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Hepatitis-C and HIV

Hepatitis-C and HIV. Michael T. Wong, MD Assistant Professor of Medicine, Harvard Medical School Division of Infectious Diseases, Beth Israel Deaconess Medical Center. HCV Primarily through blood and blood products, IDU

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Hepatitis-C and HIV

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  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

  2. 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 Modes of Transmission

  3. 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

  4. 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 3: associated with insulin resistance and steatosis (fatty liver disease).

  5. Extrahepatic Manifestations Other conditions reported in HCV include: hyper/hypothyroidism, idiopathic pulmonary fibrosis; ITP, non Hodgkins lymphoma, 1. Ferri et al. Blood 1993;81:1132. 2. DeCastro et al. Hepatology 1993;17:551. 3. Johnson et al. N Engl J Med 1993;328:465. 4. Hilsabeck et al. J Int Neuropsychol Soc. 2003;9:847.

  6. Psychosocial characterizations • VA population1: • 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%) • 2) active non-alcohol substance abuse (21, 3.6%) • 3) active untreated clinical depression (93, 16%) • 54 (10%) had medical contraindications • 1) end-stage liver disease (34, 5.9%) • 2) poorly or uncontrolled diabetes (20, 3.4%) • VA Population2: • 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;38:530. 2. Ho et al. Am J Gastroenterol, 2001: 3.

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

  8. 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

  9. HIV natural history • 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 generation time ~24 hours • T cell generation time 5-7 days • Asymptomatic period ~8-12 years • Death from HIV ~12-15 years after primary infection

  10. HIV and HCV, US • Est 800,000 – 1,000,000 persons HIV+ • 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

  11. HOPS: Mortality and Frequency of HAART Use Over 90% of HAART Regimens PI Based 100 80 60 40 20 0 35 30 25 20 15 10 5 0 Deaths Deaths per 100 person-years HAART, % patient-days Use of HAART 1994 1995 1996 1997 1998 1999 Palella. N Engl J Med 1998;338:853. Update: Palella. Personal Communication, 1999.

  12. Causes of Death in HIV-HCV Co-infection • 240 HIV/HCV co-infected patients in France who died in 2000 • At death: • 38% had CD4 count >200 cells/mm3 • 37% had a viral load <500 c/mL Dominique S et al. 42nd ICAAC; San Diego, 2002: Abstract #1719.

  13. Impact of HIV Coinfection on the Long-Term Outcome of HCV Cirrhosis DiMartino, V, et al. 8th CROI, Chicago, 2001, #567

  14. Determinants of HCV Clearance in coinfection 207 HIV+HCV+ and 121 HIV-HCV+ hemophiliacs, enrolled prospectively 1989-90 Daar, et al. #35

  15. Determinants of HCV Clearance in coinfection

  16. Virologic response at week 72 (SVR) Primary endpoint: Virologic response at week 24 Biopsy for NR: HR continue Baseline PEG IFN a-2a 180 g QW + RBV 600 mg  1 gm/day 66 27% SVR 41% ETVR 29/66 responders (44%) 133 subjects randomized 12% ETVR 12% SVR 10/67 responders (15%) 67 IFN a-2a 6 MIU tiw x12 WK then 3 MIU TIW + RBV 600  1 gm/day 48 72 0 24 ACTG 5071 Study Design Weeks Chung, NEJM 2004

  17. SVR in ACTG 5071 by Genotype 80 70 IFN/RBV 60 50 PEG/RBV 40 30 20 10 0 Genotype 1 N = 103 Genotype 2/3 N = 30 Chung, NEJM 2004

  18. Predictors of SVR in 5071 Variable Odds Ratio (95% CI) PEG/RBV 4.76 (1.49 – 15.2) Genotype non-1 15.8 (4.94 – 50.5) Previous IDU 0.48 (0.27 – 0.83) Base HIV VL >50 3.55 (1.19 – 10.6) Chung, NEJM 2004

  19. APRICOT • 868 patients with HIV/HCV enrolled at 95 centers in 19 countries • 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 • 25% (PEG/RBV) to 39% (IFN/RBV) discontinuation rate and 20% dose reduction rate Torriani, NEJM 2004

  20. SVR in Genotype 1 by HCV VL 70 60 50 40 IFN/RBV PEG-IFN 30 PEG/RBV 20 10 0 HCV VL< 800,000 IU/ml HCV VL > 800,000 IU/ml Torriani, NEJM 2004

