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Prophylaxis and HIV Prevention by Dr. Ken Mayer
- 1. Antiretroviral Chemoprophylaxis: What have we learned so far? Kenneth H. Mayer, MD March 26 th , 2011 Search for A Cure
- 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
- 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. 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
- 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%)
- 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)
- 27. New Antiretroviral Topical Microbicides
- 29. PREP: Guidelines
- 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
Notes de l'éditeur
- 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.