ࡱ> E@ bjbj &y$hhhhl$QSSSSSS$R6w5wQQ& ЀhUphQ„0ڈڈ"ڈ5ww$$D|h$$h HIV/AIDSand Substance Use Disorders Preparedby Olivera Bogunovic, MD Alcohol Medical Scholars Program April7, 2006 slide[1] INTRODUCTION Lecture addresses twoclinically important topics HIV/AIDS: a commonand deadly disease Substance use disorders:i.e., dependence on alcohol and illicit drugs It is important tounderstand how they relate Each increasesthe risk of the other Each impactson treatment Clinicians must learnabout both conditions to give optimal treatment; therefore this lectureaddresses: Importance ofHIV public health issue Connectionbetween HIV and substance use disorders Implicationsfor patient careslide[2] Vignette 40 year-oldwhite male presents to the emergency room with symptoms Diarrhea >1month Fatigue Weight loss thrush History Used heroinintravenously for past 10 years Multiplefailed inpatient rehabilitation treatment Few periods ofsustained sobriety in past 10 years On and offdepressed mood Pertinentlaboratory data CD4 <400 Platelets<130,000 slide[3] BACKGROUND ON HIV/AIDS Human immunodeficiencyvirus (HIV) Retrovirus RNA virus Attaches to the CD4receptor on the cell membrane Unique property oftranscribing RNA into DNA with reverse transcriptase Retroviral DNAintegrates into chromosomal DNA of the host cell Reproduces withcell division Progressive loss of cells over timebecause of cytopathic effect of viral reproduction Subsequentdevelopment of severe immunodeficiency Two types of HIVvirus HIV 1 virus:Accounts for most cases HIV 2 virus: Mostly found inWest Africa Lesstransmissible, has lower viral load, and slower rate of CD4 decline compared toHIV 1 Variability instrains associated with resistance to antiretroviral medication Principallyinfected cell: CD4 T-cell CD4Tcellorchestrates the immune systems response to infected cells CD4 recognizesantigens on surface of the virus-infected cell Secretes lymphokinesthat stimulate B cells (immune cells which secrete antibodies), and killer Tcells that destroy infected cells CD4Tcell countdetermines when to start treatment of HIV HIV infects cellswith CD4 receptor such as: Monocytes: White blood cells that killmicroorganisms in the blood Important cellularreservoirs allowing spread of infection to brain and other organs Macrophages:monocytes become macrophages after entering tissues Natural killercells: type of lymphocyte that destroy foreign bodies Microglia: type ofimmune cells found in brain Acquiredimmunodeficiency syndrome (AIDS) CDC (Center for Disease Control and Prevention)definition [2] Presence of opportunistic infections (infection thatdoes not occur in humans except when immunodeficiency is present) andmalignancies in the absence of severe immunodeficiency CD4 count<200 [2] Other definition: Several nonspecific conditions(dementia, wasting-loss of muscle mass) and positive HIV serology [2] slide[4] Epidemiology Worldwide 39.4million diagnosed with HIV as of 2004 [3] In the UnitedStates: Overall prevalence In 2003, anestimated 1,100,000 diagnosed with AIDS/HIV CDC estimates40,000 persons become infected each year [4,5] Prevalence inhigh-risk populations Injection drugusers 25% of allinfected individuals [4-6] 22% of injectiondrug users are HIV positive [7] Homosexual males 63% of allinfected individuals 5% homosexuals andinjection drug users [6] 2.3% of incarcerated persons diagnosedwith HIV [6] Homelessindividuals 3% of homelesspeople HIV positive compared to 1% of general population Higher prevalencein bigger cities [4,5,6]slide[5] Risk factors Injection druguse Risk ofacquiring HIV infection 1:150 (on average, of 150 exposures, 1 will result ininfection) Risk ismarkedly decreased with the use of clean