HCV and HBV co-infections · Treating HCV in HIV-infected patients • HAART treated HIV patients...
Transcript of HCV and HBV co-infections · Treating HCV in HIV-infected patients • HAART treated HIV patients...
HCV and HBV co-infections
Sanjay Bhagani Royal Free Hospital
London EACS Advanced Course 2008
Causes of Liver Disease in HIV Infection
Mortality of HIV-infected patients in France (GERMIVIC Study Group)
0
5
10
15
20
Perc
en
tag
e
1995
(n=17,487)
1997
(n=26,497)
2001
(n=25,178)
2003
(n=20,940)
Overall mortality AIDS-assoc. Mortality Liver disease assoc. mortality
Rosenthal et al. AASLD 2004; Abstract 572.
40 million
175 million
HIV HCV
Overlapping HCV & HIV Epidemics
10 million
25% of HIV
Reports of acute HCV in HIV+ MSM across Europe
Danta et al. AIDS 2007; 21: 983-991. Gambotti et al. Euro Surveill 2005; 10: 115-117.
Ghosn et al. Sex Transm Infect 2006; 82: 458-460 ; 40: 41-46.
Serpaggi et al. AIDS 2006; 20: 233-240.Vogel M et al. J Viral Hepat 2005; 12: 207-211
Risk Factors for Acute HCV in MSM
Group Sex Sexual
practice
Drug
practice
High-risk
practices
Internet
Shared
implements
‘Club drugs’
STI Danta et al, AIDS 2007
Phylogenetic Tree
Constructed from
Analysis of Paired
Samples (red) Compared
with Genebank Samples
(black)
Jones et al. CROI 2008;Oral Abstract 64LB.
Is HCV Viraemia after SVR Following Initial Infection Re-infection or Relapse?
Effect of HIV/HCV co-infection on hepatic fibrosis progression (Benhamou et al 1999)
0
0.5
1
1.5
2
2.5
3
3.5
4
10 20 30 40
HIV + Matched controls Simulated controls
Fibrosis progression influenced by
• CD4 cell count (< 200 cells/microlitre)
• Age at infection ( > 25 years)
• Male sex
• Alcohol consumption ( > 50g/d)
HIV-HCV
Alcohol
HBV
Haemochromatosis
HCV
Steatosis BMI>25
2PBC
0.00
0.17
0.33
0.50
0.67
0.83
1.00
0 20 40 60 80
Hazard
functi
on
4682 patients
Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:257-265
Age in years
Progression to cirrhosis
HIV/HCV - Cirrhosis and survival
Pineda et al. Hepatology 2005
A) Overall-Mortality
Observation time[days]]
5000 4000 3000 2000 1000 0
Cum
ulat
ive
surv
ival
1,1
,9
,7
,5
,3
P<0.0001
Patients with HAART
Patients with ART
untreated Patients
6000
Patients under observation:
HAART-group: 93 79 33 - - -
ART-group: 55 46 30 15 9 1
Untreated-group: 137 94 49 37 32 27
6000 5000 4000 3000 2000 1000 0
1,1
,9
,7
,5
,3
B) Liver-related-Mortality
P<0.018
Patients with HAART
Patients with ART
untreated Patients
Overall and Liver-related Mortality - effect of HAART
Qurishi N et al. Lancet, 2004
Cum
ulat
ive
surv
ival
Observation time[days]]
Patients under observation:
HAART-group: 93 79 33 - - -
ART-group: 55 46 30 15 9 1
Untreated-group: 137 94 49 37 32 27
% LEE by co-infection status
1. Benhamou Y, Mats V, Walcak D. Systemic overview of HAART associated liver enzyme elevations in patients infected with HIV and co-infected with
HCV. CROI 2006;#88
Interactions were not significant between drug CLASS and CO (p=0.800)
N arms 11 7 4 12 9 3 14 10 4 11 6 5 5 3 2 53 35 18 N patients 581 1242 2705 2038 1055 7621 244 737 2321 630 572 4504 337 505 384 1408 483 3117
0
10
20
30
40
NNRTI PI Mixed BPI NRTI Overall
Drug Class
% P
ati
en
ts w
ith
LE
E
All Patients HCV Co-inf HIV Only
Treating HCV in HIV-infected patients
• HAART treated HIV patients live longer
• Faster progression to liver cirrhosis
• Increased mortality due to end stage liver disease
• Higher risk of hepatotoxicity following treatment with ART drugs
