1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Hepatitis B Virus Disease Slide Set Prepared by the AETC National Resource Center based on recommendations from the CDC, National Institutes of Health, and HIV Medicine Association/Infectious Diseases Society of America

2. May 2015 www.aidsetc.org 26/05 About This Presentation These slides were developed using recommendations published in April 2015. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. – AETC National Resource Center http://www.aidsetc.org

3. May 2015 www.aidsetc.org 36/05 Hepatitis B Virus Disease: Epidemiology  HBV is leading cause of chronic liver disease worldwide  Approximately 10% of HIV-infected patients had chronic HBV infection (globally and in North America)  In low-prevalence countries, transmitted primarily through sexual contact and injection drug use  More efficient transmission than HIV-1  In higher-prevalence countries, perinatal transmission is most common

4. May 2015 www.aidsetc.org 46/05 Hepatitis B Virus Disease: Epidemiology (2)  HIV infection increases risk of chronic hepatitis B after HBV exposure  HIV/HBV-coinfected patients have higher HBV DNA levels, greater likelihood of HBe antigenemia, and increased risk of liver-related morbidity and mortality

5. May 2015 www.aidsetc.org 56/05 HBV Disease: Epidemiology (3)  Incubation period  Exposure to onset of jaundice: 90 days (range 60- 150 days)  Exposure to onset of abnormal liver enzymes: 60 days (range 40-90 days)  Genotypes A-H; GT A is most common in North America and Western Europe

6. May 2015 www.aidsetc.org 66/05 HBV Disease: Clinical Manifestations  Acute hepatitis B:  May be asymptomatic  Symptoms may include RUQ abdominal pain, nausea, vomiting, fever, arthralgias, jaundice

7. May 2015 www.aidsetc.org 76/05 HBV Disease: C linical Manifestations (2)  Chronic hepatitis B:  Most have no symptoms or nonspecific symptoms (eg, fatigue) until development of cirrhosis and signs of portal hypertension (eg, ascites, variceal bleeding, coagulopathy, jaundice, hepatic encephalopathy)  Hepatocellular carcinoma (HCC) is asymptomatic in early stages  Other manifestations: polyarteritis nodosa, glomerulonephritis, vasculitis

8. May 2015 www.aidsetc.org 86/05 HBV Disease: Diagnosis  All HIV-infected persons should be tested for HBV  Test for HBsAg, HBcAb, and HBsAb  HBsAb can be detected 4 weeks (range 1-9 weeks) after exposure anti-HBc IgM usually detectable at onset of symptoms  Chronic hepatitis B: HBsAg detected on 2 occasions ≥6 months apart  Test for HBeAg, anti-HBe, HBV DNA  HBV DNA and ALT elevation distinguish active from inactive HBV

9. May 2015 www.aidsetc.org 96/05 HBV Disease: D iagnosis (2)  Isolated positive anti-HBc:  May reflect a false-positive result, distant exposure with loss of anti-HBs, or “occult” chronic HBV infection  More common in HIV-infected patients, especially if underlying HCV infection  Test for HBV DNA: if positive, treat as chronically infected, if negative, consider susceptible to HBV and vaccinate accordingly

10. May 2015 www.aidsetc.org 106/05 HBV Disease: Diagnosis (3) Additional evaluation  To assess severity and progression of disease, check ALT, AST, albumin, bilirubin, PT, and CBC at diagnosis and every 6 months thereafter  Transient or persistent elevated ALT levels caused by many factors, including:  Discontinuation of HBV therapy, resistance to HBV therapy, before loss of HBeAg, hepatotoxicity from HIV or other medications, immune reconstitution, infection with a new hepatitis virus (HAV, HCV, delta virus [HDV])

11. May 2015 www.aidsetc.org 116/05 HBV Disease: Diagnosis (4) Additional evaluation  Screening for HCC:  Chronic HBV increases risk of HCC  Risk and natural history of HBV-related HCC in HIV-coinfected patents has not been determined  Liver imaging recommended every 6 months if cirrhotic, Asian male > age 40, Asian female >age 50, sub-Saharan African male >age 20

12. May 2015 www.aidsetc.org 126/05 HBV Disease: Diagnosis (5) Additional evaluation  Assessment of liver fibrosis:  Important for guiding when to start screening for esophageal varices and HCC in cirrhotic patients  Liver biopsy or noninvasive methods  Individualize decisions to perform biopsy, especially as treatment of both HIV and HBV is recommended for all coinfected patients, using anti-HBV ARVs in the ART regimen  Noninvasive methods (eg, transient elastography, serum biochemical indices): increasing evidence and experience in HBV

