1. Improving Adherence With Simplified HAART Regimens Improving Clinical Outcomes in HIV Patients

2. Adherence to HAART Is Essential u “Adherence to the [HAART] regimen is essential for successful treatment and has been reported to increase sustained virologic control, which is critical in reducing HIV-related morbidity and mortality.” 1 u “Conversely, suboptimal adherence has been reported to decrease virologic control and has been associated with increased morbidity and mortality. Suboptimal adherence also leads to drug resistance, limiting effectiveness of therapy.” 1 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:9. 1

3. Relationship Between Adherence and HIV Suppression * Series of 886 treatment-naive HIV patients; CD4 cell count <500 x 10 6 cells/L or plasma viral load >5000 copies/mL. † Prospective, observational study of 81 HIV patients. ‡ MEMS, Medication Events Monitoring System. 1. Low-Beer S et al. JAIDS. 2000;23:360-361. Letter. 2. Paterson DL et al. Ann Intern Med. 2000;133:21-30. 2

4. Relationship Between Adherence and CD4 Cell Count * Observational and research study of 1522 ART-naive patients initiated on HAART; adherence was measured as prescriptions refilled. 1. Wood et al. JAIDS. 2004;35:261-268. Homer Study *1 3

5. Virological Response by Daily Pill Burden* 1 1. Bartlett JA et al. AIDS. 2001;15:1369-1377. 4 * Symbol size is directly proportional to weight of the data point in analysis.

6. Adherence Impacts HIV-Related Mortality and AIDS Progression *1 *Prospective, observational study of 950 ART-naive patients treated with triple- combination therapy; adherence was estimated by prescriptions dispensed. 1. Hogg et al. 7 th CROI 2000. Abstract 73. For every 10% decrease in adherence 1.17 times higher likelihood of progression to AIDS and/or death 5 16% increase in HIV-related mortality

7. Regimen-Related Drivers of Adherence 1 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:12. 6

8. HAART Patients Commonly Miss Doses Due to Side Effects *1 1. Munk. CPS Info Pack (suppl). POZ. 1998. * Community Prescription Service (CPS) phone survey of 400 people with HIV, most of whom were on triple combination therapy. 7

9. ART-Related Toxicities Are the Largest Cause of Discontinuation Major Reasons for HAART Discontinuation 1. O’Brien et al. JAIDS. 2003;34:407-414. 2. Monforte et al. AIDS. 2000;14:499-507. * Retrospective study of 345 ART-naive patients initiated on HAART and followed for a median of 8.1 months; 211 patients (61%) discontinued therapy. † Population-based cohort of 862 ART-naive patients initiated on HAART and followed for a median of 45 weeks; 312 patients (36%) discontinued therapy. 8

10. Nausea Often Results in HAART Discontinuation *1 * Retrospective study of 345 ART-naive patients initiated on HAART and followed for a median of 8.1 months. Of 211 patients who discontinued therapy, 40% did so due to AEs. 1. O’Brien et al. JAIDS. 2003;34:407-414. 9

11. Patients Prefer QD HAART Regimens *1 * Survey of 536 HIV + patients conducted via telephone, Internet, and mail during 2001 to 2002. 1. Bass, Smith. XIV Intl AIDS Conf (IAC) 2002. Abstract MoPeB3290. 10

12. Once-Daily Regimens May Improve Adherence *1 * Percentage of patients reporting they have forgotten doses among 504 patients who underwent standardized interviews; APPT-1 pan-European survey. 1. Moyle et al. 6 th Intl Congress on Drug Ther in HIV Inf 2002. Poster 99. 11

13. ART Agents FDA-Approved for QD Dosing 1 1. Adapted from: DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:21. Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Nucleoside Reverse Transcriptase Inhibitor (NRTI) Protease Inhibitor (PI) Efavirenz (EFV)Didanosine (ddI) ECAtazanavir (ATV) Tenofovir disoproxil fumarate (TDF) Amprenavir (APV)/ ritonavir (RTV) Lamivudine (3TC) Fosamprenavir (FPV)/ ritonavir (RTV) Stavudine (d4T) XR Emtricitabine (FTC) 12

