HIV Therapy as HIV Prevention: Reducing the Risk of HIV Infection Among Uninfected Adults Sponsored for CME credit by Rush University Medical Center Supported by an independent educational grant from Gilead Sciences Medical Affairs Simply Speaking HIV HIV Therapy as HIV Prevention: Reducing the Risk of HIV Infection Among Uninfected Adults is Copyrighted 214 by Practice Point Communications, unless otherwise noted. All rights reserved. Sign-In Process Please clearly print all information on the sign-in sheet You must indicate your NAME, DEGREE, MAILING ADDRESS, EMAIL, and SIGNATURE in order to attend this lecture You must indicate a unique identification number to attend this lecture: MD/DO/PA = NPI Number NP/RN = State License Number PharmD/RPh = NAPB & Date of Birth Other = NPI or State License Number (if available) Completion is required for all healthcare providers Failure to provide complete information may disqualify you from participating in future lectures 2 Electronic Evaluation Process You will receive an electronic evaluation to the email address provided within 1 business day Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed Completion Is Required for CME/CNE/CPE credit and future attendance Incomplete evaluations will preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area 3 1
Content Faculty Kenneth H. Mayer, MD Professor of Medicine Harvard Medical School Director, HIV Prevention Research Beth Israel Deaconess Medical Center Medical Research Director The Fenway Institute, Fenway Health Boston, Massachusetts 4 Learning Objectives (CME/CNE/CPE) Upon completion of this educational activity, participants should be able to: - Screen and test patients for HIV/AIDS using the Centers for Disease Control and Prevention (CDC) recommendations - Counsel HIV-infected patients on behavioral and biomedical interventions for the prevention of HIV transmission - Counsel patients at high-risk for HIV/AIDS on the use of antiretroviral agents for pre-exposure prophylaxis of HIV infection (PrEP) - Incorporate new clinical management approaches, such as PrEP, to lower community rates of HIV transmission 5 Program Overview Treatment and prevention gaps Assessing prevention benefits of ART PrEP for prevention of HIV transmission Providing PrEP 6 2
UNAIDS Global Report 213: Treatment and Prevention Gaps 35.3 million living with HIV infection and needing ART 1.6 million on ART 2.3 million new infections 34% estimated coverage of ART in low- and middle-income countries 7 UNAIDS Global Report 213. http://www.unaids.org/en/dataanalysis/knowyourepidemic/epidemiologypublications/. New AIDS Cases and AIDS-Related Deaths in the United States 7 6 Number of Cases 5 4 3 2 1 New AIDS Cases AIDS-Related Deaths 95 96 97 98 99 1 2 3 4 5 6 7 8 9 1 Year CDC. HIV Surveillance Report, 211. Available at: http://www.cdc.gov/hiv/library/reports/surveillance/211/surveillance_report_vol_23.html. 8 HIV Cascade of Care: Missed Opportunities in the US 1 HIV-Infected: >25 Years of Age (n=896,8) ~88% 1 HIV-Infected: 13-29 Years of Age (n=78,949) 8 ~73% 8 HIV-Infected (%) 6 4 2 Diagnosed Linked To Care ~4% Retained in Care ~28% Viral Suppression HIV-Infected (%) 6 4 2 4% Diagnosed 25% Linked To Care 11% Retained in Care 6% Viral Suppression Zanoni BC, et al. AIDS Patient Care STDS. 214;28:128-135. Hall HI, et al. JAMA Intern Med. 213;173:1337-1344. 9 3
HIV Cascade of Care: Missed Opportunities in the US 1 HIV-Infected: >25 Years of Age (n=896,8) 12% Unaware of Infection 1 HIV-Infected: 13-29 Years of Age (n=78,949) HIV-Infected (%) 8 6 4 2 Diagnosed ~73% Linked To Care ~4% Retained in Care ~28% Viral Suppression HIV-Infected (%) 8 6 4 2 6% Unaware of Infection Diagnosed 25% Linked To Care 11% Retained in Care 6% Viral Suppression Zanoni BC, et al. AIDS Patient Care STDS. 214;28:128-135. Hall HI, et al. JAMA Intern Med. 213;173:1337-1344. 1 CDC National Youth Risk Behavior Surveys: Summary of Trends Among High School Students Ever Had Sexual Intercourse Overall Decreased (1991-21) No change (21-213) Had Sexual Intercourse With >4 Persons Decreased (1991-23) No change (23-213) Had Sexual Intercourse in Past 3 Months Condom Used at Last Intercourse Decreased (1991-213) Increased (1991-23) Decreased (23-213) Male Decreased (1991-1997) No change (1997-213) Decreased (1991-1997) No change (1997-213) Decreased (1991-213) Increased (1991-25) No change (25-213) Female Decreased (1991-213) Decreased (1991-213) Decreased (1991-213) Increased (1991-23) Decreased (23-213) White Decreased (1991-23) No change (23-213) Increased (1991-29) Decreased (29-213) No change (1991-213) Increased (1991-25) No change (25-213) Black Decreased (1991-213) Decreased (1991-213) Decreased (1991-213) Increased (1991-1999) Decreased (1999-213) Hispanic Decreased (1991-213) Decreased (1991-213) No change (1991-213) Increased (1991-23) No change (23-213) Blue: positive trend. Yellow: cause for concern. Red: negative trend. Kann L, et al. 2 th IAC. Melbourne, 214. Abstract WEPE126. 11 Chronic HIV in the US: New Infections and Awareness of HIV Serostatus Number (in s) 14 13 12 11 1 9 8 7 6 5 4 3 2 1 1,16,4-1,2, Prevalence ~2% Unaware of Infection ~8% Diagnosed 874,56-96, Diagnosed ~54% of New Infections ~46% of New Infections Smith MK, et al. PLoS One. 212;9:e1126. Gardner EM, et al. Clin Infect Dis. 211;52:793-8. Burns DN, et al. Clin Infect Dis. 21;51:725-731. 12 4
Estimated New HIV Infections: Most Affected Populations in the United States (211) 13 New HIV Infections (Number) 12 1 8 6 4 2 1,375 11,85 6949 5875 3117 White Black Hispanic Black Black Women Men MSM Heterosexual 1325 1318 183 White Hispanic Women Women CDC. HIV Surveillance Report, 211. Available at: http://www.cdc.gov/hiv/library/reports/surveillance/211/surveillance_report_vol_23.html. Total Estimated New HIV Infections in 211 (n=49,273) Black Male IDUs 715 Black Female US National HIV Surveillance System (21-212): HIV Transmission in the US HIV-1 pol sequences analyzed to determine potential transmission partners (n=41,294) - >13 years of age - 1 sequence per person, compared pairs of sequences >5 nucleotides/sequence Distance <1.5% between pairs: possible linkage Demographics - Men (78%), black (47%), white (26%) - MSM (61%), females-heterosexual contact (18%), male IDU (5%), female IDU (4%), MSM IDU (4%) 31% (n=12,91) of sequences fit into a transmission cluster (>1 partner) - 82% of potential transmission pairs lived in the same state Racial/ethnic common connections - Blacks with other blacks (63%) - Other groups with whites (Hispanics: 45%; Asian: 54%; Other: 4%) Oster AM, et al. 21 st CROI. Boston, 214. Abstract 213. 14 Transmission Category of Potential Transmission Partners (21-212) 1 8 Blacks Most Likely Linked With Other Blacks Potential Transmission Category White Asian/NHOPI Black Other Hispanic/Latino Percent 6 4 2 47% 27% 19% 19% 4% 4% White (n=14,89) 63% 13% 1% 4% Black (n=14,392) 54% 45% 3% 27% 21% 8% 4% 3% 5% 3% Hispanic/Latino Asian/NHOPI (n=8773) (n=1193) Pairs With >1 Person With HIV Infection 4% 39% 16% 3% 2% Other (n=1337) 15 NHOPI: Native Hawaiian or other Pacific Islander. Oster AM, et al. 21 st CROI. Boston, 214. Abstract 213. 5
