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

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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

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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information could become out of date quickly.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
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Hepatitis B Virus DiseaseEpidemiology

• 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

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Hepatitis B Virus DiseaseEpidemiology (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

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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

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HBV Disease Clinical Manifestations

• Acute hepatitis B
• May be asymptomatic
• Symptoms may include RUQ abdominal pain, nausea,
  vomiting, fever, arthralgias, jaundice

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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

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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

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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

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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)

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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 gt age 40, Asian female gtage
  50, sub-Saharan African male gtage 20

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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

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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

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HBV Disease Preventing Disease

• Vaccinate all HIV-infected patients without
  evidence of prior immunity
• Vaccine efficacy higher at CD4 count gt350
  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

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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 gt350
  cells/µL
• HAV-susceptible HIV-infected patients should
  receive HAV vaccine
• Check HAV IgG 1 month after vaccination if
  negative, revaccinate when CD4 gt200 cells/µL
• All HBV patients should avoid alcohol consumption

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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

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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

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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
  gt2,000 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

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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

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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

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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

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HBV Disease Monitoring

• Monitoring treatment response
• HBV DNA every 12 weeks
• Complete virologic response undetectable HBV DNA
  at 24-48 weeks
• Nonresponse lt1 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

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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

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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)

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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

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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

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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

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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 gt10 times
  upper limit of normal
• Jaundice is associated with severe morbidity and
  mortality discontinue offending drug(s)

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HBV Disease Treatment Failure

• Treatment failure on nucleos(t)ide analogues lt1
  log10 copies/mL decrease in HBV DNA at 12 weeks
  in adherent patient, or increase in HBV DNA gt1
  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

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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

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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

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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 lt2
  log10 copies/mL decrease in HBV DNA should be
  switched to more potent regimen (eg, tenofovir
  emtricitabine or entecavir) because of risk of
  resistance

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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

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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

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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

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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

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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

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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

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Websites to Access the Guidelines

• http//www.aidsetc.org
• http//aidsinfo.nih.gov

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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

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