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.

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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

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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

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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

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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.

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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

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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

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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

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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

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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

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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)

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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

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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. Becomes more flexible in her/his thinking

5. Understands more about her/his place in the world

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Understanding others: PrEP is wanted

A View from the Ground Source:Source: National National Minority Minority AIDS AIDS Council Council (NMAC) (NMAC)

What PrEP offers

• What PrEP-takers say PrEP offers (Gilmore et al. IAPAC 2014; Ware et al. JAIDS 2012; Ware et al. AIDS & Beh 2014; Grant & Koester Curr Opin HIV AIDS 2016) – Decreased anxiety – Increased communication, disclosure, trust – Increased self-efficacy – Increased sexual pleasure & intimacy

We all have our slips sometimes where we’re, like, engaged in sex and stuff like that and either we’re intoxicated or we just feel a certain way about a person, you know, we really don’t take, you know, the safest route all the time. - iPrEx OLE participant (Gilmore et al. IAPAC 2014)

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Barriers to PrEP • Stigma is a key barrier to PrEP use: – about antiretrovirals, – about HIV, and – about being at risk for HIV (Gilmore et al. IAPAC 2014; van der Straten JIAS 2014) • Lack of knowledge of and access to PrEP & shame and hesitation about asking prescribers for PrEP are important barriers as well • 76% of men in Boston receiving PEP were interested in taking PrEP – but 33% did not feel comfortable talking to their provider about PrEP…. (Jain et al. IDSA 2014)

PrEP at age 6: thinking differently, thinking big

5. Understands more about her/his place in the world

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PrEP at age 6: thinking differently, thinking big

PrEP pushes us to think differently

Thinking differently about: Antiretrovirals Prevention & public health HIV, sex, risk

A sign on a bar in Seattle

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PrEP is not ART

ART • is sometimes medically complicated • needs life-long adherence without breaks PrEP • is for the most part not medically complex • needs adherence during periods at risk • is not needed with risk is not present

• Success in PrEP adherence is achieved when PrEP is used during HIV exposure = a concept called “prevention-effective adherence” (Haberer et al., AIDS 2015) – Thus, use may be on and off, with the key to map adherence to periods of high risk – Importantly, we should expect PrEP use to stop.

STIs will occur for persons using PrEP

Kaiser-Permanente, CA, USA 60% PROUD Study, UK N=657 N=544 12-month cumulative STI STIs in the 12 months prior to enrollment 50% percentages 30%

40% 25% 20% z 15% 30% er o 10% 20% 5% 0% 10% Rectal GC Rectal CT Urethral Urethral Syphilis GC CT

0% • Indeed, PrEP (and ART) has its Any CT GC TP HIV • STI rates were high, but greatest benefits for those who are no HIV occurred, in one already not using condoms -- i.e., it is large PrEP program from a risk-reducing, not risk-creating, the US (Volk et al. Clin Infec Dis 2015) solution (data above from McCormack et al. Lancet 2016)

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PrEP needs new messaging

Thinking differently

• PrEP makes us think very differently about three decades of fear-based public health messaging.

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PrEP is much like another commonly prescribed primary prevention intervention…

PrEP (TDF-based) Oral contraceptive pills

Initially approved for Approved initially for Initially approved for HIV treatment of menstrual treatment, not prevention treatment disorders

Offers real benefits Individual control over prevention

Has risks & concerns Sexual behavior, adherence, side effects

Does not demand Perfect use is the ideal, but real-world use has real perfection individual and population-level benefits

Myers and Sepkowitz A pill for HIV prevention: déjà vu all over again? CID 2013

PrEP at age 6: thinking differently, thinking big

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PrEP at age 6: thinking differently, thinking big

What a difference a few years makes

2013 2016

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What PrEP looks like in real world delivery: US Demo Project in MSM

• Open-label demonstration study, 557 participants, 3 cities: – 80+% had tenofovir in blood samples sufficient for HIV protection – Condomless sex remained stable (2/3 of participants) – STI rates were high – HIV rate was low = 2 infections, incidence 0.4%/year

Liu et al. JAMA Intern Med 2016

What PrEP looks like in real world delivery: PROUD Study

• Among MSM in the UK, delivery of PrEP (compared to deferred access to PrEP) was so effective in preventing HIV that the deferred arm was discontinued early, when only 10% of the planned sample size had been enrolled. – Immediate PrEP = 3 infections, incidence 1.2%/year – Deferred PrEP = 20 infections, incidence 9.0%/year

– 86% effectiveness, NNT = 13

McCormack et al. Lancet 2016

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What PrEP looks like in real world delivery: Partners Demonstration Project

• Open-label demonstration among HIV serodiscordant couples in Kenya & Uganda. 95% reduction (95% CI 87-98%) N=83.3 infections • Open access to PrEP and ART. P<0.001 incidence = 4.9 (95% CI 3.9-6.0) • Only 4 HIV infections observed, compared with N=4 infections more than 80 infections incidence = 0.2 expected in a counterfactual (95% CI 0.0-0.6) simulation model. EXPECTED OBSERVED Baeten et al. PLoS Med 2016 and AIDS2016

Ultimately, it is about coverage and delivery

• Stable & increasing HIV incidence in the era of high ART access in high income settings show that standard ART approaches, including making ART broadly available, may not be enough. (CDC 2013; Philllips et al PLoS ONE 2014)

• UNAIDS has called for 3 million persons on PrEP by 2020.

