HIV/AIDS and the Liver : interlinking challenges

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1 HIV/AIDS and the Liver : interlinking challenges Mark W. Sonderup Division of Hepatology Department of Medicine University of Cape Town & Groote Schuur Hospital

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3 Global HIV/AIDS prevalence

4 37 million people living with HIV 25.7 million are in SSA 70 percent of the global HIV burden is borne by 12% of the global population

5 HIV prevalence by gender and age, South Africa 2012 Overall prevalence 12.2% [CI ]

6 HIV/AIDS and the Liver HIV and the liver HIV and Drug Induced Liver Injuries HIV and granulomatous disease of the liver HIV and Hepatitis B

7 The liver and HIV

8 The liver and HIV Kupffer cells, endothelium and hepatocytes all express CD4 receptors (gp120 binding) CD4 stain - liver CD8 stain - liver HIV and Hepaobiliary diseae 2002 Curr Diagnostic pathology The Liver in AIDS Sem Liv Disease1997: 17(4), HIV and the Liver, Sem Liv Disease 2003: 23(2)

9 The liver and HIV HIV can directly infect the liver (hepatocytes, Kupffer cells) Clinically - acute hepatitis may accompany HIV seroconversion - histologically mild non-specific lobular hepatitis with sinusoidal lymphoid infiltrate = infectious mononucleosis No primary liver disease directly ascribed to HIV HIV and Hepatobiliary diseae 2002 Curr Diagnostic pathology The Liver in AIDS Sem Liv Disease1997: 17(4), HIV and the Liver, Sem Liv Disease 2003: 23(2)

10 47 y.o. man Patient previously well non smoker, no alcohol HIV test in 2010 : NEGATIVE September > developed jaundice HIV POSITIVE CD4 count = 372 Hep A/B/C/E all -ve EBV / CMV / HSV all -ve VDRL negative Total Bilirubin Conj. BR ALP GGT ALT AST Total Protein Albumin INR

11 Examination Markedly jaundiced No features of chronic liver disease No oral thrush or mucocutaneous features Lymphadenopathy (large axillary & cervical nodes) Abdo 14cm mildly tender hepatomegaly No ascites; no splenomegaly CNS: no HE Plan: LN excision and liver biopsy

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13 Lymph node

14 Liver & Lymph Node Biopsy Liver Biopsy: Portal tracts markedly expanded by a severe inflammatory infiltrate consisting of lymphocytes, plasma cells, neutrophils Lymph Node Biopsy: Reactive follicles showing distortion of follicular architecture consistent with folliculysis. Very reactive lymphocytes are noted Features correlate with viral aetiology; probable HIV seroconversion

15 Hepatitis and HIV seroconversion? Elevated hepatic transaminase levels may occur in primary HIV infection in +-21% of patients but severe hepatitis is rare Case reports in literature documents hepatitis as a presenting feature of an HIV seroconversion illness Patient slowly improved elected to initiate ART Severe hepatitis as presenting feature of an HIV sero-conversion illness GR Bramkamp Int J STD AIDS October :

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19 Drug induced liver injuries in HIV/AIDS Are DILI s in HIV/AIDS more prevalent? drug hypersensitivity occurs with a greater frequency in HIV+ patients > reported at 3 20% cotrimoxazole related hpstv : HIV negative 3 5% HIV positive 10 33% TB drug related hepatotoxicity: 3 5 times more frequent in HIV+ patients Problem : many confounding variables

20 Hepatotoxicity in South Africans patients with HIV/AIDS? cohort of 868 patients median CD 4 nadir % on concomitant TB Rx, 17% HBsAg+ 1 year follow up from starting cart incidence severe hepatotoxicity 7.7 per 100 patient years (4.6% of cohort) Risks associated with severe hepatotoxicity: 1. TB Rx > 8.5 fold increased risk 2. HBsAg + : 3 fold increased risk 3. CD 4 < 100 > 1.9 fold increased risk Hoffmann et al AIDS. 21(10): , 2007

21 301 patients with HIV/AIDS liver disease/ dysfunction requiring biopsy prospective study Sonderup et al, Hepatology May 2015

22 DILI patterns n = 127 (42.2%) Non-specific hepatitis Cholestasis Mixed Submassive necrosis VBDS Steatohepatitis Granulomatous VBDS = Vanishing bile duct syndrome Sonderup et al, Hepatology May 2015

23 Multivariate Analysis of Clinical, Demographic and Drug Specific Factors associated with a specific histological pattern of DILI Sonderup et al, Hepatology May 2015

24 33 year old woman HIV positive > Atripla started during pregnancy 3rd TM CD4 nadir 640 cells/mm 3 Jaundice noted 2 month after delivery

25 At prestn 1 week TBr CBr weeks Alb 28 ALP GGT ALT AST CD4 HIV VL LDL Hep A/B/C/E/HSV/CMV/EBV/ Lepto/VDRL : all negative 1 month: EFV still detectable Causality assessment: Compatible with an Efavirenz related DILI INR

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32 South African ART programme since 2011 Increased use of Efavirenz for 3 reasons: 1. Deemed safe in pregnancy use of ART instead of PMTCT protocols 2. Use of Fixed Dose Combination ART (Atripla, Odimune, Tribuss) 3. Eligibility for ART increased to CD4 of 350 Very little data on EFV DILI in terms of histological patterns & clinical characteristics exists

