HEPATITIS B AND C

Dr. Jürgen K. Rockstroh

Department of Internal Medicine IUniversity Hospital BonnGermany

380 million HBV-infected subjects worldwide

Dienstag JL, et al. N Engl J Med 2008;359:1486–500

Hepatitis delta in HIV-infected individuals in Europe

Soriano V, et al. AIDS 2011;25:1987–92

• The EuroSIDA study was analysed for anti-HDV in chronic HBsAg positive/HIV carriers:– Prevalence of anti-HDV: 14.5%– HDV increases the risk of liver-related deaths and mortality in

HIV patients

Total no. patients 16,597

HBsAg+ 1,319 (7.9%)

Anti-HDV Ab+61/422 (14.5%)(95% CI: 11.1–17.8)

HDV-RNA+31/38 (81.6%)(95% CI: 69.3–93.9%)

HIV/HBV co-infection: Natural course of hepatitis B

Lacombe K, Rockstroh J. Gut 2012;61 (Suppl 1):i47–58

• HIV-patients 3–6x more likely to develop chronic course of HBV than HIV-negative patients undergoing acute HBV infection

• Hepatitis B in HIV is characterized by particularly high HBV replication markers

• In contrast to the increased signs of HBV replication, often only mildly elevated or even normal liver enzymes

Live

r re

late

d m

orta

lity

rate

/100

py

0

2

4

6

8

10

12

14

16

HBV HIV HIV/HBV

Mortality of HIV/HBV co-infection pre-HAART

Thio CL, et al. Lancet 2002;360:1921–6

Treatment options for HIV/HBV

Drug HBV HIV

3TC / FTC ++ ++

Tenofovir +++ +++

Adefovir ++ ?

Entecavir +++ +

Telbivudine +++ -/+

IFN / Peg-IFN +++ +

Therapy

Do you need to treat HBV?

EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

HBsAg+

Yes No

>2000 <2000

No

Elevated Normal

Cirrhosis

HBV DNA

ALT

Current guidelines for management of HIV/HBV co-infection

EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

HBV Rx indicatedNo HBV Rx indicated

CD4 >500/ul AND no indication for ART

CD4 <500/ul or symptomatic HIV or

cirrhosis

3TC experienced3TC naive

• Early ART including TDF + FTC or 3TC

• Peg-IFN if genotype A, high ALT, low HBV DNA

Monitor closelyAdd or substitute

one NRTI with TDF

as part of ART

ART including TDF

+3TC or FTC

HIV/HBV co-infection

Liver disease associated mortality in HIV 1995–2003 GERMIVIC

Rosenthal E, et al. J Viral Hepat 2007;14:183–8

• ESLD associated death: % total mortality

• ESLD associated death: % HBsAg+

1995 1997 2001 20030

2

4

6

8

10

12

14

16

1.5

6.6

14.3

12.6

1995 1997 2001 20030

5

10

15

20

25

30

35

40

45

3842

21

7

Protective effect of HBV-active cART against primary HBV-infection

Brinkman K, et al. 20th CROI; Atlanta, GA; 2013. Abstract 33

• Question: Does HBV-active cART protect against new HBV infection (HBV-PrEP)?

• Patient Selection: All HBV-susceptible patients at entry, anti-HBc and anti-HBs negative (<10 IU/L) and 2nd sample available in time for follow-up HBV serology

• All patients n=2,924, msm n=2,280, HBV susceptible + 2 samples available n=349

1 case: woman (HBsAg negative)1 case: heterosexual man (HBsAg negative)33 cases MSM

Hepatitis (ALT 2x) 7 (20.0%)HBsAg + 6 (17.1%)HBeAg + 6 (17.1%)

New HBV Cases (N=35)

2000 4000 0

20

40

60

80

100

Observation Time (Days)

Cu

mu

lati

ve

HB

V-f

ree

su

rviv

al

(%)

