1. Steve Shoptaw, Ph.D. David Geffen School of Medicine at UCLA Departments of Family Medicine and Psychiatry HIV Prevention in Substance Users HIV Prevention in Substance Users

2. Acknowledgments CHIPTS – (1MH P30 058107) – Rotheram, Reback, Veniegas, Landovitz, Kao, Gorbach, Leibowitz, Coates, Detels NIDA – (1 DA P50 018185; 1 DA R01 029804; 1 DA R01 030577) City and County of Los Angeles California HIV Research Program Medicinova – grant for clinical supplies Pfizer – grant for clinical supplies

3. Overview HIV Prevention Goals and Strategies Lowering Infectiousness in HIV+ Substance Users TasP Opioid substitution Harm reduction Access to ART Reducing Susceptibility in HIV – Substance Users PrEP PEP Immune mechanisms and drug use Behavioral Programs Drug Abuse Treatment as HIV Prevention Final Thoughts

4. HIV PREVENTION Overview

5. Aspirational Goals: 2015 Sexual transmission reduced by 50% –Youth, MSM, Sex Workers No vertical transmission Transmissions via drug use eliminated Universal access to ART HIV-TB deaths < by 50% Social justice; no stigma

6. Key Point: It’s a New Ballgame Strategic Plans!Strategic Plans! Combination Prevention:Combination Prevention: –IPrEX - Grant –EBAN – El Bassel –Female Microbicides - Abdool Qurim –HPTN 052 – Cohen –Male Circumcision - Auvert, Bailey, Grey –PEP - Schechter 2011 is for HIV Prevention what 1996 is for HIV Treatment! Substance Users, esp SU-MSM: Last on the bus

7. Compelling tools for combination prevention Prevention in PositivesPrevention in Positives –Testing and linkage to care –Assertive cART for Prevention –Positive prevention behavioral change –Facilitation of cART Adherence Prevention in Negatives –“ABC” –Male circumcision –Needle exchange and substance use therapy –Structural reform School attendance Gender empowerment and education of women –Topical/oral PrEP Sten Vermund, June 2011 HPTN Annual Mtg

8. Clinical trial evidence for preventing sexual HIV transmission – June 2011 Efficacy Study Effect size (CI) Medical male circumcision (Orange Farm, Rakai, Kisumu) 54% (38; 66) RV-144 Vaccine (Thailand) 31% (1; 51) 0% 20 40 60 80 100% STD treatment (Mwanza) 42% (21; 58) 39% (6; 60) Microbicide (CAPRISA 004 tenofovir gel) Oral PrEP for MSMs (iPrEx: Americas, Thailand, Africa) 44% (15; 63) Treatment for prevention (HPTN 052; Africa, Asia, America’s) 96% (73; 99) Sten Vermund, June 2011 HPTN Annual Mtg

9. HIV TREATMENT AS PREVENTION ART as Disease Prevention

10. Profound Effects of ART in Preventing Death CASCADE Collaboration 22 cohorts pooled with known dates of HIV seroconversion Gains not even: –MSM decreased deaths from malignancies and Ois –IDUs increased deaths due to unintentional deaths Smit et al., 2006, AIDS, 20: 741-749

11. HIV TREATMENT BENEFITS Benefits of Starting Early: Individual and Couples

13. ART in Serodiscordant Couples Attia et al., 2009, AIDS, 23: 1397-1404

14. HPTN 052 Cohen et al., 2011, NEJM, 365: 493-505

15. ART Confers Protection: Details for HPTN 052 1763 serodiscordant couples enrolled; –All sexually active in past year; ~6% had unprotected sex 886 to early therapy; 877 to delayed therapy –448 and 424 CD4 cells/mm 3 at baseline –603 and 399 CD4 cells/mm 3 at 12-months 39 HIV-transmission events –96% reduction in linked transmissions for early treatment! Hazard rate=0.04, CI=0.01-0.28 –4 in early therapy group (incidence=0.3/100ppy CI 0.1-0.6 Only 1 linked transmission in this group; problem with adherence –35 in delayed group (incidence=2.2/100ppy CI 1.6-3.1) 27 linked transmissions in this group Hazard rate for clinical events for early treatment: –0.59 CI 0.40-0.89; primarily in prevention of extrapulmonary TB

16. HIV TREATMENT AS HIV PREVENTION Lowering Infectiousness

17. Strategy for HIV Combination Prevention in HIV+ Substance Users Reduce Infectiousness: Reduce viral loads in HIV-positive groups of substance users –Reduces “transmission potential” across population –Foundation of the seek, test, treat, retain approach –Departure from advocacy strategies guiding HIV prevention –No data yet to test TasP in HIV+ drug users Kurth et al., 2011, Current HIV/AIDS Reports,1-11