needles [1] Intranasaldrug use Significantlylower risk compared with intravenous use (exact percentage not known) Intranasal useassociated with bleeding Riskassociated with shared straws use [8] High risk sexualpractices Sex withHIV-positive partners Sex with multiplepartners Risky sexualpractices No use of condom Vigorous activitysuch as during intoxication from stimulant drugs Sex with partnerswho have other sexually transmitted diseases (e.g., herpes, gonorrhea), as HIVcan more easily penetrate open lesions [9]slide [6] Maternaltransmission during childbirth In the absence ofHIV prophylaxis, ~25%infants born HIV positive Risk is greater forvaginal than cesarean births Higher rate,5%among breastfed children Higher risk ifmother has higher viral load Risk of transmissionto baby is decreased to 8% with maternal antiretroviral treatment duringpregnancy [1] (antiretroviral drugs discussed later in the lecture) Occupationalexposures Risk of acquiringHIV from a needle stick is 1:300; risk factors include depth of penetration,hollow needles (used for injections), and more advanced illness stage of thepatient [1] Risk from mucousmembrane contact (e.g., in dental occupations) is too low to quantify Blood transfusions HIV transmissionwith blood transfusion 1:100,000 Persons who engagedin unsafe behaviors are not allowed to donate blood Tattoos Case reports of HIVtransmission Convincing datalacking Much lower ratesthan with intravenous and intranasal use [11,12] slide[7] Clinical course Initialinfection Seroconversion (development of antibodies) occursapproximately 8-12 weeks after exposure 50% ofpatients with mononucleosis-like syndrome 3-6 weeks after exposure (e.g.swollen glands and lethargy) c. Symptomrange from fever to meningitis (can involve fever, malaise, arthralgia,lymphadenopathy, meningitis, and neuropathy) Latency period HIV antibodiescontinue to be detectable in blood Rate of HIVreplication is slow Phase maypersist for 10 years even without treatment Persistentgeneralized lymphadenopathy (stage 3) Persists forat least 3 months Present in atleast 2 places besides groin area (e.g. lymph nodes in axilla, neck, etc) Earlysymptomatic infection Decline in immunesystem occurs as manifested by decreased CD4 T cell count Exact triggersare poorly understood Generalsymptoms: Malaise Fever lastingone month Night sweats Weight loss>10 % of baseline body weight Diarrhealasting one month Skin problems Seborrhoeicdermatitis (faint pink patches with loose waxy scales on the scalp) Fungalinfections Bacterialinfections (e.g., staphylococcal infection-impetigo) Viralinfections (e.g., herpes infections-cold sores and genital infection) Mouth problems Hairy oralleukoplakia (white patch often corrugated or hairy in the mouth on the lateralborder; viral etiology) Dentalabscess Candidiasis(fungal infection, presenting with removable white plaques) Ulceration Hematologicalproblems Lymphopenia< 800/mL(normal 800-3500/mL) Neutropenia< 1500/mL(normal 2200-8600/mL) Anemia -hemoglobin< 12g/dl, hematocrit < 36% Thrombocytopenia< 140,000 (normal 150,000 450,000) AIDS (the 5thstage) CD4 count <200 (normal 359-1725 cells/mL) Pneumocysticcarini (respiratory opportunistic infection), tuberculosis (4% incidence),invasive cervical cancer (40% incidence of dysplasia) more frequent End stagedisease CD4 T cellcount < 50 Mycobacteriumavium (bacteria causing opportunistic respiratory, gastrointestinal infection),toxoplasmosis (parasite causing inflammation of the brain), non-Hodgkinlymphoma (malignancy of B lymphocytes), cryptoccocal meningitis (yeastinfection, life threatening), cytomegalovirus (virus causing inflammation ofthe brain and retina), disseminated