liver involvement in hiv...hev prevalence in hiv author n location prevalence maylin et al.2012 261...

Liver involvement in HIV

Chanunta Hongthanakorn, MD.

Bhumibol Adueyadej Hospital

Outline

• Infection: non-viral hepatitis B and C,

opportunistic infections

• ART induced liver injuries

• Malignant neoplasm

Smith C, et al. AIDS. 2010;24(10):1537

Disease-related death in HIV

Disease-related death in HIV

Kovari H, et al. Clin Infect Dis 2013; 56: 870-9

Crane M, et al. WJH 2012; 4: 91-98

Liver diseases in HIV

• Hepatic parenchymal dis

– Infection

• Viral hepatitis: HCV, HBV,

HDV, HAV, HEV, CMV, EBV,

HSV, VZV, HHV-6

• Mycobacterium avium complex

• Cryptococcus neoformans

• Bacillary peliosis hepatis

– Medication hepatotoxicity

– Alcoholic liver disease

– NAFLD

– Recreational drugs

– Neoplasm

– Noncirrhotic PHT

– AIH

– Hemochromatosis

– Wilson’s disease

• Biliary disease

– AIDs Cholangiopathy

– Acalculous cholecystitis

– Neoplasm

– Primary scleosing

cholangitis

– Primary biliary cirrhosis

Hepatitis Delta • Only “defective” virus infecting humans

• Requires HBsAg, concomitant (co-

infection) or prior (superinfection)

• Cause the most severe form of liver

disease

• No vaccine

• No efficacious treatment

• Transmitted through parenteral route (IVDU) or sex

Hepatitis Delta in HBsAg+ patients in EuroSADA

Sariano V, et al. AIDs 2011; 23: 1987-92

14.5%

Hepatitis Delta in HIV

• Associated with higher replication markers of HDV

and accelerated liver fibrosis progression

• Since HAART in 1996, most HIV persons have

immune recovery and severe immunodeficiency is

currently rare. The worst prognosis of viral

hepatitis in this group has ameliorated in recent

years

Soriano V, et al. AIDS 2005; 19: 221-40

Peg-IFN plus ADV vs either drug alone for hepatitis D

Wedemeyer H, et al. NEJM 2011; 364: 322-31

Hepatitis E • Single stranded RNA virus

• Four major genotypes

– 1 and 2 restricted to humans and hyperendemic in

developing regions

• Fecal-oral route. It causes major waterborne outbreaks.

Mostly asymptomatic episodes, but fatality rate in

pregnant women (8-20%)

– 3 (Europe, North America, Argentina) and 4 (Japan,

China) Zoonotic infection from meat products or animal

close contact (farmers, veterinarians)

• Self-limiting infections, but chronic hepatitis in

immunosuppressed individuals (transplant

recipients, HIV)

HEV Prevalence in HIV

Author N Location Prevalence

Maylin et al.2012 261 Paris 1.5%

Kaba et al. 2011 184 Marseille 4,4% IgG

1.6% IgM 0.5% RNA chronic

Keane et al. 2012 138 SW England 9.4% IgG

Kenfek-Foguena et al. 2011

735 Switzerland 2.6% IgG 0.1% RNA chronic

Sellier et al. 2011 108 Paris 2.8% IgG 0.9% IgM, RNA +

Renou et al. 2010 245 N&S France 9% IgG south 3% IgG north

Fainboim et al. 1999 484 Argentina 6.6% IgG

Mycobacterium Avium Complex infection

Karakousis PC, et al. Lancet Infect Dis. 2004;4(9):557

MAC infection in HIV

• Mode of transmission: inhalation and

ingestion, person-to-person transmission

is unlikely

• Risk factor

– CD4 <50 cells/mm3

– High HIV RNA levels

– Previous opportunistic infections

– Host factor: specific HLA class II alleles

(DRB1, DQB, DM)

• Symptoms: fever, night sweats, weight loss,

fatigue, abdominal pain, diarrhea Gordin FM, et al. J Infect Dis 1997;176:126–32

• Hepatomegaly, splenomegaly,

lymphadenopathy

• Laboratory finding: anemia, elevated ALP

• Diagnosis

– isolation of MAC from cultures of blood, LN, or

other sterile tissue.

