The Eras of the HIV Epidemic 19301980 1981

The Eras of the HIV Epidemic 19301980 1981 -1986 1987 -1995 1996 - 2006 - 2012+ 2005 2011 3 rd Gen. HAART

3 rd Generation Future HAART: 2012 + THE FUTURE OF ANTIRETROVIRAL THERAPY § New drugs § § § INSTI: NNRTI: Elvitegravir, Dolutegravir Lersivirine GS-7340 (TDF-prodrug) § New combinations § § § INSTI-NRTI: PI/cobi: PI/c-NRTI: § New strategies § New classes § Future needs TDF-FTC-EVG-Cobi DRV-Cobicistat booster DRV-Cobi-TDFpro-FTC

3 rd Generation Future HAART: 2012 + New Drugs: INSTI Elvitegravir: once daily therapy EVR Non-Inferior to RAL at Week 48 *TLOVR: Difference: 1. 1% (95% CI: -6. 0 to 8. 2; P =. 001). Noninferiority: lower limit of 95% CI for difference between arms ≥ -10%. Molina JM, et al. IAS 2011. Abstract WELBB 05.

3 rd Generation Future HAART: 2012 + New Drugs: INSTI Dolutegravir: active against resistanc VIKING: Dolutegravir “Functional Monotherapy” in Pts With RAL Resistance Primary Endpoint* (%) 80 100 96 100 Dolutegravir 50 mg QD (n = 27) 92 78 Dolutegravir 50 mg BID (n = 24) 60 33 40 20 0 All Patients Q 148 + ≥ 1 Other Mutation at Baseline Other Mutations *HIV-1 RNA < 400 copies/m. L or ≥ 0. 7 log 10 copies/m. L reduction from baseline at Day 11. Eron J. CROI 2011, Abstract 151 LB.

3 rd Generation Future HAART: 2012 + New Drugs: NNRTI Lersivirine: once daily without psych or CNS 100 LRV 500 mg LRV 750 mg EFV 600 mg 54/63 (86%) 80 51/65 (79%) 60 40 LRV 500 mg LRV 750 mg EFV 600 mg 20 0 02 4 8 16 24 32 40 48 HIV-1 RNA < 50 copies/m. L Through Wk 48 (%) HIV-1 RNA < 50 copies/m. L Through Wk 48 (%) Lersivirine vs Efavirenz with TDF/FTC in ART-Naive Pts Vernazza P, et al. IAS 2011. Abstract TUAB 0101. 100 80 88 80 86 82 75 62 60 40 20 0 n = 45 44 41 VL < 100, 000 20 21 22 VL ≥ 100, 000

3 rd Generation Future HAART: 2012 + New Drugs: GS-7340 TDF Prodrug 14 -day monotherapy in HIV+ patients: § Change in VL From Baseline (log 10 c/m. L) § § § Lower TDF plasma concentrations Higher intracellular concentrations Greater VL reduction 0. 5 TDF 300 mg QD (n = 10) 0 GS-7340 50 mg QD (n = 10) -0. 5 GS-7340 150 mg QD (n = 10) -1 -1. 5 -2 0 7 14 21 Day 28 35 Markowitz M, et al. CROI 2011. Abstract 152 LB. Graphic used with permission.

3 rd Generation Future HAART: 2012 + w Combinations: 3 rd STR: The “Quad”: TDF-FTC-EVR-C TDF-FTC-EVR/Cobi -vs- TDF-FTC-EFV Week 48 results in Tx-Naïve Patients Cohen AIDS 2011; 25: F 7 -12

3 rd Generation Future HAART: 2012 + THE FUTURE OF ANTIRETROVIRAL THERAPY § New drugs § New combinations § New strategies § § NRTI-sparing regimens 2 -drug potent regimens: INSTI-PI/r § New classes § § Mono-clonal antibody Zinc fingers § Future needs § § HIV Vaccine “Functional” cure

3 rd Generation Future HAART: 2012 + ew strategies: NRTI-Sparing “ 2 -Drug” CCR 5 -PI/r regime MVC vs TDF/FTC With ATV/RTV in ART-Naive Patients HIV-1 RNA < 400 copies/m. L Patients (%) 100 89. 8 86. 9 80 83. 6 74. 6 60 HIV-1 RNA < 50 copies/m. L 40 MVC + ATV/RTV (n = 59) TDF/FTC + ATV/RTV (n = 61) 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Wk Portsmouth S, et al. IAS 2011. Abstract TUAB 0103.

