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Special thanks to Raphael Landovitz, MD, MSc

A PEP and PrEP Update Jeffrey D. Klausner, MD, MPH Black AIDS Institute-UCLA African-American University September 2014. Special thanks to Raphael Landovitz, MD, MSc. Definitions. PMTCT P revention of M other- t o- C hild T ransmission of HIV

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Special thanks to Raphael Landovitz, MD, MSc

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  1. A PEP and PrEP UpdateJeffrey D. Klausner, MD, MPHBlack AIDS Institute-UCLA African-American UniversitySeptember 2014 Special thanks to Raphael Landovitz, MD, MSc

  2. Definitions • PMTCT • Prevention of Mother-to-Child Transmission of HIV • ART during pregnancy, during labor/delivery, and treatment of the infant after birth (x 6 weeks) • AZT alone reduced MTCT from 25% to 8%† • Current ART reduces MTCT to 1%‡ †Connor et al, NEJM 1994 ‡Shapiro et al, NEJM 2010

  3. Definitions • PEP • Post-exposure prophylaxis • Strategy of administering ART to uninfected, at-risk individuals, after they have had a high-risk exposure to someone who is (or might be) HIV-infected • Think of: “Morning after” pill(s) • AZT reduced risk in HCWs by 81%† • Current CDC Guidelines recommend 2- or 3-drug antiretroviral treatment up to 72 hours after exposure for 4 weeks following exposure www.aidsinfo.nih.gov †Cardo et al, NEJM 1997

  4. Definitions • PrEP • Pre-exposure prophylaxis • Strategy of administering ART to uninfected, at-risk individuals • Think of: malaria prevention, birth control pill • MSM: iPrEx study • Women: FEM-PrEP study, VOICE (MTN-003) • Heterosexual Couples: TDF2 and Partners PrEP

  5. Pre-Exposure Prophylaxis (PrEP)

  6. PrEP in MSM:The iPrEx Study

  7. iPrEx • Phase III study of PrEP with fixed dose combination emtricitabine/tenofovir (FTC/TDF) or placebo • Study population: HIV uninfected MSM or transgendered women from South America, South Africa, Thailand and U.S. (N=2499) • Ten were HIV-infected at enrollment, but inadvertently enrolled anyway • Efficacy through study end (mITT): 42% (95% CI: 18% to 60%) 0.12 Placebo FTC/TDF (Truvada) 0.10 P = .002 0.08 Cumulative Probability of HIV Infection 0.06 0.04 0.02 0 0 12 24 36 48 60 72 84 96 108 120 132 144 Wks Since Randomization Pts at Risk, n Placebo 1248 1198 1157 1119 1030 932 786 638 528 433 344 239 106 FTC/TDF 1251 1190 1149 1109 1034 939 808 651 523 419 345 253 116 Grant R, et al. CROI 2011. Abstract 92.

  8. Recorded Adherence and Efficacy <50% 50-90% >90% % of Visits 18% 33% 49% Efficacy16%34% 68% 95% CI -54 - 54 -20 - 64 36 - 84 Grant et al. NEJM 2010

  9. Drug Level Correlates of Protection in iPrEx • STRAND study determined median levels of TFV in PBMCs after 2x (11 fmol/mL), 4x (32 fmol/mL), and 7x (42 fmol/mL) per week dosing of TDF • iPrEx seroconverters had median 11 fmol/mL • iPrEx non-seroconverters had median 16 fmol/mL Anderson P. et al, Sci Transl Med, 2012

  10. How long do TFV/FTC concentrations last in serum?(Single dose) Patterson, K. Sci Transl Medicine, 2011.

  11. iPrEx Drug Level Model • Model: 90% reduction in HIV incidence at 16 fmol/mL (IQR 3-28) • 2x/week dosing would be predicted to provide 76% efficacy (56-96%) • 4x/week dosing would be predicted to provide 96% efficacy (90->99%) • 7x/week dosing would be predicted to provide 99% efficacy (96->99%) Anderson P. et al, Sci Transl Med. 2012.

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  13. PrEP in Heterosexual Men and Women:TDF2 and Partners PrEP

  14. Partners PrEP Study:Trial Design Double-Blind Tenofovir DF qd (n=1845) Randomization 1:1 Primary Endpoints HIV infection in HIV-negative partner Safety Phase 3, Double-Blind Study Kenya, Uganda Serodiscordant, heterosexual couples (n=4758) (HIV-positive partner not yet eligible for ART) Normal liver, renal, hematologic values/function Emtricitabine/Tenofovir DF qd (n=1579) Follow-Up Up to 36 months (7337 person-years) Placebo (n=1584) All patients received comprehensive HIV prevention services. Baeten J et al, CROI 2012, Abstract #29, Seattle, WA.

  15. Partners PrEP Study:Results HIV Incidence • Both PrEP treatment arms significantly reduced the risk of HIV acquisition • Similar results between arms and genders, location, VL strata • Both PrEP treatment arms were safe and well tolerated • No difference in AEs, labs, SAEs, deaths • No difference in renal function • No evidence of risk compensation 67% (44-81%) Reduction (P<0.0001) 75% (55-87%) Reduction (P<0.0001) 1.99 HIV Incidence (per 100-person-years) 0.65 0.50 Placebo Tenofovir DF Emtricitabine/ Tenofovir DF Baeten J et al, CROI 2012, Abstract #29, Seattle, WA.

