Acquired Drug Resistance and Therapeutic Drug Monitoring in HIV related TB

1
Acquired Drug Resistance and Therapeutic Drug
Monitoring in HIV related TB

• May, 2006

2
Acquired Drug Resistance (ADR)Non HIV infected

• If INH and Rif both used in regimen
• ADR lt 1
• If resistance develops, it is usually to INH
• Relapse uncommon, usually fully susceptible

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Late 1980s and Early 1990sHIV Related TB

• Appearance of acquired rifampin mono-resistance
• Much more rarely, acquired MDR (Resistance to
  both INH and Rif)

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Acquired Rifampin Resistance (ARR)

• new phenomena among HIV infected TB patients
• Associated with low serum rifampin levels
• Mechanism counter intuitive, and remains
  speculative

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Acquired Rifamycin ResistanceUSPHS Study 23

• Isoniazid Rifabutin twice-weekly in
  continuation phase
• All patients were treated daily for the initial 2
  weeks of therapy
• Involved programs used their own routine for the
  remainder of the intensive phase
• Programs used daily, thrice weekly, and twice
  weekly regimens for weeks 3-8

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Acquired Rifamycin ResistanceUSPHS Study 23

• 169 patients enrolled
• 3 treatment failures 6 relapses
  9/169 5.3
• 8/9 (89) acquired rifamycin resistance

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Acquired Rifamycin ResistanceUSPHS Study 23

• Risk factors for ARR
• Low CD4 count
• CD4 lt 100 9/73 (12)
• CD4 gt 100 0/65 (0) Plt 0.01
• Twice-weekly therapy during the first 2 months
• Use of antiretroviral therapy was protective
• Lower Rifabutin levels

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Pharmacokinetics of INH Rifabutin USPHS Study
23

• 102/169 patients had serum levels obtained 7/8
  with ARR
• ARR no ARR
  P
• Rifabutin AUC 3.3mcgml/hr 5.2 mm/h
  .06
• adjusted for CD4 3.0
  5.2 .02
• Isoniazid AUC 20.6 28.0
  .24

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Recommendations for Treatment of TB in
HIV-infected Patients

• TB/HIV patients with CD4 lt 100 should not receive
  once- or twice- weekly therapy
• Daily therapy during induction
• Daily or thrice weekly therapy during
  continuation
• MMWR 200251214-5
• Blood levels?

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Acquired Rifamycin Resistance

• ARR has occurred with
• Once-weekly INH rifapentine
• Twice-weekly INH rifabutin
• Twice-weekly INH rifampin

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Therapeutic Drug Monitoring

• Goal promote optimum drug treatment by
  maintaining serum drug concentrations in the
  normal/therapeutic range
• Most useful if narrow range of effective and safe
  concentration for a drug
• Allows for timely therapeutic dosing
  interventions

12
Therapeutic Drug Monitoring

• There is no role for TDM in most patients with
  active TB, if the standard 4 drug IRPE regimen is
  being used, i.e., the isolate is sensitive to
  first line drugs, the patient tolerates the
  drugs, and clinical response is as expected

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Therapeutic Drug Monitoring

• When TDM may be helpful
• Slow sputum conversion or clinical improvement
  despite DOT
• Malabsorption, as seen in severe diarrhea and
  advanced HIV disease
• Use of second line anti-TB drugs with narrow
  therapeutic windows
• Concomitant use of drugs with complex drug-drug
  interactions
• ? All HIV patients with CD4lt100?