• Risk of hepatotoxicity reduced with successful HCV erradication
Response to PegIFN and Ribavirin in HIV/HCV co-infected patients
0102030405060708090
Bar
celona (n
=52)
Madrid
(n=35)
Madrid
(n=68)
Rib
avic (n
=205)
ACTG
5071
(n=66)
APR
ICO
T(n=289)
Monoin
fecte
d
Overall SR G2/3 G1/4
Acute HCV/HIV: Overall virological responses:
64%
74%71%
66%
42%
RVR w12(pcr-) w12(EVR) EOT SVR
133 = 56 89 95 99 85
3rd Int HIV/Hepatitis co-infection meeting, Paris 2007
Predictors of response
Host
Acute infection
Younger age
Lack of stage 3/4 fibrosis
Ethnicity
Low BMI
Lack of hepatic steatosis
High CD4 %
Lack of insulin resistance
Virus
Genotypes 2/3
Low viral loads
Gt 1 (n = 150)
34
16 27 29
Gt 2/3 (n = 78)
47
73 62 69
APRICOT: Baseline CD4+ Count and Efficacy of Peg-IFN alpha-2a
Plus RBV • Retrospective analysis of HIV/HCV-coinfected patients treated with
peg-IFN alpha-2a + RBV in APRICOT
• SVR rates analyzed in overall population and within genotypes according to baseline CD4+ cell count quartiles (Q1-Q4)
• Rate of SVR varied according to CD4+ cell percentage quartile in genotype 1 but not in genotypes 2/3
Dieterich D, et al. ICAAC 2006. Abstract H-1888.
0
20
40
60
80
100
Pts
With S
VR (%)
Q4 (32.1% to 69.3%)
Q1 (2.5% to 19%)
Q2 (19.1% to 25.0%)
Q3 (25.0% to 32.1%)
APRICOT: SVR rates according to exposure
Genotype 1 recipients of peginterferon alfa-2a plus ribavirin
39%
SVR r
ate
(%)
≥80/80/80 exposure
0
10
20
30
40
50
11%
<80/80/80 exposure*
62
29%
All patients
n = 176
114
*Patients violated the rule if ≥1 of the three targets were not achieved Opravil M, et al. 45th ICAAC 2005; Abstract
2038
Why lower response rates to anti-HCV therapy in HIV+ patients?
• Use of lower doses of RBV in most trials
• More advanced fibrosis grade
• Higher rate of steatosis (NRTIs, PIs)
• Unfavourable baseline HCV virological
features
• Higher discontinuation due to side effects
• Lower initial HCV-RNA clearance
• Higher relapse rates
Viral Dynamic response to interferon and ribavirin
Pawlotsky Hepatology 2002; 32(4)
Does RVR predict response? (week 4 undetectable HCV RNA)
• APRICOT
– PPV 82% – NPV 79%
• RIBAVIC – PPV 97.5% – NPV 81.3%
• PRESCO
– Lack of RVR independent predictor of relapse
• Crespo M et al.
– G3 patients with RVR low rates of relapse with 24 weeks of therapy
• ROMANCE – G2/3 patients without RVR
need longer Rx (48 weeks)
APRICOT: week 12 – genotype 1
≥2 log10 drop HCV RNA
● Genotype 1 patients (n=176)
SVR: n=50
PPV=45%
No SVR: n=60
(55%)
SVR: n=1
(2%)
No SVR: n=65
NPV=98%
n=66
(37%)
n=110
(63%)
Yes
No
Torriani F, et al. 45th ICAAC 2005; Abstract 1024
≥2 log10 drop or
undetectable
HCV RNA
How can we maximise response to therapy?
Zidovudine: impact on HCV treatment
HB decrease by week 4
3.14
1.96
0
1
2
3
ZDV No ZDV
HB
lo
ss (
g/d
l)
RBV dose reduction
by week 4
52%
20%
0%
20%
40%
60%
ZDV No ZDVP
ati
en
ts w
ith
RB
V d
ecre
ase
Alvarez D et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-192). Boston, MA USA, February 22–25, 2005
Interactions between RBV & nucleoside analogues
AZT ddI d4T
anemia hepatic pancreatitis weight decomp. & lactic acidosis loss
mitochondrial DNA synthesis lactate
Blanco et al. NEJM 2002; 347: 1287
Abacavir and SVR
Vispo et al, 3rd Int. HIV/hepatitis Conference, Paris 2007. Abs 46
Study Design
n=389
Study weeks
0 96 72 48 24 60 84
Peg-
IFN +
RBV
1000-1200 m
g/day
12 36
Follow-up
G2,3
G1,4
G1,4
G2,3
Follow-up
Follow-up
Follow-up
Only patients who achieved EVR (>2 log drop in HCV-RNA at week 12) continued treatment.
