Virology Behandlung der Hepatitis B Markus Heim Universitätsspital Basel 1 2 HBV Genome HBV life cycle 3 4 HBV Genotypes Natural History 8 genotypes: A, B, C, D, E, F, G, H genotypes A and D are prevalent in Western Europe and North America, and genotypes B and C are prevalent in East Asia and Oceania immune tolerant chronic hepatitis B Interferon works better in A and B than in C and D HBeAg neg CHB inactive carrier Lamivudine works better in B than in C Lamivudine resistance more frequent in A than in D, no difference between B and C cirrhosis, HCC resolved hepatitis B 5 6
HBeAg negative chronic hepatitis B Chronic Hepatitis B Chronic necroinflammatory disease of the liver caused by persistent infection with hepatitis B virus. Chronic hepatitis B can be subdivided into HBeAg positive and HBeAg negative chronic hepatitis B. 7 8 Diagnostic criteria chronic hepatitis B Inactive HBsAg carrier state 1. HBsAg+ > 6 months 2. Serum HBV DNA > 2, IU/ml (1 5 copies/ml), lower values 2,-2, IU/ml (1 4-1 5 copies/ml) are often seen in HBeAg-negative chronic hepatitis B 3. Persistent or intermittent elevation in ALT/AST levels 4. Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation Persistent HBV infection of the liver without significant, ongoing necroinflammatory disease Diagnostic criteria: 1. HBsAg+ > 6 months 2. HBeAg-, anti-hbe 3. Serum HBV DNA < 2, IU/ml 4. Persistently normal ALT/AST levels 5. Liver biopsy confirms absence of significant hepatitis 9 1 Resolved hepatitis B Previous HBV infection without further virologic, biochemical or histological evidence of active virus infection or disease Diagnostic criteria: 1. Previous known history of acute or chronic hepatitis B or the presence of anti-hbc +/- anti-hbs 2. HBsAg negative 3. Undetectable serum HBV DNA 4. Normal ALT levels 11 Acute Exacerbation (flare) = Intermittent elevations of aminotransferase activity to more than 1 times the upper limit of normal and more than twice the baseline value Reactivation = Reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B HBeAg seroconversion = Loss of HBeAg and detection of anti-hbe in a person who was previously HBeAg positive and anti-hbe negative 12
Indications for treatment Category of response Chronic hepatitis B (HBeAG positive or negative) Diagnostic criteria: 1. HBsAg+ > 6 months 2. Serum HBV DNA > 2, IU/ml (1 5 copies/ml), lower values 2,-2, IU/ml (1 4-1 5 copies/ ml) are often seen in HBeAg-negative chronic hepatitis B 3. Persistent or intermittent elevation in ALT/AST levels 4. Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation Biochemical Virologic Primary non-response Virological relapse Histologic Complete Decrease in serum ALT to within the normal range Decrease in serum HBV DNA to undetectable levels by PCR assays, and loss of HBeAg in patients who were initially HBeAg positive Decrease in serum HBV DNA by < 2 log1 IU/ml after at least 24 weeks of therapy Increase in serum HBV DNA of 1 log1 IU/ml after discontinuation of treatment in at least two determinations more than 4 weeks apart Decrease in histology activity index by at least 2 points and no worsening of fibrosis score compared to pretreatment liver biopsy Fulfill criteria of biochemical and virological response and loss of HBsAg 13 14 Time of assessment Definition of Terms Relating to Antiviral Resistance to Nucleoside Analogue (NA) Treatment On-therapy During therapy Virologic breakthrough Increase in serum HBV DNA by >1 log1 (1-fold) above nadir after achieving virologic response, during continued treatment