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The Eras of the HIV Epidemic

The Eras of the HIV Epidemic. 1930-1980. 1996-2005. 2006-2011. 2012+ 3 rd Gen. HAART. 1987-1995. 1981-1986. 3 rd Generation Future HAART: 2012 +. THE FUTURE OF ANTIRETROVIRAL THERAPY. New drugs INSTI: Elvitegravir , Dolutegravir NNRTI: Lersivirine NRTI: GS-7340 (TDF- prodrug )

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The Eras of the HIV Epidemic

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  1. The Eras of the HIV Epidemic 1930-1980 1996-2005 2006-2011 2012+ 3rd Gen. HAART 1987-1995 1981-1986

  2. 3rd Generation Future HAART: 2012 + THE FUTURE OF ANTIRETROVIRAL THERAPY • New drugs • INSTI: Elvitegravir, Dolutegravir • NNRTI: Lersivirine • NRTI: GS-7340 (TDF-prodrug) • New combinations • INSTI-NRTI: TDF-FTC-EVG-Cobi • PI/cobi: DRV-Cobicistat booster • PI/c-NRTI: DRV-Cobi-TDFpro-FTC • New strategies • New classes • Future needs

  3. 3rd Generation Future HAART: 2012 + EVR Non-Inferior to RAL at Week 48 New Drugs: INSTI Elvitegravir: once daily therapy *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 WELBB05.

  4. 3rd Generation Future HAART: 2012 + VIKING: Dolutegravir “Functional Monotherapy” in Pts With RAL Resistance New Drugs: INSTI Dolutegravir: active against resistance 100 100 96 Dolutegravir 50 mg QD (n = 27) 92 100 78 80 Dolutegravir 50 mg BID (n = 24) 60 Primary Endpoint* (%) 33 40 20 0 All Patients Q148 + ≥ 1Other Mutationat Baseline OtherMutations *HIV-1 RNA < 400 copies/mL or ≥ 0.7 log10 copies/mL reduction from baseline at Day 11. Eron J. CROI 2011, Abstract 151LB.

  5. 3rd Generation Future HAART: 2012 + Lersivirine vs Efavirenz with TDF/FTC in ART-Naive Pts New Drugs: NNRTI Lersivirine: once daily without psych or CNS LRV 500 mg LRV 750 mg EFV 600 mg 100 54/63 (86%) 100 80 88 86 82 80 51/65 (79%) 80 75 51/65 (79%) 60 62 HIV-1 RNA < 50 copies/mL Through Wk 48 (%) 60 HIV-1RNA < 50 copies/mL Through Wk 48 (%) 40 40 LRV 500 mg LRV 750 mg EFV 600 mg 20 20 0 0 45 44 41 20 21 22 n = 0 2 4 8 16 24 32 40 48 VL < 100,000 VL ≥ 100,000 Vernazza P, et al. IAS 2011. Abstract TUAB0101.

  6. 3rd Generation Future HAART: 2012 + New Drugs: GS-7340 TDF Prodrug • 14-day monotherapy in HIV+ patients: • 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) Change in VL From Baseline (log10 c/mL) -1 -1.5 -2 21 35 28 0 14 7 Day Markowitz M, et al. CROI 2011. Abstract 152LB. Graphic used with permission.

  7. 3rd Generation Future HAART: 2012 + New Combinations: 3rd STR: The “Quad”: TDF-FTC-EVR-Cobi TDF-FTC-EVR/Cobi -vs- TDF-FTC-EFVWeek 48 results in Tx-Naïve Patients Cohen AIDS 2011; 25:F7-12

  8. 3rd 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

  9. MVC vs TDF/FTC With ATV/RTV in ART-Naive Patients 3rd Generation Future HAART: 2012 + New strategies: NRTI-Sparing “2-Drug” CCR5-PI/r regimen HIV-1 RNA < 400 copies/mL 89.8 86.9 100 80 83.6 74.6 60 HIV-1 RNA < 50 copies/mL Patients (%) 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 TUAB0103.

  10. 3rd Generation Future HAART: 2012 + New strategies: NRTI-Sparing “2-Drug” INSTI-PI/r regimen ACTG A5262: DRV/r + RAL in Tx-Naïve: Faster failure at higher VL Taiwo B. CROI IAS 2011. Abstract 551

  11. 3rd Generation Future HAART: 2012 + New Classes: BMS-663068: Oral Attachment Inhibitor Envelope polymorphisms may reduce baseline susceptibility Median Maximum Change in HIV-1 RNA From Baseline With Monotherapy in HIV-infected Patients 600 mgq12h +100 mgRTV q12h (n = 9) 1200 mgQHS +100 mgRTV QHS(n = 9) 1200 mg q12h +100 mgRTV q12h (n = 10) 1200 mg q12h +100 mgRTV QAM(n = 10) 1200 mg q12h (n = 10) Overall(N = 48) 0 -0.5 -1.0 Median Change in HIV-1 RNA From Baseline (log10 copies/mL) -1.22 -1.5 -1.59 -1.64 -1.63 -1.64 -1.78 -2.0 -2.5 Nettles R, et al. CROI 2011. Abstract 49.

