New Paradigms in the management of HIV/HCV co- infected patients Sanjay Bhagani Royal Free Hospital...
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Transcript of New Paradigms in the management of HIV/HCV co- infected patients Sanjay Bhagani Royal Free Hospital...
New Paradigms in the management of HIV/HCV
co-infected patientsSanjay Bhagani
Royal Free HospitalLondon
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.
Overlapping HCV & HIV epidemics
40 million 175
million
10 million
HIV Hep C
Prevalence of Hepatitis C (1685/4957 patients = 33.9%)
South: 623 = 44,9 %
North: 346 = 24,5 %
Central: 280 = 22,9 %
East: 412 = 47,7 %
Rockstroh J et al.,
EACS 2003; F12/4
Significant increase in new acute HCV infections amongst HIV+MSM
since 2001
• Test for trend p-value using Poisson regression p<0.001
• Error bars = 95% CI
Incid
en
ce o
f acu
te H
CV
in
fecti
on
/1000 p
t yrs
0
5
10
15
20
25
30
1997 1998 1999 2000 2001 2002 2003
Browne RE, et al. 2nd IAS 2003; Abstract 972
Acute HCV among HIV+ - beyond Europe....
1. Luetkemeyer JAIDS 2006; 2. Danta AASLD 2008; 3. Jones 4th Works. HIV & Hep. Coinf. 2008; 4. Fisher CROI 2007;5. Stand 01/2009; 6.Gambotti Euro Surveill 2005; 7. Larsen AASLD 2007; 8. van de Laar JID 2007;
9. Rauch CID 2005; 10. Gallotta 4th Works. HIV & Hep. Coinf. 2008; 11. pers.com.; 12. Matthews , CID 2009
Europe:– UK2,3,4 – Germany5 – France6,7 – Netherlands8 – Switzerland9 – Italy10
– Belgium11
Australia12:
USA1,2
:
( ) Germany, ( ) France, ( ) Australia. Australian MSM with reported IDU are marked IDU*
Cluster 1
Cluster 4
Cluster 3
Cluster 5
Cluster 7
Cluster 10
0.02
Genotype 1a
Genotype 4d
Cluster 1
Cluster 4
Cluster 3
Cluster 5
Cluster 7
Figure 1: NS5B phylogeentic tree of HCV genotypes 1a (left) and 4d (right) Monophyletic clusters are shaded, country of origin:( ) England, ( ) The Netherlands
0.020.02
Cluster 2
Cluster 6
0.02
Cluster 8
Cluster 2
Cluster 6
0.020.02
Genotype 4d
IDU*
IDU* IDU*
IDU*
IDU*
IDU*
Pair A
Pair C
Pair B
IDU* IDU*
Van der Laas et al. Gastroenterology 2009
Summary
Group SexSexual practice
Drug practice
High-risk practices
Internet
Shared implements
‘Club drugs’
STIDanta et al, AIDS 2007
Effect of HIV/HCV co-infection on fibrosis rateEffect of HIV/HCV co-infection on fibrosis rate(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
Impact of HIV RNA, CD4, or Both on Liver Fibrosis
Progression Rate
0.08
0.1
0.12
0.14
0.16
0.18
0.2
HIV RNAHIV RNA(copies/mL)(copies/mL)
0.1220.122
Ish
ak F
ibro
sis
Un
its/Y
ear
Ish
ak F
ibro
sis
Un
its/Y
ear
Brau N, et al. 39th EASL. Berlin, 2004. Abstract 99.
0.1450.145
0.1960.196
0.1210.121
0.1550.155
0.1230.123
0.1620.162
PP=0.53=0.53
PP=0.04=0.04
PP=0.005=0.005
PP=0.005=0.005 PP=0.005=0.005
<400 400-99K <400 400-99K >>100K 100K >>350 <350 <400 350 <350 <400 >>400400
CD4CD4(cells/mm(cells/mm33))
HIV RNA HIV RNA (copies/mL)(copies/mL) + +<500 CD4 cells/mm<500 CD4 cells/mm33
Physiology of hepatic fibrosis
Liver cellinjury
Chronicnecroinflammatory
responseHSC
(activated)
HSC(quiescent)
PDGFTGF-
ECM
HSC proliferationProgressive fibrosis
HCV
TNF-IL-1
KCKC
HIV & Hepatic Stellate Cells: implications for fibrosis in HIV/HCV
co-infected patients
Friedman SL and Arthur, Science and Medicine 2002; Tuyama AC, et al., Hepatology 2010; 52: 612-622.
