Management of Hepatitis B Infection in Challenging Patient Populations STEVEN FLAMM, MD Professor of...

Management of Hepatitis B Infection in Challenging Patient Populations

STEVEN FLAMM, MDSTEVEN FLAMM, MD

Professor of MedicineThe Feinberg School of Medicine

Northwestern UniversityDirector of Liver TransplantationNorthwestern Memorial Hospital

Chicago, Illinois

2

Learning Objectives (CME, CE, CPE)

● At the completion of this educational activity, participants should be able to:

- Identify special considerations when treating HBV patients in special patient populations (ie, pregnant, with cirrhosis, HIV coinfection, and nonadherent to HBV treatment)

- Discuss key efficacy and safety issues associated with initiating and maintaining HBV therapy in these special populations

- Explain the issues and management approaches to HBV patients in these special populations

3

Program Overview

● HBV and pregnancy

● HBV and patients with cirrhosis

● HIV/HBV coinfection

● Nonadherence

4

Geographic Diversity of HBV Infection:Clinical and Epidemiologic Correlations

North AmericaWestern Europe

Sub-Saharan AfricaFar East

Endemicity Low High

Age of infection Earlyadulthood

BirthToddler

Primary mode of transmission PercutaneousSexual

PerinatalHorizontal

Chronicity Rare Likely

Risk of end-stage liver disease Low High

Risk of hepatocellular carcinoma Low High

5

HBV and Pregnancy

● Perinatal transmission of HBV

- Most common cause of chronic HBV infection in regions of high HBV endemicity

- 80% to 90% of infants born to HBsAg/HBeAg-positive mothers become chronically infected with HBV

● Appropriate, timely immunoprophylaxis

- Prevents >90% of perinatal HBV infections

● HBV-related complications occur more frequently in pregnant women and are associated with a higher mortality

● HBV screening recommended for all pregnant women, even if previously vaccinated

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.Weinbaum CM, et al. MMWR Recomm Rep. 2008;57(RR-8):1-20.

6

Perinatal Transmission

● In utero transmission

- Rate: <10%

- Associated with high HBV DNA levels

- May become immunotolerant to HBV antigen

● Amniocentesis

- No transmission reported

● At birth

- HBeAg-positive mothers: 85%

- HBeAg-negative mothers: 31%

Wang Z, et al. J Med Virol. 2003;71:360-366.Alexander JM, et al. Infect Dis Obstet Gynecol. 1999;7:283-286.Towers CV, et al. Am J Obstet Gynecol. 2001;184:1514-1518.Beasley RP, et al. Am J Epidemiol. 1977;105:94-98.

7

Virologic Factors in Transmission

● HBV DNA level

● HBeAg status

● Vaccine/Ig escape mutation

- Mutations on HBsAg (“a” determinant) alter the epitope that HBsAb are directed against

● HBV genotypes

- Lower rate of perinatal transmission with genotype C

Hsu HY, et al. Gut. 2004;53:1499-1503.

8

HBV DNA Level andPerinatal Transmission of HBV

● HBsAg-positive pregnant women (n=313)

- All infants received standard prophylaxis

- 213 women with detectable HBV DNA

• 138 infants tested

● Overall transmission rate in mothers with detectable HBV DNA: 2.9% (4/138)

- Each mother was

• HBeAg positive: transmission rate 6.6% (4/61)

• HBV DNA >8 log10 copies/mL: transmission rate 8.5% (4/47)

● No cases of transmission from mothers with HBV DNA <8 log10 copies/mL

● One case of escape mutation identified

Wiseman E, et al. Hepatology. 2008;48(suppl):676A. Abstract 827.

9

New HBV Infections by Year:United States (1966-2006)

0123456789

1011121314

Inci

den

ce (

per

100

,000

)In

cid

ence

(p

er 1

00,0

00)

66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 00 02 04 06

YearYear

Wasley A, et al. MMWR Surveill Summ. 2008;57:1-24.

Infant Immunization Recommended

Vaccine Licensed

HBsAg Screening of Pregnant Women Recommended

OSHA Rule Enacted

Adolescent Immunization Recommended

10

Immunization Strategy to Eliminate Transmission of HBV in the United States

● Universal vaccination of infants beginning at birth

● Prevention of perinatal HBV infection through

- Routine screening of all pregnant women for HBsAg

- Immunoprophylaxis of infants born to HBsAg-positive women or women with unknown HBsAg status

● Routine vaccination of previously unvaccinated children

● Vaccination of previously unvaccinated adults at risk for HBV infection

Mast EE, et al. MMWR Recomm Rep. 2006;55(RR-16):1-33.

11

0

0.2

0.4

0.6

0.8

1

Taiwan Childhood Hepatoma Study Group:HBV Vaccination and Hepatocellular Carcinoma

Per

100

,000

Ch

ildre

n

0.70

0.57

0.36

Chang MH, et al. N Engl J Med. 1997;336:1855-1859.

Incidence ofHepatocellular Carcinoma

1986-19901981-1986 1990-1994

Children 6-14 years of age in Taiwan.

