Tavola RotondaLe tossicità d'organo in HIV

Fegato: overviewP. NastaClinica di Malattie Infettive e Tropicali, Azienda Ospedaliera Spedali Civili di Brescia

DiscussioneConduce: M. PuotiS.C. Malattie Infettive, A.O. Ospedale Niguarda, Ca’ Granda, Milano

Progressione di APRI SCORE e FIB 4 in pazienti mono-infetti HIV

Mendeni ICAR 2010

-Liver elevation enzyme

-Metabolic toxicity and NAFLD

-Immunoactivation and chronic inflammation

- DAA and HAT

HAART related factors and liver fibrosis progression

HAART related factors and liver fibrosis progression

Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification.

(Keiser O et al.Antivir Ther 2007; 12:1157–116.)

Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States popu lation.

(Ruhl CE et al.Gastroenterology 2009; 136:477–485).

ALT elevation was associated with deaths from liver disease (HR, 8.2; 95% CI, 2.1-31.9)

During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality

(HR 1.3; 95% CI, 1.2-1.5; P < 0.001)

2365 pts 9972 person-yearsAge 38 yrs, 66% male, CD4 426, 56% on ART

Chronic ALT elevation :16% 3,9 cases per 100 p/y (IC 95%1,3-4,3)

Related factors at multivariate analysis

IRR (IC95%)HIV-RNA 100.000 c/ml 2,2 (1,45-3,42)

BMI (25-29,9) 1,56 (1,245-1,96)BMI > 30 1,70 (1,16-2,51)Alcohol abuse 1,04 (1,00-1,08)

- NRTI or PI exposure did not remain statistical significant after adjustment for exposure to stavudine - treatment outcome and mortality did not differ in groups with or without ALT elevation (CID 2010;50:502-11)

(CID 2010;50:502-11)

HCV positive 37/194 (19,1%)

N of pts with LEE

HCV negative: 10/42 (7%)Pat

ient

s f

ree

by L

EE

(an

y gr

ade)

Long Rank 13,0( p 0,0003)

days

Probability to be free by LEE in HCV positive ( n 194) vs HCV negative ( n 143) patients treated with RAL ( Brescia n 377)

OR 3,1 (1,4-6,4) p0,001

RALTEGRAVIR

All causalities and severities, n (%)Unadjusted for duration of exposure

OBT alone

N=207*

MVC QD + OBTN=408*

MVC BID + OBTN=421*

AST:Grade 3 >5.0 to 10.0 ULNGrade 4 >10.0 x ULNTOTAL (grade 3/4)

6 (2.9)0

6 (2.9)

11 (2.7)3 (0.7)

14 (3.4)

13 (3.1)6 (1.4)

19 (4.5)

ALT: Grade 3 >5.0 to 10.0 ULN

Grade 4 >10.0 x ULNTOTAL (grade 3/4)

6 (2.9)1 (0.5)7 (3.4)

14 (3.4)2 (0.5) 16 (3.9)

6 (1.4)4 (1.0) 10 (2.4)

Total bilirubin:Grade 3 >2.5 to 5.0 x ULN

Grade 4 >5.0 x ULNTOTAL (grade 3/4)

8 (3.9) 3 (1.5)

11 (5.3)

29 (7.1)4 (1.0)

33 (8.1)

21 (5.0) 3 (0.7) 24 (5.7)

* Patients with at least one on-drug follow-up assessment

van der Ryst E, et al. 4th IAS 2007; Poster WEPEB115LB MOTIVATE 1 and 2 – Week 24

ARLI:inibitori dell’entry-Maraviroc

MARAVIROC: Hepatic tolerability

-Start HAART early (Cd4 350-500)-Avoid ddI-D4T and AZT should be avoided -Antiretroviral therapy should be promptly withdrawn in case of:•Lactic acidosis •Hypersensitivity reaction •LEE > 10 NV•Janduice •Liver decompesation

How to treat HIV How to treat HIV when HCV treatment is startedwhen HCV treatment is startedGuidelines recommendation Guidelines recommendation

How to treat HIV How to treat HIV when HCV treatment is startedwhen HCV treatment is startedGuidelines recommendation Guidelines recommendation

