TB drugs and HAART
description
Transcript of 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