1. Meningitis in HIV Diagnostic and Therapeutic Challenge Yunus Moosa AWACC- November 2015

2. Case: 59 yr. old female- 1 st Wk. Feb Known HIV positive since Oct 2014 on first line treatment Non specific symptoms- dizziness, malaise, lethargy, fatigue PMH: Cervical TB lymphadenitis – treated for 9mths(2013) Chronic medication: –Tribuss –Ecotrin –Epilim CR 400mg bid Clinically – shotty cervical L/N, otherwise NAD

3. Investigations FBC- 13.3/255/4.19 U&E- 136/4.3/100/26/3.2/60 (>89) LFT- 69/31/2-1/107/19/15/12, CCa 2.3, Mg 0.83, PO 4 0.88 HBV sAb positive HCV negative HAV negative RPR – negative, TSH normal, Total cholesterol 3.6, LDL 2.2, TGA 0.80 CD4- 24 cell/uL, VL 5420 (3.734 Log 10 ) Chest x-ray: normal.

4. Management ATV/r (300/100)- 1 Daily AZT/3TC (300/150) - 1 bid Cotrimoxazole- 960 daily Ecotrin 1 daily Epilim CR 400mg bid

5. 2 weeks later Brought in by family: two seizures at home Disoriented, responded appropriately to commands no meningism, no focal signs, no papilloedema. FBC- 14.6/328/7.25, U&E- 133/4.7/97/20/4.8/83 (>89) LFT- 84/38/17-3/117/23/15/22, CCa 2.28, Mg 0.96, PO 4 1.52 Contrast CTS- normal LP- pressure normal, CRAG > 1:320, AFB negative. DateAppearancePolysL/CRBCProteinGluPlasma GluRatio 22/02Xanthochromic1246011.321.17.10.15

6. What is the most likely diagnosis? 1. Cryptococcal meningitis 2. Tuberculosis 3. Histoplasmosis 4. CM IRIS 5. TB IRIS 6. Histoplasmosis IRIS 7. TB and CM 8. TB IRIS and CM IRIS

7. Repeat CSF 6 Days later Treatment was modified and LP repeated DateAppearancePolysL/CRBCProteinGluPlasma GluRatio 22/02Xanthochromic1246011.321.17.10.15 28/02Blood stained8184+++4.270.27.40.03

8. What is the most likely diagnosis? 1. Cryptococcal meningitis 2. Tuberculosis 3. Histoplasmosis 4. CM IRIS 5. TB IRIS 6. Histoplasmosis IRIS 7. TB and CM 8. TB IRIS and CM IRIS

9. How would you manage this patient? 1. Continue ATV/r/AZT/3TC and start AMB/FLZ 2. Continue ATV/r/AZT/3TC and start AMB/FLZ and rifafour 3. Discontinue ART and start AMB/FLZ 4. Discontinue ART and start AMB/FLZ and rifafour 5. Change ART to LPV/r/AZT/3TC and start AMB/FLZ 6. Change ART to LPV/r/AZT/3TC and start AMB/FLZ & rifafour 7. Refer to someone who thinks they know more 7. Refer to someone who thinks they know more

10. Management ART stopped Started on AMB Started on rifafour Optimized dose of epilim Continued cotrimoxazole Continued ecotrin

11. What do you think is the most central diagnostic tool for TBM? 1. Clinical presentation 2. Blood investigations 3. Immunologic tests – (IGRAS/PPD skin test) 4. CSF-chemistry and cell counts 5. CSF- microbiology 6. CSF -molecular tests 7. CSF – adenosine deaminase 8. Imaging – (CxR/Brain CTS/MRI)

12. Presentation Time from symptom to presentation –Median 10 days –Range 1 day to 9 months Symptoms/Signs –low grade fever, malaise, headache, dizziness, vomiting –Personality changes, altered mental status –Stroke, hydrocephalus –Cranial neuropathies –Seizures uncommon - should prompt search for alternate diagnoses

13. Clinical Staging of TBM StageClinical signs and symptoms I (early) Non specific symptoms Few or no signs of meningism Fully conscious and alert II (intermediate) Signs of meningitis Drowsiness and lethargy Cranial nerve palsies III (late) Systemic toxicity Stupor or coma Severe neurologic deficit

14. CSF Cell count and Biochemistry Abnormalities -not pathognomonic L/C predominant pleocytosis Total WCC usually 100 - 500 cells/μL Earlier -lower counts, neutrophil predominance Elevated protein levels, typically between 1g/L and 5 g/L Low glucose usually less than 2.5mmol/L CSF: plasma ratio <0.5.

15. Microbiology of CSF Factors influence sensitivity of smear: – CSF volume –Timing delivery to the lab –Time to analysis –Technical expertise of lab- (30 min under 1000x) AFB Smear –1 sample sensitivity 20%–40% –4 samples sensitivity >85% (10– 15 mL) Culture sensitivity 40–80% Important to determine drug susceptibility.

