Prophylaxis and HIV Prevention by Dr. Ken Mayer

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Pre and Post Exposure Prophylaxis and HIV Prevention presented by Dr. Ken Mayer, Research Director of the Fenway Health Center at the Fenway Health Center community education conference: An End To AIDS - How A State Bill Can Change Everything hosted by SearchForACure.org, the Fenway Health Center, and the MA Dept. of Public Health

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  • Slide: HIV Prevention: Current Targets HIV continues to spread rapidly in developing countries and remain at unacceptable levels in developed countries. These trends are unlikely to change because: 1 Current HIV-prevention strategies are only partially effective and underused. Preventative vaccine remains years away. Current HIV treatment strategies can not eradicate HIV infection.   Increasing attention has therefore focused on whether available antiretroviral drugs could be used to slow the epidemic. However, the initiation of HAART for prevention can manifest differently in diverse social settings, raising concerns over increased sexual risk taking behavior, viral resistance, toxicities, costs, and risk compensation, to name a few. 1 Abbreviations: IDU: injection drug user; PMTCT: prevent mother-to-child-transmission; STI: sexually transmitted disease; PEP: postexposure prophylaxis; PrEP: pre-exposure prophylaxis. Reference Mayer KM, Nenkatesh KK. Antiretroviral therapy as HIV prevention: status and prospects. Am J Public Health. 2010;100:1867-1876.
  • Slide: Why Antiretroviral Agents for HIV Prevention? The prophylactic use of antimicrobial agents have been the foundation of prevention against many infections. Data from animal studies have shown that multiple antiretroviral agents decrease HIV transmission pre- or postexposure prophylaxis (PEP). In humans, the use of antiretroviral therapy is standard of care for the prevention of mother-to-child transmission of HIV as well as for occupational postexposure prophylaxis after percutaneous exposure. 1-4 The use of antiretroviral agents for HIV prevention has gained consideration because of the improved tolerability of newer agents, the potential for lower-cost generic alternatives, and the challenges encountered with other methods (eg, vaccine). 3,4 References Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med . 1994;331:1173-1180. Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med . 1997;337:1485-1490. Grant RM. Antiretroviral agents used by HIV-uninfected persons for prevention: pre- and postexposure prophylaxis. Clin Infect Dis . 2010;50(suppl 3):S96-S101. Venkatesh KK, Lurie MN, Mayer KH. How HIV treatment could result in effective prevention. Future Virol. 2010;5:405-415.
  • Estimates of per-act risk of acquisition of HIV are approximate and vary widely depending on the viral load of the source contact, the presence of sexually transmitted diseases, and other factors.
  • Slide: Antiretroviral Systemic PrEP: Ratio of Genital:Blood Plasma Levels Concentrations of the drugs in blood plasma do not always correlate with those in the genital tract and rectum, and accumulation ratios vary between and within therapeutic classes. The mechanisms that underlie these differences have yet to be fully elucidated. 1 This slide shows the differences in genital-to-plasma ratios for antiretroviral levels in men and women. 1 Reference Nicol MR, Kashuba AD. Pharmacologic opportunities for HIV prevention. Clin Pharmacol Ther. 2010;88:598-609.
  • Slide: What If PrEP Works? There are a number of issues that need to be addressed if PrEP is shown to be efficacious and safe. These issues include: Block other steps in the HIV life cycle? Develop drugs just for prevention. New co-formulations (generic PrEP?). Topical versus oral (VOICE and beyond). Optimal drug delivery system. How best to dose. Interaction with other prevention modalities. Optimal utilization and effectiveness may require multiple modalities.
  • Slide: What If PrEP Works? There are a number of issues that need to be addressed if PrEP is shown to be efficacious and safe. These issues include: Block other steps in the HIV life cycle? Develop drugs just for prevention. New co-formulations (generic PrEP?). Topical versus oral (VOICE and beyond). Optimal drug delivery system. How best to dose. Interaction with other prevention modalities. Optimal utilization and effectiveness may require multiple modalities.
  • Slide: What If PrEP Works? There are a number of issues that need to be addressed if PrEP is shown to be efficacious and safe. These issues include: Block other steps in the HIV life cycle? Develop drugs just for prevention. New co-formulations (generic PrEP?). Topical versus oral (VOICE and beyond). Optimal drug delivery system. How best to dose. Interaction with other prevention modalities. Optimal utilization and effectiveness may require multiple modalities.
