The document discusses various forms of drug therapy for HIV prevention, including post-exposure prophylaxis (PEP) and pre-exposure prophylaxis (PrEP), highlighting their similarities, differences, and effectiveness. It also reviews recent disappointments in HIV prevention trials, ongoing research studies, and the potential of antiretroviral therapy as a preventative measure. Key studies mentioned include the West African PrEP study and the iPrEx trial, both assessing safety and efficacy in high-risk populations.

1. Drug Therapy For Prevention? J. Jeff McConnell, Sociologist GLADSTONE INSTITUTE OF VIROLOGY AND IMMUNOLOGY UNIVERSITY OF CALIFORNIA, SAN FRANCISCO September 30, 2008

2. An excellent resource available at http://www.avac.org/prep08.pdf

3. Overview HIV prevention recent disappointments Four forms of drug therapy as prevention Similarities and differences between PEP and PrEP The West African PrEP Study Iniciativa PrEx / PrEP Initiative PrEP Research Portfolio

4. Adults and Children Estimated to be Living with HIV, 2007

5. HSV-2 Suppressive therapy Management of genital infections (STIs) Cervical Barriers Male circumcision Chemoprophylaxis MTCTP PEP PrEP Vaccines Condoms HIV PREVENTION Microbicides Behavioral Counseling and Testing

6. Research Victories/ Prevention Disappointments Trials showing no efficacy or harm… Intensive counseling in MSM (Koblin Lancet 2004) Microbicides: N-9/Savvy/Cellulose Sulfate Diaphragms (Padian Lancet 2007) Mass STI treatment (Wawer Lancet 1999) Herpes suppression (Celum CROI 2008) An adenovirus-vectored vaccine (Buchbinder CROI 2008)

7. Male circumcision (Not known to be helpful for men who have sex with men) Chemoprophylaxis MTCTP (PEP PrEP have unknown efficacy) Condoms HIV PREVENTION Behavioral Counseling and Testing (Intensive not better than standard)

8. "We are really groping in the dark" Salim S. Abdool Karim Washington Post, November 1, 2007

9. Overview HIV prevention recent disappointments Four forms of drug therapy as prevention Similarities and differences of PEP and PrEP The West African PrEP Study Iniciativa PrEx / PrEP Initiative PrEP Research Portfolio

10. Why Chemoprophylaxis? HIV infection is the cause of AIDS Anti-HIV Drugs Inhibit HIV directly Are already formulated and mass produced Prevent mother to child transmission A pill is at least as individually-controlled as a topical microbicide Chemoprophylaxis is a proven concept EG: Malaria, TB pneumonia, meningitis A mainstay of prevention if no vaccine

11. ART as Prophylaxis—A Promising Self-Initiated Prevention Alternative Antiretroviral Therapy (ART) Standard of care for HIV infection (resources permitting) Inhibits HIV production directly Suppresses HIV viral load in blood and genital fluids Suppressed viral loads are associated with reduced infectivity

12. ART as Prophylaxis—A Promising Self-Initiated Prevention Alternative Antiretroviral Therapy (ART) Standard of care for HIV infection (resources permitting) Inhibits HIV production directly Suppresses HIV viral load in blood and genital fluids Suppressed viral loads associated with reduced infectivity Post-exposure Prophylaxis (PEP ) Drugs already approved for safety currently widely available Anti-HIV activity may prevent infection Use can be limited to high-risk events Limited (1 month) course of therapy unlikely to cause long-term side effects

13. ART as Prophylaxis—A Promising Self-Initiated Prevention Alternative Antiretroviral Therapy (ART) Standard of care for HIV infection (resources permitting) Inhibits HIV production directly Suppresses HIV viral load in blood and genital fluids Suppressed viral loads associated with reduced infectivity Oral pre-exposure prophylaxis (PrEP) Drugs already approved for safety currently widely available(?) Anti-HIV activity may prevent infection Use can be routine/not requiring initiation with risk events May permit a redefinition of high-risk exposure Post-exposure Prophylaxis (PEP ) Drugs already approved for safety currently widely available Anti-HIV activity may prevent infection Use can be limited to high-risk events Limited (1 month) course of therapy unlikely to cause long-term side effects

