Update on Biomedical Prevention Thomas C. Quinn, MD, MSc Associate Director of International Research National Institute of Allergy and Infectious Diseases Director, Johns Hopkins Center for Global Health
Global Prevalence of HIV infection: 37 Million Incidence 2.0 Million; 1.2 Million Deaths The HIV burden in sub-saharan Africa: 25 million living with HIV, 1.4 million new infections, 0.8 million deaths
Newly diagnosed HIV infections in the European Region, 2004-2013 Thousands
Diagnoses of HIV Infection among Adults and Adolescents, by Transmission Category, 2010 2014
Rates of Diagnoses of HIV Infection among Adults and Adolescents, by Age at Diagnosis, 2010 2014 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, but not for incomplete reporting.
HIV Transmission in Indiana 2015 United States State of Indiana: Pop 6,596,850 Scott County: Pop 24,181 Town of Austin: Pop 4,200
Indiana HIV Outbreak Summary In early 2015, 11 new HIV infections diagnosed Scott County, IN Historically <5 HIV new infections 2004-2013 As of June 14, 2015 170 new HIV diagnosis >95% coinfected with hepatitis C virus Joint response undertaken by local, state and federal public health authorities in collaboration with community Establish extent of the outbreak Identify and refer to treatment all HIV-infected persons in community Institute control measures (e.g., syringe exchange, PrEP) Transmissions occurred in a small community (Austin, pop. 4,200) where injection drug use was prevalent Opioid analgesic oxymorphone (Opana ER and generic ER)
Cases of Rectal Gonorrhea in SF
HIV Prevention Strategies Advances in four key areas are of critical focus for the next five years: Widespread testing and linkage to care, enabling people living with HIV to access treatment early. Broad support for people living with HIV to remain engaged in comprehensive care, including support for treatment adherence. Universal viral suppression among people living with HIV. Full access to comprehensive PrEP services for those whom it is appropriate and desired, with support for medication adherence for those using PrEP.
Four Prevention Opportunities Cohen et al., JCI, 2008 Cohen et al., JIAS,2008 UNEXPOSED EXPOSED (precoital/coital) EXPOSED (postcoital) INFECTED Behavioral, Structural STDS Circumcision Condoms Vaccines ART PrEP Microbicides Antibodies Vaccines ART PEP Treatment Of HIV to Reduce Infectivity YEARS HOURS 72h YEARS
Global number of new HIV infections in adults and children: 1990-2014 10 million infections averted Source: UNAIDS Global Report 2014
HIV incidence vs. ART coverage in 51 countries, weighted by epidemic size Source: Hill, Pozniak, Raymond, Heath and Ford, AIDS 2014
Global Plan for the elimination of new HIV infections in children by 2016 37-40% reduction between 2009 & 2012 Only slightly off-track for 2015 target Source: Kiragu K. UNAIDS 2013
Four Prevention Opportunities Cohen et al., JCI, 2008 Cohen et al., JIAS,2008 UNEXPOSED EXPOSED (precoital/coital) EXPOSED (postcoital) INFECTED Behavioral, Structural Vaccines ART PrEP Microbicides Antibodies Vaccines ART PEP Treatment Of HIV to Reduce Infectivity STDS Circumcision Condoms YEARS HOURS 72h YEARS
PrEP Efficacy Trials, Oral and Topical
TDF/FTC was FDA Approved for use for Prevention on July 16, 2012 Success depends entirely on adherence Alternatives to daily dosing are possible Truvada PrEP uptake has been limited to date Perhaps longer acting agents will prove more attractive?
PROUD: Immediate vs Deferred PrEP in High- Risk MSM in Real World Trial Randomized, open-label trial of daily oral TDF/FTC PrEP in HIV- MSM in 13 clinics in London Immediate (n = 267) vs Deferred for 12 mos (n = 256) Primary endpoint: HIV infection in first 12 mos 86% reduction in risk seen over 60 wks with immediate PrEP (90% CI: 58% to 96%, P =.0002) Rate difference: 7.6 (90% CI: 4.1-11.2) Number needed to treat to prevent 1 infection: 13 (90% CI: 9-25) Group HIV Incidence Infected, n Incidence/100 PY (90% CI) Immediate 3 1.3 (0.4-3.0) Deferred 19 8.9 (6.0-12.7) McCormack S, et al. CROI 2015. Abstract 22LB.