histoplasmosis (fungal infection affectinglungs) can occur AIDS-related dementia (cognitivedecline, motor slowing) and psychosis (delusions, auditory hallucinations) canoccur [13] slide[8] Basic elements oftreatment for HIV and AIDS Primaryprevention (efforts to prevent the acquisition of HIV infection) Risk factorassessment (e.g., IV drug use, unsafe sex, etc) Substance use:emphasis on preventing injection drug use Prevention ofunsafe sex Secondaryprevention (after HIV infection occurs) CD4 countevery 3-6 months Viral loadtests every 3-6 months (>5000-10000 copies/ml-start antiretroviraltreatment) Toxoplasmosisserology (positive result requires treatment of opportunistic infection) Cytomegalovirusserology (positive result requires treatment of opportunistic infection) Pneumococcalvaccine (HIV + susceptible to infection) Hepatitis Bvaccine (coinfection with hepatitis B  mortality) Women:Papanicolau (PAP) smears of the cervix every six months (due to increased>risk of cervical cancer) Haemophilusinfluenza B vaccination (HIV+susceptible to infection) PPD skintesting because of tuberculosis risk, due to decreased cellular immunity. Consider analswabs for cytologic evaluation yearly for men with history of receptive analintercourse, due to > risk of anus carcinoma slide[9] Treatment withantiretroviral drugs Antiretroviral treatment to increaseimmune function and decrease viral replication Guidelines forstarting antiretroviral treatment Use for everyone(symptomatic or not) if CD4< 500 cells/ml Use if plasmaviral load > 5000-10000 copies/ml. Reevaluate needfor treatment every 3-6 months Nucleosideand nucleotide analogs Act as chainterminators for HIV reverse transcriptase when incorporated in the elongatingstrain of DNA (e.g. they stop viral replication) Specificdrugs: Zidovudine(Retrovir) Didanosine(Videx) Zalcitabine(Hivid) Stavudine(Zerit) Lamivudine(Epivir) Protease inhibitors Act at thestage of viral release; prevent the action of proteases which are essential toproduction of viral particles (e.g. reduce production of infectious virusesfrom host cell) Specificdrugs: Saquinavir(Invirase) Indinavir(Crixivan) Ritonavir(Norvir) Nelfinavir(Viracept) Non-nucleosidereverse transcriptase Bind toreverse transcriptase of the virus; prevent RNA conversion into DNA (e.g. virusnot able to replicate in host cell) Specificdrugs: Nevirapine(Viramine) Delaviridine(Rescriptor) slide[10] Treatment andprophylaxis of Pneumocystic Carrini with antibiotics (when CD4<75) andcytomegalovirus with antiviral medication (when CD4 <50) in AIDS patients [1,14] BACKGROUND ON SUBSTANCE USE DISORDERS slide[11] Categories of the mostrelevant drugs to HIV/AIDS Opioids Naturalopioids: opium, morphine, codeine Semisyntheticdrugs: heroin, hydromorphone (Dilaudid), oxycodone (Percodan) Syntheticopioids: propoxyphene (Darvon), meperidine (Demerol) Stimulants Amphetaminesand amphetamine-like substances Amphetamine(Benzedrine) Dextroamphetamine(Dexedrine) Dietylpropion(Tenuate) Benzphetamine(Didrex) Methylphenidate(Ritalin) Methylendioxymethamphetamine(MDMA, ecstasy) Methamphetamine(Desoxyn) Cocaine Hydrochloridepowder Freebase Crack(crystallized from) [15] Alcohol Ethyl alcohol(ethanol)- scientific name for beverage alcohol Single drink:12 grams of ethanol 12 ounces ofbeer 4 ouncesnonfortified wine 1-1.5ounces of 80 proof liquorslide[12] Substance UseDisorders Misusecategory that describes substance use not meeting criteria for abuse/dependence Diagnostic and Statistical Manual, 4thedition (DSM-IV) definition ofdependence and abuse Substance dependence [16] Maladaptivepattern of use Clinicallysignificant impairment 3 within 12months Tolerance Need more for same effect Decreased