When deciding to treat HCV, the choice of anti-HIV therapy should be agreed in association with an experienced HIV physician ABC may reduce RBV level

Didanosine is contraindicated

AZT and d4T should be avoided

ABC co administration does not interfere with the suppresisve activity of RBV in an

HCV replicon system (Van de Eynde E et al. CROI 2011; #963)

In a subgenomic replicon system the antiviral effect of RBV was not modified

by the addition of ABC, 3TC or TDF

-Liver elevation enzyme

-Metabolic toxicity and NAFLD

-Immunoactivation and chronic inflammation

- DAA and HAT

HAART related factors and liver fibrosis progression

HAART related factors and liver fibrosis progression

P=0.006

P=NS

P=0.01

Liver-related(2.8% vs.0.2%, P.04)

Cardiovascular diseases(15.5% vs. 7.5%, P .04).

Long-term follow-up of patients with NAFLD

Ekstedt et al., Hepatology 2006;44:865

Nonalcoholic Fatty Liver Disease (NAFLD) among HIV-Infected Persons(Crum-Cianflon N. et al.JAIDS 2009;50:464-473)

Sixty-seven (31%) of 216 patients had NAFLD based on ultrasound evaluation. among those with NAFLD,

Mild 60%, Moderate 28%, Severe/ Marked 12%.

Variables associated at multivariate analysis:

waist circumference OR 2.1 per 10 cm, p<0.001

elevated triglycerides OR 1.2 per 100 mg/dl, p=0.03

and lower HDL levels OR 0.7, p=0.03

↑ LEPTIN

↑ RESISTIN

↑ VISFATIN

↓ ADIPONECTIN

Adipokines and liver fibrosis

Leptin and hepatic stellate cells, the effectors of liver wound healing

Leptin

TIMP-1 Proliferation

ERKPI3K/Akt

Survival Chemokines

NF-B

VEGF

HIF-1

Type I Collagen

H2O2

Jak-StatERKp38MAPK

AP-1

H2O2

Jak-StatERKp38MAPK

ERKPI3K/Akt

Marra, J Hepatol 2007;46:12 2007

clinicaloptions.com/hivImplications of New Data on Complications Associated With ARV Regimens

Patogenesi del danno metabolico da PI

- Alterata funzione di SREBP 1 e 2 e PPAR e PPAR

- Produzione delle VLDL

- Lipoprotein lipasi (LPL) VLDL circolanti (pieno di TGD)

- della captazione dei TGD nel tex adiposo (lipodistrofia)

- GLUT 4, recettori IRS1

FAA circolanti e zuccheri

Depositi di FAA in tex ectopici ( fegato, m scheletrico)

IR e leptino resistenza

LEPTINA , INSULINA

clinicaloptions.com/hivImplications of New Data on Complications Associated With ARV Regimens

(CID 2010;50:502-11)

Gut 2009;58:1654–1660.

600 patients: 500 HCV and 100 HBV positive IR is a specific feature of CHC, associated with genotype 1 and 4 and HCV RNA level. Significant fibrosis is associated with IR independent from steatosis

genotype 1-4 correlation coefficient r^2= 0,9; p<0,0001

genotype 2-3 correlation coefficient r^2 0,6= p<0,0006

correlation coefficient r^2= 0,93 ; p<0,0001

HOMA score is associated with Hepatitis C Viremia (Hsui SC et al. 2010)

N 107 pts HIV/HCV who started PegIFN/RBV, 49,5% G 1 ,HOMA IR 3,2(+2,9), Cirrhosis 33%

Nasta P et al. ICAR 2010 (#91)Nasta P er al, CROI submitted

Nasta P et al, ICAAC 2010, ABS H 1673

… and with Liver Stiffness (N Merchante et al, 2010

Triglyceride level is associated with HCV RNA

There is a linear correlation between trglyceride plasma level and HCV-RNA

N 107 pts HIV/HCV who started PegIFN/RBV 49,5% G 1Cirrhosis 33% Median TRG level 125 (82-181)mg/dl , TRG>150 mg/dl 34,5%

Nasta P

Correlation coeficient r^2 0,7 p 0,006

LDL level as prognostic tool of liver diseases progression in HIV/HCV coinfection

(M Habayeb et al. CROI 2011, # 925)

Low LDL was significantly associated with the degree of liver disaease measured

with APRI overall and among those without fibrosis at baseline .

