tb drugs and haart
DESCRIPTION
drug toxicities in patients with TB and HIVTRANSCRIPT
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Liver Disease in the era of HIV and HAART
Dr Farida AmodAugust 5 2014
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HIV and the liver
• Aetiology of Liver disease
• Mechanisms of liver injury
• TB/HIV coinfection and the liver
• Drugs and the liver
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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.
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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
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Cholestasis
• Frequently seen, multifactorial• TB liver, TB –IRIS• Drugs• Opportunistic infections• malignancies• Fatty liver• Biliary tract disease
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Common aetiologies for liver disease of HIV infected patients
Hepatocellular Pattern Viral hepatitis (A,B,C)CMVEBVAuto immuneDrugs
Mixed PatternSteatosisGallstonesalcohol use, drugs
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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
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Indications for liver biopsy
Persistent abnormal liver enzymes
Hepatomegaly
And/or fever
Focal liver mass
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TB and the liver
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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
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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
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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
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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
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Drugs and the Liver
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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
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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
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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
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Drug Induced Hepatitis
Implicated drugs• Cotrimoxazole
• ART
• TB drugs
• antifungals
• macrolides
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First line Tb drugs ass with hepatotoxicity
• INH
• Rifampicin
• PZA
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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
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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
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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
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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.
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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
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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 -
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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