Hepatitis B 101Hepatitis B 101v.2009v.2009
Melissa Osborn, MDMelissa Osborn, MDAssistant ProfessorAssistant Professor
Emory University School of MedicineEmory University School of MedicineDivision of Infectious DiseasesDivision of Infectious Diseases
21 May 200921 May 2009
Hepatitis B in 30 minutes or lessHepatitis B in 30 minutes or less
Diagnosing and monitoring HBV in Diagnosing and monitoring HBV in HIVHIV
Selecting patients for treatmentSelecting patients for treatment Treatment optionsTreatment options Development of hepatitis B Development of hepatitis B
resistanceresistance VaccinationVaccination Hepatocellular carcinoma screeningHepatocellular carcinoma screening
IgM anti-HBc
Total anti-HBcHBsAg
Acute(6 months)
HBeAg
Chronic(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52
Weeks after Exposure
Tit
erProgression to Chronic Hepatitis B Virus Infection
Typical Serologic Course
CDC
Hepatitis B Serologic DiagnosisHepatitis B Serologic Diagnosis
HBsAgHBsAg Anti-Anti-HBsHBs
HBeAgHBeAg Anti-Anti-HBeHBe
Anti-Anti-HBcHBc
IgM anti-IgM anti-HBcHBc
HBV HBV DNADNA
ALTALT
Acute Acute hepatitis Bhepatitis B
++ -- ++ -- ++ ++ ++ HighHigh
Immunity Immunity (infection)(infection)
-- ++ -- +/-+/- ++ -- -- NmlNml
Immunity Immunity (vaccination)(vaccination)
-- ++ -- -- -- -- -- NmlNml
Chronic Chronic Hepatitis BHepatitis B
++ -- ++ -- ++ -- +/-+/- HighHigh
Chronic Chronic Infection Infection (Precore (Precore Mutant)Mutant)
++ -- -- ++ ++ -- ++ HighHigh
Chronic Chronic carriercarrier
++ -- -- ++ ++ -- - or - or lowlow
NmlNml
Establishing a BaselineEstablishing a Baseline
HBeAg/anti-HBe statusHBeAg/anti-HBe status HBV DNA level by PCRHBV DNA level by PCR ALT/AST elevationALT/AST elevation Presence of Clinical CirrhosisPresence of Clinical Cirrhosis
• By history/physical and lab workBy history/physical and lab work• Jaundice, ascites, palmar erythema, spider Jaundice, ascites, palmar erythema, spider
angiomasangiomas• Low platelets, prolonged coagulation Low platelets, prolonged coagulation
parameters, low albuminparameters, low albumin• Compensated or decompensatedCompensated or decompensated
?Histology from liver biopsy?Histology from liver biopsy
Monitoring of Chronic Hepatitis BMonitoring of Chronic Hepatitis B
Regardless of whether treatment is initiated, each patient with hepatitis B should have:
Every 3 months:
ALT
AST
Every 6 months:
HBV DNA level
Every 12 months:
HBeAg (if + initially)
Anti-HBe
DNA levels and HBeAg, anti-HBe should also be checked with any flare of transaminases
HBV DNA levels can fluctuateHBV DNA levels can fluctuate
Yim, Hepatology 2005; 43:S173-81
Selecting Candidates for TreatmentSelecting Candidates for Treatment
AASLD Hepatitis B Treatment GuidelinesAASLD Hepatitis B Treatment Guidelines• Hepatology Hepatology February 2007February 2007• www.aasld.org
Recommendations from the HIV-Hepatitis Recommendations from the HIV-Hepatitis B Virus International PanelB Virus International Panel• AIDSAIDS 2008; 22: 1399-1410 2008; 22: 1399-1410
European AIDS Clinical Society Guidelines European AIDS Clinical Society Guidelines for HBV/HIVfor HBV/HIV• HIV MedicineHIV Medicine 2008; 9: 82-88 2008; 9: 82-88
Recommendations for Treatment of Recommendations for Treatment of Chronic Hepatitis BChronic Hepatitis B
HBeAg+
ALT <1 x ULN
HBV DNA <20,000 IU/mL
ALT >2x ULN
HBV DNA>20,000 IUmL
Observe: ALT q3-6mHBeAg q6-12 m
Treat
Lok, Hepatology 2007; 45:507-539
ALT 1-2 x ULN
HBV DNA>20,000 IU/mL
