HIV Prevention: How Are We Doing And What s On the Horizon?

Transcription

1 HIV Prevention: How Are We Doing And What s On the Horizon? Disclosures I have been the Principal Investigator on studies for which Gilead Sciences has donated study drug. Susan Buchbinder, MD Clinical Professor of Medicine & Epidemiology UCSF Director, Bridge HIV SF Dept of Public Health Questions 1. What s the current state of the US and local epidemic? Diagnoses of HIV Infection among Adults and Adolescents, by Transmission Category, 217 United States and 6 Dependent Areas N = 38,64 2. How are we doing with PrEP (and what can we do about it)? 3. A reminder about U=U 4. What s up with long-acting PrEP agents? 5. Where are we in vaccine development? Note. Data for the year 217 are considered preliminary and based on 6 months reporting delay. Data have been statistically adjusted to account for missing transmission category. Other transmission category not displayed as it comprises less than 1% of cases. a Heterosexual contact with a person known to have, or to be at high risk for, HIV infection.

2 New HIV Diagnoses in US MSM, 216 New HIV Diagnoses in US: Women Transgender women and men Trends in HIV in San Francisco 8 Living HIV cases New HIV diagnoses 2 Of 2351 new HIV diagnoses in transgender persons in % were in transgender women 15% were transgender men Transgender women have the highest HIV prevalence of any group Estimated 22-28% of TGW are living with HIV But 56% of African American TGW are living with HIV Number of New HIV Diagnoses/Deaths Deaths HIV-related Deaths 14,446 14,654 14,912 15,129 15,345 15,534 15,888 15,755 15,962 15,978 15,975 15, Number of Living Cases Year

3 Number of New Diagnoses by Demographic Characteristics Af. Am. Asia n Wome n PWID MSM PWID Homeless 2. How are we doing with PrEP (and how can we improve)? Small decrease in plasma TFV/FTC in Transgender women on hormone therapy Hendrix R4P OA23.3 MSM Hetero SDC MSM Women (gel) MSM Hetero Women Women May mean TGW should adhere to daily TDF/FTC; no effect of PrEP on hormones

4 PrEP works at a population level, too HIV Incidence in Persons Using TRUVADA for HIV PrEP: Worldwide Experience From 46 Studies 1, 69 persons, 62% on PrEP for > 6 months incident infections 3% > 3 days after last dose % w/i 3 mos of start DBS available for 49 on PrEP % no detectable TFV-DP 51% levels c/w < 2 doses/wk 4% levels c/w 2-3 doses/wk 2% had levels c/w doses/wk Of 49 pts, 11 resistant to FTC 1 resistant to TDF Baeten J, et al. HIVR4P 218, Madrid, Spain. OA23.1. HIV Incidence per 1 py 15 Same-day PrEP initiation is feasible with POC 4 th gen HIV test only Observational cohort study of 172 PrEP users to monitor renal function as measured by egfr in people with same day PrEP start Baseline egfr < 9 16 No participants had elevated creatinine with egfr 6 ml/min/1.73m 2 at baseline nor discontinued PrEP due to decline in egfr No HBV infections detected Same day PrEP initiation with POC HIV (but lab-based creatinine and HBV testing) was feasible and safe Patel R, et al. HIVR4P 218, Madrid, Spain. PD8.3

5 All Individuals Starting FTC/TDF for PrEP in US, (Based on data from Gilead) PrEP Use among HIV-negative MSM NHBS and STOP AIDS surveys, Prior Year 45, 4, 6 YearTotal: 177,223 38,938 39,252 35,175 35, 25 and older: 149,893 (84.6%) 12 24: 27,33 3, (15.4%) 25, 2,819 2, 15, 9,71 1, 6,683 6,663 8,1 5,639 5, 3,696 1,362 1, Proportion 17.% 17.8% 15.1% 14.6% 13.8% 16.9% years Magnuson, IAS 218 TUAC35 17 Percent ~4,4* ~1, * STOP AIDS ~12,6 * NHBS ~16,3 2,* *Based on estimated sample size of 44,154 HIV negative MSM in SF in 214 Hughes et al, J Urban Health 217 Current PrEP Use among MSM PrEP-Candidates * San Francisco City Clinic % of MSM PrEP Candidates Currently on PrEP by Race/Ethnicity San Francisco City Clinic Percent Percent % 32% African American Latino White Asian % 31% *PrEP Candidates: HIV negative AND Condomless anal sex OR STI OR HIV positive partner

