hiv&liver (1)

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IV

and the liver

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7/23/2019 HIV&liver (1)


Introduction

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Introduction

Managing liver disease is an increaimportant component to the caindividuals infected with himmunodeficiency virus (HIV).

Since the advent of effective antirettherapy (ART) for HIV, there has bsubstantial decrease in deaths relatacquired immunodeficiency syndrome (

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7/23/2019 HIV&liver (1)


HIV

and the liver

However, liver disease has emerged most common non-AIDS related caudeath among HIV-infected paaccounting for 14-18% of all deaths.

In some series, nearly half of deaths ahospitalized HIV-infected patients in thera have been attributed to liver disease

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HIV

and the liver

Just as the burden of non-AIDS morbidmortality has changed in the ART-etypes of liver disease the clinician is lencounter among these patients have cas well.

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HIV

and the liver

Landscape of liver disease has changed◦pre-ART : CMV, mycobacteria, NHL & KS

◦post-ART: HCV, HBV, DILD, alcohol abuse,

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The effect of HIV on the liver

Liver disease in human immunodeficien(HIV)-infected individuals encompassspectrum from:◦abnormal liver function tests,◦liver decompensation, with and without ev

cirrhosis on biopsy,◦non-alcoholic liver disease and its more sevnon-alcoholic steatohepatitis,

◦hepatocellular cancer.

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Pathogenesis of HIV and liver

disease

HIV may alter liver function by either diindirect mechanisms.

HIV predominantly infects CD4+ monocyte/macrophages and dendritic cells.

However, there are multiple studies now sHIV infection of a wide range of non hemacells, including cells in the liver.

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Pathogenesis of HIV and liver

disease

In addition, changes in gastrointestitract permeability via massive depletiotract associated CD4+ T-cells by HIV mindirect consequences on immune acand liver disease.

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Differential diagnosis of liver disease

in HIV infection in the ART-era

HEPATIC PARENCHYMAL DISEASE◦Infection◦ Viral Hepatitis: HCV, HBV, HDV, HAV, HEV, CMV, EBV

HHV6◦ Mycobacterium avium complex◦ Cryptococcus neoformans

◦ Microsporidium◦ Pneumocystis jirovecii◦ Bacillary peliosis hepatis◦ Histoplasma capsulatum

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Differential diagnosis of liver disease

HIV infection in the ART-era

HEPATIC PARENCHYMAL DISEASE◦Nonalcoholic fatty liver disease

◦Medication toxicity

◦Alcoholic liver disease

◦Recreational Drugs◦Cocaine

◦MDMA (Ecstasy)

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Differential diagnosis of liver disease in H

infection in the ART-era

Neoplasm◦Lymphoma◦Kaposi's sarcoma◦Hepatocellular carcinoma

Nodular regenerative hyperplasia Autoimmune hepatitisHemochromatosisWilson's disease

Alpha-1 antitrypsin deficiency

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Coinfection

People with HIV infection are often affeviral hepatitis; about one-third are coiwith either HBV or HCV, which can cauterm illness and death.

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Coinfection

Although drug therapy has extended expectancy of people with HIV, liver much of which is related to HCV and Hbecome the leading cause of non-AIDS

deaths in this population.

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Coinfection

More people living with HIV have HCHBV.

Viral hepatitis progresses faster andmore liver-related health problems people with HIV than among those whohave HIV.

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HIV Hepatitis C Virus

Overall, approximately 30% of HIV-individuals in the United States and Eurcoinfected with HCV.

Due to shared risk factors, coinfectioHCV and HIV is common.

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HIV Hepatitis C Virus

Reported prevalence rates of Hcoinfection vary depending on the routtransmission, from 10% among thohigh-risk sexual behavior to 90% with i

drug use.

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Effect of HIV on HCV

◦Less likely to clear HCV◦Higher HCV viral load◦Accelerated fibrosis and more cirrhosis (2-fold◦Higher risk of liver failure once cirrhotic (5-fo◦Probably higher risk of HCC

◦Less likely to respond to treatment

Effect of HCV on HIV less clear

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HCV HIV/HCV Coinfection

Sexual transmission islow (0-3%)

Mother-to-ChildTransmission ~5-6%

HCV meds can cause birthdefects

Sexual transmissionhigher ~ 15-25%

Mother-to-ChildTransmission ~25%

HCV meds can cause bdefects

HCV Transmission

www.hcvadvocate.org

i i C

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Hepatitis C HIV/HCV Coinfection

Antibody Test

HCV Viral load toconfirm activeinfection

Antibody Test

Note: If low cd4 cellcount use HCV RNA

HCV RNA to confirmactive infection

Diagnosing HCV

www.hcvadvocate.org

*People with a comprised immune system may not develop HCV antibodies

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Hepatitis C HIV/HCV Coinfection

