Il paziente HIV “difficile”: il ruolo delle coinfezioni Franco Maggiolo USC di Malattie...

Il paziente HIV “difficile”: il ruolo delle coinfezioni

Franco Maggiolo

USC di Malattie Infettive,

US di terapia antivirale,

Ospedali Riuniti, Bergamo

Argomenti

• Epidemiologia• Diagnosi• Effetti HIV• Effetti virus epatitici• Effetti HAART• Terapia epatite cronica

Overlapping HCV & HIV epidemicsOverlapping HCV & HIV epidemics

HIV

40million

HCV

175million

25% of HIV

10 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

Male 80% 60% <0.001

Age (yrs) 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

Liver Stiffness, kPa 6.3 6.6 0.095

Cardoso T, et al. 45th EASL; Vienna, Austria; April 14-18, 2010; Abst. 390.

Diagnostic Performance of Transient Elastography Similar in HBV and HCV

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

TE performance in HBV and HCV Patients

Accuracy Sensitivity Specificity Positive LR Negative LR

HBV F≥2 82 74 88 6.19 0.29

F≥3 82 88 81 4.63 0.14

HCV F≥2 77 68 88 5.98 0.35

F≥3 86 67 92 8.51 0.35

Cardoso T, et al. 45th EASL; Vienna, Austria; April 14-18, 2010; Abst. 390.

DL Thomas et al. Nature 461, 798-801 (2009) doi:10.1038/nature08463

Percentage of HCV clearance by rs12979860 genotype

OR 3.0 OR 3.1OR 2.6

Inosine Triphosphatase Inosine Triphosphatase Variants and AnaemiaVariants and Anaemia

rs1127354 rs7270101

05

101520253035404550

AA CA CC

%Hbdecline>3g/dl

05

101520253035404550

CC AC AA

Hb<10 g/dl

Fellay Nature 2010

Argomenti


Model Study name Statistics for each study Risk ratio and 95% CI

Risk Lower Upper ratio limit limit Z-Valuep-Value

Verma, 2006a 2.015 1.421 2.858 3.928 0.000Di Martino, 2001 2.245 0.581 8.683 1.172 0.241Brau, 2006 1.404 1.010 1.951 2.019 0.044Gaslightwala & Bini, 2006 7.289 4.93810.760 9.998 0.000Monto, 2005 0.778 0.327 1.854 -0.566 0.572Mohsen, 2003 1.814 0.958 3.434 1.830 0.067Martinez-Sierra, 2003 4.195 1.66510.567 3.042 0.002Macias, 2005 1.698 0.911 3.165 1.666 0.096

Fixed 2.290 1.919 2.732 9.197 0.000Random 2.181 1.285 3.703 2.887 0.004

0.1 0.2 0.5 1 2 5 10

Meta-Analysis

Rate ratio of Cirrhosis between HIV/HCV and HCV: HAART era

N381160656708464208188234

Causes of death (116 events)

AIDS related

Other causes

58,6

41,4

35,3

18,1

6,9

6

6

6

21,6

Cancer

Infections

Hepatopathy

Cardiovascular

Wasting

Other causes

Unknown

NHL 15KS 8Primary cerebral lymphoma 2Respiratory tract 4

GE tract 4Cerebral 2Liver 2renal 1genital 2

ADEs 16Non ADE 9

Prevalence of patients living with disease

0

1

2

3

4

5

6

diabetes cardiovasculardiseases

cirrhosis neoplasticdisease

general population Bergamo cohort

% o

f su

bje

cts

Argomenti


Fracture Rates in HIV and HIV/HCV PatientsFracture Rates in HIV and HIV/HCV PatientsFra

ctu

re R

ate

(p

er

1,0

00

pati

en

t-years

)

Risk of AMI and CVD Among HIV and Risk of AMI and CVD Among HIV and HIV/HCV Patients in the HAART era 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 Insulin Resistance and Diabetes Mellitus in HCV/HIV coinfectedcoinfected

Unadjusted Adjusted

Hep C negative

1 1

Hep C positive

1.12

(O.94-1.33)

1.32

(1.04-1.69)

Merchante N, et al., Gut 2009

Adjusted for sex,age,risk,ethnicity,previous AIDS,smoking,family history,ART drug exposure,cohort,year

Rainer CROI 2008

Argomenti


Most Common Grade 4 Events:CPCRA Cohort

0

1

2

3

per

100

Per

son

-Yea

rsp

er 1

00 P

erso

n-Y

ears

Reisler RB, et al. JAIDS. 2003;34:379-35:182-189.

