Hepatitis B in HIV Patients Mamta K. Jain, M.D., M.P.H. UT Southwestern Medical Center
Learning Objectives Identify tests to diagnoses HBV active infection, resolved infection, and need for immunization monitor HBV infection during treatment. What are problem(s) with routine HBV vaccinations and methods to overcome it. Identify three different oral agents for HBV treatment and resistance Be able to recognize HBV IRIS and its complications
Geographic Distribution of Chronic HBV Infection HBsAg Prevalence 8% - High 2-7% - Intermediate <2% - Low
Risk Factors for Acute Hepatitis B United States, 1992-1993 Heterosexual* (41%) Injecting Drug Use (15%) Homosexual Activity (9%) Household Contact (2%) Health Care Employment (1%) Unknown (31%) Other (1%) * Includes sexual contact with acute cases, carriers, and multiple partners. Source: CDC Sentinel Counties Study of Viral Hepatitis
Acute vs. Chronic Acute Acquire as adult Clear infection/symptomatic Mode of transmission more likely horizontal 15% will become chronic More likely not to resolve infection if HIV+ Chronic Acquire in childhood Asymptomatic; unable to clear infection Mode of transmission more likely vertical
Worldwide Chronic HBV Epidemiology 350 million persons chronically infected 9th leading cause of death United States 847, 000 persons living with chronic hepatitis B 14,000 deaths per year attributable to hepatitis B 2 out 3 people with hepatitis B unaware about HBV 70% of HBV is in foreign-born with prevalence in foreign-born being 3-5% Other high risk populations: MSM, IDU, household contacts of HBV infected Hoofnagle N Engl J Med. 1990 Abara Ann Intern Med 2017
HBV Diagnosis? Select the test which indicates HBV infection? A. HB core Ag (HBcAg) B. HB Surface Ag (HBsAg) C. HB Surface Ab (anti-hbs) D. HB core Ab (anti-hbc)
HBV Diagnosis? Select the test which indicates HBV infection? A. HB core Ag (HBcAg) B. HB Surface Ag (HBsAg) C. HB Surface Ab (anti-hbs) D. HB core Ab (anti-hbc)
HBV Diagnosis Select the test which indicates exposure to HBV? A. HB core Ag (HBcAg) B. HB Surface Ag (HBsAg) C. HB Surface Ab (anti-hbs) D. HB core Ab (anti-hbc)
HBV Diagnosis Select the test which indicates exposure to HBV? A. HB core Ag (HBcAg) B. HB Surface Ag (HBsAg) C. HB Surface Ab (anti-hbs) D. HB core Ab (anti-hbc)
HBV Diagnosis Select the test which indicates immunity to HBV? A. HB core Ag (HBcAg) B. HB Surface Ag (HBsAg) C. HB Surface Ab (anti-hbs) D. HB core Ab (anti-hbc)
HBV Diagnosis Select the test which indicates immunity to HBV? A. HB core Ag (HBcAg) B. HB Surface Ag (HBsAg) C. HB Surface Ab (anti-hbs) D. HB core Ab (anti-hbc)
AASLD Guidelines: Interpreting HBV Serology HBsAg Anti-HBs Total Anti-HBc IgM Anti-HBc Indicates that the person is infected Indicates recovery and immunity from HBV infection Develops in a person who has been successfully vaccinated against hepatitis B Indicates previous or ongoing infection with HBV in an undefined time frame Appears at the onset of symptoms in acute hepatitis B and persists for life Indicates recent infection with HBV ( 6 mos) This test is used to distinguish acute from chronic HBV infection CDC. Hepatitis B information for health professionals: FAQs. January 2012.
