Transcript NEW ENGLAND TB CONTROL PROGRAM

New England TB Control
Program
HIV and TB
Joseph Gadbaw, Jr., MD
Lawrence and Memorial Hospital
New London, CT
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.
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
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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
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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
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Classical pattern
Atypical pattern
Upper lobe infiltrates
Bilateral infiltrates
Cavitation
Pulmonary fibrosis
and shrinkage
• 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, 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.
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 HIVpatients 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.
• http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/
Table1.htm
• http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/
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
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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):CD002244.
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 710 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 INHresistant. 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 (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
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
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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.
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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%).