Transmission Category of Potential Transmission Partners (21-212) 1 8 MSMs Most Likely Linked With Other MSMs 88% 82% 68% Potential Transmission Category MSM Male heterosexual MSM-IDU Female heterosexual IDU Other Groups Were Commonly Linked With MSMs Percent 6 4 33% 54% 33% 44% 32% 2 4% 11% 11% 9% 7% 7% 4% 5% 5% 3% 3% 3% 2%2% 4% 3% 3% MSM (n=27,478) MSM-IDU (n=221) IDU-Male (n=957) IDU-Female (n=68) Heterosexual Male (n=1524) Pairs With >1 Person With HIV Infection 2% 3% 22% 18% 13% Heterosexual Female (n=2718) 16 Oster AM, et al. 21 st CROI. Boston, 214. Abstract 213. Potential Intervention Approaches to Prevent HIV Transmission Decrease Source of HIV Infection Barrier protection STI treatment Blood screening ART - Maternal-to-child transmission - Decrease partner s viral load - Treatment of acute HIV infection Alter Risk-Taking Behavior Condom promotion Individual intervention Couples intervention Community based intervention Structural intervention Decrease Host Susceptibility to HIV Infection Barrier protection STI treatment Oral PEP Oral PrEP Topical microbicides Vaccines Infection control Circumcision Mayer KH, et al. Am J Public Health. 21;1:1867-1876. 17 Simultaneous Use of Different Classes of Prevention Strategies Biomedical Interventions Structural Interventions Combination HIV Prevention HIV Testing, Linkage to Care, Expanded ART Coverage Community Interventions Individual and Small Group Behavioral Interventions 18 6
Targeted Combination HIV Prevention Packages Global HIV epidemic differs by region and population groups - One size fits all prevention package is less likely to be successful UNAIDS: know your epidemic and know your response - Combination prevention strategies Tailored to specific HIV risk profiles (within countries with either concentrated or generalized epidemics) Standard prevention package (HIV counselling and testing, condom promotion, safe sex counseling, STI treatment, and optional PMTCT) should be universal - Enhance with appropriate and manageable biomedical and structural interventions 19 Kurth AE, et al. Curr HIV/AIDS Rep. 211;8:62-72. UNAIDS 213. http://apps.who.int/iris/bitstream/1665/85511/1/978924155826_eng.pdf. Program Overview Treatment and prevention gaps Assessing prevention benefits of ART PrEP for prevention of HIV transmission Providing PrEP 2 Antiretroviral Agents With a Ratio of Tissue:Blood Plasma Levels >1 NRTI Rectal Cervicovaginal Semen Tenofovir DF Emtricitabine Emtricitabine Lamivudine Zidovudine Tenofovir Abacavir Tenofovir DF Zidovudine Emtricitabine Lamivudine NNRTI Etravirine Etravirine -- PI Darunavir Ritonavir Indinavir Indinavir Indinavir Entry Maraviroc Maraviroc -- Inhibitor INSTI Raltegravir Raltegravir Raltegravir Ratio of 1.: genital tract AUC=blood plasma AUC. Genital tract exposure within 2 and 1 hour of dosing for women and men, respectively. 21 Cohen MS, et al. AIDS. 212;26:1585-1598. 7
ART Does Not Completely Suppress HIV in Semen of Sexually Active MSMs Single-cohort study (n=11 sexually active MSMs on ART) - HIV RNA in blood: 18% Medication adherence (n=5) Indications of virologic failure (n=2) All other clinical and behavioral characteristics were similar to HIV negative in blood - HIV RNA in semen: 3% High prevalence of HIV seminal shedding in MSM fully suppressed on ART - Prudent to advise use of condoms and other risk-reduction strategies throughout all stages of HIV disease regardless of HIV treatment status Risk Factors for Detection of HIV in Semen From HIV-Infected MSMs on ART with Undetectable HIV in Blood (Multivariate) High TNF-α levels in seminal plasma (yes versus no) STI status (STI/urethritis versus none) UIAS with HIV-positive person (yes versus no) Odds Ratio (95% CI) 13.97 (2.85, 95.2) (P=.3) 29.3 (2.6, 523) (P=.3) 7.34 (1.59, 47.73) (P=.7) 22 Politch JA, et al. AIDS. 212;26:1535-1543. Evidence Supports Combination ART for Prevention of HIV Transmission Transmission only occurs from persons with HIV HIV RNA level is single greatest risk factor for HIV transmission Combination ART can lower HIV RNA level to undetectable levels Observational evidence in heterosexual couples Previous modeling work suggests considerable potential Knowing one s HIV status is key to prevention with combination ART When to start combination ART is not known for certainty 23 Ecologic Studies: Impact of ART on New HIV Diagnoses Washington, DC San Francisco British Columbia, Canada Denmark Data source Health department AIDS surveillance Health department AIDS surveillance Disease and treatment databases National HIV surveillance data and behavioral surveys Estimation of suppressive ART Annual mean and total or most recent HIV RNA Annual mean and total CVL Number infected receiving ART Prevalence positive on ART Sexual risk behaviors Estimation of HIV incidence Reported new diagnoses Report new diagnoses (STARHS method) New positive test/1 population Annual number of MSM notified as HIV infected Results No association between CVL and new diagnoses Reductions in CVL associated with fewer new infections (though not with STARHS method) Rising numbers of ART recipients and HIV RNA <5 copies/ml associated with decreased HIV diagnoses/year Increasing numbers treated coincides with stable numbers of newly notified HIV positives suggests reduced infectiousness CVL: community viral load. Castel AD, et al. AIDS. 212;26:345-353. Das M, et al. PloS One. 21;5:e1168. Montaner JS, et al. Lancet. 21;376:532-539. Cowen S, et al. 18 th IAC. Vienna, 21. Abstract MoAC13. 24 8
