Hep B and C: Updates and Resources

John Scott, MD, MSc

Asilomar AETC Conference

October 6, 2006

Outline

• Hepatitis C– Background & natural history – Treatment of Hep C/HIV coinfection

• New drugs• Guidelines and Internet resources

• Hepatitis B– Natural history w/ and w/o HIV– Treatment of Hep B monoinfection– Treatment of Hep B/HIV coinfection

• New drugs• Guidelines and Internet resources

Biology

• ss RNA virus• RNA-dependent RNA

polymerase, lacks proofreading function

• Flaviviridae• 6 genotypes, type 1

accounts for 70% of infections in US, types 2,3 account for rest

• No easy culture system!

www.hepcprimer.com/3dmodel.html

Liver Disease has Emerged as a Major Cause of Death in the HAART Era

Bica Clin Infect Dis 2001; Puoti JAIDS 2000; Soriano Eur J Epidemiol 1999; Soriano PRN Notebook 2002; Martin-Carbonero AIDS Res Human Retrovirus 2001

0

10

20

30

40

50

60

Mo

rtal

ity

(%)

Death from end-stage liver disease (ESLD) as a% of all deaths among HIV patients

Italy (Brescia) Spain (Madrid) USA (Boston)

13%

35%

5%

12%

45%

50%Pre-HAART era

HAART era

Impact of HIV on HCV

Cirrhosis Decompensation

Makris

Soto

Pol

Benhamou

Combined

0.76 1.0 2.07 10.83

Eyster

Telfer

Makris

Lesens

Combined

0.61 1.0 6.14 175.32

Graham CID 2001Relative Risk (95% CI)

A B

AASLD Guidelines

• Anti-HCV testing on all HIV+ pts• HCV RNA to confirm Ab+ and all Ab- w/

unexplained liver disease• Treat HIV/HCV patients in whom likelihood of

serious liver dz and tx response outweigh the side effects of tx

• PegIFN-alfa + ribavirin x 48 wks• Closely monitor pts on therapy• Use RVN carefully in pts on AZT or d4T. Avoid

RVN and ddI• Decompensated liver dz -> liver transplant eval

Strader D. Hepatology 2004.

Workup

• H&P: date HCV diagnosed, risk factors, earliest exposure, signs and symptoms of hepatitis and cirrhosis, alcohol hx, prior treatment and response

• Candidate for tx: depression, poorly controlled DM, CAD, cytopenias, autoimmune dz, pregnant

• EIA (TPR>99%, TNR=99%)• If EIA+, sensitive PCR assay• LFTs, CBC, chem 7, TSH, hepatitis serologies, CD4 and

HIV RNA, pregnancy test, eye exam, utox?• If treatment contemplated, then HCV genotype and viral

load, +/- liver biopsy

Liver Biopsy

• Currently the best way to determine how much scarring is present, but imperfect

• Needle, local anesthetic

• Risks: bleeding

• Scar Stages: 0-1-2-3-4 (Batts-Ludwig)

• VA guidelines recommend bx for all patients

Progression of Fibrosis on BiopsyProgression of Fibrosis on Biopsy

No FibrosisNo Fibrosis

Stage 1: Fibrous Stage 1: Fibrous expansion of expansion of some portalsome portal areasareas

Stage 3: Stage 3: Fibrous Fibrous expansion of expansion of most portal most portal areas areas with occasional with occasional portal to portal portal to portal bridgingbridging

StageStage 4: Fibrous 4: Fibrous expansion of expansion of portal areas with portal areas with marked bridging marked bridging (portal to portal (portal to portal and portal to and portal to central)central)

Stage 4: CirrhosisStage 4: Cirrhosis

Cirrhotic liver: Cirrhotic liver: Gross anatomy Gross anatomy of cadaverof cadaver

Courtesy of Gregory Everson, MD.Courtesy of Gregory Everson, MD.

• ACTG 5071 (Chung RT, NEJM 2004; 351:451-9)

• RIBAVIC (Carrat F, JAMA 2004; 292:2839-48)

• APRICOT (Torriani F, NEJM 2004: 351:438-50)

– All compared standard with pegylated IFN– All treated for 48 weeks, regardless of

genotype– All used low-dose RBV (avg dose 800 mg/d)

• Laguno et al (AIDS 2004: 18:27-36).

