the initiation of NAT for HIV and HCV RNA in blood donations, the nation’s blood supply has become significantly safer Since the initiation of NAT for HIV and HCV RNA in blood donations, the nation’s blood supply has become significantly safer


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