Challenges in the Management and Treatment of HIV/Hepatitis C Virus Coinfection

This presentation by Dr. Ricardo A. Franco focuses on the challenges faced in managing and treating patients with HIV/Hepatitis C virus coinfection. It discusses the burden of HCV mono-infection and HIV/HCV co-infection, the impact of HIV co-infection on survival in HCV-related cirrhosis, and the role of ART in decreasing hepatic decompensation events. The presentation aims to help healthcare professionals apply the best HCV treatment strategies, merge evolving concepts of HIV and HCV co-management, and address the unmet needs of HIV/HCV co-infected patients.

• HIV
• Hepatitis C
• Coinfection
• Treatment strategies
• HIV co-management

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1. Challenges in the Management and Treatment of HIV/Hepatitis C Virus Coinfection Ricardo A. Franco, MD Assistant Professor of Medicine University of Alabama at Birmingham Birmingham, Alabama FORMATTED: 04-05-16 Atlanta, Georgia: April 8, 2016 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

2. Learning Objectives After attending this presentation, participants will be able to: Apply best HCV treatment strategies to clinical care Merge evolving concepts of HIV and HCV co-management Address unmet needs of HIV/HCV co-infected patients Slide 2 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

3. HCV Mono-infection and HIV/HCV Co-infection Burden An estimated 2% 3% of the world's population is living with HCV >350 000 die each year of HCV-related cirrhosis and liver cancer1 Among HIV-infected individuals, HCV co-infection Ranges from 10 30% in MSM Up to 80 90% in IVDU2 Two types of HIV/HCV co-infected patients can be distinguished Those infected for decades (often have severe fibrosis and several comorbidities) Those recently infected with HCV 1) G.M. Lauer, B.D. Walker. Hepatitis C virus infection. N Engl J Med, 345 (2001), pp. 41 52 2) K.E. Sherman, S.D. Rouster, R.T. Chung, N. Rajicic. Hepatitis C Virus prevalence among patients infected with Human Immunodeficiency Virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis, 34 (2002), pp. 831 837 Slide 3 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

4. HIV Co-infection Shortens Survival in HCV-related Decompensated Cirrhosis Pineda JA, Romero-G mez M, D az-Garc a F, et al. HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis. Hepatology. 2005;41:779-789. Slide 4 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

5. HIV Control does not Completely Overturn Risk of ESLD ART decreases hepatic decompensation events: 0.72 (0.54-0.94) Lo Re V. Ann Intern Med 2014. Anderson JP. CID 2014. Slide 5 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

6. Prior Experience in HIV/HCV INF Era 1. Chung RT, Andersen J, Volberding P, et al. N Engl J Med. 2004;351:451-9. 2.Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. N Engl J Med. 2004;351:438-50. 3. Laguno M, Murillas J, Blanco JL, et al. AIDS. 2004;18:F27-36. 4. Carrat F, Bani-Sadr F, Pol S, et al. JAMA. 2004;292:2839-48. 5.N ez M, Miralles C, Berd n MA, et al. AIDS Res Hum Retroviruses. 2007;23:972-82. 6.N ez M, Miralles C, Berd n MA, et al.. AIDS Res Hum Retroviruses. 2007;23:972-82. Slide 6 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

7. Poor Rates of HCV Treatment Uptake and Cure Mehta; Sulkowski et al. Limited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic. AIDS. 20(18):2361-2369, November 28, 2006. Slide 7 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

8. HCV Therapeutics Timeline IFN-free GT1 DAA regimens BOC TPV In vitro HCV replication Consensus IFN 1989 HCV identified Peg-IFNa-2b 1995 2005 2010 2000 2016 IFN a-2b Sofosbuvir Simeprevir (US) Daclatasvir (EU) HCV replicons IFN a-2a Peg-IFNa-2a in HCV/HIV IFN a-2b + RBV Peg-IFNa-2a IFN-free Treatment Options in 2016 (FDA Approved) SOF/ LDV RBV OBV/ PTV/r SOF DCV SOF RBV GZR EBR SOF SMV DSV Slide 8 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

9. SVR12 Rates in DAA Trials (HIV/HCV vs HCV Mono) Mostly HCV GT1 Arends JE et al. Natural history and treatment of HCV/HIV coinfection: Is it time to change paradigms? Journal of Hepatology, Volume 63, Issue 5, 2015, 1254 1262 Slide 9 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

10. Treatment Nave GT1 Recommended and Alternative Options OBV/PTV/r +DSV GZR/EBR SOF/LDV SOF/SMV SOF/DCV Non- cirrhotic 12w* 12w 12w + RBV 12w 12w GT1a 24w +/- RBV** 24w +/- RBV Cirrhosis 12w* 12w 24w + RBV Non- cirrhotic 12w 12w 12w 12w 12w GT1b 24w +/- RBV 24w +/- RBV Cirrhosis 12w 12w 12w * If no baseline NS5A RAVs for elbasvir are detected; if detected, 16w + RIBA is an alternative option ** If no Q80K polymorphism is detected hcvguidelines.org Slide 10 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

