Keynote Lecture: Optimal Management of HCV-HIV Coinfection

Transcription

1 THASL Annual Meeting 2015 Keynote Lecture: Optimal Management of HCV-HIV Coinfection 26 February 2015 Prof. Chutima Pramoolsiansap

2 Today s Talk HIV/HCV-coinfection Background and epidemiology When to start treatment and which regimens Management : Treat now or wait for future options? HCV Treatment landscape of oral DAA s AASLD/IDSA and EASL Treatment guidelines Treatment monitoring: efficacy, stopping rules, SVR-guided therapy, safety Drug drug interactions among HCV antivirals and HIV antiretroviral agents Summary: Optimizing treatment success for HIV/HCV-coinfected patients

3 Background and Epidemiology D:A:D Study: causes of death in patients followed HIV/HCV epidemiology Approximately 25% of HIV+ patients are coinfected with HCV 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 HIV accelerates natural course of hepatitis C Liver disease associated with HCV infection become a leading cause of morbidity and mortality among HCV/HIV-coinfected patients Weber R, et al. Arch Intern Med. 2006;166: CDC. HIV and viral hepatitis. May Yaphe S, et al. Sex Transm Infect. 2012;88:

4 J Med Assoc Thai ;87: Am J Trop Med Hyg. 2010;83(2): Epidemiol. Infect. 2013;141: HIV-NAT, Thai Red Cross AIDS Research Centre, Thailand Prevalence of HIV/HCV coinfection Worldwide, approx. 30 % of HIV are coinfected with HCV. Burden of HIV/HCV in Asia 3.5 million HIV 32 million HCV % HCV prevalence in HIV 10.4% heterosexual MSM PWID Blood products PWID;People Who Inject Drugs 7 other In Asia, underestimation of HCV coinfection in HIV 65.3% had HCV testing. 17.7% had positive HCV Ab. Only 4.4% of those had received HCV PCR testing In Thailand, prevalence HIV/HCV coinfected patients was %

5 Chronic hepatitis B and C co-infection increased all-cause mortality in HAART-naive HIV patients in northern Thailand N= 755 HAART-naive HIV-infected patients, 700 (92.6%) patients with complete data Prevalence HCV/HIV and HBV/HIV coinfection: 3.3% and 11.9% Kaplan Meier survival probability HIV/HBV and HIV/HCV co-infection associated with a higher mortality with adjusted hazard ratios (ahrs) of 1.81 and 1.90, respectively. Epidemiol Infect 2013;141:

6 IL-28b (rs ) and HCV viral load between HIV/HCV and HCV monoinfection, Thailand 130HIV/HCV and 331 HCV monoinfection: GT3:47% ; GT1, 34% GT6:18% IL-28b (%) C/C C/T T/T Total HIV/HCV HCV mono P HCV RNA Median (IQR) 6.2( ) 6.7( ) 5.8(5.6, 6.5) <0.001 HCV RNA > 800,000 copies/ml 141 (58.75) 93(72.09) 48(43.24) <0.001 FibroScan, PKa 7.1( ) 8.5( ) 6.6( ) <0.001 <7.1 kpa, N(%) 220 ( 50.1) 33 (30.6) 187(56.5) < kpa, N (%) 91(20.7) 30 (27.8) 61(18.4) kpa, N (%) 60 (13.8) 19(17.6) 41 (12.4) >14 kpa, N(%) 68 (15.5) 26 (24.1) 42 (12.7) HIV/HCV coinfection: Higher viral load and more fibrosis 2/3 meet criteria for treatment; 1/4 require HCC screening Avihingsanon et al. APASL June

7 HIV/HCV coinfection HIV HCV viral production rates virions/day virions/day half-life < 6 hours 2.7 hours Single-stranded RNA viruses, like HIV and HCV, lack proofreading mechanisms, resulting in high mutational rates Compared with HCV monoinfected patients: HIV/HCV-coinfected patients have Less likely to clear viral infection More rapid rates of fibrosis Higher risk of hepatic decompensation

8 HIV/HCV double-trouble for liver

9 Goal of treatment of HCV infection AASLD 2014: To reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by achievement of virologic cure as evidenced by an SVR. EASL 2014: To eradicate HCV infection to prevent hepatic cirrhosis, decompensation of cirrhosis, HCC, and death. In patients with cirrhosis, HCV eradication reduces the rate of decompensation and will reduce, albeit not abolish, the risk of HCC. In these patients surveillance for HCC should be continued (Recommendation A1)