Hypothesis: Hepatic Stellate Cellsare a cellular target of HIV
Activated HSC with fibrosisNormal liver
HIV/HCV – complex immune interactions
Klenerman P, Kim A. PLOS Med 2007; 4: 1608-1614
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: 13794 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: 13794 49 37 32 27
Effect of HAART on progression to ESLD – a meta-analysis
PRE-HAART POST-HAART
Thien, H et al. AIDS 2008; 22: 1979-1991
Hepatotoxicity 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 Coinf HIV Only
Reduced risk of ART-induced hepatotoxicity after HCV clearance
Labarga P et al. JID 2007;196:670–6
0 25 50 75 100 125 150
Follow-up (months)
8943
3825
115
74
64
34
01
Number of patientsNo:Yes:
0
20
40
60
80
100
Cu
mu
lati
ve i
nci
den
ceo
f h
epat
ic e
ven
ts (
%) Sustained HCV clearance
NoYes
Log Rank: 14.01 (p <0.001)
Lipohypertrophy (fat accumulation)•Dorsocervical fat pad enlargement (buffalo
hump)
•Central or abdominal obesity
•Breast enlargement
Lipoatrophy (fat wasting or loss)•Arms and/or legs ( prominence of veins)
•Face
•Buttocks
Insulin Resistance and Hyperlipidaemia•Diabetes and impaired GTT
•Hypercholesterolaemia and hyperlipidaemia
John M, Nolan D, Mallal S. Antiviral Therapy 2001; 6: 9-20.JIAPAC Supplement, Winter 2001.Behrens GMN, Stoll M, Schmidt RE. Drug Safety 2000; 23(1): 57-76.
Lipodystrophy
Insulin Resistance/NASH and hepatic fibrosis in HIV/HCV co-infected patients
Merchante N, et al., Gut 2009 Sterling R, at al. Hepatology 2008
Main reasons to treat chronic 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
HCV/HIV HCV/HIV TREATMENT OUTCOMES
SVR 14-38% SVR 44-73%
Genotype 1 Genotype 3
Acute HCV/HIV: Overall virological responses:
64%
74%71%
66%
42%
RVR w12(pcr- ) w12(EVR) EOT SVR
133 = 56 89 95 99 85Bhagani et al. 3rd Int HIV/Hepatitis co-infection meeting, Paris 2007
Acute HCV in HIV: finding the balance
• Waiting long enough to reliably identify those that will clear virus spontaneously
• Not delaying treatment for those going on to develop ‘chronic’ infection
Acute HCV in HIV+ patients management: NEAT consensus
2010 (1)1) HCV RNA levels should be measured at initial presentation
and 4 weeks later. (BII)
2) Treatment should be offered to
a) Patients without a decrease of 2 log of HCV RNA at 4 weeks when compared with HCV RNA at diagnosis . (BII)
b) Patients with persistent serum HCV RNA 12 weeks after diagnosis of acute hepatitis C. (AII)
3) Patients showing spontaneous HCV RNA clearance before and after 12 weeks should be followed with serial HCVRNA assay until 48 weeks after onset in order to confirm resolution of acute hepatitis C. (AIII)
Acute HCV in HIV+ patients management: NEAT consensus
2010 (2)I) Pegylated-interferon and weight-based ribavirin is
recommended for the treatment of acute HCV in HIV-infected patients. (AII)
II) Duration of treatment should be based on RVR (negative HCV RNA at week 4).
a) In patients with RVR treatment duration should be limited to 24 weeks. (AII)
b) In patients without RVR treatment duration of 48 weeks should be considered. (BIII)
c) In non-RVR patients who do not show a 2log drop in HCV RNA at week 12 treatment can be discontinued. (BIII)
APRICOT – Peg IFN 2a + Ribavirin APRICOT – Peg IFN 2a + Ribavirin arm SVR by genotype and viral arm SVR by genotype and viral
loadload
40
29
62 61
18
61
0
10
20
30
40
50
60
70
Overall G1 G2/3 low G1 High G1 Low
High > 800 000 iu/l Low < 800 000 iu/lTorriani et al, NEJM 2004
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
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%)
Predictors of response
Host
Acute infectionYounger ageLack of stage 3/4 fibrosisEthnicity – genetic??Low BMILack of hepatic steatosisHigh CD4 %Lack of insulin
resistance?