11. Treatment Experienced GT1 Recommended and Alternative Options Cirrhosis Status Failed GZR/EBR SOF/LDV PrOD SOF+SMV SOF+DCV NC 12w* 12w 12w 12w 12w PR 12w + RBV or 24w 1a: 24w+R 1b: 12w 1a: 24w+/-R** 1b: 24w+/-R 24w +/- RBV C 12w* NC 12w+R* 12w NR NR 12w hcvguidelines.org PR + PI 12w + RBV or 24w 24w +/- RBV C 12w+R* NR NR 1a: 12w+R# 1b: 12w# NC 12w# 12w + RBV 12w# 12w# PR + SOF or SOF/RBV 1a: 24+R# 1b: 12w# 1a: 24w+/-R**# 1b: 24w+/-R# 24w +/- RBV# C 12w# 24w + RBV * If no baseline NS5A RAVs for elbasvir are detected; if detected, 16w + RIBA is an alternative option; ** If no Q80K polymorphism is detected; #There are no published data on retreatment of sofosbuvir-containing treatment failures with non-sofosbuvir based DAA regimens hcvguidelines.org Slide 11 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

12. GT2/3 Recommended and Alternative Options Status SOF/RBV SOF/DCV PR + SOF 12w* NR NC 12w SR-TE: 24w+/-R SR-TE: 12w** GT2 TN: NR PR-TE: 12w** SR-TE: 12w** 16-24w* SR-TE: 24w+/-R C 16-24w NC 24w# 12w 12w** GT3 TN: 24w +/- RBV## PR-TE: 24w+RBV## SR-TE: 24w+RBV## C 24w# 12w** *If not eligible to receive RBV ; ** If INF-eligible; #If DCV-ineligible; ## If INF-ineligible hcvguidelines.org Slide 12 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

13. New Paradigms Bring New Challenges Treat most patients Treat a few patients Engage the unmotivated Prefer highly motivated patients Treat regardless of liver disease stage Restrict treatment to the ones at risk of liver disease progression Many rx options to choose from W/wo ART switches Select optimal INF/RBV candidates DDI, resistance, reinfection Warehousing; harm reduction HIV co-infected patient is treated like mono-infected ones in most cases Slide 13 of 39 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

14. ART in HIV/Hepatitis C Virus Coinfection When to Start What to Start Same initial ARV combinations are recommended for HIV mono-infection and HIV/HCV co-infection Check for DDIs Avoid overlapping toxicities Hepatically metabolized ART and DAAs may be contraindicated or require dose modification (Child-Pugh class B and C) ART should be initiated regardless of CD4 count Can defer ART in TN pts w CD4 >500 and treat HCV first Pts with CD4 <200 had lower SVR and toxicity rates in PegIFN/RBV era Data is lacking on DAA response in pts with advanced immunosuppression Prompt ART and delay HCV rx until immune recovery Hepatotoxicity (DILI) The risk among newer ART options is low [monitor LFTs (>5x ULN)] Hypersensitivity reactions can occur aidsinfo.nih.gov Slide 14 of 39 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

15. 2014 Recommendations of the International Antiviral Society USA Panel EVG/c/TAF/FTC TAF/FTC/RPV TAF/FTC JAMA. 2014;312(4):410-425. doi:10.1001/jama.2014.8722 Slide 15 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

16. ART Switches Previous ART history Demonstrated or possible ARV resistance Resistance remain archived in latent cells even if not detected in resistance assays Likelihood of adherence to new regimen Patient acceptance of potential new side effects Other medications of DDIs Affordability Use available evidence to guide switch decisions Slide 16 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

17. DDIs (ART vs DAA) PTV/RTV/OBV + DSV SOF + SIM SOF/LDV SOF + DCV GZR/EBV Atazanavir + RTV Darunavir + RTV Raltegravir Dolutegravir Elvitegravir + COBI Elvitegravir/COBI/ TAF/emtricitabine * Efavirenz Rilpivirine Abacavir/lamivudine Tenofovir DF/ emtricitabine nephrotoxicity Adapted from AASLD/IDSA Guidelines. February 2016. Slide 17 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

18. DDIs (DAA vs Other Selected Drugs) Concomitant Medication SOF SIM LDV PTV/RTV/OBV + DSV DCV GZR/EBV Acid-reducing agents X X Amiodarone X X X X X X Anticonvulsants X X X X X X Digoxin X X X X Ethinyl estradiol containing products X Glucocorticoids X X X X PDE5 inhibitors X X X Rifamycin antimicrobials X X X X X X Sedatives X X X St John s wort X X X X X X Statins X X X X X Adapted from AASLD/IDSA Guidelines. February 2016. Slide 18 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