LiverLiver2.62.6

NeutropeniaNeutropenia1.51.5

AnemiaAnemia1.11.1 CVDCVD

0.90.9PancreatitisPancreatitis

0.90.9 PsychiatricPsychiatric0.80.8 RenalRenal

0.60.6

IncidenceIncidence

n=2947; CPCRA=Terry Beirn Communityn=2947; CPCRA=Terry Beirn CommunityPrograms for Clinical Research on AIDS.Programs for Clinical Research on AIDS.

Hazard Ratio For Death by Grade 4 Event (95% CI)Hazard Ratio For Death by Grade 4 Event (95% CI)3.493.49

(2.38-5.12)(2.38-5.12)PP=0.0001=0.0001

1.021.02(0.61-1.72)(0.61-1.72)

PP=0.93=0.93

1.761.76(0.99-3.09)(0.99-3.09)

PP=0.051=0.051

7.087.08(4.14-12.05)(4.14-12.05)

PP=0.0001=0.0001

3.403.40(1.82-6.33)(1.82-6.33)PP=0.0001=0.0001

1.911.91(0.79-4.63)(0.79-4.63)

PP=0.15=0.15

4.604.60(2.45-8.66)(2.45-8.66)PP=0.0001=0.0001

Mechanism of HAART related Hepatotoxicity

Direct Toxicity

HSR Mitochondrial Toxicity

IRIS

Drugs NNRTI/PI Abacavir, NNRTIs,

Fosamprenavir/Darunavir

NRTI

(AZT,D4T, DDI )

All

Dose Dependance

Yes No Yes No

Onset 2-12m <6 weeks Late Early

Other Fever,Rash,

Eosinophilia

AST>ALT

Lactic Acidosis

HBV,HCV

HAART and Liver Enzyme Elevations Meta-analysis of 20 publications of HIV-infected patients ± HCV coinfection

Grade 2 or higher liver elevations noted

Drug Class

Pat

ien

ts W

ith

LE

E,%

NNRTI0

10

32.00

18.44 15.9620

30

40

13.62

5.26

14.67

PI Mixed BPI NRTI Overall

P = .004

P = .025

P = .009

% LEE in HCV-Coinfected Patients by Drug Class

Benhamou Y, et al. CROI 2006. Abstract 88.

NRTIs

• Abacavir

• Didanosine

• Emtricitabine

• Lamivudine

• Stavudine

• Tenofovir

• Zidovudine

Drugs available for HIV therapy

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

Fleischer R, et al. 2004.

DidanosineDidanosine

Didanosine +Didanosine +stavudinestavudine

StavudineStavudine

AbacavirAbacavir

LamivudineLamivudine

ZidovudineZidovudine

0.01 0.1 1.0 10 1000.01 0.1 1.0 10 100

Odds Ratio (95% CI)Odds Ratio (95% CI)

Ribavirin +Ribavirin +

Mitochondrial ToxicityMitochondrial ToxicityRiskRisk

US FDA Adverse Event Reporting System (2002)

— HIV/HCV patients• Ribavirin + NRTIs

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)

12.412.4

8.08.0

3.33.3

1.11.1

0.20.2

0.060.06

Didanosine associated portal Hypertension

Often non-cirrhotic but associatedwith nodular hyperplasia

Associated with portal vein thrombosis

Often present late with variceal bleed

NNRTIs

• Efavirenz

• Nevirapine

• Etravirine


Incidence of Severe Hepatotoxicityof NNRTIs in Hepatitis Coinfection

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

Sulkowski MS, et al. Hepatology. 2002:35:182-189.