16. What is the rate of CSF Production? 1. 5mls/day 2. 10mls/day 3. 50mls/day 4. 100mls/day 5. 500mls/day 6. 1000mls/day

17. What is the total volume of CSF in the CNS? 1. 50-100mls 2. 90-150mls 3. 200-500mls 4. 1000-2000mls

18. Adenosine Deaminase: ADA Meta-analysis: –Sensitivity 79% –Mean specificity 91% Specificity is low –  levels seen in other CNS diseases like neurosarcoid, meningeal lymphoma, subarachnoid hemorrhage Not useful in HIV-positive patients. Journal of Clinical Medicine Research (2010), 2 (5), 220–224, European Journal of Clinical Microbiology and Infectious Diseases (2004), 23 (6), 471–476

19. CSF Molecular Tests Used as a rule in test – positive test confirms TBM Sensitivity of GXP is ~80% (50% in HIV neg) Negative test does not exclude TBM Health Technology Assessment (2007)11 (3), 1–196

20. Imaging: CTS Widely used to aid diagnosis of TBM. Features suggestive of TBM –Basal meningeal enhancement (Sn34%/Sp75%) –Hydrocephalus (Sn45%/Sp75%) –Infarcts (Sn44%/) –Tuberculoma(s) (Sn31%) Radiologic interpretations are subjective- inter-radiologists reliability of findings suggestive of TBM is very poor. Basal meningeal enhancement was most unreliable feature PLoS ONE 7(6): e38982. doi:10.1371/journal.pone.0038982

21. Value of CSF as Monitoring Tool 1. Not worth the trouble 2. Somewhat valuable 3. Very valuable

22. The most useful/reliable objective measure of response to treatment 1. CSF Pressure 2. CSF Chloride 3. CSF glucose 4. CSF protein 5. CSF pleocytosis

24. Course Completed 2 weeks AMB (Cr peaked at 196 µmol/L) 2 weeks into consolidation treatment with FLZ 400mg/d started LPV/r (200/50) 4 bid, AZT/3TC (300/150) 1 bid Within 6 days- DILI Total protein Albumi n Total bilirubin- conjugate bilirubin ALPGGTALTAST 15/03/1563305-390413438 20/03/15643070-6092131354440 22/03/15673159-50119222493879

25. Cause for DILI 1. Rifampicin 2. Isoniazid 3. PZA 4. FLZ 5. LPV/r 6. AZT 7. 3TC

26. What ART do we use? 1. LPV/r, AZT, 3TC 2. ATV/r, AZT, 3TC 3. EFV, AZT, 3TC 4. LPV/r, TDF, FTC 5. ATV/r, TDF, FTC 6. EFV, TDF, FTC

27. TB Treatment should we use? 1. INH, EMB, PZA, Rifampicin 2. INH, EMB, PZA, Rifabutin 3. INH, EMB, PZA, Moxifloxacin 4. INH, EMB, PZA, Streptomycin

28. Cytochrome P450 enzymes essential for the metabolism of many drugs Induction  increases synthesis of enzymes  increases metabolism of target drug  therapeutic failure –Effect is usually delayed Inhibition  b locks activity of enzymes  toxicity –Effect usually immediate –Often used to enhance levels of target drug

29. Rifampin and CyP450 Not metabolized by the CyP450 enzymes Potent inducer  affects drugs metabolized by CyP450 Do not modify dose when combined by CyP450 modifiers Rifabutin and CyP450 Metabolized by the CyP450 enzymes Requires adjustment when combined with drugs that modify CyP450 Poor inducer of CyP450  minimal or no adjustment for drugs metabolized by CyP450

30. How Dose of Rifabutin when using a PI 1. 450mg daily 2. 300mg daily 3. 150mg daily 4. 150mg 3 x / week

31. Back to our patient All treatment stopped from 22/03 31/03:ATV/r/AZT/3TC/ TMP- SMX/epilim/FLZ/PZA/EMB/INH/Rifabutin/pyridoxine T/PAlbTotal bil- conj biliALPGGTALTAST 15/03 63305-390413438 20/03 643070-6092131354440 22/03 673159-50119222493879 31/03 63319-6611256521 05/05 713416-464281412

32. Back to our patient Review 07/09- asymptomatic and well CD4 64 (24), VL undetectable Repeated CSF: CRAG 1:80, culture negative DateAppearancePolysL/CRBCProteinGluPlasma GluRatio 22/02Xanthochromic1246011.321.17.10.15 28/02Blood stained8184+++4.270.27.40.03 07/09Xanthochromic022302.352.04.60.43

33. Take home message The diagnosis of TBM is challenging Diagnosis is often based on clinical and CSF findings without definitive microbiologic confirmation CSF lacks sensitivity and specificity Send at least 6/8mls CSF for proper microbiology evaluation Imaging is mainly of value in evaluating for complications and exclude alternate diagnosis Rifampicin can only be used with LVP/r and not any other PI. Drug of choice with any other PI is rifabutin