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Identifying and addressing risk compensation in ARV-based HIV prevention

Kristen Underhill, D.Phil., J.D.

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ARVs for HIV Prevention

• “A major milestone”? • Gateway to an AIDS-free generation?

• Or “a catastrophe in the history of AIDS”?

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Overview

• Defining and operationalizing risk compensation behavior

• How could we test it?• How should we test it?• Summary of risk compensation research for

ARV-based HIV prevention• Future directions and research priorities

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Defining risk compensation behavior

• A change in risk-taking behavior in response to a change in perceived risk – Usually considered as a risk-increasing response to

a new protective or preventive intervention• Derived from behavioral and economic research

in 1970s-1990s– “Risk homeostasis” (1-2)– Injury prevention and auto safety (3-4)

• Long history in HIV/AIDS research– Condoms, male circumcision, vaccines (5-7)

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Risk compensation in context

• “Achilles heel of innovations” in HIV prevention (8)• Fears about risk compensation are powerful

– More likely to arise for socially stigmatized behaviors (e.g., sex, drugs, fast cars)

– Can fuel opposition to regulatory approval or implementation of new technologies

– Can affect willingness to prescribe ARVs for prevention (9-14) – Can implicitly devalue individual priorities– Can be a vehicle for implicit bias or discrimination (9)

• Little study on ways to intervene in risk compensation dynamics

Cognitive mechanism of risk compensation in HIV prevention

Figure from Eaton LA, Kalichman SC. Curr HIV/AIDS Rep. 2007;4:165-172.

• An individual’s target level of HIV risk is shaped by his/her perceived costs and benefits of HIV risk behaviors. These may change over time.

• Using ARVs for HIV prevention (e.g., PrEP, microbicides, TasP) reduces the individual’s perceived risk of HIV infection. This leads to lower perceived costs of HIV risk behaviors.

• The lower perceived cost of HIV risk behaviors changes the risk calculus, allowing the individual to consume more risk without exceeding his/her target risk level.

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Prerequisites for risk compensation

1. The protective intervention is visible.2. The individual user believes that the

intervention is protective.3. The individual has control over his or her

risk-taking behaviors.4. “Risks for reasons”: The individual has

a motivation to take more risks.(4)

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Lessons from risk compensation prerequisites

• Sometimes risk compensation won’t happen:– If people are already taking maximum risks or

obtaining all the desired benefits from their behaviors.

– If people lack opportunities to control or increase their risk behaviors.

– If people don’t know they are using an active prevention method.

– If people don’t believe their prevention method works.

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Lessons from risk compensation prerequisites (continued)

• If risk compensation occurs, it means that people are motivated to take more risks. Risk behaviors have benefits that individuals value. – E.g., intimacy, pleasure, freedom, relationships,

fertility• Risk compensation behavior could be a rational

and potentially value-optimizing individual decision.– Reallocates value from risk-reduction benefit to

another type of benefit that the individual wants.

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When is risk compensation problematic?

• When there is only a small margin of protection (e.g., ARVs with low adherence/effectiveness)– Less problematic when effectiveness is high.

• When people miscalculate risks and benefits• When people underestimate ancillary risks (e.g., STIs)• When risk compensation imposes risks on others

– Directly (partners), or through social norms• When risk compensation reduces cost-effectiveness• When risk compensation is not voluntary (e.g.,

pressure from partners)

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Specific risk compensation behaviors

• Shorthand for “less condoms” (e.g., “condom migration/substitution/replacement”)

• But could include other behavioral adjustments– Frequency of sex– Number of partners– Nonprimary partners– Partner selection strategies– Sexual positioning– Serosorting– Transactional sex– Injection drug use behaviors

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Identifying risk compensation

• Risk compensation is driven by the perception of protection, not just using ARVs.

• For ARV-based prevention, this has 2 parts:1. I know I’m using (or my partner is using) ARVs.2. I believe that ARVs are protecting me from

acquiring/transmitting HIV.• Study designs need to test the relationship

between perceived protection and behavior, not just ARV use and behavior.

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The “gold standard” design we want, but likely can’t have

Participants randomly assigned

Perceived Protection1. I know I’m on ARVs

AND2. I know ARVs work

No Protection or Uncertain Protection1. I’m not on (not sure if I’m on) ARVs

OR2. I don’t think (don’t know) ARVs work

• Ideally, we would randomize people to the perception of protection vs. no protection, and measure behaviors over long-term follow-up. But there are barriers to this design.