CDC. Hepatitis B information for health professionals: FAQs. January 2012. Interpreting HBV Serologies
4 Phases of Chronic HBV ALT activity Infection Current Understanding of HBV Infection HBeAg Anti-HBe HBV DNA Phase Immune Tolerant Immune Clearance Inactive Carrier State Reactivation Liver Minimal inflammation and fibrosis Chronic active inflammation Mild hepatitis and minimal fibrosis Active inflammation Yim HJ, et al. Hepatology. 2006;43:S173-S181. Copyright 1999-2012 John Wiley & Sons, Inc. All Rights Reserved. Optimal treatment times
Chronic Hepatitis B Disease States HBeAg positive Also known as wild type Negative for antibody to HBeAg (anti-hbe) HBV DNA generally > 20,000 IU/mL (> 10 5 copies/ml) HBeAg negative Also known as precore mutant Positive for antibody to HBeAg (anti-hbe) HBV DNA generally > 2000 IU/mL (> 10 4 copies/ml) Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Chu CJ, et al. Gastroenterology. 2003;125:444-451. Lok AS, et al. Hepatology. 2001;34;1225-1241.
What Is an Elevated ALT Level? Increased levels of the ALT enzyme can indicate liver damage Reference ranges for normal ALT vary between 2 most widely used commercial laboratories Men: 4-60 IU/L; women: 6-40 IU/L Men: 0-55 IU/L; women: 0-40 IU/L Most HBV treatment algorithms recommend lower ULN levels for ALT when making treatment-initiation decisions 30 IU/L for men 19 IU/L for women Prati D, et al. Ann Intern Med. 2002;137:1-10. Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. AASLD practice guidelines: chronic hepatitis B. September 2009.
HBV DNA Testing Indicates chronic hepatitis B when HBV DNA is still positive 6 months after acute HBV infection Can differentiate among different states of infection Change in HBV DNA level used to monitor response to therapy Increasing HBV DNA level during antiviral therapy indicates emergence of drug resistance Adapted from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.
HBV Genotype HBV Classified into 7 genotypes A: North America and Western Europe B and C: Asia D: Southern Europe and India E: Africa F: South America G: US, HIV+ H: Central America HBV Geno B associated with less active and slowly progressive disease compared to Geno C. Non-A genotypes with poor response to nucleosides?
Datta, S. Virology Journal. 2008; 5:156 HBV Genotype Distribution
HBV:Natural History Rate of progression to cirrhosis and hepatocellular carcinoma vary State of immune system Age of patient Serologic stage of infection Geographic and genetic factors Prognostic factors for development of cirrhosis HBeAg+, Older age, Elevated ALT levels Lee N Engl J Med 1997 Lok Hepatology 2001
HBV: Natural History 15-40% with chronic HBV will develop cirrhosis, HCC, or liver failure 25% die prematurely due these complications Compensated cirrhosis 5 yr survival: 84% 10 yr survival: 68% Decompensated cirrhosis 5 yr survival: 14% Abara Ann Intern Med 2017
HBV: Natural History Spontaneous seroconversion 5% to 12% per year Case reports of spontaneous seroconversion after initiation of HAART have been reported in HIVinfected patients Perrillo Gastroenterol Clin North Am 1994 Hoofnagle Ann Intern Med 1981 Proia Am J Med 2000 Carr Lancet 1997
HBV/HIV: Clinical Features HBV DNA (viral load) Liver function test Liver histology higher lower less disease
MACS Cohort: HBV Mortality 5293 MSM 326 (6%) HBsAg+ 213 (65%)- HIV+ 4967 HBsAg- 2346 (47%)- HIV+ Thio et al. Lancet 2002 360:1921-26
MACS Cohort: HBV Mortality Liver Related Mortality 1.1/1000 person years HIV/HBsAg+: 14.2/1000 person years HIV+: 1.7/1000 person years (p<0.01) HBsAg+: 0.8/1000 person years (p<0.001) Highest risk of liver-related mortality CD4 nadir Relative risk (95%CI) >250 6.8 (2.0-20.6) 101-250 8.8 (3.3-22.8) <100 11.6 (4.6-28.7) Study Period Before 1996 7.6 (4.0-14.1) 1996-2000 11.4 (3.4-38.0) Thio et al. Lancet 2002 360:1921-26
HIV/HBV Mortality Metaanalysis Nikolopoulos et al. CID 2009 360:1763-71
HBV Negatively Impacts HIV Outcomes in HIV Serconverters 2352 HIV serconverteres 20% had resolved HBV 3% isolated HBcAb 3% chronic HBV Multivariable Analysis for AIDS/death Chronic HBV vs. HBV negative HR 1.8 (95% CI 1.2-2.69) Resolved HBV vs. HBV negative HR 1.17 (95% CI 0.94-146) Isolated HBcAb vs. HBV negative HR 1.14 (95% CI 0.75-1.75) Chun J Infect Dis 2012;205:185-93
HCC Leading cause of death in HIV/HBV Even with suppressed HBV DNA Need to stage liver disease Pt may have cirrhosis or advanced liver disease and you may not know it
Relationship Between HBV DNA and HCC Development REVEAL: long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis and HCC among untreated HBsAg+ individuals in Taiwan Cumulative Incidence of HCC (%) 14 N = 3653 Taiwanese patients 12 Baseline HBV DNA Level, copies/ml 10 1 million 100,000-999,999 8 10,000-99,999 6 300-9999 4 < 300 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Yrs of Follow-up Chen CJ, et al. JAMA. 2006;295:65-73.