0

0.2

0.4

0.6

0.8

1

Per

100

,000

Ch

ildre

n 0.80

0.58

0.34

Mortality Due toHepatocellular Carcinoma

1986-19901981-1986 1990-1994

12

HBV Vaccine Schedule for Newborn Infants: Maternal HBsAg Positive

Single-Antigen Vaccine

Dose Age

1* Birth (<12 hours)

HBIG† Birth (<12 hours)

2 1 to 2 months

3‡ 6 months

Single-Antigen +Combination Vaccine

Dose Age


HBIG Birth (<12 hours)

2 2 months

3 4 months

4‡ 6 months (Pediarix) or12 to 15 months

(Comvax)

*Recombivax HB or Engerix-B should be used for the birth dose. Comvax and Pediarix can not be administered at birth or before age 6 weeks.†HBV globulin (0.5 mL) administered intramuscularly in a separate site from vaccine.‡Final dose of vaccine series should not be administered before age 24 weeks (164 days).


13

HBV Vaccine Schedule for Newborn Infants: Maternal HBsAg Unknown


Dose Age


2 1 to 2 months

3† 6 months


Dose Age


2 2 months

3 4 months

4† 6 months (Pediarix) or12 to 15 months

(Comvax)

*Recombivax HB or Engerix-B should be used for the birth dose. Comvax and Pediarix can not be administered at birth or before age 6 weeks.†Final dose of vaccine series should not be administered before age 24 weeks (164 days).


14

HBV Vaccine Schedule for Newborn Infants: Maternal HBsAg Negative


Dose Age

1*† Birth (<12 hours)

2 1 to 2 months

3‡ 6 months


Dose Age

1*† Birth (<12 hours)

2 2 months

3 4 months

4‡ 6 months (Pediarix) or12 to 15 months

(Comvax)

*Recombivax HB or Engerix-B should be used for the birth dose. Comvax and Pediarix can not be administered at birth or before age 6 weeks.†On a case-by-case basis and only in rare circumstances, the first dose may delayed until after hospital discharge for an infant who weighs >2000 g and whose mother is HBsAg negative (only if a physician’s order to withhold the birth dose and a copy of the mother’s original HBsAg-negative laboratory report are documented in the infant’s record).‡Final dose of vaccine series should not be administered before age 24 weeks (164 days).


15

HBV Immunization Management:Preterm Infants (<2000 g)

● HBIG + HBV vaccine (<12 hours of birth)

● Continue vaccine series

- Start: age 1 to 2 months

- Use recommended schedule for infants born to HBsAg-positive mothers

● Do not count birth dose as part of the vaccine series

● Test for HBsAg and antibody to HBsAg after completion of vaccine series at age 9 to 18 months (ie, next well-child visit)

Maternal HBsAg Positive

● HBIG + HBV vaccine (<12 hours of birth)

● Test mother for HBsAg

● Continue vaccine series

- Start: age 1 to 2 months

- Use recommended schedule based on mother’s HBsAg result

● Do not count birth dose as part of the vaccine series

Maternal HBsAg Unknown

● Delay first dose of HBV vaccine until age 1 month or hospital discharge

● Complete vaccine series using recommended schedule based on infants born to HBsAg-negative mothers

Maternal HBsAg Negative


16

HBV Care for Women Who Want to Get Pregnant,Are Pregnant, or Who Already Have Had a Baby

0

10

20

30

40

50

60

70

80

90

100

Res

po

nd

ents

(%

)

Survey Responses by AASLD Members (n=226)

Antiviral Therapy in PregnantWoman, New HBV Diagnosis

in 1st Trimester

InitiateTherapy

52%48%

39%

61%

25%

75%

58%

14%

28%31%

44%

25%

Salem SB, et al. Hepatology. 2008;48(suppl):742A. Abstract 971.

Wait Until AfterPregnancy

If Wait,Why?

NoEvidence

NoGuidelines

On Antiviral Therapy,Wants to Become

Pregnant

StopTherapy

ContinueTherapy

Chronic HBV,Recommend Breastfeeding?

Not onTherapy

OnTherapy

Y N U Y N U

Y: yes; N: no; U: unsure.

17

Antiviral Options for HBV:Pregnancy Category

● Telbivudine

● Tenofovir DF

● Interferon alfa

● Peginterferon alfa-2a

● Peginterferon alfa-2b

● Lamivudine*

● Adefovir

● Entecavir

Category B Category C

*Pregnancy category B for use in HIV infection.

18

0

10

20

30

40

50

60

70

80

90

100

Third Trimester Use of Lamivudine in Women With High HBV Viral Load

HBsAb Positiveat 1 Year

*P=0.014; †P=0.003; and ‡P=0.008 versus control.

Pat

ien

ts (

%)

Lamivudine (n=68)Control (n=52) 84%‡

20%†

HBsAg Positive

Outcomes in babies born to mothers assigned to either lamivudine or control during the 3 rd trimester due to high HBV viremia (>1000 mEq/mL).