Maintained End-of-treatment Off-therapy Persist throughout the course of treatment At the end of a defined course of therapy After discontinuation of therpay Viral rebound Biochemical breakthrough Increase in serum HBV DNA to >2, IU/ml or above pretreatment level after achieving virologic response, during continued treatment Increase in ALT above upper limit of normal after achieving normalization, during continued treatment Sustained (SR-6) Sustained (SR-12) 6 months after end of therapy 12 months after end of therapy Genotypic resistance Phenotypic resistance Detection of mutations that have been shown in in vitro studies to confer resistance to the NA that is being administered In vitro confirmation that the mutation detected decreases susceptibility (as demonstrated by increase in inhibitory concentrations) to the NA administered 15 16 Interferons versus Nucleoside Analogues Interferon administered for predefined duration no resistance strong side effects Nucleoside Analogues administered until specific endpoints are achieved resistance develops to all NA if applied long enough few side effects 17 18
19 Interferon alpha versus PegInterferon alpha Peginterferon, and the combination for the treatment of HBeAg pos chronic Hep B Phase II trial, Cooksley et al, J Viral Hepatitis 23 Lau et al, NEJM, 25 2 Lau et al, NEJM, 25 Lau et al, NEJM, 25 22 21 Peginterferon alpha2b alone or in combination with HBeAg seroconversion with Peginterferon alpha2b Peginterferon alpha2b Peginterferon alpha2b plus lamivudin 3 24 Janssen et al, Lancet, 25 18 12 6 22% 25% 29% 29% EOT (52 weeks) EOFU (78 weeks) 23 Janssen et al, Lancet, 25 24
Peginterferon alpha2b versus Lamivudin Peginterferon alpha2a for HBeAg negative chronic hepatitis B 5 4 3 Peginterferon alpha2b plus lamivudin Lamivudin HBeAg seroconversion Combined response: ALT normal plus HBV-DNA < 4 IU/ml PegIFN!2a PegIFN!2a + lamivudin Lamivudin 6 2 1 5% 28% 36% 14% 3 15 27% 46% 6% 15% 16% 6% EOT (48 weeks) EOFU (72 weeks) EOT (48 weeks) EOFU (72 weeks) Chan et al., 25, Annals of Internal Medicine 25 Marcellin et al., 24, NEJM 26 Predictors of response to IFN in HBeAg positive patients Lamivudine for HBeAg positive chronic hepatitis B Positive predictors: 6 HBeAg seroconversion YMDD resistant mutants high pretreatment ALT values high HAI 3 low HBV DNA level 15 22% 17% 29% 39% 4% 57% 46% 1 year 2 years 3 years Leung et al., Hepatology, 21 27 28 Adefovir Dipivoxil (Hepsera) for HBeAg positive CHB Adefovir for HBeAg negative CHB placebo adefovir 1mg adefovir 3mg placebo adefovir 6 48 week analysis 8 6 48 week analysis 3 4 15 25% 53% 59% 6% 12% 14% 8% 2 33% 64% 51% 29% 72% histologic response HBeAg seroconversion nephrotoxicity histologic response HBV < 4 IU/ml biochemical response Marcellin et al., NEJM, 23 29 Hadziyannis et al., NEJM, 23 3
Long-term results with Adefovir in HBeAg neg CHB Adefovir resistance Hadziyannis et al., Gastroenterology, 26 Hadziyannis et al., Gastroenterology, 26: Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years 31 32 Entecavir (Baraclude) for HBeAg positive CHB Entecavir for HBeAg negative CHB entecavir entecavir 8 week 48 results 9. week 48 results 6 67.5 4. 2 62% 72% 36% 67% 6% 68% 18% 21% histologic response HBV < 4 IU/ml normal ALAT HBeAg seroconversion 22.5 61% 7% 72% 9% 71% 78% histologic response HBV < 3 IU/ml normal ALAT Chang et al., NEJM, 26 33 Lai et al., NEJM, 26 34 Telbivudine (Sebivo) for HBeAg pos CHB Telbivudine (Sebivo) for HBeAg negative CHB 6 telbivudine telbivudine 9. 67.5 3 15 4% 6% 38% 54% 23% 26% 29% 34% HBV DNA neg 1 year HBV DNA neg 2 years HBeAg loss 1 year HBeAg loss 2 years. 22.5 71% 88% 53% 79% 79% 74% 67% 75% HBV DNA neg 1 year HBV DNA neg 2 years normal ALAT 1 year normal ALAT 2 years 35 36
