Case study Chronic HBV infection Marion Peters University

Case study: Chronic HBV infection Marion Peters University of California San Francisco 2009

HBV case • 45 year old man admitted with fatigue, malaise and abdominal swelling in June 2003 • He was born in Greece, came to US age 14 • His brother had a liver transplant for HBV in 1998 • On Examination: jaundice, ascites, no muscle wasting, spider nevi

HBV Laboratory and Imaging • Bilirubin 3. 7, AST 129, ALT 106, albumin 2. 4, PT 1. 7, Ammonia 51, Creatinine 0. 9 • MELD 19 • HBs. Ag and HBe. Ag positive • HBV DNA 340, 000 IU/m. L • AFP 741 mcg/L • Acites: paracentesis WCC 183, albumin <1

How would you treat his HBV? Blue Green Red Yellow Pegylated interferon for 48 week Lamivudine 100 mg per day Entecavir 0. 5 mg per day Tenofovir 300 mg per day/ Combo

HBV case-3 • June 2003 started lamivudine 100 mg daily – Well tolerated, lost ascites – Patient had improved liver function • Listed for liver transplantation • Ultrasound cirrhotic liver no masses • CT quadruple phase no masses

Date LAM 6 -03 11 - 03 AST 160 59 Bili 3. 7 0. 9 Albumin AFP HBVDNA 340, 000 2. 5 741 400, 000 3. 1 14 IU/m. L

Date LAM 6 -03 11 - 03 2 -04 AST 160 59 74 Bili 3. 7 0. 9 1. 3 Albumin AFP HBVDNA 340, 000 2. 5 741 400, 000 3. 1 14 500, 000 2. 9 193 IU/m. L

What has occurred? Blue Red Green LAM non response LAM resistance Non compliance

100 Patients With YMDD Variants (%) Patients With Resistance (%) HBV DNA at Month 6 of LAM Predicts Later Risk of Resistance N = 159 HBe. Ag-positive patients Median follow-up: 29. 6 months 80 64 60 40 20 32 13 8 12 23 41 118 0 n= ≤ 2 ≤ 3 ≤ 4 >4 HBV DNA at 6 Months (log 10 copies/m. L) Yuen ME, et al. Hepatology. 2001; 34: 785 -791.

HBV status • HBV Genotype A, HBe. Ag positive • Polymerase mutations – L 180 M, +M 204 V – no precore mutations detected – No ADV mutations detected • HIV negative • HDV negative

HBV: How would you treat his HBV now with LAM resistance? Blue Red Green Yellow Switch to Adefovir/TDF Switch to Entecavir 0. 5 mg per day Add Adefovir/TDF

HBV: How would you treat his HBV now? Blue Red Green Yellow Switch to Adefovir/TDF Switch to Entecavir 0. 5 mg per day Add Adefovir/TDF

Date LAM 6 -03 11 - 03 add ADV 2 -04 AST 160 59 74 Bili 3. 7 0. 9 1. 3 Albumin AFP HBVDNA 340, 000 2. 5 741 400, 000 3. 1 14 500, 000 2. 9 193 IU/m. L

Date LAM 6 -03 11 - 03 add ADV 2 -04 5 -04 AST 160 59 74 69 Bili 3. 7 0. 9 1. 3 1. 5 Albumin AFP HBVDNA 340, 000 2. 5 741 400, 000 3. 1 14 500, 000 2. 9 193 320, 000 3. 0 169 IU/m. L

What has occurred? Blue Red Green Yellow ADV resistance ADV primary non response ADV suboptimal response Non compliance

Change in HBV DNA (log 10 IU/m. L) 1. 0 Nonresponse, Suboptimal Response, and Virologic Breakthrough Antiviral Drug Primary nonresponse 0 Virologic breakthrough -1. 0 Suboptimal response -2. 0 -3. 0 Nadir -4. 0 0 6 12 Months Lok AS, et al. Hepatology. 2007; 45: 507 -539. 1 log 18

HBV DNA at Week 48 of ADV Predicts Risk of Resistance at Wk 144 Resistance (%) 100 N = 114 patients, primarily HBe. Ag negative[1] 80 67 100 80 60 60 40 40 26 20 20 4 0 <3 3 -6 >6 N = 124 patients, HBe. Ag negative[2] 0 49 6 <3 HBV DNA at Week 48 (log 10 copies/m. L) 1. Locarnini S, et al. EASL 2005. Abstract 36. 2. Hadziyannis SJ, et al. Gastroenterology. 2006; 131: 1743 -1751. >3

HBV-case: What would you do? Blue Red Green Yellow Continue ADV Add Tenofovir 300 mg Change to TDF and ETV Change to TDF and Lam/FTC

Date LAM 6 -03 11 - 03 add ADV 2 -04 5 -04 8 -04 Switch To TDF 11 -04 +LAM 5 -06 5 -07 AST 160 59 74 69 68 67 52 28 Bili 3. 7 0. 9 1. 3 1. 5 1. 8 1. 0 1. 1 1. 0 Albumin AFP HBVDNA 340, 000 2. 5 741 400, 000 3. 1 14 500, 000 2. 9 193 320, 000 3. 0 169 15, 400, 000 3. 4 42 19, 200 3. 7 16. 2 518 4. 0 8 4. 4 2. 9 undetectable IU/m. L

Adefovir Resistance Not Observed With Lamivudine Combination Therapy Incidence of Resistance (%) Adefovir monotherapy (Study 438: naive patients) 60 Adefovir + lamivudine (Studies 435 and 460 i: lamivudine resistance*; Study 435: pre- and post-OLT; Study 460 i: HIV/HBV) 40 30 20 19 11 0 0 0 Year 1 3 0 0 Year 2 Year 3 0 Year 4 Year 5 *2 patients enrolled in Study 435 initially received combination therapy with adefovir + lamivudine and subsequently selected adefovir resistance mutation N 236 T. However, they had switched to adefovir monotherapy at time when adefovir resistance mutation was detected. Lee YS, et al. Hepatology. 2006; 43: 1385 -1391. Lampertico P, et al. AASLD 2006. Abstract LB 5. Schiff E, et al. Liver Transpl. 2007; 13: 349 -360. Hepsera [package insert].

Management of HBV • Check response at 12 and 24 weeks • If no response switch • When virologic breakthrough occurs – “Switch to” another drug – “Add on” another drug – “Switch to” and “add on” another drug • Choice of second drug generally dictated by lack of cross-resistance

Combination therapy • Sequential monotherapy with nucleos(t)ide analogues has led to HBV resistance • Resistance has been low with combination therapy • Peg IFN and LAM showed more HBV DNA suppression while on therapy, but lost after end of therapy, no increased HBe. Ag serconversion • ADV and LAM/FTC less resistance but no increase in efficacy Lampertico Gastro 2007; Yim HJ, et al. Hepatology. 2006: 43: S 173 -181; Shaw T, et al. AASLD 2007. Abstract 986; Schildgen O, et al. N Engl J Med. 2006; 354: 1807 -1812; Reijnders JG, AASLD 2007. Abstract 951; Colonno R, et al. Hepatology. 2006; 44: 1656 -1665.