– Higher dose RBV, 24 weeks for GT2 or 3

Prospective, Randomized Multicenter Trials of Pegylated Interferons in

HIV/HCV

HIV/HCV Coinfection TrialsACTG RIBAVIC APRICOT Laguno

# pts 134 412 860 95

% genotype 1 78% 66% 61% 49%

fibrosis score 2.5 2.3 16% cirrhotic 30% st 3 or 4

Mean CD4 475 515 530 560

Overall SVR 27% 26% 40% 44%

SVR GT 1 5% 15% 29% 38%

SVR non-1 30% 43% 62% 53%

d/c rate (ea arm)

12% 42% 30-40% 17%

Side Effects of PegIFN/Ribavirin

• Depression ranging from mild to suicidality• Irritability, aggressive behavior• Worsening of mania• Fatigue• Insomnia• Myalgias, fever, flu-like symptoms• Hair loss• Cytopenias“Interferon Man”

0

1

2

3

4

5

6

7

8

0 1 2 3 4 12 24 48 72

Time (wks)

Lo

g (

10)

HC

V R

NA

Non-response (NR)

Slow response with relapse

Early virologic response(EVR)

Rapid virologic response(RVR)

Therapy

High relapse rate (33-44%) in HIV/HCV

Torriani, F. 2004 NEJM 351:438-51Soriano, V. 2004 AIDS Research Human Retrovirus 20:351-3.

Extended treatment for HCV

• Mathematical models show that viral suppression necessary for at least 36 weeks

• HCV monoinfected trial showed that if HCV RNA + at wk 12 but – at wk 24, SVR increased from 17% to 29% with add’l 24 weeks of therapy

• Goal: reduce relapse rateDrusano GL. 2004 J Infect Dis 189:964-70Berg T. 2006 Gastro 130:1086-97.

Duration of Detectability (DUD)

4 12 24 48 Time (weeks)

RVR

EVR

SlowVR

Detectable

Detectable

Detectable

Undetectable

Undetectable

Undetectable

44 wks

36 wks

24 wks

Ferenci 2005, Fried 2006

PRESCO

• Ongoing Spanish study of 398 stable coinfected pts (mean CD4 562 cells/mm3)

• All are receiving 180 mcg PegIFNα2a (Pegasys) and wt-based RBV (1000 or 1200 mg/d)

• Comparing extended tx w/ std tx:– 48 weeks for GT non-1– 72 weeks for GT 1

Soriano, et. al., 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) October 30 - November 2, 2004, Washington, DC (abstract)

% HCV Responders at Week 4

Genotype Study # patients HCV-RNA reduction> 1 log10

HCV-RNA reduction> 2 log10

SerumHCV-RNA-negative

Genotype 1

PRESCO 94 69.2 46.2 33.8

Fried 298 78.8 55.3 31.2

APRICOT 176 68 40 13

Genotype 3

PRESCO 70 93.8 89.6 85.4

Fried 140 95 90.7 84.2

APRICOT 96 87 80 37

Soriano V. 2nd Intl Workshop on HIV and HCV 2006

PRESCO: Interim Analysis

• End-of-treatment results for 181 pts:– Overall, 63% response rate– 50% for GT 1– 85% for GT 2/3

• Highest response rates reported so far for coinfected pts.

HRN-004 SLAM-C ENDURE

Patient population Nonresponse F > 0/CPT < 6

AnyF > 0/CPT < 6

AnyCPT ≤ 8

Number of patients 100 300 468

Endpoint Histology/clinical

Histology/clinical

Clinical

Arm 1 PEG-IFN alfa2a 90 mcg

PEG-IFN alfa-2a 180 mcg

PEG-IFN alfa2b 0.5 mcg/kg

Arm 2 Observation Observation Observation

Treatment duration (years)

1.5 1.5 1.5

Recruitment status Complete Enrolling Launch 2006

2nd Intl Workshop on HIV and HCV 2006

Maintenance Therapy Trials for Prior Non-responders

Drugs in development

• Serine protease inhibitors• Polymerase inhibitors• Helicase inhibitors• Antisense therapy• siRNA• Toll-like receptor

agonists• Therapeutic vaccination• Cyclosporine analog• Improved Ribavirin and

Interferon Review: McHutchison JG. 2006 J Hepatol 44:411-21

Source: www.clinicalcareoptions

Hepatitis B: Epidemiology

• HBV very common worldwide, ~350 million infected

• 1.25 million Americans chronically infected

• 70,000 new cases annually in US

• HBV is 10x more common in HIV+ than in general population

• Highest rates among HIV+ seen in MSM (6-10%)

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006.Nunez M, et al. Lancet Infect Dis 2005.

