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Prep at Age 6: Thinking Differently, Thinking Big

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Prep at Age 6: Thinking Differently, Thinking Big 17/11/2016 PrEP at age 6: thinking differently, thinking big Jared Baeten MD PhD Departments of Global Health, Medicine, and Epidemiology University of Washington 2016 Australasian HIV/AIDS Conference Adelaide, November 2016 Disclosures & Off-Label Use • I have received research funding for PrEP and related HIV prevention options from the Bill & Melinda Gates Foundation, the US NIH, and USAID. For some research studies, medication has been donated by Gilead Sciences. I have no other conflicts of interest. • Combination FTC/TDF (Truvada®) PrEP, used daily, has a formal label indication in the United States, Australia, and several other countries. Other dosing strategies for combination FTC/TDF and other uses of antiretrovirals for HIV prevention, both PrEP and ART, have normative agency recommendations without formal label approval. 1 17/11/2016 PrEP at age 6: thinking differently, thinking big In late 2010 and 2011, the first, pivotal evidence emerged that PrEP was effective and safe for HIV prevention. Deborah Birnkrant, director of the Division of Antiviral Products, US FDA, 16 July 2012 PrEP at age 6: thinking differently, thinking big So, PrEP is 6 years old (more or less). What should we expect of a 6 year-old? What are important developmental milestones? http://www.webmd.com/children/tc/milestones -for-6-year-olds-topic-overview http://www.cdc.gov/ncbddd/childdevelopment/ positiveparenting/middle.html http://raisingchildren.net.au/articles/child_dev elopment_6-8_years.html 2 17/11/2016 PrEP at age 6: thinking differently, thinking big 1. Begin to understand cause-and-effect relationships 2. Magical thinking quickly fades 3. Starts to understand the feelings of others 4. Becomes more flexible in her/his thinking 5. Understands more about her/his place in the world PrEP at age 6: thinking differently, thinking big 1. Begin to understand cause-and-effect relationships = Take it, it works 2. Magical thinking quickly fades 3. Starts to understand the feelings of others 4. Becomes more flexible in her/his thinking 5. Understands more about her/his place in the world 3 17/11/2016 Cause and effect: when taken, PrEP works It seems obvious now…. “All truth passes through three stages: First, it is ridiculed Second, it is violently opposed Third, it is accepted as self-evident.” - A. Schoepenhauer Cause and effect in trials of PrEP Partners PrEP 81% adherence / IPERGAY & PROUD 75% efficacy ~100% adherence / 86% efficacy iPrEx TDF2 51% adherence / 79% adherence / 44% efficacy Bangkok 62% efficacy 67% adherence / 49% efficacy % adherence % HIV protection effectiveness Cause and effect = in studies with high adherence, high HIV protection was seen 4 17/11/2016 Cause and effect in trials of PrEP Partners PrEP 81% adherence / IPERGAY & PROUD 75% efficacy ~100% adherence / 86% efficacy iPrEx TDF2 51% adherence / 79% adherence / 44% efficacy Bangkok 62% efficacy 67% adherence / 49% efficacy % adherence % HIV protection effectiveness Notably, the more recently completed trials – done after PrEP’s efficacy and safety were known – had the highest adherence. Cause and effect in trials of PrEP FEM-PrEP and VOICE % adherence % ≤30% adherence / No efficacy HIV protection effectiveness Trials where only a minority where adherent did not / could not demonstrate HIV protection. 5 17/11/2016 Cause and effect in trials of PrEP ART real-world ~75% adherence / HPTN 052 64% effectiveness >95% adherence / 96% efficacy % adherence % HIV protection effectiveness An easy comparison can be made to ART for HIV prevention, where a similar cause & effect relationship has been seen. (Cohen et al. NEJM 2011 & 2016; Anglmyer et al. Cochrane Reviews 2013) Cause & big effects: at the individual level, 90+% protection • For those with tenofovir detected in blood samples HIV protection from PrEP was extremely high: HIV risk reduction Partners PrEP any tenofovir 90% iPrEx / iPrEx OLE any tenofovir 92-100% Baeten et al. NEJM 2012; Grant et al. NEJM 2010 & Lancet Infect Dis 2014 6 17/11/2016 Cause and effect: PrEP works for high-risk • Subgroup analyses of PrEP trials show that PrEP is effective for those at greatest HIV risk: • Heterosexuals (Partners PrEP) Murnane et al. AIDS 2013; Heffron et al. AIDS 2014 – Reporting sex without condoms ; With an STI ; With an HIV+ partner who has a high plasma HIV viral load ; Women <30 years of age ; Women using DMPA for contraception • MSM/TGW (iPrEx) Buchbinder et al. Lancet ID 2014; Solomon et al. Clin Infect Dis 2014; PROUD – Used cocaine ; Had syphilis ; Had anal sex with an HIV+ partner • HIV protection estimates for high risk groups were often as high or higher than for study populations as a whole, because adherence was often greater Side note on cause & effect: more medicine ≠ more protection In contrast to ART, where multiple medications are essential, single