Rifabutin for TB for people on ART

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Rifabutin for TB for people on ART
Reuben Granich WHO HIV/AIDS Department

• HIV/TB Core Group MeetingAddis Ababa, Ethiopia,
• 11-12 November 2008

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Towards Universal Treatment Access
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Gains in Access to Care and Treatment

• Nearly one million more people on antiretroviral
  therapy
• 54 increase in one year in sub-Saharan Africa.
• Access among women is higher than or equal to
  that among men.
• 97 of adults and children on therapy in low- and
  middle-income countries on first-line
  antiretroviral drug regimens.
• First-line antiretroviral drug regimens are
  increasingly affordable.

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Rifabutin and WHO Essential Medicines List

• Rifabutin is currently not used as standard
  therapy for TB
• Experience with rifabutin for TB disease in
  resource-constrained settings is limited
• Limitations in the data have hampered the
  development of clear WHO policy recommendations
  regarding the inclusion of rifabutin on the
  Essential Medicine List (EML).
• Rifabutin on the EML, as a first step toward EOI
  and PQ, may serve to increase the availability
  for large scale use and affordable costs
• High cost of rifabutin has rendered it thus far
  inaccessible to tuberculosis control programs in
  resource-limited settings

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TB and second-line ART demand assumptions

• UNAIDS/WHO ART roll-out scenario
• Around 80,000 per month are placed on ART
• Patients failing first-line ART and needing
  ritonavir-boosted PI-based therapy
• Annual migration from first to second-line is
  2 to 4
• Annual TB rates during ART around 3-7
• Estimated 2008-2015 patients on PI-based ART that
  will develop TB
• 2 scenario 221,580 to 508,550
• 4 scenario 392,760 to 901,810

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Rifabutin international availability

• Pfizer Inc., NYC, NY, USA innovator (Mycobutin
  capsules 150 mg)
• Lupin laboratories Ltd. Mumbai, India generic
  capsules 150 mg not prequalified
• Sichuan Med. Shine Pharmaceuticals, China
  generic capsules 150 mg not prequalified
• Macleods, India generic capsules 150 mg, not
  prequalified

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Range of costs

• Reported Lupin price for one capsule rifabutin
  150 mg 0.84 USD. Estimated 6 months rifabutin
  regimen is around 70 USD, of with gt 95 of the
  cost is due to rifabutin.
• MedShine (RisingPharm) 3 per dose (information
  communicated by the Clinton foundation)
• The Pfizer product cost is 4.86 per dose.  
• Macleods pricing information not available

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Rough costing analysis
Unit values (USD) LPV/r (median) LPV/r (median) LPV/r (average) LPV/r (average)
LIC MIC LIC MIC
Estimated cost of the ARV protocol during Rifampicin based TB treatment (6 months) 453.6 2764.8 939.6 2689.2
Estimated cost of the ARV protocol during Rifabutin based TB treatment (6 months) 270 1846.8 572.4 1706.4
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Next steps

• WHO Essential Medicines List
• Complete costing analysis
• Continue dialogue with manufacturers and
  stakeholders
• Scientific advocacy
• Additional research

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Thank you

• Edde Loeliger (intern)
• Mark O'Connor (intern)
• Charlie Gilks (WHO)
• Fabio Scano (WHO)
• Barbara Milani (WHO)
• David Ripin (Clinton)
• Renee Ridzon (Gates)

TB/HIVmatch made in heaven!
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Rifampicin and PI background

• Rifampicin essential for short-course
  chemotherapy
• WHO-recommended anti-retroviral therapy (ART)
  recommends standardised antiretroviral drugs
• Ritonavir-boosted Protease-Inhibitor (PI) based
  antiretroviral therapy reserved for second-line
  therapy
• patients no longer responding to first-line
  therapy
• alternative option in those with adverse
  reactions or contraindications to NNRTIs used in
  standard first-line therapy

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Rifampin and ART

• Rifampin leads to sub-therapeutic concentrations
  of PIs mediated by CYP3A4
• Rifampicin and ATZ/r results in greater than 90
  reduction of plasma levels during
  co-administration
• Rifampicin can only be used in combination with
  LPV boosted with high-doses of ritonavir (eg.
  super-boosting with ritonavir 400 mg twice
  daily),

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Advantages of Rifabutin

• Little effect on PI serum concentrations
• Can be used with ritonavir-boosted PIs (no need
  for "super-boosting")
• Should be dose-reduced by 75 (150mg QOD) with
  boosted-PI-containing at standard dosing

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Evidence for rifabutin for TB

• The evidence from the RCTs, dominated by HIV
  negative individuals, suggests that rifabutin is
  as effective as rifampicin for the treatment of
  TB
• The Cochrane review of five RCT found no
  statistical difference between the two rifamycins
  with
• RR of 1.00 (95 CI 0.96 -1.04) for cure of TB
• RR of 1.23 (95CI 0.45 3.35) favouring
  rifampicin for relapse
• RR of 1.05 (95 CI 0.96 1.15) favouring
  rifabutin
• RR 1.00 (95 CI 0.98 1.03), for culture status
  at 2 and 3 month respectively.
• The only comparative RCT in HIV positive patients
  found both rifamycins to be safe and effective
  and demonstrated more rapid clearance of
  acid-fast bacilli in the rifabutin arm (log rank
  plt 0.05)

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Thank you
WHO Three I's Meeting, Geneva, April 2-4, 2008
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Rifabutin safety and efficacy

• Rifabutin is equally safe and effective as
  rifampicin for TB
• However randomised clinical trials include mostly
  HIV- negative individuals
• Observational cohort studies including in
  HIV-infected patients treated with ART does not
  point to inferior performance of rifabutin

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Side effects

• Neutropenia
• Leucopenia
• ALAT/ASAT elevations
• Rash and upper gastrointestinal complaints
• More rarely uveitis