Transcript Hepatitis B Virus Disease

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
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become out of date quickly.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 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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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
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HBV Disease: Epidemiology (3)
 Incubation period
 Exposure to onset of jaundice: 90 days (range 60150 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 > age 40, Asian
female >age 50, sub-Saharan African male
>age 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 >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)
 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
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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-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: <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,
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 >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 interferonalfa:
 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
 See the AETC NRC website for the most
current version of this presentation:
http://www.aidsetc.org
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