13. May 2015 www.aidsetc.org 13 HBV Disease: Preventing Exposure  Counsel all HIV-infected patients about reducing risk of exposure to HBV  Emphasize transmission risks of sharing needles and syringes, tattooing, body piercing, unprotected sex 6/05

14. May 2015 www.aidsetc.org 14 HBV Disease: Preventing Disease  Vaccinate all HIV-infected patients without evidence of prior immunity  Vaccine efficacy higher at CD4 count >350 cells/μL, but do not defer for lower counts  Decreased response to vaccination in coinfected patients: check anti-HBs titers 1 month after 3- shot series  If no response, consider revaccination  Some experts might wait to revaccinate until sustained CD4 increase with effective ART 6/05

15. May 2015 www.aidsetc.org 15 HBV Disease: Preventing Disease (2)  Optimum vaccination strategy not entirely clear, especially for patients with advanced immunosuppression  Schedule of 4 double-dose vaccines yielded higher anti-HBs titers in 2 studies, and higher overall response rate in 1  In 1 study, increased response rate in patients with CD4 count >350 cells/µL 6/05

16. May 2015 www.aidsetc.org 16 HBV Disease: Preventing Disease (3)  Vaccination Schedule  HBV vaccine IM (Engerix-B 20 mcg/mL or Recombivax HB 20 mcg/mL) at 0,1, and 6 months, or  HBV vaccine IM (Engerix-B 40 mcg/mL or Recombivax HB 20 mcg/mL) at 0, 1, 2, and 6 months, or  Combined HAV and HBV vaccine (Twinrix) 1 mL as 3- dose series at 0,1, and 6 months or as 4-dose series at days 0, 7, and 21, and at 12 months  Vaccine non-responders  Revaccinate with 2nd vaccine series  If low CD4 count at time of first series, consider revaccination until sustained increase in CD4 with ART 6/05

17. May 2015 www.aidsetc.org 17 HBV Disease: Preventing Disease (4)  HAV-susceptible HIV-infected patients should receive HAV vaccine  Check HAV IgG 1 month after vaccination; if negative, revaccinate when CD4 >200 cells/µL  All HBV patients should avoid alcohol consumption 6/05

18. May 2015 www.aidsetc.org 186/05 HBV Disease: Treatment  Goals of anti-HBV therapy: reduce morbidity and mortality  Treatment indicated for all with HIV/HBV coinfection, regardless of CD4 count or HBV treatment status  Treat with ART that includes 2 drugs active against both HIV and HBV (ie, tenofovir plus emtricitabine or lamivudine)  Regimen should fully suppress both HIV and HBV

19. May 2015 www.aidsetc.org 196/05 HBV Disease: Treatment (2)  Most drugs active against HBV are also active against HIV: lamivudine, emtricitabine, tenofovir, entecavir, probably telbivudine, adefovir (at full dose)  HIV may develop resistance to these agents if they are not coadministered in fully suppressive ART regimens  Avoid HBV monotherapy with emtricitabine or lamivudine – high rates of HBV resistance

20. May 2015 www.aidsetc.org 206/05 HBV Disease: Treatment (3)  Preferred  ART regimen should include tenofovir 300 mg PO QD + [emtricitabine 200 mg PO QD or lamivudine 300 mg PO QD] or 2 other drugs active against HBV (+ additional therapy active against HIV)  Continue treatment indefinitely  Alternative  If patients do not want ART or are unable to take it:  Treatment indicated when presence of active liver disease, elevated transaminases, and HBV DNA >2,000 IU/mL, or significant fibrosis  Peginterferon-alfa 2a or 2b for 48 weeks  If tenofovir cannot be used:  Fully suppressive ART regimen (without tenofovir), plus entecavir

21. May 2015 www.aidsetc.org 21 HBV Disease: Treatment (4)  When changing ART, continue agents active against HBV to avoid HBV flare, IRIS  If anti-HBV therapy is discontinued and disease flares, reintroducing anti-HBV therapy can be life-saving