19. Virologic Barriers to Resistance Genetic barrier Number and type of nucleotide changes required for a virus to acquire resistance to an antiviral regimen[1] Viral fitness Relative capacity of a viral variant to replicate in a given environment .75 % Fitness Fitness of Polymerase Inhibitor Mutants[2,3] 1 .5 .25 0 1. 2. 3. Rong L, et al. Sci Transl Med. 2010;2:30ra32. Le Pogam S et al. J Virol. 2006;80:6146-6154. Le Pogam S, et al. J Infect Dis. 2010;202:1510-1519 Slide 19 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

20. AASLD/IDSA Guidance for Resistance Testing When Considering SMV + SOF In pts with both genotype 1a HCV infection and compensated cirrhosis, if considering SMV + SOF, test for Q80K polymorphism If Q80K variant is present, consider a regimen other than SMV + SOF Applies to treatment-naive and treatment-experienced pts Q80K testing not required for: Pts with genotype 1b HCV infection Pts without cirrhosis Pts in whom you are considering other DAAs AASLD/IDSA. HCV Guidance. Slide 20 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

21. Resistance Analysis of Select NS5A Inhibitors in Genotype 1 HCV Fold-Change in EC50 Genotype 1a Genotype 1b Position M28T Q30R L31M/V Y93H/N L31V Y93H/N FDA approved Daclatasvir[1,3] > 100 x > 1000 x > 100 x > 1000 x < 10 x < 100 x Ledipasvir[1] 20 x > 100 x > 100 x > 1000 x > 1000 x/? < 3 x Ombitasvir[2] > 1000 x > 100 x > 10,000 x < 10 x < 100 x > 100 x > 100 x 3 to 100 x < 3 x 1. Cheng G, et al. EASL 2012. Abstract 1172. 2. Krishnan P, et al. Antimicrob Agents Chemother. 2015;59:979-987. 3. Yang G, et al. EASL 2013. Abstract 1199. 4. Ng T, et al. CROI 2014. Abstract 639. Slide 21 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

22. GT1 Pts: Who Needs Resistance Testing? GT1a patients needs testing at baseline when considering GZR/EBR If previous failure of any NS5A inhibitors (DCV + SOF, LDV/SOF, OMV/PTV/RTV + DSV) and minimal liver disease, deferral preferred pending further data If cirrhosis or other need for urgent treatment, test for NS3 and NS5A RAVs Applies to genotype 1a and 1b HCV infection NS3 and NS5A testing not required for: Previous failure of NS3/4A PIs (including simeprevir, boceprevir, telaprevir) Previous failure of NS5B inhibitors (sofosbuvir) Tx-naive pts (unless considering SMV + SOF in cirrhotic GT1a) AASLD/IDSA. HCV Guidance. Slide 22 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

23. Selecting Treatment Based on Resistance Testing Results If genotype 1a or 1b HCV infection and previous failure with any NS5A inhibitors and cirrhotic or other need for urgent treatment: RAV Testing Result No NS5A RAVs NS5A but no NS3 RAVs NS5A and NS3 RAVs Retreatment Regimen Ledipasvir/sofosbuvir + ribavirin Simeprevir + sofosbuvir + ribavirin Retreatment in a clinical trial setting Duration 24 wks 24 wks AASLD/IDSA. HCV Guidance. Slide 23 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

24. Despite Declining HCV Infections, Healthcare Costs Will Increase due to ESLD 4.5 4.0 3.5 3.0 2.5 16 14 Healthcare Cost ($ Billion) Prevalence (Millions) 12 10 8 2.0 6 1.5 4 1.0 0.5 2 0 0 Razavi H, et al. Hepatology. 2013;57:2164-2170. Slide 24 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

25. Cost of FDA Approved Regimens Regimen SOF + P/R SOF + RIBA SOF + RIBA SOF + SMV SOF + SMV SOF + LDV SOF + LDV PAR/r/OMB + DAS PAR/r/OMB + DAS GZR/EBR HIV ART* Duration 12 weeks 12 weeks 24 weeks 12 weeks 24 weeks 12 weeks 24 weeks 12 weeks 24 weeks 12 weeks 35 years $$$ (in US) $94,500 $91,500 $183,000 $150,000 $300,000 $94,500 $189,000 $90,900 $90,900 $54,000 $20,000/year *~30% of PLWH in US are on therapy and virally suppressed ($7.2 billion/year) - This same budget could accommodate ~75,000 HCV patients / year - Federal Budget for domestic and global HIV efforts 2016: $31.7 billion Slide 25 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.

26. Increasing Use of High SVR Therapy (~ 90%) Will Eliminate HCV in the US by 2029 Treated No more pts available to treat 200,000 150,000 100,000 50,000 0 Cured 160,000 120,000 80,000 40,000 0 Razavi H, et al. Hepatology. 2013;57:2164-2170. Slide 26 of 26 From RA Franco, MD, at Atlanta, GA: April 8, 2016, IAS-USA.