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Problems with double-blinded RCTs

• Both groups are uncertain about protection• Cannot test relationship between perceived

protection and behavior– Between-group comparisons / Longitudinal comparisons

Participants randomly assigned

Blinded ARVs1. I don’t know if I’m on ARVs2. I don’t know if ARVs work

Blinded Placebo1. I don’t know if I’m on ARVs2. I don’t know if ARVs work

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Problems with open-label RCTs

• Closer, but not an ideal test. Active arm participants are still uncertain about efficacy.

• Similar issues arise with RCTs that have a delayed arm. (15)

Participants randomly assigned

Open-label ARVs1. I know I’m on ARVs2. I don’t know if ARVs work

Open-label Placebo1. I know I’m not on ARVs2. I don’t know if ARVs work

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Amending Phase II/III study designs to study risk compensation

• Compare participants based on preventive misconception (16)– Identify participants who believe they have

received effective prevention. (17-18)• Conduct two trials or a nested trial

– Use different probabilities of assignment to active/control groups.

– Participants in the trial with greater likelihood of active-arm assignment may have higher expectations of protection. (19)

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Identifying risk compensation after efficacy is known (Phase IV)

• Now ARV users have the perceptions we need: 1. I know I’m on ARVs2. I believe that the ARV drug is protecting me

• But now we cannot randomize to active/control.– Equipoise: Once efficacy is known or suspected, it is

ethically problematic to randomize people to active prevention or control.

• We also cannot lie to control groups.– Deception: It is ethically problematic to deceive

participants to develop a perception of protection vs. no protection.

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Open-Label Extension Studies

Participants randomly assigned

ARVs1. I don’t know if I’m on ARVs2. I don’t know if ARVs work

Opt in to open-label ARVs1. I know I’m on ARVs2. I know ARVs work

Opt out of open-label ARVs1. I know I’m not on ARVs(2. I know ARVs work)

No ARVs1. I don’t know if I’m on ARVs2. I don’t know if ARVs work

• Closer, but nonrandom assignment into the open-label extension.

• Could be self-selection reasons for opting in or out of continuing ARVs for HIV prevention.

• Longitudinal analyses after unblinding are helpful, but lack controls.

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What else can we do?

• Identify natural experiments – are ARVs ever allocated by lottery?

• Look for associations between high/low effectiveness expectations and behavior among ARV users and their partners

• Population-level longitudinal studies examining ARV use and behavior

• Qualitative interviews with ARV users and partners

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What we know now: PrEP

• Double-Blinded Trials (55-59)– Between-group analyses: no differences – Longitudinal analyses: reduced risks over time

• iPrEx analysis by perceived assignment (18)– Among participants reporting no condomless RAI

at baseline, no difference by perceived assignment or perceived PrEP efficacy in condomless RAI during follow-up.

– No differences in HIV or syphilis by perceived assignment.

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What we know now: PrEP (continued)

• MSM safety study with delayed active arm (15)– No between-group differences. – Perceived PrEP efficacy positively correlated with number of

partners. – Perceived active assignment negatively correlated with

unprotected anal sex.• Open-Label Partners Extension (20)

– No change in frequency of condomless sex with HIV-infected primary partners after unblinding.

– Increases in total sex and unprotected sex with outside partners over time.

• Acceptability studies– Some participants predict risk behavior increases (21-29)

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What we know now: PEP and nPEP

• Behavior during PEP/nPEP use – Reduced sexual activity (30); risk-taking during nPEP use

linked to depression (31)• Behavior after PEP use

– nPEP use not linked to increased risk behavior (32-35) – Counseling may help decrease risk-taking among nPEP

users (36)

• Behavior when anticipating PEP use – MSM who plan to use nPEP report more risk behavior (37)– MSM given nPEP in advance reported reductions in risk

behavior (38)– Awareness of nPEP availability not linked to risk behavior

(39-40)

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What we know now: ARV Microbicides

• Double-Blinded Trials– Longitudinal analyses: decreased risk (41-42)– Between-group analysis: no differences (42)