6 PrEP only works if you continue to take it Average duration on PrEP in many populations is relatively brief in US: MSM: 38% - 57% at 6 months; 43% - 63% at 1 year Women: 37.5% at 6 mos HIV infections high if stop PrEP Many anecdotal cases of infections when stop PrEP 18 seroconversions in people who had stopped PrEP in SF STD clinic 3.9/1 py in MSM stopping PrEP in Montreal.95 infections/1py in people stopping vs..25 in people remaining on PrEP in Los Angeles Lack of PrEP persistence accentuates disparities San Francisco Primary Care Clinics Blackstock, AIDS Care 217;29:866 9 Chan, JIAS 216;19: 293 Greenwald, CROI 218, Abstract #138 Hojilla, AIDS and Behav; 218:22:196 9 Liu, JAMA Intern Med 216;176:75 84 Montgomery PLOS One 216;11:e Rusie, CID 218;67:283 7 Shover, CROI 218, Abstract #19 Scott, CROI 217, Abstract #24 Top 5 reasons why people stop PrEP 1. Self-perceived low risk 2. Cost or changes in insurance coverage 3. Medication side effects (actual or anticipated) 4. Pill fatigue 5. Difficulty adhering to provider/lab appointments 1. Assisting accurate HIV risk assessment: mysexpro.org Piloted in 24 MSM in SF, NY, Lima, Rio de Janeiro Found to be easy to use and desirable, esp. young MSM Interactive, online HIV risk assessment tool for MSM using data from several large cohorts of MSM. Calculates HIV personalized risk score (scale 1 2, with positive frame).

7 Validation of SexPro Risk Score in 2 cohorts of MSM 2. Cost and insurance issues External Validation (C statistic = 7.) 12 1 Predicted 8 Observed HVTN 55: MSM in 21 US cities External validation (C statistic = Predicted 8 Observed HPTN 61: Black MSM in 6 cities Receiving PrEP navigation services is associated with increased persistence in San Francisco Primary Care Clinics Predictor Adjusted OR 95% CI Transgender woman Illicit substance use Patient navigation Addressing side effects Adherence with PrEPMate in EPIC Study Impact of Prepmate on Adherence (n=121) Patterned after the WelTel model of weekly text message check ins to support ARV adherence Impact primarily through personalized communication between participants and clinic staff Ok How is PrEP going? Not great. Lester et al, Lancet 21;76: Chiang et al, JMIR mhealth & uhealth 218;6:e87 Prepmate Standard of Care % with protective TFV DP levels 72% 57% Odds ratio (OR) for Adherence (Prepmate vs.standard of Care) 2.5 (95% CI ) P= Adjusted OR* (95% CI ) P=.3 Prepmate efficacy did not differ significantly by age, race/ethnicity, education, or insurance Liu, CID 218; in press

8 4. Coping with pill fatigue Could on-demand PrEP (2-1-1) help with pill fatigue? Montreal cohort offered intermittent vs. daily PrEP Consistent use 43% for intermittent 34% for daily P=.2 Greenwald et al, CROI 218, Abstract Simplifying Visits: Magnet Express Rapid in and out STI testing No Appointment needed Drop in during operating hours May be tested for HIV Gonorrhea/Chlamydia, Syphilis Hepatitis C Magnet Express 3 Registration Blood Draw Magnet Express 31 Magnet Express 32

9 Self-Swabbing Leave Magnet Express 33 Magnet Express 34 Outcomes Since July 217- (Full launch Dec 217) 2,895 Magnet Express visits 71% decrease in turn-aways 46% White, 54% other ethnicities/race 3. Remember, U=U (Undetectable = Untransmittable) Magnet Express 35

10 Persons Living with Diagnosed or Undiagnosed HIV Infection HIV Care Continuum Outcomes, 215 United States HIV Care Continuum in San Francisco, 216 Note. Receipt of medical care was defined as 1 test (CD4 or VL) in 215. Retained in continuous medical care was defined as 2 tests (CD4 or VL) 3 months apart in 215. Viral suppression was defined as <2 copies/ml on the most recent VL test in 215. What s Not Working? We need to change the structure of care available Examining the Treatment Cascade Shift in focus from patient factors to program factors to improve engagement Malebranche, IAS 218 plenary

11 Max Clinic Seattle, Washington For PLWH who fail to engage in traditional HIV care with lower intensity support Walk in access to care High intensity support Incentives (food, $, phone, bus pass) Cross agency coordinated care (esp. jail and housing agencies) Abstract 1125 (Poster Session Wed afternoon) Percent of Patients Viral Suppression ( 1 VL<2) among Patients Enrolled in the Max Clinic and (N=5) and Standard-of-Care Control (N=1) in the 12 Months Pre- and Post-Baseline Max Patients Control Patients arr* (95% CI): 3.2 ( ) Pre Post *Adjusted for substance use, psychiatric dx, housing status Home collected DBS among pts saying they are undetectable Teran et al, CROI 218, Abstract 997 So, for your HIV uninfected patients who are having sex with people outside of a relationship, recommend PrEP What are the problem LA agents are trying to solve? 4. Long-Acting PrEP Agents Adherence Adherence Adherence