– DNA probes distinguish MAC from TB

MAC infection in HIV

Treatment of MAC

• Combined drug treatment:

– 1st drug: clarithromycin, azithromycin

– 2nd drug: ethambutol, rifabutin, amikacin, streptomycin, and fluoroquinolones

• Duration: at least 12 months

Bacillary peliosis hepatis

• Presence of cystic blood-filled cavities distributed

randomly throughout the liver parenchyma

• Can also involve the spleen, bone marrow, lungs,

abdominal lymph nodes, and other organs.

• Bartonella henselae infection

• Cat scratch, trench fever

• Advanced immunodefeciency (CD4 <50 cells/µl)

• Warthin-Starry stain demonstrated numerous

bacilli

Bacillary peliosis hepatis

• Asymptomatic, slow progress disease

• Liver biopsy:

– parenchymal peliosis (cavities are not lined by

sinusoidal cell, or by fibrous tissue)

– phlebectatic peliosis (cavities lined by endothelium

and/or fibrosis)

• EM: pleomorphic bacilli with a trilaminar wall

• IFA and EIA: reliability in diagnosing Bartonella

infections in HIV pts is not clear

Yanoff M, et al. Arch Patho 1964;77: 159

Peliosis hepatis

• No specific treatment except for Bacillary form.

• Oral erythromycin (500 mg four times daily) or

oral doxycyclin (100 mg twice daily) for at least

4 months

• Pt with intrahepatic or peritoneal hemorrhage

may required angiography intervention or

surgery

Rolain JM, et al. Antimicrob Agent Chemother 2004;48: 1972 Oriordan K, et al. HPB Surg 2000; 11: 353

Antiretroviral drugs

• Nucleos(t)ide analogue reverse transcriptase

inhibitors (NRTIs) eg: LAM, zidovudine, DDI

(didanosine), tenofovir

• Non-nucleoside reverse transcriptase inhibitors

(NNRTIs) eg: efavirenz, nevirapine, delavirdine

• Protease inhibitors (PIs) eg: indinavir, nelfinavir,

ritonavir

• Fusion inhibitor: enfuvirtide

• CCR5 blocker: Maraviroc

• Integrase inhibitor: Raltegravir

Drug Class Drug Severe ALT Elevation (%)

NRTI Lamivudine 3.7-3.8

Tenofovir 4

Zidovudine 4.1

Emtricitadine 2-5

Abacavir 6

Didanosine 6

Stavudine 6-13

NNRTI Rilpivirine <1-2

Etravirine 2.6

Delavirdine 4.1-5.1

Efavirenz 2-8

Nevirapine 5.3-14

PI Nelfinavir 1-2

Indinavir 2.6-4.9

Darunavir/ritonavir 5.6-6.9

Fosamprenavir/ritonavir 4-8

Ritonavir 5.3-8.5

I Atazanavir/ritonavir 3-9

Tipranavir/rotpanvir 9.7

Lopinavir/ritonavir 3-11

CCR5 blocker Maraviroc 2.4

Integrase inhibitor Raltegravir 4

Fusion inhibitor Enfuvirtide 5.4-6.2

Mechanism of Drug-induced liver injury

• Idiosyncratic drug reaction

• Mitochondrial toxicity

• Hypersensitivity reactions

• Immune reconstitution after HAART

• Dose-dependent toxicity



• Mitochondrial toxicity – NRTI toxic to mitochondria

– Inhibit replication of mtRNA by interating with human

gamma polymeraase

– Mitochondrial impaired function may decrease fat

oxidation (steatosis), increase anaerobic metabolism

leading to accumulation of pyruvate and acetyl CoA (lactic

acidosis)

Ability of NRTI to inhibit mtRNA

“Zalcitabine > DDI > stavudine > LAM = abacavir = TNF”

Birkus G, et al. Antimicrob Agents Chemother 2002; 46: 716-23





– Prototype “phenytoin”

– Antiretroviral drug “abacavir, enfuvirtide,

zalcitabine, and nevirapine”





• Immune reconstitution after HAART

• Dose-dependent toxicity

Antiretroviral drugs induced liver injury

Main pattern of liver injury

(ALT/ULN)/(AP/ULN) = R

Hepatocellular R 5

Cholestatic R 2

Mixed 2 R 5

ALT = alanine aminotransferase, ULN = upper limit of normal, AP = alkaline phosphatase, R = ratio

Benichou C, et al. J Hepatol 1990; 11: 272-6.


