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Moving Forward: HIV Prevention and Treatment 2011

Moving Forward: HIV Prevention and Treatment 2011. Donna E. Sweet, MD, AAHIVS, MACP Professor of Medicine The University of Kansas School of Medicine - Wichita. 33 Million Living with HIV worldwide…. 2.6 Million new Cases of HIV worldwide…. 56,300 HIV/AIDS Cases Annually in US.

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Moving Forward: HIV Prevention and Treatment 2011

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  1. Moving Forward: HIV Prevention and Treatment 2011 Donna E. Sweet, MD, AAHIVS, MACP Professor of Medicine The University of Kansas School of Medicine - Wichita

  2. 33 Million Living with HIV worldwide… 2.6 Million new Cases of HIV worldwide… 56,300 HIV/AIDS Cases Annually in US

  3. Health Resources and Services Administration (HRSA) continuum of HIV care, describing the spectrum of engagement in HIV care. Gardner E M et al. Clin Infect Dis. 2011;52:793-800 © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  4. The spectrum of engagement in HIV care in the United States spanning from HIV acquisition to full engagement in care, receipt of antiretroviral therapy, and achievement of complete viral suppression. Gardner E M et al. Clin Infect Dis. 2011;52:793-800 © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. Six simple simulations (a–f) assessing different levels of engagement in care. Gardner E M et al. Clin Infect Dis. 2011;52:793-800 © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Percentage of Patients in Each Study Group According to CD4 Cell Count 24 Months After Initiating HAART

  7. Recent Developments in HIV Clinical Care • Antiretroviral treatment • New antiretroviral drugs • Biologic Prevention • Treatment as prevention

  8. Life Expectancy Increased • A 20-year-old HIV-positive person starting antiretroviral (ARV) therapy today can expect to live, on average, to the age of 69. • a life expectancy increase of 37 percent over projections for 20-year-olds starting ARVs during the early years of combination treatment.  • The average life expectancy for a 20-year-old who remains HIV negative, at least in industrialized nations, is an additional 60 years—with death occurring, on average, at the age of 80 Source:http://www.thelancet.com/journals/lancet/article/PIIS0140673608611137/abstract

  9. 2011 DHHS Guidelines: When to Start Adapted from the Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. US Dept of Health and Human Services; 2009. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed December 1, 2009.

  10. Recommendations of the IAS–USA Panel (Thompson MA, Aberg JA, Cahn P, et al. JAMA. 2010;304(3):321-333) In December 2010. http://jama.ama-assn.org/content/304/3/321.full.pdf

  11. Antiretroviral Regimens Recommended for Treatment-Naïve Patients • Regimens 2-4 are currently under study in an ACTG-sponsored, multicenter, randomized clinical trial DHHS Guidelines, January 10, 2011, www.aidsinfo.nih.gov

  12. Updated DHHS Guidelines No change in when to start criteria or preferred initial antiretroviral regimens Given HIV VL blips at low viral loads, the panel suggests a confirmed HIV VL > 200 copies/mL as a definition for virologic failure Panel suggests CD4 testing less frequently once CD4 counts are above the range for opportunistic infection risk (e.g. CD4 every 6-12 months) Consider integrase genotyping in ARV-naïve patients if transmitted resistance is a concern DHHS Guidelines, January 10, 2011, www.aidsinfo.nih.gov

  13. Recent Developments in HIV Clinical Care • Antiretroviral treatment • New antiretroviral drugs • Biologic Prevention • Treatment as prevention

  14. HIV Replication Cycle and Sites of Drug Activity Protease New HIV particles Capsid proteins and viral RNA CD4 Receptor Viral RNA Reverse Transcription Attachment Translation Uncoating Integration Transcription • NRTIs • NNRTIs • Integrase Inhibitors Attachment Inhibitors • Protease Inhibitors Cellular DNA Nucleus HIV Virions Reverse Transcriptase Integrase Entry Inhibitors Unintegrated double stranded Viral DNA gag-pol polyprotein Integrated viral DNA Viral mRNA CCR5 or CXCR4 co-receptor 1 3 4 5 2 6 Assembly and Release Adapted:Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:9-11 .