effect with same amount used Withdrawal Withdrawal syndrome (opposite of initial effects) Use substance to relieve/avoid withdrawal Larger amounts/longer period thanintended Persistent desire/unsuccessful effortsto cut down Much time spent getting/using/recovering Giveup/reduce important social/occupational/recreational activities Continued usedespite physical/psychological problem Substanceabuse [16] Maladaptivepattern of use Clinicallysignificant impairment 1 within 12month period Inability tofulfill major roles Use inphysically hazardous situations Legalproblems Continued usedespite social/interpersonal problems Dependencecriteria never met slide[13] Prevalence of use anddependence for each drug category relevant to HIV Opioids Lifetime use:1.3% Americans report using heroin in their lifetime [17] Lifetime abuseor dependence of heroin: 0.7% [18] Stimulants Amphetamine Lifetime use:7% [17] Lifetimeabuse or dependence: 1.5% [18,19] Cocaine Lifetime use:10%[17] Lifetimeabuse or dependence: 2% [18,19] Alcohol Lifetime use:80% Lifetime rate of abuse or dependence: 10-15% men, 8-10% women [19,20] slide[14] Relevant routes ofadministration for drugs Injection:highest risk of transmission Intravenous(injecting into veins; rapid effect;  risk of overdose) Intramuscular(injecting into muscle tissue; onset slower/less powerful) Skinpopping/subcutaneous (injecting under the surface of the skin) Intranasal(sniffing powdered forms) Smoking(heating drug and inhaling vapors; onset rapid) Oral - lowestdirect risk of HIV infection, (indirect  risk for risky sexualbehavior) less efficient oral highslide[15] Key elements oftreatment Chronicdisease model: like diabetes, asthma Needs longterm treatment Patient haslife-long disorder No substanceuse safe Treatmentincludes: Individual orgroup psychotherapy Motivationalinterviewing Therapy helpsresolve ambivalence and build motivation for abstinence Cliniciancollaborates not confronts: listens to patient, highlights concerns Clinician moves patient through stagesof change: precontemplation (no interest in quitting use) contemplation (considering behavior change), preparation (making some specific plans for quitting substanceuse). action(has started making changes), maintenance (continued work to avoid relapse), relapse(process with therapist and work to get back on track as soon as possible) Cognitivebehavioral therapy Lifestylechange (health: sleep, diet, exercise, and identification of sources of distress; seeksober social support network; healthy activities/hobbies) Relapseprevention Identify high-risk situations and problem-solve withpatient how to avoid them Learn that cravings and urges to use are feelingsthat will pass with time; teach use of coping skills Pharmacotherapy Opioiddependence Methadone Oral opioid with long half-life, given once daily s cravings andwithdrawal; relapse Buprenorphinesimilar maintenance to methadone Alcohol dependence: Disulfiramaversive agent for alcohol ingestion Naltrexone-blocks reinforcing effects Acamprosate-blocks reinforcing effects and reduces craving Self helpgroups 12-step (AAand NA) meetings - free and widelyavailable Group support Treatment complianceimportant in controlling illness Outcomespoorest if patient noncompliant Relapse ratesrelatively high in substance use disorders Compliancehelps patient avoid triggers and increases coping [21] slide[16] SUBSTANCE USE DISORDERS AND HIV What is connection? slide[17] Highprevalence of HIV in patients with substance use disorders 35% of cocaineusers HIV positive [22] 22% opioidusers HIV positive [7] Highprevalence of substance use disorders in patients with HIV 25% rate ofalcohol dependence [23] 25% rate ofuse of