10 HCV treatment SVR (%) FDA approved RBV PegIFN (BOC,TVR) IFN 6 mo IFN 12 mo IFN/R 6mo IFN/R 12 mo pegifn 12 mo Olysio (simeprevir) in November 2013 Sovaldi (sofosbuvir) in December 2013 Harvoni (ledipasvir and sofosbuvir) in October pegifn/r 12 mo 80 pegifn/r/ 1st gen. DAA pegifn/r/ Combination SOF or SMP DAAs Viekira Pak (ombitasvir, paritaprevir, ritonavir tab. co-packaged with dasabuvir) in December 2014 EU and Japan approved Daclatasvir in August 2014

11 Treatment of HIV/HCV coinfection

12 AASLD/IDSA Guidance: When to start treatment in HCV/HIV-coinfected patients Treatment is recommended for patients with chronic HCV infection Prioritized in patients at high risk for liver-related complications HCV/HIV coinfection, regardless of fibrosis stage High risk for transmitting HCV to others may decrease transmission and HCV disease prevalence MSM with high-risk sexual practices Active injection drug users AASLD and IDSA. HCV Management Guidance. September 2014.

13 Guidelines for use of antiretroviral agents in HIV-1-infected adults and adolescents ART should be initiated in most HIV/HCV-coinfected patients, regardless of CD4 count Naïve HIV/HCV coinfection CD4 counts <200 cells/mm3 CD4 counts >500 cells/mm3 ART regimen CD4 counts <200 cells/mm 3 had lower HCV treatment responses and higher toxicity rates to PegIFN/RBV than CD4 count > 350 cells/mm 3 (no data in DAAs) until patient is stable antihcv Rx Prefer defer ART until HCV treatment is completed to avoid drug-drug interactions antihcv Rx ART regimen EASL 2014:If the patient has severe immunodeficiency, with a CD4 count <200 cells/ll, should be improved using highly active antiretroviral therapy prior to commencing anti-hcv treatment Last updated November 13, 2014; last reviewed November 13,2014

14 AASLD 2014: Grading system used to rate the level of the evidence and strength of the recommendation for each recommendation

15 EASL 2014: Evidence grading used

16 Recommendation for treatment of HIV/HCV coinfection Indications for HCV treatment in HCV/HIV co-infected persons are identical to those in patients with HCV mono-infection (Recommendation A1) The same treatment regimens can be used in HIV-coinfected patients as in patients without HIV infection, as the virological results of therapy are identical (Recommendation A1)

17 Drugs treatment for HCV/HIV-coinfection Older Medications Pegylated Interferon PegIntron or Pegasys Ribavirin Older Direct Acting Antivirals Boceprevir (Victrelis) (2011) Telaprevir (Incivek) (2011) New Direct Acting Antivirals Olysio (simeprevir) in November 2013 Sovaldi (sofosbuvir) in December 2013 Harvoni (ledipasvir and sofosbuvir) in October 2014 Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir ) in December 2014

18 Patients with SVR (%) PEG + RBV versus PEG versus INF + RBV in HCV & HIV APRICOT Study: Results APRICOT Study: SVR24 by Treatment Regimen and Genotype Peginterferon + Ribavirin Peginterferon + Placebo Interferon + Ribavirin All Genotype 1 Genotype 2 or 3 Torriani FJ, et. al. N Engl J Med. 2004;351:

19 Patients with SVR (%) Peginterferon + RBV versus Interferon + RBV in HCV & HIV RIBAVIC Study: Design N = 412; 48% genotype 1, CD4 >200 cells/mm 3 PegIFN alfa-2b 1.5 µg 1x/week + Ribavirin 800 mg/day vs IFN alfa-2b: 3 million IU 3x/week + Ribavirin 800 mg/day for 48 weeks Peginterferon + Ribavirin Interferon + Ribavirin RIBAVIC Study: SVR24 by Treatment Regimen and Genotype All Genotype 1 or 4 Genotype 2 or 3 or 5 Carrat F, et. al. JAMA. 2004;292:

20 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. SVR Range, % PegIFN/RBV ( mg) HIV/HCV Coinfection HCV Monoinfection GT1 or GT4 GT2 or GT3 GT1 or GT4 GT2 or GT * Carrat F, et al. JAMA. 2004;292: Laguno M, et al. Hepatology. 2009;49: Chung RT, et al. N Engl J Med. 2004;351: Torriani FJ, et al. N Engl J Med. 2004;351: Núñez M, et al. AIDS Res Hum Retroviruses. 2007;23: Peginterferon alfa 2a [package insert].