14. NRTIs and Food Restrictions 1 13 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:59. Generic Name/Trade NameFood Effect Abacavir (ABC) Ziagen ® Take without regard to meals; Alcohol increases abacavir levels 41%; has no effect on alcohol Didanosine (ddI) Videx ®, Videx EC ® Levels decrease 55%; Take 1/2 hour before or 2 hours after meal Emtricitabine (FTC) Emtriva ™ Take without regard to meals Lamivudine (3TC) Epivir ® Take without regard to meals Stavudine (d4T) Zerit ® Take without regard to meals Tenofovir Disoproxil Fumarate Viread ® Take without regard to meals Zalcitabine (ddC) Hivid ® Take without regard to meals Zidovudine (AZT, ZDV) Retrovir ® Take without regard to meals

15. NNRTIs and Food Restrictions 1 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:59. Generic Name/Trade NameFood Effect Delavirdine/Rescriptor ® Take without regard to meals Efavirenz/Sustiva ® High-fat/high-caloric meals increase peak plasma concentrations of capsules by 39% and tablets by 79%; take on an empty stomach Nevirapine/Viramune ® Take without regard to meals

16. PIs and Food Restrictions 1 Generic Name/Trade NameFood Effect Amprenavir/Agenerase ® High-fat meal decreases blood concentration curve 21%; can be taken with or without food, but high fat meal should be avoided. Atazanavir/Reyataz™ Administration with food increases bioavailability. Take with food Fosamprenavir (f-APV)/Lexiva™ No significant change in amprenavir pharmacokinetics in fed or fasting state Indinavir/Crixivan ® Levels decrease 77%. Take 1 hour before or 2 hours after meals; may take with skim milk or low-fat meal 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:59.

17. PIs and Food Restrictions 1 ( continued) Generic Name/Trade NameFood Effect Lopinavir +Ritonavir/Kaletra ® Moderate fat meal Increases AUC of capsules and solution by 48% and 80%, respectively. Take with food. Nelfinavir/Viracept ® Levels increase 2-3 fold. Take with meal or snack Ritonavir/Norvir ® Levels increase 15%. Take with food if possible; this may improve tolerability Saquinavir hard gel capsule/Invirase ® No food effect when taken with ritonavir Saquinavir soft gel capsule/Fortovase ® Levels increase 6-fold. Take with large meal 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:59.

18. Recommendations for Once-Daily Therapy u “The Panel recommends once-daily dosing with antiretroviral agents that have pharmacokinetic profiles that justify once-daily use (didanosine, lamivudine, tenofovir, efavirenz and atazanavir).... Once-daily therapy is desired for patient convenience and adherence.” *1 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:20. 15

19. Half-lives of NRTIs 1 14 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:59-60, Table 15. * XR, extended release.

20. Half-lives of Once-Daily NRTIs 1 1. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:59-60, Table 15. 14 * XR, extended release.

21. NRTI Product Loyalty in 2003 1. NDC Retail Pharmacy Patient Database, Update Feb. 2004. Patient Persistency in December 2003 January 2003 New to Product Patients 1

22. Conclusions u HAART adherence in HIV+ patients may improve with simplified regimens 1 u Once-daily regimens may improve patient adherence 1 and virologic suppression 2-4 u ART agents with pharmacokinetic profiles that support once-daily use are recommended 5 u ART-related toxicities are the leading cause of compromised adherence/discontinuation 6-7 and should be considered in the selection of HIV treatment 1. Moyle G et al. 6 th Intl Congress on Drug Ther in HIV Inf 2002. Poster 99. 2. Low-Beer S et al. JAIDS. 2000; 23:360-361. Letter. 3. Paterson DL et al. Ann Intern Med. 2000;133:21-30. 4. Bartlett J et al. 7 th CROI 2000. Abstract 519. 5. DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. Mar 23, 2004:20. 6. O’Brien ME et al. JAIDS. 2003;34:407-414. 7. Monforte A et al. AIDS. 2000;14:499-507. 24

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