Grade If baseline transaminase is normal

If baseline

transaminase is elevated

1 1.25-2.5xULN 1.25-2.5xbaseline AT

2 2.6-5xULN 2.6-3.5xbaseline AT

3 5.1-10xULN 3.6-5xbaseline AT

4 >10xULN >5xbaseline AT

AIDs clinical trails group 1996, Sulkowski, Modification to ACTG for pts with abnormal baseline enzymes, 2000

Transaminase included AST and/or ALT


• Risk factors

– Hepatitis B and/or hepatitis C Co-infection

– Liver fibrosis

– Alcohol consumption

– Baseline ALT

– Female gender

Increase in serum ALT or AST levels

Grade 1 or 2 increase ( <5 times

Upper limit of normal or <3.5 times Abnormal baseline level)

Grade 3 or 4 increase ( >5times

Upper limit of normal or >3.5 times

Abnormal baseline level)

Signs or symptoms of acute

Hepatitis or mitochondrial toxicity or Acute hypersensitivity reaction (eg,

To abacavir or nevirapine) ?

Exclude hepatitis A,B,C Wilson’s, Autoimmune

hepatitils,Alcohollc liver disease, Billary

disease if evidence of lactic acidosis, stop

HAART if evidence of hypersensitivity, stop

HAART Consider of selected antiretrovirals and monitor levels weekly

No Yes

Continue

antiviral therapy

Monitor ALT and

AST levels every

2 weeks for 6-8 weeks

Follow

algorithm for

grade 3 or 4

Increase in

serum ALT or AST levels

Decrease in serum ALT

or AST levels after

discontinuation of antiretroviral therapy

No changes or increase in

serum ALT or AST levels

after discontinuation of antiretroviral therapy

Strongly consider liver biopsy

Consider treatment of underlying liver disease (eg,

hepatitils C virus infection)

Reinitiate antiretroviral

therapy with new drug

regimen Monitor serum

ALT and AST levels closely

Noncirrhotic portal hypertension

• First described form Maida in 2006

• Definition: ↑ portal venous pressure > 10

mmHg

• Liver histology: variable

– Hepatic venopathy (portal vein occlusion and focal

fibrous obliteration of small portal veins) in setting of

nodular regenerative hyperplasia

– Periportal or perisinusoidal fibrosis, low grade

inflammation and steatosis

Vispo E, et al. AIDS 2010; 24: 1171-6, Saifee S, et al. Clin Gastroenterol Hepatol 2008; 1167-9 Maida I, et al J Acquir Immune Defic Syndr 2006; 42: 177-182

Mechanism

Maida I, et al. Antivir Ther 2008; 13: 103-7

Kovari et al. Clin Inf Dis 2009; 49: 626-635

Management

• Variceal bleeding

• Hepersplenism (Splenic embolization and

surgical selective shunts)

Trend of cancer in HIV in US from 1980-2002

AIDS 2006

Non-Hogkin’s Lymphoma in HIV • Systemic NHL

– Diffuse large B cell lymphoma (DLBCL) (75%)

– Burkitt lymphoma (25%)

– Indolent B cell lymphoma (<10%)

• Extranodol form

• Risk of lymphoma development in HIV between

23 and 353 fold relative to non-

immunocompromised population

• Aggressive lymphoma, predominantly other variants of DLBCL

Cote TR, et al. Int J Cancer 1997; 73: 645, Dal Maso L, et al. Lancet Onco 2003; 4: 10

Risk factors

• CD4 count

• HIV viral load >100,000 copies/ml

• Effect of HAART

• B cell abnormalities

• Genetic factors: CCR5-32 deletion

• Family history

• Frequent B symptoms

• Extranodol form: involvement of unusual

locations (body cavity, rectum)

• Systemic form: one-third of pts involved

liver

• Diagnosis: biopsy

Non-Hogkin’s Lymphoma in HIV

AIDs-related Kaposi sarcoma (KS)

• Associated with Human herpesvirus 8 (HHV-8),

steroids

• Poor immune deficiency: CD4 < 200 cell/mm3

• Form

– Cutaneous lesion is most common in lower

extremities, face, oral mucosa, genitalia

– Visceral disease is common in oral cavity, GI tract,

respiratory system, rare in liver.

Moore PS, et al. NEJM 1995; 332: 1181

AIDs-related Kaposi sarcoma (KS)

Diagnosis from biopsy: angiogenesis,

inflammation, and proliferation.

Thank you

liver involvement in hiv...hev prevalence in hiv author n location prevalence maylin et al.2012 261...

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