22. May 2015 www.aidsetc.org 226/05 HBV Disease: Treatment (5)  HBV/HCV/HIV triple infection:  Faster progression of liver fibrosis, higher risk of HCC, increased mortality  Try to treat both hepatitis viruses, if feasible  Include anti-HBV therapy with ART; introduce HCV therapy as needed  If ART is not desired, consider treatment with interferon-alfa-based therapy for both HBV and HCV

23. May 2015 www.aidsetc.org 236/05 HBV Disease: Starting ART  ART strongly recommended for all with HIV/HBV coinfection, regardless of ART  ART that includes agents with activity against both viruses is recommended

24. May 2015 www.aidsetc.org 246/05 HBV Disease: Monitoring Monitoring treatment response:  HBV DNA every 12 weeks  Complete virologic response: undetectable HBV DNA at 24-48 weeks  Nonresponse: <1 log 10 copies/mL decrease in HBV DNA at 12 weeks  Sustained virologic response: undetectable HBV DNA 6 months after stopping therapy  HBeAg every 6 months (if HBeAg positive)  HBeAg loss, development of HBeAb (uncommon)  Liver histology, transaminases

25. May 2015 www.aidsetc.org 256/05 HBV Disease: Adverse Events  Tenofovir  Renal toxicity; more frequent if underlying renal disease or prolonged treatment  Check electrolytes and serum creatinine at baseline and every 3-6 months; urinalysis every 6 months  Change to alternative therapy if renal toxicity occurs  Dosage adjustment required if used in patients with baseline renal insufficiency  Entecavir  Lactic acidosis reported in patients with cirrhosis

26. May 2015 www.aidsetc.org 266/05 HBV Disease: Adverse Events (2)  Telbivudine  CPK elevations and myopathy reported; check CPK at baseline and every 3-6 months, and if symptoms occur  Discontinue if CPK elevation  Adefovir  Renal tubular disease at higher dosages; uncommon at HBV treatment dosage  Interferon-alfa  “Flulike” symptoms (fever, myalgia, headache, fatigue), depression (may be severe), cognitive dysfunction, cytopenias including CD4 decrease, retinopathy, neuropathy, autoimmune disorders, hypo- or hyperthyroidism (monitor TSH)

27. May 2015 www.aidsetc.org 276/05 HBV Disease: Adverse Events (3) Discontinuation flares  Discontinuation of nucleos(t)ide analogues active against HBV (eg, lamivudine, adefovir, tenofovir, or emtricitabine) associated with HBV flare in ~30% of cases; may cause decompensation  If anti-HBV therapy is discontinued, monitor transaminases every 6 weeks for 3 months, then every 3 months  In case of flare, reinstitute HBV treatment

28. May 2015 www.aidsetc.org 28 HBV Disease: IRIS  Immune reconstitution in HIV/HBV-coinfected patients can cause rise in transaminases and symptoms of acute hepatitis flare, usually in first 6-12 weeks after starting ART  Monitor transaminases monthly for first 3-6 months, then every 3 months  Flares can be deadly; treat HBV when treating HIV  Continue anti-HBV drugs to prevent flares when switching to ART regimens not containing lamivudine, emtricitabine, or tenofovir 6/05

29. May 2015 www.aidsetc.org 29 HBV Disease: IRIS (2)  If severe flare or suspected HBV drug resistance, consult with hepatologist  Distinguishing IRIS and other causes of transaminase elevation (eg, hepatotoxicity, acute HCV or HAV, HBV drug resistance, HBeAg seroconversion) is difficult  Test HBV DNA, HBeAg, HIV RNA, CD4  Consider liver histology  Test for other viral hepatitis as appropriate (hepatitis A, C, D, E)  Review medication list  Review drug and alcohol use 6/05

30. May 2015 www.aidsetc.org 30 HBV Disease: IRIS (3)  Hepatotoxicity is associated with all classes of ARVs, but is uncommon  Discontinuation of ART usually not necessary unless symptoms of hypersensitivity are present (fever, lymphadenopathy, rash), symptomatic hepatitis, or transaminase elevations >10 times upper limit of normal  Jaundice is associated with severe morbidity and mortality: discontinue offending drug(s) 6/05

31. May 2015 www.aidsetc.org 316/05 HBV Disease: Treatment Failure  Treatment failure on nucleos(t)ide analogues: 1 log 10 above nadir  Usually attributable to drug resistant HBV; change in treatment is needed  Many experts suggest HBV resistance testing  May help distinguish noncompliance and resistance, evaluate patients with unclear treatment history, assess different adefovir resistance pathways, and predict level of resistance to entecavir