• CAPRISA 004 analysis by preventive misconception: – Women who perceived protection from product were

less likely to report consistent condom use, more likely to report never using condoms, and more likely to present with STI symptoms. (17)

• Acceptability studies – Suggest possible risk compensation (43-44)

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What we know now: Treatment as Prevention

• HPTN 052: No between-group differences in condom use or STI (45)

• Temprano-ANRS 12136: Early ART initiators reported reduced risk behavior over time, no difference from later initiators (46)

• Systematic reviews – Mixed findings linking HAART to risk behavior (47) – No increase in risk behavior among HAART users (48-

50)– Positive association between HIV treatment optimism

and risk behavior (51-52)

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Summarizing what we know

• Oral PrEP: No evidence from trials, but possible based on acceptability studies.

• PEP and nPEP: Does not appear to occur• Microbicides: Possible based on

acceptability studies and findings from a preventive misconception analysis

• TasP: No evidence from trials, but additional research needed.

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How to handle risk compensation in PrEP implementation?

• Won’t happen for everyone– Not for people already at maximum risk or with little

opportunity/power to modify risk behaviors• Should not be a barrier to access

– Very difficult to measure at individual level– Autonomy perspective

• Development and evaluation of context-specific interventions for counseling ARV users.– Promote adherence to maximize margin of protection– Education to limit miscalculating– Early ideas: framing (53), behavioral counseling (36, 54),

product labeling

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Future research priorities• Understanding “risks for reasons” with ARV

use• Studies among real-world users• Timing and persistence of risk compensation

effects• Linkages between risk compensation and

biological outcomes• Development of interventions to address all

risk behavior (not just risk compensation) in context of ARV prevention, including individual, dyad-based, and community interventions

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Future research priorities (continued)

• Interventions to ensure that individuals are making informed decisions about behaviors during ARV use.

• Education to address the fear of risk compensation, where it may limit ARV access

• Identifying potential benefits of risk compensation?– E.g., increased demand for ARVs, motivator for

adherence, potential for reduced HIV stigma?

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References1. Wilde 20012. Adams 19953. Peltzman 19754. Hedlund 20005. Crosby et al. 20126. Eaton & Kalichman 20077. Pinkerton 20018. Cassell et al., 20069. Calabrese et al. 201410. Tripathi et al 201211. Krakower et al. 201312. Tang et al. 201413. Tellalian et al. 201314. White et al. 201215. Liu et al. 201316. Simon et al., 200717. Dellar et al. 201418. Marcus et al. 201319. Malani 2006

20. Mugwanya et al. 201321. Golub et al. 201022. Brooks et al. 201123. Brooks et al. 201224. Holt et al. 201225. Koblin et al. 201126. Galea et al. 201227. Smith et al. 201228. Tripathi et al. 201329. Whiteside et al. 201130. de la Tribonniere et al. 199831. Golub et al. 200832. Donnell et al. 201033. Martin et al. 200434. Poynten et al. 200935. Schechter et al. 200436. Roland et al. 37. Kalichman 199838. Schechter et al. 200439. Waldo et al. 200040. Van der Straten et al. 1998

41. Marlow et al. 201242. Abdool Karim et al. 201043. McMahon et al. 201144. Ramjee et al. 200745. Cohen et al. 201146. Jean et al. 201447. Kaye et al. 201348. Kennedy et al. 200749. Venkatesh et al. 201150. Zakher et al. 201451. Chen 201352. Crepaz et al. 200453. Golub 201354. Kalichman et al. 201155. Grant et al. 201056. Choopanya et al. 201457. Baeten et al. 201258. Thigpen et al. 201259. Van Damme et al. 2012

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Images

• Slide 1 (T-shirt): http://gaytherapyla.com/prep-hiv-mental-health-specialist-therapist-weighs-one-hottest-topics-gay-men-today

• Slide 6 (risk compensation model): Eaton LA, Kalichman SC. Curr HIV/AIDS Rep. 2007;4:165-172

• Slide 11 (condom): "Red condom" by josef325 - KONDOMI. Licensed under Creative Commons Attribution 2.0-de via Wikimedia Commons.

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Acknowledgements

• NIMH #1-K01-MH093273• Yale Center for Interdisciplinary Research

on AIDS

No conflicts of interest to declare