18. Lowering Infectiousness in IDUs: Modeling Findings Simultaneous scale-up of NSP, VCT, OST and ART implemented when CD4 cell counts drop < 350 can reduce HIV incidence up to 63% (Degenhardt et al., 2010) In countries where HIV epidemics among IDUs are established or emerging, benefits of these combinations are amplified by structural interventions that optimize access or efficacy (Strathdee et al., 2010)

19. Reducing HIV Incidence in IDUs Degenhardt et al., 2010, Lancet, 376:285-301

20. IDUs and Their Risk Environments Ensuring access to ART, OST and NSP is important; IDUs interact with individuals outside IDU networks Opportunities for structural interventions Strathdee et al., 2010, Lancet, 376, 268-284

21. ART in IDUs and NIDUs: Access Denied EVER Get ART? N=1730 ART for 95%+ of Time N=1275 Age (per year)1.03 CI 1.02-1.041.02 CI 1.01-1.04 Baseline CD4<200 cell4.43 CI 3.19-6.161.15 CI 0.89-1.48 Baseline PVL>5 log 10 1.68 CI 1.2-2.350.68 CI 0.47-0.81 Black Race0.57 CI 0.44-0.730.65 CI 0.51-0.83 IDU History0.47 CI 0.33-0.670.63 CI 0.44-0.90 NIDU History0.62 CI 0.47-0.810.66 CI 0.52-0.85 McGowan et al., 2011. PLOSOne, 6:e18462

22. Effects of ART Among IDUs Nolan et al., 2011. AIDS Care, 23:980-987

23. Current Status Models suggest, but no data exist to determine benefits of TasP for IDU or non- IDU substance users –Proof of concept studies excluded these due to concerns over medication adherence problems. HPTN 074 will address TasP among IDUs in countries with  HIV incidence –Measuring incidence in networks of IDUs and sexual partners Virtually no other studies planned to guide policy on TasP among HIV+ substance users

24. Apathy, Addictophobia, Inattention Limited access to ARTs for HIV+ IDUs in resourced and in developing countries –Begs the question of starting ART early Political stances against opioid substitution therapies and needle and syringe programs present structural barriers to averting infections Inattention to marginalized groups (e.g., street youth, sex workers; itinerant workers) who engage IDU Strathdee et al., 2012, Curr Opin HIV/AIDS

25. HIV TREATMENT AS HIV PREVENTION Reducing Susceptability

26. Strategy for HIV Combination Prevention in HIV- Substance Users Lower susceptibility: Reduce infection in HIV- negative groups –Biobehavioral approaches – PrEP, PEP for substance using MSM; other groups at high risk –Behavioral programs – condom distribution, EBIs can address structural determinants of risk related to substance use; no evidence of infections averted –Surveillance of emerging epidemics linked to drug use Kurth et al., 2011, Current HIV/AIDS Reports,1-11

27. iPrEX: Pre-Exposure Prophylaxis Truvada: Tenofovir + Emtracitabine taken daily Tenofovir 1% gel reduced HIV infection in heterosexual women by 39% (Abdool Karim et al. 2010) Preclinical work shows efficacy in protecting against HIV transmission in mice and non- human primates 2,441 MSM followed to 12-months for seroconversion

28. iPrEX Results Grant RM et al N Engl J Med. 2010 363:2587-99.

29. iPrEX Findings Of 100 seroconversions, 36 in Truvada group, a reduction of 44% over placebo (p=0.005) Efficacy was higher in men who reported UAI (58%) than those who did not Adherent men (90%+) showed 73% efficacy Efficacy of all subjects was 47% (p=0.001) Questions remain about adverse effects, feasibility/acceptability/ethics No indication about substance users as they were excluded from trials

30. PEP in MSM In Project EXPLORE, MSM who reported any non-injection drug use increased odds for PEP by 50% (aOR: 1.5, 95% CI:1.1, 1.9) –Smoked cocaine, poppers, crack cocaine, amphetamines and hallucinogens increased odds –IDUs significantly higher odds of PEP use (aOR: 2.44, 95%CI: 1.69, 3.51). –Marijuana or cocaine that was snorted or sniffed or alcohol drinking did not associate with increased odds for PEP –No evidence of risk compensation Donnell et al., 2010, AIDS Behav 14:1182–1189

