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Rifabutin for TB for people on ART

Rifabutin for TB for people on ART. Reuben Granich WHO HIV/AIDS Department. HIV/TB Core Group Meeting Addis Ababa, Ethiopia, 11-12 November 2008. Towards Universal Treatment Access. Nearly one million more people on antiretroviral therapy 54% increase in one year in sub-Saharan Africa.

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Rifabutin for TB for people on ART

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  1. Rifabutin for TB for people on ART Reuben Granich WHO HIV/AIDS Department HIV/TB Core Group MeetingAddis Ababa, Ethiopia, 11-12 November 2008

  2. Towards Universal Treatment Access

  3. 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. Gains in Access to Care and Treatment

  4. 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

  5. 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

  6. 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

  7. 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 > 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

  8. Rough costing analysis

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

  10. 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/HIV—match made in heaven!

  11. 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 NNRTI’s used in standard first-line therapy

  12. 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),

  13. 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

  14. 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 (95%CI: 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 p< 0.05)

  15. Thank you WHO Three I's Meeting, Geneva, April 2-4, 2008

  16. 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

  17. Side effects • Neutropenia • Leucopenia • ALAT/ASAT elevations • Rash and upper gastrointestinal complaints • More rarely uveitis

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