Log-rank

P = 0.004

P < 0.001

Log rankP < 0.001

Numbers in ObservationNo TreatmentTreatment, No TDFTreatment, with TDF

10786

189

506749

193638

8

1612

Kaplan Meier: HBV-free survival (MSM)

Brinkman K, et al. 20th CROI; Atlanta, GA; 2013. Abstract 33

No treatmentHBV-active treatment, no TDFHBV-active treatment, with TDF

0 6000

170 million people infected with HCV3–4 million new infections each year

Dienstag JL, et al. N Engl J Med 2008;359:1486–500; Lavanchy D. Clin Microbiol Infect 2011;17:107–15

Prevalence of HCV in the HIV population (1960/5957 patients = 33%)

Rockstroh J, et al. J Inf Dis 2005;192:992–1002

South: 695 = 41.4%

North: 359 = 23.2%

Central: 293 = 19.6%

East: 613 = 46.9%

Regions:SouthCentralNorthEast

HCV co-infection in EuroSIDA

1. Rockstroh J, et al. J Infect Dis 2005;192:99–1002; 2. Soriano V, et al. J Infect Dis 2008;198:1337–1344

• Prevalence of HCV seropositivity in EuroSIDA is 33%1

• Of 1940 HCV Ab+ patients, 77% were serum HCV RNA-positive (95% CI: 75% to 79%)2

Distribution of HCV by Genotype (1–4) in European Regions2

Northern Europe

0

20

40

60

1 2 3 4Southern

EuropeCentral Europe

Eastern Europe

1 2 3 4 1 2 3 4 1 2 3 4Genotype

Background

1. Rockstroh J, et al. Am J Gastroenterol 1996;91:2563–2568; 2. Graham CS, et al. Clin Infect Dis. 2001;33:562–569; 3. Weber R, et al. Arch Intern Med 2006;166:1632–41

• HIV accelerates the natural course of hepatitis C1

• Successful HAART can slow down fibrosis progression but not back to the rate in HCV mono-infection²

• Liver disease associated with HCV infection has becomea leading cause of morbidity and mortality among HIV-infected patients³

Impact of ART on overall liver mortality in HIV/HCV co-infected patients

Qurishi N, et al. Lancet 2003:362:1708–13

• Bonn cohort (1990–2002)– 285 HIV/HCV co-infected

patients• Liver-related mortality rates per

100 person-years– HAART: 0.45– ART: 0.69– No therapy: 1.70

• Predictors for liver-related mortality– No HAART– Low CD4 cell count– Increasing age

0 1000 2000 3000 4000 5000 60000.2

0.4

0.6

0.8

1

Days

Overall Mortality

Cu

mu

lati

ve s

urv

ival

ART

HAART*

No therapy*P < 0.001

0.2

0.4

0.6

0.8

1

Days

Liver-Related MortalityC

um

ula

tive

su

rviv

al

0 1000 2000 3000 4000 5000 6000

HAART*ART

No therapy

*P = 0.018

Standardized cumulative incidenceof hepatic decompensation

Lo Re V, et al. 19th IAC; Washington, DC; 2012; Abstract WEAB0102

0

0.1

0.2

0 1 2 3 4 5 6 7 8 9 10

Cu

mu

lati

ve I

nci

den

ce

Years to Hepatic Decompensation

P < 0.001

HIV/HCV co-infectedHCV monoinfected

0.074

0.048

Hepatic decompensation risk 83% higher in the co-infected group(aHR 1.83, 95% CI: 1.54 to 2.18)

EACS guidelines: When to start

• Initiation of ART– ART is always recommended if CD4 count <350 cells/mm3

– Serodiscordant couples: Early ART should be considered and actively discussed

– Serodiscordant couples: Early ART should be considered and actively discussedCondition

Current CD4 + lymphocyte count

350–500 >500

Asymptomatic HIV infection C D

Symptomatic HIV disease (CDC B or C conditions) incl. tuberculosis R R

Primary HIV infection C C

Pregnancy (before third trimester) R R

Conditions (likely or possibly) associated with HIV, other than CDC stage B or C disease:

HIV-associated kidney disease R R

HIV-associated neurocognitive impairment R R

Hodgkin's lymphoma R R

HPV-associated cancers R R

Other non-AIDS-defining cancers requiring chemo- and/or radiotherapy C C

Autoimmune disease — otherwise unexplained C C

High risk for CVD (>20% estimated 10 yr risk) or history of CVD C C

Chronic viral hepatitis

HBV requiring anti-HBV treatment R R

HBV not requiring anti-HBV treatment C/R D

HCV for which anti-HCV treatment is being considered or given R D

HCV for which anti-HCV treatment not feasible R C

C = CONSIDER; D = DEFER; R = RECOMMENDED

EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

Median CD4-Nadir according to year of ART start and different HIV transmission groups (n=3094)

Rockstroh J. Antivir Ther 2012;17:1223–5

• Median CD4-Nadir 45 days prior to and up to 15 days after ART initiation (treatment was initiated ≥1996 and only inclusion of patients with treatment start after being in the cohort for at least 3 months)

0

50

100

150

200

250

300

350

400

450

CD

4 ce

ll c

ou

nt

(cel

ls/μ

l)

Months prior to start of ART

MSM IDU HET HPL unknown Total

Current and cumulative exposure to HCV treatment

Mocroft A, et al. EACS Conference 2009. Abstract PS2/3

0

200

400

600

800

1000

0

5

10

15

20

25

30

2003 2004 2005 2006 2007 2008

On treatment Ever started treatment N Under follow-up

Calendar year

Pro

port

ion

N u

nde

r follo

w-u

p

Pivotal RCTs for Peg-IFN/RBV in HIV/HCV co-infection

1. Carrat F, et al. JAMA 2004;292:2839–48; 2. Laguno M, et al. Hepatology 2009;49:22–31; 3. Chung RT, et al. N Engl J Med 2004;351:451–9; 4. Torriani FJ, et al. N Engl J Med 2004;351:438–50; 5. Núñez M, et al. AIDS Res Hum Retroviruses 2007;23:972–82

Study Regimen SVR (%) G1 or G4

SVR (%)G2 or G3 Take home observations

RIBAVIC1

France(N = 412)

Peg-IFN α-2bRBV 800 mg 17 44

Low-dose RBVToxicity with ddI + RBVFailure to suppress HCV RNA at week 4 <460,000 IU/mL → 100% NPV

Laguno et al2

Spain(N = 182)

Peg-IFN α-2bRBV 800 – 1200 mg

28 62Weight-based RBV → higher SVRShort (24-week) therapy for genotype 2/3 not effective

ACTG A50713

USA(N = 133)

Peg-IFN α-2aRBV 600 - 1000 mg

14 73Low-dose RBVFailure to achieve week 12 EVR → 100% NPV ZDV + RBV → more anemia

APRICOT4

International(N = 868)

Peg-IFN α-2aRBV 800 mg 29 62

Low-dose RBVDecompensation with advanced fibrosis Genotype 1/High HCV RNA –18% SVR

PRESCO5

Spain(N = 389)

Peg-IFN α-2aRBV 1000 – 1200 mg

35 72Weight-based RBV → higher SVRNo increase in anemiaLong (72-week) therapy not well tolerated

HCV infection can be cured

1. Torriani FJ, et al. New Engl J Med 2004;351:438–50; 2. Soriano V, et al. Antivir Ther 2004;9:987–92; 3. Berenguer J, et al. Hepatology 2009;50:407–13

• Testing and counseling• Treatment of chronic infection

– Sustained virologic responseis possible1

– Sustained virologic responseis durable2

– Sustained virologic responseprevents death3

Survival after HCV treatment for493 with no SVR and 218 with SVR

Months after HCV treatment

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36 42 48

P = <0.001 by log-rank test

No SVR

SVR

Proposed optimal duration of HCV therapy in HCV/HIV co-infected patients

EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

*In patients with baseline low viral load & minimal liver fibrosis W, week; neg, negative; pos, positive; G, genotype**Where no access to DAA available or high chances of cure even with dual therapy (favourable IL28B genotype, low HCV viral load and no advanced fibrosis)