  • Both the study article and the supplemental material are available free of charge that the NEJM website until approximately December 30, when the manuscript will be published in the print edition of the Journal. The supplemental material contains important graphs and tables and additional discussion about the findings.
  • All iPrEx participants were followed very closely throughout the study to protect their safety and to monitor for any possible adverse effects from the PrEP regimen. The FTC/TDF combination was chosen for this study because both drugs stay active in the body for long periods, allowing for once daily dosing; both drugs are approved for the treatment of HIV and have been shown to be safe; and both drugs have demonstrated protection against HIV in animal studies of PrEP, with the two drugs having shown higher levels of protection together. Both drugs are also available in patented and generic formulations.
  • All iPrEx study participants received the same comprehensive package or prevention services designed to reduce their risk of HIV infection throughout the trial, including HIV testing, intensive safer sex counseling, condoms and treatment and care for sexually transmitted infections. Half of study participants also received the PrEP pill, while the other half received a placebo.
  • The majority of iPrEx study participants came from the Americas. The iPrEx study began in Peru and Ecuador, and expanded to include participants in Brazil, the United States, South Africa and Thailand.
  • Efficacy was evident in all of the analyses. The intention to treat analysis included all enrolled participants. The modified intention to treat analysis included all enrolled participants except for the 10 who were subsequently found to be viral RNA positive at the enrollment visit. The as treated analysis (50%) considered visits when pill use was recorded on 50% or more of days, based on pill counts, self-report, and pill dispensation records. The as treated analysis (90%) considered visits when pill use was recorded on 90% of days, as above. The efficacy was higher among those reporting unprotected receptive anal intercourse at enrollment (URAI). URAI was the strongest risk factor for HIV acquisition in this study, and other studies of MSM.
  • A nested case control study was performed that included drug level analysis of blood specimens of 34 of the 36 seroconverters on the FTC/TDF arm of the study, and a set of seronegative controls also from the active arm. One timepoint per person was analyzed. In the HIV infected cases, the timepoint was the first laboratory evidence of HIV infection, whether that evidence was antibody or RNA. The seronegative controls were selected from the same sites at comparable timepoints. Emtricitabine and Tenofovir was measured in blood plasma, and emtricitabine-tri-phosphate and tenofovir-di-phosphate were measured in peripheral blood mononuclear cells. All measurements were by tandem mass spectroscopy. No drug was detected in a sample of placebo arm participants. Drug detection was more than 95% concordant between the different measurements. Overall, one or more drugs were detected in the active arm of the study in 51% of the seronegatives and 9% of the HIV cases. This contrasts with reported adherence which was more than 90% on average. Over-reporting of adherence is common in treatment and prevention trials.
  • There were differences in mild side effects between the arms. TDF is known to decrease renal function a small amount in HIV infected persons. We also observed a trend toward more creatinine elevations in the active arm of the study. Most the creatinine elevations resolved without stopping study drug and many remained within the normal range (they were elevations only in that they increased more than 50% from the participant’s baseline). Only 5 (0.4%) of the active arm had creatinine elevations that persisted until the following visit; all resolved after stopping FTC/TDF. Four of these were rechallenged without recurrence in the creatinine elevation. Headache, nausea, and unintentional weight loss of 5% was reported more frequently in the active arm, typically in the first few weeks of pill use. The proportion affected was less than 1 in 20 participants. There were no differences between groups in diarrhea or depression and a large number of other adverse events and lab markers.
  • Nausea was also assessed by medical history at all visits. Nausea was reported in 1 in 10 (9%) of the active arm participants and 5% of placebo users, and decreased to comparable levels at subsequent visits. This is consistent with start up symptoms that occur in some persons starting antiviral therapy. People’s long term adherence to therapy, and possibly PREP, could be enhanced if they receive supportive counseling for side effects in the first 4 weeks of pill use.
  • Slide: Topical TDF or FTC/TDF Gel: Complete Protection From SHIV Exposure Parikh and colleagues evaluated tenofovir with or without emtricitabine as preexposure prophylaxis by using a twice-weekly repeat challenge macaque model and showed that a preexposure vaginal application of gel with 1% tenofovir DF alone or in combination with 5% emtricitabine could fully protected macaques from a total of 20 exposures to SHIV. 1 Reference Parikh UM, Dobard C, Sharma S, et al. Complete protection from repeated vaginal simian-human immunodeficiency virus exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine. J Virol . 2009;83:10358-10365.
