Epidemiology Updates 12/8/16. Disclosures. HIV Prevention Update

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1 Disclosures I have no financial disclosures. HIV Prevention Update Hyman M. Scott, MD MPH Medical Director, Clinical Research Bridge HIV, San Francisco Department of Public Health Assistant Clinical Professor Division of HIV, ID, and Global Medicine, UCSF The views expressed herein do not necessarily reflect the official policies of the City and County of San Francisco; nor does mention of the San Francisco Department of Public Health imply its endorsement. Diagnoses of HIV Infection among Adult and Adolescent Males, by Transmission Category, United States and 6 Dependent Areas Epidemiology Updates Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting. a Heterosexual contact with a person known to have, or to be at high risk for, HIV infection. b Includes hemophilia, blood transfusion, perinatal exposure, and risk factor not reported or identified. 3 1

2 Diagnoses of HIV Infection among Men Who Have Sex with Men, by Age Group, United States and 6 Dependent Areas Diagnoses of HIV Infection among Men Who Have Sex with Men Aged Years, by Race/Ethnicity, United States and 6 Dependent Areas Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting. Data on men who have sex with men do not include men with HIV infection attributed to male-to-male sexual contact and injection drug use. Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting. Data on men who have sex with men do not include men with HIV infection attributed to male-to-male sexual contact and injection drug use. a Hispanics/Latinos can be of any race. Lifetime risk of HIV among MSM High rates of HIV in adolescent girls and young women in South Africa One in n 95% CI MSM Overall 1:6 6-6 American Indian/Alaskan Native 1: Asian 1: Black 1:2 2-2 Hispanic/Latino 1:4 4-5 Native Hawaiian/Other PI 1:7 4-7 White 1: Age Group (years) HIV Prevalence (21) % (95% Confidence Interval) Male (n=1252) Female (n= 1423) ( ) 2.6 (1.2-4.) (.2-2.) 6.1 ( ) ( - 3.7) 13.6 ( ) ( - 3.9) 24.7 ( ) Hess et al, CROI 216 Abs# 52 2

3 The Youth Bulge in Southern Africa Cycle of HIV transmission Schematic of sexual networks from clusters with heterosexual transmission Men 25-4 years (N=79) Community HIV prevalence: 4.3% 25 M 1-24 yo females Rest of SSA M 1-24 yo females Most young women <25 years acquire HIV from older men (Mean age difference = 8.7 years) 39% of the men linked to a woman < 25 are simultaneously also linked to a woman 25-4 years Most men & women 25-4 years acquire HIV from similarly aged partners (Mean age difference = 1.1 years) Females Males Females Males Southern Africa Females Males Females Males Source: Census, courtesy D. Birx Young women <25 years (N=43) 62% of male partners are 25-4 years When young women reach >25 years they continue the cycle Women 25-4 years (N=56) 63% of male partners are 25-4 years Community HIV prevalence: 22.3% Community HIV prevalence: 59.8% Adapted from Oliveira, Khanyile TUSS63, AIDS216 HIV Acquisition IL-8 IL-1α TNF-α IL-1β IL-1 MIP-1β MIP-1α MCP-1 IP-1 IL-6 IL-7 GM-CSF Max Later became HIV-infected (n=58) Remained HIV-uninfected (n=58) Women who later became HIV-infected had pre-infection genital inflammation what is the cause? Min Passmore & Williams TuSS64, AIDS

