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HIV History and Future - Kathleen Squires MD

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HIV History and Future - Kathleen Squires MD

  1. 1. HIV at 30: History and Future Kathleen E. Squires, M.D. Professor of Medicine Director, Division of Infectious Diseases Thomas Jefferson University and Hospital Presented at the 41st Annual Symposium “Global Movement of Infectious Pathogens and Improved Laboratory Detection” Eastern PA Branch-American Society for Microbiology November 17, 2011 Thomas Jefferson University, Philadelphia
  2. 2. HIV/AIDS: The Beginning
  3. 3. Initial Cases • Young previously healthy males • Presenting with rarely encountered conditions – Pneumocystis carinii pneumonia – Kaposi‟s sarcoma • Rapidly progressive disease and death • Common risk factor-MSM
  4. 4. Global Summary: People Living With HIV 47% of Cases are Women Western Eastern Europe Europe & Central Asia 850,000 1,500,000 North America 1,400,000 East Asia North Africa & Pacific Caribbean & Middle East 850,000 240,000 310,000 South & South East Asia Sub-Saharan 3,800,000 Latin America Africa 2,000,000 22,400,000 Australia & New Zealand 59,000 6% of Cases are Children Most via Mother-to-Child Transmission UNAIDS 2010.
  5. 5. CDC Revises Estimation of New Cases of HIV Infection  Methodology  New non-AIDS HIV cases from 22 states  Use of BED assay to identify recent infections  Stratified extrapolation approach confirmed with back calculation  Revised estimate 2006  56,300 (95% CI: 48,200 - 64,500) Risk Groups MSM Racial 80000 IDU MSM/IDU 70000 Distribution 60000 Heterosexual Hispanic Infections 50000 17% White 40000 35% 30000 20000 Black 10000 45% 0 1977- 1980- 1982- 1984- 1986- 1988- 1991- 1994- 1997- 2000- 2003- 1979 1981 1983 1985 1987 1990 1993 1996 1999 2002 2006 Period Hall HI, et al. JAMA 2008;300:520-529.
  6. 6. A simplified lineage scheme of retroviruses. This phylogenetic tree is not intended to quantitatively represent evolutionary distances between viruses but to illustrate the relative relatedness between these infectious agents. As can be seen, there is a greater sequence homology between HIV-1 and SIVcpz, and between HIV-2 and SIVsm/mac, than there is between the two human pathogens HIV-1 and HIV-2. Also of note in this phylogenetic tree is the obvious parallel between infection of human and non-human primates. For each class of human pathogen represented, there is a closely related simian retrovirus.
  7. 7. Origin of HIV: Lentivirus Family Tebit, DN, Arts, EJ et al. The Lancet 2011:11;46-48
  8. 8. Worldwide Spread of HIV-1 Tebit, DN, Arts, EJ et al. The Lancet 2011:11;46-48
  9. 9. Exposure to HIV at Day 0 mucosal surface (sex) Virus collected by Day 0-2 dendritic cells, carried to lymph node HIV replicates in Day 4-11 CD4 cells, released into blood Day 11 on Virus spreads to other organs Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.
  10. 10. The Pathogenesis of HIV-1 Infection: Compartments Colon, Duodenum and Brain Macrophages Rectum Chromaffin Cells and Glial Cells Lymphocytes in Blood, Lymph Nodes Semen and Vaginal Fluid Thymus Gland Bone Marrow Lung Alveolar Skin Langerhans‟ Cells Macrophages
  11. 11. Gut is area of massive T cell loss
  12. 12. Natural History of Untreated HIV-1 Infection CD4 Cell Count 1000 800 600 CD4 + Early Opportunistic Infections Cells Late Opportunistic Infections 400 200 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Infection Time in Years
  13. 13. HIV Replication Cycle and Sites of Drug Activity NRTIs NNRTIs Integrase Inhibitors Fusion Inhibitors Protease Inhibitors Nucleus Cellular DNA HIV Virions New HIV particles Reverse Integrase Protease Transcriptase Capsid CD4 proteins Receptor and viral RNA Viral RNA Unintegrated double stranded Viral DNA Integrated Viral gag-pol CCR5 or viral DNA mRNA polyprotein CXCR4 co-receptor 1 2 3 4 5 6 Attachment Uncoating Reverse Integration Transcription Translation Assembly and Fusion Transcription And Release Adapted:Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:9-11
  14. 14. FDA-Approved Drugs for HIV Therapy: 2011 NRTIs PIs Abacavir (ABC) Amprenavir (APV) Didanosine (ddI) Atazanavir (ATV) Emtricitabine (FTC) Darunavir (DRV) Lamivudine (3TC) Fosamprenavir (FPV) Stavudine (d4T) Indinavir (IDV) Tenofovir (TDF) Lopinavir/ritonavir (LPV/RTV) Zalcitabine (ddC) Nelfinavir (NFV) Zidovudine (ZDV) Ritonavir (RTV) 3TC/ABC Saquinavir (SQV hgc) 3TC/ABC/ZDV Tipranavir (TPV) 3TC/ZDV FTC/TDF Fusion Inhibitors (FIs) Enfuvirtide (ENF) NNRTIs Delavirdine (DLV) Efavirenz (EFV) Nevirapine (NVP) Rilpivirine (RLP)
  15. 15. FDA-Approved Drugs for HIV Therapy: 2011 CCR5 Inhibitors Integrase Inhibitors Maraviroc (MRV) Raltegravir (RAL) Multiple Class EFV/FTC/TDF RLP/FTC/TDF
  16. 16. When to Begin HIV Treatment DHHS Guidelines < 12/1/2009 HIV Infection Asymptomatic History of AIDS- CD4+ T cells/mm3 defining illness or severe symptoms >350 Nov 2008 <350 Treat Treat Consider Treatment RISKS BENEFITS DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents; Available at: http://aidsinfo.nih.gov.