0

5

10

15

20

25Nevirapine (n=256)Nevirapine (n=256)

Cas

es/1

00 P

erso

n-E

xpo

sed

Cas

es/1

00 P

erso

n-E

xpo

sed

No PI PI AddedNo PI PI Added

6.16.1

HCV-HCV-HCV+HCV+ 18.118.1 18.118.1

14.414.4

0

5

10

15

20

25Efavirenz (n=312)Efavirenz (n=312)

Cas

es/1

00 P

erso

n-E

xpo

sed

Cas

es/1

00 P

erso

n-E

xpo

sed

No PI PI AddedNo PI PI Added00

HCV-HCV-HCV+HCV+

5.85.8

20.920.9

9.79.7

Stern JO et al. XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain.

NVP (n = 1731) Control (n = 1912)

0-12 Months

Probability(%)

Months of Treatment

6 weeks

0 2 4 6 8 10 120

5

10

15

20

NVPControl

12

3-12 Months

Months of Treatment

3 4 6 100

5

10

15

20

5 7 8 9 11

NVPControl

Time to Onset of Asymptomatic ALT or AST >5 x ULN on NVP in Controlled Trials

It has been shown that HCV patients It has been shown that HCV patients receiving NNRTIs, especially NVP, receiving NNRTIs, especially NVP, have lower HCV-RNA levelshave lower HCV-RNA levels1,21,2.

HIV can induce HCV replication HIV can induce HCV replication through TGF-beta1, which is through TGF-beta1, which is produced in the liver in response to produced in the liver in response to proinflamatory cytokinesproinflamatory cytokines33.

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.

1) Bani-Sadr F et al. AIDS 2007; 21: 16451) Bani-Sadr F et al. AIDS 2007; 21: 1645 2) Mata R et al. EACS Conference 2009, Cologne, Germany. 2) Mata R et al. EACS Conference 2009, Cologne, Germany.

3) Lin W et al. Gastroenterology 2008; 134:803–8113) Lin W et al. Gastroenterology 2008; 134:803–8114) Virgili N et al. J Acquir Immune Defic Syndr 2009; 50: 552-5534) Virgili N et al. J Acquir Immune Defic Syndr 2009; 50: 552-553

HCV-RNA level among individuals receiving PI-, EFV- or NVP-based ART22

DiscussionImpact of NVP on HCV-RNA viral load

10610819N =

Antiretroviral drug

PIEFVNVPM

ea

n H

CV

-RN

A (

Lo

g1

0 I

U/m

L)

leve

l

9

8

7

6

5

4

3

p=0.012

Protease Inhibitors

• Atazanavir

• Darunavir

• Fos-Amprenavir

• Indinavir

• Lopinavir

• Nelfinavir

• Ritonavir

• Saquinavir

• Tipranavir


Incidence of Severe HepatotoxicityDuring Therapy With PI-Based Regimens

0

10

20

30

40

Nelfinavir Kaletra Indinavir + RTV Saquinavir + RTVNelfinavir Kaletra Indinavir + RTV Saquinavir + RTV n=605 n=89 n=94 n=273 n=605 n=89 n=94 n=273 (1250 mg bid) (400/100 mg bid) (100-200/200 mg bid) (400/400 mg bid)(1250 mg bid) (400/100 mg bid) (100-200/200 mg bid) (400/400 mg bid)

HIV monoinfectionHIV monoinfectionHepatitis coinfectionHepatitis coinfection

6.5%6.5%

Inci

den

ce (

%)

Inci

den

ce (

%)

15.8%15.8%

6.0%6.0%

12.8%12.8%14.8%14.8%

11.4%11.4%

26.2%26.2%

10.0%10.0%

Sulkowski MS, et al. AIDS. 2004;18:1-8.