  15. 1987: zidovudine (Retrovir) 1991: didanosine (Videx) 1992: zalcitabine (Hivid) 1994: stavudine (Zerit) 1995: lamivudine (Epivir) saquinavir (Invirase) 1996: ritonavir (Norvir) indinavir (Crixivan) nevirapine (Viramune) 1997: nelfinavir (Viracept) delavirdine (Rescriptor) 1998: efavirenz (Sustiva) abacavir (Ziagen) 1999: amprenavir (Agenerase) 2000: lopinavir/ritonavir (Kaletra) 2001: tenofovir (Viread) 2003: enfuvirtide (Fuzeon) 6/03: atazanavir (Reyataz) 7/03: emtricitabine (Emtriva) *8/04: lamivudine/abacavir sulfate (Epzicom) emtricitabine/tenofovir disoproxilfumarate (Truvada) 6/05: tipranavir (Aptivus) 6/06 darunavir (Prezista) *7/06: efavirenz/emtricitabine, tenofovir DF (Atripla) 8/07 maraviroc (Selzentry) 10/07 raltegravir (Isentress) 1/08 etravirine (Intelence) 5/20/11 rilpivirine(Edurant) *8/11/11 rilpivirine/tenofovir/emtricitabine (Complera) Licensure of Antiretroviral Agents by Year *Fixed dose combinations of existing drugs

  16. New Fixed Dose Combination Approved Approved 8/11/11 rilpivirine/tenofovir/emtricitabine (Complera)

  17. THRIVE (TMC278-C215) RPV 25 mg QD + 2 NRTIs* (n=340) N=678 patients 1:1 EFV 600mg QD + 2 NRTIs* (n=338) *Investigator’s choice: TDF/FTC; AZT/3TC; ABC/3TC ECHO and THRIVE: Study Designs 48 weeks primary analysis 96 weeks final analysis ECHO (TMC278-C209) RPV 25 mg QD + TDF/FTC (n=346) 1:1 N=690 patients EFV 600 mg QD + TDF/FTC (n=344) • Primary endpoint: HIV VL < 50 at 48 wks (ITT-TLOVR) • Main inclusion criteria: VL ≥ 5000 copies/mL; no NNRTI/NRTI resistance Cohen C, et al. 6th IAS 2011;Abstract TULBPE032.

  18. Pooled ECHO and THRIVE: < 50 Copies/mL by Baseline Viral Load (Week 96, ITT-TLOVR) Other Reasons Discontinuations: Adverse Events/Death Virologic Failure Cohen C, et al. 6th IAS 2011;Abstract TULBPE032.

  19. Rilpivirine: Positive Attributes • Once a day dosing • Better tolerated than efavirenz, especially fewer CNS side effects. • No significant lipid effects • Pregnancy category B • Inclusion in a new single tablet regimen (the second “one pill once a day” option)

  20. Rilpivirine: Negative Attributes • It is less potent than efavirenz. It will likely be an alternative choice as opposed to supplanting efavirenz as the preferred initial NNRTI. • The pattern of virologic failure potentially removes etravirine as a future treatment option. • The need to take a high calorie meal may blunt some of its lipid advantages. • Reduced absorption with PPIs will be an issue in some patients.

  21. Rilpivirine: Who Might Get this Drug? • Anti-retroviral naïve • No baseline drug resistance • Baseline HIV RNA level < 100,000 copies/ml • At risk for efavirenz CNS side effects • Not on proton pump inhibitors • Women of child-bearing age • Adherent patients • Switch off efavirenz due to CNS side effects (?)

  22. Status of Selected Investigational Antiretroviral and Boosting Agents

  23. Recent Developments in HIV Clinical Care • Antiretroviral treatment • New antiretroviral drugs • Biologic Prevention • Treatment as prevention

  24. Sexual Transmission Efficiency in Different HIV Intervals Acute “Early” HIV patients responsible for 8-43% of HIV transmission in serodiscordant couples (Pinkerton, AIDS Behavior, 2008) Source: Galvin/Cohen, 2004

  25. http://ottostorto.it/articolo3.pdf

  26. EXPOSED UNEXPOSED EXPOSED (precoital/coital) (postcoital) Behavioral, Structural Vaccines ART PEP Vaccines ART PrEP Microbicides Circumcision Condoms YEARS HOURS 72h Four Prevention Opportunities INFECTED Treatment Of HIVReduced Infectivity YEARS Cohen et al, JCI, 2008 Cohen IAS 2008

  27. The Problem With Condoms…No One Uses Them! Great Britain’s new “Viagra” Condom CSD500 Lined with a vasodilating gel, which increases blood flow to the penis and helps maintain erection. New Idea!

  28. Slide 29 December 13, 2006 Circumcision Halves H.I.V. Risk, U.S. Agency Finds Circumcision appears to reduce a man’s risk of contracting AIDSfrom heterosexual sex by half, United States government health officials said yesterday, and the directors of the two largest funds for fighting the disease said they would consider paying for circumcisions in high-risk countries.

  29. Circumcision Effects The impact of male circumcision on female partners was presumed to be beneficial… • New findings in a randomized trial of discordant couples in the Rakai district of Uganda: • Did not provide protection for female partners • May increase the risk of transmission if the couple resumed sex before the circumcision wound was healed During 2 years of follow-up, the annual incidence rate of HIV in wives of circumcised HIV+ men was 14.4 per 100 person-years vs 9.1 per 100 person years among women whose husbands remained uncircumcised!