Clinical-Epidemiologic CorrelationsHBV Endemicity

LocationAge of

InfectionMode of

TransmissionChronicity

HCC Risk

High 10-15%Asia

Sub-Sahara Africa

BirthToddler

PerinatalHorizontal

Likely High

Low < 2%N. AmericaW. Europe

Scandinavia

EarlyAdulthood

PercutaneousSexual

Rare Low

Available at: http://www.who.int/mediacentre/factsheets/fs204/en/. Accessed February 6, 2006.Designed by Jules Dienstag, MD

clinicaloptions.com/hep

Prevalence of Chronic Hepatitis B

HBsAg Prevalence

> 8% - High 2-8% - Intermediate< 2% - Low

Immigration numbers summed by continent from 1996-2002

~ 2 million Asians

~ 400,000South Americans

~ 350,000 Africans

~ 930, 000 Europeans

Centers for Disease Control. Hepatitis B fact sheet. Available at: http://www.cdc.gov/hepatitis. Accessed January 31, 2006. Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366. Hepatitis B Foundation. Hepatitis B statistics. Available at: http://www.hepb.org/hepb/statistics.org. Accessed January 31, 2006.

clinicaloptions.com/hep

Natural History of Chronic HBV Infection

0 10 20 30 40 50 60 70

Years

SerologyHBeAg Anti-HBe

ALT level

HBV DNA level

(viremia)

DiseaseChronic active

hepatitisCirrhosis/HCC

Immune tolerant (phase I)

Immune Active (phase II)

Non-Replicative (phase III)

Chronicity Stage

Minimal inflammation

Resolved

Normal to cirrhosis/HCC

HBsAg Anti-HBs

clinicaloptions.com/hep

Outcomes of Acute HBV Infection

Recover

Subclinical Hepatitis

Fulminant Hepatitis

Acute Hepatitis

ACUTE INFECTION

Chronic InfectionDEATH

< 1% 0.1-2.7%

5-20%

Risk is Related to Age at Infection

Outcome Neonates, % Children, % Adults, %

Chronic carrier 90 20 < 5

Recover 10 80 > 95

Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25. clinicaloptions.com/hep

Possible Outcomes of HBeAg+ Chronic HBV Infection

Patient Populations in Chronic Hepatitis B

MarkerImmuneTolerant

HBeAg+ CHB

Inactive HBsAg Carrier

HBeAg– CHB(Precore Mutant)

HBsAg + + + +

HBeAg + + – –

Anti-HBe – – + +

ALT Normal Normal

HBV DNA (copies/mL)

> 105 > 105 < 103 > 104

Histology Normal/Mild Active Normal Active

Lai CL, et al. Lancet. 2003:362:2089-2094. Lok AS, et al. Gastroenterology. 2001;120:1828-1853.

clinicaloptions.com/hep

Annual Risk of HBV Progression

HBeAg+ chronic hepatitis B

HBeAg-Neg chronic hepatitis B

Cirrhosis

Decompensation HCC

5.0%

1.0%-2.0%

3.0% 2.0%

All HBsAg +individuals

0.4%

Factors linked with progression

– Duration of “active”disease– Heavy alcohol use– Immune suppression (HIV)

Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25. clinicaloptions.com/hep

HBV DNA Level and Risk of HCCHBV DNA (copies/ml)

Cumulative incidence of

HCC

<300 1.30

300-9999 1.37

10,000-99,999 3.57

100,000-999,999 12.17

>1 million 14.89

Chen C-J. JAMA 2006; 295:67-73.

HBV Treatment Guidelines

HBeAgHBV DNA(IU/ml)*

ALT Management

+< 20,000 Normal#

Follow, no treatment

+≥ 20,000 Normal

Consider biopsy;treat if diseased

+ ≥ 20,000 Elevated Treat

–< 2,000 Normal

Follow, no treatment

–≥ 2,000 Normal

Consider biopsy;treat if diseased

– ≥ 2,000 Elevated Treat

*1 IU = 5.6 copies; #Normal ALT for men = 30 U/ml and for women = 19 U/mlKeeffe EB, et al. Clin Gastroenterol Hepatol.2006.

HBV/HIV Patient

• 41 yo gay white man with C3 HIV, hep B, cirrhosis

• eAg+, baseline HBV DNA 10 million copies/ml, ALTs in 40-50’s

• HIV well-controlled, CD4 787, HIV <30, on NVP, ddI, Kaletra (highly ARV experienced)

• Started on LAM 100 mg/d 9/05• Seen by me 6/06: VL 5.5 million, ALT 49• Any mistakes in treatment?• What medication should we use next?

Goals of Therapy in Patients With Chronic HBV Infection

• Eradication of infection– HBsAg seroconversion– Undetectable HBV DNA

• Prevent complications of liver disease– Histologic progression to cirrhosis– Decompensated liver disease– Liver cancer

clinicaloptions.com/hep

Therapeutic Endpoints• HBeAg-positive patients (wild type)

– HBeAg seroconversion is KEY– Sustained suppression of HBV DNA to low or

undetectable levels– ALT normalization– Reduced necroinflammation on biopsy

• HBeAg-negative patients (precore and core promoter mutants)– HBeAg seroconversion not an endpoint– Sustained suppression of HBV DNA to low or

undetectable levels– ALT normalization– Reduced necroinflammation on biopsy

clinicaloptions.com/hep

Approved anti-HBV drugs and those in development

Drug Class Phase Anti-HIV Active against YMDD

Interferon- Immune modulator

Approved Yes Yes

Peg-IFN- Immune Approved Yes Yes

Lamivudine Nucleoside Approved Yes No

Adefovir Nucleotide Approved Weak No

Entecavir Nucleoside Approved Yes Yes

Tenofovir Nucleotide I Yes Yes

FTC Nucleoside I Yes No

Telbivudine Nucleoside III No No

Clevudine Nucleoside III No Yes

DAPD Nucleoside II Yes Yes

Nunez M, et al. Lancet Infect Dis 2005.