32. May 2015 www.aidsetc.org 326/05 HBV Disease: Treatment Failure (2)  HBV monotherapy should not be used: risk of resistance mutations to both HBV and HIV  Lamivudine resistance:  ~20% per year in HIV/HBV patients treated with lamivudine alone  Cross-resistance to emtricitabine, telbivudine, perhaps entecavir  If lamivudine-resistant HBV is suspected or documented, add tenofovir to lamivudine

33. May 2015 www.aidsetc.org 33 HBV Disease: Treatment Failure (3)  Treatment failure with tenofovir:  Consider entecavir (especially if experienced with lamivudine or emtricitabine)  In vivo resistance to tenofovir not yet reported  Treatment failure with entecavir:  Cross-resistance with lamivudine, emtricitabine, telbivudine  Replace entecavir with tenofovir (+/– emtricitabine)  Failure of response to pegylated interferon- alfa:  Nucleos(t)ide analogues

34. May 2015 www.aidsetc.org 346/05 HBV Disease: Treatment Failure (4)  HBV DNA may decline slowly over months/years (especially when high before treatment)  Patients on adefovir or L-nucleosides with <2 log 10 copies/mL decrease in HBV DNA should be switched to more potent regimen (eg, tenofovir + emtricitabine or entecavir) because of risk of resistance

35. May 2015 www.aidsetc.org 356/05 HBV Disease: Treatment Failure (5)  ESLD management as in HIV-uninfected patients  Refer to hepatologist  IFN contraindicated  Nucleos(t)ide analogues safe and effective  HCC screening:  Imaging every 6-12 months if cirrhosis (ultrasound, CT, MRI, depending on expertise of the imaging center and whether patient has cirrhosis)  Liver transplantation  Not contraindicated in HIV infection, if on effective ART  HBV treatment is needed after transplant

36. May 2015 www.aidsetc.org 366/05 HBV Disease: Preventing Recurrence  Most patients should continue HBV therapy (except interferon) indefinitely  Relapses may occur on therapy, particularly if CD4 count is low  Hepatitis flare may occur if treatment is stopped

37. May 2015 www.aidsetc.org 376/05 HBV Disease: Considerations in Pregnancy  All pregnant women should be screened for HBsAg, HBcAb, and HBsAb and vaccinated against HBV if sAg negative and sAb negative  Hepatitis A vaccination can be given  Acute HBV: treatment is supportive (including maintaining normal blood glucose levels and clotting status); higher risk of preterm labor and delivery

38. May 2015 www.aidsetc.org 386/05 HBV Disease: Considerations in Pregnancy (2)  Perinatal HBV transmission (including failure of prophylaxis) correlated with high maternal HBV DNA levels  ART including HBV-active drugs recommended for all coinfected pregnant women  Drugs with anti-HBV activity will lower HBV levels and may decrease risk that HBV immune globulin and vaccine will fail to prevent perinatal HBV transmission  HBV treatment may lower risk of IRIS-related HBV flare on ART  Indefinite treatment is recommended; if ARVs are discontinued postpartum, monitor LFTs frequently

39. May 2015 www.aidsetc.org 396/05 HBV Disease: Considerations in Pregnancy (3)  Tenofovir/emtricitabine or tenofovir/lamivudine is recommended as NRTI backbone for ART in pregnant HIV/HBV-coinfected women  More experience in pregnancy with lamivudine  Entecavir, adefovir, telbivudine: not teratogenic in animals; limited experience in human pregnancy  Consider whether other options are inappropriate; use only with a fully suppressive ARV regimen  Interferon should not be use during pregnancy: antigrowth and antiproliferative effects

40. May 2015 www.aidsetc.org 406/05 HBV Disease: Considerations in Pregnancy (4)  Infants born to HBsAg+ women: hepatitis B immune globulin and hepatitis B vaccine within 12 hours of birth  2nd and 3rd doses of vaccine at 1 and 6 months

41. May 2015 www.aidsetc.org 416/05 Websites to Access the Guidelines  http://www.aidsetc.org  http://aidsinfo.nih.gov

42. May 2015 www.aidsetc.org 426/05  This presentation was prepared by Susa Coffey, MD, for the AETC National Resource Center in July 2013 and updated in May 2015.  See the AETC NRC website for the most current version of this presentation: http://www.aidsetc.org About This Slide Set