HCV-RNA negative

W4 W12 W24 W48 W72

G2/3

G1/4**

Stop

Stop

G2/3

G1/4

24 weeks’therapy*

48 weeks’therapy

72 weeks’therapy

HCV-RNA positive

HCV-RNA negative

HCV-RNA positive

>2 log drop in HCV-RNA

<2 log drop in HCV-RNA

Se-ries1

0

10

20

30

40

50

60

70

80

90

71 69

8074

33

50 5045

100

Pat

ient

s w

ith u

ndet

ecta

ble

HC

V R

NA

(%

)

No ARTEFV/TDF/FTCATV/r/TDF/FTCTotal

n/N = 5/7 11/16 12/15 28/38

T/PR PR2/6 4/8 4/8 10/22

*Prior to Week 24 visit, 1 patient in this cohort was lost to follow up. SVR24 was imputed based on SVR12 for this patient

Study 110: SVR at post-treatment week 24 (SVR24)

Sulkowski MS, et al. Ann Intern Med 2013 [Epub ahead of print]

Interim analysis: SVR rates 12 weeks post-treatment (SVR12)

Mallolas J, et al. EASL 2012; Abstract 50

• Interim efficacy analysis– 3 BOC patients had not yet reached SVR12 time point

0

20

40

60

80

100

SV

R12

(%

)

P/R

n/N = 9/34

26.5

37/61

60.7*

BOC + P/R*3 patients with missing data achieved SVR4

W4 W8 W12 W160%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

<LLOQ (<15 IU/mL) U

% H

CV

-RN

ATelaprevir + Peg-IFN + RBV in HIV/HCV co-infected patients with virologic failure on IFN + RBV: Virologic response

Cotte L, et al. 20th CROI; Atlanta, GA; 2013. Abstract 36

TND

RVR8 EVR16

88% 88%88%

1.5%

UndetectableTND <LLOQ (<15 IU/mL)

Associated ARVs Fibrosis Stage Previous Response

0%

20%

40%

60%

80%

100%88%

92%85%

92%87%

83%

92%

82%

100%

80%

94%

86%

% H

CV

-RN

A <

15 I

U/m

LTelaprevir + Peg-IFN + RBV in HIV/HCV co-infected patients with virologic failure on IFN + RBV: Early virologic response by patient group

Cotte L, et al. 20th CROI; Atlanta, GA; 2013. Abstract 36

n= 34 13 12 10 12 30 11 16 27 6 15 21

ATVrEFV

RAL

Other

sF1 F2 F3 F4 RR

BrkTh

PR NR

Grade 3–4 AEs and treatment discontinuations up to week 16

  N (%), n=69Grade 3 AEs

BloodGeneralGICutaneousNeurologicalPsychiatricOthers

18 (26%)6 (9%)5 (7%)2 (3%)3 (4%)2 (3%)1 (1%)2 (3%)

Grade 4 AEsBloodPsychiatric

5 (7%)4 (6%)1 (1%)

Reasons for treatment discontinuationsPsychiatric AEsCutaneous AEsOthers AEsVirological failure

3 (4%)3 (4%)1 (1%)1 (1%)

BOC/IFN/RBV following virologic failure: Results by ARV regimen

Pizot-Martin I, et al. 20th CROI; Atlanta, GA, 2013; Abstract 37

All (n=64) 2NRTI/ATVr (n=32)

2NRTI/RAL (n=27)

Others (m=5)0%

10%20%30%40%50%60%70%80%90%

100%

44%37%

52%

40%

63%56%

70%

60%

Patients (%) with HV-RNA <15 IU/mL

W4 W6 W8 W12 W16

RVR 8

EVR 16

BOC/IFN/RBV following virologic failure: Results by previous response to Peg-IFN + RBV

Pizot-Martin I, et al. 20th CROI; Atlanta, GA; 2013. Abstract 37

Relapse n= 20 (31%)