Viremia

61%

46%

Terrault N, et al. Semin Liver Dis. 2007;27(suppl 1):18-24.

18%*

39%

19

Initiating or Continuing Antiviral Therapy in Pregnant Women

● Should depend on the stage of the mother’s liver disease and the potential benefit to her versus the small risk to the fetus

- Young women are likely to have only mild liver disease, postponement of therapy until after pregnancy might be prudent

● Women who are candidates for therapy

- Chronic HBV, HBV DNA levels >107 copies/mL, and elevated ALT levels

- Previous delivery of a HBsAg-positive child

● Recommended antiviral options during the 3rd trimester

- Lamivudine, telbivudine, or tenofovir DF

- Peginterferon can be considered for patients who have significant fibrosis on biopsy

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

20

Program Overview




● Nonadherence

21

HBV DNA and Disease Progression

● Ongoing HBV replication

- Strong relationship with the risk of progression to cirrhosis, hepatocellular carcinoma, or both

• Large, long-term population-based studies of HBsAg+ patients

● Patients with cirrhosis who are seropositive for HBeAg, HBV DNA, or both

- ~4-fold higher risk of further disease progression to decompensation, hepatocellular carcinoma, and death compared with HBeAg- patients

• Natural history and therapeutic studies


22

REVEAL-HBV Study: Risk Evaluation of Viremia Elevation and Associated Liver Diseases

● Prospective, observational cohort study (1991-2004)

- 7 Taiwanese townships

• 89,293 individuals screened

- 3653 HBsAg+, anti-HCV seronegative

• ALT <45 U/L: 94%

• No cirrhosis: 98%

• No hepatocellular carcinoma: 100%

● Newly diagnosed cases

- Cirrhosis (n=365)

- Hepatocellular carcinoma (n=164)

Chen CJ, et al. JAMA. 2006;295:65-73.Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

CirrhosisHepatocellular

Carcinoma

HBV DNA (copies/mL)

<300 339 108

300 - <104 430 111

104 - <105 774* 297†

105 - <106 1879* 962*

>106 2498* 1152*

Incidence per 100,000 Patient-Years by Baseline HBV DNA

*P<0.001 and †P=0.006 versus <300 copies/mL.

23

REVEAL-HBV Study:HBV DNA Levels and HBV Progression

Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

0

1

2

3

4

5

6

7

8

Mu

ltiv

aria

ble

Ad

just

ed R

elat

ive

Ris

k

1.4

300 - <104 104 - <105

All patients (n=3582)HBeAg negative

Only (n=3037)

Normal ALT (n=2923)

105 - <106 >106

Baseline HBV DNA (copies/mL)

Risk of Cirrhosis(11-year follow-up)

*P<0.001 versus <300 copies/mL.

1.4 1.4

2.5* 2.4* 2.5*

5.6* 5.4* 5.6*

6.5* 6.7* 6.6*

24

REVEAL-HBV Study: 13-Year Cumulative Incidence of Hepatocellular Carcinoma

Chen CJ, et al. JAMA. 2006;295:65-73.

0

2

4

6

8

10

12

14

16

18

20

<300

Cu

mu

lati

ve In

cid

ence

(%

)

1.3

300 - <104 104 - <105


Only (n=3088)

Normal ALT (n=2966) Normal ALT and no cirrhosis (n=2925)

105 - <106 >106

1.2 0.98 0.741.37

0.891.21 1.25

3.57 3.68 3.42 3.15

12.17

9.54

8.557.96

14.89

17.88

19.51

13.50


25

REVEAL-HBV Study:HBV DNA Levels and HBV Progression

Chen CJ, et al. JAMA. 2006;295:65-73.

0

2

4

6

8

10

12

14

16

18

20

Mu

ltiv

aria

ble

Ad

just

ed H

azar

d R

atio

1.1

300 - <104 104 - <105


Only (n=3088)

Normal ALT (n=2966) Normal ALT and no cirrhosis (n=2925)

105 - <106 >106

1.0 1.3 1.4


Risk of Hepatocellular Carcinoma(13-year follow-up)

2.3* 2.6† 2.7*

4.5‡

6.6‡ 6.1‡7.2‡

11.3‡

6.1‡

10.6‡

14.3‡

17.7‡

*P=0.02, †P=0.01, and ‡P<0.001 versus <300 copies/mL.

26

REVEAL-HBV Study: Effect of Persistent HBV DNA Elevations on Hepatocellular Carcinoma Risk

Chen CJ, et al. JAMA. 2006;295:65-73.