opioids 33% rate ofcocaine use [24] slide[18] Drug use andtransmission of HIV Risk withinjection, intranasal and other routes of use Highest:intravenous use Increased:intranasal use Increased if: Numberof sexual partners Unsafesex practices Anal sex Useof condoms Associatedwith concurrent alcohol use Higherimpulsivity Poor judgment[25] slide[19] Effects ofdrugs/alcohol on natural history of HIV Opioids Causeimmunosuppression functioning of T & Blymphocyte production of antibodies effect of natural killer cells 20 % decreaseof CD4 count Induceapoptosis (programmed cell death) of macrophages viral replication Injection druguse results in coinfection of HIV and blood borne pathogens (i.e hepatitis B,hepatitis C) [25-31] slide[20] Cocaine Causesuppression on T cell Degree ofimmunosupression related to the amount used (two-three fold higher) Viralreplication throughout the body Increases permeabilityof the blood-brain barrier to viral strains Braincells infected: macrophage and microglia Viral productsreleased by HIV infected cells result in immunosuppression and neurotoxicity(dopaminergic brain sites affected cause cognitive and motor impairment)[26,31,32,33,34] Amphetamine Not much data:assume similar to cocaine Research beginning to accumulate Use results inimmunosuppression - decreasedCD4 count [31] slide[21] Alcohol Crosses cellmembranes:immune responsiveness (i.e lymphocyte response to HIV infection) Suppresseslymphocyte response to HIV infection Viral replication Promotesprogression from asymptomatic to symptomatic illness Permeability of the blood brain barrier to infectious agents [35,36] slide [22] Effects ofdrugs/alcohol on antiretroviral medications slide[23] Opioids Associatedwith high risk behavior and noncompliance with therapy ( 40%active users noncompliant) Methadonereduces blood levels of didanosine, zidovudine and stavudine Methadoneconcentrations are decreased by efavirenz, nevirapine (50%) nelfinavir (40%),lopinavir and ritonavir (32%) Opioid withdrawal symptoms can occur Adjustment ofmethadone dose may be necessary [37] slide[24] Cocaine Associated with high risk behavior Increasedresistance to antiretroviral medications in 30% as consequence of noncompliance[38] slide[25] Alcohol Associatedwith high risk behavior and noncompliance with therapy Alters immuneresponses response to antiretroviral therapy as alcohol  HIV replication Heavy HIVdrinkers less likely to achieve suppression of viral replication and CD4 count>500 Alcohol : drugabsorption, protein binding and rate of drug clearance Induces/inhibits the metabolizing enzymes of antiretroviral medication medications[39,40] slide[26] Substance usedisorders and compliance with HIV medications slide[27] Inconsistentoutpatient medical care (> 50% of patients) Noncompliancewith medication regimen 44% of activedrug users noncompliant compared to 22% of non drug users Suboptimalvirologic and immunologic responses associated with noncompliance Substancedependent often lack of medical insurance Poor socialsupport Methadone andbuprenorphine maintenance programs Associatedwith better adherence to HIV/AIDS medical treatments Methadoneprograms require daily follow up Associatedwith less active drug use [25, 46-52]slide[28] Effects of substanceuse disorders in HIV patients in relation to psychiatric disorders: Drugs/alcohol can cause/exacerbate most psychiatric symptoms Psychiatric symptoms more common among substanceusers HIV+ moresensitive to illicit drugs [41,42,43,44,45] slide[29] GUIDELINESFOR TREATMENT slide[30] Treatmentfor substance use disorders and HIV/AIDS should consider both Case management model: patient shouldhave a single clinician who coordinates treatment plan