Systematic Review/Meta-Analysis: Impact of ART on HIV Transmission in Heterosexual Discordant Couples HIV RNA (copies/ml) On ART (-1.27) <4 (-1.27) >4 All studies 92% Reduction in HIV Transmission Risk With ART (from 5.64 to.46 transmissions/1 person-years).46 (.19-1.9) Not on ART <4 4-3499 35-9999 1K-49.9K >5K All studies.16 (.2-1.13) 2.6 (.57-7.47) 4.17 (.84-2.65) 8.12 (2.78-23.77) 9.3 (3.87-21.9) 5.64 (3.28-9.7).1.1.2.5 1 2 5 1 2 Transmission Rate (per 1 Person-Years) 25 Attia S, et al. AIDS. 29;23:1397-144. HPTN 52: Stable Heterosexual Couples Randomization Phase 3 study 1:1 Americas, African, Asian sites (n=1763 couples) Stable, healthy, sexually active, serodiscordant couples CD4 35-55 cells/mm 3 Similar baseline demographic characteristics and sexual history/behavior both arms and between HIV-negative partner and HIVpositive, treatment naïve index patient Early ART CD4 35 to 55 cells/mm 3 Primary Endpoints Transmission - Virologically linked transmission events Clinical Delayed ART CD4 <25 cells/mm 3 - WHO stage 4 clinical events - Pulmonary TB - Severe bacterial infection and/or death Cohen MS, et al. N Engl J Med. 211;365:493-55. 26 HPTN 52: HIV Prevention in Stable Heterosexual Couples DSMB halts trials after a median follow-up: 1.7 years - HIV RNA <4 copies/ml Early ART: 9% Delayed ART: 93% Linked HIV transmission to HIVnegative partner (n=28) - Early therapy (n=1).1 per 1 person-years - Delayed therapy (n=27) 1.7 per 1 person-years Early ART led to a 96% reduction of sexual transmission of HIV in serodiscordant couples Cumulative Probability Linked HIV Transmission HR:.4 (95% CI.1-.27) (P<.1) Delayed ART Early ART 1 2 3 4 5 Years Cohen MS, et al. N Engl J Med. 211;365:493-55. 27 9
HPTN 52: Clinical Events 1 9 8.9% Delayed ART (n=875) Early ART (n=886) Patients (%) 8 37% reduction (P=.7) 7 6.4% 6 5 4 3.9% 3 2 1.9% 1 All Primary TB Clinical Events 2.3% 1.5% Severe Bacterial Infection 1.7% 1.2% Death.9%.2%.1%.2%.2% Chronic Bacterial Esophageal Herpes Pneumonia candidiasis Simplex 28 Median follow-up: 2.1 years (1.6-2.9). Patients in the delayed arm initiating ART (24%). Grinsztein B, et al. 19 th IAC. Washington, DC, 212. Anstract ThLBB5. HPTN 52: Key Questions Generalizability of results to other contexts? - High-risk heterosexual couples with CD4 counts lower and higher than HPTN 52 - MSM and IDUs Does ART reduce infectivity through anal sex by the same order of magnitude as for vaginal sex? - PARTNER study (The Partners of People on ART: A New Evaluation of the Risks) - Opposites Attract study 29 Cohen MS, et al. AIDS. 212;26:1585-1598. http://www.partnerstudy.eu/ http://www.oppositesattract.net.au/ PARTNER Study: HIV Transmission Risk Through Condomless Sex in Serodiscordant Couples Observational study (interim analysis) - Serodiscordant couples (n=767; 894 couple-years follow-up) in international multi-centered settings HIV positive: on ART (HIV RNA <2 copies/ml) HIV negative: not on PEP or PrEP - Condomless sex Phylogenetically linked transmissions HIV negative: condomless penetrative sex during follow-up - MSM Receptive anal: 7% Receptive anal with ejaculation: 4% Only insertive anal sex: 3% - Heterosexual Vaginal sex with ejaculation: 73% Rodger A, et al. 21 st CROI. Boston, 214. Abstract 153LB. 3 Study entry HIV(-): condomless sex (years) HIV(+): on ART (years) During follow-up HIV(-): years in study Diagnosed with STI (%) HIV(-) HIV(+) HIV(-): condomless sex Number of acts/year Total number Characteristics (Couples With Eligible Follow-Up) Heterosexual (n=445) MSM (n=282) Male (n=245) Female (n=24) 1.5 5 1.1 16 16 43 16,4 2.7 7 1.5 5 4 37 14, 3.5 1 1.5 6 5 38 14, 1
HIV Transmission According to Sexual Behavior Reported by HIV-Negative Partner Overall HIV transmission rate - Zero through condomless sex with a partner on ART (HIV RNA <2 copies/ml), despite a significant number of sex acts Uncertainty over the upper limit of risk remains - Particularly with receptive anal sex with ejaculation Additional follow-up needed to provide more precise estimates for transmission risk - Duration of prior ART without transmission may have selected for lowest risk discordant couples Rate of Couple Transmission (per 1 Couple-Years Follow-Up) Heterosexual (Male) Vaginal sex with ejaculation (192 CYFU) Heterosexual (Female) Vaginal sex (272 CYFU) MSM Receptive anal sex: With ejaculation (93 CYFU) Without ejaculation (157 CYFU) Insertive anal sex (262 CYFU) 1 2 3 4 Rate (95% CI) 31 CYFU: couple-years follow-up. Rodger A, et al. 21 st CROI. Boston, 214. Abstract 153LB. Program Overview Treatment and prevention gaps Assessing prevention benefits of ART PrEP for prevention of HIV transmission Providing PrEP 32 DHHS Rating Scheme for Recommendations A B C Strength of Recommendation Strong recommendation for the statement Moderate recommendation for the statement Optional recommendation for the statement I II Quality of Evidence for Recommendation One or more randomized trials with clinical outcomes and/or validated laboratory endpoints One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes III Expert opinion DHHS. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf. Revision May 1, 214. 33 11
US Public Service: PrEP for the Prevention of HIV Infection PrEP is recommended as one prevention option for - Sexually active MSMs at substantial risk of HIV acquisition (I-A) - Adult, heterosexually active, women and men whose partners are at substantial risk of HIV acquisition (I-A) - Adult IDUs at substantial risk of HIV acquisition (I-A) Heterosexually active discordant couples - PrEP should be discussed as one of several options to protect the uninfected partner during conception and pregnancy (II-B) Adolescents - Currently, insufficient efficacy and safety data of PrEP - Risks and benefits of PrEP should be weighed carefully in the context of local laws and regulations about autonomy in health care decisionmaking by minors (III-B) 34 CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. US Public Service: PrEP for the Prevention of HIV Infection Emtricitabine/tenofovir DF (2/3 mg) once daily - The only medication FDA approved as PrEP with all specified populations (I-A) Tenofovir DF alone - Alternative regimen in IDUs and heterosexually active adults (I-C) Not recommended - Use of other ART, either in place of or in addition to emtricitabine/tenofovir DF (III-A) - Coitally timed or other noncontinuous daily use (III-A) CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 35 US Public Service: PrEP for the Prevention of HIV Infection Acute and chronic HIV infection - Must be excluded by symptom history and HIV testing immediately before PrEP is prescribed (I-A) Assessments - HIV infection every 3 months (I-A) - Renal function at baseline and at least every 6 months (III-A) When PrEP is prescribed - Provide access, directly or by facilitated referral, to proven effective risk-reduction services (high adherence is critical to PrEP efficacy) (III-B) Encouraged and enabled patients to use PrEP in combination with other effective prevention methods CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 36 12