0

2

4

6

8

10

12

Mu

ltiv

aria

ble

Ad

just

edH

azar

d R

atio

<104

Not Tested

104-105

<104

HBV DNA (copies/mL)

Risk of Hepatocellular Carcinoma

Baseline:Follow-Up:

104-105

104-105

104-105

>105

>105

<104

>105

104-105

>105

>105

1.0(referent)

1.60.5

3.5 3.8

7.3

10.1

27

Suppression of HBV ReplicationWith Antiviral Therapy

● Sustained suppression of HBV replication to lowest levels possible with antiviral therapy promotes

- Histologic improvement

- Decreased or normalized serum ALT

- HBeAg loss or seroconversion in HBeAg-positive patients

- HBsAg loss or seroconversion (rarely achieved)

● Treatment-induced decreases in HBV DNA

- Lack of long-term, randomized, clinical trials with clinical outcomes (ie, cirrhosis and hepatocellular carcinoma)

Lok AS, et al. Hepatology. 2007;45:507-539.Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.NIH Consensus Development Conference Statement. Available at: http://consensus.nih.gov/2008/2008HepatitisBCDC120main.htm.

28

Disease Progression for Patients With Chronic HBV and Advanced Liver Disease Receiving Lamivudine

Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

*P=0.001 versus placebo. >2 point increase in Child-Pugh score or major event.

Pat

ien

ts W

ith

Dis

ease

Pro

gre

ssio

n (

%)

Time to Disease Progression (months)

21%*

9%

25

20

15

10

5

030181260 3624

Placebo (n=215) n=198 n=173 n=43Placebo (n=215) n=198 n=173 n=43

Lamivudine (n=436) n=417 n=385 n=122Lamivudine (n=436) n=417 n=385 n=122

Lamivudine

Placebo

29

Time to Disease Progression by YMDD Status Among Patients Receiving Lamivudine for Chronic HBV

Liaw YF, et al. N Engl J Med. 2004;351:1521-1531.

Pat

ien

ts W

ith

Dis

ease

Pro

gre

ssio

n (

%) Wild-type (n=221)

YMDD (n=209) (49%)

Time After Randomization (months)

0

5

10

15

20

25

0 6 12 18 24 30 36

Placebo (n=215)

5%

13%

21%

30

Chronic HBV Treatment: Simplified Flow Chart for Patients With Cirrhosis

Compensated Decompensated

HBV DNA <2000 IU/mL

Any HBV DNA Level

Observe or Treat

Wait Listfor Transplant

HBV DNA >2000 IU/mL

Treat Treat


31

Recommendations for Treatment:Patients With Cirrhosis

CirrhosisHBV DNA(IU/mL) Treatment Options

Compensated <2000 Tenofovir DF or entecavir are preferred*

>2000 Tenofovir DF or entecavir are first-line optionsLong-term treatment required; combination therapy maybe preferred†

Decompensated Any Detectable

Tenofovir DF + lamivudine or possibly entecavir is preferredLong-term treatment required; combination therapy maybe preferred‡


*Although there are no data available for peginterferon alfa-2a, it might be an option in patients with early, well-compensated cirrhosis. No data are available for telbivudine, whose intermediate risk of resistance is a liability in patients with cirrhosis.†Tenofovir DF + lamivudine or possibly entecavir has a theoretical advantage of a lower likelihood of resistance.‡Limited data are available for entecavir, no data are available for tenofovir DF, and no data are available for telbivudine, whose intermediate risk of resistance is a liability in patients with cirrhosis. Peginterferon alfa-2a is contraindicated.

32

HBeAg Seroconversion Does Not Always Protect Against Long-Term Complications

● Chang Gung Memorial Hospital, Taiwan (n=283)

- Median age of seroconversion: 32 years

- Patients without evidence for cirrhosis at time of HBeAg seroconversion

• 7.8% and 2.2% developed cirrhosis and hepatocellular carcinoma, respectively, over a median follow-up of 8.6 years

● Queen Mary Hospital, Hong Kong (n=3233)

- Median age of seroconversion: 35 years

- Median age for the development of hepatocellular carcinoma and/or cirrhosis: 57 years

• 73.3% of patients with clinical complications were anti-HBe positive

Hsu YS, et al. Hepatology. 2002;35:1522-1527.Yuen MF, et al. Gut. 2005;54:1610-1614.

33

Patients With Cirrhosis:Duration of Treatment

● Therapy for patients with cirrhosis should be long-term

- Compensated: no data on the benefit of therapy continuation

- Decompensated: patients who undergo HBeAg seroconversion still might develop hepatocellular carcinoma or have progression of liver disease

● Continue therapy until patient becomes HBV DNA negative and has lost HBsAg

● On-treatment monitoring every 3 months

● Monitor renal function before and during therapy

- Adjust dosing frequency of entecavir, tenofovir DF, and lamivudine per manufacturer’s recommendations as needed


34

Program Overview




● Nonadherence

35

Liver Disease is the Second Leading Cause of Death in HIV-Infected Patients (1999-2004)

● D:A:D study (n=23,441)

- Median follow-up: 3.5 years

● Baseline characteristics

- Nadir CD4: 200 cells/µL

- Previous AIDS: 26.5%

- HCV positive: 22.5%

- Active HBV infection: 6.8%

• Inactive HBV infection: 21.4%

- Receiving combination antiretroviral therapy: 88.7%

● Mortality

- Total: 5.3%

- Incidence: 1.62 per 100 person-years

- Median age: 44 years

Weber R, et al. Arch Intern Med. 2006;166:1632-1641.