31. PEP in Methamphetamine Using MSM When integrated with CM, PEP use among meth-using MSM appears to be safe and feasible Time to PEP initiation (37 h) and reported adherence rates (96%) are comparable to non-meth-using PEP findings CM increased PEP adherence 2% for each MA-negative urine sample; CM increased PEP completion by 17% Meth-using MSM had high rates of risk behavior: high prevalent STI rates Small sample size (n=53), 1 incident seroconversion – non-adherent to meds and multiple exposures Landovitz et al. 2012 AIDS Pt Care STDS, 26:320-328

32. Where Will All the Drug Come From? At the end of 2010, 6.6 million on ART (UNAIDS) –42% of those in need (CD4 ≤ 350 cells/mm) 9 million eligible and in need of treatment now; 28 million HIV-infected globally –Attrition cascade at all points from testing to ART initiation to chronic care New infections: 2.6 million in 2010 1 Advancements in TasP, PEP and PrEP create even more demand for ART 1 http://wwwunaidsorg/unaids_resources/aidsat30/aids-at-30pdf

33. INTERACTIONS OF DRUG ABUSE, IMMUNE AND HIV Mechanisms Rationale

34. Cocaine-use Linked Deaths in the WIHS In the WIHS, crack cocaine use associated with ↑ plasma VL, ↓ CD4, and ↑ morbidity mortality compared to non-drug users Cook et al., 2008, AIDS, 22:1355-1363

35. Drug Use and CD4/CD8 Ratios in the MACS Exposure Variables HIV – Coefficient (95% CI) HIV + Coefficient (95% CI) 2001-2003 Cohort vs pre- 2001 cohort**1.38 (1.24, 1.55) * Cumulative medication adherence (10 ART-years) N/A 4.07 (3.52, 4.71)* Cumulative cigarette smoking (10 pack-years) 1.10 (1.02, 1.18)* ** Cumulative meth use (10 use-years) ** 0.93 (0.88, 0.98)* Cumulative cocaine use (10 use-years) ** 0.93 (0.89, 0.96)* Shoptaw et al., 2012, Int J STD & AIDS, 23:576-580

36. Methamphetamine Use in HIV: ART Adherence Use of drugs, especially stimulant drugs, reduces ART adherence 3-day reported adherence rates: – On stimulants: 51% – Off stimulants: 72% Main effects of meth observed on behavioral organization Hinkin et al., 2007, AIDS & Behav 11:185–194; Arnsten et al., 2002, J Gen Intern Med 17:377-381

37. Methamphetamine and HIV Disease Outcomes Meth  TNF-  in infected mice splenocytes Cocaine  TNF-  and HIV replication in PBMCs in humans Careful analysis suggested ARV in meth users  high VLs, perhaps from incomplete adherence Ellis et al., 2003, JID: 188:1820-26

38. GALT Immune Activation in ART naïve: HIV+/Meth+ (n=5) vs Meth– (n=3) Shoptaw, Gorbach, Anton, in prep

39. Summary Stimulants can have independent negative effects on immune functioning in HIV+ substance users – Question of patterns of use; individual stimulants – Active methamphetamine use in the absence of ART increases pro-inflammatory environment in GALT, perhaps enhancing HIV replication. ART, even in the presence of stimulant use, appears to have strong positive effects on CD4/CD8 levels

40. TREATMENT OF SUBSTANCE USE DISORDERS AS HIV PREVENTION

41. OPIOID REPLACEMENT Opioid Agonist: Medications that bind and activate opioid receptors (methadone) Opioid Antagonist: Medications that bind but do not activate the opiate receptors (naltrexone) Opioid Partial Agonist: Medication that binds, but does not fully activate opioid receptors (buprenorphine)

42. Methadone Promotes ART Use Uhlmann et al., 2010. Addiction, 105, 917-913

43. ART Adherence and MMT in 545 Homeless IDUS in Vancouver Palepu et al., 2011. J Urban Health, 88: 545-555

44. Mechanism: Opioid Replacement as HIV Prevention Reduced craving for and use of illicit opioids Reduced frequency of injecting drug use Concomitant reductions in sex for money or drugs Better cognitive function and ability to understand prevention messages Less sharing of paraphernalia Regular contact with NTP, which increases chance for medical and psychosocial interventions Gowing et al., 2008

45. Studies on Seroconversion Incidence for Replacement = 3/100 person years Incidence for No Replacement = 10/100 person years Metzger et al., 1993

