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. Slide 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”. 1.When to start 2.When and what to substitute to 3.When to switch for treatment failure 4.When to stop Gilks C, et al. Lancet Aug 5, 2006

3. Slide 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. Slide 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” 3 rd OGAC to report to congress

5. Slide 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. Slide 6 Regimen Durability Intolerance and toxicities are the most common reasons for treatment failure and have important cost and safety ramifications : 1.Degree of complexity necessary for safe and appropriate medication change. 2.Degree of complexity required for the appropriate management of the side effects

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

8. Slide 8 All Clinical Reasons for Therapy Switch N (%) Clinical Failure240 (3.6) Drug Interaction324 (4.9) Patient Preference31 (0.4) Poor Adherence40 (0.6) Pregnancy94 (1.4) Toxicity1164 (17.5) Unlisted495 (7.6) Total2388 (36.6) Amoroso et al. 14th CROI. Los Angeles, 2007. Abstract 789 Causes of ART Switch 1/08/2004 - 01/08/2006 : Kenya, Uganda, Zambia N=6520

9. Slide 9 DrugsTotal StartedObserved % Switched Due to Toxicity Median time to toxicity (days) D4T214924.6%141 AZT143313.2%81 TDF29380.7%58 NVP42886.6%83 EFV36573.4%119 LPV/r6222.0%25 Amoroso et al. 14th CROI. Los Angeles, 2007. Abstract 789

10. Slide 10 SUMMARY Recent Abstracts Country/studyDateDrug Observed Toxicity S. Africa/MSF2006D4T Neuropathy 8.5% switch Uganda/Forna2006D4T Neuropathy 31% / 8% grade 3-4 Kenya/Kim2006D4T Neuropathy 23% / 3% grade 3-4 Rwanda/MSF2006D4T Lipoatrophy 23% Uganda/Zimbabwe/ DART2005AZT Anemia 22% / 5.5% <6.5 Hb S. Africa/MSF2006AZT Anemia 8.9% switch

11. Slide 11 Study 903 – Week 144 Patients (%) with Lipodystrophy † Gallant et al. JAMA 2004

12. Slide 12 TDF Attributable Toxicity N (%) Renal Toxicity3 (13.6) Other/Not documented19 (86.0) Total22

13. Slide 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. Slide 14 Zidovudine and Severe Anemia Financial 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. Slide 15 The Difficulty of Late Treatment Failure There are few specific treatment strategies which have clinical evidence once patients have clinically failed recommended 1 st line regimens Broad cross-resistance among drugs within a class

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

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

18. Slide 18 Resistance Patterns after Initial Failure of Common NRTI Backbones AZT/3TC D4T/3TC TIME TO DEVELOPMENT M184VMultiple TAMS ABC/3TC M184V TDF/FTC M184V K65R 74V > K65R

19. 19 Predicted NRTI activity based on median phenotypes by genotype* # MutationsRT genotypeZDVd4TddI3TC/ FTC ABCTDF 1 184V/I 65R 2 65R + 184V/I 74V/I + 184V/I 41L + 184V/I 3 67N + 70R + 184V/I 215Y/F* +184V/I 4 67N + 70R +219E/Q + 184V/I 41L + 215Y/F* + 184V/I 5 41L + 210W + 215Y/F* + 184V/I *215Y and 215F both require 2 mutations from wild type Resistant Susceptible Lanier R, et al. 10 th CROI, Boston 2003, #586 Partial

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

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

23. Slide 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 1 st line treatment recommendations with guidelines in the U.S. and Europe Ends the endorsement of substandard ART to the poor of the world