33 Efavirenz drug induced liver injury Patients who initiated EFV-based ART and presented with DILI Causality assessment of EFV related DILI was made after: i. Temporal relationship between exposure and the injury ii. Excluding acute viral hepatitis iii. Radiological exclusion of biliary obstruction iv. Exclusion of alcohol, herbal toxins v. Effects of de-challenge vi. Compatible histological pattern with a DILI First 50 patients evaluated (retro and prospectively)

34 3 Histological patterns of EFV DILI identified 32% n = 16 32% n = 16 Submassive necrosis 38% n = 18 Mixed cholestatichepatitic Nonspecific hepatitis NSH: portal and/or lobular inflammation particularly in zone 3 with/without cholate stasis in zone 1, with inflammatory cells including lymphocytes & eosinophils Mixed: combination of portal tract inflammation/interface hepatitis with inflammatory cells, including lymphocytes and eosinophils together with marked zone 3 bilirubinostasis and a ductular reaction Submassive necrosis: zonal or panzonal necrosis was present

35 Drug Induced Liver Injuries in HIV/AIDS Frequent Complicate HIV management Careful causality assessment is required Liver biopsy is invaluable Phenomenon of Efavirenz DILI is an emerging concern - late onset - immunoallergic pattern - submassive necrosis pattern characterized by jaundice and coagulopathy - steroids (low dose) recommended

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40 301 patients with HIV/AIDS

41 TB Immune Reconstitution Inflammatory Syndrome (TB-IRIS) cart Viral suppression CD4 recovery Restoration of pathogen-specific immunity Clinical deterioration treated infection unmasked subclinical infection immuno-pathogenesis driven by a cytokine storm peripheral blood and PBMC data suggest both Th1 and Th2 mechanisms upregulated

42 TB- IRIS TB-IRIS following cart reported to range between 11% and 43% in developing world Complicates the initiation of cart : DDx -? DILI? IRIS Patients present jaundice/hepatomegaly/abnormal liver profile Looked at 2 groups histologically: TB vs. TB IRIS 1. SD Lawn, L Myer et al. AIDS 2007, 21: G Meintjes, M Rangaka et al. Clin Infect Dis (5):

43 Baseline Liver profile Parameter TB IRIS (n = 24) TB liver (n=12) p Total Bilirubin (umol/l) 17 [4 203] 23 [2 89] 0.49 ALT (U/L) 90 [16 303] 102 [24 451] 0.29 ALP (U/L) 630 [ ] 585 [ ] 0.73 GGT (U/L) 1005 [ ] 463 [ ] 0.02 ALT/AST normal range 5 40 U/l ALP normal range U/l GGT normal range 0 35 U/l Sonderup M, Hepatology 2009; 50, (Suppl 4): 1246A

44 Histological characteristics Parameter TB IRIS (n = 24) TB liver (n=12) # Granulomas/core 29 [4 117] 6 [3 71] 0.01 Inflammatory cells * : Lymphocytes Plasma cells Neutrophils Eosinophils 24 (100%) 17 (71%) 4 (17%) 20 (83%) 12 (100%) 5 (43%) 2 (14%) 4 (33%) p Fibrosis * Nil Incomplete Complete Replacement 0 9 (38%) 14 (58%) 1 (4%) 6 (50%) 5 (42%) 1 (8%) 0 ZN+ or MTB cultured 1 (4%) 4 (33%) * associated with the granulomas from liver tissue Sonderup M, Hepatology 2009; 50, (Suppl 4): 1246A

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47 HIV/Hepatitis B co-infection Patterns of Co-Infection in Africa Majority - infected or exposed to HBV in childhood prior to HIV acquisition as adults Less commonly Perinatal transmission of HIV (and HBV) Reactivation of infection in immunocompromised De novo adult acquisition of both HBV and HIV Developed world HIV and HBV share a similar mode of transmission Liver International 2005: 25: AIDS Read 2004; 14(3): J Hep 44 (2006) S6-S9

48 HIV Co-infection Increases the Risk of ESLD due to HBV MACS, 4,967 men HIV, 47% HBV, 6% (n=326) HIV/HBV, 4.3% (n=213) 15 Liver Mortaility by HIV and HBV Status 14.1 HIV/HBV: 17-fold higher risk of liver death compared to HBV alone No HIV or HBV HBV only HIV only HIV and HBV Thio C et al. Lancet 2002;360:9349.

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51 Modified Histological Activity Index (Ishak) Necroinflammatory activity (n=64, ART naive) p = HBV mon0-infected (n=32) median 4.0 [2 9] mean 4.5 ± 2.0 HBV/HIV co-infected (n=32) median 6.0 [2 15] mean 7.6 ± 4.0 Sonderup et al Hepatology November 2008

52 Fibrosis (n=64, ART naive) 4.0 p = HBV mon0-infected (n=32) median 1 [0 5] mean 1.6 ± 1.4 HBV/HIV co-infected (n=32) median 3 [1 6] mean 2.7 ± 1.2 Sonderup et al Hepatology November 2008

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