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

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 Unit values (USD)LPV/r (median)LPV/r (average) LICMICLICMIC Estimated cost of the ARV protocol during Rifampicin based TB treatment* (6 months) 453.62764.8939.62689.2 Estimated cost of the ARV protocol during Rifabutin based TB treatment* (6 months) 2701846.8572.41706.4

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

10. Edde Loeliger (intern) Mark O'Connor (intern) Charlie Gilks (WHO) Fabio Scano (WHO) Barbara Milani (WHO) David Ripin (Clinton) Renee Ridzon (Gates) Thank you 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. WHO Three I's Meeting, Geneva, April 2-4, 2008 Thank you

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