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Best Practices in the Management of HCV/HIV Coinfection: Optimizing Treatment Success

Best Practices in the Management of HCV/HIV Coinfection: Optimizing Treatment Success. Jürgen K. Rockstroh, MD Professor of Medicine University of Bonn Bonn, Germany. This program is supported by an educational grant from. Background and Epidemiology.

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Best Practices in the Management of HCV/HIV Coinfection: Optimizing Treatment Success

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  1. Best Practices in the Management of HCV/HIV Coinfection: Optimizing Treatment Success Jürgen K. Rockstroh, MD Professor of Medicine University of Bonn Bonn, Germany This program is supported by an educational grant from

  2. Background and Epidemiology

  3. 1. Rockstroh JK, et al. Am J Gastroenterol. 1996;91:2563-2568. 2. Graham CS, et al. Clin Infect Dis. 2001;33:562-569. 3. Weber R, et al. Arch Intern Med. 2006;166:1632-1641. 4. CDC. HIV and viral hepatitis. May 2013. 5. Yaphe S, et al. Sex Transm Infect. 2012;88:558-564. Background and Epidemiology • HIV accelerates the natural course of hepatitis C[1] • Successful antiretroviral therapy can slow fibrosis progression but not back to the rate in HCV monoinfection[2] • Liver disease associated with HCV infection has become a leading cause of morbidity and mortality among HCV/HIV-coinfected patients[3] • HIV/HCV epidemiology[4] • Approximately 25% of HIV+ patients are coinfected with HCV • Approximately 80% of HIV+ patients who inject drugs are coinfected with HCV • All patients with HIV infection should be tested for HCV • HIV+ patients are at 4.1 times the risk of HCV as HIV- patients[5]

  4. Sexual Transmission of HCV Among HIV+ MSM: An Emerging Population • Reports of epidemic of sexually transmitted HCV among HIV+ MSM • United States: 6-fold higher incidence rate in HIV+ vs HIV- MSM[6] • Swiss HIV Cohort Study: HCV incidence increased 18-fold from 1998 to 2011[7] • Sydney, Australia: 9% of HIV+ MSM coinfected with HCV vs 1.9% HIV- MSM[8] • Amsterdam, Netherlands: HIV/HCV coinfection prevalence increased from 14.6% to 20.9% from 2000-2007[9] • Phylogenic analysis indicates HCV transmission clusters in some areas[9,10] 6. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 7. Wandeler G, et al. Clin Infect Dis. 2012;55:1408-1416. 8.Lea T, et al. Sexual Health. 2013;10:448-451. 9. Urbanus AT, et al. AIDS. 2009;23:F1-F7. 10. MMWR. 2011;60:945-950.

  5. Risk Factors for Sexual HCV Transmission Among HIV+ MSM • Multiple factors associated with HCV transmission[11,12] • Unprotected receptive anal intercourse • Online casual sexual partners • Sex at sex venues • Older age • Syphilis • Recreational drug use • Drinking > 13 alcoholic drinks per week 11. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 12. Larsen C, et al. PLoS ONE. 2011;6:e29322.

  6. Screening Guidelines

  7. Screening, Surveillance, Treatment Initiation for HCV in HIV+ Patients • US and international treatment guidelines recommend[13-16]: • HCV screening at HIV diagnosis, then annually and as indicated • More frequent surveillance if ongoing risk (eg, MSM, IDU) • HCV RNA if HCV Ab+ or suspected acute infection 13. EACS Guidelines, Version 7.0. October 2013. 14. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 15. Brook G, et al. HIV Med. 2010;11:1-30. 16. Ghany MG, et al. Hepatology. 2009;49:1335-1374.

  8. Treat or Wait? Treatment Decisions in 2013

  9. Why Is HCV Therapy Deferred in Many HIV/HCV-Coinfected Patients? • Challenges with interferon- and/or ribavirin-based regimen • Anticipated approval of new agents • Greater efficacy • All-oral regimens • Shorter duration • Improved tolerability • Fewer drug-drug interactions

  10. Challenges With Telaprevir- or Boceprevir-Based HCV Therapy in Coinfected Patients • Regimen complexity[17,18] • High pill burden • Long duration, complex RGT rules • Multiple drug-drug interactions • Overlapping toxicities • With/without food dosing requirements • Tolerability • Additional AEs beyond peginterferon/ribavirin 17. Taylor LE, et al. Clin Infect Dis. 2012;55(suppl 1):S33-S42. 18. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013.

  11. Specific Risks of Deferring Therapy in HIV/HCV-Coinfected Patients • Accelerated rate of HCV-related hepatic fibrosis progression in coinfected patients with increasing immune deficiency[19-22] • Progression to cirrhosis risk 3-fold higher in coinfected vs HCV-monoinfected patients[20] • Relative risk of decompensated liver disease 6-fold higher in coinfected vs HCV-monoinfected patients[21] • Coinfected patients have reduced access to liver transplantation and reduced survival 19. Taylor LE, et al. Clin Infect Dis. 2012;55(suppl 1:S33-42). 20. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 21. Naggie S, et al. Gastroenterology. 2012;142:1324-1334. 22. Macías J, et al. Clin Infect Dis. 2013;57:1401-1408.