Program Overview Treatment and prevention gaps Assessing prevention benefits of ART PrEP for prevention of HIV transmission - MSMs - Heterosexual men and women - IDUs Providing PrEP 37 PrEP Trials: Evidence Among MSMs US MSM safety trial iprex trial 38 Grohskopf LA, et al. JAIDS. 213;64:79-86. Grant RM, et al. N Engl J Med. 21;363:2587-2599. US MSM Safety Trial Phase 2 study (3 Sites in US) HIV-negative MSM Creatinine clearance >7 ml/min No HBV infection Screened (n=679) Immediate Treatment Randomization 1:1 9-Month Delayed Treatment Randomization 1:1 Double-Blind Tenofovir DF (n=11) Placebo (n=99) Tenofovir DF (n=1) Placebo (n=1) 9-month delayed treatment arms: Assess risk behavior changes associated with taking study drug. Study Outcomes (immediate and delayed cohorts) Clinical and laboratory safety Exposure to study drug Adherence Exclusion criteria: Active untreated syphilis; uncontrolled hypertension; mutual monogamy for >1 year with an HIV-uninfected partner; chronic renal disease; osteoporosis, osteomalacia, or osteopenia; treatment for low BMD; current ART, potentially nephrotoxic agents; immunosuppressive/ immunomodulatory therapy; gastrointestinal malabsorption syndrome or chronic nausea/vomiting. Grohskopf LA, et al. JAIDS. 213;64:79-86. 39 13
US MSM Safety Trial: Seroconversions Completed study: 87% Seroconversions: 7 out of 4 participants - Taking tenofovir DF (n=) - Placebo (n=4) Acute infection at enrollment (n=1) - Delayed tenofovir arm (not yet started tenofovir DF) (n=3) No K65R mutations were noted among any seroconverting participants Grohskopf LA, et al. JAIDS. 213;64:79-86. 4 US MSM Safety Trial: Safety, Toxicity, and Adherence Adverse events: 9% - Most of these were mild-to-moderate severity (97%) - Frequencies of adverse events and laboratory abnormalities (regardless of severity) were similar between tenofovir DF and placebo arms Only back pain associated with tenofovir DF (P=.4) No grade 3/4 creatinine elevations Serious adverse events were infrequent and similar between the 2 arms (P=.62) Bone mineral density subset analysis (n=184) - Tenofovir DF associated with 1% and.8% decrease in femoral neck and total hip BMD, respectively Estimated percentage of study drug taken - Pill count: 92% (range 79% to 98%) - MEMS: 77% (57% to 92%) Grohskopf LA, et al. JAIDS. 213;64:79-86. 41 iprex Study: MSM and Transgender Women Double-Blind Multinational study HIV-negative men or transgender women who have sex with men Screened (n=495) Randomization 1:1 Emtricitabine/tenofovir DF (n=1251) Similar baseline demographic characteristics (except mean age), sexual risk factors, STIs, and HBV status Placebo (n=1248) Study Outcomes HIV seroconversion Adverse events Metabolic effects HBV exacerbations Risk behavior and STIs (including HSV) Adherence Follow-Up 3324 person-years (median 1.2 years) Drug resistance, HIV RNA level, immunologic response, and CD4 cell count assessed in people who become HIV positive during the study. Grant RM, et al. N Engl J Med. 21;363:2587-2599. 42 14
iprex Study: Comprehensive Package of Prevention Services All subjects received HIV testing, risk-reduction counseling, condoms, and diagnosis and treatment of symptomatic STIs At 24-week intervals, subjects screened for - Asymptomatic urethritis, syphilis, antibodies to HSV-2, genital warts/ulcers - Treatment was provided when indicated Sexual partners - Offered treatment of STIs As needed, linkage to local prevention and treatment services Counseled on the use of conventional methods to protect from HIV HBV vaccination offered to susceptible subjects 43 Grant RM, et al. N Engl J Med. 21;363:2587-2599. iprex Study Results: Cumulative Probability of HIV Infection Cumulative Probability of HIV Infection Placebo (n=1248) P=.5 Emtricitabine/ Tenofovir DF (n=1251) 12 24 36 48 6 72 84 96 18 12 132 Weeks 44 Grant RM, et al. N Engl J Med. 21;363:2587-2599. iprex Study: Drug Resistance Samples analyzed at first evidence of seroconversion - Infected at study entry (n=1) - Infected on study (n=1) Tested (n=91) Incident infection - No drug resistance in participants on emtricitabine/tenofovir DF - Minor variant drug resistance in 2 on placebo K65R (.69%) M184V (1.26%) Acute infection at entry - Acquired emtricitabine resistance (M184V) Resistance waned to undetectable levels through 33 weeks of follow-up 45 Liegler T, et al. 18 th CROI. Boston, 211. Abstract 97LB. 15
iprex Study: Unprotected Receptive Anal Intercourse Overall Patient Population Patients Who Believed They Were Receiving FTC/TDF 1 Emtricitabine/tenofovir DF Placebo 1 Emtricitabine/tenofovir DF Placebo 8 8 Patients (%) 6 4 P=.3 Patients (%) 6 4 P=.44 2 2 12 24 36 48 6 72 84 96 18 12 132 144 Weeks 12 24 36 48 6 72 84 96 18 12 132 144 Weeks Marcus JL, et al. PLoS One. 213 ;8:e81997. 46 iprex Study: Additional Results Nausea - More frequent in the emtricitabine/tenofovir DF arm during weeks 1 to 4 (P<.1) No difference between the two arms - Sexual practices - Decrease in high-risk sexual behavior - STIs - Self-reported pill use (except weeks 4 and 8) Grant RM, et al. N Engl J Med. 21;363:2587-2599. 47 iprex Study: Renal Safety Elevation in serum creatinine >1.1xULN - FTC/TDF versus placebo: 2% versus 1% (P=.8) - Normalized after treatment discontinuation 4 of 5 participants who restarted FTC/TDF did not experience a new elevation Similar safety findings in other PrEP trials - Partners PrEP study - TDF2 study - FEM-PrEP Krakower D, et al. Ann Intern Med. 212;157:49-497. Grant RM, et al. N Engl J Med. 21;363:2587-2599. 48 16
