TB drugs and HAART

Liver Disease in the era of HIV and HAART

Dr Farida AmodAugust 5 2014

HIV and the liver

• Aetiology of Liver disease

• Mechanisms of liver injury

• TB/HIV coinfection and the liver

• Drugs and the liver

Definition of Hepatic Injury

• Hepatotoxcity:3-5 fold increase from baseline in serum ALT and AST levels (>120 IU/L).

• many drugs increase GGT, does not reflect liver injury

• only when increased GGT associated with a proportionate increase in alkaline phosphatase (ALP) should a significant cholestatic injury be contemplated.

Cholestatic liver injury (↑ ALP & GGT and / or Bilirubin

• Liver ultra-sound: mainstay in the initial evaluation of the investigation of cholestatic liver injury

• non – invasive, relatively inexpensive and more accessible.

• If ultra-sound reveals normal ducts, a liver biopsy is recommended

Cholestasis

• Frequently seen, multifactorial• TB liver, TB –IRIS• Drugs• Opportunistic infections• malignancies• Fatty liver• Biliary tract disease

Common aetiologies for liver disease of HIV infected patients

Hepatocellular Pattern Viral hepatitis (A,B,C)CMVEBVAuto immuneDrugs

Mixed PatternSteatosisGallstonesalcohol use, drugs

Common aetiologies for liver disease of HIV-infected patients

Cholestatic Pattern• Bacteria → (Mycobacteria)• Fungal• Lymphoma• Kaposi’s sarcoma• Drugs - co- trimoxazole, erythromycin, co- amoxicillin

clavulanate, ARVs, TB drugs• Steatosis

Indications for liver biopsy

Persistent abnormal liver enzymes

Hepatomegaly

And/or fever

Focal liver mass

TB and the liver

HIV and TB

• SA – 3rd highest TB burden in the world• SA- 4th highest MDR TB rate• 60 -80% of new cases of TB are coinfected• 2 fold higher risk of adverse events in HIV-

infected persons• DILI complicates TB treatment in 5-30% of

patients

TB Liver

• Extra-pulmonary TB commonly involves the liver and abdomen

• AIDS defining• Fever, weight loss, hepatosplenomegaly • Liver biopsy : culture and histology

Histology : hepatic granulomas, may or may not be AFB +

• Drug induced liver injury more common

Anti-tuberculous drugs and HAART

TB and HIV therapy should not be initiated simultaneously due to • overlapping toxicities • drug interactions • adherence requirements • possible paradoxical reactions

TB Therapy and HAART

• The current recommendation are:- CD4 < 50 cells/ul ART should be initiated as

• soon as TB drugs are tolerated.(2 weeks)- CD4 50-200 cell//ul → ART therapy after 2-8

• weeks TB therapy • - Efavirenz based ART preferred to nevirapine • - Nevirapine : increased risk of hepatotoxicity

and alteration of drug levels

Drugs and the Liver

Definition of DILI

ALT >200 IU/L and asymptomatic OR

ALT >120 IU/L and symptomatic OR

Total serum bilirubin concentration >40umol/l

Elevated GGT and ALP not included in DILI definition

Risk factors for DILI

• In patients receiving TB treatment or ART• Age >35 years• Female• Hep B sAg positivity, Hep C• Alcohol use• Slow acetylator status• Extensive TB• Increase in baseline ALT

Four main mechanisms of drug- related liver toxicity

• direct drug toxicity;

• immune reconstitution following initiation of antiretroviral therapy in the presence of HCV/HBV/ or other OIs involving the liver;

• hypersensitivity reactions with liver involvement;

• mitochondrial toxicity

Drug Induced Hepatitis

Implicated drugs• Cotrimoxazole

• ART

• TB drugs

• antifungals

• macrolides

First line Tb drugs ass with hepatotoxicity

• INH

• Rifampicin

• PZA

Management of TB-DILI patients

• Re-introduction of first line drugs preferred (mild to moderate DILI)

• Rechallenge NOT recommended for those with fulminant hepatitis, treat as MDR TB. Avoid RIF, INH, PZA

• If intensive phase interrupted, restart full treatment course from day that alternate treatment is successfully re-introduced

• ART is indicated in all TB/HIV patients independent of CD4

DILI whilst on TB drugs and ARVs

• If on NVP based regimen, change to efavirenz• If on efavirenz, start on PI (lopinavir/r) with

dose adjustment• If DILI develops on PI based regimen (double

dose Lop/r), replace with 150mg rifabutin 3 times a week and atazanavir/r (or std dose aluvia)

• After ART rechallenge, check ALT 2 weekly for 2 months

HIV/HBV co-infection

• Chronic Hep B - persistence of serum HBsAg for longer than 6 months,

• Chronic HBV liver disease : cause of morbidity and mortality in HIV + patients

• Liver disease is accelerated in HBV/HIV- coinfected patients

•toxicity of antiretroviral drugs is also increased

Treatment of HIV/Hep B co-infection

• antiretrovirals i.e. lamivudine, emtricitabine, tenofovir show anti-HBV activity in addition to anti-HIV activity

• Their use in co-infected subjects could provide a benefit in treatment of liver disease, but this still has not been fully assessed.

Hepatotoxicity vs IRIS• 30 yr old male (on TDF/

FTC/ boosted atazanavir)

• Hep BsAg +/ eAg -/ cIgM -/ cIgG+

• All ARVs stopped (week 20)

• Hepatitis resolved by week 24

Visit CD4 VL ALT

scr 54 >750000 58

20 174 513 1048

24 73 450 000 146

Hepatotoxicity vs IRIS

Diff diagnosis• Hep B IRIS

• drug-induced hepatotoxicity

Visit Hep B Viral load

Hep B serology

scr >1000000 sAg +/ eAg-

Wk 20 6 400 sAg +/ eAg-cIgM -

Conclusion

• Hepatotoxicity reported increasingly in patients with HIV infection and or TB

• Aetiology is often multifactorial and confounded by chronic Hepatitis B or C, alcohol consumption, herbal therapies, and a multitude of drug – drug interactions.

• Management often requires consultation with an ID physician