  17. 17. When to Begin Treatment DHHS Guidelines >12/1/09 HIV Infection h/o AIDS-defining Asymptomatic illness , severe sx, CD4+ T cells/mm3 pregnancy, HepB, HIVAN >500 Dec 1, 2009 <500 Treat Treat Acute OIs Consider Treatment 50% of 50% of panel panel say say optional treat DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents; Available at: http://aidsinfo.nih.gov.
  18. 18. What Antiretroviral Agents To Start DHHS guidelines 2011 Preferred regimens Efavirenz + tenofovir + emtricitabine (Atripla®) Raltegravir + tenofovir + emtricitabine Ritonavir-atazanavir + tenofovir + emtricitabine Ritonavir-darunavir + tenofovir + emtricitabine Alternative regimens: NNRTIs (NVP or EFV) or other PIs (FPV/r, LPV/r, SQV/r) PLUS ABC/3TC* or AZT/3TC or TFV/FTC Acceptable or may be acceptable regimens: EFV+ ddI + (3TC or FTC); Unboosted ATV with (ABC or AZT)/3TC; Maraviroc + AZT/3TC or Raltegravir + (ABC or AZT)/3TC or (DRV/r or SQV/r) + (ABC or AZT)/3TC *Other major combination NRTI agent of ABC/3TC demoted to alternative Dec „09
  19. 19. Improving Outcomes With Evolving Antiretroviral Regimens 400 CD4+ RNA CD4+ RNA Change in CD4+ Cell Count From Baseline Monotherapy Monotherapy Change in HIV-1 RNA From Baseline 300 Dual-NRTI combinations Dual-NRTI combinations HAART HAART 200 (log10 copies/mL) (cells/mm3) 100 0 0 –1 –2 –3 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 02 04 06 08 10 12 Years Slide courtesy of C. J. Cohen, MD.
  20. 20. Improving Outcomes With Evolving Antiretroviral Regimens 400 CD4+ RNA CD4+ RNA Change in CD4+ Cell Count From Baseline Monotherapy Monotherapy Change in HIV-1 RNA From Baseline 300 Dual-NRTI combinations HAART 200 (log10 copies/mL) (cells/mm3) 100 0 0 –1 –2 –3 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 Years Slide courtesy of C. J. Cohen, MD.
  21. 21. Improving Outcomes With Evolving Antiretroviral Regimens 400 CD4+ RNA CD4+ RNA Change in CD4+ Cell Count From Baseline Monotherapy Monotherapy Change in HIV-1 RNA From Baseline 300 Dual-NRTI combinations Dual-NRTI combinations HAART 200 (log10 copies/mL) (cells/mm3) 100 0 0 –1 –2 –3 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 Years Slide courtesy of C. J. Cohen, MD.
  22. 22. Improving Outcomes With Evolving Antiretroviral Regimens 400 CD4+ RNA CD4+ RNA Change in CD4+ Cell Count From Baseline Monotherapy Monotherapy Change in HIV-1 RNA From Baseline 300 Dual-NRTI combinations Dual-NRTI combinations HAART HAART 200 (log10 copies/mL) (cells/mm3) 100 0 0 –1 –2 –3 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 02 04 06 08 10 12 Years Slide courtesy of C. J. Cohen, MD.