  • Slide: CAPRISA 004 Results: HIV Incidence HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm ( P =0.017). 1 In high adherers (gel adherence >80%), HIV incidence was 54% lower ( P =0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50% to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38% and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. 1 Reference Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science . 2010;329:1168-1174.
  • Slide: Intermittent PrEP in Macaques With Oral FTC/TDF Garcia-Lerma and colleagues demonstrated maximum protection from 14 weekly SHIV exposures when an oral pre-exposure dose 22 hours before exposure is followed by a postexposure dose at 2 hours after the exposure (hazard ratio 16.7). This protection decreases when the pre-exposure dose is administered as early as 3 and 7 days before infection (hazard ratio 15.4 and 9.3, respectively) or if the postexposure dose is delayed by 22 hours after the infection (hazard ratio 4.1). 1 Reference García-Lerma JG, Paxton L, Kilmarx PH, et al. Oral pre-exposure prophylaxis for HIV prevention. Trends Pharmacol Sci . 2010;31:74-81.
  • Slide: New Antiretroviral Topical Microbicides This slide provides an overview of microbicides in development and their clinical development status.
  • Slide: What If PrEP Works? There are a number of issues that need to be addressed if PrEP is shown to be efficacious and safe. These issues include: Block other steps in the HIV life cycle? Develop drugs just for prevention. New co-formulations (generic PrEP?). Topical versus oral (VOICE and beyond). Optimal drug delivery system. How best to dose. Interaction with other prevention modalities. Optimal utilization and effectiveness may require multiple modalities.
  • Slide: HPTN 065: Testing, Linkage to Care, Treatment, Plus Lots More… HPTN 065 is a study to assess the feasibility of a community-level test, link to care, plus treat strategy (TLC-Plus) in the United States. The primary outcomes of the TLC-Plus package of interventions will be determined through measurement of change over the duration of the study in key parameters in two intervention communities. Observations in the four non-intervention control communities will help assess the influence of current trends in HIV testing and care expansion in the United States. 1 TLC-Plus is uses innovative approaches, including: 1 A community focus. Multi-component strategies that include behavioral and biomedical interventions. The use of routinely reported HIV surveillance data to determine key outcomes. A partnership with local Departments of Health and the Centers for Disease Control and Prevention. This study will serve as a proof-of-concept formative study. It will provide key information that could guide the design and anticipate the costs of a future large randomized, community-level clinical trial of full implementation of a test-and-treat strategy in the United States. Findings from this study could also inform test-and-treat efforts in other developed countries with epidemics similar to that in the United States. 1 Reference Available at: www.hptn.org.
  • Slide: What If PrEP Works? There are a number of issues that need to be addressed if PrEP is shown to be efficacious and safe. These issues include: Block other steps in the HIV life cycle? Develop drugs just for prevention. New co-formulations (generic PrEP?). Topical versus oral (VOICE and beyond). Optimal drug delivery system. How best to dose. Interaction with other prevention modalities. Optimal utilization and effectiveness may require multiple modalities.
  • Prophylaxis and HIV Prevention by Dr. Ken Mayer

    1. 1. Antiretroviral Chemoprophylaxis: What have we learned so far? Kenneth H. Mayer, MD March 26 th , 2011 Search for A Cure
    2. 2. HIV Prevention: Current Targets Condom and HIV testing promotion Individual interventions Couples interventions Community-based interventions Structural interventions Barrier protection Blood screening IDU harm reduction Antiretroviral therapy (PMTCT, treat infected partners) STI treatment Barrier protection Infection control Circumcision PEP, PrEP Topical microbicides Vaccines STI treatment Alter Behavior Decrease Host Susceptibility Decrease Source of Infection
    3. 3. Why Antiretroviral Agents for HIV Prevention? <ul><li>Animal data </li></ul><ul><ul><li>Multiple drugs have decreased HIV transmission as PEP or PrEP </li></ul></ul><ul><li>Human data </li></ul><ul><ul><li>PMTCT </li></ul></ul><ul><ul><li>Occupational PEP after percutaneous exposures </li></ul></ul><ul><ul><li>- Non-occupational PEP experience (no RCT) </li></ul></ul><ul><li>Tolerability of newer antiretroviral agents </li></ul><ul><li>Increased affordability </li></ul><ul><li>Challenges with other approaches (eg, vaccine) </li></ul>Connor EM, et al. N Engl J Med. 1994;331:1173-1180. Cardo DM, et al. N Engl J Med. 1997;337:1485-1490. Grant RM, et al. Clin Infect Dis. 2010;50(suppl 3):S96-S101. Venkatesh KK, et al. Future Virol. 2010;5:405-415.
