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Steve Shoptaw, Ph.D. David Geffen School of Medicine at UCLA Departments of Family Medicine and Psychiatry

HIV Prevention in Substance Users. Steve Shoptaw, Ph.D. David Geffen School of Medicine at UCLA Departments of Family Medicine and Psychiatry. Acknowledgments. CHIPTS – (1MH P30 058107) – Rotheram, Reback, Veniegas, Landovitz, Kao, Gorbach, Leibowitz, Coates, Detels

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Steve Shoptaw, Ph.D. David Geffen School of Medicine at UCLA Departments of Family Medicine and Psychiatry

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

  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. Overview HIV Prevention

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

  9. ART as Disease Prevention HIV Treatment as 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. Benefits of Starting Early: Individual and Couples HIV Treatment benefits

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

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

  14. 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/mm3 at baseline • 603 and 399 CD4 cells/mm3 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

  15. Lowering Infectiousness HIV Treatment as HIV Prevention

  16. 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

  17. 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)

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

  19. 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

  20. ART in IDUs and NIDUs: Access Denied McGowan et al., 2011. PLOSOne, 6:e18462

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

  22. 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

  23. 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

  24. Reducing Susceptability HIV Treatment as HIV Prevention

  25. 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

  26. 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

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

  28. 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

  29. 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

  30. 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

  31. 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 20101 • Advancements in TasP, PEP and PrEP create even more demand for ART 1http://wwwunaidsorg/unaids_resources/aidsat30/aids-at-30pdf

  32. Mechanisms Rationale Interactions of Drug abuse, immune and HIV

  33. 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

  34. Drug Use and CD4/CD8 Ratiosin the MACS Shoptaw et al., 2012, Int J STD & AIDS, 23:576-580

  35. 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 & Behav11:185–194; Arnsten et al., 2002, J Gen Intern Med 17:377-381

  36. 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

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

  38. 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

  39. Treatment of Substance Use Disorders as HIV Prevention

  40. 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) Opioid Replacement

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

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

  43. 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

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

  45. 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)

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

  47. 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

  48. Methamphetamine 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

  49. 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

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