Slow rate of diseaseprogression – usuallyover 10, 20, 30 years

Faster rate of diseaseprogression to cirrhosiup to 2-3 times faster &can occur in as little as years

HCV coinfection is theleading cause of deathamong people with HIV

HCV Disease Progression

www.hcvadvocate.org

Guidelines for Prevention of Opportunisti

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Guidelines for Prevention of OpportunistiInfections

HIV–

Infected persons should be screened for HC Patients should be advised on alcohol use

Patients should be screened for HAV & HBV ifnegative, they should be vaccinated

Patients should be evaluated for liver disease and

possible need for treatment Liver enzymes should be monitored after initiatio

HAART

*U.S. Public Health Service and the Infectious Disease Society of America

www.hcvadvocate.org

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Treatment of hepatitis C virus

infection in the HIV-infected patient

HCV REGIMEN SELECTIONRegimen options by genotype

- Genotype 1 infection

- Genotype 2 infection- Genotype 3 infection

- Genotypes 4 infection

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Treatment of hepatitis C virus

infection in the HIV-infected patie

Potential drug interactions with ART- Ribavirin

- Sofosbuvir

- Ledipasvir-sofosbuvir- Ombitasvir-paritaprevir-ritonavir plus da

- Simeprevir

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Clinical management of

HCV/HIV patients

The key issue in the clinical management of HCV/HIV

patients is the treatment decision for each condition ainitiate it.

By the end of the laboratory and clinical assessment with HCV/HIV coinfection, patients can be split

categories:◦ 1. patients not requiring hepatitis C or HIV/AIDS treatmen◦ 2. patients requiring only hepatitis C treatment◦ 3. patients requiring only HIV/AIDS treatment◦ 4. patients requiring both hepatitis C and HIV/AIDS treatm

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1. Coinfected patients not

requiring any treatment

Coinfected patients not requiring any trmeet the following criteria:

◦ CD4 count >350 cells/mm3 and absence of HIV-relatedand

◦ HCV antibodies, but absence of HCV RNA replication.

Coinfected patients not needing treatment smonitored every six months (clinical followfunction tests) and every three years for hisliver lesions (using alternatives to liver biopsie

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2. Coinfected patients requiring

only HCV treatment

Coinfected patients requiring onltreatment meet the following condition◦ CD4 count >350 cells/mm3 and absencerelated symptoms, and

◦ active or chronic hepatitis CHCV treatment offers the possiberadicating HCV within a defined treperiod.

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only HCV treatment

In the following situations, where the outweigh the risks, there are two main reconsider all HCV/HIV-coinfected patients treatment:◦ The liver disease progresses more rapidly to complications and at earlier ages than

monoinfected patients.◦ Patients are at higher risk for developing hepafollowing the initiation of ART than HIV-mopatients. Efficient HCV treatment will hence facsubsequent management of ART.

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only HIV/AIDS treatment

Coinfected patients requiring only Htreatment satisfy at least one condition inthe following◦ CD4 count ≤350 cells/mm3 in symptomaticor patients with viral load >100 000 copies/mcount ≤200 cells/mm3 irrespective of symptoand◦ HCV antibodies but no HCV RNA replichepatitis C with contraindications to treatme

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Why Is HCV Therapy Deferred in

Many HIV/HCV-Coinfected Patient

Challenges with interferon- and/or ribavirregimen

Anticipated approval of new agents◦Greater efficacy

◦All-oral regimens◦Shorter duration◦Improved tolerability◦Fewer drug-drug interactions

clinicaloptions.com/hepatitisBest Practices in the Management of HCV/HIV Coinfection

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Assessing HIV+ Patients for Immediate or Defer

Therapy

Antiretroviral therapy for HIV treatment-naive HIV/HCVcoinfected patients

– CD4+ cell count < 500 cells/mm3: initiate antiretroviraltherapy for HCV treatment optimization[24,25]

– CD4+ cell count > 500 cells/mm3: may defer antiretroviratherapy until HCV therapy completed[25]

24. EACS Guidelines, Version 7.0. October 2013. 25. DHHS Antiretroviral Guidelines for Adults and

Adolescents. February 2013. 26. Macías J, et al. Clin Infect Dis. 2013;2013;57:1401-1408.