Hepatotoxicity with Newer PIs

02468

101214161820

ATZr LPVr

02468

101214161820

FPVr LPVr

% G

rade

3/4

% G

rade

3/4

% G

rade

2/4

% G

rade

3/4

CASTLE KLEAN

TITAN RESIST

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

Impact of ART on Overall Liver Mortalityin HIV/HCV-Coinfected Patients

Bonn cohort (1990-2002) 285 HIV/HCV coinfected patients

Liver-related mortality rates per 100 person-years HAART: 0.45 ART: 0.69 No therapy: 1.70

Predictors for liver-related mortality No HAART Low CD4 cell count Increasing age

Qurishi N, et al. Lancet. 2003:362:1708-1713.

0.2

0.4

0.6

0.8

1

DaysDays

Overall MortalityOverall Mortality

Cu

mu

lati

ve S

urv

ival

Cu

mu

lati

ve S

urv

ival

0 1000 2000 3000 4000 5000 60000 1000 2000 3000 4000 5000 6000

ARTART

HAART*HAART*

0.2

0.4

0.6

0.8

1

DaysDays

Liver-Related MortalityLiver-Related Mortality

Cu

mu

lati

ve S

urv

ival

Cu

mu

lati

ve S

urv

ival

0 1000 2000 3000 4000 5000 60000 1000 2000 3000 4000 5000 6000

HAART*HAART*

No therapyNo therapy

ARTART

No therapyNo therapy

**PP=0.018=0.018

**PP<0.001<0.001

Renato Maserati

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)

• 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

IFN-alpha

Pegylated-Interferon-alpha

Polymerase Inhibitors

Lamivudine

Adefovir

Entecavir

Telbivudine

Tenofovir

Emtricitabine

LAM MonoTherapy: Major Issues

LAM MonoTherapy ?M204V/I X Telbivudine

/ClevudineL180M

A181T/VX Adefovir

T184S X Entecavir

T184G/S202I/M250V

V214A/Q215S AdefovirX

L80V/I X Adefovir

A194T X Tenofovir

A181T/V

HCV/HIV TREATMENT OUTCOMESHCV/HIV TREATMENT OUTCOMES

SVR 14-38% SVR 44-73%

Genotype 1 Genotype 3

QoL Scores Decline in Pts Receiving QoL Scores Decline in Pts Receiving HCV TherapyHCV Therapy

• 412 HCV-infected pts randomized to open-label treatment with pegIFN alfa-2a vs IFN alfa-2b + RBV

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.

PFVTRPSF

BPREGH

MHStandard IFN alfa + RBV PegIFN alfa-2a

Week

SF

-36

Do

ma

in S

core

PosttreatmentTreatment

BL4 12 24 48 60 72

90

60

30

Week

SF

-36

Do

ma

in S

core

Treatment

BL4 12 24 48 60 72

90

60

30

Immune

modulators

Oligonucleotides

Cyclophiline Binhibitors

Nucleosidic

polymerase

inhibitorsInterferons

Analogues

of ribavirin

Protease

InhibitorsGlucosidase αinhibitors

RNAinterference

New HCV Treatments in Development

Therapeutic

Vaccines

Non-nucleosidic

polymerase

inhibitors

Disclaimer

01-13-RTG-2010-IT-4769-AV01-13-RTG-2010-IT-4769-AV

Servizio scientifico offerto alla Classe Medica da MSD Italia S.r.l.

Questa pubblicazione riflette i punti di vista e le esperienze dell’autore [o degli autori] e non necessariamente quelli della MSD Italia S.r.l.Ogni farmaco menzionato deve essere usato in accordo con il relativo riassunto delle caratteristiche del prodotto fornito dalla ditta produttrice.

Servizio scientifico offerto alla Classe Medica da MSD Italia S.r.l.

Questa pubblicazione riflette i punti di vista e le esperienze dell’autore [o degli autori] e non necessariamente quelli della MSD Italia S.r.l.Ogni farmaco menzionato deve essere usato in accordo con il relativo riassunto delle caratteristiche del prodotto fornito dalla ditta produttrice.

Il paziente HIV “difficile”: il ruolo delle coinfezioni Franco Maggiolo USC di Malattie...

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