HIV/AIDS Medical Update

1. HIV/AIDS Medical Update Arthur C. Johnson, III, M.D. HIV Clinical Director Tripler Army Medical Center

2. Human Immunodeficiency Virus

3. 2004 • No new major developments in HIV care • No new antiretrovirals approved

4. Global estimates foradults and childrenend 2004 • People living with HIV • New HIV infections in 2004 • Deaths due to AIDS in 2004 39.4 million [35.9 – 44.3 million] 4.9 million [4.3 – 6.4 million] 3.1 million [2.8 – 3.5 million]

5. Adults & children living with HIV Adults & children newly infected with HIV Adult prevalence [%] * Adult & child deaths due to AIDS 3.1 million [2.7 – 3.8 million] 2.3 million [2.1 – 2.6 million] 7.4 [6.9 – 8.3] 25.4 million [23.4 – 28.4 million] Sub-Saharan Africa 0.3 [0.1 – 0.7] 540 000 [230 000 – 1.5 million] 92 000 [34 000 – 350 000] 28 000 [12 000 – 72 000] North Africa & Middle East 7.1 million [4.4 – 10.6 million] 890 000 [480 000 – 2.0 million] 0.6 [0.4 – 0.9] 490 000 [300 000 – 750 000] South and South-East Asia 1.1 million [560 000 – 1.8 million] 290 000 [84 000 – 830 000] 51 000 [25 000 – 86 000] 0.1 [0.1 – 0.2] East Asia 0.6 [0.5 – 0.8] 1.7 million [1.3 – 2.2 million] 240 000 [170 000 – 430 000] 95 000 [73 000 – 120 000] Latin America 2.3 [1.5 – 4.1] 440 000 [270 000 – 780 000] 53 000 [27 000 – 140 000] 36 000 [24 000 – 61 000] Caribbean 1.4 million [920 000 – 2.1 million] 210 000 [110 000 – 480 000] 0.8 [0.5 – 1.2] 60 000 [39 000 – 87 000] Eastern Europe & Central Asia 610 000 [480 000 – 760 000] 21 000 [14 000 – 38 000] 6 500 [ <8 500] 0.3 [0.2 – 0.3] Western & Central Europe 1.0 million [540 000 – 1.6 million] 44 000 [16 000 – 120 000] 0.6 [0.3 – 1.0] 16 000 [8 400 – 25 000] North America 0.2 [0.1 - 0.3] 35 000 [25 000 – 48 000] 5 000 [2 100 – 13 000] 700 <1 700] Oceania TOTAL 39.4 million [35.9 – 44.3 million] 4.9 million [4.3 – 6.4 million] 1.1 % [1.0 - 1.3%] 3.1 million[2.8 – 3.5 million] * The proportion of adults [15 to 49 years of age] living with HIV in 2004, using 2004 population numbers The ranges around the estimates in this table define the boundaries within which the actual numbers lie, based on the best available information. Regional HIV and AIDS statistics and features, end of 2004

6. GlobalAntiretroviral Therapy • 440,000 are currently being treated • 9 out of 10 not receiving therapy

7. Antiretroviral Drugs • Nucleoside Analog Reverse Transcriptase Inhibitors • Nucleotide Analog Reverse Transcriptase Inhibitors • Non-Nucleoside Analog Reverse Transcriptase Inhibitors • Protease Inhibitors • Fusion Inhibitors

8. Combivir Viread Hivid Epivir Rescriptor Ziagen Retrovir Videx Zerit Viramune Sustiva Trizivir Emtriva Invirase Viracept Kaletra Fuzeon NRTI Fortovase Agenerase Reyataz Lexiva nNRTI Norvir PI Crixivan FI FDA-Approved Antiretrovirals 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04

9. Nucleoside Analog Reverse Transcriptase Inhibitors • Zidovudine AZT,ZVD Retrovir • Didanosine ddI Videx • Zalcitabine ddC Hivid • Stavudine d4T Zerit • Lamivudine 3TC Epivir • Abacavir ABC Ziagen • Emtricitabine FTC Emtriva

10. Nucleotide Analog Reverse Transcriptase Inhibitors • Tenofovir DF TDF Veriad

11. Non-Nucleoside Reverse Transcriptase Inhibitors • Nevirapine NVP Viramune • Delavirdine DLV Rescriptor • Efavirenz EFV Sustiva

