New England TB Control Program HIV and TB Joseph Gadbaw, Jr., MD Lawrence and Memorial Hospital New London, CT

Case Presentation Jan yo Haitian male, employed in US for 9 years. c/o flu-like symptoms for 1 month with fever, headaches, chills, neck and back pain. Hx of MVA in Dec. 03. No hx of IVDU, 3 sex partners in US, 4 children, all healthy, youngest 4 month old.

Case presentation 4 ER visits before admission LP no cells, glucose 57, protein 38, routine bacterial cultures sterile HIV serology pending

Physical Exam HEENT: oral candidiasis involving buccal, soft and hard palate mucosa, no meningismus, shotty cervical adenopathy.

Lab Data WBC 6,500 H/H 11.5/34.7 plat. 302,000 Albumin/globulin 3.1/5.1 AST 81 ALT 168 Alk Phos 88 CXR clear CT scan head, non-contrast is normal

Lab Data LP no cells, normal protein and glucose, crypto antigen negative Toxoplasmosis serology negative RPR NR HIV PCR 343,000 CD4 25 (4%) PPD NR

Lab Data Cultures: blood routine sterile Cultures: CSF routine bacterial and fungal no growth Hepatitis serology: negative HAV,HBV, HCV

Clinical Course After obtaining mycobacterial blood cultures, Clarithromycin/ETH/RIF were prescribed for presumed disseminated MAI. Fever resolved in 48 hours. HA improved with imitrex and decadron 6mg IV once. Oral candidiasis resolved with clotrimazole troches.

Clinical course Retrosternal discomfort and swallowing difficulty improved with oral fluconazole Patient discharged on SXT, MAI therapy and fluconazole.

Clinical Course Mycobacterial blood cultures negative after three weeks so Chlarithromycin/ETH/RIF discontinued HAART prescribed (Lpv/r,AZT/3TC) Within 48 hours fever, retrosternal pain Admitted for evaluation and HAART discontinued

Procedure CT scan of the chest: lung fields clear with lymphadenopathy in the right supraclavicular, anterior and middle mediastinum Gastroesophagoscopy: sharply demarcated ulcer at 22cm Pathology: granulomatous reaction with positive AFB smear Sputum smears for AFB positive

Clinical Course Pt. prescribed INH/RIF/ETH/PZA Fever resolved in 48 hours HAART withheld Probe for MTb positive Patient discharged on daily DOT (INH/RIF/ETH/PZA), SXT

TB and HIV Overlapping epidemics in resource poor countries and their emigrants Clinical and radiological presentations will reflect the degree of immune suppression

CXR and TB/HIV Classical pattern Upper lobe infiltrates Bilateral infiltrates Cavitation Pulmonary fibrosis and shrinkage Atypical pattern Interstitial infiltrates (especially lower zones) Intrathoracic lymphadenopathy No cavitation No abnormalities WHO TB/HIV A Clinical Manual

HIV/TB The severity of the illness and atypical presentations may lead to other diagnoses. Kramer et al. Am.J.Med 89,451, HIV infected patients are more likely to be colonized and susceptible to symptomatic disease with MOTT Horsburgh NEJM 19, 132, Be aggressive in pursuit of the diagnosis of TB if suspected to avoid mortality. Pablos-Mendez JAMA 276, 1223, 1996.

HIV/TB Extrapulmonary disease is more common in immunosuppression of HIV 70% patients (30/43) with extrapulmonary TB when the CD4 count is 100 cells per mm3 or less. Jones et al AARD 148, 1292, 1993.

Diagnosis Clinical suspicion TST problems with anergy Sputum: 289 Haitians with MTb and MOTT the sensitivity of AFB smears in 55 HIV positive patients with cultures positive was 67.3%; 181 HIV negative patients with cultures positive was 79%. Long et al, Am J Publ Health 81,1326,1991.

HIV/TB Treatment In general, treatment is the same as HIV- patients with a few exceptions. INH-rifapentine once weekly continuation phase is contraindicated. Patients with CD4 less than 100 cells per mm3 should receive daily or three times weekly treatment. Consult experts.