12 Will long-acting agents solve our persistence problems? Challenges with long-acting agents When administering agents with long t 1/2 in non removable method May require oral lead in to assess toxicity before administering LA formulation May have prolonged subtherapeutic tail; great concern for poorly adherent Data from 99% retail pharmacies, 1.7 million women Nelson et al, Obstet Gynecol 28 What are the problems LA agents may solve? Adherence Pill fatigue Privacy Drug cost Toxicity ARV resistance Choice Cabotegravir Long Acting Injectable (CAB LA) Cabotegravir is an analog of dolutegravir, differing by one carbon atom Oral t 1/2 : 4 hours CAB LA: milled nanocrystals Injectable t 1/2 : 21 5 days Muller et al. European Journal of Pharmaceutics and Biopharmaceutics 211 Spreen 7 th IAS 213; Min ICAAC 29 Taoda Int l Congress on Drug Therapy in HIV Infection 212 McPherson et al, Expert Opin on Investig Drugs 218

13 Summary of non-human primate challenge studies with CAB-LA CAB-LA PLASMA CONCENTRATIONS CORRELATE WITH PROTECTION IN MACAQUE MODEL Challenge Model # of Challenges Level of Protection High dose IV 1 7/8 Low dose rectal 8 8/8 High dose vaginal 3 6/8 Low dose vaginal 22 4/4 Low dose penile 12 5/6 1% 97% 74% Andrews et al, AIDS 217;31:461 7 Andrews et al, Science 214;343: Andrews et al, Sci Transl Med 215;7:27ra4 Radzio et al, Sci Transl Med 215;7:27ra275 Dobard et al, CROI 218, #83 Andrews et al, Science 214 Dosing regimen for ÉCLAIR Low-risk men (n=127), randomized 5:1, Q12 week injections Plasma CAB Conc-Time Profiles following 8mg IM Q12W in ÉCLAIR 1 Plasma CAB ( g/ml) 1.1 Two 2 ml injections IM 12 weeks apart Markowitz et al, Lancet HIV 217;4:e Simulated CAB 8mg IM Q12W (males, n=663) Observed CAB 8mg IM Q12W (ECLAIR, n=94) 8x PA-IC9 (1.35 g/ml) 4x PA-IC9 (.664 g/ml) 1x PA-IC9 (.166 g/ml) Time (Weeks)

14 HPTN 77 Study Design HIV-uninfected men and women at low risk for acquiring HIV infection, ages 18 to 65 (n=199) 3:1 3:1 Oral Oral Oral Oral Injection Phase Follow-up (8mg every 12 weeks) Phase Injection Phase Follow-up (PBO every 12 weeks) Phase Injection Phase (6mg every 8 weeks) Injection Phase (PBO every 8 weeks) Follow-up Phase Follow-up Phase Markowitz, CROI 216 CAB LA Pharmacokinetics CAB LA pharmacokinetic Tail Weeks 6 and 76 ) Male: Female : <LLOQ LLOQ 1x PA-IC 9 1x 4x PA-IC 9 > 4x PA-IC 9 BLQ LLOQ 1x PA-IC 9 1x 4x PA-IC 9 > 4x PA-IC 9 Landovitz, IAS 217 Landovitz, R et al. HIV R4P, Madrid, 218. Abstract #OA15.6LB.

15 Two Efficacy Trials of CAB-LA for PrEP HPTN 83 for MSM/TGW globally HPTN 84 for women in sub-saharan Africa Both have 3 steps: 1. Oral lead-in 2. Loading at and 4 weeks, q 8 week injections 3. Oral to cover the PK tail x 1 year Both double-blind, double-dummy with TDF/FTC as comparator group Both currently enrolling Implantable devices Drug must be extremely potent, as total mass dose to be loaded is small E.g., Nexplanon.6mg/day Chua, CROI 217 Durham, CROI 218 Hendrix, MTN 217 Formulation PK profiles compared Advantages and disadvantages of implantables vs. injectables Advantages Removable when needed More consistent and predictable drug release; lower dose per day Avoids long PK tail May remain in place for years, requiring fewer visits Potential for improved adherence Disadvantages Requires specialized device and sterile technique to insert Requires small surgical procedure to remove unless biodegradable Potential for scarring Potential to migrate More challenging when need to combine agents