iprex DEXA Substudy HIV uninfected MSMs - Even distribution by race - <3 years of age (~66%) - Similar baseline body composition, risk factors, and bone density Emtricitabine/tenofovir DF (n=247) - Small (.7% to 1.%) decrease in spine and total hip BMD relative to placebo at week 24 (P<.1) No differences in bone fractures between groups Difference in BMD Change: Emtricitabine/Tenofovir - Placebo (95% CI) Total Hip Spine Week 24 -.69* (-1.6 to -.33) 48 -.94 (-1.53 to -.35) 72 -.34 (-1.1 to.42) *P<.1; P=.2. -.94* (-1.5 to -.39) -.58 (-1.24 to.7) -1.3 (-1.88 to -.19) 49 Mulligan K, et al. 18 th CROI. Boston, 211. Abstract 94LB. iprex Study: Changes in Renal Function 5 Small yet statistically significant decrease in estimated creatinine clearance - Between group difference range: -.8 to -2.7 ml/min - Resolved with drug discontinuation No statistically significant effect of emtricitabine/tenofovir DF - Serum phosphorous levels - Indicators of renal proximal tubulopathy Emtricitabine/tenofovir DF for PrEP - May lead to very mild and subclinical glomerular dysfunction without proximal tubular dysfunction Solomon M, et al. 2 th CROI. Atlanta, 213. Abstract 998. Change From Baseline (ml/min) 1 8 6 4 2-2 -4-6 -8-1 Creatinine Clearance Emtricitabine/tenofovir DF Placebo 12 24 36 48 6 72 84 96 18 12 132 144 Weeks Gaps in PrEP Prior to the iprex Open-Label Extension (OLE) iprex participants were eligible to enroll in the openlabel extension (6/211-6/212) - HIV-seronegative (n=1529) PrEP stopped between iprex and randomization in the open-label phase - Gap (per protocol) of 7 to 19 months - Gap allowed study of possibility of higher HIV incidence in treatment group off PrEP Condomless receptive anal intercourse (%) No Yes Age (%) <25 years 25 to 3 years >3 years Prior randomized group (%) Placebo Emtricitabine/tenofovir DF Drug detected in iprex (%) Never Any Enrolled in OLE No Yes 37 33 38 36 27 34 36 43 28 63* 67* 62 64 73 66 64 57 72 *P=.3 and P<.1 versus not in OLE. Grant RM, et al. 2 th CROI. Atlanta, 213. Abstract 27. 51 17
HIV Incidence During the Gap HIV incidence: 3.7/1 person years (n=78 infections) Risk factors for HIV seroconversion during the gap - Condomless receptive anal intercourse: HR 2.1 (P=.2) - Age: HR.93 (P=.2) - HSV infection: HR 2.7 (P<.1) Conclusion - No evidence of prevention futility during PrEP use among MSM and transgendered women - No excess incidence of HIV infections after participants stopped using oral PrEP HIV Incidence (per 1 person-years) Randomized Phase Placebo 3.9 (n=2113) Emtricitabine/ tenofovir DF (fmol/m vpbmc) <1 >1 3.1 (n=15).3 (n=624) Gap Phase 4.1 (n=144) 3.3 (n=148) 52 Grant RM, et al. 2 th CROI. Atlanta, 213. Abstract 27. iprex Open-Label Extension (OLE): PrEP Uptake, Sexual Practices, and HIV Incidence HIV-negative participants of iprex were eligible to enroll in OLE (n=163) - 72-week follow-up - Men or transgender women who have sex with men - PrEP offered if HIV seronegative and no acute viral syndrome - PrEP could be started through week 48 or stopped anytime Elected to receive PrEP (76% at enrollment, 6% started PrEP later) Concern about adverse events was major reason for not choosing PrEP - PrEP uptake was highest among those Reporting condomless receptive anal intercourse (P=.3) Having serologic evidence of herpes (P=.3) No difference in PrEP uptake by age; education; transgender; prior randomized group; or use of alcohol, methamphetamine, or cocaine Grant RM, et al. 2 th IAC. Melbourne, 214. Abstract TUAC15LB. Grant RM, et al. Lancet Infect Dis. 214;July 22, 214. [Epub ahead of print]. 53 iprex Open-Label Extension (OLE): HIV Incidence and Predictors of Detectable Drug 54 HIV incidence in iprex OLE - PrEP versus no PrEP 1.8 versus 2.6 infections/1 person-years (adjusted HR:.51, 95% CI:.26-1.1) - PrEP, but no drug detected 4.7 infections/1 person-years HIV incidence in original iprex: placebo recipients - 3.9 infections/1 person-years Grant RM, et al. 2 th IAC. Melbourne, 214. Abstract TUAC15LB. Grant RM, et al. Lancet Infect Dis. 214;July 22, 214. [Epub ahead of print]. Predictors of Detectable Drug Adjusted Odds Ratio Non-condom intercourse (reference: none) Receptive, anal Male sexual partners (reference: -1) 2-4 >5 Age (reference: 18-24 years) 3-39 >4 Education (reference: <secondary) Secondary Post-secondary 1.66 (P<.1) 1.33 (P=.5) 1.82 (P<.1) 1.64 (P=.2) 3.29 (P<.1) 1.99 (P<.1) 1.93 (P<.1) 18
iprex Open-Label Extension (OLE): HIV Incidence and Risk Reduction by Detectable Drug Tablets/Week: (% patients): <2 (26) 2 to 3 (12) 4to 6 (21) 7 (12) Risk Reduction: 5 44% 84% 1% 1% HIV Incidence (per 1 person-years) 4 3 2 1 On PrEP Off PrEP 55 35 5 7 1 125 15 Tenofovir Diphosphate From Dried Blood Spots (fmol/punch) Grant RM, et al. 2 th IAC. Melbourne, 214. Abstract TUAC15LB. Grant RM, et al. Lancet Infect Dis. 214;July 22, 214. [Epub ahead of print]. iprex Open-Label Extension (OLE): Conclusions PrEP uptake was high across a broad range of demographic groups when provided free of charge Sexual risk was associated with - Higher retention and greater PrEP uptake - Greater adherence Adherence has to be good, not perfect - Risk reduction of 2-3 versus >4 tablets/week: 84% versus 1% PrEP fails if people stop while still at risk for HIV Tenofovir diphosphate concentrations (dried blood spot) - Convenient markers of long-term average PrEP use - Correlate strongly to PrEP protection Grant RM, et al. 2 th IAC. Melbourne, 214. Abstract TUAC15LB. Grant RM, et al. Lancet Infect Dis. 214;July 22, 214. [Epub ahead of print]. 56 US Public Service: Recommended Indications for PrEP in MSMs Adult man without acute or established HIV infection, any male sex partners in past 6 months, not in a monogamous partnership with a recently tested, HIVnegative man AND at least one of the following - Any anal sex without condoms (receptive or insertive) in past 6 months - Any STI diagnosed or reported in past 6 months - Is in an ongoing sexual relationship with an HIV-positive male partner 57 CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 19
US Public Service: Risk Behavior Assessment for MSMs In the past 6 months - Have you had sex with men, women, or both? If men or both sexes, how many men have you had sex with? - How many times did you have receptive anal sex (you were the bottom) with a man who was not wearing a condom? - How many of your male sex partners were HIV-positive? If any positive, with these HIV-positive male partners, how many times did you have insertive anal sex (you were the top) without you wearing a condom? - Have you used methamphetamines (such as crystal or speed)? CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 58 Program Overview Treatment and prevention gaps Assessing prevention benefits of ART PrEP for prevention of HIV transmission - MSMs - Heterosexual men and women - IDUs Providing PrEP 59 PrEP Trials: Evidence Among Heterosexual Men and Women Partners PrEP trial TDF2 trial FEM-PrEP trial VOICE trial Baeten J, et al. N Engl J Med. 212;367:399-41. Thigpen MC, et al. N Engl J Med. 212;367:423-434. Van Damme L, et al. N Engl J Med. 212;367:411-422. Marrazzo J, et al. 2 th CROI. Atlanta, 213. Abstract 26LB. 6 2
