Identifying and addressing risk compensation in ARV-based HIV prevention

1. Identifying and addressing risk compensation in ARV-based HIV prevention Kristen Underhill, D.Phil., J.D.

2. ARVs for HIV Prevention • “A major milestone”? • Gateway to an AIDS-free generation? • Or “a catastrophe in the history of AIDS”?

3. 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

5. 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)

6. 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

7. Cognitive mechanism of risk compensation in HIV prevention • 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. Figure from Eaton LA, Kalichman SC. CurrHIV/AIDS Rep. 2007;4:165-172.

8. Prerequisites for risk compensation • The protective intervention is visible. • The individual user believes that the intervention is protective. • The individual has control over his or her risk-taking behaviors. • “Risks for reasons”: The individual has a motivation to take more risks. (4)

9. 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.

10. 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.

11. 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)

12. 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

13. Identifying risk compensation • Risk compensation is driven by the perception of protection, not just using ARVs. • For ARV-based prevention, this has 2 parts: • I know I’m using (or my partner is using) ARVs. • 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.

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

15. Problems with double-blinded RCTs • Both groups are uncertain about protection • Cannot test relationship between perceived protection and behavior • Between-group comparisons / Longitudinal comparisons

16. 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)

17. 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)

18. Identifying risk compensation after efficacy is known (Phase IV) • Now ARV users have the perceptions we need: • I know I’m on ARVs • 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.

19. Open-Label Extension Studies • 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.

20. 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

21. 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.

22. 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)

23. 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)

24. 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)

25. 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)

26. 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.

27. 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

28. 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

29. 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?

30. References 20. Mugwanya et al. 2013 21. Golub et al. 2010 22. Brooks et al. 2011 23. Brooks et al. 2012 24. Holt et al. 2012 25. Koblin et al. 2011 26. Galea et al. 2012 27. Smith et al. 2012 28. Tripathi et al. 2013 29. Whiteside et al. 2011 30. de la Tribonniere et al. 1998 31. Golub et al. 2008 32. Donnell et al. 2010 33. Martin et al. 2004 34. Poynten et al. 2009 35. Schechter et al. 2004 • Roland et al. 37. Kalichman 1998 38. Schechter et al. 2004 39. Waldo et al. 2000 40. Van der Straten et al. 1998 41. Marlow et al. 2012 42. Abdool Karim et al. 2010 43. McMahon et al. 2011 44. Ramjee et al. 2007 45. Cohen et al. 2011 46. Jean et al. 2014 47. Kaye et al. 2013 48. Kennedy et al. 2007 49. Venkatesh et al. 2011 50. Zakher et al. 2014 51. Chen 2013 52. Crepaz et al. 2004 53. Golub 2013 54. Kalichman et al. 2011 55. Grant et al. 2010 56. Choopanya et al. 2014 57. Baeten et al. 2012 58. Thigpen et al. 2012 59. Van Damme et al. 2012 1. Wilde 2001 2. Adams 1995 3. Peltzman 1975 4. Hedlund 2000 5. Crosby et al. 2012 6. Eaton & Kalichman 2007 7. Pinkerton 2001 8. Cassell et al., 2006 9. Calabrese et al. 2014 10. Tripathi et al 2012 11. Krakower et al. 2013 12. Tang et al. 2014 13. Tellalian et al. 2013 14. White et al. 2012 15. Liu et al. 2013 16. Simon et al., 2007 17. Dellar et al. 2014 • Marcus et al. 2013 19. Malani 2006

31. 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.

32. Acknowledgements • NIMH #1-K01-MH093273 • Yale Center for Interdisciplinary Research on AIDS No conflicts of interest to declare