16 MK-8591 (EFdA): Reverse Transcriptase Translocation Inhibitor Highly potent (1.8 log 1 reduction in VL) Good drug levels in both rectal and vaginal tissue Long intracellular half-life (~12 hours) Good activity against NRTI resistance Models in humans suggest high levels with weekly or less frequent oral dosing Implants t 1/2 1 days in rats, allowing for dosing 1 year or longer MK-8591-treated animals weekly dosing with weekly low-dose rectal challenge Aviremic (%) Days Placebo MK-8591 MK 8591 treated animals have a 41.5 fold lower risk of infection (95% C.I. 7.3, 237.9) P<.1 log rank test Markowitz, AIDS Where are we with HIV vaccines? The Impact of Vaccines in the United States DISEASE BASELINE 2 TH CENTURY PRE VACCINE ANNUAL CASES 28 CASES* PERCENT DECREASE Measles 53, % Diphtheria 175,885 1.% Mumps 152, % Pertussis 147,271 1, % Smallpox 48,164 1.% Rubella 47, % Haemophilus influenzae type b, invasive <5 yrs.) 2, % Polio, paralytic 16,316 1% Tetanus 1, % *Provisional Source: MMWR 4/2/99, 12/25/9, 3/12/21

17 HIV Vaccines >3 Phase 1 and 2 HIV vaccine trials trials to date Current efficacy trials in the field Passive infusion of antibodies AMP = Antibody-mediated prevention Parallel trials: MSM/Transgender women and men in the Americas Women in sub-saharan Africa Active vaccination HVTN 72: Follow-up from Thai vaccine trial in South African women and men HVTN 75: Mosaic (global vaccine) in women in 5 African countries There is a long history of using antibodies to prevent viral infections VIRUS PRODUCT DESCRIPTION INDICATION Measles Concentrated human gamma globulin Prevention Polio Concentrated human gamma globulin Prevention CMV Cytomegalovirus Immune Globulin Prevention Hepatitis A Immune serum globulin (ISG) Prevention (travel) Hepatitis B Hepatitis B Immune Globulin Post Exposure Rabies Rabies Immune Globulin Post Exposure RSV mab (palivizumab) for prophylaxis of high risk infants Prevention in High Risk Infants VZ Varicella Zoster Immune Globulin Post Exposure Most effective vaccines induce antibodies that neutralize the pathogen. John Mascola

18 Breadth and potency of bnabs Ling Xu et al. Science 217;358:85-9 Advantage: no ARV resistance concerns Future developments: Increase durability (decrease interval of administration) Subcutaneous administration Combinations RV144 HIV Vaccine Trial in 16, Thai men and women HVTN 72 Schema 6% reduction at 1 year 31% reduction at study end Group N 1 27 Primary vaccine regimen Booster* Month Month 1 Month 3 Month 6 Month 12 ALVAC HIV (vcp2438 ) ALVAC HIV (vcp2438) 2 27 Placebo Placebo ALVAC HIV (vcp2438) + Bivalent Subtype C gp12/mf5 9 Placebo + Placebo ALVAC HIV (vcp2438) + Bivalent Subtype C gp12/mf59 Placebo + Placebo ALVAC HIV (vcp2438) + Bivalent Subtype C gp12/mf59 Placebo + Placebo Total 54 Rerks Ngarm et al. N Engl J Med. 29 Dec 3;361(23): /27/218 72

19 High Level Target Product Profile: Prophylactic vaccine offering protection against all clades of HIV 1 through an heterologous prime boost regimen Vectors that elicit optimal immune responses Mosaic inserts for global coverage (Gag Pol Env) Trimeric gp14 env proteins for improved humoral immunity HVTN 75/HPX28 will be using Clade C gp14 HVTN 75 Study Schema Grou N Month Month 3 Month 6 Month 12 p Prime Boost Ad26.Mos4.HIV Ad26.Mos4.HIV 1 13 Ad26.Mos4.H + + Ad26.Mos4.HI Clade C gp14 Clade C gp14 IV V (25 mcg + (25 mcg + adjuvant) adjuvant) 2 13 Placebo Placebo Placebo + Placebo Total: 26 females in sub Saharan Africa Placebo + Placebo Why we need all prevention methods Acknowledgements Pierre Cedric-Crouch Diane Havlir Alison Hughes Raphy Landovitz Albert Liu Susan Scheer Hyman Scott Matt Spinelli Ariane Van der Straten Harmon, PLOS One 216