0

10

20

30

40

AIDS Liver-RelatedDiseases

CVD

Cause of Death (n=1246)

Pat

ien

ts (

%)

31.1%

14.5%

11.0%

CVD: cardiovascular disease.

36

Hepatitis C or B Coinfection is aChief Cause of Liver Failure

0

10

20

30

40

50

60

70

Mo

rtal

ity

(%)

AIDS-related death

Liver-related death

Other causes of death

Hepatitis CSerologic Tests Positive

Hepatitis BSeropositive,

Active Infection

Hepatitis C Seropositive,Active Hepatitis B Infection

23.7%


66.1%

33.4%

8.5%

16.9%

10.0% 8.0% 7.1%2.7%

37

Independent Predictorsof Liver-Related Death

Latest CD4 Cell Count (cells/µL)<50

50-99

100-199

200-349

350-499

>500

HIV Acquisition via IDU

Hepatitis C StatusNegative

Positive

Hepatitis B StatusNegative

Positive


0.2 1.0 10 100

Relative Rate of Death

16.06

11.54

7.14

3.95

1.67

2.01

6.66

3.73

Multivariate analysis.Not shown: Age per 5 years (1.32).

38

Impact of HIV onInfection With HBV

● Higher risk of chronic carrier state

● Lower rate of spontaneous loss of HBeAg/HBsAg

● Lower seroconversion to anti-HBe/anti-HBs

● Higher rate of viral reactivation and HBV replication

● Higher rate of occult HBV

39

HIV Coinfection Increases theRisk of Liver Mortality Due to HBV

● MACS (n=5293 men)

- HBsAg positive (n=326)

• HIV coinfected (n=213)

- HBsAg negative (n=4967)

• HIV infected (n=2346)

● Follow-up: 10.5 years

- 55,123 person-years

● Relative risk of death due to liver disease in HIV/HBV-coinfected versus

- HIV monoinfected: 4.8 (P<0.001)

- HBV monoinfected: 18.7 (P<0.001)

Thio CL, et al. Lancet. 2002;360:1921-1926.

0

2

4

6

8

10

12

14

16

HIV-HBV-

Liver-Related Mortality

Per

100

0 P

erso

n-Y

ears

00.8*

14.2†

HIV-HBV+

HIV+HBV-

1.7†

HIV+HBV+

*P=0.04 versus HIV-/HBV-.†P<0.0001 versus HIV-/HBV-.

40

Benefits of HAART inHIV/HBV-Coinfected Patients

● Effective antiretroviral therapy can lead to

- Decreases in HBV replication

- Spontaneous anti-HBe or anti-HBs seroconversion

- Decreases in HBV-associated liver disease

- Increases in hepatic flares (eg, ALT elevations)

● Primary mechanisms

- Restoration of immunity

- Suppression of HBV replication by dually active antiretroviral drugs

• Tenofovir DF, lamivudine, emtricitabine

41

HIV/HBV Coinfection:Goals of Therapy

● Sustained suppression of HBV replication and hepatic disease

● Prevent cirrhosis, hepatic failure, and hepatocellular carcinoma

● HBV is not curable, but rather is controlled by suppressing viral replication (as with HIV)

- Key surrogate markers

• HBV DNA

• HBeAg or HBsAg seroconversion

• Hepatic enzymes

• Liver histology

42

Response to HBV Treatment in HIV/HBV-Coinfected Patients

StandardInterferon Lamivudine Entecavir Emtricitabine

Tenofovir DF Adefovir

Treatmentduration (wk)

12-24 48 48 48 48 48-192

Anti-HBV activity tested in HIV patients

Wild type Wild type 3TC HBV resistant

Wild type Wild type,3TC HBV resistant

3TC HBV resistant

HBV DNA decline(log10 copies/mL)

-- 2.7 4.2 -- 4.4 4.7-6

HBeseroconversion (%)

9 11 -- -- 4 7

ALTnormalization (%)

12-20 30-50 49 -- 35-66

Histologic improvement (%)

-- -- -- -- -- 33-50

Benhamou Y. JAIDS. 2007;45(suppl 2):S57-S65.

43

DHHS Guidelines forTreating HIV/HBV-Coinfected Patients

Treatment needed for HIV Fully suppressive HAART that includes emtricitabine + tenofovir DF or lamivudine to treat both virusesAvoid using a single NRTI as the only anti-HBV agent due to risk of resistance

Treatment needed for HBV Treat both viruses with a fully suppressive HIV regimen that includes emtricitabine + tenofovir DF or lamivudineAvoid using a single NRTI as the only anti-HBV agent due to risk of resistance

To treat HBV not HIV Peginterferon or adefovir (theoretical risk of HIV resistance)Due to risk of HIV resistance, the use emtricitabine, lamivudine, tenofovir DF, or entecavir without HAART should be avoided

Stop NRTI Monitor clinical course with frequent liver function testsConsider interferon, adefovir, or telbivudine to prevent flares, especially in patients with marginal hepatic reserve

Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision November 3, 2008.