4 Vaginal Lumen Stratified Squamous Epithelia Vaginal microbial dysbiosis *The majority of women with dysbiosis are undiagnosed by Nugent score Healthy vagina ê ph Burgener & Klatt, TUSS65, AIDS 216 Lactobacilli Gardnerella Microbial dysbiosis é ph Mobiluncus How do vaginal bacteria impact PrEP effectiveness? Prevotella Atopobium Probability of HIV infection Tenofovir gel effective against HIV with Lactobacillus dominance Efficacy, 61% 95% CI, 11 to 84% A. Lactobacillus dominant Tenofovir Years in Study HR =.39 (95% CI:.2;.83) Placebo P=.13 Probability of HIV infection B. Non-Lactobacillus dominant Efficacy, 18% 95% CI, -77 to 63% Tenofovir Years in Study HR =.82 (95% CI:.4; 1.65) Placebo Lactobacillus dominant non- Lactobacillus dominant Tenofovir Placebo Tenofovir Placebo # HIV-1 infections HIV-1 incidence per 1 person-years HIV-1 protection effectiveness 95% CI, P-value Burgener & Klatt, TUSS65, AIDS % (11, 84), p=.13 18% (-77, 63), p=.644 P=.644 Tenofovir is rapidly depleted by Gardnerella but not Lactobacillus Sero-different Couples Tenofovir Fold Change Tenofovir (supernatant) Time (hours) 4 hours: G. vag vs. L. iners: P=.2 G. vag vs Abiotic: P=.5 24 hours: G. vag vs. L. iners: P<.1 G. vag vs Abiotic: P<.1 Abiotic L. iners G. vaginalis Tenofovir (mg/ml) Tenofovir (cell) Time (hours) 4 hours: G. vag vs. L. iners: P<.1 24 hours: G. vag vs. L. iners: P<.1 L. iners G. vaginalis Burgener & Klatt, TUSS65, AIDS 216 PARTNERS (Rodger, JAMA 216;316(2): ) 888 sero-different heterosexual and MSM couples from 14 European countries HIV positive partner on ART, VL < 2 and intend to have sex in upcoming months Median 5-11 years on ART before study (MSM, hetero) Median 1.3 years of f/u NO NEW INFECTIONS BETWEEN PARTNERS, BUT 95% CI as high as 2.7/1 couple years for receptive anal sex 22 HIV negatives acquired HIV infection in the study (all outside partnerships) Opposites Attract (Bavinton, THAC11, AIDS216) 359 sero-different MSM couples from Australia, Brazil, Thailand) No HIV transmissions to date within couples, but Nearly 9% of anal sex acts were protected by condoms or ARVs 4

5 Significant Increase in PrEP Uptake (a partial) PrEP Update Unique Individuals 87% increase in PrEP Starts 172% for women and 1,45% for men. Quarters 17 Slide courtesy of Keith Rawlings Bush,S. et al. HIV Drug Therapy 216; Glasgow, Scotland Disparities in PrEP Uptake 8 Males Receiving FTC/TDF for PrEP by Race/Ethnicity: KPNC Compared to National Database Total FTC/TDF for PrEP Utilization by Race/Ethnicity, Sept 215, US a Estimated New HIV Infections, 214, US % 1% 12% 27 % % 23 % KPNC Bush 4% 3% 2% 1 AA White Hispanics Asians Multiracial/Other White Hispanic Asian/Pacific Islander Black Other 19 Adapted from Bush S, et al. ASM/ICAAC 216; Boston, MA #2651 Slide courtesy of Keith Rawlings Bush,S. et al. HIV Drug Therapy 216; Glasgow, Scotland 5

6 Racial Distribution of PrEP Users 216 Compared to Newly Diagnosed HIV Cases 215 1% 9% 8% 7% 6% 5% 4% 3% 2% 17% 1% 26% % Black Latino API White -- New HIV infxns Kaiser SF SFDPH PC Clinics STD clinic Strut CBO Testing Sites 12% 42% Scheer S et al. HIVR4P 216abstract OA24.3 Age Distribution of PrEP Users 216 Compared to Newly Diagnosed HIV Cases 215 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% 1% % 36% 3% 22% 11% < New HIV infxns Kaiser SF SFDPH PC Clinics STD clinic Strut CBO Testing Sites Scheer S et al. HIVR4P 216abstract OA24.3 Gender Distribution of PrEP Users 216 Compared to Newly Diagnosed HIV Cases 215 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % 88% 9% Male Female Transfemale -- New HIV infxns Kaiser SF SFDPH PC Clinics STD clinic Strut CBO Testing Sites Scheer S et al. HIVR4P 216abstract OA24.3 2% Disparities in PrEP Persistence, SFDPH PCC Chart review, lab and pharmacy databases Overall persistence 67% in past year No difference by gender or age By clinic, ranges 3%-1% Differences in appointments, adherence to protocol, panel management. Racial/Ethnic Differences in PrEP Persistence: Race/Ethnicity % of Patients Persistence Duration (median) Asian 8% 75% 9 months African American 9% 5% 4 months Latino 18% 57% 6 months White 43% 68% 12 months Other 19% 69% 7 months 6