Establish andmaintain treatment plan that supports patients complete set of needs Maximizecare for HIV/AIDS and substance use disorders Medical treatment Variesdepending on stage of infection Asymptomatic infection Treat withantiretroviral therapy Risk of disease progression (assessed by CD4 countand viral load) Willingness to begin therapy and remain adherent Patients withgood adherence have morbidity, mortality Symptomatic infection Treatopportunistic infections Prophylactictreatment for Pneumocystis carrini and cytomegalovirus Treat acuteand chronic pain Localmeasures as first line therapy Use ofnarcotics for a limited time and as a last resort slide[31] Substance usedisorder treatment Abstinence isthe goal Reduce HIV risk behavior: Safe sex practices Use of cleanneedles should any injection drug use occur, but emphasize that abstinence isthe ultimate and best goal Harm reductionapproaches may be appropriate Methadonemaintenance programs more available (associated with normalization of immunefunction, spread of HIV infection, use of medical services, spread of HIV infection) Syringeexchange programs provide information about safer injection techniques (e.g.,use of clean needles, use of disinfectant) and reduce spread of HIV and otherinfectious diseases Mental healthtreatment Highcomorbidity in HIV+ patients with substance use disorders Assessment anddiagnosis challenging Patients atincreased risk of suicide (20% increased risk compared to general population) Standardpharmacologic approaches may be used to treat psychiatric disorders [53] slide[32] Vignette: What next: Treat withantiretroviral meds: educate re management of pills, Substance use disorder treatment: Considermethadone maintenance program to reduce risk of reinfection andneedle sharing; consider need dose of antiretroviralregimen when determining methadone dose Encourageself-help meetings re both for HIV and opioid dependence Mental healthtreatment: Evaluatepossible need for treatment Use meds(e.g. antidepressants) if an independentdisorder is indicated Initiatecognitive behavioral therapy re: coping skills and positive behaviors topromote improvement of mood Monitorcompliance with HIV medications, maintenance of safe sexual practices,compliance with substance use disorder treatment, and mood state slide[33] D. Summary slide[34] V. REFERENCES HollanderH., Katz HM: HIV Infection, chapter 31, Edited by Tierney LM, McPhee SJ,Papadakis MA, Lange Medical Books/McGraw-Hill 2003, pp 1272-1302. Centersfor disease control. 1993 revised classification system for HIV infection andexpanded surveillance case definition for AIDS among adolescents and adults.MMWR 1993; 41(RR-17): 1-20. UNAIDS/WHO-2004,joint United Nations programme on HIV/AIDS (UNAIDS), World Health Organization,UNAIDS/04.45E, Dec 2004. GlynnM, Rhodes P: Estimated HIV prevalence in the United States at the end of 2003.National HIV Prevention Conference; June 2005; Atlanta. Abstract 595. CDC,HIV/Aids Surveillance Report, 2003 (Vol.15) Atlanta: US Department of Healthand Human Services, CDC; 2004:1-46. Available athttp//www.cdc.gov/hiv/stats/2003 surveillance report.pdf.pdf Accessed March 16,2005. BatkiLS, Selwyn PA: 37.TIP 37: Substance abuse treatment for persons with HIV/AIDS.SAMHSA/CSAT treatment improvement protocols. DHHS Publication No. (SMA)00-3410. MetzgerDS, Woody GE, McLellan AT, OBrien CP, Druley P, Navaline H et al:Human immunodeficiency virus seroconversion among intravenous drug users in-and out-of-treatment: an 18-month prospective follow up. J Acquir Immune DeficSyndr. 