• PrEP delivery is just now moving out of demonstration projects – Regulatory approvals: US, Canada, France, Israel, South Africa, Kenya, Peru + AUSTRALIA – PEPFAR DREAMS initiative and country programming

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Choosing not to deliver has risks

• Mathematical modeling data has emphasized the role PrEP has in combination prevention interventions

“Without PrEP, HIV incidence in MSM in the UK is unlikely to decrease substantially by the end of this decade.” Punyacharoensin et al. Lancet HIV 2016

PrEP is not one size fits all

Pill Gel Vaginal film Vaginal ring Injectable Tenofovir-containing pills are not feasible for everyone. There is an encouraging pipeline of new PrEP prevention products that will deliver additional options. However, we would be naïve to imagine that any one of these will work or be workable for every person.

What is wanted = prevention options (think: contraception)

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PrEP at age 6: thinking differently, thinking big

Acknowledgements

• University of Washington, Partners PrEP Study and Partners Demonstration Project Teams: Connie Celum, Deborah Donnell, Renee Heffron, Stephen Asiimwe, Elizabeth Bukusi, Nulu Bulya, Jim Campbell, Craig Cohen, Carey Farquhar, Ken Fife, Grace John-Stewart, Elly Katabira, James Kiarie, Nelly Mugo, Kenneth Ngure, Josephine Odoyo, Patrick Ndase, Allan Ronald, Jordan Tappero, Edna Tindimwebwa, Elioda Tumwesigye, Jonathan Wangisi, Edwin Were, ICRC team, David Bangsberg, Ruanne Barnabas, Justin Brantley, Robert Coombs, Katie Curran, Lisa Frenkel, Jessica Haberer, Tim Hallett, Craig Hendrix, Britta Jewel, Erin Kahle, Ann Kurth, Dara Lehman, Jai Lingappa, Jenny Lund, Mark Marzinke, Julie McElrath, Kenneth Mugwanya, Andrew Mujugira, Pam Murnane, Julie Overbaugh, Laura Pattacini, Christina Psaros, Sarah Roberts, Steve Safren, Bettina Shell-Duncan, Kerry Thompson, Norma Ware, Christina Wyatt, Monique Wyatt • MTN / ASPIRE: Thes Palanee, Katie Schwartz, Elizabeth Brown, Lydia Soto-Torres, Sharon Hillier, Ian McGowan, Linda-Gail Bekker, Mike Chirenje, Zakir Gaffoor, Vaneshree Govender, Nitesha Jeenarain, Flavia Matova Kiweewa, Bonus Makanani, Francis Martinson, Barbara Mensch, Nyaradzo Mgodi, Liz Montgomery, Felix Muhlanga, Clemensia Nakabiito, Logashvari Naidoo, Gonasagrie Nair, Duduzile Nwandwe, Arendevi Panther, Gita Ramjee, Samantha Siva, Ariane van der Straten, ASPIRE/MTN Team, Zeda Rosenberg, Annalene Nel, IPM • Funders: Bill & Melinda Gates Foundation (OPP47674, OOP52516, OPP1056051, Salif Sow, Stephen Becker, Lut Van Damme, Mary Aikenhead); US National Institutes of Health (R01 MH095507, R21 NR012663, R01 AI096968, R01 MH098744, R01 MH101027, R21 AI104449, R21 HD074439, R21 TW009908, K99/R00 HD076679, UM1 AI068615, Mike Stirratt, Roberta Black, Cyndi Grossman); US Agency for International Development (AID-OAA-A- 12-00023, Benny Kotiri, Sarah Sandison) • Research participants

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PrEP: costs/benefits of a primary prevention intervention

iPrEx

PrEP daily Intervention for HIV prevention Placebo frequency of outcome 4% per year 44% overall Relative risk reduction 90%+ w/ adherence 62 overall Number needed to treat for 1 year to prevent outcome ≤15 among higher-risk w/ adherence

PrEP: costs/benefits of a primary prevention intervention WOSCOPS/HOPE- iPrEx 3/USPSTF PrEP daily Statin daily Intervention for HIV prevention for MI/CV death prevention Placebo frequency of outcome 4% per year <2% per year 44% overall Relative risk reduction 31% (CV death) / 36% (MI) 90%+ w/ adherence 62 overall Number needed to treat for 1 year to 250 prevent outcome ≤15 among higher-risk w/ adherence Every clinician in this room has easily prescribed multi-year primary prevention therapy with a statin, at an NNT of 250 and no promises of 100% perfection (in either adherence or disease prevention).

iPrEx: Grant et al N Engl J Med 2010; WOSCOPS: Shepherd et al N Engl J Med 1995 HOPE-3: Yusuf et al N Engl J Med 2016; USPSTF: Chou et al JAMA 2016