  30. 15 Overall 58 ( 66, 48) Impact of MC on HIV: Evidence from Observational Studies and RCTs Reduction of risk (95% CI) Weiss et al. AIDS 2000, 14:2361-70 7 1 Auvert et al. PLoS Med 2005(11): e298.2006 South Africa (RCT) 60 ( 76, 33) 1 Bailey et al. Lancet 2007; 369: 643–56 59 ( 76, 30) Kenya (RCT) 1 Gray et al. Lancet, 2007, 657–66 51 ( 82, 14) Uganda (RCT) 60 85 80 70 .50 1 Reduction of risk (0%)

  31. Slide #32 Topical ART for HIV-1 Prevention Klasse et al Annu Rev Med 2008 Current Microbicide Candidates (listed in latest stage of development) Tenofovir Gel Reservoir and Matrix Vaginal Rings www.microbicide.org, July 2008

  32. CAPRISA OO4 Study: Tenofovir Gel Reduction in HIV Infections • Randomized, placebo-controlled trial of tenofovir 1% vaginal gel self-administered before sex or within 12 hours after sex • Incidence of new HIV significantly reduced compared to placebo and gel well tolerated Abdool K, et al. Science DOI: 10.1126/science.1193748.

  33. HIV Incidence in CAPRISA 004 No K65R resistance mutations among seroconverters

  34. HIV infection rates in the tenofovir and placebo gel groups: Kaplan-Meier survival probability Slide #35 p=0.017 (0.017) From M Cohen, MD, at New York, NY: April 5, 2011, IAS–USA.

  35. Strategies for an HIV Vaccine Vaccine Success Transmission Cell-Mediated Immunity protection against HIV sterilizing immunity! protection against disease A reduced HV peak and “set point” no protection HIV Infection and RNA set point initial infection “controlled” chronic infection with low set point Infection prevented

  36. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand • Healthy men and women ages 18-30 years • Double-blind, placebo controlled efficacy study • Prime boost vaccine strategy: • Vaccine #1: ALVAC-HIV weeks 0, 4, 12, 24 • Vaccine #2: AIDSVAX B/E weeks 12 and 24 • HIV testing day 0, weeks 24/26, and q 6 months for 3 years N Engl J Med 2009;361. October 20, 2009.

  37. Thai Vaccine Trial Results • Marginal protective efficacy • Intention to treat: 26.4% (p = 0.08) • Per protocol: 26.2% (p = 0.16) • Modified ITT: 31.2% (p = 0.04) • No impact on post seroconversion viral load • Effects may wane after one year • May be most effective in individuals at low risk • May provide a “signal” to tease out immunogenic markers of protection N Engl J Med 2009;361. October 20, 2009.

  38. Recent Developments in HIV Clinical Care • Antiretroviral treatment • New antiretroviral drugs • Biologic Prevention • Treatment as prevention

  39. Risk of HIV Infection following Occupational Transmission Through December 2001: 57 documented cases of occupational HIV transmission to health care workers in the United States. Only 1 reported case has been confirmed since 2001 Source: CDC HIV Surveillance Report, 2008, vol. 20

  40. Perinatal HIV infection has diminished to <2% in the United States and Europe This is due to the following: • Universal prenatal HIV counseling and testing • ART prophylaxis • Scheduled cesarean section delivery • Avoidance of breastfeeding www.aidsetc.org

  41. ARVs: Mechanisms of Action • ARVs reduce perinatal transmission by several mechanisms: • Decreasing maternal antepartum viral load • Pre- and post-exposure infant prophylaxis • Combined antepartum, intrapartum, and infant ARV prophylaxis is recommended (AI) www.aidsetc.org

  42. Transmission and Maternal HIV RNA • Risk of perinatal transmission greater with higher maternal HIV RNA viral load (VL) • However, perinatal transmission can occur at any maternal VL, even when maternal VL is undetectable • Plasma VL may not accurately predict transmission risk • Discuss with and provide ARV drugs to prevent perinatal transmission to all HIV-infected pregnant women regardless of VL (AI) www.aidsetc.org

  43. ART to Prevent Sexual Transmission of HIV • Post-exposure prophylaxis (nPEP) • Pre-exposure prophylaxis (PrEP) • Treatment of the infected person

  44. nPEP US Guidelines • A clinical trial to PROVE that nPEP works cannot be developed, but animals are protected • With the availability of ART, nPEP usage became very common…and erratic with failures • A CDC Advisory Committee helped generate guidelines MMWR Jan 21, 2005 Vol 54: 1-20 “Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States”

  45. Recommendations for Use of ARVs for nPEP AETC National Resource Center, www.aidsetc.org

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