1993; 6:1049-1056. DesJarlais DC, Friedman SR, Sotheran JL, Wenston J, Marmor M, Yancovitz SR et al.:Continuity and change within an HIV epidemic. Injecting drug users in New YorkCity, 1984 through 1992. JAMA 1994; 271:121-127. VittinghoffE: Per contact risk of human immunodeficiency virus transmission between malesexual partners. Am J Epidemiol 1999; 150:306-311. Landesman SH, Kalish LA, Burns DN,Minkoff H, Fox HE, Zorrilla C et al.: Obstetrical factors and the transmissionof human immunodeficiency virus type 1 from mother to child. The women andinfants transmission study. N Engl J Med 1996; 334:1617-1623. Nishioka Sde A, Gyorkos TW: Tattoos asrisk factors for transfusion-transmitted disease. Int J Infect Dis.2001;5:27-34. Long GE, Rickman LS:Infectious complications of tattoos. Clin Infect Dis.1994; 18:610-619. Mindel A, Tenant-FlowersM: Natural history and management of early HIV infection. BMJ 2001;322:1290-1293. Fauci AS et al:Guidelines for the use of antiretroviral agents in HIV-infected adults andadolescents. February 2001. Available atHYPERLINK "http://www.hivatis"  HYPERLINK "http://www.hivatis.org/" www.hivatis.org (updated consensusguidelines on the use of antiretroviral medication. Schuckit MA: Drug andalcohol abuse, chapters 2-9, edited by Springer science and business media2000; pp 28-221. American PsychiatricAssociation: Diagnostic and Statistical Manual of mental Disorders, FourthEdition (DSM-IV-TR). Washington D.C., American Psychiatric Association, 2000. Rouse BA: Epidemiologyof illicit and abused drugs in the general population, emergency departmentdrug-related episodes, and arrestees. Clin Chem. 1996; 42:1330-1336. Anthony JC, Warner LA,Kessler RC: Comparative epidemiology of dependence on tobacco, alcohol,controlled substances, and inhalants: basic findings from the NationalComorbidity Survey. Exp Clin Psychopharmacol. 1994; 2:244-268. Warner LA, Kessler RC,Hughes M, Anthony JC, Nelson CB: Prevalence and correlates of drug use anddependence in the United States. Results from the National Comorbidity Survey.Arch Gen Psychiatry 1995; 52:219-229. Grant BF: Prevalence andcorrelates of alcohol use and DSM-IV alcohol dependence in the United States. JStud Alcohol. 1997; 58: 464-473. Hsu JH: Substance abuseand HIV. Hopkins HIV Rep. 2002; 14: 8-12. Chaisson RE, Bachetti P,Osmond D, Brodie B, Sande MA, Moss AR: Cocaine use and HIV infection inintravenous drug users in San Francisco. JAMA 1989; 261:1471-1472. Lefevre F, OLearyB, Moran M, Mossar M, Yarnold PR, Martin GI et al: Alcohol consumption amongHIV-infected patients. J Gen Intern Med. 1995; 10:458-460. Ostrow DG: SubstanceAbuse and HIV infection. Psychiatr Clin North Am. 1994; 17:69-89. Fiellin DA: Substanceuse disorders in HIV-infected patients: impact and new Treatment strategies.Top HIV med. 2004; 12:77-82. Kapadia F, Vlahov D,Donahoe RM, Friedland G: The role of substance abuse in HIV diseaseprogression: reconciling differences from laboratory and epidemiologicinvestigations. Clin Infect Dis. 2005; 41:1027-1034. Cohn JA: HIV-1 infectionin injection drug users. Infect Dis Clin North Am. 2002; 16: 745-770. Donahoe RM, Vlahov D:Opiates as potential cofactors in progression of HIV-1 infections to AIDS. JNeuroimmunol. 1998; 83:77-87. Friedman H, EisensteinTK: Neurological basis of drug dependence and its effects on the immune system.J Neuroimmunol. 2004; 147:106-108. Everall IP: Interventionbetween HIV and intravenous heroin abuse. J Neuroimmunol. 2004; 147:13-15. Basso MR, Bornstein RA:Neurobehavioural consequences of substance abuse and HIV infection. JPsychopharmacol. 2000; 14:228-237. Goodkin K, Shapshak P, Metsch LR, McCoyCB, Crandall KA, Kumar M et al: Cocaine abuse and HIV-1 infection: epidemiologyand neuropathogenesis. J Neuroimmunol. 1998; 83: 88-101. 