HIV/AIDS and Substance Use Disorders

Prepared by Olivera Bogunovic, MD

Alcohol Medical Scholars Program

April 7, 2006 slide[1]

I. INTRODUCTION

A. Lecture addresses two clinically important topics

1. HIV/AIDS: a common and deadly disease

2. Substance use disorders: i.e., dependence on alcohol and illicit drugs

B. It is important to understand how they relate

1. Each increases the risk of the other

2. Each impacts on treatment

C. Clinicians must learn about both conditions to give optimal treatment; therefore this lecture addresses:

1. Importance of HIV – public health issue

2. Connection between HIV and substance use disorders

3. Implications for patient care slide[2]

D. Vignette

1. 40 year-old white male presents to the emergency room with symptoms

a. Diarrhea >1 month

b. Fatigue

c. Weight loss

d. thrush

2. History

a. Used heroin intravenously for past 10 years

b. Multiple failed inpatient rehabilitation treatment

c. Few periods of sustained sobriety in past 10 years

d. On and off depressed mood

3. Pertinent laboratory data

a. CD4 <400

b. Platelets <130,000 slide[3]

II. BACKGROUND ON HIV/AIDS

A. Human immunodeficiency virus (HIV)

1. Retrovirus

a. RNA virus

b. Attaches to the CD4 receptor on the cell membrane

c. Unique property of transcribing RNA into DNA with reverse transcriptase

d. Retroviral DNA integrates into chromosomal DNA of the host cell

e. Reproduces with cell division

f. Progressive loss of cells over time because of cytopathic effect of viral reproduction

g. Subsequent development of severe immunodeficiency

2. Two types of HIV virus

a. HIV 1 virus: Accounts for most cases

b. HIV 2 virus:

i. Mostly found in West Africa

ii. Less transmissible, has lower viral load, and slower rate of CD4 decline compared to HIV 1

3. Variability in strains associated with resistance to antiretroviral medication

4. Principally infected cell: CD4 T-cell

a. CD4Tcell orchestrates the immune system’s response to infected cells

b. CD4 recognizes antigens on surface of the virus-infected cell

c. Secretes lymphokines that stimulate B cells (immune cells which secrete antibodies), and killer T cells that destroy infected cells

d. CD4Tcell count determines when to start treatment of HIV

5. HIV infects cells with CD4 receptor such as:

a. Monocytes:

i. White blood cells that kill microorganisms in the blood

ii. Important cellular reservoirs allowing spread of infection to brain and other organs

b. Macrophages: monocytes become macrophages after entering tissues

c. Natural killer cells: type of lymphocyte that destroy foreign bodies

d. Microglia: type of immune cells found in brain

B. Acquired immunodeficiency syndrome (AIDS)

1. CDC (Center for Disease Control and Prevention) definition [2]

a. Presence of opportunistic infections (infection that does not occur in humans except when immunodeficiency is present) and malignancies in the absence of severe immunodeficiency

b. CD4 count<200 [2]

2. Other definition: Several nonspecific conditions (dementia, wasting-loss of muscle mass) and positive HIV serology [2] slide[4]

C. Epidemiology

1. Worldwide 39.4 million diagnosed with HIV as of 2004 [3]

2. In the United States:

a. Overall prevalence

i. In 2003, an estimated 1,100,000 diagnosed with AIDS/HIV

ii. CDC estimates 40,000 persons become infected each year [4,5]

b. Prevalence in high-risk populations

i. Injection drug users

(a) 25% of all infected individuals [4-6]

(b) 22% of injection drug users are HIV positive [7]

ii. Homosexual males

(a) 63% of all infected individuals

(b) 5% homosexuals and injection drug users [6]

iii. 2.3% of incarcerated persons diagnosed with HIV [6]

iv. Homeless individuals

(a) 3% of homeless people HIV positive compared to 1% of general population

(b) Higher prevalence in bigger cities [4,5,6] slide[5]

