HCV and HBV co-infections Sanjay Bhagani Royal Free Hospital London EACS Advanced Course 2008.
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Transcript of HCV and HBV co-infections Sanjay Bhagani Royal Free Hospital London EACS Advanced Course 2008.
HCV and HBV co-infections
Sanjay BhaganiRoyal Free Hospital
LondonEACS 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
Per
cen
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
40 million
175 million175
million
HIVHIVHCVHCV
Overlapping HCV & HIV Epidemics
10 million
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 SexSexual practice
Drug practice
High-risk practices
Internet
Shared implements
‘Club drugs’
STIDanta 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 Effect of HIV/HCV co-infection on hepatic fibrosis progression 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)
Fibro
sis
gra
de
HIV-HCV
Alcohol
HBV
Haemochromatosis
HCV
Steatosis BMI>25
2PBC0.00
0.17
0.33
0.50
0.67
0.83
1.00
0 20 40 60 80
Haza
rd f
un
ctio
n
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]]
500040003000200010000
Cu
mu
lati
ve s
urv
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 1Untreated-group: 137 94 49 37 32 27
6000500040003000200010000
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
Cu
mu
lati
ve s
urv
ival
Observation time[days]]
Patients under observation:HAART-group: 93 79 33 - - - ART-group: 55 46 30 15 9 1Untreated-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
atie
nts
wit
h L
EE
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 Response to PegIFN and Ribavirin in HIV/HCV co-infected patientsHIV/HCV co-infected patients
0102030405060708090
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 853rd Int HIV/Hepatitis co-infection meeting, Paris 2007
Predictors of response
Host
Acute infectionYounger ageLack of stage 3/4 fibrosisEthnicityLow BMILack of hepatic steatosisHigh CD4 %Lack of insulin resistance
Virus
Genotypes 2/3Low viral loads
Gt 1 (n = 150)
34
162729
Gt 2/3 (n = 78)
47
7362 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
Wit
h 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 APRICOT: SVR rates according to exposureto exposure
Genotype 1 recipients of peginterferon alfa-2a plus ribavirin
39%
SV
R r
ate
(%
)S
VR
rate
(%
)
≥80/80/80exposure
0
10
20
30
40
50
11%
<80/80/80exposure*
62
29%
Allpatients
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 Viral Dynamic response to interferon and ribavirinribavirin
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 How can we maximise response to therapy?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
atie
nts
wit
h R
BV
dec
reas
e
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 weeks0 96724824 60 84
Peg
-IFN
+ R
BV
1000-1
200 m
g/d
ay
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 Treatment of Chronic HCVHCV
Extending TherapyExtending Therapy
6152
32
45
0
20
40
60
80
48 72
Weeks of Treatment
% H
CV
RN
A (
-)
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 96No. of patients (389)
31%
53%
67%
82%
G 1/4
G 2/3
5924
4664
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 2SVR
2) S261. 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-RNAneg
HCV-RNApos
> 2 log dropin HCV-RNA
< 2 log dropin HCV-RNA
HCV-RNAneg
HCV-RNApos
G2/3
G1/4
Stop
Stop
G2/3
G1/4
24 weekstherapy *
48 weekstherapy
72 weekstherapy
* In patients with baseline low viral load and minimal liver fibrosis.
EACS Guidelines 2008
40 million
40 million
400 million400
million
HIVHIVHBVHBV
HBsAg+
Overlapping HBV & HIV Epidemics
4 million
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 Transplantati
on
Clearance
Phases of chronic HBV InfectionPhases 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-negativeEmergence of the e-negativePrecore MutantPrecore Mutant
HBeAg+
HBV-DNA (mutant)
HBeAg / anti-HBe Anti-HBe+
HBV-DNA (wild)
Transaminases
Chronic hepatitismild
Chronic moderate tosevere hepatitis
Cirrhosis & hepato-cellular carcinoma
HBV tolerance HBV wild-typeclearance
Continued HBVprecore mutant
replication
0 5 10 15 20 YearsYears
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
AfricaE & DE & D
IndiaAA
Rare types:
F – Latin America
G –France, USA
H –Mexico,Latin America
Far EastB & C
Hepatitis B SerologyIsolated 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
6.55.6
2.51.4
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
6.65.6
2.51.4
*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 carriersmean 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
< 3001.0-9.9 x 10 4
1.0-9.9 x 10 5
> 1.0 x 10 6
1.02.36.66.1
Subcohort (N = 2925)
HBV-DNA (cp/ml) RR
< 3001.0-9.9 x 10 4
1.0-9.9 x 10 5
> 1.0 x 10 6
1.04.5
11.317.7
•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.)Author(Yr.) n. Tx n. Tx n. Controlsn. ControlsHoofnagle(88)Hoofnagle(88) 1010 4 4Brook (89)Brook (89) 1616 6 6Brook (89)Brook (89) 6 6 9 9Pol (92)Pol (92) 1616 1414Wong (95)Wong (95) 1313 1313
All All 6161 4646
100100 1010 00 0,10,1 0,010,01
8,98,9
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
log
HB
V D
NA
Lamivudine Placebo
Serum HBV DNA
Dore GJ, et al. J Infect Dis. 1999;180:607-613.