14. ART as Prophylaxis—A Promising Self-Initiated Prevention Alternative Antiretroviral Therapy (ART) Standard of care for HIV infection (resources permitting) Inhibits HIV production directly Suppresses HIV viral load in blood and genital fluids Suppressed viral loads associated with reduced infectivity Oral pre-exposure prophylaxis (PrEP) Drugs already approved for safety currently widely available(?) Anti-HIV activity may prevent infection Use can be routine/not requiring initiation with events May permit a redefinition of high-risk exposure Post-exposure Prophylaxis (PEP ) Drugs already approved for safety currently widely available Anti-HIV activity may prevent infection Use can be limited to high-risk events Limited (1 month) course of therapy unlikely to cause long-term side effects Pre-exposure ART microbicides Drugs already approved for safety currently widely available(?) Anti-HIV activity may prevent infection at the exposure site Can be initiated as part of routine preparation for intercourse Safety concerns about systemic use may be averted (?)

15. ART as Prophylaxis—A Self-Initiated Prevention Alternative Antiretroviral Therapy (ART) Oral pre-exposure prophylaxis (PrEP) SAFETY : In HIV-uninfected individuals unknown, but PROMISING EFFICACY : UNKOWN, but under investigation PERSONAL ACCEPTABILITY : UNKOWN, but promising POLITICAL ACCEPTABILITY : To be determined (by the POLIS) Post-exposure Prophylaxis (PEP ) Pre-exposure ART microbicides

16. Overview HIV prevention recent disappointments Four forms of drug therapy as prevention Similarities and differences of PEP and PrEP The West African PrEP Study Iniciativa PrEx / PrEP Initiative PrEP Research Portfolio

17. ART as Prophylaxis—A Promising Self-Initiated Prevention Alternative Antiretroviral Therapy (ART) Standard of care for HIV infection (resources permitting) Inhibits HIV production directly Suppresses HIV viral load in blood and genital fluids Suppressed viral loads associated with reduced infectivity Oral pre-exposure prophylaxis (PrEP) Drugs already approved for safety currently widely available(?) Anti-HIV activity may prevent infection Use can be routine/not requiring initiation with events May permit a redefinition of high-risk exposure Post-exposure Prophylaxis (PEP ) Drugs already approved for safety currently widely available Anti-HIV activity may prevent infection Use can be limited to high-risk events Limited (1 month) course of therapy unlikely to cause long-term side effects Pre-exposure ART microbicides Drugs already approved for safety currently widely available(?) Anti-HIV activity may prevent infection at the exposure site Can be initiated as part of routine preparation for intercourse Safety concerns about systemic use may be averted (?)

18. Pre vs. Post-exposure prophylaxis 0h 36h 72h HIV 28 d 3 m 6 m

19. Pre vs. Post-exposure prophylaxis 0h 36h 72h HIV 28 d 3 m 6 m HIV infection

20. Pre vs. Post-exposure prophylaxis 0h 36h 72h HIV Post-exposure prophylaxis 28 d 3 m 6 m HIV infection

21. Pre vs. Post-exposure prophylaxis 0h 36h 72h HIV Pre -exposure prophylaxis 28 d 3 m 6 m HIV infection

22. Why Pre-exposure? People have difficulty recognizing exposure Access Denial (Schechter JAIDS 2004) Substance use Imperfect communication with partners Pre-exposure dosing increases efficacy SHIV exposed nonhuman primates (Garcia Lerma 2008) For those at highest risk Pre- and post-exposure periods overlap