ANRS IPERGAY: On-Demand Oral PrEP in High-Risk MSM Randomized double-blind trial of event-driven oral TDF/FTC* (n = 199) vs placebo (n = 201) (both with prevention services) in France 2 tablets taken 2-24 hrs before sex 1 tablet 24 hrs after sex 1 tablet 48 hrs after first eventdriven dose Primary endpoint: HIV seroconversion 86% reduction in risk seen in PrEP arm (95% CI: 40% to 99%, P =.002) Probability of HIV Infection 0.20 0.16 0.12 0.08 0.04 Kaplan-Meier Estimate of Time to HIV Infection 14 infections; incidence 6.6/100 PY 2 infections; incidence 0.94/100 PY Placebo P =.002 TDF/FTC 0.00 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Pts at Risk, n Mos Placebo 201 141 74 55 41 TDF/FTC 199 140 82 58 43 Molina JM, et al. CROI 2015. Abstract 23LB. Reproduced with permission.
Priorities for New Technologies On Demand Sustained Release Long-acting Injectable Used around time of intercourse For those who have intermittent sex or want more direct control over their protection User-initiated, does not require daily action Should increase adherence and effectiveness Co-administration of products targeting separate indications Equal duration of effectiveness for the co-administered products
ASPIRE Dapivirine Ring Study Baeten JM et al. N Engl J Med 2016.
ASPIRE Dapivirine Ring Study Baeten JM et al. N Engl J Med 2016.
Long Acting Injectable Nano-Suspensions TMC278LA (Rilpivirine; PATH) Cabotegravir (GSK 744; ViiV) NNRTI (Rilpivirine) Oral formulation in Complera TM Long acting: up to 3 months? Multiple trials: Dose ranging PK; PK/PD Phase-2: HPTN 076 Integrase inhibitor Similar to Dolutegravir Safe in humans with oral run-in Activity up to 3 months NHP model efficacy Phase 2: Éclair and HPTN 077
Neutralizing Antibody Epitopes on Native Trimer (since 2009) gp41 MPER: 2F5, 4E10 10e8 CD4 Binding Site: VRC01, PG04, CH31 3BNC117, 12A12 CH103, VRC07 Trimer (gp120/41) 8ANC195 PGT151 35022 Cryo-EM of viral spike by Subramaniam group. Fit with atomic level structures from Kwong and Wilson groups V1V2 Glycan: PG6, PG16, CH01-04 PGT141-45 CAP256-VRC26 N332 Glycan Supersite: PGT121, PGT128 10-1074 Highly selected donors
VRC01 Protects against Mucosal SHIV162P3 Challenge in NHP 20 mg/kg infusion of VRC01 RECTAL CHALLENGE 4/4 protected VAGINAL CHALLENGE 4/4 protected 100 100 Percent uninfected 80 60 40 20 VRC01 Control 0/4 protected Percent uninfected 80 60 40 20 1/4 protected VRC01 Control 0 0 5 10 15 20 25 30 Days post challenge 0 0 5 10 15 20 25 30 Days post challenge
Enrolled participants 2400 MSM and TG + 1500 women 18 to 50 y.o. Study duration 92 weeks (infusions given through week 72) HVTN 703 / HPTN 081 A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection Regimen Total Note VRC01 10 mg/kg 800 500 VRC01 30 mg/kg 800 500 Control* 800 500 1300 Total 2400 1500 3900 MSM and transgender persons Sub-Saharan African women 2600 Infusions every 8 weeks through Week 72 (10 total infusions per participant) Primary objective: HIV incidence, safety and tolerability
Conclusions Global progress on scale-up of ART has been extraordinary and the target of 90-90-90 can be reached by 2020 with the right resources Further scale-up must address disparities and inequities (countries, key populations) Countries face strategic choices and should take advantage of new opportunities of treatment and prevention (early ART, TasP, PrEP) in combination ARVs for treatment and prevention are a powerful tool towards ending the HIV epidemic, but only if retention in care, adherence to medication and behavioral change are emphasized.