'F t  v )STEFYZhit%v%%%%%%%&&6'8'}**,,B-C---/\/]///////+0-0N0<1P1Z1d1+2A2J334444777@8A8e8htO{56\]htO{OJQJ^J htO{H*htO{OJQJ htO{5\htO{T'(IJlmE F ??????+??+??+??+?? ??t;??+??+?pddd[$\$^`pedDdedDdedD$ddd[$\$a$edDedDedKF+F t u   E F y z ) * ; < E ?t;?? ?? ??t;?? ??? ?????? ?? ?? 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J Leukoc Biol. 2005;78:1198-1203. Nath A, Booze RM, Huser KF, Mactutus CF,Bell J, Cass WA et al: Interactions of drugs of abuse and HIV dementia.NeuroAids 1999; Vol.2, issue10. Bagasra O, Kajdacsy-Balla A, LischnerHW: Effects of alcohol ingestion on in vitro susceptibility of peripheral bloodmononuclear cells to infection with HIV and of selected T-cell functions. AlcoholClin Exp Res. 1989; 13:636-643. Cook RT, Stapleton JT,Ballas ZK, Klinzman D: Effect of a single ethanol exposure on HIV replicationin human lymphocytes. J Investig Med. 1997; 45:265-271. Gourevitch MN, FriedlandGH: Interactions between methadone and medications used to treat HIV infection:a review. Mt Sinai J med. 2000; 67:429-436. Sharpe TT, Lee LM,Nakashima AK, Elam-Evans LD, Fleming PL: Crack cocaine use and adherence toantiretroviral treatment among HIV-infected black women. J Community Health 2004;29:117-127 Miguez MJ, Shor-PosnerG, Morales G, Rodrigez A, Burbano X: HIV treatment in drug abusers: impact ofalcohol use. Addict Biol. 2003; 8:33-37. Cook RL, Sereika SM,Hunt SC, Woodward WC, Erlen JA, Conigliaro J: Problem drinking and medicationadherence among persons with HIV infection. J Gen Intern Med. 2001; 16:83-88. Batki SL,Ferrando SJ,Manfredi LB et al: Psychiatric disorders, drug use and medical status ininjection drug users with HIV disease. Am J Addict 5:249-258, 1996. Lyketsos CG, Hanson A,Fishman M, McHugh PR, Treisman GJ: Screening for psychiatric morbidity in amedical outpatient clinic for HIV infection: the need for a psychiatricpresence. Int J Psychiatry Med. 1994; 24:103-113. Lyketsos CG, FedermanEB: Psychiatric disorders and HIV infection:impact on one another. EpidemiolRev. 1995; 17:152-164. Weiser SD, Wolfe WR,Bangsberg DR: The HIV epidemic among individuals with mental illness in theUnited States. Curr HIV/AIDS Rep 2004; 1:186-192. Galanter M, Kleber HD: Textbook ofsubstance abuse treatment, chapter 44. Second edition. The American psychiatricpress 1999, pp 503-510. Minkoff HL, McCalla S,Delke I, Stevens R, Salwen M, Feldman J: The relationship of cocaine use tosyphilis and human immunodeficiency virus infections among inner cityparturient. Am J Obstet Gynecol. 1990; 163: 521-526. Poundstone KE, ChaissonRE, Moore RD: Differences in HIVdisease progression by injection drug use and by sex in the era of highlyactive antiretroviral therapy. AIDS. 2001; 15:1115-1123. Celentano DD, Galai N,Sethi AK, Shah NG, Strathdee SA, Vlahov D et al: Time to initiating highlyactive antiretroviral therapy among HIV-infected injection drug users. AIDS.2001; 15: 1727-1728. Junghans C, Low N, ChanP, Witschi A, Vernazza P, Egger M: Uniform risk of clinical progression despitedifferences in utilization of highly active antiretroviral therapy: Swiss HIVCohort Study. AIDS. 1999; 13: 2547-2554. Aceijas C, Stimson GV,Hickman M, Rhodes T: Global overview of injecting drug use and HIV infectionamong injecting drug users. AIDS. 2004; 18:2295-2303. Lucas GM, Cheever LW,Chaisson RE, Moore RD: Detrimental effects of continued illicit drug use on thetreatment of HIV-1 infection. J Acquir Immune Defic Syndr. 2001; 27:251-259. Kohli R, Lo Y, HowardAA, Buono D, Floris-Moore M, Klein RS et al: Mortality in an urban cohort ofHIV-infected and at-risk drug users in the era of highly active antiretroviraltherapy. Clin Infect Dis. 2005; 41:864-872. 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