ALT q3m
HBeAg q6m
Consider bx if persistent or age>40
Treat as needed
Recommendations for Treatment of Recommendations for Treatment of Chronic Hepatitis BChronic Hepatitis B
HBeAg-
ALT <1 x ULN HBV DNA <2000 IU/mL
ALT >2x ULN HBV DNA >20000 IU/mL
Observe: ALT q3m x 3, then q6-12m if ALT still <1xULN
Treat
Lok, Hepatology 2007; 45:507-539
ALT 1-2 x ULN HBV DNA 2000-20000 IU/ml
ALT and HBV DNA q3m
Consider bx if persistent
Treat as needed
Hepatitis B Treatment in HIV/HBVHepatitis B Treatment in HIV/HBV
Previously depended on whether HIV Previously depended on whether HIV needed to be treated as wellneeded to be treated as well
Latest versions of HIV treatment Latest versions of HIV treatment guidelines now list concurrent HBV guidelines now list concurrent HBV as a reason for initiating HAARTas a reason for initiating HAART• DHHSDHHS• IAS USAIAS USA
Special cases may exist where ONLY Special cases may exist where ONLY hepatitis B will be treatedhepatitis B will be treated
Goals of HBV TherapyGoals of HBV Therapy
Biochemical response: normalization Biochemical response: normalization of transaminasesof transaminases
Virologic responseVirologic response• Suppression of HBV DNASuppression of HBV DNA• Loss of HBeAg (+/- development of anti-Loss of HBeAg (+/- development of anti-
HBe)HBe) Histologic responseHistologic response Complete response: biochemical + Complete response: biochemical +
virologic response and loss of HBsAgvirologic response and loss of HBsAg
Available HBV TherapiesAvailable HBV TherapiesActive against HIV and hepatitis B
Active against hepatitis B only
Lamivudine (LAM, 3TC)*
Emtricitabine (FTC)
Tenofovir (TDF)*
Adefovir (ADV)*
Telbivudine (LdT)*
Interferon-α2b*
Peg-interferon- α2a*
*FDA approved for hepatitis B
Entecavir (ETV)*
ACTG 5127: Tenofovir Noninferior ACTG 5127: Tenofovir Noninferior to Adefovir for HBV/HIVto Adefovir for HBV/HIV
Peters, Hepatology 2006; 44:1110-6
ADV (n=25) TDF (n=27)
Mean change in HBV -4.03 log -5.74 log DNA from baseline
HBV DNA<200 at w36 8.6% 5.7%
HBV DNA<200 at w48 11.4% 20%
Nml ALT at w48 25% 36%
HBeAganti-HBe 1 pt 0 pts
Entecavir in HIV/HBV: ETV-038Entecavir in HIV/HBV: ETV-038
Pessoa, CROI 2005, #123 Colonno, CROI 2006, #832
ETV 1 mg QDN=51
PlaceboN=17
ETV 1 mg QDN=17
ETV 1 mg QDN=48
Continued LAM as part of HAART
Wk 2 12 24 48
DOUBLE-BLIND PHASE OPEN-LABEL PHASE
Virologic Response: ETV in HIVVirologic Response: ETV in HIV Median HBV DNA reduction of 4.2 log copies/ml Median HBV DNA reduction of 4.2 log copies/ml
by wk 48 (0.83-7.36)by wk 48 (0.83-7.36) Two patients showed emerging changes of Two patients showed emerging changes of
primary ETVr residues T184 and S202primary ETVr residues T184 and S202• No virologic rebound or suboptimal responseNo virologic rebound or suboptimal response
Only 2 pts had emerging genotypic changes that Only 2 pts had emerging genotypic changes that appeared to significantly decrease ETV susc appeared to significantly decrease ETV susc beyond what would be expected for LAM-R virusbeyond what would be expected for LAM-R virus
In general, LAM-R substitutions result in an 8-fold In general, LAM-R substitutions result in an 8-fold decrease in ETV susceptibility and are a decrease in ETV susceptibility and are a prerequisite for viral rebound due to ETV prerequisite for viral rebound due to ETV resistanceresistance
Colonno, CROI 2006, Poster 832
Entecavir: Anti-HIV Activity?Entecavir: Anti-HIV Activity?