Telbivudine resistance Genotypic resistance = mutations in YMDD motif (only M24I but not M24V) 1 year 1 year telbivudine 2 years 2 years telbivudine 4 3 2 1 9.1% 4.4% 35% 22% 9.8% 2.7% 22% 8.6% HBeAg positive HBeAg negative Lok and McMahon, Hepatology, 27 37 38 Treatment costs (Swiss Francs, 27) Drug Cost/month Cost for treatment (length in months) Pegasys 1851.85 22 222 (12 m) Zeffix 1mg 186.6 1 821 (12 m) Hepsera 1mg 951.95 11 423 (12 m) Baraclude.5mg 951.95 11 423 (12 m) Baraclude 1mg 951.95 11 423 (12 m) Sebivo 6mg 769.8 9 238 (12 m) Viread 3mg 71.5 8 418 (12 m) Lok and McMahon, Hepatology, 27 39 4 Antiviral Drug-Resistant HBV: Nomenclature Nonresponse, Suboptimal Response, and Virologic Breakthrough 1. Antiviral Drug Change in HBV DNA (log 1 IU/mL) -1. -2. -3. -4. Primary nonresponse Suboptimal response Nadir 1 log Virologic breakthrough 6 12 18 Months Lok AS, et al. Hepatology. 27;:57-539. 41 42
Rates of Antiviral-Resistant HBV Mutations Reported in Clinical Trials HBV Resistance Mutations Terminal protein Pol/RT Spacer GVGLSPFLLA I(G) II(F) LAM resistance A rtl8v/i B C rtv173l rtm24v/i/s rtl18m rta181t/v ADV resistance ETV resistance LdT resistance TDF resistance RNaseH rtl18m rtt184s/a/i/l rtl18m rta194t rtl18m rtl8v/i 8 a.a. YMDD rtm24v/i rts22g/c rtm24i rtm24v D E rtn236t rtl233v? rtm25i/v Allen MI, et al. Hepatology. 1998;27:167-1677. Qi X, et al. J Hepatol. 24;4(suppl 1):2-21. Tenney D, et al. Antimicrob Agents Chemother. 24;48:3498-357. Tyzeka [package insert]. Lai CL, et al. Gastroenterology. 25;129:528-536. Schildgen O, et al. N Engl J Med. 26;354:187-1812. Locarnini S. 26 IDRW. Abstract P2. 43 44 Emergence of Resistance During Antiviral Therapy Early, Profound Suppression Correlates With Greater Sustained Response Wild-type virus Naturally occurring viral variants 1 Drug-resistant mutant virus Patients PCR Negative at Follow-up (%) HBV Replication Treatment begins Factors contributing to resistance include those related to the drug, the patient, and the virus Predicting Resistance Based on Level of HBV DNA Suppression 84 6 Patients Developing Resistance, % HBV DNA levels < 13 copies/ml at Week 24 13 (Week 12) HBV DNA levels! 13 copies/ml at Week 24 63 (Week 12) HBV DNA levels < 13 copies/ml at Week 48 4 (Week 144) HBV DNA levels > Telbivudine[3 ] copies/ml at Week 48 5 4 33 31 2 2 n = 7 < 4 c/ml 16! 4 c/ml 146 317 16 < QL! QL 153 < QL! QL 23 255 < QL! QL HBV DNA at Week 24 Best Outcomes With Low Baseline HBV DNA, Rapid Suppression Week 14 Telbivudine Treatment 1 2 (Week 14) HBV DNA levels! 13 copies/ml at Week 24 3-6 (Week 14) 89 91 8 67 (Week 144) HBV DNA levels < 13 copies/ml at Week 24 46 Patients (%) Predictor 16 LdT at Week 52 HBeAg+ Patients 95 Zeuzem S. EASL 26. Abstract 51. Farci P, et al. J Hepatol. 25;42(suppl 2):175. Yurdaydin C, et al. EASL 26. BMS symposium. Adefovir[2] ETV at Week 52 HBeAg+ Patients 96 61 HBV DNA at Week 12 Time Fung SK, et al. Antivir Ther. 24;9:113-126. Locarnini S, et al. Antivir Ther. 24;9:679-693. Lamivudine[1 ] LAM at Week 52 HBeAg+ Patients 8 Therapy PegIFN alfa-2a at Week 72 HBeAgPatients 6 81 83 HBeAg-positive patients BL HBV DNA < 9 log1 copies/ml Week 24 HBV DNA < 3 copies/ml HBeAg-negative patients BL HBV DNA < 7 log1 copies/ml Week 24 HBV DNA < 3 copies/ml 52 4 2 1. Yuen Y, et al. Hepatology. 21;34:785-791. 2. Locarnini S, et al. EASL 25. Abstract 36. 3. Zeuzem S, et al. AASLD 27. Abstract 994. N/A 1.8 2. HBeAg HBV DNA ALT Resistance Seroconversion Negative Normalization Zeuzem S, et al. AASLD 27. Abstract 994. 47 48