46. Summary: Methadone and HIV Seroconversion Early cohort studies demonstrated effects of methadone for reducing HIV-incidence Continuous methadone maintenance is seroprotective; interrupted maintenance is not (Moss et al., 1994) Opioid substitution may slow transmission of treatment resistant virus (Tetrault et al., 2013)

47. The Majority of Substance Users at Risk for HIV Do Not Inject …

48. Meth Use and HIV Transmission in MSM Meth use correlates with 2-4 fold increases in risk for HIV transmission in: –Cohort Studies (Plankey et al., 2007) –New Infections (Drumright et al., 2007; 2009) –STI settings (Buchacz et al., 2005; Buchbinder et al., 2005) Carey et al., AIDS & Beh, 2008

49. HIV Transmission A Probabilistic Event Determined by: –Characteristics of the behavior Unprotected anal (  receptive;  insertive) Unprotected vaginal (  receptive;  insertive) Oral behaviors –Characteristics of the individual Other STIs Bruised/bleeding mucosa Viral load Concurrency –Characteristics of the event Single; multiple sources of virus Cohen, 2006 Methamphetamine

50. Attributable Risk for HIV Transmission from Stimulant Use in MSM 1 Koblin et al., 2006, AIDS, 20, 731-739 2 Ostrow et al., 2009, Journal of Acquired Immune Deficiency Syndrome, 51(3), 349-355

51. Behavioral Drug Abuse Treatment as HIV Risk Reduction Behavioral Therapies –Friends Getting Off (Reback & Shoptaw, 2011) –Contingency Management (Shoptaw et al., 2005) Limits to treatment settings (Menza et al., 2010) Heterosexual meth users show parallel reductions in injection and sex risk behaivors (Corsi et al., 2012) Medication Therapies –Mirtazapine (30 mg/d) for meth-dependent MSM (Colfax et al., 2011) showed reductions in meth use and concomitant HIV sexual transmission behaviors

52. Summary Opioid substitution therapy increases ART access and ART adherence –Also reduces HIV-related transmission behaviors –May reduce resistant transmission Indications that stimulants negatively effect immune function –ART access and adherence has profound positive effects in HIV+ stimulant users No addiction medications with same signal size as opiate and nicotine medications

53. HIV PREVENTION IN SUBSTANCE USE GROUPS Standard Approaches

54. Behavioral Prevention for HIV+ Substance Users After 30+ years, behavioral prevention reliably reduces risk behaviors, but no demonstration of infections averted –Need for inclusion of HIV biomarkers in designs CDC Compendium and SAMHSA NREPP programs catalog interventions with efficacy in reducing risk behaviors –Project EDGE (Mausbach et al., 2007) safer sex program for MSM HIV+ meth users.

55. Behavioral Prevention for HIV- Negative Substance Users Woman focused HIV risk reduction program for African American crack smokers (Wechsberg et al., 2004) Fast Lane, HIV-risk reduction program for HIV-negative heterosexual meth users (Mausbach et al., 2007)

56. FINAL THOUGHTS

57. Substance Use Groups at Risk Drug trends change, as do ways drugs are integrating with HIV risks –Monitor high-risk subgroups of substance users: non- injection substances, from racial/ethnic groups and where substance use, homosexuality or sex-work are illegal –Compelling need for data from low and middle-income countries with ongoing generalized HIV epidemics (e.g., sub-Saharan Africa, south and southeast Asia) or emerging epidemics (e.g., Central Asia) –Monitoring of HIV risks in novel drug use groups (e.g., synthetic marijuana, methcathinone) Need consistent inclusion of HIV biomarkers

58. Emerging HIV/Substance Epidemics Monitor where HIV incidence among IDU has declined and HIV transmissions in substance users shifted from drug risk to sex risk (e.g., Brazil; Thailand) –South Africa has a methamphetamine epidemic, with users reporting non-injection routes. Other countries in sub-Saharan Africa have witnessed emerging epidemics of heroin and cocaine use, and their impact on HIV incidence within the context of high HIV prevalence in the general population is unknown Need surveillance studies with HIV biomarkers and measures of resistance

59. Combination Prevention in Drug Users Crucial need to study implementation of combination prevention approaches (e.g., PrEP, TasP, PEP) in substance users with HIV Combination HIV prevention of PrEP and PEP in HIV- negative substance users at high-risk merits consideration. Efforts to quantify and address potential problems with medication adherence in substance users, including structural and behavioral approaches New Medications: depot formulations of ART in drug users; novel medications for drug abuse Combination HIV prevention research that addresses co- occurring infections in substance users, particularly hepatitis C, tuberculosis and STIs.

60. Thank You