hepatitis b

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