3 rd Generation Future HAART: 2012 + ew strategies: NRTI-Sparing “ 2 -Drug” INSTI-PI/r regime ACTG A 5262: DRV/r + RAL in Tx-Naïve: Faster failure at higher VL Taiwo B. CROI IAS 2011. Abstract 551

3 rd Generation Future HAART: 2012 + New Classes: BMS-663068: Oral Attachment Inhibitor Median Maximum Change in HIV-1 RNA From Baseline With Monotherapy in HIV-infected Patients Median Change in HIV-1 RNA From Baseline (log 10 copies/m. L) 600 mg q 12 h + 100 mg RTV q 12 h (n = 9) 1200 mg QHS + 100 mg RTV QHS (n = 9) 1200 mg q 12 h + 100 mg RTV q 12 h (n = 10) 0 1200 mg q 12 h + 100 mg RTV QAM (n = 10) 1200 mg q 12 h (n = 10) Overall (N = 48) -0. 5 -1. 0 -1. 22 -1. 5 -1. 64 -2. 0 -1. 59 -1. 78 -1. 63 -1. 64 -2. 5 Envelope polymorphisms may reduce baseline susceptibility Nettles R, et al. CROI 2011. Abstract 49.

3 rd Generation Future HAART: 2012 + New Classes: Ibalizumab: IV Entry Inhibitor Ibalizumab + OBR in Treatment-Experienced Patients § § Monoclonal antibody to non-HIV binding epitope of CD 4 Blocks HIV-1 entry into cell IV infusion gp 41 Ibalizumab gp 120 V 3 loop CD 4 100 HIV-1 RNA <50 (%) § 800 mg q 2 w 2000 mg q 4 w 80 60 < 400 c/m. L 40 < 50 c/m. L 20 0 0 Khanlou H, et al. ICAAC 2011. Abstract H 2 -794 b. 4 8 12 Wk 16 20 24

3 rd Generation Future HAART: 2012 + New Classes: Zinc Finger Nuclease (ZFN) Disruption of CCR 5 Gene in Autologous CD 4+ Cells ZFP ∆32 mutation Fokl DNA Fokl CCR 5 ZFN modification Site 165 ZFP Mechanism: § T: ZFN cleavage results in doublestranded DNA break with nonhomologous end repair leading to permanent CCR 5 gene modification § Treated CD 4+ cells anticipated to be resistant to HIV infection Early HIV-infected patient studies : § Engraftment with rapid clonal expansion and persistence of ZFN-modified cells in circulation and rectal mucosa § Median ~100 cells/mm 3 increase in CD 4+ count after 1 year § Most AEs mild; no SAEs by median 337 d Mitsuyasu R. ICAAC 2011. Abstract H 1 -375; Lalezari J. CROI 2011. Abstract 46.

3 rd Generation Future HAART: 2012 + New Classes: Investigational Targets § LEDGF/p 75 Inhibitors § § Cellular tethering factor for integration In-vitro identification of inhibitory peptides § Gag Inhibitors § § Viral factor for particle assembly at cell membrane In-vitro identification of inhibitory molecules § CXCR 4 Zinc Finger Nucleases § Cell culture-mouse model proof of concept tested § Capsid Assembly Inhibitors § § Formation of viral core In-vitro identification of inhibitory molecules Desimmie CROI 2011 #526; Urano CROI 2011 #525; Wilen CROI 2011 #47; Titolo CROI 2010 #50.