21 PegIFN/RBV therapy in HIV/HCV-coinfected patients 2013 European treatment guidelines Wk 4 Wk 12 Wk 24 Wk 48 Wk 72 HCV RNA negative HCV RNA positive GT2/3 GT1/4** > 2 log drop in HCV RNA < 2 log drop in HCV RNA EACS Guidelines, Version 7.0. October 2013 Stop 24-wk therapy* HCV RNA negative HCV RNA positive GT2/3 GT1/4 Stop 48-wk therapy 72-wk therapy *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).

22 Drugs treatment for HCV/HIV-coinfection Older Medications Pegylated Interferon PegIntron or Pegasys Ribavirin Older Direct Acting Antivirals Boceprevir (Victrelis) (2011) Telaprevir (Incivek) (2011) New Direct Acting Antivirals Olysio (simeprevir) in November 2013 Sovaldi (sofosbuvir) in December 2013 Harvoni (ledipasvir and sofosbuvir) in October 2014 Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir ) in December 2014

23 SVR (%) Telaprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection Phase II randomized controlled trial Telaprevir TID + pegifn/rbv vs pegifn/rbv alone for 48 weeks HCV treatment-naive HIV+ patients with CD4 > 500 cells/mm 3 (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 HCVmonoinfected patients (75%) Sulkowski MS, et al. Ann Intern Med. 2013;159: Jacobson IM, et al. N Engl J Med. 2011;364: n/n = / 7 11/ 16 12/ / 38 Telaprevir + PegIFN/RBV No ART EFV/TDF/FTC ATV/ritonavir + TDF/FTC Total 33 2/ / 8 4/ / 22 PegIFN/RBV

24 SVR (%) Boceprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection Phase II randomized controlled trial 100 PegIFN/RBV lead-in 4 weeks then boceprevir + pegifn/rbv for 44 weeks vs pegifn/rbv alone for weeks 63 HCV treatment-naive HIV+ patients (N = 98) 60 All with HIV-1 RNA < 50 cells/ml on antiretroviral therapy 40 No difference in HIV breakthrough Safety and tolerability 29 Increased anemia, pyrexia, and 20 decreased appetite SVR comparable to GT1 HCVmonoinfected n/n = 40/64 10/34 patients (68%) 0 Boceprevir + PegIFN/RBV PegIFN/RBV Sulkowski M, et al. Lancet Infect Dis. 2013;13: Poordad F, et al. N Engl J Med. 2011;364:

25 Recommendations for coadministration of TVR and BOC in HCV/HIV-coinfection with select antiretroviral agents Antiretroviral Agent Telaprevir Boceprevir Europe US Europe US Atazanavir / ritonavir Monitor for hyperbilirubinemia Standard dose Case-by-case consideration Do not use Darunavir / ritonavir; fosamprenavir / ritonavir; lopinavir /ritonavir Not recommended Not recommended Not recommended Not recommended Raltegravir No dose adjustment No dose adjustment No dose adjustment No dose adjustment Efavirenz Increase dose (1125 mg q8h) Increase dose (1125 mg q8h) Not recommended Do not use Rilpivirine No dose adjustment No guidance No dose adjustment No dose adjustment Note: Telaprevir and boceprevir interact with CYP3A4/5 and p-glycoprotein.