Virus
Genotypes 2/3Low viral loads
Thio C, Thomas D. Gastroenterology 2010
IL28B SNPs and SVR in HIV/HCV
Pineda, et al. CID 2010 (in Press)
Chromosome 20 SNPs and Ribivirin associated Anaemia
Viral Dynamic response to interferon and Viral Dynamic response to interferon and ribavirinribavirin
Pawlotsky Hepatology 2002; 32(4)
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
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)
How can we maximise How can we maximise response to therapy?response to therapy?
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
29
45
20
52
31
38
0
10
20
30
40
50
60
% p
atie
nts
ach
ievi
ng
SV
R
ITT RBV <13.2mg/kg/day
RBV ≥13.2mg/kg/day
Patients (n=256) taking 1 PI or 1 NNRTI and ABC plus LDV or TDF plus LDV or FTC as
N(t)RTI backbone during HCV therapy
ABC TDF
Mira JA, et al. J Antimicrob Chemother 2008; 62(6): 1365–1373 Medscape® www.medscape.com
ABC
ABV-MP
Adenylosuccinatesynthase-lyase
RBV
RBV-MPCBV-MP
Adenylate kinase
Guanylate kinase
RBV-DPCBV-DP
Nucleoside diphospho-kinase
RBV-TPCBV-TP
p=0.02p=0.02 p=0.03p=0.03 p=0.4p=0.4
Dose of Ribavirin?Dose of Ribavirin?
Importance of weight-based Ribavirin(1000mg <75kg/1200mg >75kg)
Soriano, et al. AIDS 2007. 21: 1073-89
Extended duration of Extended duration of therapy?therapy?
• Retrospective analysis of genotype 1 patients receiving 48 weeks of pegIFN alfa-2a + RBV (N = 453)
Longer Duration of Undetectability on Treatment Increases Chance
for SVR
HCV RNA Positive
at Week 24
4 12 24Week Became HCV RNA Negative
91
66
45
2
Ferenci P, et al. J Hepatol. 2005;43:425-433.
20
40
60
80
100
SV
R (
%)
0
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
Induction or higher Induction or higher doses of Peg-IFN?doses of Peg-IFN?
• 270 mcg vs. 180 mcg PegIFN – alpha 2a + R (1000mg/1200mg) for 4 weeks followed by 180mcg + R
• No difference in RVR or EVR
Untreated Follow-up
SLAM-C trial in HIV–HCV co-infected non-responders (Sherman)
Peg-IFNα-2a 180 µg plus
RBV 800–1200
mg
HCV RNA 2 log dropNR and
naïve n=200
HCV RNA
<2 log drop12 weeks
Peg-IFNα-2a 180 µg plus
RBV 800–1200 mg
Peg-IFNα-2a 180 µg
Stop treatment, observation period
60 weeks
72 weeks
24 weeks
Randomisation
Slam-C results
• Interim analysis April 2007– 45 patients with paired liver biopsies in the non-
EVR arm
• Insufficient fibrosis progression to determine a difference between the groups
• BUT – HALT-C results– No sig. reduction in fibrosis or diff between arms– No reduction in primary end-points
Sherman et al, CROI 2008
Anti-HCV drugs in development
Slide courtesy Tracy Swann 2010
Slide courtesy Tracy Swann 2010
NS5A inhibitors
Slide courtesy Tracy Swann 2010
Nitazoxinide
Slide courtesy Tracy Swann 2010
New Interferons
Slide courtesy Tracy Swann 2010
Even the best are only human……
Pertinent issues with the Stat-Cs
• NS3/NS4 PIs – cytochrome P450 metabolised – anti-HIV PIs/NNRTIs
• NS5b – Nucleosides – potential interaction with anti-HIV NAs
• NS5b – Non-nucleosides – Cyp450 interactions?
• Very high HCV mutation rates – rapid emergence of drug resistance
• Potential for X-resistance amongst classes• Mutations not archived but continued
circulation dependent on fitness
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.
Rockstroh, Bhagani, Bruno et al, EACS Guidelines 2008