Low Adherence to HCC Screening Among HIV Providers Examined 144 HIV/HBV and 225 HBV monoinfected seen minimum 2 times over 2 years 36% of HIV/HBV in HIV practices had HCC screening 81.8% HBV monoinfected obtain HCC screening (p<0.00001) HIV providers less frequently monitored HBV viral loads (p<.0001) HBeAg/HBeAb (p<.00001) HBsAg/anti-HBS (p<.00001) But screened more for Hep A immunity (p=0.028) Self-reported adherence and knowledge scores were the same (19 HIV providers and 16 hepatologist) Hearn Clin Infect Dis 2015;61: 1742-8
Occult HBV Defined HBsAg-negative, anti-hbcore+ HBV DNA detectable with very sensitive assays Prevalence reported <1-15%? Higher prevalence in HIV/HCV co-infected 3030 HIV-infected, 2.5% Clinical significance? No increased risk of transaminitis due to ART Liver histology similar to those without occult HBV Palacios. HIV Clin Trials 2008;337-40
Hepatitis B and HCV Treatment with DAA FDA Black Box Warning Reactivation of hepatitis B seen in patients with HBV/HCV who were treated with DAA. 24 cases with confirmed reactivation of HBV Occurred within 4-8 weeks of starting treatment 3 patients decompensated; 2 died and 1 had liver transplant 12 of 24 cases received HBV treatment 5 were delayed and 1 patient died 4 pts were HBsAg+ undetectable HBV DNA 3 patients HBsAg- and undetectable HBV DNA 10 patients HBsAg status was not known https://www.fda.gov/drugs/drugsafety/ucm522932.htm
https://www.fda.gov/drugs/drugsafety/ucm522932.htm
Prevention of Hepatitis B
Hepatitis B Vaccination Most effective measure to prevent hepatitis B 90% healthy adults are protected with a complete series Immunity lasts > 3 decades Abara Ann Intern Med 2017
Comparison of Standard vs. Double Dose or recombinant HBV vaccine dose Number schedule Anti-Hbs >10mIU/mL 20 μg 94 0,1,6 months 40 μg 98 0, 1, 6 monts 34% 47% P=0.07 *Those with CD4 >350 cells/μl had significantly higher rates of response (64% vs. 39%, p=0.01) **No difference occurred in those with CD4 <350 cells/μl Fonseca Vaccine 2005; 23: 2902-2908
HBV Vaccine Response in HIV patients Intervention CD4 >200 recombinant vaccine A (n=145) recombinant vaccine B (n=148) Dose Schedule route Response at 28 weeks ; Response (95% CI) 20μg 0, 4, 24 weeks 40μg 0, 4, 8, 24 weeks IM 65% (56-72% IM 82% (77-88%)* recombinant vaccine C (n=144) 4μg 0, 4, 8,24 weeks interdermal 77% (69-84%)** * p<.001 ( A vs B) ** p=0.02 (A vs. C) Launay JAMA 2011; 305: 1432-1440
New HBV Vaccination Guidelines All immunosuppressed patients HBV vaccine 40 mcg 3 doses at 0, 1, and 6 months (Recombivax) Or 4 doses of 40 mcg at 0, 1, 2, and 6 months (Engerix-B) Check anti-hbs 1 month after completion of series
Vaccination Against Anti-HBc Ab 54 patients Given 1 dose 20μg of recombinant HBV vaccine Those with anti-hbs <10mIU/ml at 4 weeks received 3 additional double dose (40 μg at 5, 9, 24 weeks) At wk 4, 46% were responders Non-responders at wk 4 who received further vaccination: 89% had anti-hbs 10mIU/mL at 28 weeks Piroth J Infect Dis 2016;213:1735-42
Strategies to Increase HBV Vaccination Response reduction in HIV viral load Increase in CD4 cell count Make sure pts receive 3 or more doses Re-vaccinate those who are initial nonresponders to vaccination series No trials to show that double dose increases response rates in prior nonresponders Whitaker Lancet Infect Dis 2012; 12:966-976 Okulicz Plos One 2014; 9: e105591
Prevention of HBV with ART in MSM Incident Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Men Who Have Sex With Men From Pre-HAART to HAART PeriodsA Cohort StudyA Cohort Study Falade- Nwulia et al. Ann Intern Med. 2015;163(9):673-680.