26 Why is HCV therapy deferred in many HIV/HCV- coinfected patients? Dual therapy with interferon- and/or ribavirin-based regimen Lower rates of efficacy High incidence of adverse effects, and Limited access to therapy. Challenges anticipated approval of new agents Greater efficacy All-oral regimens Shorter duration Improved tolerability Fewer drug-drug interactions

27 New drugs treatment for HCV/HIV-coinfection Older Medications Pegylated Interferon PegIntron or Pegasys Ribavirin Older Direct Acting Antivirals Boceprevir (Victrelis) (2011) Telaprevir (Incivek) (2011) New Direct Acting Antivirals Olysio (simeprevir) in November 2013 Sovaldi (sofosbuvir) in December 2013 Harvoni (ledipasvir and sofosbuvir) in October 2014 Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir ) in December 2014

28 C212 Study: Simeprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection N= 106 HCV/HIV coinfected patients, 39 sites in 7 countries Baseline median CD4 = 629 cells/mm3, 88% on ART (VL < 50 cells/ml) Excluded: boosted PIs, NNRTIs other than RPV

29 C212 Study: Simeprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection

30 C212 Study: Simeprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection

31 Simeprevir: Drug Interactions with HIV Medications

32 Simeprevir: Drug Interactions

33 SVR12 (%) SVR12 (%) Sofosbuvir + PegIFN/RBV for 12 Wks in Treatment-Naive GT1 HCV Monoinfection and HCV/HIV Coinfection NEUTRINO: N=327 Single-arm study in HCV Monoinfection: SVR12 [1] Single-Arm Study in HCV/HIV Coinfection: SVR12 [2] n/n = 0 295/327 Overall 261/292 GT /19 13/15 4/4 GT1 GT1a GT1b 1. Lawitz E, et al. N Engl J Med. 2013;368: Rodriguez-Torres M, et al. ID Week Abstract 714.

34 PHOTON-1: Sofosbuvir + RBV in HCV/HIV Coinfection N = 223, SOF + RBV for 12-wk (GT2/3 naive) or 24-week (GT1 t-naive, GT2/3 treatment experienced Stable ART (HIV-1 RNA < 50 copies/ml for > 8 wks before enrollment) Cirrhosis at baseline: GT1, 4%; GT2/3 tx naive, 10%; GT2/3 tx-exp d: 24%

35 PHOTON-1: Sofosbuvir + RBV in HCV/HIV Coinfection

36 Sofosbuvir plus Ribavirin for HCV-HIV Coinfection PHOTON-2 Trial: Treatment Arms N = 274 HCV-HIV coinfected patients; GT1 (n=112); GT2 (n=25); GT3 (n=106); GT4 (n=31), 20% Compensated cirrhosis On ART with HIV RNA 50 copies/ml and CD4 >200 cell/mm 3 or not on ART if CD4 > 500 cell/mm 3

37 Sofosbuvir plus Ribavirin for HCV-HIV Coinfection PHOTON-2 Trial: Treatment Arms

38 Sofosbuvir plus Ribavirin for HCV-HIV Coinfection PHOTON-2 Trial: Treatment Arms

39 Current Medications for HCV/HIV Older Medications Pegylated Interferon PegIntron or Pegasys Ribavirin Older Direct Acting Antivirals Boceprevir (Victrelis) (2011) Telaprevir (Incivek) (2011) New Direct Acting Antivirals Olysio (simeprevir) in November 2013 Sovaldi (sofosbuvir) in December 2013 Harvoni (ledipasvir and sofosbuvir) in October 2014 Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir) in December 2014

40 New DAAs in HIV/HCV Coinfection ERADICATE trial: Harvoni (ledipasvir and sofosbuvir) in HIV/HCV coinfection TURQUOISE I: Paritaprevir/RTV/Ombitasvir + Dasabuvir + RBV in HIV/HCV coinfectiongt1 Ledipasvir Sofosbuvir Harvoni

41 Sofosbuvir-Ledipasvir in GT1 with HCV/HIV Coinfection NIAID ERADICATE Trial N = 50, Fibrosis stage 0-3 (patients with cirrhosis excluded) Oshinusi A,JAMA: 15 Feb 2015

42 Sofosbuvir-Ledipasvir in GT1 with HCV/HIV Coinfection NIAID ERADICATE Trial: Results SVR 12: over all 98% 1 relapse in TE (resistance to LDV) Common AE: nasal congestion 16%, myalgia 14%) Oshinusi A,JAMA: 15 Feb 2015

43 Sofosbuvir-Ledipasvir Fix-Dose Combination +/- RBV ION-1, ION-2, and ION-3

44 Assumptions: 1) Production of new virions = ~10 12 /day 2) HCV genome length = ~9600 nucleotides 3) Error rate = ~10-5 /per nucleotide copied Therefore, average number of changes/genome = 0.096/replication cycle # of Nucleotide Changes How many DAAs do we need in HCV/HIV-coinfected patients? Probability # of Virions/Day x # of All Possible Mutants If the theory is right: should need 3 DAAs % of All Possible Mutants/Day x x x x x x x 10-5 Rong L, et al. Sci Transl Med. 2011;2:30-32.

