Il paziente HIV “difficile”: il ruolo
delle coinfezioni
Franco Maggiolo
USC di Malattie Infettive,
US di terapia antivirale,
Ospedali Riuniti, Bergamo
Argomenti
•
•
•
•
•
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Epidemiologia
Diagnosi
Effetti HIV
Effetti virus epatitici
Effetti HAART
Terapia epatite cronica
Overlapping HCV & HIV epidemics
HIV
HCV
25% of HIV
40
million
10 million
175
million
Argomenti

Epidemiologia

Diagnosi

Effetti HIV

Effetti virus epatitici

Effetti HAART

Terapia epatite cronica
Fibroscan
Diagnostic Performance of Transient
Elastography Similar in HBV and HCV



Study comparing
diagnostic performance of
transient elastography
(TE) for assessment of
liver fibrosis in chronic
HBV and HCV (N=613)
Liver biopsy and TE on
same day
METAVIR score used for
histological analysis
HBV
(n=202)
HCV
(n=363)
P
80%
60%
<0.001
41
49
<0.001
BMI (kg/m2)
24.2
24.6
0.199
Obesity
7%
6%
0.838
Insulin Resistance
20%
27%
0.215
Diabetes
5%
5%
0.700
ALT
52
75
<0.001
Prothrombin
Time
90
94
<0.001
Significant
Steatosis (>30%)
14%
26%
0.001
Significant
fibrosis (F≥2)
42%
54%
0.005
Advanced
Fibrosis (≥3)
17%
24%
0.0048
6.3
6.6
0.095
Male
Age (yrs)
Liver Stiffness, kPa
Cardoso T, et al. 45th EASL; Vienna, Austria; April 14-18, 2010; Abst. 390.
Diagnostic Performance of Transient
Elastography Similar in HBV and HCV
TE performance in HBV and HCV Patients
HBV
HCV

Accuracy
Sensitivity
Specificity
Positive LR
Negative LR
F≥2
82
74
88
6.19
0.29
F≥3
82
88
81
4.63
0.14
F≥2
77
68
88
5.98
0.35
F≥3
86
67
92
8.51
0.35
Conclusions:


TE reliably predicts absence or the presence of significant and
advanced liver fibrosis in HBV and HCV
Cutoff values previously proposed for HBV and HCV patients appear
valid
Cardoso T, et al. 45th EASL; Vienna, Austria; April 14-18, 2010; Abst. 390.
Percentage of HCV clearance by rs12979860 genotype
OR 3.0
OR 2.6
OR 3.1
DL Thomas et al. Nature 461, 798-801 (2009) doi:10.1038/nature08463
Inosine Triphosphatase
Variants and Anaemia
50
45
40
35
30
25
20
15
10
5
0
%Hb
decline>3g/dl
AA
CA
CC
rs1127354
50
45
40
35
30
25
20
15
10
5
0
Hb<10 g/dl
CC
AC
AA
rs7270101
Fellay Nature 2010
Argomenti
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Epidemiologia
Diagnosi
Effetti HIV
Effetti virus epatitici
Effetti HAART
Terapia epatite cronica
Rate ratio of Cirrhosis between HIV/HCV and HCV:
HAART era
Model
Study name
N
381
Verma, 2006a
160
Di Martino, 2001
656
Brau, 2006
Gaslightwala & Bini, 2006 708
464
Monto, 2005
208
Mohsen, 2003
Martinez-Sierra, 2003
188
Macias, 2005
234
Fixed
Random
Statistics for each study
Risk Lower Upper
ratio limit limit Z-Valuep-Value
2.015 1.421 2.858 3.928 0.000
2.245 0.581 8.683 1.172 0.241
1.404 1.010 1.951 2.019 0.044
7.289 4.93810.760 9.998 0.000
0.778 0.327 1.854 -0.566 0.572
1.814 0.958 3.434 1.830 0.067
4.195 1.66510.567 3.042 0.002
1.698 0.911 3.165 1.666 0.096
2.290 1.919 2.732 9.197 0.000
2.181 1.285 3.703 2.887 0.004
Risk ratio and 95% CI
0.1 0.2
Meta-Analysis
0.5
1
2
5
10
Causes of death
(116 events)
NHL
KS
Primary cerebral lymphoma
Respiratory tract
35,3
GE tract
Cerebral
Liver
renal
genital
6
41,4
6
21,6
58,6
6
ADEs
16
Non ADE 9
6,9
18,1
AIDS related
Cancer
Wasting
Other causes
Infections
Other causes
Hepatopathy
Unknown
Cardiovascular
15
8
2
4
4
2
2
1
2
Prevalence of patients living with disease
% of subjects
6
5
4
3
2
1
0
diabetes
cardiovascular
diseases
general population
cirrhosis
Bergamo cohort
neoplastic
disease
Argomenti
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Epidemiologia
Diagnosi
Effetti HIV
Effetti virus epatitici
Effetti HAART
Terapia epatite cronica
Fracture Rate (per 1,000 patient-years)
Fracture Rates in HIV and HIV/HCV Patients
4.5
4.06
4
3.5
3
3.35
2.86
2.54
2.5
2
1.5
1
0.5
0
HIV
HIV/HCV
HAART Era ('96-'09): 258,326 PY
HIV
HIV/HCV
Entire Period ('88-'09): 303,678 PY
HAART Era ('96-'09): 258,326 PY HIV
HAART Era ('96-'09): 258,326 PY HIV/HCV
Entire Period ('88-'09): 303,678 PY HIV
Entire Period ('88-'09): 303,678 PY HIV/HCV
Risk of AMI and CVD Among HIV and
HIV/HCV Patients in the HAART era
Events
Acute Myocardial Infarction
Cerebrovascular Disease
HIV
HIV/HCV
HIV
HIV/HCV
Event Rate/1000
Patient-Years
3.36
4.19
11.12
12.47
Unadjusted Hazard
Ratio (95% CI;
P value)
1.25 (0.98-1.59) p=0.075
1.12 (0.98 - 1.29) p=0.105
Adjusted Hazard
Ratio (95% CI;
P value)
1.25 (0.98-1.61) P=0.072
1.20 (1.04 - 1.38) p=0.013
Insulin Resistance and Diabetes Mellitus in HCV/HIV
coinfected
Unadjusted Adjusted
Merchante N, et al., Gut 2009
Hep C
negative
1
1
Hep C
positive
1.12
1.32
(O.94-1.33) (1.04-1.69)
Adjusted for sex,age,risk,ethnicity,
previous AIDS,smoking,family history,ART
drug exposure,cohort,year
Rainer CROI 2008
Argomenti
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Epidemiologia
Diagnosi
Effetti HIV
Effetti virus epatitici
Effetti HAART
Terapia epatite cronica
Most Common Grade 4 Events:
CPCRA Cohort
per 100 Person-Years
3
Incidence
Liver
2.6
2
Neutropenia
1.5
Anemia
1.1
1
CVD
0.9
Pancreatitis
0.9
Psychiatric
0.8
Renal
0.6
0
Hazard Ratio For Death by Grade 4 Event (95% CI)
3.49
(2.38-5.12)
P=0.0001
1.02
(0.61-1.72)
P=0.93
1.76
(0.99-3.09)
P=0.051
n=2947; CPCRA=Terry Beirn Community
Programs for Clinical Research on AIDS.
7.08
(4.14-12.05)
P=0.0001
3.40
(1.82-6.33)
P=0.0001
1.91
(0.79-4.63)
P=0.15
4.60
(2.45-8.66)
P=0.0001
Reisler RB, et al. JAIDS. 2003;34:379-35:182-189.
Mechanism of HAART related
Hepatotoxicity
Drugs
Direct
Toxicity
HSR
Mitochondrial
Toxicity
IRIS
NNRTI/PI
Abacavir,
NNRTIs,
Fosamprenavir/
Darunavir
NRTI
All
(AZT,D4T,
DDI )
Dose
Dependance
Yes
No
Yes
No
Onset
2-12m
<6 weeks
Late
Early
Fever,Rash,
AST>ALT
HBV,HCV
Eosinophilia
Lactic
Acidosis
Other
HAART and Liver Enzyme Elevations