N=192
N=45
N=96
N=56
PRESCO
Importance of weight-based Ribavirin
(1000mg <75kg/1200mg >75kg)
Soriano, et al. AIDS 2007. 21: 1073-89
Treatment of Chronic HCV Extending Therapy
61 52
32
45
0
20
40
60
80
48 72
Weeks of Treatment
% H
CV R
NA (-)
EOT
SVR
Extending the duration of therapy reduced relapse from 47% to 13%
Sanchez-Tapias et al. AASLD 2004. Abstract 126.
Results (On Treatment analysis)
56
15 (8%)
36 (80%)
9 (16%)
Voluntary withdrawals (64) 4 (4%)
Short arm
Extended arm
PRESCO
192 45 96 No. of patients (389)
31%
53%
67%
82%
G 1/4
G 2/3
59 24
46
64
p=0.004
p=0.04
Adapted from Manns MP et al. Nat Rev Drug Discovery. 2007;6:991-1000.
New oral small molecule ARVs in development for the treatment of HCV
Drug name Drug class Preclinical Phase I Phase II Phase III
MK-0608 (Merck)
R7128 (Pharmasset & Roche)
NIM811 (Novartis)
ITMN-191 (InterMune & Roche)
MK-7009 (Merck)
BI12202 (Boehringer)
R1626 (Roche)
DEBIO-025 (Debiopharm)
BI 1220 (Boehringer)
Telaprevir (Vertex Pharmaceuticals)
Boceprevir (Schering-Plough)
TMC435350 (Tibotec & Medivir)
Nucleoside polymerase inhibitor
Nucleoside polymerase inhibitor
Cyclophilin inhibitor
Protease inhibitor
Protease inhibitor
Protease inhibitor
Nucleoside polymerase inhibitor
Cyclophilin inhibitor
Nucleosite polymerase inhibitor
Protease inhibitor
Protease inhibitor
Protease inhibitor
X
X
X
X
X
X
X
X
X
X
X
X
X
TELAPREVIR: PROVE 2 SVR
2) S26 1. Dusheiko et al .Treatment of chronic hepatitis C with telaprevir in combination with peginterferon alfa 2a with or without ribavirin: further interim
analysis results of the PROVE2 study. J Hepatology 2008; 48 (suppl)
Take home messages: • HIV/HCV co-infection is common
• Increasing incidence of acute HCV
• ESLD major cause of morbidity/mortality
• Early HAART beneficial – Avoid d-thymidine analogues/AZT
• Treat HCV with PegIFN and Ribavirin – Best results if HCV treated in the acute phase
– Maximal doses of Ribavirin (1000/1200mg)
– Avoid AZT, d4T and DDI,
– ?Avoid Abcavir
– EPO and G-CSF – avoid dose reductions
Take home messages: • Duration of therapy individualised
– Genotype
– Pre-Rx viral load
– Fibrosis stage
– RVR/EVR
• No role for maintenance low-dose IFN
• Give some thought to hepatic steatosis
• New anti-HCV drugs (STAT-Cs!) will be available in the future…
• …be careful out there….!!!
Proposed optimal duration of HCV therapy in HCV/HIV-coinfected patients.
W4 W12 W24 W48 W72
HCV-RNA neg
HCV-RNA pos
> 2 log drop in HCV-RNA
< 2 log drop in HCV-RNA
HCV-RNA neg
HCV-RNA pos
G2/3
G1/4
Stop
Stop
G2/3
G1/4
24 weeks
therapy *
48 weeks
therapy
72 weeks
therapy
* In patients with baseline low viral load and minimal liver fibrosis.