49 Managing Suboptimal Responses in the Treatment of Chronic Hepatitis B Complete response HBV DNA negative by PCR Week 12 Assess for primary nonresponse Week 24 Assess early predictors of efficacy Partial response HBV DNA 6 to < 2 IU/mL Inadequate response HBV DNA! 2 IU/mL Management of Virologic Breakthrough! Management options Switch to another drug Add on another drug Switch to and add on another drug! Choice of second drug generally dictated by lack of crossresistance Continue Monitor every 6 months Add another drug without cross-resistance or continue Monitor every 3 months Add a more potent drug Monitor every 3 months Keeffe E, et al. Clin Gastroenterol Hepatol. 27;5:89-897. 5 In Vitro Fold Change of Phenotypic Resistance HBV Lamivudine [1,2] Adefovir [3] Clevudine [1,4] Telbivudine [5] Entecavir [2,6] Tenofovir [7] Wild type 1. 1. 1. 1. 1. 1. L8I + M24I > 1 > 1 > 12 > 1 NA > 1 M24I > 1.7 > 12 > 1 3 5 L18M + M24V > 1.2 > 12 133 3 1 A181T/V 2-6 1-5 NA NA NA 1-3 N236T 3-8 7-1 4.7 2.4.67 5 V214A/Q214S 1-2 7-1 NA NA NA > 1 I169T/M25V* > 1 1. NA > 1 > 1 NA T184G/S22I* > 1 2. NA > 1 > 1 NA NA, not available. *+ rtl18m + M24V. 1. Chin R, et al. Antimicrob Agents Chemother. 21;:2495-251. 2. Delaney WE, et al. Antivir Chem Chemother. 21;12:1-35. 3. Angus P, et al. Gastroenterology. 23;125:292-297. 4. Ono-Nita SK, et al. Antimicrob Agents Chemother. 22; 46:262-265. 5. Levine S, et al. Antimicrob Agents Chemother. 22;46:2525-2532. 6. Angus P, et al. Antivir Ther. 24;9:1-148. 7. Sheldon J, et al. Antivir Ther. 25;1:727-734. Switch vs Add in Primary Nonresponse! 27 AASLD guidelines Patients who failed to achieve primary response as evidenced by < 2 log decrease in serum HBV DNA level after at least 6 months of NA therapy should be switched to an alternative treatment! NIH Clinical Research Workshop No data show that using 2 nucleos(t)ide analogues results in deeper viral suppression vs single agent Level of suppression equal to most potent agent in regimen Current evidence does not support combination therapy for CHB! Except potentially with -resistant disease Adefovir + appears preferable to adefovir alone Lok AS, et al. Hepatology. 27;:57-539. Hoofnagle J, et al. Hepatology. 27;:156-175. 51 52 AASLD Recommendations for Managing Virologic Breakthrough Resistance Lamivudine Adefovir Entecavir Telbivudine *Off label. Rescue Therapy! Add adefovir (superior to adefovir switch)! Switch to entecavir (increased risk of entecavir-r development)! Add tenofovir* or switch to emtricitabine/tenofovir*! Add (superior to switch)! Switch to or add entecavir (only in the absence of -R)! Switch to emtricitabine/tenofovir*! Add or switch to adefovir or tenofovir*! Add adefovir (superior to adefovir switch)! Switch to entecavir (increased risk of entecavir-r development)! Add tenofovir* or switch to emtricitabine/tenofovir* Lok A, et al. Hepatology. 27;:57-539. Summary! Clinical experiences with sequential monotherapy are not always predictable by current state of knowledge Increasing number and complexity of resistance mutations likely to result from increasing number of nucleos(t)ide analogues Vigilance for incomplete virologic control Early change to more potent drug Vigilance for resistance Add on or switch to combination likely to provide better long-term control when resistance is detected 53 54