23. Pre vs. Post-exposure prophylaxis 0h 36h 72h HIV 28 d 3 m 6 m HIV HIV Pre -exposure prophylaxis

24. Which ART? Preclinical Evaluation of Tenofovir (TDF) + Emtricitabine (FTC) Either FTC or TDF were protective 70% to 100% Effective Emtricitabine + Tenofovir The combination was 100% effective Even after repeated rectal exposures (14) Even if given once prior to exposure, and once after Protection probably reflects High concentrations in genital tissues and fluids Long intracellular half life Activity in Macrophages Tsai ‘95; Van Rompay ‘99 ‘00 ‘01 ‘04; Subbarao ’05; Heneine’06 ‘07 ‘08

25. PEP & PrEP Similarities and Differences Post-exposure Prophylaxis (PEP) Fears of risk compensation and controversy about the impacts of efficacy PREEMPTED plans for randomized clinical trials (RCT) It is unclear whether communities were prepared for research or research results Observational studies provided data on safety but not on efficacy Demands for public health supported PEP were not helped by the lack of efficacy data, perhaps hindered by it Community knowledge of PEP appears to be low Utilization of PEP, even where it is openly available, appears low Oral pre-exposure prophylaxis (PrEP) Fears of risk compensation and controversy about the impacts of efficacy INFORMED plans for RCT Community consultation regarding trial plans have helped prepare the target population for outcomes in some locations RCT are in the field and designed to provide data on safety and efficacy Strong efficacy data would aid efforts for widespread access in high-risk populations, but WILL NOT GUARANTEE IT Community knowledge of PrEP appears low?* Access to and utilization of PrEP is yet to be determined even if effective?*

26. Overview HIV prevention recent disappointments Four forms of drug therapy as prevention Similarities and differences of PEP and PrEP The West African PrEP Study Iniciativa PrEx / PrEP Initiative PrEP Research Portfolio

27. Conducted between June 2004 and March 2006 West Africa Daily dose of 300 mg oral Tenofovir DF vs. placebo All participants received testing, condoms, and counseling. Safety evaluated in N=936 including 428 person years 2007

28. Overview HIV prevention recent disappointments Four forms of drug therapy as prevention Similarities and differences of PEP and PrEP The West African PrEP Study Iniciativa PrEx / PrEP Initiative PrEP Research Portfolio

29. The iPrEx Study: Safety, Efficacy, Behavior, and Biology Sponsored by NIH/NIAID/DAIDS with co-funding by the Bill and Melinda Gates Foundation and drug donated by Gilead Sciences

31. The iPrEx Study: Safety, Efficacy, Behavior, and Biology Gladstone Institute of Virology and Immunology

32. A double-blind HIV-prevention clinical trial targeting men who have sex with men (MSM) at high-risk for HIV infection Plan to enroll 3,000, randomize 1:1 Truvada vs. placebo (one pill once per day) and follow for an average of 20 months Monthly HIV-testing, risk reduction counseling, and free condoms Quarterly lab and medical assessment for safety and sexual exposure/behavior change assessment PrEP & iPrEx iPrEx (Pre-Exposure Initiative) Can drugs used to treat HIV infection (antiretroviral therapy or ART) prevent infection? In a Macaque model tenofovir or FTC were 70-100% protective per exposure Truvada—ART that includes both drugs (but is 1 pill 1x daily) was 100% protective

33. “ Let’s Communicate” From February 2004, the iPrEx study communicated with participants, activists, government, sponsors, physicians…

34. Overview HIV prevention recent disappointments Four forms of drug therapy as prevention Similarities and differences of PEP and PrEP The West African PrEP Study Iniciativa PrEx / PrEP Initiative PrEP Research Portfolio

35. The PrEP Research Portfolio http://www.avac.org/prep08.pdf

36. Current PrEP Portfolio

37. Acknowledgements Various slides previously prepared and presented by.. Carl W. Dieffenbach , Ph.D., Director of the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) Robert M. Grant , Senior Investigator, Gladstone Intitute of Virology and Immunology, UCSF Albert Liu , MD, MPH, Director of HIV Prevention Intervention Studies at the HIV Research Section of the San Francisco Department of Public Health Opinions and errors of interpretation are those of the presenter