Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV) Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University

Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV) Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University

Current And Future Treatment of HCV: The Count Down To The Demise of Hepatology Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University

True or False Hepatitis C is incurable. Treatment only suppresses the virus Interferon and ribavirin therapy are associated with minor adverse events HCV genotype is a major determinant of response to interferon based therapy. Boceprevir and telaprevir are effective against all genotypes. Sofosbuvir in combination with IFN and ribavirin cures around 90% of HCV infected patients

Outline HCV structure and life cycle HCV genotypes Standard treatment of HCV ( ) Standard treatment of HCV genotype 1 ( ) Current treatment of HCV genotypes 1-6 The future

HCV Polyprotein Processing and Viral Protein Function McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:

HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6: Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside Block replication complex formation, assembly NS5A inhibitors RNA replication

HCV Genotypes

The Prevalence of HCV Genotype 4 in Kuwait Hasan et al. Hepatogastroenterology 2002 * Eastern province of Syria

Seroprevalence of HCV in Kuwait Ameen R et al. Transfusion ;45: Chehada W et al. J infect Public Health 2011 ;4:200-6 *Al Khalidi J et al. Unpublished data

Treatment of HCV Pegylated Interferon plus Ribavirin combination was the standard treatment of HCV regardless of genotype until 2011

Sustained Virologic Responses By Genotype *Hasan F, et al. Am J Gastroenterol 2004;99:

Interferon Plus Ribavirin Therapy Limitations % do not respond Numerous side effects

Factors that affect outcome Treatment regimen PEG-IFN Ribavirin DAA Host factors Age, gender, race obesity, co-morbidities Genetic factors (IL28B and ITPA) Disease features Fibrosis, steatosis, co-infection (HBV, HIV) Viral factors Genotype / Subtype Quasispecies / Resistance Viral load Factors That Influence Response to Interferon Based Therapy

Most Important Factors that Influence Treatment Outcome HCV Genotype IL 28 B Polymorphism Degree of Fibrosis HCV RNA level

Side Effects of PegIFN/Ribavirin “Interferon Man” Fever Myalgias Hair loss Depression Anemia Rash Many others !

Was it the Interferon Man ?

Contraindications of Pegylated Interferon and Ribavirin De-compensated cirrhosis Coronary artery disease, heart failure, serious dysrythmia Proliferative diabetic retinopathy Kidney transplant patients Renal impairment (ribavirin)

2011: Telaprevir and Boceprevir for HCV Genotype 1

Sustained Virologic Response: Telaprevir plus Peg Interferon Plus Ribavirin PR T12/PR 683/903 PR48 166/361 n/N = 74–79* INCIVO (telaprevir) EU SmPC *p< T12/PR vs PR48 (79% versus 46%) in ADVANCE SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

SVR rates with boceprevir plus PR versus PR alone BOC RGT 233/368 BOC44/PR48 242/366 PR48 137/363 n/N = VICTRELIS (boceprevir) EU SmPC * * *p<0.001 for both boceprevir arms versus PR48 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week value was carried forward

Adverse Events with Telapravir and Bocepravir Telaprevir Telaprevir plus P/RP/R Pruritis45-50%28% Nausea40-43%31% Rash56%34% Anemia37-39%19% Diarrhea28-32%17% Anorectal discomfort11%3% Boceprevir Anemia50%30% Dysgeusia35-43%16% Neutropenia25%19% Nausea46%42%

Contraindicated Drugs and Other Precautions for Telaprevir *These interactions have been studied; † Impaired renal/hepatic function; ‡ No clinical data are available regarding the treatment of organ transplant patients with TRADENAME in combination with peg-IFN/RBV. Therefore, the use of TRADENAME in organ transplant patients is not recommended; § Normal renal/hepatic function. Important Safety Information

December 2013 Simeprevir and Sofosbuvir

Efficacy With Simeprevir + P/R in Tx- Naive GT1 Patients: Phase III Trials SMV + P/R for 12 wks followed by wks of P/R (placebo control) Jacobson I, et al. EASL Abstract / 31 n/N = 5/ / / No CirrhosisCirrhosis n/N = 419/ / / / 83 49/ 84 23/ / / SVR (%) Simeprevir + P/R Placebo + P/R OverallGT1a Without Q80K GT1a With Q80K GT1b

Simeprevir Is Well Tolerated BilirubinHemoglobin Mean (µmol/L) Wks  Mild unconjugated hyperbilirubinemia → transporter  No anemia signal beyond P/R  Rash up to 25% (mild) Manns M, et al. EASL Abstract SMV + P/R P/R

Efficacy With Sofosbuvir + P/R in Tx-Naive GT1/4/5/6 Patients: Phase III Trials Single-arm study of sofosbuvir + P/R for 12 wks SVR12 (%) No Cirrhosis Cirrhosis 252/27343/54 SVR12 According to Fibrosis Level SVR12 (%) GT1GT4GT5/6 261/29227/287/7 SVR12 According to GT n/N = Lawitz E, et al. N Engl J Med. 2013;368:

Efficacy of Sofosbuvir in GT2 1. Gane E, et al. EASL Abstract Jacobson I, et al. N Engl J Med. 2013;368: SVR12 (%) No CirrhosisCirrhosis 58/5944/5410/118/13n/N = wks of SOF + RBVPegIFN/RBV Treatment Naive [1] 6/1025/267/923/23 No CirrhosisCirrhosis GT2 n/N = wks of SOF + RBV 100 Treatment Experienced [2]

FDA Approved Indications for Sofosbuvir TreatmentDuration HCV genotype 1 &4Sofosbuvir+Peg-IFN+RBV12 wks HCV genotype 2Sofosbuvir + RBV12 wks HCV genotype 3Sofosbuvir + RBV24 wks HCV plus HCC Decompensated Cirrhosis Sofosbuvir + RBV48 wks or Tx

DO NOT USE TELAPREVIR OR BOCEPREVIR

The Future Interferon Free Regimens

IFN-Free Therapy for Tx-Naive GT1 HCV 1. Kowdley K, et al. EASL Abstract Lawitz E, et al. AASLD Abstract Everson GT, et al. AASLD Abstract LB Lawitz E, et al. AASLD Abstract 76. AI [3] Daclatasvir + Asunaprevir + BMS for 12 wks MK MK mg + RBV MK MK mg + RBV MK MK mg C-WORTHY 12-wk regimens [4] SOF/LDV FDC 8 wks SOF/LDV + RBV 8 wks SOF/LDV FDC 12 wks LONESTAR [2] wks AVIATOR [1] ABT-450/RTV + ABT ABT RBV SVR12/24 (%) 24 wks n =

Is the demise of Hepatology imminent ? HCV cure rate approaching 95% HBV incidence declining rapidly due to vaccination Treatment of HBV and HCV using direct acting antivirals is safe, simple and can be handled by internists. Alcoholic liver disease and NASH can be handled by internists Only end stage liver disease and liver transplant patients need specialty care ?