HIV RNA levels dropped by at least 1 log in three patients treated for HBV with ETV monotherapy
CD4 counts also rose
McMahon, NEJM 2007; 356: 2614-21
Entecavir: Anti-HIV Activity?Entecavir: Anti-HIV Activity?
Suspected activity against HIV confirmed Suspected activity against HIV confirmed by cell culture assays that showed the ICby cell culture assays that showed the IC5050 for HIV to be in the low nanomolar range, for HIV to be in the low nanomolar range, much lower than pre-licensing assays much lower than pre-licensing assays (done differently) had suggested(done differently) had suggested
The dose-response curve for ETV was The dose-response curve for ETV was atypicalatypical• Anti-HIV activity reached plateau at low Anti-HIV activity reached plateau at low
nanomolar concentrations and concentrations nanomolar concentrations and concentrations above 10 nM did not cause increased inhibitionabove 10 nM did not cause increased inhibition
McMahon, NEJM 2007; 356: 2614-21
Development of M184VDevelopment of M184V
4 of 13 patients with >0.5 log decline had 4 of 13 patients with >0.5 log decline had HIV rebound after achieving a nadirHIV rebound after achieving a nadir• All ART-experiencedAll ART-experienced• 3 had developed M184V at time of HIV RNA 3 had developed M184V at time of HIV RNA
rebound after a median of 98 daysrebound after a median of 98 days• 2 other ART-experienced patients had M184V 2 other ART-experienced patients had M184V
before ETV initiationbefore ETV initiation 2 ARV-naïve patients developed M184V 2 ARV-naïve patients developed M184V
after median 132 days of ETVafter median 132 days of ETV• 1 more without a baseline geno did as well1 more without a baseline geno did as well
Sasadeusz, AIDS 2008; 22:947-55
Associated with: longer time on entecavirHBV reduction to nadir
Telbivudine in HIVTelbivudine in HIV
No RCT for its use in HIV+No RCT for its use in HIV+ Cross-resistance limits usefulness in Cross-resistance limits usefulness in
ARV-experienced patientsARV-experienced patients AASLD Guidelines currently do not AASLD Guidelines currently do not
recommend its use in HIV+recommend its use in HIV+ EACS Guidelines present it as EACS Guidelines present it as
alternative to ADV in those not alternative to ADV in those not requiring HIV therapyrequiring HIV therapy
Not reported to have any HIV activityNot reported to have any HIV activity
LamivudineLamivudine
17%
7%
39%
53%57%
75%
70%
91%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Year 1 Year 2 Year 3 Year 4
HIV-
HIV+
Leung, Hepatology, 2001, 33: 1527-32 Benhamou, Hepatology, 1999, 30:1302-6
Resistance
Entecavir ResistanceEntecavir Resistance
Requires “two hits”Requires “two hits” M204V/I as first hitM204V/I as first hit Then mutation in I169, T184, S202 or Then mutation in I169, T184, S202 or
M250M250• These mutations on their own have minimal These mutations on their own have minimal
effect on sus to entecavireffect on sus to entecavir In presence of M294V/I, one of these leads In presence of M294V/I, one of these leads
to 10-250 fold decrease in ETV suscto 10-250 fold decrease in ETV susc M204V/I + 2 mutations M204V/I + 2 mutations 500 fold 500 fold
decrease in ETV suscdecrease in ETV susc
Telbivudine ResistanceTelbivudine Resistance
Most frequent genotypic change M204I Most frequent genotypic change M204I • Only mutation causally associated with Only mutation causally associated with
