New England TB Control Program

1
New England TB Control Program

• HIV and TB
• Joseph Gadbaw, Jr., MD
• Lawrence and Memorial Hospital
• New London, CT

2
Case Presentation

• Jan. 04 34yo 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.

3
Case presentation

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

4
Physical Exam

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

5
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

6
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

7
Lab Data

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

8
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.

9
Clinical course

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

10
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

11
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

12
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

13
TB and HIV

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

14
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
15
HIV/TB

• The severity of the illness and atypical
  presentations may lead to other diagnoses. Kramer
  et al. Am.J.Med 89,451, 1990.
• HIV infected patients are more likely to be
  colonized and susceptible to symptomatic disease
  with MOTT Horsburgh NEJM 19, 132, 1991.
• Be aggressive in pursuit of the diagnosis of TB
  if suspected to avoid mortality. Pablos-Mendez
  JAMA 276, 1223, 1996.

16
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.

17
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.

18
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.

19
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-intermedia
  te, rifabutin-least potent.

20
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.

21
Rifamycins and TB/HIV

• Rifabutin dose is decreased with ritonovir
  boosted PIs.
• Rifabutin dose is increased with efavirenz.
• http//www.cdc.gov/nchstp/tb/tb_hiv_drugs/Table1.h
  tm
• http//www.cdc.gov/nchstp/tb/tb_hiv_drugs/Table2.h
  tm

22
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.

23
Meningitis in HIV

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

24
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

25
First Line Therapy and CNS

• Isoniazid CNS levels similar to serum levels
• RifampinCNS 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.

26
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)CD002244.

27
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 7-10
  months, although optimal duration of therapy is
  not defined.
• Treatment of TB, ATS,CDC,IDSA MMWR June
  20, 2003

28
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

29
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.

30
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.

31
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

32
(No Transcript)
33
(No Transcript)
34
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.

35
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.

36
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

37
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.

38
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

39
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

40
(No Transcript)
41
(No Transcript)
42
Clinical course

• Therapeutic drug monitoring
• Rifabutin (0.3-0.6mcg/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) 43.45 mcg/ml
  and 65.59 mcg/ml at 2 and 6 hours post dose.
• Ethambutal (2-6mcg/ml target) 3.36 mcg/ml

43
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.

44
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.

45
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.

46
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

47
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 lt50 copies/ml, CD4 349 (23).