HBV active ART To Prevent Incident HBV Hazard ratios (HRs) of the different factors influencing hepatitis B virus (HBV) incidence. Shilaih et al. J Infect Dis. 2016;214:599-606
Treatment of HBV
FDA-Approved HBV Therapies Peginterferon alfa-2a Lamivudine Entecavir Tenofovir 1990 1998 2002 2005 2006 2008 Interferon alfa-2b Adefovir Telbivudine
Goals of Treatment HBV DNA suppression Decreased risk of HCC Decreased progression to ESLD HBeAg+: HBeAg seroconversion HBeAg-: HBsAg loss HBsAg loss (ultimate goal)
HBV Treatment: Interferon Long term follow up limited Delayed clearance of HBsAg: 12-65% within 5 yrs Lower incidence of HCC and higher survival rate HBeAg-: 20% cleared HBsAg in 5 yr f/u Reduced risk HCC and liver deaths Lok Hepatology 2001
HBV/HIV: YMDD Resistance Author, yr Resistance Time Interval Comments Pillay, 2000 14% Est. 1 yr CAESAR subanalysis Benhamou, 1999 50%; Annual incidence of 20% After 2 years Resistance only in HBeAg carriers
Treatment of HBV in HIV- Infected Treatment Log Reduction HBeAg Seronversion Resistance (YMDD) Lamivudine 2.7 log 22-29% Tenofovir 3-5 log 25% 14-38% at 1 yr 50% at 2 yr Active against YMDD; 1 reported case Emtricitabine 2.92 log* 33%* Combination pills: Combivir (lamivudine and zidovudine) Trizivir (lamivudine, abacavir, and zidovudine) Truvada (tenofovir and emtricitabine) Atripla (efavirenz, tenofovir, and emtricitabine) Dore. J Infect Dis 1999; 180:607-13 Hoff. Clin Infect Dis 2001; 32:963-9 Pillay. AIDS 2000;14:1111-6 9% at 48 weeks* 18% at 96 weeks* * Data not available in HIV/HBV Benhamou. N Engl J Med 2003;348:177-8 Sheldon. Antivr Ther 2005;10:727-34 Gish. Arch Int Med 2006;166:49-56
Complications During Therapy
Acute Flares in Chronic HBV Spontaneous reactivation of chronic HBV Reactivated hepatitis due to immunosuppressive medications Cancer chemotherapy Antirejection drugs Corticosteroids Resulting from antiviral therapy Interferon Nucleoside analogues Corticosteroid withdrawal Induced by HBV genotypic variation Precore mutant Core promoter mutant HBV DNA polymerase mutant Due to superimposed infection with other hepatotropic viruses Hepatitis A,C,delta viruses Caused by interaction with HIV infection Reactivated hepatitis Effect of immune reconstitution therapy Perrillo Gastroenterology 2001
Acute Flare Withdrawal of HBV treatment Never stop lamivudine/emtricitabine/tenofovir in pt with HBV if you are changing HIV regimen due to HIV resistance.