7 We still need options! NEW PREP AGENTS Injectable PrEP Cabotegravir (CAB) Long acting injectable HIV integrase inhibitor. Being developed for both HIV prevention and treatment. Favorable attributes for PrEP: High genetic barrier to resistance PK profile half life of 21-5 days -- allows once-daily oral or 1-3 month injectable dosing using nanosuspension formulation ÉCLAIR: Cabotegravir LA in HIV- Negative Men at Low Risk for HIV Infection Cabotegravir: potent INSTI formulated as oral tablet and for LA IM injection Randomized, double-blind phase IIa trial Primary endpoint: safety, tolerability of CAB LA IM injections 2 HIV seroconversions, none during CAB LA dosing period Healthy adult men at low risk of HIV infection (N = 127) Oral Phase CAB 3 mg PO QD Placebo PO QD Injection Phase Wk 4 Wk 41 CAB LA 8 mg IM every 12 wks (n = 16) Saline Placebo IM every 12 wks (n = 21) 4-Wks of followup Muller et al. European Journal of Pharmaceutics and Biopharaceutics 211 Spreen 7 th IAS 213; Min ICAAC 29 Taoda International Congress on Drug Therapy in HIV Infection 212 Markowitz M, et al. CROI 216. Abstract 16. Slide credit: clinicaloptions.com 7

8 ÉCLAIR: Patient Satisfaction With IM Therapy vs Oral Phase Long Pharmacologic Tail Pt satisfaction assessed by questionnaire at Wk 18 of IM treatment; asked pts to compare satisfaction of current IM vs past oral therapy [1] Pts (%) How satisfied are you with your current treatment? CAB (n = 91) Placebo (n = 21) More Neutral Less How satisfied would you be to continue with your present form of treatment? CAB (n = 91) Placebo (n = 21) In separate macaque study, CAB LA conferred 88% protection (21/24 animals) against IV exposure to SIVmac251; results may be relevant to humans who inject drugs [2] 1. Markowitz M, et al. CROI 216. Abstract Andrews CD, et al. CROI 216. Abstract 15. Reproduced with permission. Slide credit: clinicaloptions.com Ford S. HIVR4P 216Abstract OA12.6LB. Step 1 Step 2 Injectable Cabotegravir HPTN 83: Efficacy of injectable cabotegravir (CAB) for PrEP in MSM and transgender women N = 45; Goals: 1% TGW overall; 5% of US BMSM; 5% overall < 3 year old Study duration: 3-5 years Sites in North and South America; Asia; SSA (limited) CAB TDF/FTC Step 3 Daily oral CAB and oral TDF/FTC placebo CAB injection x 2, 4 weeks apart then every 8 weeks plus daily oral TDF/FTC placebo Daily oral TDF/FTC and oral CAB placebo Placebo injection x 2, 4 weeks apart then every 8 weeks plus daily oral TDF/FTC Open-label daily oral TDF/FTC to cover the PK tail, for up to 48 weeks Primary objective: HIV Incidence MTN-2/ASPIRE & IPM-27: Dapivirine Vaginal Ring for HIV Prevention in Women Silicone elastomer vaginal matrix ring containing NNRTI dapivirine 25 mg; ring replaced every 4 wks Randomized, double-blind phase III trials MTN-2/ASPIRE [1,2] : Malawi, South Africa, Uganda, Zimbabwe IPM-27 (The Ring Study) [3] : South Africa, Uganda Primary endpoints: efficacy and safety Sexually active HIV-uninfected adult women (ASPIRE: N = 2629; IPM-27: N = 1959) 1. Baeten JM, et al. CROI 216. Abstract 19LB. 2. Baeten JM, et al. N Engl J Med. 216;[ 3. Nel A, et al. CROI 216. Abstract 11LB. Dapivirine 25 mg Vaginal Ring every 4 wks + HIV Prevention Service Package (ASPIRE: n = 1313; IPM-27: n = 13) Placebo Vaginal Ring every 4 wks + HIV Prevention Service Package (ASPIRE: n = 1316; IPM-27: n = 65) 1 yr; endpointdriven duration Slide credit: clinicaloptions.com 8