    4. 4. Per-Act Risk for HIV Acquisition 01/05 Exposure Route Risk per 10,000 exposures Blood transfusion 9,000 Needle-sharing injection drug use 67 Receptive anal intercourse 50 Percutaneous needle stick 30 Receptive penile-vaginal intercourse 10 Insertive anal intercourse 6.5 Insertive penile-vaginal intercourse 10 Receptive oral intercourse 1 Insertive oral intercourse 0.5
    5. 5. Not all ART may be equal for Prevention: Ratio of Genital:Blood Plasma Levels Nicol MR, et al. Clin Pharmacol Ther. 2010;88:598-609. Women Men Genital Tract:Blood Plasma AUC Ratio of 1.0: genital tract AUC=blood plasma AUC. Genital tract exposure within 2 and 1 hour of dosing for women and men, respectively. NRTI NNRTI PI Entry Inhibitor INSTI 6.0 5.0 4.0 3.0 2.0 1.0 0.5 0 ddI ABC d4T APV RTV ATV LPV SQV Genital Tract:Blood Plasma AUC NRTI NNRTI PI Entry Inhibitor INSTI 6.0 5.0 4.0 3.0 2.0 1.0 0.5 0 d4T APV, ATV,LPV DRV,SQV, RTV TDF ZDV FTC 3TC ETV NVP EFV DRV IDV MRV RAL TDF ZDV 3TC FTC NVP EFV IDV MRV RAL ABC
    6. 6. PEP: Guidelines
    7. 7. PEP vs. PrEP <ul><li>PEP has been associated with decreased subsequent risk when coupled with counseling, but not as a stand alone (Roland, CID, 39:82-89, 2005) </li></ul><ul><li>MSM in Brazilian study who took AZT/3TC PEP were less likely to become HIV-infected (Schechter, JAIDS, 5:519-525, 2004) </li></ul><ul><li>But, most of those infected assumed their partner was not HIV-infected </li></ul><ul><li>So, “teachable moment” makes the case for PEP </li></ul><ul><li>Inability to assess risk in real time, esp. for those who are frequently risky make the case for PrEP </li></ul>
    8. 8. PEP: Fenway Experience <ul><li>Fenway Health 1997-2007 </li></ul><ul><li>558 PEP cases (368 not part of clinical trial, 190 part of 2 tenofovir-based Phase IV PEP trial) </li></ul><ul><li>Most common regimens: TDF/FTC, AZT/3TC, AZT/3TC or TDF/FTC + PI, TDF/FTC + RAL </li></ul><ul><li>TDF/FTC </li></ul><ul><ul><li>most common regimen used </li></ul></ul><ul><ul><li>most often completed overall regimen (73%) </li></ul></ul><ul><li>4 total infections – all had documented adherence problems and/or ongoing sexual risk taking before and after PEP administration </li></ul>Mayer et al, JAIDS, 47:494-99, 2008
    9. 9. PEP: Guidelines <ul><li>Drug Choice </li></ul><ul><li>2 drugs or 3? Increased tolerability vs. Extra protection </li></ul><ul><li>Early OPEP studies confirm monotherapy is very successful, so key is to pick regimen that will contain at least one active drug and maintain adherence for 28 day course </li></ul><ul><li>Once-a-day regimen is more likely to maintain adherence </li></ul><ul><li>Newer drugs are associated with increased tolerability and completion rates </li></ul><ul><li>Must consider prevalence of drug resistance in addition to source patient data </li></ul>Bassett IV, et al. CID. 2004;39:395-401. Mayer KH, et al. AJPH. 2010;100:1867-1876
    10. 18.