Partners PrEP Study: Serodiscordant Heterosexual Couples Randomization 1:1 Double-Blind Tenofovir DF qd (n=1584) 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 Primary Endpoints HIV infection in HIV-negative partner Safety Emtricitabine/Tenofovir DF qd (n=1579) Follow-Up Up to 36 months (median 23 months; 783 person-years) Placebo (n=1584) All patients received comprehensive HIV prevention services. 61 Baeten J, et al. N Engl J Med. 212;367:399-41. Partners PrEP Study: Comprehensive Prevention Services Risk reduction counseling (individuals and partners) Free condoms and condom counseling Contraception counseling and provision Screening and treatment for STIs Counseling and referral for other HIV-prevention interventions (eg, male circumcision), per national policies 62 Baeten J, et al. N Engl J Med. 212;367:399-41. Partners PrEP Study: DSMB Interim Monitoring (July 1, 211) 96 newly acquired HIV infections - 14 had HIV RNA retrospectively detected in specimens from enrollment Of 82 infections developing after randomization - Tenofovir DF (n=17) - Emtricitabine/tenofovir DF (n=13) - Placebo (n=52) 63 Baeten J, et al. N Engl J Med. 212;367:399-41. 21
Partners PrEP Study: Cumulative Acquired HIV Infections Cumulative Acquired HIV Infection.5.4.3.2.1 Placebo (n=1568) Emtricitabine/ Tenofovir DF (n=1568) Tenofovir DF (n=1572) 3 6 9 12 15 18 21 24 27 3 33 36 Months Baeten J, et al. N Engl J Med. 212;367:399-41. 64 Partners PrEP Study: Results Both PrEP arms significantly reduced the risk of HIV acquisition - Similar results between males and females - Safe and well tolerated Mild diarrhea No difference in renal function Tenofovir DF levels significantly correlated with HIV protection - Relative risk reduction 86% to 9% associated with detectable tenofovir DF No evidence of risk compensation No evidence of resistance among those who became HIV infected HIV Incidence (per 1-person-years) 2 1.5 1.5 1.99 Placebo HIV Incidence 67% Reduction (P<.1).65 Tenofovir DF 75% Reduction (P<.1).5 Emtricitabine/ Tenofovir DF Baeten J, et al. N Engl J Med. 212;367:399-41. 65 Partners PrEP Study: Follow-Up Results After July 211 Total follow-up: 8791 person-years - Additional since July 211: 3569 person-years Median follow-up: 35.9 months for hose initially assigned to PrEP and 12 months for those re-randomized from placebo on HIV protection similar between tenofovir DF and emtricitabine/ tenofovir DF Tenofovir levels significantly correlated with HIV protection - Relative risk reduction 85% to 9% associated with detectable tenofovir DF HIV Incidence (After July 211) FTC/ TDF TDF HIV infections (number) Overall Pre-July 211 Post July 211 HIV incidence (1 person-years) Hazard ratio for HIV protection with FTC/TDF versus TDF 31 17 14 21 13 8.7.48.67 (P=.16) 66 Baeten J, et al. 21 st CROI. Boston, 214. Abstract 43. 22
Partners PrEP Study: Low Frequency Resistance Testing Among Seroconverters Double-blind, phase 3 study of serodiscordant, heterosexual couples - PrEP significantly reduced the risk of HIV infection by 67% to 75% (P<.1) - Ultra-deep versus standard sequencing Detect drug resistance at frequencies >1% versus >2%, respectively Ultra-deep sequencing on samples from 121 seroconverters Overall resistance: 7.4% (9/121) - HIV positive at enrollment (n=3) - Acquired HIV after enrollment (n=6) TDF (2/38): 1 M184V, 1 K65R/M184V TDF/FTC (5/25): 4 M184V, 1K65R/K7E Detection of PrEP drug in blood plasma was associated with an increased risk of resistance (P=.9) Seroconverters (%) Resistance Detected Above Frequencies of 1% in 121 Seroconverters 1 8 6 4 2 Emtricitabine/tenofovir DF Tenofovir DF Placebo 2% 5.3% 3.5% Overall (n=25/38/58) 5% 12.5% 14.3% Before (n=4/8/6) % 3.3%3.8% After (n=21/3/52) Found to Be HIV Positive Before or After Study Enrollment 67 Lehman DA, et al. 21 st CROI. Boston, 214. Abstract 59LB. Partners PrEP Study: Subsets of High-Risk Participants HIV Incidence (per 1-person-years) 7 6 5 4 3 2 1 Placebo Tenofovir DF Emtricitabine/tenofovir DF 3.9 75% Reduction (P=.5).9 86% Reduction (P=.2).6 Unprotected Sex Prior 3 Months (n=857/896/893) HIV Incidence 3.9 76% Reduction (P=.9).9.9 Partner HIV RNA >5K Copies/mL (n=289/269/271) 78% Reduction (P=.6) 4.3 52% Reduction (P=.5) 2. 87% Reduction (P=.2).5 Partnership Duration <2 Years (n=257/236/242) 68 Murnane P, et al. AIDS. 213;27:2155-216. Partners PrEP Study: Subsets of High-Risk Women HIV Incidence (per 1-person-years) 7 6 5 4 3 2 6.5 HIV Incidence 75% 74% Reduction Reduction (P=.3) (P=.37) 5.49 84% Reduction (P=.16) 72% Reduction (P=.27) 1.6 1.6 1.7 Placebo Tenofovir DF Emtricitabine/tenofovir DF 4.6 79% Reduction 78% (P=.43) Reduction (P=.46) 1.9.8.9 Unprotected Sex Prior 3 Months (n=329/314/319) Partner HIV RNA >5K Copies/mL (n=154/144/146) Male Partner >1 Years Older (n=143/149/136) 69 23
Partners PrEP Study: HIV Prevention Among Women Using DMPA Contraception PrEP efficacy among women using DMPA or men exposed to DMPA by their female partners - 67% (2429/3638) in PrEP arm - Sex acts in past month With study partner: 4 (none unprotected) PrEP efficacy - Women using DMPA: 71% - Men whose female partners used DMPA: 9% PrEP efficacy did not differ based on exposure status to DMPA or hormonal contraception Women All (FTC/TDF only) Using DMPA No hormonal contraception or DMPA Men All (FTC/TDF only) DMPA exposure No exposure to hormonal contraception or DMPA PrEP Efficacy Versus Placebo.1.16.16.29.34.34.2.4.6.8 1. 1.2 Unadjusted Hazard Ratio (95% CI) 7 DMPA: depot medroxyprogesterone acetate. Heffron R, et al. 21 st CROI. Boston, 214. Abstract 95. Partners PrEP Study: When to Stop PrEP in Serodiscordant Partners Situations under which PrEP could be discontinued - Ending sexual activity with the HIV-infected partner - HIV-infected partner initiating ART Serodiscordant couples still sexually active as a couple and not initiated ART (n=4747) - 12 months: 75% - 24 months: 54% - 36 months: 39% PrEP might serve as a time-limited bridge to ART initiation in couples - Studies are needed to evaluate simple strategies for PrEP discontinuation Baeten J, et al. 2 th CROI. Atlanta, 213. Abstract 12. 