Breakthrough n= 5 (8%)

Partial Responsen= 18 (28%)

Null Respondern= 21 (33%)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

70%

40%

55%

10%

90%

60% 61%

38%

W4 W6 W8 W12 W16

% H

V-R

NA

<1

5 U

I/m

L

RVR 8

EVR 16

Breakthroughn= 5 (8%)

Summary of key DAA and ARV DDI recommendations

Telaprevir EU SmPC; Boceprevir EU SmPC; Kakuda TN, et al. IWCPHT 2012. Abstract O-18

  TVR BOC

ATV/rMonitoring for hyperbilirubinemia

recommendedConsider on a case by case basis if deemed necessary

DRV/r/, FPV/r LPV/r

Not recommended Not recommended

EFV Increase TVR to 1250 mg q8h Not recommended

ETR No dose adjustment needed No dose adjustment needed

RPV No dose adjustment needed No dose adjustment needed

RAL No dose adjustment needed No dose adjustment needed

TDFIncreased monitoring is

warrantedNo dose adjustment needed

New treatment options for HIV/HCV genotype 1 patients: EACS guidelines

EACS Guidelines, September 2012, Version 7.0. Available at: http://www.viraled.com/modules/info/files/files_50b4f84a4a3ac.pdf. Accessed June 2013

• With first pilot studies in HIV/HCV-co-infected subjects demonstrating significant higher SVR12 rates with triple therapy compared to dual therapy HCV protease inhibitor based therapy with either boceprevir or telaprevir is now the new standard of treatment in HCV genotype 1 infection in HIV-infected individuals where available

• Although shorter treatment durations of triple therapy have been demonstrated to be very efficacious in HCV monoinfected subjects with rapid virological response this data so far is not available for HIV/HCV co-infected subjects

Ongoing or upcoming clinical trials in HIV/HCV co-infection

• Boceprevir ACTG Study (RVR guided therapy)• Vertex 115 (RVR guided therapy)• Vertex Study in cirrhosis and HIV/HCV co-infection• BI 201335 + Peg-IFN/RBV in HIV/HCV

co-infected patients 1220.19 study • C212 TMC-435 (RVR guided therapy)• COMMAND-HIV (AI444-043) BMS790052 (RVR guided therapy)• PHOTON 1 Study: GT1 HIV/HCV co-infected treatment-naïve (TN)

and GT- 2/3 TN and experienced subjects with sofosbuvir + RBV 12–24 weeks

• AbbVie IFN-free treatment trial

Newly diagnosed chronic HCV GT 1 infection

F2F3a

In general, treatment can be deferred

Consider treatment with Peg/RBV and an HCV protease inhibitor or Peg/RBV alone if low HCV viral load, IL28B CC genotype, absence of insulin resistance and high CD4 count

Treatment with Peg/RBV and an HCV protease inhibitor if compensated disease

Treatment should be undergone in specialised centres

aMetavir fibrosis score: F0=no fibrosis; F1= portal fibrosis, no septae; F2= portal fibrosis, few septae; F3=bridging fibrosis; F4=cirrhosis; Peg, pegylated interferon; RBV, ribavirin

Management of newly diagnosed HIV/HCV co-infected genotype-1 patients

Ingiliz P. & Rockstroh J. Liver Int 2012;32:1194–9; EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

Perform Fibroscan® and/or serum marker and/or liver biopsy

F0F1a F4a

Treatment with Peg/RBV and an HCV protease inhibitor

F0F1

F2F3

F4

Naive Relapser Nonresponder

Individual decision

Individual decision/

triple therapyDefer

Triple therapy Triple therapy

Individual decision according to

disease progression

Triple therapy Triple therapy Triple therapy

Management of HIV/HCV GT1-co-infected patients (chronic) according to prior treatment outcome

Ingiliz P. & Rockstroh J. Liver Int 2012;32:1194–9

DISCUSSION / Q&A

CLOSING REMARKS

Dr. Nicholas Paton

Singapore