9 MTN-2/ASPIRE & IPM-27: Efficacy and Safety of Dapivirine Vaginal Ring Efficacy for HIV prevention similar in both studies No clinically relevant safety differences between arms MTN-2/ASPIRE Subcohort: Adherence vs HIV Protection 3 Mos Before Detection Sustained adherence associated with 92% reduction in risk of HIV infection 1 Outcome ASPIRE [1,2] : 15 Sites ASPIRE [1,2] : 13 Sites* The Ring Study [3] Dapivirine (n = 138) Placebo (n = 136) Dapivirine (n = 1198) Placebo (n = 1197) Dapivirine (n = 13) Placebo (n = 65) HIV infections, n HIV incidence (per 1 PYs) HIV protection efficacy, % (P =.46) 37 (P =.7) 31 (P =.4) HIV Infection Risk Reduction (%) 5-5 Risk reduction 11% (95% CI: -78 to 55) Risk reduction 29% (95% CI: -52 to 66) Risk reduction 58% (95% CI: -7 to 83) Risk reduction 92% (95% CI: 38 to 99) Among women older than 21 yrs *Excludes 2 sites with low adherence. 1. Baeten JM, et al. CROI 216. Abstract 19LB. 2. Baeten JM, et al. N Engl J Med. 216;[ 3. Nel A, et al. CROI 216. Abstract 11LB (P <.1) 37 (P =.1) Slide credit: clinicaloptions.com No use Bottom third Middle third Top third Adherence* *For seroconversions, adherence level taken from visit with lowest adherence of 3 months (3 visits) before HIV detection. Brown E, et al. AIDS 216. Abstract TUAC15LB. Reproduced with permission. Slide credit: clinicaloptions.com Tenofovir alafenamide (TAF)/FTC NHP rectal SHIV challenges DISCOVER STUDY Phase 3 Safety/Efficacy study of TAF/FTC vs TDF/FTC Non-inferiority design 5, men and transwomen across 97 clinical sites in US, Canada, and Europe. Recruiting started in Fall 216, results anticipated in 22. Massud Abstract 17 CROI 216 ClinicalTrials.gov Identifier:NCT

10 Building on RV144 HIV Vaccines 6% Reduction Early Effect? 31% HIV Reduction 37 Rerks-Ngarm et al. N Engl J Med. 29 Dec 3;361(23):229-2 HVTN 72 HVTN 72 If shown to efficacious, this vaccine will likely be the first licensed HIV vaccine in the world 1

11 HVTN 72 Neutralizing Ab to HIV-1 V3-glycan gp41 MPER V1V2-glycan CD4 binding site gp12/41 interface V1V2-Glycan bind to trimer cap V3-glycan, N332 supersite gp41 MPER near membrane gp12/41 interface bind to parts of both gp12 and gp41 CD4 binding site of gp12 where the virus attaches to CD4 Christina Corbaci, Andrew Ward, Only antibodies that have advanced the clinic (VRC1, 3BNC117) Corey, WEPL14, AIDS 216 VRC1 Blocks Attachment to CD4 gp41 trimer VRC1 Protects Against Mucosal SHIV-Challenge in NHP 2 mg/kg infusion of VRC1: Challenge with SHIV SF162P3 RECTAL CHALLENGE VAGINAL CHALLENGE CD4 Target Cell CCR5 gp12 trimer CD4 binding site on gp12 is functionally conserved: All viruses must bind CD4 VRC1 neutralizes ~ 9% of diverse viral isolates Corey, WEPL14, AIDS 216 Percent uninfected Days post challenge 4/4 protected VRC1 Control /4 protected Corey, WEPL14, AIDS 216 Percent uninfected /4 protected VRC1 Control 1/4 protected Days post challenge Pegu et al. Science Transl Med (214) Ko et al. Nature (214) Rudicell et al. J Virol (214) 11

12 The AMP Study Cohort IV Treatment n= Schedule North + South American MSM (24) HVTN 74 / HPTN 85 Sub-Saharan African women (15) HVTN 73 / HPTN 81 VRC1 1 mg/kg 8 VRC1 3 mg/kg 8 Placebo Control 8 VRC1 1 mg/kg 5 VRC1 3 mg/kg 5 Placebo Control 5 Every 8 wks x 1 doses Every 8 wks x 1 doses PEP TasP PrEP Microbicides HIV Prevention Tools HIV Testing Condoms STI Treatment HIV Vaccine Adherence support Individual and Couples Counseling & psychosocial support Improving risk perception and uptake Two different infusion doses: Important to know if lower dose of 1 mg/kg can protect Powered to associate mab serum level with protection Addressing stigma Addressing Inequalities Decriminilization Sex Work Homosexuality Drug use 46 Thank you! Susan Buchbinder Albert Liu Susan Scheer Jonathan Volk 12