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Therapeutic Drug Monitoring

• How
• Oral Anti-TB drugs
• 2 hour post dose blood draws generally capture
  Peak concentration
• 6 hour post dose blood draws generally separate
  delayed absorption from malabsorption
• Injectable agents some controversy
• 30 60 minutes post dose used in normal non-TB
  hospital practice
• Peloquin of National Jewish recommends 2 hours
  post dose

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TDM Goals

• INH 3-5 mcg/ml if daily
• 9-15 mcg/ml if b.i.w.
• Rifampin 8-24 mcg/ml
• PZA 20-40 mcg/ml
• Ethambutal 2-6 mcg/ml
• Streptomycin 25-45 mcg/ml Peak
• lt 5 mcg/ml Trough

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TDM GoalsSecond Line Agents

• Amikacin 25-45 mcg/ml Peak
• lt 5 mcg/ml Trough
• Capreomycin and Kanamycin same
• Cycloserine 20-35 mcg/ml
• Ethionamide 1-5 mcg/ml
• Levofloxacin 8-12 mcg/ml
• Moxifloxacin 2.5-4.5 mcg/ml
• PAS 20-60 mcg/ml (6 hrs
  post)
• Rifabutin 0.3-0.9 mcg/ml (3
  hrs post)
• Linezolid 12-24 mcg/ml

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Role for Therapeutic Drug Monitoring

• Individualize Therapy
• Optimize any pharmacodynamically-linked variables
• Avoid concentration-related toxicities
• Unravel complicated multidrug interactions

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References

• Burman W, Benator D, Vernon A, Khan A, Jones B,
  et al. Acquired Rifamycin Resistance with
  Twice-Weekly Treatment of HIV-related
  Tuberculosis. Am J Respir Crit Care Med 2006Vol
  173. pp 350-356.
• El-Sadr W, Perlman DC, Matts, JP, Nelson ET, Cohn
  DL, Salomon N, Olibrice M, Medard F, Chirgwin KD,
  Mildvan D, et al. Evaluation of an intensive
  intermittent-induction regimen and a short course
  duration of treatment for HIV-related pulmonary
  tuberculosis. Clin Infect Dis 1998261185-1191.

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Contd - References

• Jelliffe R. Goal-oriented model-based drug
  regimens setting individualized goals for each
  patient. Therapeutic Drug Monitoring.
  200022325-329.
• Li J, Mansiff SS, Driver CR, Sackoff J. Relapse
  and acquired rifampin resistance in HIV-infected
  patients with tuberculosis treated with
  rifampin-, or rifampin-based regimens in New York
  City, 1997-2000. Clin Infect Dis 20054183-91
• Nettles, RE, Mazo D, Alwood K, Gachuhi R, Maltas
  G, Wendel K, Cronin W, Hooper N, Bashai W,
  Sterling TR. Risk factors for relapse and
  adquired rifamycin resistane after directly
  observed tuberculosis treatment a comparison by
  HIV serostatus and rifamycin use. Clin Infect
  Dis 200438731-736 .

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Contd - References

• Peloquin CA, Berning SE, Nitta AT, Simone PM,
  Gable M, Huitt GA, Iseman MD, Cook JL,
  Curran-Everett D. Aminoglycoside toxicity daily
  versus thrice-weekly dosing for treatment of
  mycobacterial diseases. Clin Infect Dis.
  2004381538-1544.
• Tappero JW, Bradford WZ, Agerton TB, Hopewell P,
  Reingold A, Lockman S, Oyeri R, Talbot E, Kenyon
  T, Moetti T, Moffat H, Peloquin CA. Serum
  Concentration of Antimycobacterial drugs in
  patients with pulmonary tuberculosis in Botswana.
  Clin Infect Dis. 200541461-469.

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Contd - References

• Weiner M, Burman W, Vernon A, Benator D, Peloquin
  CA, Khan A, Weis S, King B, Shah N, Hodge T and
  the Tuberculosis Trials Consortium. Low
  isoniazid concentration associated with outcome
  of tuberculosis treatment with once-weekly
  isoniazid and rifapentine. Am J Respir Crit Care
  Med. 2003 1671341-1347.
• Weiner M, Burman W, Vernon A, Benator D, Peloquin
  CA, Khan A, Weis S, King B, Shah N, Hodge T and
  the Tuberculosis Trials Consortium. Low
  isoniazid concentration associated with outcome
  of tuberculosis treatment with once-weekly
  isoniazid and rifapentine. Am J Respir Crit Care
  Med. 2003 1671341-1347.