resistanceresistance Other mutations:Other mutations:
• L80 (n=26)L80 (n=26)• L180 (n=4)L180 (n=4)• L229 (n=6)L229 (n=6)
No L180M/M204V-based resistance No L180M/M204V-based resistance changes seen for telbivudinechanges seen for telbivudine
Seifer, DDW 2007; Abs #93 Standring, DDW 2007; Abs. S1781
Cross-ResistanceCross-Resistance
Both entecavir and telbivudine share some Both entecavir and telbivudine share some cross-resistance with lamivudinecross-resistance with lamivudine• Neither works as effectively in patients with Neither works as effectively in patients with
pre-existing LAM-Rpre-existing LAM-R Adefovir and tenofovir also share some Adefovir and tenofovir also share some
resistance mutationsresistance mutations• TDF has been used successfully in some ADV-R TDF has been used successfully in some ADV-R
patientspatients• TDF remains useful in those with a primary TDF remains useful in those with a primary
nonresponse to the less potent ADVnonresponse to the less potent ADV
Resistance SummaryResistance Summary
0%
10%
20%
30%
40%
50%
60%
70%
1 yr 2 yr 3 yr 4 yr 5 yr
Lamivudine Adefovir Entecavir (naïve)
Entecavir (LAM-R) Telbivudine (e+) Telbivudine (e-)
Hadziyannis, NEJM 2005; 352: 2673-81 Leung, Hepatology, 2001, 33: 1527-32 Lok, Hepatology 2007; 45:507-539
Resistance SummaryResistance Summary
Soriano, AIDS 2008; 22:1399-1410
Consider Potency and Potential for Consider Potency and Potential for ResistanceResistance
Genetic Barrier
Po
ten
cy
FTCLAM
LdT
ADV
ETV TDF
IFN
Adapted from Soriano, AIDS 2008; 22: 1399-1410
Early Add-On Therapy for HBVEarly Add-On Therapy for HBV
Soriano, AIDS 2008; 22: 1399-1410
When Treatment FailsWhen Treatment Fails
Soriano, AIDS 2008; 22:1399-1410
HIV and Liver CancerHIV and Liver Cancer
Compared to SEER data, Compared to SEER data, standardized rate ratio was 7.7 (95% standardized rate ratio was 7.7 (95% CI 5.7, 10.1) for liver cancer in the CI 5.7, 10.1) for liver cancer in the HIV+ populationHIV+ population
Among HIV+ patients, coinfection Among HIV+ patients, coinfection with hepatitis B or C was associated with hepatitis B or C was associated with a RR of 3.63 (with a RR of 3.63 (pp<0.0001) for liver <0.0001) for liver cancercancer
Patel, Annals 2008; 148: 728-36
Hepatocellular Cancer ScreeningHepatocellular Cancer Screening
In Japan, annual incidence in In Japan, annual incidence in hepatitis B carriers 0.5%hepatitis B carriers 0.5%
With known cirrhosis, 2.5%/yearWith known cirrhosis, 2.5%/year May be less in North America where May be less in North America where
epidemiology of HBV differentepidemiology of HBV different Recommendations for screening Recommendations for screening
differ for Asian vs non-Asian differ for Asian vs non-Asian
Bruix, Hepatology 2005; 57: 1208-36
Hepatitis B Carriers: Who to ScreenHepatitis B Carriers: Who to Screen
Asian males>40 yearsAsian males>40 years Asian females >50 yearsAsian females >50 years All cirrhotic hepatitis B carriersAll cirrhotic hepatitis B carriers Family history of HCCFamily history of HCC Africans over age 20Africans over age 20 ““For non-cirrhotic HBV carriers not listed above For non-cirrhotic HBV carriers not listed above