12. Protease Inhibitors • Saquinavir SQV Fortavase • Ritonavir RTV Norvir • Indinavir IDV Crixivan • Nelfinavir NFV Viracept • Amprenavir APV Agenerase • Lopinavir LPV Kaletra • Atazanavir ATZ Agenerase • Fosamprenavir FAV Lexiva

13. Fusion Inhibitors • Enfuviritide EFT Fuzeon

14. 0 -0.5 -1 -1.5 -2 -2.5 -3 Antiretroviral Activity:An Historical Perspective 1987: AZT Monotherapy 1994: Two-Drug Therapy 1997: HAART 0 0 -0.5 -0.5 -1 -1 -1.5 -1.5 HIV RNA change (log10 c/mL) -2 -2 -2.5 -2.5 -3 -3 24-week response 24-week response 24-week response Fischl, NEJM, 1987 Hamilton, NEJM, 1992 Eron, NEJM, 1995;Hammer, NEJM, 1996 Gulick, NEJM, 1997; Cameron, Lancet, 1998

15. New Agents • Inhibit binding of HIV to CCR5 and/or CXCR4 • Antibody-based approaches to entry blocking • Fusion inhibitors-enfuvirtide/Fuzeon • HIV integrase inhibitors • Dendritic cell-specific ICAM-3 receptor blockers • Maturation inhibitors

17. LPV/r Monotherapy in Treatment –Naïve Patients • Study by Joe Gathe in Houston, TX • 30 pts. Treated • 400/100 bid < 70 kg or 533/133 bid > 70kg • Mean CD4+ 170 Mean VL 262,000 • 43% CD4+ < 50 > 50% VL > 100,000 • After 48 weeks: • 20 (67%) < 400 and 60% < 50 • Mean CD4+ increase was 317

18. Atazanavir • Kathleen Squires et al study • International, randomized, double blind, treatment naïve • 600mg EFV/d vs 400 ATZ/d w COM bid

19. Atazanavir • Week 48 EFV ATZ • VL<400 64% 70% • VL<50 37% 32% • Tube type can affect HIV VL results • ATZ negative interactions with therapies that increase gastric pH

20. ACTG A5095

21. A5095 • Gulick, Ribaudo, Shikuma, et al • AZT/3TC/ABC was virologically inferior to AZT/3TC/ABC + EFV or AZT/3TC + EFV • Conclusions • Time to virologic failure shorter in triple nuc • Suppression did not signify longer term success • 3 nuc combination that include a thymidine analogue fare much better that other 3 nuc combinations

22. NNRTI resistance in Perinatal Nevirapine • Martinson et all-NNRTI resistance 6 wks postpartum in 39% of mothers and 42% of positive infants after single dose NVP. Transmission a mere 8.6% • Jourdain et al-AZT alone vs. AZT + single dose NVP. • MTCT 1% vs. 6% • NNRTI resistance in almost 1/3 who got NVP

23. Geonomics of EFV Toxicity • Haas et al-Looked at polymorphisms in P450 enzymes • AAs more likely to have polymorphism at CYP2B6 (T/T @G516T) than EAs (20% vs. 3%) • Gene associated with greater plasma concentrations of EFV and CNS side effects

24. Evolving Drug Resistance • Kantor et al-Pts with know tx hx, 2 genotypes > 2 mo. apart, no change in tx • 106 pts, tx mean of 29 mo before 1st genotype, 14 mo between genotypes • Median VL 3.7log10 and CD4+ 336 1st • Median VL 4.0log10 and CD4+ 339 2nd

25. Evolving Drug Resistance • In period between genotypes: • 75% developed new drug resistance mutation • 62% PI mutations • 42% NRTI mutations • 29% NNRTI mutations • “Resistant” drugs increase from a median of 8 to 10 • Patients with low-level viremia (400-20,00) over ~4 yrs do not experience progression of their HIV disease at rates that exceed those with and undetectable HIV-RNA level

26. The Stability of Low-Level Viremia • Re et al-How long can low levels of viremia be maintained before virologic failure ensues? • Stable AVR, VL 50-500 for 3 months • Median VL 139 and median CD4+ 455 • Follow up was 693 days • Main end point was VL > 1,000

27. The Stability of Low-Level Viremia • >1,000 VL seen in 37% at median of 357 days • 38% <50 at last follow-up • 40% with detectable VL still < 1,000 at 3 yr. These 2 studies suggest 1/3 of pts will rebound and the same with VL<5,000 will develop new resistance mutations

28. Microbicide • Marla Keller et al • Study of 10 HIV + women • Topical vaginal gel, called PRO 2000 • Significantly reduced viral levels without causing an inflammatory response

29. Questions?