  12. 3rd Generation Future HAART: 2012 + Ibalizumab + OBR in Treatment-Experienced Patients New Classes: Ibalizumab: IV Entry Inhibitor • Monoclonal antibody to non-HIV binding epitope of CD4 • Blocks HIV-1 entry into cell • IV infusion gp41 Ibalizumab gp120 100 V3 loop 800 mg q2w2000 mg q4w 80 CD4 60 < 400 c/mL HIV-1 RNA <50 (%) 40 < 50 c/mL 20 0 0 4 8 12 16 20 24 Khanlou H, et al. ICAAC 2011. Abstract H2-794b. Wk

  13. 3rd Generation Future HAART: 2012 + New Classes: Zinc Finger Nuclease (ZFN) Disruption of CCR5 Gene in Autologous CD4+ Cells Mechanism: • T: ZFN cleavage results in double-stranded DNA break with nonhomologous end repair leading to permanent CCR5 gene modification • Treated CD4+ cells anticipated to be resistant to HIV infection ZFP ∆32 mutation Fokl DNA Fokl CCR5ZFN modificationSite 165 ZFP • Early HIV-infected patient studies : • Engraftment with rapid clonal expansion and persistence of ZFN-modified cells in circulation and rectal mucosa • Median ~100 cells/mm3 increase in CD4+ count after 1 year • Most AEs mild; no SAEs by median 337 d Mitsuyasu R. ICAAC 2011. Abstract H1-375; Lalezari J. CROI 2011. Abstract 46.

  14. 3rd Generation Future HAART: 2012 + New Classes: Investigational Targets • LEDGF/p75 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 • CXCR4 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.

  15. 3rd Generation Future HAART: 2012 + Future Needs: Potential for HIV Vaccine • Concept proven: Thai RV144 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

  16. 3rd Generation Future HAART: 2012 + Future Needs: Functional Cure -vs- Microbial Eradication Early Treatment: • Smaller latent reservoir • Subsequent therapeutic vaccination boosting of immune control Novel Therapies: • Therapies to eliminate latent reservoir • Gene therapy to inactivate or excise incorporated virus Comments, A. Fauci, NIH, 2011

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

  18. Challenges Facing the Global AIDS Pandemic: 2012 + Efficacy of HIV Prevention Strategies From Randomized Clinical Trials Multi-Pronged Prevention Approach Study Effect Size, % (95% CI) ART for prevention; HPTN 052, Africa, Asia, Americas 96 (73-99) PrEP for discordant couples;Partners PrEP, Uganda, Kenya 73 (49-85) PrEP for heterosexual men and women; TDF2, Botswana 63 (21-84) Medical male circumcision; Orange Farm, Rakai, Kisumu 54 (38-66) PrEP for MSMs; iPrEX, Americas, Thailand, South Africa 44 (15-63) Sexually transmitted diseases treatment; Mwanza, Tanzania 42 (21-58) Microbicide;CAPRISA 004, South Africa 39 (6-60) HIV vaccine;RV144, Thailand 31 (1-51) 0 20 40 60 80 100 Efficacy (%) Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].

  19. Challenges Facing the Global AIDS Pandemic: 2012 + Gender Inequality

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

  21. Challenges Facing the Global AIDS Pandemic: 2012 + Comprehensive Reduction Of Women’s Vulnerability http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/20110607_JC2069_30Outlook_en.pdf

  22. Challenges Facing the Global AIDS Pandemic: 2012 + Stigma and Discrimination http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/20110607_JC2069_30Outlook_en.pdf

  23. Challenges Facing the Global AIDS Pandemic: 2012 + Country Policies That Impede Access To HIV Services http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2011/20110607_JC2069_30Outlook_en.pdf

  24. Challenges Facing the Global AIDS Pandemic: 2012 + Health Infrastructure

  25. 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)

  26. Challenges Facing the Global AIDS Pandemic: 2012 + Patient Engagement in HIV Care Not in HIV Care Engaged in HIV Care • Unawareof HIVinfection • Source of infectionspread • Increasedtesting • Aware of HIVinfection • not in care • Risk of infectionspread • “Test andTreat” • Receivingmedical carenot HIV care • Risk of diseaseprogression • Outreach to medicalproviders • Entered HIVcare but lost • to follow-up • Risk of diseaseprogression • Outreach to patients • Intermittentuser ofHIV care • Risk of ARVresistance • Outreach to patients • Fullyengaged • in HIV care • Potentialeventualepidemiccontainment Adapted from Gardner Clin Inf Dis 2011;52:181

  27. The Eras of the HIV Epidemic 1930-1980 1996-2005 2006-2011 2012+ 1987-1995 1981-1986

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