Rifamycins and TB/HIV Rifamycins induce the activity of CYP3A4, a cytochrome enzyme in the intestinal wall and liver. This interaction may substantially decrease serum concentrations of protease inhibitors and NNRTIs. Rifamycins differ in the potency of the interaction: rifampin-most, rifapentine-intermediate, rifabutin-least potent.

Rifamycins and TB/HIV Rifabutin can be used safely with most protease inhibitors and NNRTIs, except saquinavir and delavirdine. Unlike rifampin and rifapentine, rifabutin is also a substrate for CYP3A4. Its serum concentration is affected by the degree to which CYP3A4 is inhibited or induced by PIs and NNRTIs Ritonovir is the most potent inhibitor of CYP3A4 increasing concentrations of other PIs as well as rifabutin and its metabolite.

Rifamycins and TB/HIV Rifabutin dose is decreased with ritonovir boosted PIs. Rifabutin dose is increased with efavirenz. Table1.htmhttp:// Table1.htm Table2.htmhttp:// Table2.htm

Readmission April 04 Headache for 2 weeks with nausea, fever, dry cough, back discomfort, anorexia PE: no local neurologic signs, dry excoriated skin over shins CT scan head with contrast negative LP: prot. 96, glucose 27, cells 3410 WBC, Segs 82%, Lymphs 14% Toxo serology, India ink, crypto antigen, gram stain, AFB smears, routine bacterial cultures negative.

Meningitis in HIV Tuberculosis Cryptococcus Pneumococcus N. meningitis Neurosyphilis Viral Drug Powderly,W., NeuroAids v4, issue 3, March 2001

Tuberculous meningitis Immunosuppressed with CD4 less than 100 cells per mm3 May have extrapulmonary sites Symptoms are nonspecific with headache, fever, flu-like symptoms. Mental status changes and focal neurologic deficits. CSF: elevated protein, decreased glucose, lymphocytic pleocytosis AFB smears and MTb cultures. Powderly, W., NeuroAids v4, issue 3, March 2001

First Line Therapy and CNS Isoniazid: CNS levels similar to serum levels Rifampin:CNS levels are 10-20% of serum levels, sufficient for clinical efficacy Pyrazinamide: CNS levels similar to serum levels Ethambutal: Penetration with inflammed meninges but of questionable clinical effect.

Corticosteroids and TB meningitis Six trials of 595 patients met inclusion criteria Steroids were associated with fewer deaths, a reduced incidence of death and severe residual disability. An effect on mortality in children but results in a smaller number of adults inconclusive. Little evidence that the severity of disease influences the effects of steroids on mortality. Prasad K et al, Cochrane Database Sys Rev, 2000;(3):CD

Duration of therapy for TB meningitis in HIV After 2 months of four-drug therapy for meningitis caused by susceptible strains, continue INH and RIF for an additional months, although optimal duration of therapy is not defined. Treatment of TB, ATS,CDC,IDSA MMWR June 20, 2003

Clinical course Ceftriaxone prescribed pending initial bacterial cultures Analgesics. MTb from sputum and esophagus cultures reported INH- resistant. INH discontinued. Levofloxacin prescribed LP repeated 4 days later: protein 127, glucose 22, cells 290 WBC, Segs 52%, Lymphs 33%, RBC 370. MRI scan brain reveals no acute process. Rifabutin substituted for rifampin. Headache improved. HAART (Lpv/r,AZT,3TC) prescribed. Pt. discharged on DOT

Clinical course May 04: CSF mycobacterial cultures reported positive. Sent for cultures. Patient stable with some headache. Repeat LP: Protein 113, glucose 44, cells WBC 51, Segs. 15%, Lymphs. 82%. AFB smear negative, AFB culture pending.

Clinical course Patient admitted with a community acquired pneumonia to RML. Ceftriaxone prescribed and good response. Repeat gastroesophagoscopy abnormal at 28 cm. with biopsy of abnormal mucosa. Pathology revealed a single giant cell and rare AFB. AFB smears of sputum negative as were mycobacterial cultures.

