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Transcript of HEPATITIS B AND C Dr. Jürgen K. Rockstroh Department of Internal Medicine I University Hospital...
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