EACS Guidelines 2008
40 million
400 million
HIV HBV
HBsAg+
Overlapping HBV & HIV Epidemics
4 million
5–15% of HIV
HBsAg Prevalence
≥8% – High 2–7% – Intermediate
<2% – Low
Geographic Distribution of Chronic HBV Infection
Hepatitis B Disease Progression
Acute Infection
Chronic Infection
Cirrhosis
Death
1. Torresi, J, Locarnini, S. Gastroenterology. 2000. 2. Fattovich, G, Giustina, G, Schalm, SW, et al. Hepatology. 1995. 3. Moyer, LA, Mast, EE. Am J Prev Med. 1994. 4. Perrillo, R, et al. Hepatology. 2001.
5%-10% of chronic HBV-infected individuals1
Liver Failure
(Decompensation)
30% of chronic HBV-infected individuals1
• >90% of infected children progress to chronic disease
• <5% of infected immunocompetent adults progress to chronic disease1
23% of patients decompensate within 5 years of developing cirrhosis 3
Liver Cancer (HCC)
Chronic HBV is the 6th leading cause of liver transplantation in the US 4
Liver Transplantation
Clearance
Phases of chronic HBV Infection
• Immune tolerant phase – High levels of HBV DNA – Very little inflammation
• Chronic hepatitis
– HBeAg positive • High levels HBV DNA, inflammation/progressive fibrosis
– HBeAg negative • Low levels HBV DNA, progressive inflammation and fibrosis
• Inactive HbsAg carrier state (non replicative phase)
– HBeAg negative, low/absent HBV DNA, no inflammation/fibrosis
Emergence of the e-negative Precore Mutant
HBeAg+
HBV-DNA (mutant)
HBeAg / anti-HBe Anti-HBe+
HBV-DNA (wild)
Transaminases
Chronic hepatitis mild
Chronic moderate to severe hepatitis
Cirrhosis & hepato- cellular carcinoma
HBV tolerance HBV wild-type
clearance Continued HBV precore mutant
replication
0 5 10 15 20 Years
Carman WF et al Viral Hepatitis. Scientific Basis and Clinical Management. NY: Churchill Livingstone; 1993:121.
Geographical distribution of HBV genotypes A to H
North Europe & USA - A
Mediterranean basin - D
Africa E & D E & D
India A A
Rare types: F – Latin America G –France, USA H –Mexico, Latin America
Far East B & C
Hepatitis B Serology Isolated HBcAb+
• HIV negative – 50% true positive HBcAb
– <2% with detectable serum HBV DNA
• HIV positive – 60-90% true positive HepBcAb
– Many with detectable HBV DNA (~15% at RFH)
– ~40% with necro-inflammation on liver biopsy
• Isolated anti-HBc more common in HIV/HCV
• Implications for 3TC based HAART and vaccination strategies
Hofer, Euro J Clinical Micro 1998. Ghandi, CID. June 15, 2003. Nebya, BHIVA 2006
HIV/HBV Coinfection • Increased incidence of chronic HBV in HIV+ patients
(Lazizi JID 1988). Will vary greatly with subpopulation
• HIV+ pts 3-6x more likely to develop chronic HBV than HIV- (Bodsworth JID 1991)
• HBeAg and HBV DNA higher levels in HIV+ but AST/ALT lower (Perillo 1986)
• Increased hepatic fibrosis
• Decreased spontaneous seroconversion (Krogsgaard 1987) or seroreversion of prior HBV infection with loss of anti-HBs and return of HBsAG (Waite AIDS 1988)
• Atypical serologies: anti-HBc may indicate chronic infection (Hofer 1998)
Liver Mortality Rate (per 1000 PY) MACS
0
2
4
6
8
10
12
14
16
HIV-/HBV- HIV-/HBV+ HIV+/HBV- HIV+/HBV-
Thio et al. Lancet 2004
* Adjusted for age, sex, cigarette smoking, and alcohol consumption.