the risk varies depending on the severity of the risk varies depending on the severity of underlying liver disease, and current and past underlying liver disease, and current and past hepatic inflammatory activity. Patients with high hepatic inflammatory activity. Patients with high HBV DNA concentrations and those with ongoing HBV DNA concentrations and those with ongoing hepatic inflammatory activity remain at risk for hepatic inflammatory activity remain at risk for HCC”HCC”
My recommendation:Screen those with evidence of ongoing
inflammation / hepatitis B activity(high ALT, high HBV DNA +/- treatment)
Bruix, Hepatology 2005; 57: 1208-36
Hepatitis B VaccinationHepatitis B Vaccination
Seroconversion rates to primary Seroconversion rates to primary vaccine series lower in HIV+vaccine series lower in HIV+
May need alternative strategies in May need alternative strategies in order for patients to be protectedorder for patients to be protected
Double Dose Vaccine in Primary SeriesDouble Dose Vaccine in Primary Series
Standard DoseStandard Dose
(n=94)(n=94)
Double DoseDouble Dose
(n=98)(n=98)
PP
Overall seroconversionOverall seroconversion 32 (34.0%)32 (34.0%) 46 (46.9%)46 (46.9%) 0.070.07
Stratified by CD4 countStratified by CD4 count
CD4<350CD4<350 10 (26.3)10 (26.3) 10 (23.8)10 (23.8) 0.800.80
CD4CD4≥350≥350 22 (39.3%)22 (39.3%) 36 (64.3%)36 (64.3%) 0.0080.008
Stratified by viral loadStratified by viral load
<10,000 copies/mL<10,000 copies/mL 28 (37.3%)28 (37.3%) 42 (53.8%)42 (53.8%) 0.010.01
≥≥10,000 to <30,00010,000 to <30,000 2 (25%)2 (25%) 2 (18.2%)2 (18.2%) 0.720.72
≥≥30,000 copies/mL30,000 copies/mL 1 (10.0%)1 (10.0%) 10 (100.0%)10 (100.0%) 0.750.75
Fonseca, Vaccine 2005; 23:2902-2908
Double Dose in NonrespondersDouble Dose in Nonresponders
144 nonresponders to primary series (anti-144 nonresponders to primary series (anti-HBs<10 IU/L)HBs<10 IU/L)
Received double dose (20 ug) at 0, 1 and 2 Received double dose (20 ug) at 0, 1 and 2 months, starting a median of 5 weeks after months, starting a median of 5 weeks after initial seriesinitial series
73/144 (50.7%) responded with median 73/144 (50.7%) responded with median titer 107.9 IU/L.titer 107.9 IU/L.• 96 (66.7% were on HAART, 89 (61.8%) had HIV 96 (66.7% were on HAART, 89 (61.8%) had HIV
viral load <50 copies/mL at revaccinationviral load <50 copies/mL at revaccination
De Vries-Sluijs, JID 2008; 197:292-4
If you only remember three things If you only remember three things from this talk:from this talk:
1. Adefovir isn’t a great HBV drug. Neither 1. Adefovir isn’t a great HBV drug. Neither is lamivudine (for different reasons). If is lamivudine (for different reasons). If your patient needs HBV treatment, your patient needs HBV treatment, strongly consider treating HIV as wellstrongly consider treating HIV as well
2. HBV resistance is real, and common in 2. HBV resistance is real, and common in lamivudine-experienced patients. HBV lamivudine-experienced patients. HBV needs to be monitored as much as HIV to needs to be monitored as much as HIV to detect early resistance or reactivation.detect early resistance or reactivation.
3. Most HIV+ patients with HBV don’t 3. Most HIV+ patients with HBV don’t need HCC screening, but data is minimalneed HCC screening, but data is minimal
Open for Long-Distance ConsultsOpen for Long-Distance Consults
Melissa OsbornMelissa [email protected]
404-686-3741 direct line404-686-3741 direct line
404-686-8114 clinic at Emory 404-686-8114 clinic at Emory University Hospital MidtownUniversity Hospital Midtown