1. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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] 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.

2. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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.

3. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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.

4. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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.

5. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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

6. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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.

7. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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.

8. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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) P <.001 HIV/HCV coinfected HCV monoinfected 0.074 0.048 23. Lo Re V, et al. IAC 2012. Abstract WEAB0102. 0 0.1 0.2 012345678910 Yrs to Hepatic Decompensation

9. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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

10. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection Assessing HIV+ Patients for Immediate or Deferred HCV Therapy  Antiretroviral therapy for HIV treatment-naive HIV/HCV- coinfected patients –CD4+ cell count < 500 cells/mm 3 : initiate antiretroviral therapy for HCV treatment optimization [24,25] –CD4+ cell count > 500 cells/mm 3 : 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. HCV Therapy in HIV/HCV-Coinfected, HCV Treatment-Naive Patients Liver Fibrosis Consider HCV Therapy Eligible to Defer HCV Therapy No/minimal fibrosis (F0-F2) [24,25] ● Advanced fibrosis (F3-F4); cirrhosis [26] ●

11. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection SVR With PegIFN/RBV by Genotype: Coinfection vs Monoinfection 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 Range, % HIV/HCV CoinfectionHCV Monoinfection GT1 or GT4 [27-31] GT2 or GT3 [27-31] GT1 or GT4 [32] GT2 or GT3 [32] PegIFN/RBV (600-1200 mg) 14-3544-730-82*76-82 *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.

12. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection Proposed Optimal Duration of PegIFN/RBV Therapy in Coinfected Patients 33. EACS Guidelines, Version 7.0. October 2013. *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). HCV RNA negative Wk 4Wk 12Wk 24Wk 48Wk 72 GT2/3 GT1/4** Stop GT2/3 GT1/4 24-wk therapy* 48-wk therapy 72-wk therapy HCV RNA positive HCV RNA negative HCV RNA positive > 2 log drop in HCV RNA < 2 log drop in HCV RNA

13. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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 ATV/ritonavir + TDF/FTC Total SVR (%) n/N = 5/ 7 11/ 16 12/ 15 28/ 38 Telaprevir + PegIFN/RBV PegIFN/RBV 2/ 6 4/ 8 10/ 22 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. 100 80 60 40 20 0 71 69 80 74 33 50 45

14. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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] 0 20 40 60 80 100 SVR (%) PegIFN/RBV n/N =10/34 29 40/64 63 Boceprevir + 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.

15. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection Recommendations for Coadministration of TVR and BOC With Select Antiretroviral Agents Antiretroviral Agent TelaprevirBoceprevir Europe [38-40] US [41] Europe [38-40] US [41] Atazanavir/ritonavir Monitor for hyperbilirubinemia Standard dose Case-by-case consideration Do not use Darunavir/ritonavir; fosamprenavir/ritonavir ; lopinavir/ritonavir Not recommended Raltegravir No dose adjustment Efavirenz Increase dose (1125 mg q8h) Not recommended Do not use Rilpivirine No dose adjustment No guidance No dose adjustment No dose adjustment [44] 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]. 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]

16. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection Advantages of Future HCV Therapies  Once-daily dosing  Shorter duration  Simpler regimens—no response-guided therapy  Fewer adverse events  Interferon-free  High efficacy

17. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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

18. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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] 7/ 10 16/ 28 100 80 60 40 20 0 SVR12 (%) 78/ 106 74 Overall 70 42/ 53 79 Naive 57 13/ 15 87 Relapsers n/N = PartialNull 45. Dieterich D, et al. EACS 2013. Abstract LBPS9/5. 46. Jacobson I, et al. EASL 2013. Abstract 1425.

19. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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 47. Sulkowski MS, et al. AASLD 2013. Abstract 212. n/N 87/ 114 Virologic Outcomes for Treatment-Naive Patients by GT 76 88 67 0 20 40 60 80 100 GT1GT2GT3 SVR12 (%) 23/ 26 28/ 42

20. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection STARTVerso4: Faldaprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection  Phase III open-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 *24 wks of therapy; † 12 wks of therapy 49. Rockstroh JK, et al. AASLD 2013. Abstract 1099. 72 79 84 0 20 40 60 80 100 Faldaprevir 120 mg* Faldaprevir 240 mg † Faldaprevir 240 mg* n/N = 89/ 123 66 84 72/ 86 SVR4 (%)

21. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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

22. clinicaloptions.com/hepatitis Best Practices in the Management of HCV/HIV Coinfection 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