300 - < 104 104 - 105
HBV DNA copies/mL
105 - 106
All Participants (n = 3582)
*
RR * (95% CI)
*P < .001
6.5 5.6
2.5 1.4
0
2
4
6
8
10
12
14
> 106
*
*
HBeAg(-), Normal ALT (n = 2923)
300 - < 104 104 - 105 > 106
HBV DNA copies/mL
105 - 106
6.6 5.6
2.5 1.4
*P < .001
*
*
*
0
2
4
6
8
10
12
14
Level of HBV DNA (PCR-assays) at entry & progression to cirrhosis in population-based cohort studies
3582 HBsAg untreated asian carriers mean follow-up 11 yrs → 365 patients newly diagnosed with cirrhosis
Iloeje UH, Gastroenterology 2006; 130: 678-686
HBV-DNA viral load (> 104 cp/ml) strongest predictor of progression to cirrhosis independent of ALT and HBeAg status
HBV-DNA levels (> 104 cp/ml) strong predictor of HCC, independent of HBeAg, ALT and cirrhosis
Entire cohort (N = 3653)
HBV-DNA (cp/ml) RR
< 300 1.0-9.9 x 10 4
1.0-9.9 x 10 5
> 1.0 x 10 6
1.0 2.3 6.6 6.1
Subcohort (N = 2925)
HBV-DNA (cp/ml) RR
< 300 1.0-9.9 x 10 4
1.0-9.9 x 10 5
> 1.0 x 10 6
1.0 4.5 11.3 17.7
• Population based cohort study of HBsAg asian carriers, mean follow-up= 11.4
Chen CJ et al JAMA 2006;295:65-73
13.5 %
7.9 %
0.9 %
0.7 %
3.1 %
>6log
5-6log
4-5log
<4log
Level of HBV DNA (PCR-assays) at entry & risk of HCC
HBeAg (), Normal ALT, No cirrhosis at entry
(n = 2925) >6log
5-6log
4-5log
<4log
14.9%
12.1%
3.5%
1.3% 1.3%
Entire cohort (n = 3653)
How?
Restoring immune control • Type I interferons
– Interferon-alpha – Pegylated interferon-
alpha-2a
• ?others
Viral replication suppression with antivirals
• Lamivudine • Adefovir • Entecavir • (Tenofovir) • (FTC) • Telbivudine • (Clevudine)
Author(Yr.) n. Tx n. Controls Hoofnagle(88) 10 4 Brook (89) 16 6 Brook (89) 6 9 Pol (92) 16 14 Wong (95) 13 13 All 61 46
100 10 0 0,1 0,01
8,9
16 RCT IFN- vs placebo 837 HBsAg+ - 107 HIV+ included in 5 studies
HBe seroconversion/negativation : HIV+ vs HIV: – 0.38 (CI 0.06-0.7 P =.02)
IFN- in HBV /HIV co-infection
IFN Placebo
Puoti et al. personnal comm.
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 4 8 12 20 28 36 44 52
Time in Weeks
Me
dia
n c
ha
ng
e in
lo
g H
BV
DN
A
Lamivudine Placebo
Serum HBV DNA
Dore GJ, et al. J Infect Dis. 1999;180:607-613.
HIV/HBV Lamivudine
-2.7 log10 copies/mL
HBV D
NA (log 1
0 c
opies/
ml)
- 6.2 log10 c/ml p<0.001*
-7.0
-6.0
-5.0
-4.0
-3.0
-2.0
-1.0
0.0
0 24 48 72 96 120 144 168 192
ADV (weeks)
- 5.9 log10 c/ml p<0.001*
- 4.7 log10 c/ml P<0.001* - 5.5 log10 c/ml
p<0.001*
31 29 31 30 31 29 27† 27 n = 35
†27 patients remain on study
* p<0.001 Wilcoxon Sign Rank Test
Benhamou et al. Lancet. 2001;358: 718-23. & J Hepatol. 2006;44:62-7.
HBV DNA (< 2.6 log10 copies/ml) 8/35
HBeAg negative 3/33*
HBe seroconversion 2/33*
HIV/HBV LAM-R ADV
Tenofovir for HBV - Gilead Study 903
HIV/HBV Coinfected Patients Mean Change from Baseline in HBV DNA (95% CI)
TDF+LAM+EFV: 5
d4T+LAM+EFV: 6
5
6
5
6
4
5
5
6
C
ha
ng
e F
rom
Ba
se
lin
e i
n l
og
10 H
BV
-DN
A
(co
pie
s/m
L)
-8
-7
-6
-5
-4
-3
-2
-1
0
Weeks BL 12 24 36 48
-2.95
-4.70
TDF+LAM+EFV
d4T+LAM+EFV
Cooper D. 10th CROI, Boston MA, February 10-14, 2003, Abstract # 825
Similar (better?) Anti-HBV Activity of Tenofovir compared to Adefovir in Coinfected
Patients • Interim data from ACTG A5127: HBV/HIV-1 coinfected pts
– HBV DNA ≥ 100,000 – Stable antiretroviral therapy; HIV-1 RNA ≤ 10,000
• Reduction in HBV DNA with tenofovir noninferior to adefovir
Peters M, et al. CROI 2006 Abstract 124.
