Download Hepatitis B - HIV Coinfection

HBV/HIV co-infection
Hartwig Klinker
University of Würzburg Medical School
Medical clinic II
Division of Infectious diseases
Mwanza, Bugando Hospital, 11. 2. 2015
1
Chronic viral hepatitis – clinical symptoms
•Uncharacteristic!:
weakness, tiredness, loss of appetite, nausea, flatulence,
itch, bone pain
Only seldom characteristic:
jaundice, brown colour of urine
2
Chronic viral hepatitis
- complications Chronic Hepatitis B in Germany: 300.000-500.000
Chronic Hepatitis C in Germany: 500.000-800.000
acute hepatitis B/C
5-10%
60-80%
Chronic hepatitis
Fibrosis
Normal liver tissue
20%-30%
5%
Cirrhosis
Hepatocell. carcinoma
3
Chronic viral hepatitis – disease burden
Razavi H et al., J Viral Hep, 2014; Suppl 1, 34-59
4
Hepatitis B
5
Diagnosis of hepatitis B
HBsAg
Infectious
HBeAg
„high“ viral replication
Anti-HBc
Contact with wild-type HBV
Anti-HBe
„low“ viral replication
Anti-HBs
Immunity
HBV-DNA
Most sensitive test
for viral replication6
Clinical course of hepatitis B
Chronic disease
HBV-infection > 6 months
Risk:
vertical transmission
> 90% (immunsystem insuff.)
adults
5-10%
Inflammatory activity
AST/ALT, histologically (HAI)
Fibrosis/Cirrhosis
HAI, clinical examination
7
Elastography
- advantages towards biopsy
• fast (5-10 min)
• To be carried out by medical assistents
• Mobile machine
• Free of pain, to be carried out in an outpatient unit
• Reproducible
– Intra-investigator ~ 98%
– Inter-investigator ~ 90-98%
• Investigated volumen of the liver much larger
– 4cm³ with fibroscan
– ~0,04cm³ with biopsy (4cm long cylinder)
8
Clinical course of hepatitis B
Chronic disease
HBV-infection > 6 months
Risk:
vertical transmission
> 90% (immunsystem insuff.)
adults
5-10%
Inflammatory activity
AST/ALT, histologically (HAI)
Fibrosis/Cirrhosis
HAI, clinical examination
Viral activity
Viral load
9
Hepatitis B viral load and development of cirrhosis
Prospective Cohort-study, n = 3.582, mean follow-up 11 years, 40.038
patient-years
10
U. H. Iloeje et al.: Gastroenterology 2006; 130: 678-686
Hepatitis B-viral load and risk of HCC
Prospective Kohortstudy, mean follow-up 11,4 years, 41.779 patient-years
>106
105 -106
>106
105 -106
104 - 105
<104
All patients (n= 3.653)
104 - 105
<104
HBeAg negative patients with normal
liver enzymes and without cirrhosis at
the time of enrollment (= 2.925)
11
C. J. Chen et al.: JAMA 2006; 295: 65-73
Aims of HBV-treatment
Longterm
decrease of
HB-viral-load
optimized and persistent
clinical outcome
Requires a shortterm, definite treatment in
some patients, many other patients need a
longterm viral-supressive therapy
12
Therapy of chronic Hepatitis B: indication
Hepatitis B Leitlinie 2011
13
Therapy of chronic Hepatitis B: algorithm
Nukleos(t)idanaloga
Modifiziert nach Hepatitis B Leitlinie 2011
14
Therapy of chronic hepatitis B
• HBV-genotype A
• low viral-load
• High liver enzymes
• Significant inflammation in
histological examination
HBeAg-Serokonversion
Standard I: PEG-Interferon α-2a 1x180 µg/week for 48 weeks
60
52
50
40
• HBV-infection as an adult
• Compensated liver disease
HBeAg-Serokonversion
• Female
31
30
30
22
20
10
0
Typ A
• HBeAg positive
HBV-genotype
45
40
35
30
25
20
15
10
5
0
41
Typ B
Typ C
Typ D
ALT-level
30
29
ALT 2-5 x ULN
ALT < 2 x ULN
15
ALT > 5x ULN
Interferon-therapy of HBeAg-positive
chronic hepatitis B
Analysis from 15 studies, 837 patients,
IFN 5-10 Mio IU 3x/week for 4-6 months
Interferon
Placebo
Patients (%)
50
40
33%
30
Reduced efficacy
in case of precore-mutation
20
(HBeAg -/HBV-DNA +)
12%
10
!!!!!!!!!