Hepatitis B IRIS 1800 800 1600 700 ALT (I/U) 1400 1200 1000 800 600 600 500 400 300 CD4 Count 400 200 200 100 0 baseline 1mo 2mo 3mo 5mo 0 Jain et al., AIDS Patient Care & STDs, 2006
Elevation of Transaminases Drug-Induced Hepatotoxicity ALT increase 3-12 weeks after initiation of meds High likelihood for hepatotoxicity i.e. Nevarapine Hep B core IgM negative HBe Ag serconversion not seen Rash and fever may be seen Immune Reconstitution/HBV flare Increase in CD4 Decrease in HIV VL ALT increase 6-12 weeks after initiation of meds Hep B core IgM often positive HBeAg seroconversion may be seen during or following flare
Mutations HBeAg-negative variants occur naturally (HBV DNA +) Precore stop codon G1896A Basal core promoter A1762T/G1764A Mutations abolish or decrease HBeAg production
Entecavir Activity Against HIV 5 4.5 On entecavir // 4 Wild type HIV M184V HIV 3.5 log HIV viral load 3 2.5 2 Oct- 04 Dec- 04 Feb- 05 Apr- 05 Jun- 05 Aug- 05 Oct- 05 Dec- 05 Feb- 06 Apr- 06 Jun- 06 Aug- 06 Oct- 06 Dec- 06 Feb- 07 Jain and Zoellner AIDS, 2007
Resistance Nucleos(t)ide therapy and potential mutations in RT polymerase gene Drug RT Polymerase mutation lamivudine, telbivudine, emtricitabine rtm204v/i+rtl180m; rtv173l adefovir entecavir rta181v; rtn236t rtm204v+rt180m plus rt184a/c/f/g/i/l/m/s or rts202c/g/i or rtm250v/l rtm204i plus rt184i/s or rtm250i/l
Monitoring During HBV Treatment
Evaluation of HBV We asked how well do HIV providers evaluate and monitor HBV in HIV/HBV patients? To evaluate response to HBV therapy, measurement of HBV DNA is need at baseline and then during therapy.
HIV/HBV Patients Initiating HAART 1999-2003 Baseline Characteristics (n=155) N (%) CD4 (cells/μl), median [range] 137 [1-1089] CD4<200 cells/μl 90 (58) Log HIV viral load (copies/ml), median [range] 4.81 [1.69-6.11] ALT (IU/L), median [range] 34 [6-481] AST (IU/L), median [range] 37 [13-389] Jain. Clin Infect Dis 2007
Active HBV Therapy HBV Therapy N (%) Any active HBV therapy 142 (92) Lamivudine 137 (88) Tenofovir 18 (12) Emtricitabine 2 (1) Adefovir 1 (<1) Jain. Clin Infect Dis 2007
Monitoring of HBV in HIV/HBV Patients Testing for HBV or HIV prior to starting HAART HIV RNA prior to HAART 99% HBV DNA prior to HAART 16% Monitoring of HIV and HBV during the first year of HAART HIV RNA 1 st year of Rx 497 (median 3/pt) HBV DNA 1 st year of Rx 85 (median <1/pt) Jain. Clin Infect Dis 2007
HBV Tests vs. HIV Tests HBV testing HIV viral load testing 100 80 60 40 20 0 1999 2000 2001 2002 2003 HBV Tests: HBV DNA or HBeAg/anti-HBe HIV Tests: HIV RNA Jain. Clin Infect Dis 2007
HIV vs. HBV Kinetics HIV viral load becomes undetectable in 2-8 weeks HBV viral load may take >6 months Much higher baseline HBV DNA level
Management of Hepatitis B HIV/HBSAg+ to begin ART: Hepatitis B DNA quantify HBV viral load prior to initiation of ART Hepatitis B e Antigen indicates ongoing viral replication and can be used as a marker of active disease Hepatitis B e Antibody will become positive when patient has seroconverted Ultrasound of liver Cirrhosis and HCC Consider Liver biopsy to stage disease
Management of HBV Confirm HBV viremia Start HAART Truvada should be used as back-bone If tenofovir can not be used then entecavir should be added to ART regimen Stage Liver Disease US Fibroscan Liver biposy Fibrasure/APRI/FIB-4
Management of HBV Monitor HBV DNA Every 3-4 months Once HBV DNA suppressed Check HBeAg to determine if seroconversion has occurred Monitor for HCC Ultrasound and AFP yearly If cirrhotic then every 6 months