71 Cumulative Probability Discontinuation of Sex and/or ART Initiation in HIV-Infected Partner 1.8.6.4.2 Stopped sex Initiate ART Either 3 6 9 12 15 18 21 24 27 3 33 36 Months Partners PrEP Study: Pregnancy and Birth Outcomes Among Serodiscordant Heterosexual Couples Pregnancy incidence among initially HIV-uninfected women (n=1785) - 1.3 per 1 women-years No difference between tenofovir DF exposure and placebo - Pregnancy incidence - Congenital abnormalities No evidence of adverse pregnancy outcome as measured by birth outcome and infant growth during the first year of life Outcome (%) 1 8 6 4 2 Pregnancy and Delivery Outcomes Tenofovir DF Emtricitabine/tenofovir DF Placebo 72% 68% 58% Live Births (n=112/8/96) 3% 5% 7% Preterm Delivery (n=73/4/54) Mugo M, et al. 7 th IAS Conference. Kuala Lumpur, 213. Abstract WeAC11. 72 24
TDF2 Study: PrEP in Heterosexually Active Young Adults in Botswana Phase 2 trial in heterosexual men and women (n=1219) - 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 [1 males/14 females]) Results in women differed than that seen in the FEM-PrEP study Proportion HIV Seroconversion (ITT) Placebo (n=66) 62% Reduction (P=.3) Emtricitabine/ Tenofovir DF (n=61) 1 2 3 Years 73 Thigpen MC, et al. N Engl J Med. 212;367:423-434. TDF2 Study: Open-Label Extension (Botswana 213) Offered PrEP with efficacy during the TDF2 study (n=267) - Started PrEP (n=229) Most felt at risk or their partner was at risk (P<.2) Completed 12 months of follow-up: 54% - ~7% of those completing follow-up perceived their HIV risk to medium or high at baseline (P=.3) Severe adverse evens (n=1) - Grade 3 hypophosphatemia (n=6, 2 discontinued); grade 3 hyperamylasemia (n=3), grade 1 hypercreatinemia Next steps - Motivations and risk behaviors - Drug levels and adherence 74 Chirwa LI, et al. 2 th IAC. Melbourne, 214. Abstract TUAC14MOAB15LB. 75 FEM-PrEP Study PrEP for HIV prevention among heterosexual women - Women at high risk for HIV infection in 3 African nations (goal: approximately 39 women; actual: 212 women) Emtricitabine/tenofovir DF or placebo New HIV infections (n=68) - Emtricitabine/tenofovir DF (n=33) - Placebo (n=35) Potential reasons for disappointing results - Low genital exposure of emtricitabine/tenofovir DF following oral administration - Overall pregnancy rate: 9% Highest rates: women using oral contraceptives - Differential nonadherence Van Damme L, et al. N Engl J Med. 212;367:411-422. 25
FEM-PrEP Study: Final Results 76 Adherence too low to access the efficacy of daily, oral PrEP - <4% of visits with tenofovir detected in plasma No safety concerns Pregnancies (tenofovir DF versus placebo) - Overall: 11.2% verus 7.5% (P=.13) - Among OC users: 31.9% versus 25.5% (reflects adherence problem) No resistance to tenofovir DF - Emtricitabine (n=5, including one in the placebo arm) HIV Incidence (per 1-person-years) 6 5 4 3 2 1 5. HIV Incidence 6% Reduction (P=.81) Placebo Overall Censored* Emtricitabine/Tenofovir DF *When product last available. Van Damme L, et al. N Engl J Med. 212; 367:411-422. 4.7 18% Reduction (P=.44) 4.2 VOICE Study (MTN-3): Vaginal and Oral Interventions to Control the Epidemic 77 Phase 2b, double-blind PrEP study for preventing sexual transmission of HIV in women (29-211) (n=529) - 15 trial sites (Uganda, South Africa, Zimbabwe) - Comprehensive HIV prevention counseling, condoms, contraception, pregnancy test, STI evaluation and treatment - Randomized arms Oral tenofovir DF (stopped 9/11) Tenofovir gel (stopped 11/11) Oral emtricitabine/tenofovir DF Placebo (oral, gel) Oral tenofovir DF and topical tenofovir arms were safe but not effective Marrazzo J, et al. 2 th CROI. Atlanta, 213. Abstract 26LB. Overall Baseline Characteristics Patients (n=529) Age Mean (years) <25 years of age (%) 25.3 51 Married (%) 21 Contraceptive (%) Injectable Oral Male partner (>2 past 3 months (%) Condom on last vaginal sex (%) 71 23 22 85 Baseline characteristics were similar among the randomized arms. VOICE Study (MTN-3): Overall Outcomes Overall HIV incidence: 5.7% Pregnancy incidence: 7.8% Adherence was 89% by self report Pharmacokinetic substudy (n=773): detectable TDF in 25% to 3% of patients (sub-therapeutic in ALL) - Predictors of tenofovir detection Age >25 years (P=.3) Married (P<.1) Male partner >28 years of age (P=.2) Results consistent with FemPrep Understanding HIV risk perception and biomedical social and cultural determinants of adherence in this highrisk population is urgently needed Primary Efficacy Results HIV Incidence (per 1 patient-years) Hazard Ratio* (95% CI) Gel placebo 6.8 1. Tenofovir gel 5.9.85 (.6, 1.2) Oral TDF 6.3 1.49 (.97, 2.3) Oral FTC/TDF *HIV protection versus placebo. 4.4 1.4 (.7, 1.5) Marrazzo J, et al. 2 th CROI. Atlanta, 213. Abstract 26LB. 78 26
US Public Service: Recommended Indications for PrEP in Heterosexual Men and Women Adult person without acute or established HIV infection, any sex with opposite sex partners in past 6 months, not in a monogamous partnership with a recently tested HIVnegative partner AND at least one of the following - Is a man who has sex with both women and men (behaviorally bisexual) - Infrequently uses condoms during sex with 1 or more partners of unknown HIV status who are known to be at substantial risk of HIV infection (IDU or bisexual male partner) - Is in an ongoing sexual relationship with an HIV-positive partner CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 79 US Public Service: Risk Behavior Assessment for Heterosexual Men and Women In the past 6 months - Have you had sex with men, women, or both? If opposite or both sexes, how many men/women have you had sex with? - How many times did you have vaginal or anal sex when neither you nor your partner wore a condom? - How many of your sex partners were HIV-positive? If any positive, with these HIV-positive male partners, how many times did you have vaginal or anal sex without a condom? CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 8 Program Overview Treatment and prevention gaps Assessing prevention benefits of ART PrEP for prevention of HIV transmission - MSMs - Heterosexual men and women - IDUs Providing PrEP 81 27