agent PrEP may work as well as dual agent therapy. years - % reduction in incident HIV 85% 93% associated with detection of HIV incidence,HIV tenofovir in per 100 person100per plasma Baeten et al. NEJM 2012 & Lancet Infect Dis 2014 7 17/11/2016 PrEP at age 6: thinking differently, thinking big 1. Begin to understand cause-and-effect relationships = Take it, it works 2. Magical thinking quickly fades 3. Starts to understand the feelings of others 4. Becomes more flexible in her/his thinking 5. Understands more about her/his place in the world PrEP at age 6: thinking differently, thinking big 1. Begin to understand cause-and-effect relationships = Take it, it works 2. Magical thinking quickly fades = Only 5 year-olds believe in magic bullets 3. Starts to understand the feelings of others 4. Becomes more flexible in her/his thinking 5. Understands more about her/his place in the world 8 17/11/2016 Magical thinking: PrEP and perfection PrEP isn’t perfect, and PrEP doesn’t demand we be perfect either. PrEP and perfection: safety • The risk-benefit calculus for a prevention product is different than for a therapeutic. Nevertheless, PrEP has been surprisingly positive in its safety. • TDF-based PrEP results in a small but nonprogressive decline in GFR and BMD, that reverses with discontinuation and does not result in a substantial increase in the risk of clinically relevant toxicity Mugwanya et al. JAMA Intern Med 2015; Grant et al. CROI 2016 9 17/11/2016 PrEP and perfection: resistance • Antiretroviral resistance is a risk with any use of antiretrovirals. • For PrEP, resistance risk appears nearly completely limited to those with acute infection when starting PrEP. – WHO has reiterated that use of 3rd generation HIV tests prior to PrEP start achieves a sufficient risk/benefit balance (Grant et al. AIDS2016) – Importantly, resistance risk is dwarfed by the # of persons protected against HIV (Partners PrEP: 2-5 cases of resistance vs. 123 HIV infections averted) – Finally, resistance risk has been modeled to contribute just a fraction to community-level resistance, above and beyond what ART is already contributing, even under the most pessimistic scenarios (Abbas et al., J Infect Dis 2013) PrEP and perfection: adherers adhere • In clinical trials, not everyone used PrEP. But, those who did use it tended to be consistent users: Adherers generally stuck with it, at least until they discontinued . Non-adherers rarely started adhering Partners PrEP Study, Baeten et al., Lancet ID 2014 10 17/11/2016 What is enough adherence for protection? • In iPrEx OLE (MSM/TGW), HIV incidence declined with greater tenofovir concentrations in blood spots. 100% protection was seen with levels consistent with taking ≥4 tablets/week, showing that consistent PrEP taking, even when not necessarily perfect, can be highly protective. HIV incidence Risk reduction (per 100 person-years) (versus off-PrEP) Not on PrEP 3.9 - On PrEP: 2-3 tablets/wk 0.56 84% On PrEP: 4-6 tablets/wk 0.00 100% On PrEP: 7 tablets/wk 0.00 100% Grant et al. Lancet ID 2014 Effectiveness >> Efficacy In health interventions, we expect Efficacy Effectiveness that clinical trial efficacy will be the best we can hope for (an “efficacy Proof of concept Use in more real- in idealized world settings to effectiveness drop off”) settings But, PrEP has shown the Efficacy Effectiveness opposite, with effectiveness in iPrEx = 44% PROUD = 86% implementation exceeding (51% adherent) (nearly all adherent) Partners PrEP = 75% Partners Demo = 95% clinical trials. (81% adherent) (85% adherent) 11 17/11/2016 How much is good enough? • Intermittent PrEP use has been assessed in one trial (IPERGAY): – Average of 16 pills used/month (IQR 10-23) [~4/week à la iPrEx OLE?] – High background HIV rate; high STI rates – Near complete HIV protection (86%, only 2 cases, neither was using PrEP) – Whether intermittent dosing works for heterosexual exposure is unknown (Cottrell et al. J Infect Dis 2016) IPERGAY = on-demand PrEP 2 tablets 2-24 hours before sex 1 tablet 24 & 48 hours later Molina et al. N Engl J Med 2015 Friday Saturday Sunday Monday Tuesday Wednesday Thursday Friday Saturday Sunday PrEP is not perfect • A recent case of a breakthrough infection received attention – but a rare event does not diminish the substantial prevention benefits PrEP offers 12 17/11/2016 PrEP at age 6: thinking differently, thinking big 1. Begin to understand cause-and-effect relationships = Take it, it works 2. Magical thinking quickly fades = Only 5 year-olds believe in magic bullets 3. Starts to understand the feelings of others 4. Becomes more flexible in her/his thinking 5. Understands more about her/his place in the world PrEP at age 6: thinking differently, thinking big 1. Begin to understand cause-and-effect relationships = Take it, it works 2. Magical thinking quickly fades = Only 5 year-olds believe in magic bullets 3. Starts to understand the feelings of others = PrEP is wanted, and wanted in deep ways 4.
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