Download Hepatitis B

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 Coordinating Resource Center based on
recommendations from the CDC, National Institutes of Health, and HIV
Medicine Association/Infectious Diseases Society of America
About This Presentation
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field of HIV care, this information could become out of date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
www.aidsetc.org
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Hepatitis B Virus
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Epidemiology
Clinical Manifestations
Diagnosis
Preventing Exposure
Preventing Disease
Treatment
Monitoring
Preventing Recurrence
Considerations in Pregnancy
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HBV 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
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HBV 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
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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
 Test 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 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 > age 40, Asian female >age 50, sub-Saharan African
male >age 20
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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
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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 >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
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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
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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
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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
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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 >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
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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-alfabased 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: <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
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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, hypoor 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
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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 >10 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: <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
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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 <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
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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
and updated in May 2015.
 See the AETC NRC website for the most current
version of this presentation:
http://www.aidsetc.org
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