8%
2%
0
HBeAg loss
HBsAg loss
Wong et al, Ann Intern Med
16 1993
Therapy of chronic Hepatitis B: algorithm
Nukleos(t)idanaloga
Modifiziert nach Hepatitis B Leitlinie 2011
17
Therapy of chronic Hepatitis B: algorithm
2011
Standard I: PEG-Interferon α-2a 1x180 µg/week für 48 weeks
Standard II: Nukleos(t)de analogues for ? months/years
Licenced:
Lamivudine 100 mg 1x/d
Adefovir 10 mg 1x/d
Entecavir 0,5 mg 1x/d
Telbivudin 600 mg 1x/d
Tenofovir 245 mg 1x/d
18
Therapy of chronic hepatitis B
example
HBeAg
+
75
Patients
67
60%
46
Week 24
Week 48
Week 72
44
41
40%
26
20%
23
14
23
14
13
8
Viral load
<400 copies/ml
Normal
liver enzymes
HBeAg
loss
HBeAg
HBeAg-antibodies
Marcellin et al. Hepatology. 2002; 36 (4 pt19
2): 373A.
Therapy of chronic hepatitis B
example
Change of viral load (log)
Viral load: 7 log10 copies/ ml
0
=70.000.000
copies/ml
Placebo
- 1,0
Change of viral load
- 2,0
- 3,0
ADV
- 4,0
0
4
8
12 16 20 24 28 32 36 40 44 48
= Reduction
99,99%
Week
P < 0,001
Reduction
3,91 log10 copies/ ml
20
Antiviral efficacy of HBV-nucleos(t)ides
(Data after 48-52 weeks of treatment)
* No “head-to-head” studies
HBeAg(+)
100
80
HBV DNA unter der
Nachweisgrenze
(% Patienten)
76
60
80
67
Entecavir
94 90
Telbivudine*
88
60
60
40
40
36
20
0
*Undetectable <300 copies/mL
#Undetectable <400 copies/mL
§Undetectable <1000 copies/mL
30.04.2017
Tenofovir
HBeAg(-)
25
72
63
51
Lamivudine*
Peg IFN#
21
20
Adefovir§
0
Lai CL, et al. Hepatology 2005; 42:748A (AASLD Abstract
LB01); Lau G, et al. NEJM 2005; 352:2882–2695; Chang T-T,
et al. NEJM 2006; 354:1000–1010; Marcellin P, et al. NEJM
2003;348:808–816; Marcellin et al., AASLD 2007, Heathcote
et al., AASLD 2007
21
21
Therapy of chronic Hepatitis B
- Nucleosideanalogues -
To begin is easy….
…. the problems
are coming later!
22
Cumulative incidence of HBV- resistance during
treatment of chronic hepatitis B with
nukleos(t)idanalogues
Problem:
Development of resistance
EASL Clincal Practice Guidelines, J Hepatol 2009; 50: xxx, 23
in press
Potenz und genetische Resistenzbarriere
HBV-wirksamer Virustatika
V. Soriano et al., AIDS 2008, 22: 1399-1410
24
Crossresistance in vitro
YMDD
V173L
L180M
A181V A184G
S202I
M204I
M204V N236T
M250V
LAM
Lamivudine
ETV
Entecavir
LdT
Telbivudine
FTC*
Emtricitabine
ADV
Adefovir
TDF*
Tenofovir
25
Yang H. et al. Hepatology 2003;38:705A Lai CL et al Hepatology 2003;38:262A, adopted from S Locarnini rt al
Antivir Ther 2004;9:679-93 *Bisher nur zur Behandlung der HIV-Infektion zugelassen
Therapy of chronic Hepatitis B: algorithm
2011
Standard I: PEG-Interferon α-2a 1x180 µg/week für 48 weeks
Standard II: Nukleos(t)de analogues for ? months/years
Licenced:
*
Lamivudin
100 mg 1x/d
*
Adefovir
10 mg 1x/d
Entecavir 0,5 mg 1x/d
*
Telbivudin
600 mg 1x/d
Tenofovir 245 mg 1x/d
26
Entecavir: Virological response and HBeAg-status
(HBV DNA below the limit of detection)
HBeAg negative
HBeAg positive
100%
100
88% 87%
96%
99% 100%
90%
80
66%
Patients %
Patients %
80
100
94%
98%
60
41%
40
74%
60
40
20
20
0
0
6
12
24
36
48
54
Months
6
12
24
36
48
54
67
66
48
35
29
12
Patients on f-up
338
327
296
260
167
58
Lampertico P, et al. EASL 2012; Poster #522
27
Improvement of histological findings during
antiviral longterm-treatment
- Decline of fibrosis/cirrhosis -
before
Lamivudin