44

ACTG A5127: Tenofovir DF Versus Adefovir for HBV in HIV/HBV Coinfection

● Randomized, double-blind, non-inferiority study (n=52)

- On stable HAART

- Baseline

• HBV DNA: 9.1 log10 copies/mL

• HBeAg positive: 79%

• Lamivudine resistant: 94%

● Study ended early

- Primary non-inferiority endpoint for tenofovir DF was met without safety issues at a pre-specified interim analysis

Peters MG, et al. Hepatology. 2006;44:1110-1116.

-7

-6

-5

-4

-3

-2

-1

0

Ch

ang

e (l

og

Ch

ang

e (l

og

1010

cop

ies/

mL

) c

op

ies/

mL

)

0 4 12 24 360 4 12 24 36 48 48Week

Change in HBV DNA

Adefovir

Tenofovir DF

45

Long-Term Use of Tenofovir DF Decreases Liver Fibrosis in HIV/HBV-Coinfected Patients

● Open-label study in HIV/HBV-coinfected patients (n=130)

- 2002-2006 French HIV/HBV Cohort Study

- Median duration of tenofovir DF: 29.5 months

● Baseline

- Fibrosis levels

• F0-F1 (n=45), F2 (n=29), F3-F4 (n=56)

● Conclusions

- Tenofovir DF induced a significant decrease in fibrosis level

• Particularly in patients with extensive fibrosis and cirrhosis

Lacombe K, et al. Hepatology. 2008;48(suppl):716A. Abstract 914.

0.2

0.4

0.6

0.8

1

DA

VG

Fib

rom

eter

DA

VG

Fib

rom

eter

®® S

core

Sco

re

0 12 24 0 12 24 36 36Week

METAVIR Fibrosis Score

Baseline F0-F1Baseline F2Baseline F3-F4

F3-F4

F2

F-F1

Dotted lines: cutoff Fibrometer® score corresponding to METAVIR fibrosis F0-F1 versus F2 and F2 versus F3-F4.

46

Emtricitabine as Part of Triple-Drug Therapy in HIV/HBV-Coinfected Patients

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts (

%)

36%

HBV DNA HIV RNA

Undetectable HBV DNA and HIV RNA

90%

3612 24 48

HBV DNA <4700 copies/mL and HIV RNA <400 copies/mL.Emtricitabine was the only active anti-HBV agent included in the triple-drug regimens.Harris J, et al. 11th CROI. San Francisco, 2004. Abstract 836.

Week

45%

97%

60%

95%

59%

94%

47

Tenofovir DF + Lamivudine VersusTenofovir DF Rescue in Lamivudine Resistance

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts (

%)

76%

84%

Loss of HBeAgHBV DNA<1000 Copies/mL

ALT <45 U/L Loss of HBsAg

Schmutz G, et al. AIDS. 2006;20:1951-1954.

60%64%

36%

24%

4% 6%

Tenofovir DF + lamivudineTenofovir DF rescue

HIV/HBV Coinfection

48

Lamivudine + Tenofovir DF for HIV/HBV (HBeAg-Positive) Coinfected Patients

Week 24

-7

-6

-5

-4

-3

-2

-1

0

LamivudineExperienced

*P<0.001 and †P=0.045 versus lamivudine.

Ch

ang

e in

HB

V D

NA

(lo

g1

0 c

op

ies/

mL

)

-0.82

LamivudineNaïve

Nelson M, et al. 13th CROI. Denver, 2006. Abstract 831.

-3.41*

-3.93*

-4.66-5.03†

LamivudineTenofovir DFLamivudine + tenofovir DF

Week 48

-7

-6

-5

-4

-3

-2

-1

0

LamivudineExperienced

Ch

ang

e in

HB

V D

NA

(lo

g1

0 c

op

ies/

mL

)

-2.5

LamivudineNaïve

-3.07

-4.5

-5.41

-6.23

-3.31

-4.55

LamivudineTenofovir DFLamivudine + tenofovir DF

Tenofovir DF added at week 24 for lamivudine-naïve patients and could be added in lamivudine-experienced patients at MD discretion.

49

Impact of Entecavir onHIV RNA and Resistance

● HIV/HBV-coinfected patients with stable HIV disease not on HAART (n=3)

● Changes following 2 to 6 months of entecavir monotherapy for HBV

- HBV DNA decreases ranged from 4.0 to 5.65 log10 copies/mL

- HIV RNA decreases ranged from 0.85 to 1.23 log10 copies/mL

- CD4 cell increases ranged from 60 to 81 cells/mm3

● Accumulation of M184V (HIV) detected (n=1)

- M184V confers resistance to entecavir

● Caution on use of entecavir in patients not receiving fully suppressive HAART

McMahon MA, et al. N Engl J Med. 2007;356:2614-2621.

