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

2. 2 May 2015www.aidsetc.org These slides were developed using recommendations published in July 2013. The intended audience is clinicians involved in the care of patients with HIV. Certain sections have been updated to reflect changes in the published guidelines. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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 Coordinating Resource Center http://www.aidsetc.org About This Presentation

3. 3 May 2015www.aidsetc.org  Epidemiology  Clinical Manifestations  Diagnosis  Preventing Exposure  Preventing Disease  Treatment  Monitoring  Preventing Recurrence  Considerations in Pregnancy Hepatitis B Virus

4. 4 May 2015www.aidsetc.org  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 HBV Disease: Epidemiology

5. 5 May 2015www.aidsetc.org  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 HBV Disease: Epidemiology (2)

6. 6 May 2015www.aidsetc.org  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 HBV Disease: Epidemiology (3)

7. 7 May 2015www.aidsetc.org  Acute hepatitis B:  May be asymptomatic  Symptoms may include RUQ abdominal pain, nausea, vomiting, fever, arthralgias, jaundice HBV Disease: Clinical Manifestations

8. 8 May 2015www.aidsetc.org  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 HBV Disease: Clinical Manifestations (2)

9. 9 May 2015www.aidsetc.org  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 HBV Disease: Diagnosis

10. 10 May 2015www.aidsetc.org  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 HBV Disease: Diagnosis (2)

11. 11 May 2015www.aidsetc.org  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]) HBV Disease: Diagnosis (3)

12. 12 May 2015www.aidsetc.org  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 HBV Disease: Diagnosis (4)

13. 13 May 2015www.aidsetc.org  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 HBV Disease: Diagnosis (5)

14. 14 May 2015www.aidsetc.org  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 HBV Disease: Preventing Exposure

15. 15 May 2015www.aidsetc.org  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 HBV Disease: Preventing Disease

16. 16 May 2015www.aidsetc.org  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 HBV Disease: Preventing Disease (2)

17. 17 May 2015www.aidsetc.org  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 HBV Disease: Preventing Disease (3)

18. 18 May 2015www.aidsetc.org  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 HBV Disease: Preventing Disease (4)

19. 19 May 2015www.aidsetc.org  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 HBV Disease: Treatment

20. 20 May 2015www.aidsetc.org  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 HBV Disease: Treatment (2)

21. 21 May 2015www.aidsetc.org  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 HBV Disease: Treatment (3)

22. 22 May 2015www.aidsetc.org  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 HBV Disease: Treatment (4)

23. 23 May 2015www.aidsetc.org  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 HBV Disease: Treatment (5)

24. 24 May 2015www.aidsetc.org  ART strongly recommended for all with HIV/HBV coinfection, regardless of ART  ART that includes agents with activity against both viruses is recommended HBV Disease: Starting ART

25. 25 May 2015www.aidsetc.org  Monitoring treatment response:  HBV DNA every 12 weeks  Complete virologic response: undetectable HBV DNA at 24-48 weeks  Nonresponse: <1 log10 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 HBV Disease: Monitoring

26. 26 May 2015www.aidsetc.org  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 HBV Disease: Adverse Events

27. 27 May 2015www.aidsetc.org  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) HBV Disease: Adverse Events (2)

28. 28 May 2015www.aidsetc.org  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 HBV Disease: Adverse Events (3)

29. 29 May 2015www.aidsetc.org  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 HBV Disease: IRIS

30. 30 May 2015www.aidsetc.org  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 HBV Disease: IRIS (2)

31. 31 May 2015www.aidsetc.org  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) HBV Disease: IRIS (3)

32. 32 May 2015www.aidsetc.org  Treatment failure on nucleos(t)ide analogues: 1 log10 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 HBV Disease: Treatment Failure

33. 33 May 2015www.aidsetc.org  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 HBV Disease: Treatment Failure (2)

34. 34 May 2015www.aidsetc.org  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 HBV Disease: Treatment Failure (3)

35. 35 May 2015www.aidsetc.org  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 HBV Disease: Treatment Failure (4)

36. 36 May 2015www.aidsetc.org  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 HBV Disease: Treatment Failure (5)

37. 37 May 2015www.aidsetc.org  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 HBV Disease: Preventing Recurrence

38. 38 May 2015www.aidsetc.org  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 HBV Disease: Considerations in Pregnancy

39. 39 May 2015www.aidsetc.org  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 HBV Disease: Considerations in Pregnancy (2)

40. 40 May 2015www.aidsetc.org  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 HBV Disease: Considerations in Pregnancy (3)

41. 41 May 2015www.aidsetc.org  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 HBV Disease: Considerations in Pregnancy (4)

42. 42 May 2015www.aidsetc.org  http://www.aidsetc.org  http://aidsinfo.nih.gov Websites to Access the Guidelines

43. 43 May 2015www.aidsetc.org  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