3 rd Generation Future HAART: 2012 + Future Needs: Potential for HIV Vaccine § Concept proven: Thai RV 144 study: 31% protection § Human studies on-going to determine correlates of immunity from elite controllers: § Broadly reacting neutralizing antibodies § Specific neutralizing envelope epitopes § Precise B-cell clonal expansion § Animal studies on-going to elucidate immune response Comments, A. Fauci, NIH, 2011

3 rd Generation Future HAART: 2012 + uture Needs: Functional Cure -vs- Microbial Eradicatio Early Treatment: Novel Therapies: § Smaller latent reservoir §Therapies to eliminate latent reservoir § Subsequent therapeutic vaccination boosting of immune control §Gene therapy to inactivate or excise incorporated virus Comments, A. Fauci, NIH, 2011

Challenges Facing the Global AIDS Pandemic: 2012 Efforts + Expanded Prevention Uganda mobile male circumcision clinic

Challenges Facing the Global AIDS Pandemic: 2012 Approach + Multi-Pronged Prevention Efficacy of HIV Prevention Strategies From Randomized Clinical Trials Study Effect Size, % (95% CI) ART for prevention; HPTN 052, Africa, Asia, Americas Pr. EP for discordant couples; Partners Pr. EP, Uganda, Kenya Pr. EP for heterosexual men and women; TDF 2, Botswana Medical male circumcision; Orange Farm, Rakai, Kisumu Pr. EP for MSMs; i. Pr. EX, Americas, Thailand, South Africa Sexually transmitted diseases treatment; Mwanza, Tanzania Microbicide; CAPRISA 004, South Africa HIV vaccine; RV 144, Thailand 0 20 96 (73 -99) 73 (49 -85) 63 (21 -84) 54 (38 -66) 44 (15 -63) 42 (21 -58) 39 (6 -60) 31 (1 -51) 40 60 Efficacy (%) Abdool Karim SS, et al. Lancet. 2011; [Epub ahead of print]. 80 100

Challenges Facing the Global AIDS Pandemic: 2012 + Gender Inequality

Challenges Facing the Global AIDS Pandemic: + Maternal Child 2012 Health

Challenges Facing the Global AIDS + Vulnerability Comprehensive Pandemic: Reduction Of 2012 Women’s http: //www. unaids. org/en/media/unaids/contentassets/documents/unaidspublication/20110607_JC 2069_30 Outlook_en. pdf

Challenges Facing the Global AIDS Pandemic: 2012 + Stigma and Discrimination http: //www. unaids. org/en/media/unaids/contentassets/documents/unaidspublication/20110607_JC 2069_30 Outlook_en. pdf

Challenges Facing the Global AIDS + To HIV Services Country Policies Pandemic: That Impede 2012 Access http: //www. unaids. org/en/media/unaids/contentassets/documents/ unaidspublication/20110607_JC 2069_30 Outlook_en. pdf

Challenges Facing the Global AIDS Pandemic: 2012 + Health Infrastructure

Challenges Facing the Global AIDS Pandemic: 2012 + External Factors: § Competing health problems § Global financial downturn § Donor fatigue and shifting priorities De Cock; Jaffe; Curran. Emerging Infectious Diseases. 2011; 17(6) (CDC)

Challenges Facing the Global AIDS Pandemic: 2012 + Care Patient Engagement in HIV Not in HIV Care Engaged in HIV Care Unaware of HIV infection Aware of HIV infection not in care Receiving medical care not HIV care Entered HIV care but lost to follow-up Intermittent user of HIV care Fully engaged in HIV care • Source of infection spread • Increased testing • Risk of infection spread • “Test and Treat” • Risk of disease progression • Outreach to medical providers • Risk of disease progression • Outreach to patients • Risk of ARV resistance • Outreach to patients • Potential eventual epidemic containment Adapted from Gardner Clin Inf Dis 2011; 52: 181

The Eras of the HIV Epidemic 19301980 1981 -1986 1987 -1995 1996 - 2005 2011 2012+