HBV D
NA (log10)
0
2
4
6
8
10
0 20 40 60 80 90
Weeks
48
Adefovir Tenofovir DF
GLOBE: Year 1 Results of Telbivudine (LdT) for Chronic Hepatitis B
Lai et al. AASLD;2005. Abstract LB01.
Summary of Year 1 Results With Telbivudine
Outcome HBeAg-Positive Patients HBeAg-Negative Patients
LdT, % (n = 458)
LAM, % (n = 463)
LdT, % (n = 222)
LAM, % (n = 224)
Undetectable HBV DNA • Week 52 • Week 76
75*
75* (n = 163)
67
58 (n = 165)
88*
84* (n = 68)
71
67 (n = 67)
Virologic breakthrough by Week 48
3* 10 2* 9
Normalized ALT • Week 52 • Week 76
77
78* (n = 163)
75
68 (n = 165)
74
76 (n = 68)
79
64 (n = 67)
Fibrosis decline by Wk 52 68 61 59 46
HBeAg seroconversion by Week 76
41* (n = 100) 26 (n = 93) N/A N/A
*P < .05 vs lamivudine.
Potent Anti-HBV Activity From Addition of Entecavir to Continued 3TC in Coinfection
• ETV-038: HBV/HIV coinfected pts – HBV DNA ≥ 100,000, HBeAg+ or -,
HBsAg+, compensated – HIV RNA < 400 for ≥ 12 weeks – 3TC-containing HAART for ≥ 24
weeks or YMDD mutation, no other agent with anti-HBV activity
• Entecavir (1 mg QD) vs placebo added to continued 3TC for 24 wks
• 84% ETV had HBV DNA < 400 or 2 log reduction by Week 24
• No difference in AEs
• RT sequencing for mutations M204V/I, L180M (3TC mutations) and T184, S202 and M259 (ETV mutations) at baseline and at week 48
Pessoa W, et al. CROI 2005, Abstract 123, Colonno et al, CROI 2006, Abstract 832
51 17
46 16
48 16
n = n =
49 16
*P < .0001
-3.66
-5
-4
-3
-2
-1
0
1
0 2 12 24
+0.11
*
*
*
Weeks
Placebo Entecavir
Mean
HBV D
NA b
y P
CR (log10)
03
11
18
28
38
19
42
50
18
37
52
63
78
0
10
20
30
40
50
60
70
80
% P
atients
Clinical lamivudine resistance (phenotypic resistance)
1
Detection of lamivudine-resistant mutations (genotypic resistance)
2 3 4 5 years
Adefovir-resistance
(van Bömmel F, Mihm U, Jung C, Berg T. AASLD 2003
Locarnini S et al EASL 2005, Abstract 36)
(Hadziyannis S et al. AASLD 2005 Abstract LB14)
Resistance development – Nucleos(t)ides
Comparative Incidence of HBV Resistance in Patients Treated with ADV or LAM
1. Benhamou Y. et al., Lancet (2001) 358:718-723
2. Qi, et al., EASL 2004, Apr 16, 2004, Berlin
3. Lai C.L., et al., Clinical Infectious Diseases (2003) 36:687
4. Benhamou Y et al. Hepatology 1999; 30:1302-6 * Year 4 resistance rate for ADV not yet available
Incid
ence o
f R
esis
tance
ADV1,2,*
(N236T or A181V)
LAM3
(YMDD )
LAM4
(YMDD in HIV/HBV)
0%
24%
2%
42% 47%
3.9%
53%
70%
90%
0%
20%
40%
60%
80%
100%
year 1 year 2 year 3 year 4
Resistance Mutations Associated with Viral Breakthrough in Patients on Treatment
Locarnini S et al. Antivir Ther 2004;9:679–93.