  12. HCV Coinfection vs Monoinfection: Cumulative Incidence of Decompensation • 10-year hepatic decompensation risk 83% higher in coinfected patients • Adjusted HR 1.83 (95% CI: 1.54-2.18) 0.2 HIV/HCV coinfectedHCV monoinfected 0.1 0.074 0.048 P < .001 0 0 1 2 3 4 5 6 7 8 9 10 Yrs to Hepatic Decompensation 23. Lo Re V, et al. IAC 2012. Abstract WEAB0102.

  13. Importance of Informed Deferral:Know What You Are Waiting for • Need for individualized decision-making and informed consent • Stepwise progress in HCV therapy anticipated • New interferon-based regimens • All-oral regimens retaining ribavirin • All-oral regimens of just DAAs • Uncertain timeline • Initial DAA studies excluded coinfected patients

  14. Assessing HIV+ Patients for Immediate or Deferred HCV Therapy • Antiretroviral therapy for HIV treatment-naive HIV/HCV-coinfected patients • CD4+ cell count < 500 cells/mm3: initiate antiretroviral therapy for HCV treatment optimization[24,25] • CD4+ cell count > 500 cells/mm3: may defer antiretroviral therapy until HCV therapy completed[25] 24. EACS Guidelines, Version 7.0. October 2013. 25. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 26. Macías J, et al. Clin Infect Dis. 2013;2013;57:1401-1408.

  15. HCV Therapy in 2013

  16. 27. Carrat F, et al. JAMA. 2004;292:2839-2848. 28. Laguno M, et al. Hepatology. 2009;49:22-31. 29. Chung RT, et al. N Engl J Med. 2004;351:451-459. 30. Torriani FJ, et al. N Engl J Med. 2004;351:438-450. 31. Núñez M, et al. AIDS Res Hum Retroviruses. 2007;23:972-982. 32. Peginterferon alfa 2a [package insert]. SVR With PegIFN/RBV by Genotype: Coinfection vs Monoinfection *SVR rates for GT1 or GT4 unaffected by baseline viral titer. PegIFN/RBV for 48 weeks using 1000 mg or 1200 mg dose of pegIFN resulted in higher rates of SVR compared with 24 weeks of therapy and/or 800 mg dose of pegIFN.

  17. 33. EACS Guidelines, Version 7.0. October 2013. Proposed Optimal Duration of PegIFN/RBV Therapy in Coinfected Patients Wk 4 Wk 12 Wk 24 Wk 48 Wk 72 24-wk therapy* GT2/3 HCV RNA negative GT1/4** 48-wk therapy GT2/3 HCV RNAnegative > 2 log drop in HCV RNA 72-wk therapy GT1/4 HCV RNApositive Stop HCV RNA positive < 2 log drop in HCV RNA *In patients with baseline low viral load and minimal liver fibrosis. **Where no access to DAA available or high chances of cure even with dual therapy (favorable IL28B genotype, low HCV viral load, and no advanced fibrosis). Stop

  18. Study 110: Telaprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection • Phase II randomized controlled trial[34] • Telaprevir TID + pegIFN/RBV vs pegIFN/RBV alone for 48 weeks • HCV treatment-naive HIV+ patients (N = 60) • No HIV breakthrough • Safety and tolerability • Increased pruritus, headache, nausea, rash, and dizziness with telaprevir-based therapy • Anemia: 18% in both groups • SVR comparable to GT1 HCV-monoinfected patients (75%)[35] No ART EFV/TDF/FTC 100 ATV/ritonavir + TDF/FTC 80 80 Total 74 71 69 60 50 50 SVR (%) 45 40 33 20 5/7 11/16 12/15 28/38 2/6 4/8 4/8 10/22 n/N = 0 Telaprevir + PegIFN/RBV PegIFN/RBV 34. Sulkowski MS, et al. Ann Intern Med. 2013;159:86-96. 35. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

  19. Study P05411: Boceprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection • Phase II randomized controlled trial[36] • PegIFN/RBV lead-in 4 weeks then boceprevir + pegIFN/RBV for 44 weeks vs pegIFN/RBV alone for 48 weeks • HCV treatment-naive HIV+ patients (N = 98) • All with HIV-1 RNA < 50 cells/mL on antiretroviral therapy • No difference in HIV breakthrough • Safety and tolerability • Increased anemia, pyrexia, and decreased appetite with boceprevir-based therapy • SVR comparable to GT1 HCV-monoinfected patients (68%)[37] 100 80 63 60 SVR (%) 40 29 20 n/N = 40/64 10/34 0 Boceprevir + PegIFN/RBV PegIFN/RBV 36. Sulkowski M, et al. Lancet Infect Dis. 2013;13:597-605. 37. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

  20. Recommendations for Coadministration of TVR and BOC With Select Antiretroviral Agents Note: Telaprevir and boceprevir interact with CYP3A4/5 and p-glycoprotein. Simeprevir should not be coadministered with any boosted or unboosted PI or any NNRTI except rilpivirine.[42] Sofosbuvir has no reported DDIs with HIV drugs except tipranavir/ritonavir.[43] 38. Telaprevir [EU package insert]. 39. Boceprevir [EU package insert]. 40. Kakuda TN, et al. IWCPHT 2012. Abstract O-18. 41. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 42. Simeprevir [package insert]. 43. Sofosbuvir [package insert]. 44. Boceprevir [package insert].