Clinical course Baseline HIV PCR 343,571 copies/ml, CD4 25 (4%). On HAART, 5/25/04 HIV PCR 1335, CD4 45 (8%). June 25, 05 Patient admitted with worsening headache over past 2 weeks. MRI scan abnormal

IRIS Immune reconstitution inflammatory syndrome Immune reaction to foreign antigen TB meningitis and HAART. Timing of HAART based on CD4. Continue TB therapy, HAART and add steroids.

Clinical course Solumedrol 60mg IV daily started and patient responded with resolving headache. 6/28/04 HIV PCR 899, CD4 111 (95). Discharged on DOT (Rifabutin 150mg 3 times a week, ETH, PZA, Moxifloxacin), HAART (Lpv/r,AZT,3TC) prednisone, SXT.

Clinical course Treatment fatigue despite DOT. Missing pm AZT/3TC. 8/31/04 HIV PCR 4627, CD4 56 (7%), RT mutation M184V CSF mycobacterial culture remained negative from LP in May 04. Steroid taper but patient appeared Cushingoid, hyperglycemia

Clinical course 9/25/04 Admitted with headaches. Repeat LP similar to previous. AFB smear negative but cultures positive in 11/04. MRI less abnormalities (IRIS). TDF/FTC substituted for AZT/3TC. 10/04 pneumothorax treated with chest tube. 10/22/04 HAART discontinued per patient request.

Clinical course 1/17/05 LP Protein 77, glucose 51, cells WBC 5 AFB smears negative 12/01/04 HIV PCR 79,414, CD4 28 (4%). Headaches returned. CSF cultures positive from LP in Jan 05

Clinical course 3/9/05 Patient admitted. Cycloserine prescribed tapering up from 250mg BID to 500mg BID Streptomycin one gram prescribed daily Urinary retention MRI of spine Steroids prescribed

Clinical course Therapeutic drug monitoring : Rifabutin ( mcg/ml target): 0.21 mcg/ml Cycloserine (20-35mcg/ml target): 34.1 mcg/ml and 41.3 mcg/ml at 2 and 6 hours post dose. Pyrazinamide (20-60 mcg/ml target): mcg/ml and mcg/ml at 2 and 6 hours post dose. Ethambutal (2-6mcg/ml target): 3.36 mcg/ml

Clinical course Adjustments to medication: Cycloserine reduced to 500 mg in AM and 250 in PM Pyrazinamide reduced from 2500mg to 2250mg. Repeat MRI of the spine revealed improvement. Urinary retention resolved Hyperglycemia treated with insulin while on prednisone.

Clinical course Streptomycin discontinued after 2 weeks. PAS prescribed 4gm BID. 4/29/05 repeat MRI favorable PAS discontinued HAART prescribed (Lpv/r,TDF.FTC). Rifabutin 150mg three times a week.

Clinical course Therapeutic drug monitoring on HAART : Rifabutin 300mg dose: 0.6 mcg/ml, CSF small amount Cycloserine 500/250mg BID dose: 34.3 and 38.4 mcg/ml at 2 and 6 hours post dose, CSF 21 mcg/ml Pyrazinamide 2000mg dose: 34.6 and 23mcg/ml at 2 and 6 hours post dose, CSF 19.2mcg/ml. Moxifloxacin 400mg dose (3-5 mcg/ml target): 3.30 mcg/ml.

Second –Line Drugs and CNS Cycloserine: Concentrations in CSF approach those in serum. Ethionamide: CSF concentrations are equal to those in serum. Streptomycin: Slight diffusion of SM into CSF, even in patients with meningitis. PAS: CSF concentrations 10-50% of serum; marginal efficacy in meningitis. Fluoroquinolones: Levofloxacin preferred; CSF concentration 16-20% of serum. Treatment of TB, ATS,CDC,IDSA, MMWR June 20, 2003

Clinical course TB medication discontinued after one year a megatherapy. Patient is healthy with no headache, back pain and continues on HAART. 2/22/06 HIV PCR <50 copies/ml, CD4 349 (23%).