17th Expert Committee on the Selection and Use of Essential Medicines Geneva, 2009 APPLICATION FOR LISTING OF ATAZANAVIR FOR THE TREATMENT OF HIV-1 INFECTION ON THE WHO MODEL LIST OF ESSENTIAL MEDICINES FEBRUARY 2009 Atazanavir – HIV infection 1 TABLE OF CONTENTS 1. Summary statement of proposal for inclusion, change, or deletion......................3 2. Name of focal point in WHO submitting the application.....................................3 3. Name of the organisation(s) consulted and/or supporting the application ...........3 4. International Nonproprietary Name (INN) ...........................................................3 5. Formulation proposed for inclusion......................................................................3 6. International availability .......................................................................................3 7. Category of listing requested ................................................................................3 8. Information supporting the public health relevance .............................................3 8.1 Epidemiological information on disease burden............................................3 8.2 Assessment of current use..............................................................................5 8.3 Target population...........................................................................................5 9. Treatment details...................................................................................................5 9.1 Dosage regimen .............................................................................................5 9.2 Treatment duration.........................................................................................5 9.3 Reference to WHO and other clinical guidelines ..........................................5 9.4 Need for special diagnostic or treatment facilities and skills ........................6 10. Summary of comparative effectiveness................................................................7 10.1 Identification of clinical evidence..................................................................7 10.1.1 Search strategy.......................................................................................7 10.1.2 Systematic reviews identified ................................................................7 10.1.3 Selection/exclusion of particular data....................................................7 10.2 Summary of available data.............................................................................9 10.2.1 Appraisal of quality................................................................................9 10.2.2 Outcome measures...............................................................................10 10.2.3 Summary of results – second-line treatment – randomized trials........11 10.2.4 Summary of results – second-line treatment – non-randomized studies ..................................................................................................16 10.3 Summary of available estimates of comparative effectiveness ...................18 11. Summary of comparative evidence on safety .......................................................18 11.1 Estimate of total patient exposure to date....................................................18 11.2 Description of adverse effects/reactions ......................................................19 11.3 Identification of variation in safety due to health systems and patient factors........................................................................................21 11.4 Summary of comparative safety against comparators .................................22 12. Summary of available data on comparative cost and cost-effectiveness............22 12.1 Range of costs of the proposed medicine ....................................................22 12.2 Comparative cost-effectiveness (presented as range of cost per routine outcome) ......................................................................................................22 13. Regulatory status.................................................................................................24 14. Availability of pharmacopoeial standards ...........................................................24 15. Proposed text for the WHO Model Formulary ....................................................24 References....................................................................................................................24 Attachment 1................................................................................................................28 A1.1 Summary of results – first-line treatment – randomized trials...................28 A1.2 Summary of results – first-line treatment – non-randomized studies ........31 Attachment 2................................................................................................................32 Attachment 3................................................................................................................35 Atazanavir – HIV infection 2 WHO MODEL LIST OF ESSENTIAL MEDICINES APPLICATION Atazanavir capsules (100mg and 300mg) for the treatment of HIV-1 infection 1. Summary statement of proposal for inclusion, change, or deletion Atazanavir capsules (100mg and 300mg) are proposed for inclusion on the WHO Model List of essential medicines for the treatment of HIV infection. 2. Name of focal point in WHO submitting the application 3. Name of the organization(s) consulted and/or supporting the application 4. International Nonproprietary Name (INN) atazanavir 5. Formulation proposed for inclusion 100mg capsule and 300mg capsule. 6. International availability Section 13 (see Table 13.1) provides a list of the manufacturers. Atazanavir is available in six African countries and India. In these countries the 150mg capsule has WHO pre-qualification status. 7. Category of listing requested Listing is requested as an individual drug. 8. Information supporting the public health relevance 8.1 Epidemiological information on disease burden Current estimates indicate that 33 million people were living with HIV in 2007, with a total of 2.7 million new infections in 2007 (WHO 2008). Developing countries, in particular sub-Saharan African countries, are the most affected countries in the world, with 27 million people with HIV (82%). The majority of AIDS-related deaths occur in sub-Saharan Africa (1.5 million of the 2 million deaths in 2007) (UNAIDS 2008). Table 8.1.1 summarises the number of people living with HIV, the number of AIDS deaths and the number of new infections world-wide in 2007. Table 8.1.1: Summary of HIV infection and AIDS deaths in 2007 People living with HIV 2007 AIDS deaths 2007 Region (low-high estimate) (low-high estimate) Sub-Saharan Africa 27,000,000 1,500,000 (20,500,000-23,600,000) (1,300,000-1,700,000) South and 4,200,000 340,000 Southeast Asia (3,500,000-5,300,000) (230,000-450,000) Atazanavir – HIV infection 3 People living with HIV 2007 AIDS deaths 2007 Region (low-high estimate) (low-high estimate) East Asia 740,000 40,000 (480,000-1,100,000) (24,000-63,000) Latin America 1,700,000 63,000 (1,500,000-2,100,000) (49,000-98,000) North America 1,200,000 23,000 (760,000-2,000,000) (9,100-55,000) Western and 730,000 8,000 Central Europe (580,000-1,000,000) (4,800-17,000) Eastern Europe 1,500,000 58,000 and Central Asia (1,100,000-1,900,000) (41,000-88,000) Middle-east and 380,000 27,000 North Africa (280,000-510,000) (20,000-35,000) Caribbean 230,000 14,000 (210,000-270,000) (11,000-16,000) Oceania 74,000 1,000 (66,000-93,000) (<1,000-1,400) Total 33,000,000 2,000,000 (30,000,000-36,000,000) (1,800,000-2,300,000) Source: http://www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/2008_Global _report.asp Table 8.1.2 provides the number of people receiving antiretroviral (ART) therapy in 2007 in low and middle income countries. Table 8.1.2: Summary of ARV treatment Number receiving ARV therapy ARV therapy Number requiring coverage Region December 2007 therapy 2007 December 2007 Sub-Saharan Africa 2,120,000 7,000,000 30% Latin America and 390,000 630,000 62% Caribbean East, South and 420,000 1,700,000 25% Southeast Asia Eastern Europe 54,000 320,000 17% and Central Asia Middle-east and 7,000 100,000 7% North Africa Total 2,990,000 9,700,000 31% Source: www.who.int/hiv/pub/towards_universal_access_report_2008.pdf Although the proportion of people receiving ARV therapy of those requiring therapy in low and middle income countries has increased to 31% in 2007, from 24% in 2006 and 7% in 2003, the proportion treated in these countries remains low (WHO, UNAIDS and UNICEF 2008). Another aspect of treatment that has been recognised as critical is the need in resource-limited countries to make second-line treatment regimens available (WHO 2007). An expert meeting was convened by the WHO in May 2007 to develop guidance for second-line drugs. The working group ranked atazanavir boosted with ritonavir as one of the highest priorities for the protease inhibitor (PI) component of second-line treatment (WHO 2007). Atazanavir has a low pill burden and there is evidence of beneficial effects on Atazanavir – HIV infection 4 lipid levels (see Section 10.2) which offers advantages for adherence and longer-term treatment. Thus, inclusion of atazanavir on the WHO Model Lists of Essential Medicines is sought. Evidence demonstrating the efficacy and safety of atazanavir is provided in Sections 10.2 and 11 and Attachments 1 and 2. 8.2 Assessment