Regimen Selection to Support a “Public Health” Approach

1. Regimen Selection to Support a “Public Health” Approach Anthony Amoroso, MD Assistant Professor of Medicine University of Maryland School of Medicine Institute of Human Virology

2. Can a regimen be the cornerstone to support a public health approach? Challenge: • Enable mid- and low-level providers to deliver quality HIV treatment • to 100,000’s of patients • in community health clinics and dispensaries Simplify clinical decision-making protocols centered on “four Ss”. • When to start • When and what to substitute to • When to switch for treatment failure • When to stop Gilks C, et al. Lancet Aug 5, 2006

3. Characteristics of an ideal public health regimen Simple and convenient dosing Durable and efficacious • Low rate of dose limiting toxicities • Predictable degree of viral suppression across different viral populations Superior safety profile • not exacerbated by prevalent co-morbidities, • avoids common drug-drug interactions. • easily diagnosable toxicities. Predictable resistance pattern • mutational pattern which simplifies switching therapy decisions • rational second line treatment options after clinical failure Accessible pricing

4. Cost of Access • Only $109,843,477 million spent directly on the purchase of ARV drugs within the 3rd year of PEPFAR (2006) • ARV drug related costs are estimated to be less than 7% of total care, treatment and prevention package to 15 focus countries $1,601,986,513. • “Drug costs are no longer the fundamental obstacle for treatment” 3rd OGAC to report to congress

5. Simple Dosing • Durable viral suppression is absolutely linked to extraordinary tight adherence. • Lack of viral load monitoring amplifies the need to ensure adherence. • Availability of once a day therapy supports patients and adherence programs. • 3TC and FTC • ABC, TDF, and DDI • EFV, NVP • Kaletra, Atazanavir, fosamprenavir • FTC/TNF, 3TC/ABC • FTC/TNF/EFV

6. Regimen Durability • Intolerance and toxicities are the most common reasons for treatment failure and have important cost and safety ramifications : • Degree of complexity necessary for safe and appropriate medication change. • Degree of complexity required for the appropriate management of the side effects

7. N=331 N=485 N=349 N= 1265

8. Causes of ART Switch 1/08/2004 - 01/08/2006 : Kenya, Uganda, Zambia N=6520 Amoroso et al. 14th CROI. Los Angeles, 2007. Abstract 789

9. Amoroso et al. 14th CROI. Los Angeles, 2007. Abstract 789

10. SUMMARY Recent Abstracts

11. TDF+3TC+EFV TDF+3TC+EFV * * 19 19 20 20 d4T+3TC+EFV d4T+3TC+EFV 18 18 16 16 14 14 * * 12 12 12 12 % Patients with Selected Toxicities % Patients with Selected Toxicities 10 10 8 8 6 6 4 4 * * 3 3 4 4 * * 1 1 1 1 2 2 0 0 Week 48 Week 48 Week 96 Week 96 Week 144 Week 144 Investigator Investigator - - defined defined † † *p value < 0.001 *p value < 0.001 Study 903 – Week 144 Patients (%) with Lipodystrophy† Gallant et al. JAMA 2004

13. DART Trial: Toxicity Profile mismatch with targeted population Anemia 22.4% anemia by Wk 24 • 6.6% grade 4 Risk factors: • Female; • low baseline BMI; • low baseline Hb; • low baseline CD4+; (Ssali F, et al. Abstract 24)

14. Zidovudine and Severe AnemiaFinancial Implications at one hospital • 15 consecutive cases of Hb <= 6.5 g/dl • Range 2.4-6.5, median 5.4 • 9 admissions • 14 units of blood transfused • 3 deaths • 1 directly attributable to anemia • Combined hospital bill = $1264 • Hospital left with $720 USD unpaid by patients • 1.3% of 2004 hospital operating deficit

15. There are few specific treatment strategies which have clinical evidence once patients have clinically failed recommended 1st line regimens Broad cross-resistance among drugs within a class The Difficulty of Late Treatment Failure

16. Example of virologic failure in relation to CD4 decline Accumulation of mutations

17. M184V only M184V plus other mutations Example of in Subjects With Virologic Rebound on AZT/ABC/3TC Stepwise Accumulation of Mutations CNA3005 0 WT 28 weeks of M184V only 1 3 4 1 3 3 4 1 1 2 400 c/mL 50 c/mL Melby T, et al. 8th CROI, 2001: Abst. 448.

18. AZT/3TC D4T/3TC ABC/3TC TDF/FTC M184V M184V K65R Resistance Patterns after Initial Failure of Common NRTI Backbones M184V Multiple TAMS 74V > K65R TIME TO DEVELOPMENT

19. Predicted NRTI activity based on median phenotypes by genotype* *215Y and 215F both require 2 mutations from wild type Resistant Susceptible Lanier R, et al. 10th CROI, Boston 2003, #586 Partial

20. Above cutoff Below cutoff Rational Second Line Therapy AZT Remains Susceptible in K65R+M184V Viruses PhenoSense Results for K65R + M184V (n=58) 100% 90% 55% 42% 18% 3% 100 80 % of viruses 60 40 20 0 ZDV TDF ABC ddI ddC 3TC Miller et al. (2003) 43rd ICAAC, #H-904

21. Clinical and cost implications of first line therapies AZT/D4T+3TC • Risk of accumulation of resistance mutations over time • Switching patients at time of clinical failure will limits second line options for many • Necessitate the use of viral load measurements for the “four Ss” decision making process. • viral load measurements and genotype assays are costly to set-up, train, quality assure, and provide logistical access to. TDF+3TC/FTC • No additional “mutational costs” with allowing patients to present with clinical failure as the indication for switch to second line. • Eliminates the need for viral load measurements in most cases

22. Cost of maintaining 100 pts on 1st and 2nd line regimens 2nd lineLPV/r+CBV 1st line NRTI 2nd line LPV/r+ABC+TDF

23. Good medical outcomes should drive treatment strategies Strongly recommend implementing current WHO guidelines to move away from D4T (and AZT) which carry significant toxicities and complicate care delivery • Supports the accepted knowledge and practice within the HIV treating community. • Aligns 1st line treatment recommendations with guidelines in the U.S. and Europe • Ends the endorsement of substandard ART to the poor of the world