HCV Therapy in HIV/HCV-Coinfected, HCV Treatment-Naive Patients

Liver FibrosisConsider

HCV Therapy

Eligible to

Defer HCV The

No/minimal fibrosis (F0-F2)[24,25] ●

Advanced fibrosis (F3-F4); cirrhosis[26] ●

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HCV/HIV patients

1. Coinfected patients not requiring any

2. Coinfected patients requiring only HCV ◦ Indicationsfor HCV treatment◦ Predictors of sustained virological response ◦ Contraindications for hepatitis C treatm◦ Treatment of acute hepatitis C

◦ Treatment of chronic hepatitis C (doseschedules)

◦ Treatment duration

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HCV/HIV patients

3. Coinfected patients requiring HIV/AIDS treatment◦ Initiation of HAART

◦ Considerations in choosing a

regimen◦ First-line HAART regimens

◦ Second-line HAART regimens

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HCV/HIV patients

4. Coinfected patients requiring bothand HIV/AIDS treatment

◦ Strategy for initiationof treatment◦ Considerations of ARVs when

both HCV and HIV infections

◦ Hepatotoxicity of ARV drugs◦ ARV dose adjustment in patients

cirrhosis

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HBV

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HIV Hepatitis B Virus

Although the prevalence of Hcoinfection varies by geographic lapproximately 10% of HIV-infected indworldwide are also chronically infect

HBV.

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Effect of HIV on HBV

Like HIV-HCV coinfection, HIV alters thehistory of HBV.

Individuals with HIV infection are 3-6 timlikely to develop chronic HBV after aexposure than individuals without HIV inand hepatitis B surface antibody (adevelopment is improved with higher counts.

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Effect of HIV on HBV

In addition, HIV-infected patients have a lowe

spontaneous clearance of HBeAg, increased HBV rand a higher rate of loss of anti-HBs and reactivatio

Coinfected individuals also experience an progression to cirrhosis and higher liver-related

compared to HBV monoinfected individuals.

The impact of HBV infection on the natural historless clear.

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HBV/HIV patients

The decision to initiate HBV treatment on whether the patient meets indicationseither the HIV or HBV.

Treatment regimens for either virus must both infections, as many anti-viral agendual activity, including tenofovir, lamemtricitabine, entecavir, and adefovir a>10mg.


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HBV/HIV patients

Treatment for HBV is indicated in any paticirrhosis and detectable HBV DNA.

Although a specific HBV DNA threshtreatment in the absence of cirrhosis has n

determined, treatment should be consipatients with HBV DNA ≥ 2,000 IU/mL athan mild liver disease on biopsy


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HBV/HIV patients

Rx: initiation depends on meeting criteria for either virus

~ dual activity of antivirals: TDF, LAM, emtricitabine, entecavir• Rx if HBV DNA > 2000 iu/ml & > mild disease on Bx

• Use Truvada or TDF and LAM

• Use entecavir if TDF contraindicated

• If ART not feasible try pIFN, adefovir, telbivudine

• Worsening ALT and AST during ART:

~ DILD, HBV reactivation on drug withdrawal esp LAM, HBeAg

loss or IRIS

• Screen for HCC

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Drug Induced liver Disease

Risk factors for DILD:

• ~ HBV or HCV coinfection~ advanced hepatic fibrosis

~ pre-Rx ALT, AST

~ alcohol

~ older age

~ first exposure to ART~ CD4

~ concomitant anti-TB rx

~ cocaine use

Partial list of potentially hepatotoxic non-A

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medications prescribed to HIV-infected

individuals

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Most common ART agents associated

with liver injury in HIV-infected patien

MEDICATION TYPICAL DOSE DOSE ADJUSTMENT

FOR HEPATICINSUFFICIENCY

MEC

NNRTI

Nevirapine (NVP) 200 mg po bid Child-Pugh Class B or

C: Contraindicated

H

rea

Etravirine (ETR) 200 mg po bid Child-Pugh Class A or

B: No adjustment

Child-Pugh Class C: Not

H

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MEDICATION TYPICAL DOSE DOSE ADJUSTMENT FOR

HEPATIC

INSUFFICIENCY

MECH

PI

Ritonavir (RTV) full-

dose

No longer used Di

Tipranavir (TPV) + RTV

low-dose

(TPV 500 mg + RTV 200 mg) po

bid

Child-Pugh Class A: Use with

caution

Child-Pugh Class B or C:Contraindicated

Di

Atazanavir (ATV) 400 mg po once daily Child-Pugh Class B : 300 mg po

once daily

Child-Pugh Class C:

Contraindicated

Indi

doe

Indinavir (IDV) 800 mg po q8h Mild to moderate hepatic

insufficiency:

Indi

doe

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with liver injury in HIV-infected patient


HEPATIC

INSUFFICIENCY

MECH

NRTI

Stavudine (D4T) ≥60 kg: 40 mg po bid

<60 kg: 30 mg po bid

Not defined M

Zidovudine (AZT, ZDV) 300 mg po bid Not defined M

Didanosine (ddI) Enteric coated:

≥60 kg: 400 mg po once daily

<60 kg: 250 mg po once daily

Oral Solution:

≥60 kg: 200 mg po bid or 400

mg po once daily

<60 kg: 150 mg po bid or 250

mg po once daily

No adjustment M

cry

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with liver injury in HIV-infected patient


HEPATIC

INSUFFICIENCY

MECH

NRTI

Abacavir (ABC) 300 mg po bid Child-Pugh Class A: 200 mg po

bid (use

oral solution)

Hy

es

Lamivudine (3TC) 300 mg po once daily or 150

mg po bid

No adjustment H

me

Emtricitabine (FTC) Oral capsule: 200 mg po once

daily

Oral solution: 240 mg po once

daily

Not defined H

me

Tenofovir (TDF) 300 mg po once daily No adjustment H

me


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HEPATICINSUFFICIENCY

M

Other

Enfuvirtide (T20) 90 mg subcutaneous

bid

Not defined H

Maraviroc (MVC) Recommended dose

depends on other

drugs in

regimen

Not defined, caution

advised

H

rea

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Fatty liver disease in HIV

NAFLD is now commonly reported ihigh income countries in the presenabsence of HIV infection.

The spectrum of NAFLD ranges frosteatosis to NASH, which may progsevere fibrosis and cirrhosis.

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Fatty liver disease in HIV

NAFLD has been identified in up to 30%

mono-infected Americans, although thwas unable to demonstrate whethprevalence of NAFLD was different negative individuals.

While risk factors for NAFLD may be sipeople with or without HIV

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• Screen all HIV-infected patients with HCV antibody

• Test HCV RNA in patients with positive HCV antibody If Ab negat

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HCV

• Test HCV RNA in patients with positive HCV antibody. If Ab negatif suspected acuteHCV, or significant risk factors and advanced immunosuppression

• If chronic HCV, immunize against HBV and HAV if not immune

HBV

• All HIV-infected patients should be screened with HBsAg, anti-HB

• Vaccinate patients without HBV immunity

• When initiating or adjusting ART, regimen must include adequatecoverage

• Vaccinate against HAV, if not immune

• Requires concomitant HBV infection for replication

• Acquired during simultaneous infection with HBV or as superinfection in set

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HDV• HDV superinfection is associated with fulminant acute hepatitis and severe

hepatitis

HEV

• Consider in patients with travel to endemic areas; autochthonous cases havreported inUnited Kingdom, France, Germany, and the United States

• Chronic infection has been reported in HIV-infected patients

HAV• Can cause fulminant hepatitis especially in presence of underlying liver dise

• Rarely symptomatic; may present with fever, malaise, weight loss

• Usually mild transaminitis and mild cholestasis

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CMV

• Usually mild transaminitis and mild cholestasis

• May present as mass and mimic neosplasm on CT

• Liver biopsy with large intranuclear and small cytoplasmic inclusigranulomas

Mycobacterium

avium complex

• Presents with fever, night sweats, weight loss, abdominal pain, nHSM

• Marked elevation of AP (>10-20x ULN) is hallmark

• U/S shows diffusely hyperechoic liver +/− focal lesions

• Liver biopsy with poorly formed non-caseating granulomas, foamacid-fast bacilli

• Presents with fever, night sweats, weight loss, LAD, and hepatomegaly

• AP usually elevated with mildly elevated aminotransferases and bilirubin

U/S h diff l h h i li / f l l i b h l b

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Mycobacterium

tuberculosis

• U/S shows diffusely hyperechoic liver +/- focal lesions; abscesses have also been

• Liver biopsy with well formed granulomas

Pneumocystis

jirovecii

• More common in patients receiving inhaled pentamidine for PCP prophylaxis

• Usually moderate increases in aminotransferases and AP, but high elevations hav

• CT may show hepatic calcifications

• Liver biopsy with foamy nodules with pneumocystis cysts on methamine silver st

Microsporidium

• May cause increased bilirubin, transaminases, and especially AP

• Consider in patients with a history of cat contact

• May present with HSM, liver failure, portal hypertension, fever, anemia, LAD

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Bartonella

henselae

• AP elevated; may develop coagulopathy

• U/S may show irregular hypoechoic regions

• CT may reveal multiple hypoattenuating lesions of varying size

• Liver biopsy with multiple blood-filled cavities of varying size

Histoplasma

capsulatum

• May be asymptomatic or present with constitutional symptoms, LAD and HSorganfailure in fulminant cases

• Labs usually show cholestasis with increased AP, variable bilirubin

• Liver biopsy with poorly formed granulomas, rounded yeast with budding on

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hiv&liver (1)

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