    11. 19. Drug Resistance Grant et al, CROI 2010 Genotypic Resistance HIV Status at Enrollment Infected Uninfected Placebo N=8 FTC/TDF N=2 Placebo N=83 FTC/TDF N=48 65R 0 (0%) 0 (0%) 0 (0%) 0 (0%) 70E 0 (0%) 0 (0%) 0 (0%) 0 (0%) 184I 0 (0%) 1 (50%) 0 (0%) 0 (0%) 184V 1 (13%) 1 (50%) 0 (0%) 0 (0%) TDF Resistance 0 (0%) 0 (0%) 0 (0%) 0 (0%) FTC Resistance 1 (13%) 2 (100%) 0 (0%) 0 (0%)
    12. 20. Topical TDF or FTC/TDF Gel: Complete Protection From SHIV Exposures Protection From SHIV Uninfected (%) 1% TDF (n=6) Challenges 0 2 4 6 8 10 12 14 16 18 20 <ul><li>Twice-weekly repeat vaginal SHIV challenge macaque model (n=23) </li></ul><ul><ul><li>Total of 20 challenges </li></ul></ul><ul><li>Topical gel (matrix + preservative) </li></ul><ul><ul><li>1% tenofovir DF </li></ul></ul><ul><ul><li>5% emtricitabine/ 1% tenofovir DF </li></ul></ul><ul><li>Dosing </li></ul><ul><ul><li>3 mL applied 30 minutes before vaginal challenge with R5 virus inoculum (10 TCID 50 ) </li></ul></ul>Parikh UM, et al. J Virol. 2009;83:10358-10365. 5% FTC/1% TDF (n=6) Placebo Gel (n=9) No Gel (n=2) SHIV: simian (SIV)-human (HIV) hybrid.
    13. 21. CAPRISA 004 Results: HIV Incidence Abdool Karim Q, et al. Science. 2010;329:1168-1174. HIV Incidence Rate (%) 12 30 10.5% 5.2% 9.1% 5.6% Follow-Up (months) 50% ( P =0.007) 39% ( P =0.017) Overall Placebo Tenofovir DF gel HIV Incidence Rate (%) >80% 9.3% 4.2% 10.0% 8.6% 54% ( P =0.025) 38% ( P =0.34) By Adherence Placebo Tenofovir DF gel 6.3% 6.2% 28% ( P =0.30) 50%-80% <50% Adherence Level (months)
    14. 22. Investigation: Ongoing PrEP efficacy studies <ul><li>Safety, efficacy, resistance & costs of TDF & FTC-TDF will inform choice of drugs for PrEP roll-out </li></ul>Location Sponsor/ Funder Population N PrEP Agent Status Thailand Bangkok Tenofovir Study CDC IDU 2400 TDF Fully enrolled Results 2012 Kenya, Uganda Partners PrEP Study UW / BMGF HIV discordant couples 4758 TDF, FTC/TDF Fully enrolled Results 2012 Kenya, South Africa , Tanzania, Zimbabwe FEM-PrEP FHI / USAID & BMGF Women 3900 FTC/TDF 49% enrolled Results 2013 South Africa, Uganda, Zimbabwe VOICE / MTN 003 MTN / NIH Women 5000 TDF, FTC/TDF, Vaginal tenofovir gel ( daily ) 65% enrolled Results 2013
    15. 23. Peri-Exposure Prophylaxis in Macaques With Oral FTC/TDF Protection From SHIV Uninfected (%) Rectal Exposures (number) 0 2 4 6 8 10 12 14 <ul><li>Macaque model of rectal transmission of HIV </li></ul><ul><ul><li>Rectal exposure with R5 virus inoculum (10 TCID 50 ) </li></ul></ul><ul><li>2 doses of FTC/TDF </li></ul><ul><ul><li>Before SHIV exposure (-) </li></ul></ul><ul><ul><li>After SHIV exposure (+) </li></ul></ul><ul><li>Extended window of protection </li></ul><ul><ul><li>Associated with extended long intracellular persistence of drug </li></ul></ul><ul><li>No drug resistance in macaques failing PrEP </li></ul>Garcia-Lerma JG, et al. Sci Transl Med. 2010;2:14ra4. FTC/TDF Dosing HR -22h/+2h -3d/+2h -7d/+2h -2h/+22h 16.7 15.4 9.4 4.1 Untreated Controls P Value .006 .008 .003 .02
    16. 24. What about intermittant PrEP? <ul><li>IAVI studies in East Africa: MSM and FSW, small size, but many missed post-coital doses </li></ul><ul><li>HPTN 066: dose proportionality study of weekly TDF/FTC, twice weekly, and double dose twice weekly. Sampling all relevant tissues. </li></ul><ul><li>HPTN 067: 180 MSM in Bangkok and 180 high risk women in Capetown, to compare adherence to coitally dependent vs. fixed intermittant PrEP. </li></ul>
