Contents:

CHAPTER 1 EXECUTIVE SUMMARY 3 Scope of the analysis 3 Insight into the Hepatitis B and C market 4 Despite substantial prevalence for both HBV and HCV, the incidence of new infections within the seven major markets has reduced over the last decade due to HBV vaccination, increased blood and pre-natal screening along with awareness campaigns regarding routes of transmission. Our recent physician survey indicates that while diagnosis rates of HBV have remained flat since 2002, HCV diagnosis rates have increased 2–4 fold, with highest growth in Japan. 4 Average treatment rates for HBV and HCV within the seven major markets are calculated at 53% and 58%, respectively. Based on current estimates of prevalence and diagnosis, this determines current patient pools of between 1.8–2.0m per disease, where a large majority (60–80%) are receiving first-line therapy. To increase the treatment pool, manufacturers of hepatitis treatments can either tap into a substantial amount of unidentified cases or meet the needs of non-responder or ‘difficult-to-treat’ patients. 4 Lamivudine dominates first-line therapy for hepatitis B, with adefovir a first switch for resistant virus. This standard sequence is modulated by market cost-sensitivity, HIV co-infection and increasing use of peginterferon monotherapy (20–30%). Our research has also uncovered off-label use of tenofovir and experimental combinations but, in general, current options are suboptimal for growing numbers of HBeAg- patients and the ultimate goal of cccDNA clearance. 4 Increased uptake and aggressive life-cycle management of peginterferons (plus ribavirin) have driven the current standard of care to 73% of first-line choice for HCV. Our physician research (180 respondents) reveals higher use of branded peginterferon plus ribavirin packages, where consistency was cited as key selection criterium. Again, the treated patient pool will be increased by higher diagnosis, redefinition of ‘normal’ ALT and maintenance therapy. However, the needs of non-responders, genotype 1 and intolerant patients will not be satisfied in the short term. 5 CHAPTER 2 COVERAGE 16 Coverage of the Stakeholder Insight Survey 16 CHAPTER 3 ETIOLOGY AND EPIDEMIOLOGY 17 HBV and HCV epidemiology 17 HBV epidemiology 18 HCV epidemiology 20 Disease definition and etiology 23 HBV 24 Basic virology and serology 24 Disease progression 27 Complications and risk factors 34 Transmission 35 HCV 39 Basic virology and serology 39 Disease progression 41 Clinical manifestations 44 Risk factors 44 Transmission 45 Key patient segmentations 47 Comorbidities and complications 52 Liver fibrosis/cirrhosis 52 Hepatocellular carcinoma (HCC) 54 Coinfection with other viruses (HDV, HIV and HBV/HCV) 55 Coinfection with HDV 56 Coinfection with HIV 56 HBV/HCV coinfection 57 Fatty liver (steatosis) 58 Transplant patients 59 CHAPTER 4 DIAGNOSIS AND TREATMENT RATES 60 Presentation and diagnosis rates 60 HBV 60 HCV 64 Treatment rates 69 HBV 69 HCV 70 CHAPTER 5 TREATMENT OPTIONS 71 HBV Therapy 72 Approved treatment options 76 Interferons 77 Antivirals 78 Combination therapy 81 Actual prescription choices 83 Prevention 92 Active immunization: HBV vaccination 92 Passive immunization: immune prophylaxis with HBIG 94 HCV therapy 95 Approved treatment options 97 Interferon (IFN) monotherapy 98 Combination therapy 100 Actual prescription choices 101 Treatment guidelines 113 HBV 113 Normal versus elevated ALT levels 115 Viral threshold: HBV DNA levels 117 HCV 118 Prolongation of treatment & maintenance therapy 120 Normal versus elevated ALT levels 121 Liver histology as assessed by liver biopsy 121 Niche populations 122 HBV 122 HBeAg- patients 122 Others 122 HCV 123 Partial responders, non-responders and relapsers 123 Genotype 1 and racial differences 124 CHAPTER 6 PRESCRIBING TRENDS AND INFLUENCING FACTORS 126 Factors influencing physician decision making: HBV therapy 127 Rating of drugs currently used for HBV therapy 128 Conclusions 135 Factors influencing physician decision making: HCV therapy 137 Rating of drugs currently used for HCV therapy 138 PegIntron versus Pegasys 140 Conclusions 150 Treatment outcomes 151 HBV 151 Durability of treatment response 151 Complications, morbidity and mortality 152 HCV 153 Durability of treatment response 153 Complications, morbidity and mortality 154 Unmet needs 154 HBV 154 Diagnostic unmet needs 154 Physician/patient education 155 Patient perspective 156 Therapeutic unmet needs 157 HCV 160 Diagnostic unmet needs 160 Physician/patient education 160 Patient perspective 161 Therapeutic unmet needs 162 CHAPTER 7 COUNTRY TREATMENT TREES 166 CHAPTER 8 OPINION LEADER TRANSCRIPTS 181 Key opinion leader 1 – Spanish Infectious Disease physician 181 SECTION 1 – Epidemiology 181 SECTION 2 – Presentation and diagnosis 181 SECTION 3 – Disease treatment and management 182 HBV 182 HCV 188 Key opinion leader 2 – Japanese Hepatologist 193 SECTION 1 – Epidemiology 193 SECTION 2 – Presentation and diagnosis 194 SECTION 3 – Disease treatment and management 195 HBV 195 HCV 199 Key opinion leader 3 – Italian Infectious Disease physician 202 SECTION 1 – Epidemiology 202 SECTION 2 – Presentation and diagnosis 202 SECTION 3 – Disease treatment and management 204 HBV 204 HCV 211 Key opinion leader 4 – French Hepatologist 218 SECTION 1 – Epidemiology 218 SECTION 2 – Presentation and diagnosis 218 SECTION 3 – Disease treatment and management 219 HBV 219 HCV 225 Key opinion leader 5 – UK Infectious Disease physician 229 SECTION 1 – Epidemiology 229 SECTION 2 – Presentation and diagnosis 229 SECTION 3 – Disease treatment and management 232 HBV 232 HCV 240 Key opinion leader 6 – Spanish Hepatologist 249 SECTION 1 – Epidemiology 249 SECTION 2 – Presentation and diagnosis 249 SECTION 3 – Disease treatment and management 251 HBV 251 HCV 257 Key opinion leader 7 – German Hepatologist, Gastroenterologist and Internal Medicine physician 262 SECTION 1 – Epidemiology 262 SECTION 2 – Presentation and diagnosis 263 SECTION 3 – Disease treatment and management 264 HBV 264 HCV 270 Key opinion leader 8 – US Internal Medicine and Infectious Disease physician 275 SECTION 1 – Presentation and diagnosis 275 SECTION 2 – Disease treatment and management 276 HBV 276 HCV 280 APPENDIX A 285 Bibliography 285 Journal articles 285 Conference abstracts 290 Epidemiology sources 293 Country populations 293 Prevalence Data 293 Key associations and websites 295 News and press releases 296 Miscellaneous 298 APPENDIX B 300 Physician research methodology 300 Physician sample breakdown 300 US 300 Japan 301 France 301 Germany 302 Italy 302 Spain 303 UK 303 APPENDIX C 304 APPENDIX D 321 Non-weighted drug rating 321 HBV 321 US 321 Japan 322 France 322 Germany 323 Italy 323 Spain 324 UK 324 HCV 325 US 325 Japan 325 France 326 Germany 326 Italy 327 Spain 327 UK 328 Disclaimer 329