PrEP Trials: Evidence Among IDUs Bangkok Tenofovir study Choopanya K, et al. 7 th IAS Conference. Kuala Lumpur, 213. Abstract WeLBC5. Choopanya K, et al. Lancet. 213;381:283-29. 82 The Bangkok Tenofovir Study: Antiretroviral Prophylaxis for HIV in IDUs Double-Blind Phase 3, Double-Blind Study HIV-negative IDUs from 17 drug-treatment clinics in Bangkok, Thailand (25-21) Screened (n=494) Randomization 1:1 Tenofovir DF 3 mg qd (n=124) Similar baseline demographic characteristics (except MSMs), sexual risk factors (except sex with casual versus live-in partner) Placebo (n=129) Study Outcomes HIV seroconversion (primary) Adherence (DOT patients only) Risk of HIV infection by tenofovir plasma concentrations Adverse events Follow-Up 9665 person-years (mean 4. years) Adherence measures: either daily directly observed taking study drug (DOT) or monthly visits without DOT. Drug resistance, HIV RNA level, immunologic response, and CD4 cell count assessed in people who become HIV positive during the study. Choopanya K, et al. 7 th IAS Conference. Kuala Lumpur, 213. Abstract WeLBC5. Choopanya K, et al. Lancet. 213;381:283-29. 83 The Bangkok Tenofovir Study: Antiretroviral Prophylaxis for HIV in IDUs Cumulative Probability of HIV Infection (%) 1 8 6 4 2 Tenofovir DF Efficacy: 48.9% Reduction in HIV Incidence (P=.1) Placebo (n=127) Tenofovir DF (n=124) 12 24 36 48 6 72 84 Months Choopanya K, et al. 7 th IAS Conference. Kuala Lumpur, 213. Abstract WeLBC5. Choopanya K, et al. Lancet. 213;381:283-29. 84 28
The Bangkok Tenofovir Study: Tenofovir DF Efficacy and Adherence Efficacy in DOT participants taking study drug >71% of days with <2 consecutive days off study drug - Overall: 56% (-25.1 to 84.5; P=.12) - Those with detectable tenofovir DF: 74% (16.6 to 94.; P=.3) Odds of HIV infection in unmatched case-control study (tenofovir DF recipients) - 3 times lower among tenofovir DF detectable versus undetectable (odds ratio:.3; P=.4) 7% reduction in risk No tenofovir DF resistance mutations No significant safety concerns Efficacy (%) Tenofovir DF Efficacy by Adherence 1 84% 8 68% 72% 6 58% 54% 49% 4 2 Overall >67 >75 >9 >95 >97.5 Adherence Level (%) 85 Choopanya K, et al. 7 th IAS Conference. Kuala Lumpur, 213. Abstract WeLBC5. Choopanya K, et al. Lancet. 213;381:283-29. The Bangkok Tenofovir Study: Changes in HIV-Associated Risk Behavior Risk behavior (injecting, needle sharing, sex) declined during follow-up (P<.1) - No difference between tenofovir DF and placebo groups Independent risk factors for incident HIV infection (multivariate, hazard ratio) - Young age (2-29 versus >3 years): 1.9 (P=.2) - Sharing needles: 8.9 (P=.1) - Incarceration: 2.7 (P=.2) Patients (%) Patients (%) 8 6 4 2 Injecting and Needle Sharing 8 Tenofovir DF (n=121) Placebo (n=124) 6 4 2 Injecting Sharing 12 24 36 48 6 72 Study Visit (month) Sex Tenofovir DF (n=121) Placebo (n=124) Casual partners >1 partner 12 24 36 48 6 72 Study Visit (month) 86 Vanichseni S, et al. 7 th IAS Conference. Kuala Lumpur, 213. Abstract MoLBPE27. US Public Service: Recommended Indications for PrEP in IDUs Adult person without acute or established HIV infection, any injection of drugs not prescribed by a clinician in past 6 months AND at least one of the following - Any sharing of injection or drug preparation equipment in past 6 months - Been in a methadone, buprenorphine, or suboxone treatment program in past 6 months - Risk of sexual acquisition CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 87 29
US Public Service: Risk Behavior Assessment for IDUs Have you ever injected drugs that were not prescribed to you by a clinician? - If yes, when did you last inject unprescribed drugs? In the past 6 months, have you - Injected by using needles, syringes, or other drug preparation equipment that had already been used by another person? - Been in a methadone or other medication-based drug treatment program? CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 88 Program Overview Treatment and prevention gaps Assessing prevention benefits of ART PrEP for prevention of HIV transmission - MSMs - Heterosexual men and women - IDUs Providing PrEP 89 Providing PrEP: Goal of Therapy Reduce the acquisition of HIV infection with its resulting morbidity, mortality, and cost to individuals and society 9 CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 3
US Public Service: PrEP for the Prevention of HIV Infection Consider for HIV-negative people at substantial risk for acquiring HIV infection MSM Heterosexual Women and Men HIV-positive sexual partner Recent bacterial STI High number of sex partners Inconsistent or no condom use Commercial sex work High-prevalence area or network IDU HIV-positive sexual partner Sharing injection equipment Recent drug treatment (but currently injecting( Clinically eligible Regimens Preferred Documented negative HIV test result before prescribing PrEP No signs/symptoms of acute HIV infection Creatinine clearance >6 ml/min; no contraindicated medications HBV status known and, if appropriate, vaccination given Emtricitabine/tenofovir DF (2/3 mg) qd Daily, continuing, oral dose, <9-day supply Alternative None Tenofovir DF (3 mg) qd Daily, continuing, oral dose, <9-day supply 91 CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. US Public Service: PrEP for the Prevention of HIV Infection Specific tests MSM Oral/rectal Gonorrhea and Chlamydia NAAT, and syphilis serology Heterosexual Women and Men Assess pregnancy intent Pregnancy test every 3 months IDU Access to clean needles/ syringes and drug treatment services Other services Every 3 months HIV test, medication adherence counseling, behavioral risk reduction support, side effect assessment, STI symptom assessment At 3 months and every 6 months thereafter Assess renal function Every 6 months Test for bacterial STIs CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 92 Providing PrEP: Time to Achieving Protection Time to maximal protection against HIV infection is unknown - No scientific consensus on what intracellular concentrations are protective for either drug or the protective contribution of each drug in specific body tissues - Pharmacokinetics of tenofovir DF and emtricitabine vary by tissue Preliminary pharmacokinetic data on lead-time to achieve maximal intracellular concentrations tenofovir diphosphate with daily dosing of tenofovir DF - Blood: ~2 days - Rectal tissue: ~7 days - Cervicovaginal tissues: 2 days - Penile tissues: no data 93 CDC. May 14, 214. http://www.cdc.gov/hiv/pdf/prepguidelines214.pdf. 31