after Lamivudin (3 years)
28
J. L. Dienstag: Gastroenterology 2003; 124: 105-117
Tenofovir: Fibrose-Scores at baseline, year 1 and 5
P < 0.001*
0.001
P < 0.001*
0.001
100
Ishak Fibrosis
Scores
12%
90
6
38%
80
70
5
60
4
50
3
40
2
63%
30
1
39%
20
10
0
0
Baseline
Year 1
Year 5
Results from 348 patients
Afdhal N, et al. EASL 2012; Poster #497
29
Cumulative development rates of HCC (%)
Hepatocellular carcinoma incidence rates
with/withou antiviral therapy (Entecavir)
50
40
Log-rank test: p<0.001
30
20
Control (n=316)
13.7%
10
7.2%
4.0%
0.7%
0
0
No at risk
ETV 316
Contro 316
l
1
1.2%
10.0%
2.5%
3
ETV (n=316)
3.7%
5
7
Treatment duration (yr)
316
316
264
277
185
246
101
223
4
200
4
2
187
2
170
Hosaka T, et al. AASLD 2012, Boston, MA. Poster 357.
30
Risk of Hepatitis B-reactivation during chemotherapy in
patients with malignant lymphoma
Kusumoto S et al., Int J Hematol 2009; 90: 13-23
31
How to avoid Hepatitis B reactivation
32
HBV/HCV/HIV
coinfection
33
Hepatitis B, Hepatitis C, HIV-infection
- Prevalence -
350.000.000
170.000.000
34.000.000
34
Viral hepatitis and HIV-infection
Epidemiology in Germany
• Chronic hepatitis B-infection: 300.000 - 500.000
• Chronic hepatitis C-infection: 500.000 - 800.000
• HIV-infection: 80.000
• AIDS: 6.000
• Chronic hepatitis B/HIV-Coinfection: 4.000
• Chronic hepatitis C/HIV-Coinfection: 8.000
RKI 12.14
Chronic hepatitis B/C/D in HIV-infection
- general problems • Influence of viral hepatitis on the course of HIV-infection
• Influence of HIV-disease on the course of viral hepatitis
In HIV-patients in europe, USA and australia liver
• Chronic liver disease due to viral hepatitis
disease
is theof main
cause(enzyme
of non-AIDS-related
 Alteration
drug metabolism
induction or inhibition)
• (additional) liver impairment due to antiretroviral drugs
death!
(D:A:D Study, R. Weber et al., Arch Intern Med 2006; 166:1632-1641)
• Pharmacological interactions between antiviral drugs used for
HBV-/HCV-/HIV-treatment
36
Mechanisms of liver toxicity due to antiretroviral
drugs
M. Nunez, J Hepatol 2006, 44 (Suppl 1) 132-139
37
Hepatotoxicity under ART
Autor
N
ART
HCV
CD4
rate
predictive
Rodriguez1
132
PI-based
62%
324
11%
HCV, Alc.
Sulkowski2
211
PI-based
51%
109
12%
HCV, CD4
Saves3
1249
2 NRTIs
44%
234
6%
HCV, HBV
den Brinker4
394
PI-based
22%
150
18%
HCV, HBV
Martínez5
610
NVP-based 51%
279
9.7%
HCV, ALT
Núñez6
222
ART
337
9%
HCV, Age,
40%
Alc.
1. Rodriguez-Rosado et al. AIDS 1998;12:1256.
4. den Brinker et al. AIDS 2000;14:2895.
2. Sulkowski et al. JAMA 2000;283:74. 3. Saves et al. AIDS 1999;13:F115.
5. Martínez et al. AIDS 2001;15:1261. 6. Núñez et al. J AIDS 2001;27:426.
38
Chronic viral hepatitis
- complications acute hepatitis B/C
5-10%
60-80%
Chronic hepatitis
Fibrosis
Normal liver tissue
20%-30%
20-30 years Cirrhosis
5%
Hepatocell. carcinoma
39
Chronic viral hepatitis
- complications -
*
Peculiarity in HIV-coinfection
acute hepatitis B/C
*
5-10%
60-80%
Chronic hepatitis
Fibrosis
Normal liver tissue
20%-30%
*
20-30 years Cirrhosis
5%
Hepatocell. carcinoma
40
Viral hepatitis and HIV- coinfection
General recommendations
1st European Consensus Conference on the Treatment of Chronic Hepatitis B and C in HIV Co-infected Patients
Diagnostic of viral hepatitis in the same way as in patients without HIV!