Meta-analysis of 20 publications of HIV-infected patients ± HCV
coinfection
Grade 2 or higher liver elevations noted
% LEE in HCV-Coinfected Patients by Drug Class
Patients With LEE,%
P = .025
40
P = .004
32.00
P = .009
30
18.44
20
15.96
14.67
13.62
10
5.26
0
NNRTI
PI
Mixed
BPI
Drug Class
Benhamou Y, et al. CROI 2006. Abstract 88.
NRTI
Overall
Drugs available for HIV therapy
NRTIs
• Abacavir
• Didanosine
• Emtricitabine
• Lamivudine
• Stavudine
• Tenofovir
• Zidovudine
Mitochondrial toxicity
1.
Lichterfeld M, Haasen S, Fischer HP, Voigt E, Rockstroh JK, Spengler U: Liver histopathology in human immune deficiency virus/hepatitis C coinfected
patients with fatal liver disease. J Gastrol Hepatol 20: 739-745, 2005
Risk of Mitochondrial Toxicity: NRTI +
Ribavirin in HIV/HCV-Coinfected Patients
 US FDA Adverse Event
Reporting System (2002)
— HIV/HCV patients
• Ribavirin + NRTIs
Mitochondrial Toxicity
Risk
Ribavirin +
12.4
 31 cases (58 adverse events)
suggestive of mitochondrial
toxicity
— Pancreatitis and/or increased
lipase (n=21)
— Lactic acidosis (n=20)
— Elevated LFTs (n=8)
— Hepatic steatosis (n=6)
— Elevated creatinine,
neuropathy, multiorgan failure
(n=1 each)
8.0
Didan
Didano
stav
3.3
Stav
1.1
Ab
0.2
Lamiv
0.06
0.01
0.1
Zidov
1.0
10
100
Odds Ratio (95% CI)
Fleischer R, et al. 2004.
Didanosine associated portal
Hypertension
Often non-cirrhotic but associated
with nodular hyperplasia
Associated with portal vein thrombosis
Often present late with variceal bleed
Drugs available for HIV therapy
NNRTIs
• Efavirenz
• Nevirapine
• Etravirine


Prospective study on the incidence
severe hepatotoxicity (grade 3 or 4
AST/ALT)

Johns Hopkins HIV cohort (n=568)

HCV (43%) and HBV (7.7%)
Overall incidence of severe
hepatotoxicity

Nevirapine: 15.6%

Efavirenz: 8.0%
Hepatotoxicity risk was significantly
greater in:

Hepatitis coinfection

NNRTI + PI
Cases/100 Person-Exposed

25
Cases/100 Person-Exposed
Incidence of Severe Hepatotoxicity
of NNRTIs in Hepatitis Coinfection
25
20
Nevirapine (n=256)
HCVHCV+
18.1
14.4
15
10
5
0
20
18.1
6.1
No PI
PI Added
Efavirenz (n=312)
HCVHCV+
20.9
15
10
5.8
5
0
9.7
0
No PI
PI Added
Sulkowski MS, et al. Hepatology. 2002:35:182-189.
Time to Onset of Asymptomatic ALT or
AST >5 x ULN on NVP in Controlled Trials
0-12 Months
20
3-12 Months
6 weeks
20
NVP
Control
15
NVP
Control
15
Probability10
(%)
5
10
0
0
5
0
2
4
6
8
10
Months of Treatment
NVP (n = 1731)
12
3
4
5
6
7 8 9 10 11 12
Months of Treatment
Control (n = 1912)
Stern JO et al. XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain.
Discussion
Impact of NVP on HCV-RNA viral load


It has been shown that HCV
patients
receiving
NNRTIs,
especially NVP, have lower HCVRNA levels1,2.
Mean HCV-RNA (Log10 IU/mL) level

HIV can induce HCV replication
through TGF-beta1, which is
produced in the liver in response
to proinflamatory cytokines3.
NVP has been associated with
higher decreases in levels of
TNF-alpha receptor than other
antiretroviral drugs4, which might
decrease TGF-beta1 secretion in
the liver and reduce HCV
replication.
HCV-RNA level among individuals
receiving PI-, EFV- or NVP-based ART2
9
p=0.012
8
7
6
5
4
3
N=
19
108
106
NVP
EFV
PI
Antiretroviral drug
1) Bani-Sadr F et al. AIDS 2007; 21: 1645
2) Mata R et al. EACS Conference 2009, Cologne, Germany.
3) Lin W et al. Gastroenterology 2008; 134:803–811
4) Virgili N et al. J Acquir Immune Defic Syndr 2009; 50: 552-553
Drugs available for HIV therapy
Protease Inhibitors
• Atazanavir
• Darunavir
• Fos-Amprenavir
• Indinavir
• Lopinavir
• Nelfinavir
• Ritonavir
• Saquinavir
• Tipranavir
Incidence of Severe Hepatotoxicity
During Therapy With PI-Based Regimens
Incidence (%)
40
HIV monoinfection
Hepatitis coinfection
30
26.2%
20
15.8%
14.8%
12.8%
10.0%
10
6.5%
11.4%
6.0%
0
Nelfinavir
n=605
(1250 mg bid)
Kaletra
n=89
(400/100 mg bid)
Indinavir + RTV
n=94
(100-200/200 mg bid)
Saquinavir + RTV
n=273
(400/400 mg bid)
Sulkowski MS, et al. AIDS. 2004;18:1-8.
Hepatotoxicity with Newer PIs
KLEAN
20
18
16
14
12
10
8
6
4
2
0
% Grade 3/4
% Grade 3/4
CASTLE
ATZr
LPVr
FPVr
TITAN
LPVr
RESIST
% Grade 3/4
% Grade 2/4
20
18
16
14
12
10
8
6
4
2
0
Drugs available for HIV therapy
New Classes
Fusion Inhibitors
• Enfuvirtide
R5 Inhibitors
• Maraviroc
Integrase Inhibitors
• Raltegravir
Hepatotoxicity and New Agents
Motivate 1 and 2
Benchmark 1
Rates of Grade ¾ rises in ALT
Bonn cohort (1990-2002)