  21. APRICOT: SVR in Cirrhosis 40 35 30 25 IFN/RBV 20 PEG/Pl 15 PEG/RBV 10 5 0 All Patients Cirrhotic 3 deaths in cirrhotics: two decompensation, one suicide Sasadeusz, #372 , AASLD 2004

  22. Prediction of SVR with Weeks 4, 12 or 24 ERV in APRICOT Positive predictive value = probability of SVR after an EVR Rodriguez-Torres, ICAAC 2004, H1751

  23. Predictors of SVR for PEG-IFN/RBV Arm in APRICOT Variable Odds Ratio Genotype non-1 3.37 ALT quotient (I unit incr) 1.17 Age (per 10 year decr) 1.28 No cirrhosis 1.96 HCV VL <800,000 IU/ml 3.56 *Baseline CD4 count did not predict SVR Cooper, Bangkok IAC 2004

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

  25. Adverse events in APRICOT Adverse event PEG-IFN/Placebo PEG-IFN + ribavirin Number Patients 286 288 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

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

  27. APRICOT Summary • PEG-IFN + RBV was the most effective regimen for clearance of HCV • 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 Torriani, NEJM 2004

  28. Interaction between Ribavirin and NRTIs • FDA Adverse Event Reporting System • 85 cases of ribavirin/NRTI events; 31 cases consistent with mitochondrial toxicity • ddI OR 12.4 (3.8, 40.8) • d4T OR 3.3 (1.3, 8.5) • AZT OR 0.057 ( 0.007, 0.448) • 5/31 died from lactic acidosis, all on ddI • Don’t combine ddI and ribavirin Fleisher, 10th CROI, #763

  29. 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 • 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 • 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 Bräu, Hepatotolgy, 2004; 39:989

  30. Drug-Drug Interactions: NRTI and HCV Therapy • 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 • 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/RBV1 • 16% of 416 patients with ddI and IFN developed MT over 48 weeks2 • Competition among AZT, d4T, and ribavirin in vitro for thymidine kinase phosphorylation is not clinically important 1Gonzalez-Benayas et al. 42nd ICAAC; San Diego, 2002: Abs #H1727. 2Hor ICAAC 2002 Abs H1735.

  31. Incidence of Elevated ALT/AST with HAART: The TARGET Cohort Risk of ALT/AST >5 x ULN among 2198 patients who received antiretroviral therapy between 1997 and 2001 5 4 3 Rate (per 100 person-years) 2 1 0 ddl IDV d4T 3TC EFV ZDV RTV APV NVP SQV ABC NFV Combivir NNRTIs NRTIs Pls Imperiale et al. 4th International Workshop on Adverse Events and Lipodystrophy in HIV; 2002: Abstract 89.

  32. Incidence and Relative Risk of Grade 3-4 Hepato-toxicity* Associated With Antiretroviral Regimens Person-Time (100 Person-Month) 246 795 96 79 98 520 153 1041 ART Regimen NRTI PIs RTV (single PI) RTV + SQV SQV IDV NFV Total Relative Risk (95% CI) 1.0 2.2 (0.9-5.4) 4.8 (1.6-14.1) 5.6 (2.1-15.3) 1.0 (0.1-8.2) 1.2 (0.4-3.5) 1.0 (0.3)-4.1) NA No. of Subjects 87 211 22 28 17 117 51 298 Cases 5 26 6 9 1 8 3 31 Incidence (Cases/100 Person-Months) (95% CI) 246 795 96 79 98 520 153 1041 *>5 x ULN AST or ALT levels; > 10 x ULN AST or ALT Sulkowski. JAMA 2000;283(1):74.

  33. N* Cases (Grade 4) Incidence (95% CI) NVP 203 34 16.7 (11.8-22.6) EFV 97 8 8.2 (3.6-15.6) Hepatotoxicity associated with NNRTI Sulkowski, M. et al. 8th 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.

  34. Impact of PI Containing regimens on HCVBenhamou Y et al, Hepatology 2001;34:283-7 Multivariate factors associated with HCV progression: absence of PI based therapy; CD4 count <200 cells/mL; alcohol consumption >5g/d; age >20 at time of infection.

  35. Summary • 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 • Must balance HIV therapy with liver health • 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 • 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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