D. Risk factors

1. Injection drug use

a. Risk of acquiring HIV infection 1:150 (on average, of 150 exposures, 1 will result in infection)

b. Risk is markedly decreased with the use of clean needles [1]

2. Intranasal drug use

a. Significantly lower risk compared with intravenous use (exact percentage not known)

b. Intranasal use associated with bleeding

c. Risk associated with shared straws use [8]

3. High risk sexual practices

a. Sex with HIV-positive partners

b. Sex with multiple partners

c. Risky sexual practices

i. No use of condom

ii. Vigorous activity such as during intoxication from stimulant drugs

d. Sex with partners who have other sexually transmitted diseases (e.g., herpes, gonorrhea), as HIV can more easily penetrate open lesions [9] slide [6]

4. Maternal transmission during childbirth

a. In the absence of HIV prophylaxis, ~25%infants born HIV positive

b. Risk is greater for vaginal than cesarean births

c. Higher rate,» 5%among breastfed children

d. Higher risk if mother has higher viral load

e. Risk of transmission to baby is decreased to 8% with maternal antiretroviral treatment during pregnancy [1] (antiretroviral drugs discussed later in the lecture)

5. Occupational exposures

a. Risk of acquiring HIV from a needle stick is 1:300; risk factors include depth of penetration, hollow needles (used for injections), and more advanced illness stage of the patient [1]

b. Risk from mucous membrane contact (e.g., in dental occupations) is too low to quantify

6. Blood transfusions

a. HIV transmission with blood transfusion 1:100,000

b. Persons who engaged in unsafe behaviors are not allowed to donate blood

7. Tattoos

a. Case reports of HIV transmission

b. Convincing data lacking

i. Much lower rates than with intravenous and intranasal use [11,12]

slide[7]

E. Clinical course

1. Initial infection

a. Seroconversion (development of antibodies) occurs approximately 8-12 weeks after exposure

b. 50% of patients with mononucleosis-like syndrome 3-6 weeks after exposure (e.g. swollen glands and lethargy)

c. Symptom range from fever to meningitis (can involve fever, malaise, arthralgia, lymphadenopathy, meningitis, and neuropathy)

2. Latency period

a. HIV antibodies continue to be detectable in blood

b. Rate of HIV replication is slow

c. Phase may persist for 10 years even without treatment

3. Persistent generalized lymphadenopathy (stage 3)

a. Persists for at least 3 months

b. Present in at least 2 places besides groin area (e.g. lymph nodes in axilla, neck, etc)

4. Early symptomatic infection

a. Decline in immune system occurs as manifested by decreased CD4 T cell count

b. Exact triggers are poorly understood

c. General symptoms:

i. Malaise

ii. Fever lasting one month

iii. Night sweats

iv. Weight loss >10 % of baseline body weight

v. Diarrhea lasting one month

d. Skin problems

i. Seborrhoeic dermatitis (faint pink patches with loose waxy scales on the scalp)

ii. Fungal infections

iii. Bacterial infections (e.g., staphylococcal infection-impetigo)

iv. Viral infections (e.g., herpes infections-cold sores and genital infection)

e. Mouth problems

i. Hairy oral leukoplakia (white patch often corrugated or hairy in the mouth on the lateral border; viral etiology)

ii. Dental abscess

iii. Candidiasis (fungal infection, presenting with removable white plaques)

iv. Ulceration

f. Hematological problems

i. Lymphopenia < 800/mL (normal 800-3500/mL)

ii. Neutropenia < 1500/mL (normal 2200-8600/mL)

iii. Anemia - hemoglobin< 12g/dl, hematocrit < 36%

iv. Thrombocytopenia < 140,000 (normal 150,000 –450,000)

5. AIDS (the 5^th stage)

a. CD4 count < 200 (normal 359-1725 cells/mL)

b. Pneumocystic carini (respiratory opportunistic infection), tuberculosis (4% incidence), invasive cervical cancer (40% incidence of dysplasia) more frequent