No alcohol consumption (AII)
Prevention of sexual transmission/safer sex (AII)
In case of sero-negativity HBV-/HAV-Immunisation (AII)
In case of advanced fibrosis/cirrhosis HCC-Screening
(US/AFP) (AI) + EGD (varices?) (AII)
A. Alberti et al, J Hepatol 2005; 42: 615-624
41
HIV/HBV
42
HBV-HIV-coinfection:
liver associated mortality
DT Dietrich: Topics in HIV Medicine 2003; 11: 16-19
nach: Thio et al.: Lancet 2002; 360: 1921-192643
Hepatitis B - Infection in
patients with HIV -infection
- course of acute hepatitis Homosexual males
HIV-AB + HIV-AB (n=31)
(n=46)
Jaundice
Chronic hepatitis
CD4-cells in case of chronic hep.
CD4-cells in case of self-limiting hep.
3/31 (10%) 11/46 (24%)
7/31 (23%) 2/46 (4%)
352  33 /µl
547  51
N. Bodsworth, J.Infect.Dis. 1991,163:1138-1140
44
Hepatitis B - infection in
patients with HIV - infection
- Course of chronic hepatitisHIV-AB neg
Age (years)
Duration of HBV-infection (Mo)
Alcoholabuse (%)
ALT (U/l)
HBV-DNA (pg/ml)
HAI-Score
(n = 67)
35 8
36 37
9
188 127
86
7,4 3,2
HIV-AB pos.
(n=65)
35  8
31  35
6
103  76*
200 **
8,1  3,9
* p = 0,001
** p = 0,01
Colin, Hepatology 1999; 29:1306-1310
45
Why treat hepatitis B in HIV-infected patients?
• HIV-infection makes the course of HBV-infection worse.
• higher risk for development of liver cirrhosis in case of
HIV/HBV-coinfection
• improved HIV-treatment enhances the probability to
„experience“ the complications of chronic hepatitis B
• Higher risk for hepatotoxicity during HAART in patients with
chronic hepatitis B-infection
Therapy of chronic hepatitis B
• HBV-genotype A
• low viral-load
• High liver enzymes
• Significant inflammation in
histological examination
HBeAg-Serokonversion
Standard I: (alfa-Interferon 3-7x5 Mio IU/week for 6 months)
PEG-Interferon α-2a 1x180 µg/week for 48 weeks
60
52
50
40
• HBV-infection as an adult
• Compensated liver disease
HBeAg-Serokonversion
• Female
31
30
30
22
20
10
0
Typ A
• HBeAg positive
HBV-genotype
45
40
35
30
25
20
15
10
5
0
41
Typ B
Typ C
Typ D
ALT-level
30
29
ALT 2-5 x ULN
ALT < 2 x ULN
47
ALT > 5x ULN
Nucleosides for the treatment of chronic
hepatitis B
Efficacy only against HBV:
Adefovir
Telbivudin
Efficacy against HBV and HIV:
Lamivudin
Emtricitabine
(Entecavir)
Tenofovir
48
Indications for Initiating ART:
Chronic Infection
Clinical Category or CD4 Count
Recommendation
History of AIDS-defining illness
CD4 count <350 cells/µL
Pregnant women
HIV-associated nephropathy
Hepatitis B coinfection, when
HBV treatment is indicated*
Initiate ART
* Treatment with fully suppressive drugs active against both HIV and HBV is
recommended.
November 2008
AETC National Resource Center, www.aidsetc.org
Tenofovir-Alafenamid (TAF)
Tenofovir-Alafenamid (TAF) vs. Tenofovir-Disoproxil-Fumarat bei
HIV-Infektion
Viral load
Ruane PJ et al., J AIDS 2013; 63:449-455
Sax PE et al., J AIDS 2014; 67:52-58
50
HBV/HIV co-infection
Hartwig Klinker
Thank you for your attention!
University of Würzburg Medical School
Medical clinic II
Division of Infectious diseases
Mwanza, Bugando Hospital, 11. 2. 2015
51