Liver-related mortality rates per
100 person-years




285 HIV/HCV coinfected patients
HAART: 0.45
ART: 0.69
No therapy: 1.70
Predictors for liver-related
mortality



No HAART
Low CD4 cell count
Increasing age
Overall Mortality
1
HAART*
0.8
0.6
ART
0.4
*P<0.001
0.2
0
1
Cumulative Survival

Cumulative Survival
Impact of ART on Overall Liver Mortality
in HIV/HCV-Coinfected Patients
1000
2000
No therapy
3000 4000
Days
5000
6000
Liver-Related Mortality
0.8
HAART*
ART
0.6
No therapy
0.4
0.2
*P=0.018
0
1000
2000
3000 4000
Days
5000
6000
Qurishi N, et al. Lancet. 2003:362:1708-1713.
QUANDO COMINCIARE
• PAZIENTI CON CD4+ <200 cells/ µL : è fortemente raccomandato (AI)
• PAZIENTI CON CD4+ 200 -350 cells/ µL è fortemente raccomandato (AII) il paziente va ben
preparato all’inizio della terapia
• PAZIENTI CON CD4+ 350 - 500 cells/ µL
• moderatamente raccomandato (BII)
• fortemente raccomandato :
• decremento di CD4+ ≥100 cells/ µL ogni anno (AII)
• carica virale > 100000 copie /ml (AII)
• età > 50 (AII)
• epatite cronica da HCV (AII)
• rischio CV elevato : diabete mellito o pregressi eventi CV, o rischio>20% nei
succ.10 anni (Framingham) (BIII)
Renato Maserati
• PAZIENTI CON CD4+ > 500 cells/ µL non raccomandato
Argomenti

Epidemiologia

Diagnosi

Effetti HIV

Effetti virus epatitici

Effetti HAART

Terapia epatite cronica
Anti-HBV Therapies
Immune modulators
Polymerase Inhibitors
IFN-alpha
Lamivudine
Pegylated-Interferonalpha
Adefovir
Entecavir
Telbivudine
Tenofovir
Emtricitabine
LAM MonoTherapy: Major Issues
A181T/V
X
Adefovir
?
LAM MonoTherapy
T184S
X
Entecavir
X
Telbivudine/
Clevudine
X
Adefovir
X
Tenofovir
X
Adefovir
T184G/S202I/M250V
L180M
M204V/I
L80V/I
A181T/V
A194T
V214A/Q215S
HCV/HIV TREATMENT OUTCOMES
Genotype 1
SVR 14-38%
Genotype 3
SVR 44-73%
QoL Scores Decline in Pts Receiving
HCV Therapy
•
Posttreatment
90
SF-36 Domain Score
SF-36 Domain Score
Standard IFN alfa + RBV
Treatment
90
60
30
BL4 12
Week
24
48
60
72
BP
RE
GH
MH
PF
VT
RP
SF
412 HCV-infected pts randomized to open-label
treatment with pegIFN alfa-2a vs IFN alfa-2b + RBV
PegIFN alfa-2a
Treatment
60
30
BL4 12
Week
24
Comparison of quality of life, work productivity and medical resource utilization of peginterferon
alpha 2a vs the combination of interferon alpha 2b plus ribavirin as initial treatment in patients
with chronic hepatitis C, Perrillo R, et al. J Viral Hepat. 2004;11:157-165. Copyright © 2004.
Reproduced with permission of Blackwell Publishing, Ltd.
48
60
72
New HCV Treatments in Development
Nucleosidic
Interferons
polymerase
inhibitors
Immune
Cyclophiline B
inhibitors
modulators
Oligonucleotides
Analogues
Non-nucleosidic
of ribavirin
Therapeutic
polymerase
Protease
Inhibitors
Vaccines
inhibitors
Glucosidase α
inhibitors
RNA
interference
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