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Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents Hepatitis B Virus Disease Slide Set.

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  1. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and AdolescentsHepatitis 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. About This Presentation These slides were developed using recommendations published in May 2013. 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 Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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 6/05 www.aidsetc.org

  3. 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 6/05 www.aidsetc.org

  4. 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 6/05 www.aidsetc.org

  5. 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 6/05 www.aidsetc.org

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

  7. HBV Disease: Clinical 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 6/05 www.aidsetc.org

  8. 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 6/05 www.aidsetc.org

  9. HBV Disease: Diagnosis (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 Some recommend that patients with isolated anti-HBc be tested for HBV DNA: if positive, treat as chronically infected, if negative, consider susceptible to HBV and vaccinate accordingly 6/05 www.aidsetc.org

  10. HBV Disease: Diagnosis(3) Additional evaluation To assess severity and progression of disease, check ALT, AST, albumin, bilirubin, PT, and CBC at diagnosis and at least 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]) 6/05 www.aidsetc.org

  11. 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 6/05 www.aidsetc.org

  12. HBV Disease: Diagnosis(5) Additional evaluation Liver biopsy: Valuable for characterizing activity and severity of liver disease, may help to monitor disease progression, guide treatment, exclude other diseases 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 to evaluate fibrosis not yet validated in HIV/HBV coinfection 6/05 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 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 www.aidsetc.org

  15. HBV Disease: Preventing Disease (2) • Double dose of vaccine (40 mcg) recommended by some experts • In one study, increased response rate in HIV-infected patients with CD4 count >350 cells/µL • 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 www.aidsetc.org

  16. 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 6/05 www.aidsetc.org

  17. 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 6/05 www.aidsetc.org

  18. 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 6/05 www.aidsetc.org

  19. 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 www.aidsetc.org

  20. 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 6/05 www.aidsetc.org

  21. 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 6/05 www.aidsetc.org

  22. HBV Disease: Monitoring 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 6/05 www.aidsetc.org

  23. 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 6/05 www.aidsetc.org

  24. 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) 6/05 www.aidsetc.org

  25. 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 6/05 www.aidsetc.org

  26. 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 www.aidsetc.org

  27. 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 www.aidsetc.org

  28. 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 www.aidsetc.org

  29. HBV Disease: Treatment Failure Treatment failure on nucleos(t)ide analogues: <1 log10 copies/mL decrease in HBV DNA at 12 weeks in adherent patient, or increase in HBV DNA >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 6/05 www.aidsetc.org

  30. 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 6/05 www.aidsetc.org

  31. 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 www.aidsetc.org

  32. 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 log10 copies/mL decrease in HBV DNA should be switched to more potent regimen (eg, tenofovir + emtricitabine or entecavir) because of risk of resistance 6/05 www.aidsetc.org

  33. 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 6/05 www.aidsetc.org

  34. 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 6/05 www.aidsetc.org

  35. 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 6/05 www.aidsetc.org

  36. 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 6/05 www.aidsetc.org

  37. 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 6/05 www.aidsetc.org

  38. 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 6/05 www.aidsetc.org

  39. Websites to Access the Guidelines http://www.aidsetc.org http://aidsinfo.nih.gov 6/05 www.aidsetc.org

  40. About This Slide Set • This presentation was prepared by Susa Coffey, MD, for the AETC National Resource Center in July 2013 • See the AETC NRC website for the most current version of this presentation: • http://www.aidsetc.org 6/05 www.aidsetc.org

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