Agenda

1. Agenda Next generation ARVs and dose optimization How the next generation of optimized ARVs can improve treatment, increase program value, and change the paradigm of manufacturing and pricing for ARVs David Ripin Clinton Health Access Initiative

2. The number of total patients on treatment in low-and middle-income countries is expected to grow to 20M by 2018 CHAIhasemployedanumberofmarketinterventionstocontribute toourgoal of expandingaccesstokeycommodities Historical and estimated scale up in low- and middle-income countries 15.6M Millions of Patients • 25.9M people are eligible for ART under the 2013 WHO guidelines • Additional efforts are needed to reach universal coverage • UNAIDS is setting even more aggressive targets of 90/90/90 by 2020 Source: CHAI ARV forecasting model; WHO/UNAIDS for historical numbers

3. Universal access could be affordable: CHAI’s MATCH study found the facility-level cost of treatment at $200 per patient per year in LMICs Cost of treatment per ART patient-year by country (USD) Simple average and median cost of treatment per ART patient-year by country (USD) *Lab category includes consumables only in all countries except SA ** Simple average numbers are not representative of the countries. Weighted average numbers are currently being calculated which will be a better representation of the countries ***Facility-level costs below are from 2009-2010. Costs from South Africa include updated ARV prices, which were renegotiated by the RSA government in early 2010 and are 53% lower than the prices observed during the costing period.

4. Benefits of early initiation and high retention Costs of delaying initiation • Not treating is not zero cost: Healthcare utilization for HIV+ not on treatment ranges from $5 - $63 per year depending on disease stage* • Pre-ART costs are estimated at $55 -$91 per patient per year (pppy)* • Patients initiated later are more expensive: Established, more complex patients cost an estimated $242 pppy** We need to start talking about the cost of not delivering quality care Example of Zambia • Reduced incidence of OIs and the need for in-patient care leads to lower burden on the health system • No pre-ART costswith universal treatment • Patients initiated earlier cost less: We estimate a $40 reduction in cost for less complex patients due to differences in the intensity of care required** *Eaton et al. Lancet Global Health. December 2013. **CHAI 2014 HIV scale up costing analysis

5. Improving quality of care may require an investment but will reduce overall costs • Across 4 countries, a 5% increase in retention results in the following by 2020: • 4-6% reduction in new infections • 4-6% reduction in AIDS-related deaths • Up to 4% reduction in treatment and testing costs • We can improve retention through: • Better commodities (e.g., more tolerable ARV regimens with less side effects or more forgiving missed doses) • Proper patient monitoring to ensure VL is suppressed • Innovative models of care (e.g., community support clubs to retain patients) Costs of Achieving Universal Access* by 2020 vs. Retention • *Universal Access defined here as 95% coverage under the 2013 WHO Guidelines. • Note: Figures do not include spending required for finding patients who have been LTFU. Additional analysis is underway to account for these costs. **CHAI and HSPH, HIV scale up costing analysis, 2014.

6. As part of this effort, we need to accelerate the development and market entry of optimized ARVs CHAIhasemployedanumberofmarketinterventionstocontribute toourgoal of expandingaccesstokeycommodities • Lower-priced regimens: Even marginal reductions in per patient per year prices will lead to large total savings due to the number of patients on ART • Improved tolerability and durability: Products that improve outcomes (increase patient retention and suppress VL) will save money over time

7. The target product profile for the ideal ARV regimen was developed at the CADO 1 meeting and still holds CHAIhasemployedanumberofmarketinterventionstocontribute toourgoal of expandingaccesstokeycommodities Source: CADO 2 (Conference on Antiretroviral Dose Optimization) meeting report, April 2013

8. Several emerging products look particularly promising CHAIhasemployedanumberofmarketinterventionstocontribute toourgoal of expandingaccesstokeycommodities EFV 400mg • At 48 weeks, 400mg was non-inferior to 600mg; lower frequency of adverse events and discontinuations (ENCORE) • TDF/3TC/EFV with 400mg may be $10-15 less than ceiling price for FDC with 600mg • Well-tolerated integrase inhibitor with high barrier to resistance; • TDF/3TC/DTG may be $10-25 less than current ceiling price for FDC with EFV 600mg • No approved generic producersto date DTG 50mg • Efficacy, safety, and high barrier to resistance make it ideal for 2L • With process chemistry improvements: • 800/100 could reduce to $220-250 at scale • Dose optimized 400/100 could reduce to $125-145 at scale DRV/r

9. Two emerging alternatives to TDF are also promising CHAIhasemployedanumberofmarketinterventionstocontribute toourgoal of expandingaccesstokeycommodities • Low dose and distinct metabolism expected to provide improved safety profile and lower costs • Before generic development can occur, clinical data must be generated supporting the use of TAF in the absence of ritonavir or cobicistat as part of a combination appropriate in RLS TAF • Innovator product reformulated with functional excipients to block gut metabolism of API • Dosage form containing >30% less TDF while maintaining identical systematic pharmacological and efficacy profile • Greater than 30% reduction in COGs • Potential to save $200M – $750M TDF(hx) API: Activepharmaceuticalingredient COG: Cost of goods

10. It will be critical to ensure a portfolio of ARVs continues to flow into the market CHAIhasemployedanumberofmarketinterventionstocontribute toourgoal of expandingaccesstokeycommodities Phase III Phase I Phase II Pre-clinical Submit for Approval Rilpivirine Long-Acting ATV/r Dose Reduction 300/100 mg 200/100 mg bid Tenofovir Reformulation 300 mg 200 mg qd Zidovudine Dose Reduction 300 mg 200 mg bid Festinavir BMS-986001 MK-1439 c. 2012 BMS 663068 Albuvirtide Cenicriviroc EVG/COBI/FTC/TAF CMX157 S/GSK1265744 Efavirenz Dose Reduction 600 mg 400 mg bid EVG/COB/ FTC/TAF DRV/COB/ FTC/TAF Legend DRV/COB/ FTC/TDF ATV/COB MVC/ATV/RTV MVC/DRV/RTV RAL/DRV/RTV RAL/LPV/RTV DRV/COB ATV/RAL Fusion Inhibitor CCR5 Inhibitor NNRTI NRTI Integrase Inhibitor AttachmentInhibitor Source:: Adapted from 2012 i-Base/TAG Pipeline Report (draft version) and clinicaltrials.gov. PK Booster PI

11. Bottom line: Universal coverage is affordable and ‘commoditizing retention’ will help us get there CHAIhasemployedanumberofmarketinterventionstocontribute toourgoal of expandingaccesstokeycommodities • Moretolerable and durable HIV regimens will result in fewer side effects for patients and will be more forgiving of missed doses – this will, in turn, increase patient retention and improve viral suppression • Proper patient monitoring, supported by quality laboratory services, will ensure that treatment is successfully suppressing viral load • Innovative models of care that maximize treatment compliance and patient retention will be critical Better health for patients Better treatment value Fewer new infections