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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 • 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 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 Overview HIV PREVENTION 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 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 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 Clinical trial evidence for preventing sexual HIV transmission – June 2011 Study Effect size (CI) Treatment for prevention 96% (73; 99) (HPTN 052; Africa, Asia, America’s) Medical male circumcision 54% (38; 66) (Orange Farm, Rakai, Kisumu) Oral PrEP for MSMs 44% (15; 63) (iPrEx: Americas, Thailand, Africa) STD treatment 42% (21; 58) (Mwanza) Microbicide 39% (6; 60) (CAPRISA 004 tenofovir gel) RV-144 Vaccine 31% (1; 51) (Thailand) 0% 20 40 60 Efficacy Sten Vermund, June 2011 HPTN Annual Mtg 80 100% ART as Disease Prevention HIV TREATMENT AS PREVENTION 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 Benefits of Starting Early: Individual and Couples HIV TREATMENT BENEFITS ART in Serodiscordant Couples Attia et al., 2009, AIDS, 23: 1397-1404 HPTN 052 Cohen et al., 2011, NEJM, 365: 493-505 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 Lowering Infectiousness HIV TREATMENT AS HIV PREVENTION 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 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) Reducing HIV Incidence in IDUs Degenhardt et al., 2010, Lancet, 376:285-301 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 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 1.02-1.04 1.02 CI 1.01-1.04 Baseline CD4<200 cell 4.43 CI 3.19-6.16 1.15 CI 0.89-1.48 Baseline PVL>5 log10 1.68 CI 1.2-2.35 0.68 CI 0.47-0.81 Black Race 0.57 CI 0.44-0.73 0.65 CI 0.51-0.83 IDU History 0.47 CI 0.33-0.67 0.63 CI 0.44-0.90 NIDU History 0.62 CI 0.47-0.81 0.66 CI 0.52-0.85 McGowan et al., 2011. PLOSOne, 6:e18462 Effects of ART Among IDUs Nolan et al., 2011. AIDS Care, 23:980-987 Current Status • Models suggest, but no data exist to determine benefits of TasP for IDU or nonIDU 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 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 Reducing Susceptability HIV TREATMENT AS HIV PREVENTION Strategy for HIV Combination Prevention in HIV- Substance Users • Lower susceptibility: Reduce infection in HIVnegative 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 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 nonhuman primates • 2,441 MSM followed to 12-months for seroconversion iPrEX Results Grant RM et al N Engl J Med. 2010 363:2587-99. 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 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 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 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 Mechanisms Rationale INTERACTIONS OF DRUG ABUSE, IMMUNE AND HIV 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 Drug Use and CD4/CD8 Ratios in the MACS Exposure Variables 2001-2003 Cohort vs pre2001 cohort Cumulative medication adherence (10 ART-years) Cumulative cigarette smoking (10 pack-years) Cumulative meth use (10 use-years) Cumulative cocaine use (10 use-years) HIV – Coefficient (95% CI) HIV + Coefficient (95% CI) ** 1.38 (1.24, 1.55) * N/A 4.07 (3.52, 4.71)* 1.10 (1.02, 1.18)* ** ** 0.93 (0.88, 0.98)* ** 0.93 (0.89, 0.96)* Shoptaw et al., 2012, Int J STD & AIDS, 23:576-580 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 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 2000 p = 0.053 Meth 30 0 1 Meth 0 1 p = 0.053 RFI Gut pg/mg Total Protein in Rectal Fluid GALT Immune Activation in ART naïve: HIV+/Meth+ (n=5) vs Meth– (n=3) 1000 20 10 p = 0.051 0 0 INF g IL-1b IL-6 IL-12 MIP-1a RANTES TNFa Total Rectal IGG Shoptaw, Gorbach, Anton, in prep Total Rectal IGA 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 TREATMENT OF SUBSTANCE USE DISORDERS AS HIV PREVENTION 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 Methadone Promotes ART Use Uhlmann et al., 2010. Addiction, 105, 917-913 ART Adherence and MMT in 545 Homeless IDUS in Vancouver Palepu et al., 2011. J Urban Health, 88: 545-555 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 Studies on Seroconversion 35 Percent HIV + 30 25 20 Replacmt (n=138) No Replacmt (n=88) 15 10 5 0 Metzger et al., 1993 Incidence for Replacement = 3/100 person years Baseline 18 Months Incidence for No Replacement = 10/100 person years 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) The Majority of Substance Users at Risk for HIV Do Not Inject … 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) 50 45 40 35 28.8 30 25 20 15 11.4 10 5 0 Meth 47.7 32.4 22.5 9.6 Poppers HIV- (n=333) EDDs HIV+ (n=111) Carey et al., AIDS & Beh, 2008 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 HIV Transmission 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 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 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 Standard Approaches HIV PREVENTION IN SUBSTANCE USE GROUPS 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. Behavioral Prevention for HIVNegative 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) FINAL THOUGHTS Substance Use Groups at Risk • Drug trends change, as do ways drugs are integrating with HIV risks – Monitor high-risk subgroups of substance users: noninjection 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 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 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 HIVnegative 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 cooccurring infections in substance users, particularly hepatitis C, tuberculosis and STIs. Thank You