0

10

20

30

40

50

60

70

80

90

100

Clo

nes

Wit

h M

184V

(%

)C

lon

es W

ith

M18

4V (

%)

0(n=19)

4(n=18)

6(n=27)

Duration of EntecavirMonotherapy (months)

Selection of M184V

2(n=41)

50

Anti-HIV Activity of Entecavirand Selection of M184V

● Retrospective study

- 17 HIV/HBV-coinfected patients who received entecavir monotherapy

• HAART-naive (n=10)

• HAART-experienced (n=7)

- Median follow-up 144 days (30-470 days)

- Polymerase sequencing (n=12)

● HIV RNA reduction by entecavir

- HAART-naïve: 1.1 log10 copies/mL after a median of 96 days

- HAART-experienced: 1.0 log10 copies/mL after a median of 113 days

● M184V mutation was selected in HAART-naïve and HAART-experienced patients

● Entecavir monotherapy for HBV treatment in HIV/HBV-coinfected patients should be avoided

Sasadeusz J, et al. AIDS. 2008;22:947-955.

0

10

20

30

40

50

60

70

80

Pat

ien

ts (

%)

Pat

ien

ts (

%)

AllPatients

(n=12)

Experienced(n=5)

Selection of M184V

Naïve(n=7)

50%

43%

60%

148 days 98 days

51

Summary: HBV Treatment inHIV/HBV-Coinfected Patients

● HBV coinfection complicates disease course and management of HIV patients

- HBV coinfection does not substantially affect the course of HIV infection

- HIV coinfection significantly alters the course of HBV disease

● Early use of HAART is beneficial for HIV/HBV-coinfected patients who meet the criteria for antiretroviral therapy

- Patients with low CD4 cell counts and high HBV DNA levels at initiation of HAART should be monitored

- Agents with dual activity against HIV and HBV are preferred and facilitate management of both infections

52

Program Overview




● Nonadherence

53

Adherence Issues in theTreatment of Hepatitis B

● Antiviral therapy plays a critical role in the management of chronic HBV infection

● Limitations of antiviral therapy

- Emergence of viral resistance

- Poor sustained response off treatment

- Commits many patients to lifelong therapy and risks the selection of HBV resistant strains

● Adherence and antiviral therapy in HBV

- Data are lacking

- Experience from the HIV field

• Medication nonadherence adversely promotes the development of resistance and disease progression

54

Implications ofResistance to HBV Therapies

● Loss of clinical benefits

- Loss of initial HBV DNA response with rebound

- ALT increase and eventual reversion of histologic improvement

- Progressive liver disease

- In patients with cirrhosis, decompensation

● Development of multidrug resistance

- Cross resistance

- New resistance mutations

● Transmission of resistant virus


55

HBV Virion Half-Life

Dandri M, et al. Hepatology. 2008;48:1079-1086.

HBeAg-Negative

Virion Half-Life: 46 minutes(range: 4 to 224 minutes)

Virion Half-Life: 150 seconds(range: 24 seconds to 13 minutes)

HBeAg-Positive

56

Rate of Generation ofHBV Mutants at Peak Infection

Base Changes Fraction

Number Created per Day

Number of Possible Mutants*

Fraction of All Possible Mutants Created per Day

0 0.9968 9.97 x 1012 - -

1 0.0032 3.2 x 1010 9.6 x 103 1

2 5 x 10-6 5 x 107 4.6 x 107 0.66

3 5.4 x 10-9 5.4 x 104 1.5 x 1011 3.6 x 10-7

*Computed as 3i( ) where n=3200 is the genome length, i is the number of base changes,

and ( ) is a binomial coefficient.

ni

ni

High rate of mutations predisposes the virus to antiviral resistance.Whalley SA, et al. J Exp Med. 2001;193:847-854.

57

Appearance of Resistance-Related Mutations Is Associated With Virologic Breakthrough

Wild-Type

Mutant

HB

V D

NA

lo

g10 c

op

ies/

mL

Mixture

Lee CZ, et al. World J Gastroenterol. 2006;12:5301-5305.

58

Viral Persistence and Mechanism for Selection of Mutant HBV Strains

Fournier C, et al. Clin Liver Dis. 2007;11:869-892.

Virus cccDNA Half-Life

HepatocyteHalf-Life

Spontaneous Errors in Viral Polymerase

Quasi-Species

Viral Persistence

Host

Selection of Resistant StrainsPhenotypic Resistance

Treatment Failure

Antivirals

Immune Response

59

Antiviral Resistance: Nomenclature

Treatment failure

Primary (nonresponse) <1 log10 decrease in HBV DNA at 6 months

Secondary (breakthrough) >1 log10 increase in HBV DNA above nadir in compliant patient

Lok AS, et al. Hepatology. 2007;46:254-265.