45 New DAAs in HIV/HCV Coinfection Viekira pak Ombitasvir Paritaprevir Ritonavir booster for paritaprevir Dasabuvir TURQUOISE I: Ombitasvir / Paritaprevir / Ritonavir + Dasabuvir + RBV in HIV/HCV coinfection GT1

46 TURQUOISE I: Ombitasvir / Paritaprevir / Ritonavir + Dasabuvir + RBV in HIV/HCV Coinfection GT1 Phase II/III, RCT multicenter, 3D + RBV in naïve or previously treated with PEG + RBV, include cirrhosis Child A for 12 and 24 weeks; HCV-RNA >10,000 IU/ml. CD4 >200 cell/mm 3, HIV RNA < 40 copies/ml, receiving atarzanavir or raltegravir based regimen Sulkowski MS, JAMA : Feb23, 2015

47 TURQUOISE I: Ombitasvir / Paritaprevir / Ritonavir + Dasabuvir + RBV in HIV/HCV Coinfection GT1 N=63 SVR 12: 12 wk vs 24 wk 94% vs 92% 2 virological relapse or breakthrough 2 HCV reinfection Common AE: fatiuqe (48%), insomnia (19%), nausea (16%), headache (18%) Sulkowski MS, JAMA : Feb23, 2015

48 AbbVie Regimen Phase 3 Clinical Development Program

49 Drug Drug Interactions and Dose Recommendations Ombitasvir / Paritaprevir / Ritonavir + Dasabuvir Class Drug Recommendation During Coadministration Antiarrhythmics Antiarrhythmics Caution warranted during coadministration; therapeutic monitoring recommended Antifungals Ketoconazole Do not exceed daily ketoconazole 200 mg/day Voriconazole Coadministration not recommended unless justified by benefit risk ratio Calcium channel blockers Amlodipine Consider amlodipine dose reduction Corticosteroids Fluticasone Consider alternative corticosteroids Diuretics Furosemide Clinical monitoring and individualized therapy recommended HIV antivirals Atazanavir/RTV Administer atazanavir (without RTV) only in the morning HMG CoA reductase inhibitors Darunavir/RTV, Lopinavir/RTV Rilpivirine Rosuvastatin Pravastatin Coadministration not recommended Coadministration not recommended Rosuvastatin dose should not exceed 10 mg/day Pravastatin dose should not exceed 40 mg/day Ombitasvir/paritaprevir/ritonavir and dasabuvir [package insert].

50 Drug Drug Interactions and Dose Recommendations Ombitasvir / Paritaprevir / Ritonavir + Dasabuvir Class Drug Recommendation During Coadministration Immunosuppressants Cyclosporine Reduce cyclosporine dose to 1/5th of current dose, monitor Long-acting betaadrenoceptor agonists Narcotic analgesics Tacrolimus Salmeterol Buprenorphine/ naloxone Dose adjustment required; see prescribing information Coadministration not recommended No dose adjustment needed; closely monitor for sedation and cognitive effects PPIs Omeprazole Monitor for decreased omeprazole efficacy; increase if needed, not to exceed 40 mg/day omeprazole Sedative/hypnotics Alprazolam Clinical monitoring recommended; decrease dose as needed No dose adjustments needed with coadministration of the following with OMV/PTV/RTV + DSV: Digoxin, duloxetine, tenofovir DF/emtricitabine, escitalopram, methadone, progestin only contraceptives, raltegravir, warfarin, zolpidem Ombitasvir/paritaprevir/ritonavir and dasabuvir [package insert].