HCV may utilize the LDL receptor to enter in the hepatocyte and co-opt the very LDL secretion pathway for virion maturation and secretion.

They may cause disruption of Lipoprotein metabolismLow LDL levels may serve as biomarker of intra-hepatic HCV replication

Liver disease progression and HAART related Liver disease progression and HAART related factorsfactors

Liver disease progression and HAART related Liver disease progression and HAART related factorsfactors

-Liver elevation enzyme

-Metabolic toxicity and NAFLD

-Immunoactivation and chronic inflammation

- DAA and HAT

HAART related factors and liver fibrosis progression

HAART related factors and liver fibrosis progression

Activation of KC and inflammatory cells

Toll-like Pattern recognitionreceptors

LPSLTAPGN

Paik et al., Hepatology 2003;37:1043Brun et al., AJP-GI 2005 289: G571Seki et al. Nat Med 2007

Hepatic stellate cellsMCP-1

TLR4TLR2PGRP-LCD14PGRP-S

TGF-

Microbial translocation and immunoactivation in HIV/virus hepatitis co-infection

- 55 HIV/HBV coinfected pts from Thailand and 20 uninfected control

Markers of microbial translocation and immunoactivation studied before and

after initiation of anti HBV containing HAART ,

LPS, sCD14, and CXCL10 are elevated in HIV/HBV coinfected compared

with uninfected control and the levels return to normal following HBV effective

HAART.

No significant association between LPS and liver disease severity,

Persistent elevation of CCL2 on HAART may potentially play a role in ongoingdiseases progression (M Crane , CROI 2011; #937)

Plasma soluble sCD14 levels are associated with severity of liver diseases and predict clinical outcome in HBV and HCV infection

( Sandler N et al, CROI 2011; #939)

- 16 minimal fibrosis HBV or HCV-HIV co-infected - 68 with cirrhosis HBV or HCV-HIV co-infected - 40 uninfected control - Analysis: I-FABP(Intestinal fatty acid binding protein: marker of enterocyte death), LPS,

sCD14 and IL6

• Low platlets count (consistent with portal hypertension) were associated with high I-FABP• sCD14 was higher in pts with severe fibrosis and predicted the disease progression• Successful HAART induce reduction of IL6 and I-FABP , but not of sCD14 and LPS,

suggesting reduction in enterocyte death and IL6 production occur more quickly than reduction of MT and monocyte activation

LPS ng/ml sCD14 (x106 pg/ml) I-FABP*(pg/ml) IL-6(pg/ml)

Healthy 20,4 1,71 20 0,0

HBVHCV

38,5 p=0,1729,3

1,85 p=0,052,08

211,0 p= 0,04303,1

4,4 p=0,028,5

NO FibrosisCirrhosis

31,5 p=0,4134,8

1,74 p=0,012,06

138,5 p=0,39212,1

6,7 p=0,627,3

No ProgressionProgression

35,2 p=0,4235,6

1,81 p=0,00092,22

164,7 p=0,74 223,3

6,2 p=0,947,5

-Liver elevation enzyme

-Metabolic toxicity and NAFLD

-Immunoactivation and chronic inflammation

- DAA and HAT

HAART related factors and liver fibrosis progression

HAART related factors and liver fibrosis progression

Discussion Strong association between liver-related mortality and elevated ALTlevels in general population (Ruhul CE et al.,Gastroenterology 2009).

and in HIV infected population without chronic viral hepatitis(Keiser O et al.Antivir Ther 2007).

Prolonged exposure to stavudine and zidovudine were associated with chronic ALT elevation (Kovari H et al. CID 2010)

The main causes of chronic liver disease in HIV-infected patients

without hepatitis B and C co- infections are alcohol consumption, non-

alcoholic fatty liver disease (NAFLD) and antiretroviral drugs.(Kovari H et al CID 2010)

Immunoactivation due to microbial translocation may contribute to the

liver fibrosis progression despite an effective HAART (Sandler N et al, CROI 2011; #939 )