LAM
ADV
ETV
LdT
FTC
Selection of LAM-Resistant Mutants Affects Future Treatment Options
Envelope changes Polymerase changes Ag–Ab binding
[IC50 (μg/ml)]
Wild type Wild type 1.09
HBIG escape
sG145R
Anti-viral drug resistant
sE164D
sW196S
sI195M
sM198I
sE164D/I195M
rtW153G
rtV173L
rtM204I
rtM204V
rtV207I
rtV173/rtL180/rtM204V
>55.0
14.86
8.29
5.26
12.5
54.53
Cooley L et al. AIDS 2003;17:1649–57.
Envelope/Polymerase Mutations and the Antigen/Antibody Binding Capacity in Genotype A and D HBV/HIV
Co-infected Subjects (n=9) with LAM Resistance
Anti-HIV activity of entecavir
• 17 HIV/HBV coinfected pts (10 naïve, 7 treatment-experienced from US and Australia) who received entecavir (ETV) monotherapy for HBV therapy.
• ETV monotherapy results in clinically-significant reduction in plasma HIV-RNA in the majority but not all pts, and can select for the M184V mutation even in naive pts
• HIV/HBV co-infected individuals should not receive ETV monotherapy
Selection of M184V following ETV tx
0
10
20
30
40
50
60
70 ART naïve
Total
Median time to M184V 148 days 98 days
% w
ith
M1
84
V
3/7
3/5
6/12 ART experienced
Risk factor p value
Total duration on ETV 0.05
Magnitude of HBV-DNA reduction on ETV
0.04
HIV-RNA pre-ETV therapy 0.87
HBV-DNA pre-ETV therapy 0.69
Nadir CD4+ count 0.20 1. Audsley J, et al. 15th CROI, Boston 2008, No.63
Univariate analysis for selection of M184V
Conclusion:
• TDF/3TC superior to 3TC alone
but not TDF in HBV naïve
• No benefit continuing 3TC in
experienced HBV viraemic patients
• No difference between adding or
switching TDF
TDF vs TDF/3TC vs 3TC in drug-naïve HIV/HBV coinfected
3TC - Naive
P=0.045
vs. 3TC
N = 10 11 6
1. Nelson M, et al. A 48 week study of tenofovir or lamivudine or a combination of tenofovir and lamivudine for the
treatment of chronic hepatitis B in HIV/HBV co-infected individuals. 13th CROI. Denver, CO, February 5-8, 2006; Abst. 831.
-6
-5
-4
-3
-2
-1
0 BL 24 weeks
TDF 3TC TDF/3TC
LdT
FTC
Anti HBV Drugs in HIV Infection
TDF
ADF
ETV ETV in LAM exp
LAM
Genetic Barrier
Pote
ncy
No anti-HIV activity
Anti-HIV activity
IFN
Cumulative toxicity with ART (AZT, ddI)
1 Log HIVRNA
CD4 counts = %
Partial Anti-HIV Activity M184V accumulation
Treatment Algorithm: Patients with Compensated Liver Disease and No indication for HIV therapy (CD4 count >
350/µl)
•No treatment
•Monitor every 6–12 months
• Monitor ALT every 3-12 months
• Consider biopsy
and treat if disease present***
• PEG IFN**** (favorable response factors are: HBeAg+ -
HBV Genotype A – elevated ALT and low HBV-DNA)
• Telbivudine (if HBV-DNA ist still detectable at week 24
add adefovir to minimize resistance development risk)
• Adefovor and telbivudine de novo therapy
• Early HAART initiation including Tenofovir+3TC/FTC
ALT
Elevated
ALT Normal
HBV DNA
2,000 IU/mL
HBV DNA
<2,000 IU/mL**
HIV/HBV*
Soriano V, et al. 4th IAS, Sydney 2007, #MoBS104; Benhamou Y, 3rd International Workshop on HIV and hepatitis coinfection, Paris 2007
Immediate indication for HIV treatment
HBV-DNA
> 2000 IU/ml
HBV-DNA
< 2000 IU/ml
HAART including
TDF + 3TC or FTC
Substitute one NRTI by
Tenofovir or add
Tenofovir*
Patients without
HBV associated 3TC
resistance
Patients with
cirrhosis
ECC Statement J Hepatol 2005
Patients with
HBV associated 3TC
resistance
HAART regimen
of choice
HAART including
TDF + 3TC or FTC
Management and therapeutic options in HIV-HBV co-infected
patients with an indication of anti-HIV therapy
*if feasible and appropriate from the perspective of maintaining HIV
suppression
Refer patient for
liver transplantation
evaluation if liver
decompensation
occurs