51 Contraindications and Selected Precautions: Ombitasvir / Paritaprevir / Ritonavir + Dasabuvir + RBV Not recommended for decompensated cirrhosis CTP-B: not recommended CTP-C: contraindicated Creatinine clearance CrCl > 30 ml/min, no dosage adjustment needed CrCl < 30 ml/min, consult with expert, limited safety and efficacy data available Contraindicated with drugs dependent on CYP3A for clearance, strong CYP3A and CYP2C8 inducers, strong CYP2C8 inhibitors Ribavirin contraindications and warnings/precautions apply Avoid if known hypersensitivity to ritonavir HCV/HIV coinfection: risk of HIV PI resistance Coinfected patients should be receiving suppressive ART AASLD/IDSA HCV Guidelines Ombitasvir/paritaprevir/ritonavir and dasabuvir [package insert].

52 Precautions: ALT Elevations ALT elevations of > 5 x ULN seen in ~ 1% of patients in clinical trials More common in women receiving ethinyl estradiol containing treatment Typically asymptomatic, in first 4 wks of therapy, declined in 2-8 wks with continued dosing of OMV/PTV/RTV + DSV Discontinue ethinyl estradiol prior to use of OMV/PTV/RTV + DSV May resume 2 wks after stopping OMV/PTV/RTV + DSV Coadminister with caution in patients receiving other estrogens Monitor hepatic labs at baseline, in first 4 wks, and after as needed Repeat and monitor if ALT elevated above baseline levels Consider discontinuation if ALT persistently > 10 x ULN; discontinue if ALT elevation accompanied by liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR Ombitasvir/paritaprevir/ritonavir and dasabuvir [package insert].

53 Optimal Management of HCV-HIV Coinfection Same recommendations as in HCV-monoinfected patients Treatment monitoring Monitoring of treatment efficacy Stopping (futility) rules Virological response-guided triple therapy Monitoring treatment safety Consider drug drug interactions Antiretroviral drug switches, when needed, should be done in collaboration with the HIV practitioner

54 2014 EASL Recommendations on Treatment of Hepatitis C Genotype 1,4 Sofosbuvir 400 mg/d + PEG + RBV x 12 wks Simeprevir 150 mg/d x 12 wks + PEG + RBV x 24 wks* (Q80K neg) Daclatasvir 60 mg/d +PEG + RBV + x weeks** (G 1b) IFN ineligible Sofosbuvir 400 mg/d + RBV x 24 weeks or Simeprevir 150 mg/d + Sofosbuvir 400 mg/d ± RBV x 12 wks Sofosbuvir 400 mg/d+ daclatasvir 60 mg/d x 12 weeks (naïve) or 24 weeks (TE**, failed PEG + RBV and either telaprevir or boceprevir) 2 Sofosbuvir 400 mg + RBV X weeks 3 Ribavirin and sofosbuvir 400 mg/d x 12 week or weeks (in cirrhosis, especiallyte) Sofosbuvir 400 mg/d and daclatasvir 60 mg/d 12 wks (naïve) or 24 wks (TE) Sofosbuvir 400 mg/d + PEG + RBV x 12 wks 5,6 Sofosbuvir 400 mg/d + PEG + RBV x 12 wks IFN ineligible Sofosbuvir 400 mg/d + RBV x 24 weeks April AASLD same recommndations, except no Daclatasvir-containing regimen *Treatment should be stopped if HCV RNA level is 25 IU/ml at treatment week 4, week 12 or week 24 **If HCV RNA level <25 IU/ml at week 4 and undetectable at week 10, PEG + RBV + daclatasvir 60 mg/d x 12 weeks then PEG + RBV x 12 weeks (total 24 weeks) TE; treatment experienced; weight-based ribavirin (1000 or 1200 mg/d in patients <75 kg or 75 kg, respectively

55 EASL 2014: Treatment monitoring Triple therapy: Stopping rules PegIFN-α, ribavirin and simeprevir Stop treatment if HCV RNA level is 25 IU/ml at treatment week 4, week 12 or week 24 (Recommendation A2) Virological response-guided therapy: pegifn-α, ribavirin and daclatasvir 0 4wk 10 wk 12 wk 24 wk HCV RNA <25 IU/ml undetectable Peg/RBV/daclatasvir Peg/R HCV RNA >25 IU/ml undetectable Peg/RBV/daclatasvir