Resistance

Genotypic Detection of HBV polymerase mutation(s) associated with resistance

Phenotypic Decreased in vitro susceptibility to an antiviral drug

Breakthrough

Virologic >1 log10 increase in HBV DNA over nadir on therapy

Biochemical Increase in ALT on treatment

60

Manifestations ofAntiviral Resistance

0

1

2

3

4

5

6

7

8

HB

V D

NA

(lo

g10

IU/m

L)

AL

T (

U/L

)

-1 0 1 2 3

Years on Treatment


HBV DNA

ALT

Upper Limit of Normal

GenotypicResistance

VirologicBreakthrough

VirologicRebound

BiochemicalBreakthrough

HepatitisFlare

61

Emergence of HBV-Resistant VariantsHBV Resistance at Year of Therapy (% patients)

1 2 3 4 5

Lamivudine 23 46 55 71 90

Adefovir Naïve HBeAg-negative Lamivudine resistant

018

3--

11--

18--

29--

Entecavir Naïve Lamivudine resistant

0.16

0.414

1.232

1.2--

1.2--

Emtricitabine 9-16 19-37 -- -- --

Telbivudine HBeAg-positive HBeAg-negative

4.42.7

21.68.6

----

----

----

Tenofovir DF Naïve Lamivudine resistant

00

00

----

----

----Thio C, et al. AIDS Rev. 2007;9:40-53.

Benhamou Y. JAIDS. 2007;45(suppl 2):S57-S65.Heathcote EJ, et al. Hepatology. 2008;48(suppl):92A. Abstract 158.Marcellin P, et al. Hepatology. 2008;48(suppl):88A. Abstract 146.Tenney DJ, et al. APASL. Seoul, 2008. Abstract PL02.

62

Monitoring for Antiviral Resistance

● Test serum HBV DNA prior to therapy and at 3-month intervals

● Primary non-responders should be offered combination or alternative therapy

● Inquire about medication compliance when virologic breakthrough is seen

● Genotyping should be performed to confirm resistance and determine specific mutations


63

Factors Influencing Development of Resistance to HBV Antiviral Agents

● Adherence

- Inconsistent medication levels

- Persistent viral replication, increasing the likelihood of the formation of viral quasispecies

● Viral persistence

● Pharmacokinetics

64

Determining Nonadherence toAntiviral Therapy for HBV Infection

● No current "gold standard" for measuring antiviral adherence

● Tools available

- Clinical trials

• Patient self-reports

• Clinical assessments

• Pill counts

• Measurements of plasma drug levels

• Medication event monitoring systems

- Practical tools

• Prescription-refill percentages

• Untimed drug concentration measurements

● These methods have not been evaluated specifically in the HBV-infected population

- Principles are generalizable to include therapy for any virus with a high mutation rate

65

Factors ImpactingMedication Adherence

● Number of pills

● Frequency of daily regimen

● Cost

● Side-effect profile

● Presence of depressive symptoms

● Presence of alcohol or substance abuse

66

Strategies Used in the HIV Fieldto Enhance Medication Adherence

● Case management

● Couple-based counseling

● Pharmacist-based counseling

● Telephone support

● Reminder devices

● Home visits by a nurse

● Directly observed therapy

● Identify and treat psychiatric conditions prior to and throughout antiviral therapy

67

AASLD Guidelines: Options for Lamivudine/Telbivudine Resistance

● Add adefovir or tenofovir DF

- No evidence of resistance at 3 years when used in combination with lamivudine

● Switch to emtricitabine + tenofovir DF (fixed-dose combination)

● Switch to entecavir

- Risk of subsequent entecavir resistance and multidrug resistance


68

AASLD Guidelines:Options for Adefovir Resistance

● Add lamivudine

● Switch to emtricitabine + tenofovir DF (fixed-dose combination)

● Add/switch to entecavir

- Caution with switch if prior lamivudine resistance


69

AASLD Guidelines:Options for Entecavir Resistance

● Add adefovir or tenofovir DF

● Note

- Clinical data on efficacy of alternative therapies is not currently available


70

AASLD Guidelines:Options for Multidrug Resistance

● Multidrug resistance to lamivudine and adefovir

- Consider tenofovir DF + emtricitabine, tenofovir DF, entecavir

● Multidrug resistance to lamivudine and entecavir

- Consider tenofovir DF or tenofovir DF + emtricitabine

● Therapy with two nucleosides or two nucleotides not recommended due to competitive inhibition


71

Summary: AASLD Guidelines for Management of Antiviral-Resistant HBV

Resistance Rescue Therapy

LamivudineTelbivudine

Add adefovir or tenofovir DFSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (risk of entecavir resistance)

Adefovir Add lamivudineSwitch to: Emtricitabine + tenofovir DF (fixed-dose combination) Entecavir (if no prior lamivudine resistance)

Entecavir Add adefovir or tenofovir DF

Multidrug Multidrug resistance to lamivudine + adefovir: Consider emtricitabine + tenofovir DF (fixed-dose combination), tenofovir DF, entecavirMultidrug resistance to lamivudine + entecavir: Consider tenofovir DF or emtricitabine + tenofovir DF (fixed-dose combination)


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Management of Hepatitis B Infection in Challenging Patient Populations STEVEN FLAMM, MD Professor of...

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