    17. 25. Human studies of intermittent PrEP <ul><li>IAVI E001/E002 : Daily, twice weekly & post-coital dosing of FTC/TDF (Mutua, IAS 2010) </li></ul><ul><ul><li>Adherence measured by MEMS </li></ul></ul><ul><ul><li>Highest adherence: daily dosing & among discordant couples </li></ul></ul><ul><ul><li>Post-coital dosing significantly lower than twice weekly dosing </li></ul></ul>Dosing strategy HIV discordant couples, Uganda (N=72) High risk women & MSM, Kenya (N=72) Daily dosing, adjusted rate 96-97% 82-92% Fixed twice weekly dosing 91% 55% Post-coital dosing 45% 26%
    18. 26. What about rectal gel? <ul><li>Tenofovir protects monkeys after rectal challenge </li></ul><ul><li>Vaginal tenofovir gel used rectally was not optimal in LA/Pittsburgh study </li></ul><ul><li>New formulation will be studied in MTN 007: Pittsburgh, Boston, Birmingham </li></ul><ul><li>New formulation will also be studied in younger MSM (Project Gel): Pittsburgh, Boston, San Juan </li></ul><ul><li>MTN 017: To assess rectal efficacy </li></ul>
    19. 27. New Antiretroviral Topical Microbicides
    20. 28. PrEP Delivery Platforms: Long-acting topical & systemic delivery Gel with applicator Vaginal ring (sustained delivery) <ul><li>Ideal: long acting, safe, effective, low cost and user-friendly </li></ul><ul><li>Maximize choice & optimize effectiveness </li></ul><ul><li>Potential for combination ARVs to increase effectiveness </li></ul><ul><li>Potential to combine ring or injections with contraception </li></ul>Vaginal film Injectable (long-acting) Pill
    21. 29. PREP: Guidelines
    22. 30. Combination Antiretroviral Prevention Modified from www.hptn.org. Decrease in HIV Transmission Maintain Viral Suppression Treat Enroll in Care Address concomitant concerns, e.g. depression, substance use, relationship dynamics HIV Negative Test Interventions to Increase Testing Positive Prevention Linkage To Care Adherence to ART ART Initiation Risk Assessment PrEP, Adherence Counseling HIV Positive
    23. 31. Optimizing ART for Prevention <ul><li>Block other steps in the HIV life cycle? </li></ul><ul><ul><li>Develop drugs just for prevention (Maraviroc)? </li></ul></ul><ul><li>New co-formulations; Generic PrEP? </li></ul><ul><li>Topical versus oral (VOICE and beyond): role of culture, belief systems, as well as lifestyles </li></ul><ul><li>Optimal drug delivery system (ring; depot?) </li></ul><ul><li>Who are the priority populations? </li></ul><ul><li>How to best train providers? Which providers? </li></ul><ul><li>Interaction with other prevention modalities </li></ul><ul><li>Optimal utilization and effectiveness may require multiple modalities: one size will not fit all </li></ul>
    24. 32. Many thanks <ul><li>Marcy Gelman Steve Boswell </li></ul><ul><li>Chris Chianese Janet Dargon </li></ul><ul><li>Lori Panther Jim Maynard </li></ul><ul><li>Rodney Vanderwarker Jackie White </li></ul><ul><ul><li>Matthew Mimiaga Doug Krakower </li></ul></ul><ul><li>Vanessa Marquez Jo Trufant </li></ul><ul><li>Coco Alisung Bill O’Brien </li></ul><ul><li>Ralph Miele Danny Tu </li></ul><ul><li>Amy Pechukas Bill O’Brien </li></ul><ul><li>Jesse Ripton Ronn Bill </li></ul><ul><li>Bob Grant Craig Hendrix </li></ul><ul><li>Susan Buchbinder Connie Celum </li></ul><ul><li>The Participants IRB and CAB </li></ul><ul><li>NIH, BMGF, Gilead </li></ul>

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