Responses to anti-HBV agents in HIV/HBV coinfected patients

IFN LAM ADV ETV FTC TDF

# pts 87 230 35 51 33 200

HBV DNA ↓

26% 2.7 log 4.7-6 log 3.6 log - 4.4 log

E sero-

Convert

9% 11% 7% - - 4%

ALT normalize

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

Histology

improve

- - 33-50% - - -

Benhamou Y. J Hepatol 2006.

HBV Treatment Algorithm in HIV/HBV Coinfected Patients

HBVsAg-positive

ALT

HBVeAg

HBV DNA >104

Biopsy

Normal Elevated

Negative Positive

No Yes No Yes

Normal Hepatitis

Rx

Rx

Rx

Rx

Nunez M. Lancet Infect Dis 2005

Lamivudine (3TC, Epivir)

• Nucleoside analog• Different dose for HBV (100 mg)

monotherapy, use 300 mg for HIV+ and never alone

• Well-tolerated and cheap• eAg conversion rate b/t 21-28%• High rates of resistance!

– 47% develop YMDD mutation at 2 yrs, 90% at 4 yrs

Adefovir (Hepsera)

• Nucleotide analog

• At 10 mg/d dose, no HIV activity

• Effective for LAM resistant HBV, no cross-resistance

• Side effects: renal toxicity, Fanconi’s Syndrome

Tenofovir (Viread)

• Nucleotide analog not approved for HBV

• Perhaps more potent than Adefovir– 48 wk mean decline in HBV DNA (log10) 4.4

vs 3.2

• 63% had HBV suppression by wk 48, 15% had anti-HBe seroconversion

• Rare cases of ADV resistance but TDF sensitivity

Schildgen O. 2006 N Engl J Med 354:1807-12Peters M. CROI 2005; Abstract 124.

Entecavir (Baraclude)

• Nucleoside analog

• No HIV activity

• Good for LAM failures– 84% of patients had 2 log decline or <400

copies/ml after 24 wks

• Cross-resistance can occur w/ LAM

• Start w/ higher dose (1.0 mg/d) Entecavir in HIV/HBV patients

Peg-interferon (Pegasys)

• Long acting form of IFN, once weekly• Pros: defined duration (48 wks), low resistance• Cons: Many side effects, expensive, not for

decompensated cirrhosis• No data in HIV+, probably lower response than

in HIV-• In HIV-, PEG better than LAM

– 27% seroconversion, 4.5 log HBV DNA reduction, 3% sAg loss

Treatment Options for HIV/HBV Coinfected Patients

Only HBV therapy indicated

HBeAg-positive Pegylated IFN

Entecavir

Adefovir

HBeAg-negative Entecavir

Adefovir

HIV and HBV therapy indicated

HAART including TDF +/- LAM or FTC

HAART + (ADV or ETV)

Only HIV therapy At least one HBV active drug to avoid flares

Nunez. Lancet Infect Dis 2005.

Back to the patient

• 41 yo gay white man with C3 HIV, hep B, cirrhosis

• eAg+, baseline HBV DNA 10 million copies/ml, ALTs in 40-50’s

• HIV well-controlled, CD4 787, HIV <30, on NVP, ddI, Kaletra (highly ARV experienced)

• Started on LAM 100 mg/d 9/05• Seen by me 6/06: VL 5.5 million, ALT 49• Any mistakes in treatment?• What medication should we use next?

Web Resources• www.aasld.org• www.hivandhepatitis.org• www.hepwebstudy.org• www.cdc.gov/ncidod/

diseases/hepatitis/c/index.• www.idsociety.org

Good Reviews

• Sulkowski MS. Treatment algorithm for the management of hepatitis C in HIV-coinfected person. 2006. J Hepatol 44:S49-55

• Nunez M, Soriano V. Management of patients coinfected with hepatitis B virus and HIV. 2005. Lancet Infect Dis 5:374-82

• Tien P, Wright T. Management and treatment of hepatitis C virus infection in HIV-infected Adults: Recommendations from the Veterans Affairs Hepatitis C Resource Center Program and National Hepatitis C Program Office. 2005. Am J Gastro 100: 2338-54.

• Benhamou Y. Treatment algorithm for chronic hepatitis B in HIV-infected patients. 2006. J Hepatol 44:S90-94.

Thanks!