56 2014 AASLD/IDSA/IAS-USA: HCV Treatment Guideline December 19, 2014 Revised for HCV/HIV Date: January 26, 2015 Population Regimen Duration GT 1a (3 options) GT 1b (3 options) SOF/LDV OMV/PTV/RTV-dasabuvir + RBV SOF + SMV SOF/LDV OMV/PTV/RTV-dasabuvir (naïve), add RBV (cirrhosis) SOF + SMV 12 wks 12 wks (naïve), 24 wks (cirrhosis) 12 wks (naïve), 24 wks(cirrhosis) 12 wks 12 wks 12 wks (naïve), 24 wks(cirrhosis) GT2 SOF + RBV 12 wks GT3 GT 4 (3 options) GT 5 GT 6 SOF + RBV pegifn/r/sof(alternative regimen) SOF/LDV OMV/PTV/RTV + RBV SOF + RBV pegifn/r/sof pegifn/r (alternative regimen) SOF/LDV pegifn/r/sof(alternative regimen) 24 wks 12 wks 12 wks 12 wks 24 wks 12 wks 48 wks 12 wks 12 wks American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), International Antiviral Society USA (IAS USA) SOF, sofosbuvir; RBV, ribavirin; LDV, ledipasvir; PTV, paritaprevir; RTV, ritonavir; OMV, ombitasvir; DSV, dasabuvir

57 AASLD 2014: Recommended monitoring during antiviral therapy. Recommendations for discontinuation of treatment because of lack of efficacy ALT Recommendations for discontinuation of treatment because of safety > 10 x ULN < 10 x ULN + symptomatic* Stop Rx < 10 x ULN + asymptomatic Closely monitor Repeat ALT at week 6 and week 8. *weakness, nausea, vomiting, or jaundice, or increased bilirubin, ALP, or INR

58 Monitoring treatment safety Patients receiving Peg IFN-α and ribavirin should be assessed for clinical side effects at each visit, while haematological side effects should be assessed at weeks 2 and 4 of therapy and at 4 to 8 week intervals thereafter Recommendation A1 Headache and fatigue have been reported with sofosbuvir Renal function should be checked regularly in patients receiving sofosbuvir Recommendation B1 Rashes and bilirubin elevations may be seen with simeprevir Recommendation A1 Eefficacy and toxicity of concurrent drugs given for comorbidities and potential drug-drug interactions should be monitored during treatment Recommendation A1 AASLD/IDSA HCV Guidelines 2015.

59 Antiretroviral Treatment Options for Patients on DAAs for Hepatitis C PI;Protease Inhibitors January 22, 2015

60 Antiretroviral Treatment Options for Patients on DAAs for Hepatitis C NNRTIs; nonnucleoside Reverse Transcriptase Inhibitors January 22, 2015

61 Antiretroviral Treatment Options for Patients on DAAs for Hepatitis C InSTIs;Integrase Strand Transfer Inhibitors, NRTIs; Nucleoside Reverse Transcriptase Inhibitors January 22, 2015

62 Summary Optimal Management of HCV-HIV Coinfection

63 Summary: Optimal Management of HCV/HIV Coinfection 2015 Same recommendations as in HCV-monoinfected patients (treatment naïve and - experienced patients), after recognizing and managing interactions with ARV. FDA-approved first-line pegifn-free regimens for GT 1, 2, 3, 4 PegIFN/RBV/SOF 12 weeks for GT5 and alternative treatment for GT3,6 PegIFN/RBV 48 weeks: alternative treatment for GT 5 The following regimens are NOT recommended for naive or -experienced PEG-IFN and RBV +/- telaprevir, boceprevir, or simeprevir, Monotherapy with PEG-IFN, RBV, or DAA Do not interrupt ARV Antiretroviral drug switches, when needed, should be done in collaboration with the HIV practitioner

64 Summary: Optimal Management of HCV/HIV Coinfection Consider drug drug interactions RBV should NOT be used with didanosine, stavudine, or zidovudine Simeprevir should NOT be used with EFV, ETR, NVP, cobicistat, or any HIV PI. LDV / SOF should NOT be used with cobicistat, EVG, tipranavir Potential for LDV-mediated increase TDF levels, especially if TDF used with RTV Avoid LDV if CrCl < 60 ml/min or if receiving TDF with RTV-boosted PI OMV/PTV/RTV + DSV; Need to adjust or withhold RTV if receiving a boosted PI Should NOT used with EFV, RPV, DRV, or RTV-boosted lopinavir. ETR; etravirine, NVP; nevirapine, EVG elvitegravir

65 Thank you