HIV/HBVLamivudine
-2.7 log10 copies/mL
HB
V D
NA
(lo
g1
0 cop
ies/m
l)
- 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†27n = 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 HBV DNA (< 2.6 log(< 2.6 log1010 copies/ml) copies/ml) 8/358/35
HBeAg negativeHBeAg negative
3/33*3/33*
HBe seroconversion HBe seroconversion 2/33*2/33*
HIV/HBV LAM-RADV
Tenofovir for HBV - Gilead Study 903 HIV/HBV Coinfected Patients
Mean Change from Baseline in HBV DNA (95% CI)
TDF+LAM+EFV: 5d4T+LAM+EFV: 6
5 6
5 6
4 5
5 6
Ch
ang
e F
rom
Bas
elin
e in
log
10 H
BV
-DN
A
(co
pie
s/m
L)
-8
-7
-6
-5
-4
-3
-2
-1
0
WeeksBL 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.
HB
V D
NA
(lo
g1
0)
0
2
4
6
8
10
0 20 40 60 80 90
Weeks
48
AdefovirTenofovir 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)
6758 (n =
165)
88*84* (n =
68)
7167 (n = 67)
Virologic breakthrough by Week 48
3* 10 2* 9
Normalized ALT• Week 52• Week 76
7778* (n =
163)
7568 (n =
165)
7476 (n =
68)
7964 (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
5117
4616
4816
n =n =
4916
*P < .0001
-3.66
-5
-4
-3
-2
-1
0
1
0 2 12 24
+0.11
*
*
*
Weeks
PlaceboEntecavir
Mean
HB
V D
NA
by P
CR
(l
og
10)
03
11
18
28
38
19
42
50
18
37
52
63
78
0
10
20
30
40
50
60
70
80
% P
atie
nts
Clinical lamivudine resistance (phenotypic resistance)
1
Detection of lamivudine-resistant mutations (genotypic resistance)
2 3 4 5years
Adefovir-resistance
(van Bömmel F, Mihm U, Jung C, Berg T. AASLD 2003Locarnini 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) 358:718-7232. Qi, et al., EASL 2004, Apr 16, 2004, Berlin 3. Lai C.L., et al., Clinical Infectious Diseases (2003) 36:6874. Benhamou Y et al. Hepatology 1999; 30:1302-6 * Year 4 resistance rate for ADV not yet
available
Inci
den
ce o
f Re
sist
an
ce
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.
V214A/Q215S
V84M/S85A
A181V/T
M250V
L180M
T184G/S
S202IN236T
M204/I
LAM
ADV
ETV
LdT
FTC
Selection of LAM-Resistant Mutants Affects Future Treatment Options
Envelope changesPolymerase changes
Ag–Ab binding [IC50 (μg/ml)]
Wild type Wild type 1.09HBIG escape sG145R Anti-viral drug resistant sE164D sW196S sI195M sM198I sE164D/I195M
rtW153G
rtV173LrtM204IrtM204VrtV207IrtV173/rtL180/rtM204V
>55.0
14.868.295.2612.5
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 monotherapySelection of M184V following ETV tx
0
10
20
30
40
50
60
70ART naïve
Total
Median time to M184V 148 days 98 days
% w
ith
M18
4V
3/7
3/5
6/12ART 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 0.201. 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 3TCin drug-naïve HIV/HBV
coinfected
3TC - Naive
P=0.045vs. 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
0BL 24 weeks
TDF 3TC TDF/3TC
LdT
FTC
Anti HBV Drugs in HIV Infection
TDF
ADF
ETVETV in LAMexp
LAM
Genetic Barrier
Pot
ency
No anti-HIV activity
Anti-HIV activity
IFN
Cumulative toxicity with ART (AZT, ddI)Cumulative toxicity with ART (AZT, ddI) 1 Log HIVRNA1 Log HIVRNA
CD4 counts = %CD4 counts = %
Partial Anti-HIVActivityM184V 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 biopsyand 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 DNA2,000 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/mlHBV-DNA
< 2000 IU/ml
HAART includingTDF + 3TC or FTC
Substitute one NRTI byTenofovir 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 includingTDF + 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