  23. 23. Role of Assays in HIV Management • HIV resistance assays – Genotype – Phenotype – Virtual Phenotype • Tropism assays – Trophile – Genotype
  24. 24. HIV: The Future • Chronic Infection – High rates of virologic suppression in patients on therapy – ? Nearly normal life span • Persistent elevated levels of inflammatory markers • Higher risk of specific co-morbidities – Cardiac disease, hepatitis B &C/cirrhosis/hepatocellular carcinoma, non-AIDS associated neoplasm • Is there a cure? – NIAID RFA • 5 funded program project grants
  25. 25. US HIV Epidemic—For Context ~1,100,000 ~42-59% chronically ~21% ~56,000 New People Living People with People with HIV Who Infections, 2006 with HIV/AIDS HIV/AIDS Don't Know Not In Care They Are Infected NOTE: Data are estimates. SOURCE: Hall HI, et al., "Estimation of HIV Incidence in the United States". JAMA, Vol. 300, No. 5, August 2008; CDC, MMWR, Vol. 57, No. 39, 2008; Fleming P, et al., "HIV Prevalence in the United States 2000", 9th Conference on Retroviruses and Opportunistic Infections, 2002. Slide 26
  26. 26. National HIV/AIDS Strategy http://www.whitehouse.gov/sites/default/files/microsites/ONAP_rpt.pdf Slide 27
  27. 27. HIV Prevention • Vaccine-the Holy Grail • Circumcision • Pre-exposure prophylaxis • Treatment as prevention • Bio-medical prevention • Can we treat our way out of this epidemic? • Community viral load
  28. 28. Efficacy of HIV Prevention Strategies From Randomized Clinical Trials Study Effect Size, % (95% CI) ART for prevention; HPTN 052, Africa, 96 (73-99) Asia, Americas PrEP for discordant couples; 73 (49-85) Partners PrEP, Uganda, Kenya PrEP for heterosexual men and women; TDF2, Botswana 63 (21-84) Medical male circumcision; 54 (38-66) Orange Farm, Rakai, Kisumu PrEP for MSMs; iPrEX, Americas, 44 (15-63) Thailand, South Africa Sexually transmitted diseases 42 (21-58) treatment; Mwanza, Tanzania Microbicide; 39 (6-60) CAPRISA 004, South Africa HIV vaccine; 31 (1-51) RV144, Thailand 0 20 40 60 80 100 Efficacy (%) Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].
  29. 29. Current CDC Guidance on PrEP http://www.cdc.gov/nchhstp/newsroom/PrEPMSMGuidanceGraphic.html
  30. 30. HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples Immediate ART HIV-infected, sexually active Initiate ART at CD4+ cell count 350-550 cells/mm3 serodiscordant (n = 886 couples) couples; CD4+ cell count of the infected partner: 350-550 cells/mm3 Delayed ART Initiate ART at CD4+ cell count ≤ 250 cells/mm3* (N = 1763 couples) (n = 877 couples) *Based on 2 consecutive values ≤ 250 cells/mm3. • Primary efficacy endpoint: virologically linked HIV transmission • Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death • Couples received intensive counseling on risk reduction and use of condoms DSMB recommended release of results as soon as possible following April 28, 2011, review; follow-up continues but all HIV-infected partners offered ART after release of results Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
  31. 31. HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P < .0001) Linked Transmissions: Unlinked or TBD 28 Transmissions: 11 Single transmission in patient in Delayed Arm: Immediate immediate ART arm believed 27 Arm: 1 to have occurred close to time therapy began and prior to HIV-1 RNA P < .001 suppression Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
  32. 32. HPTN 052: Multivariate Analysis of Factors Associated With Linked Transmissions Variable HR 95% CI Treatment, immediate vs delayed 0.04 0.01-0.28 Baseline CD4+ count, per 100 cells/mm3 decrease 1.24 1.00-1.54 Baseline HIV-1 RNA, per 1 log10 copies/mL increase 2.85 1.51-5.41 Baseline condom use, 100% vs < 100% 0.33 0.12-0.91 Sex of infected partner, male vs female 0.73 0.33-1.65  61% of transmissions occurred from infected patient with CD4+ cell count > 350 cells/mm3  All transmissions occurred prior to starting ART  82% of transmissions occurred in African patients Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
  33. 33. HPTN 052: Primary Clinical Events During Follow-up • 41% reduction in HIV-related clinical events in HIV-infected patients randomized to immediate vs delayed therapy – Excess events in delayed arm driven mainly by TB (33 vs 17 cases), particularly extrapulmonary TB (17 vs 3 cases) HR: 0.6 (95% CI: 0.4-0.9; P = .01) 0.25 Delayed (n = 65) Failure Probability 0.20 0.15 Immediate (n = 40) 0.10 0.05 0 877 701 317 86 32 25 Number at risk 886 700 333 85 36 29 0 1 2 3 4 5 Yrs Since Randomization Grinsztejn B, et al. IAS 2011. Abstract MOAX0105. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].
  34. 34. HIV: The Future • Can incidence be decreased? – Routine HIV testing • CDC 2006 guidance-every person 13-64 should be tested at least once and undergo repeat testing based on ongoing risk factors • Emphasis on point-of-care testing – Aligned with National AIDS Strategy to identify HIV-positive individuals and facilitate entry to care – Rapid HIV testing, STI test and treat, ? CD4 cell counts and HIV viral load • Use of 4th generation Ag/Ab tests to identify individuals with acute infection
  35. 35. HIV: The Future • Can incidence be decreased? – Access to and retention in care • Treatment for personal health • Treatment as prevention (HPTN 052) • Tension between “mainstreaming” HIV care and evidence that HIV expert care improves outcomes
  36. 36. HIV at 50 • Point of care HIV testing – as routine as RPR • ART for all diagnosed patients • Point of care CD4 and HIV VL – Primary care venues • ??? Functional cure • ??? Preventive vaccine

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