  21. The Treatment Pipeline

  22. Advantages of Future HCV Therapies • Once-daily dosing • Shorter duration • Simpler regimens—no response-guided therapy • Fewer adverse events • Interferon-free • High efficacy

  23. Caveats to Future HCV Therapies • Clinical trial data in HIV/HCV coinfection still emerging • DDI data incomplete • Performance outside select trial populations yet to be seen • Timeline • Late 2013: FDA approval of simeprevir (GT1) and sofosbuvir (GT1-4) • 2014: anticipated FDA approval of faldaprevir (GT1); first all-oral regimens for GT1 expected to be approved • Costs uncertain, but likely an issue in many regions

  24. C212 Study: Simeprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection • Phase III randomized controlled trial[45] • 24- or 48-week regimens: SPV + pegIFN/RBV for 12 weeks, then pegIFN/RBV alone • HCV treatment-naive or -experienced HIV+ patients (N = 106) • 88% on ART (VL < 50 cells/mL) • Excluded: boosted PIs, NNRTIs other than RPV • Safety profile similar to monoinfected pts • Pruritus and photosensitivity in 20% and 2%, respectively • SVR comparable to GT1 HCV-monoinfected pts (80%)[46] 100 87 79 13/ 15 74 80 70 42/53 78/106 7/10 57 60 16/28 SVR12 (%) 40 20 n/N = 0 Overall Naive Relapsers Partial Null 45. Dieterich D, et al. EACS 2013. Abstract LBPS9/5. 46. Jacobson I, et al. EASL 2013. Abstract 1425.

  25. PHOTON-1: Sofosbuvir + RBV in GT1/2/3 HIV/HCV Coinfection • Phase III open-label study • 12- (GT2/3 treatment-naive) or 24-week regimens (GT1 treatment-naive, GT2/3 treatment experienced): sofosbuvir + RBV • HCV treatment-naive or -experienced HIV+ patients (N = 223) • Approx 76% on ART (VL < 50 cells/mL), various standard regimens • Safety profile similar to monoinfected patients; consistent with RBV • Most frequent AEs: fatigue, insomnia, headache, nausea, diarrhea • 2 patients had transient HIV rebound due to nonadherence Virologic Outcomes for Treatment-Naive Patients by GT 100 88 80 76 67 60 SVR12 (%) 40 20 87/114 23/26 28/42 n/N 0 GT1 GT2 GT3 47. Sulkowski MS, et al. AASLD 2013. Abstract 212.

  26. STARTVerso4: Faldaprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection • Phase IIIopen-label study • 24- or 48-week regimens: faldaprevir + pegIFN/RBV for 12 or 24 weeks, then pegIFN/RBV alone • HCV treatment-naive or previous relapser HIV+ patients (N = 308) • 96% on ART (VL < 50 cells/mL) • Safety profile similar to monoinfected pts • Most frequent AEs: nausea, fatigue, diarrhea, headache • Decrease in hemoglobin consistent with pegIFN/RBV historical data • 1 patient had HIV rebound requiring new ART regimen 100 84 79 80 72 60 SVR4 (%) 40 20 89/123 6684 72/86 n/N = 0 Faldaprevir240 mg† Faldaprevir120 mg* Faldaprevir240 mg* *24 wks of therapy; †12 wks of therapy 49. Rockstroh JK, et al. AASLD 2013. Abstract 1099.

  27. Selected Ongoing or Upcoming Clinical Trials in HIV/HCV Coinfection • Boceprevir + pegIFN/RBV: HIVCOBOC-RGT study, RVR-guided therapy • Telaprevir + pegINF/RBV : INSIGHT, RVR-guided therapy; additional study in coinfected cirrhotic patients • Daclatasvir + pegIFN lambda + RBV: DIMENSION study, GT1-4 naive patients, 24-48 weeks • Daclatasvir + asunaprevir + pegINF/RBV: QUADRIH study, GT1/4 nulls, 28 weeks • Sofosbuvir + RBV: GT1/4 naive and GT2/3 naive/experienced patients, 12-24 weeks • ABT450/r/ABT-267 + ABT-333 + RBV: TURQUOISE-1 study, GT1 naive/experienced patients, 12-24 weeks • MK-5172 + MK-8742 + RBV: 047 study, GT2,4,5,6 naive patients

  28. Summary • Liver disease leading cause of morbidity and mortality in HIV/HCV coinfection • Antiretroviral therapy may slow progression • HCV screening at HIV diagnosis and at least annually • HCV treatment considerations • Treat now or wait for future options? • First-generation DAAs complex, long duration, AEs, DDIs • New agents may improve outcomes with shorter therapy, fewer AEs • Consider HCV disease stage and risk of progression

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