  16. Partners PrEP • Resistance • 2 of 8 acute seroconverters on therapy • 1 K65R (TDF) • 1 M184V (TDF/FTC) • 0 of 27 seroconversions ON STUDY had treatment emergent resistance • 4 with NNRTI resistance (2 TDF, 1 TDF/FTC, 1 PBO) Baeten J et al, CROI 2012, Abstract #29, Seattle, WA. Baeten J et al, NEJM 2012.

  17. Partners PrEP • Adherence/Drug levels • Case cohort: 30 seroconverter cases, 200 controls in active arms (randomly selected) • TDF testing at mos 1, 3, 6, 12, 24, 36 + seroconversion (if applicable) If detectable drug (@ 0.3 ng/mL): • TDF efficacy 86% • TDF/FTC efficacy 90% Donnell D et al, CROI 2012, Abstract #30, Seattle, WA. Baeten J et al, NEJM 2012.

  18. Partners PrEP • 9 seroconverters had detectable drug • 4 had drug levels > 40 ng/mL • 4 had lower, but consistently detectable levels • 3 adherence patterns noted • 70% stayed > 40 ng/mL at most time points • 10% had low but detectable levels • 20% had undetectable levels – consistently • Self-report, pill count, and drug levels well correlated (!) Donnell D et al, CROI 2012, Abstract #30, Seattle, WA.

  19. TDF2 Study: PrEP in Heterosexual Adults HIV Seroconversion (ITT) • Phase 2 trial in heterosexual men and women (n=1200) in Botswana • Women: 45% • Married: 94% • Completed study: 67% • Primary results • HIV seroconversion (n=33) • Daily oral emtricitabine/tenofovir DF (n=9 [2 males/7 females]) • Placebo (n=24 [10 males/14 females]) Placebo (n=599) 63% Reduction (P=0.013) Proportion Emtricitabine/ Tenofovir DF (n=601) 0 1 2 3 Years Thigpen MC, et al. NEJM 2012.

  20. Summary of Oral PrEP Efficacy Data Murnane et al, CROI 2013, Abstract #1000

  21. Adherence and Efficacy in PrEP Trials Donnell et al CROI 2012 Grant et al N Engl J Med 2010 Van Damme et al CROI 2012 Paxton et al FDA 2012

  22. What are the Concerns?

  23. Risk Compensation • PrEP trials have not seen risk compensation But …. • These were trials in which participants knew they might be getting a “placebo” • People were counseled REPEATEDLY that the pill had not been shown to “work” yet, so condoms MUST be used all the time • What will happen now that we know it works, and there are no more placebos?

  24. Implementation • Who should be delivering PrEP? • What services should be co-packaged with PrEP? • Where should PrEP be delivered? • When should people/laboratory testing be done (at what interval)? • How will PrEP and its services be paid for? • Will the people most at risk use it and adhere to it?

  25. CDC Guidance for PrEP for MSM: (Interim: 1/27/11) • Before starting: • Document HIV Antibody- and r/o acute infection • CrCl >60, screen for STIs and HBV • Prescribe FTC/TDF daily X 90 days • Provide risk reduction, adherence counseling, condoms • On treatment: • Check HIV Antibody every 2-3 months • Check kidney function at 3 months and yearly • Risk reduction, condoms, STI assessments/rx http://www.cdc.gov/hiv/prep/index.htm

  26. http://www.cdc.gov/hiv/pdf/PrEPguidelines2014.pdf

  27. CDC PrEP Guidance 2014 • Daily oral PrEP with the fixed-dose combination of tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine (FTC) 200 mg has been shown to be safe and effective in reducing the risk of sexual HIV acquisition in adults; therefore, • PrEP is recommended as one prevention option for sexually-active adult MSM (men who have sex with men) at substantial risk of HIV acquisition (IA) • PrEP is recommended as one prevention option for adult heterosexually active men and women who are at substantial risk of HIV acquisition. (IA) • PrEP is recommended as one prevention option for adult injection drug users (IDU) at substantial risk of HIV acquisition. (IA) • PrEP should be discussed with heterosexually-active women and men whose partners are known to have HIV infection (i.e., HIV-discordant couples) as one of several options to protect the uninfected partner during conception and pregnancy so that an informed decision can be made in awareness of what is known and unknown about benefits and risks of PrEP for mother and fetus (IIB)

  28. Community Discussion • What will be the adverse effects profile in other populations? • Who will pay for it? If it is effective in demonstration projects, will it be made available to those most at risk? • Will biomedical prevention increase health disparities? • What will the real world risk-compensation consequences be? • Resistance

  29. What’s next? • Open label “demonstration projects” of daily FTC/TDF • Intermittent FTC/TDF dosing (HPTN 066, 067, ANRS Study in France/Quebec) • Daily dosing of alternative agents (HPTN 069) • Long(er) acting preparations (TMC278LA and S/GSK1265744), Topical patches, vaginal rings (Dapivirine, TDF, others) • Daily FTC/TDF in IDUs

  30. Thank you!Questions?

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