6. End stage disease

a. CD4 T cell count < 50

b. Mycobacterium avium (bacteria causing opportunistic respiratory, gastrointestinal infection), toxoplasmosis (parasite causing inflammation of the brain), non-Hodgkin lymphoma (malignancy of B lymphocytes), cryptoccocal meningitis (yeast infection, life threatening), cytomegalovirus (virus causing inflammation of the brain and retina), disseminated histoplasmosis (fungal infection affecting lungs) can occur

c. AIDS-related dementia (cognitive decline, motor slowing) and psychosis (delusions, auditory hallucinations) can occur [13] slide[8]

F. Basic elements of treatment for HIV and AIDS

1. Primary prevention (efforts to prevent the acquisition of HIV infection)

a. Risk factor assessment (e.g., IV drug use, unsafe sex, etc)

b. Substance use: emphasis on preventing injection drug use

c. Prevention of unsafe sex

2. Secondary prevention (after HIV infection occurs)

a. CD4 count every 3-6 months

b. Viral load tests every 3-6 months (>5000-10000 copies/ml-start antiretroviral treatment)

c. Toxoplasmosis serology (positive result requires treatment of opportunistic infection)

d. Cytomegalovirus serology (positive result requires treatment of opportunistic infection)

e. Pneumococcal vaccine (HIV + susceptible to infection)

f. Hepatitis B vaccine (coinfection with hepatitis B mortality)

g. Women: Papanicolau (PAP) smears of the cervix every six months (due to increased> risk of cervical cancer)

h. Haemophilus influenza B vaccination (HIV+ susceptible to infection)

i. PPD skin testing because of tuberculosis risk, due to decreased cellular immunity.

j. Consider anal swabs for cytologic evaluation yearly for men with history of receptive anal intercourse, due to > risk of anus carcinoma slide[9]

3. Treatment with antiretroviral drugs

a. Antiretroviral treatment to increase immune function and decrease viral replication

b. Guidelines for starting antiretroviral treatment

i. Use for everyone (symptomatic or not) if CD4< 500 cells/ml

ii. Use if plasma viral load > 5000-10000 copies/ml.

iii. Reevaluate need for treatment every 3-6 months

c. Nucleoside and nucleotide analogs

i. Act as chain terminators for HIV reverse transcriptase when incorporated in the elongating strain of DNA (e.g. they stop viral replication)

ii. Specific drugs:

(a) Zidovudine (Retrovir)

(b) Didanosine (Videx)

(c) Zalcitabine (Hivid)

(d) Stavudine (Zerit)

(e) Lamivudine (Epivir)

d. Protease inhibitors

i. Act at the stage of viral release; prevent the action of proteases which are essential to production of viral particles (e.g. reduce production of infectious viruses from host cell)

ii. Specific drugs:

(a) Saquinavir (Invirase)

(b) Indinavir (Crixivan)

(c) Ritonavir (Norvir)

(d) Nelfinavir (Viracept)

e. Non-nucleoside reverse transcriptase

i. Bind to reverse transcriptase of the virus; prevent RNA conversion into DNA (e.g. virus not able to replicate in host cell)

ii. Specific drugs:

(a) Nevirapine (Viramine)

(b) Delaviridine (Rescriptor) slide[10]

4. Treatment and prophylaxis of Pneumocystic Carrini with antibiotics (when CD4<75) and cytomegalovirus with antiviral medication (when CD4 <50) in AIDS patients [1,14]

III. BACKGROUND ON SUBSTANCE USE DISORDERS slide[11]

A. Categories of the most relevant drugs to HIV/AIDS

1. Opioids

a. Natural opioids: opium, morphine, codeine

b. Semisynthetic drugs: heroin, hydromorphone (Dilaudid), oxycodone (Percodan)

c. Synthetic opioids: propoxyphene (Darvon), meperidine (Demerol)

2. Stimulants

a. Amphetamines and amphetamine-like substances

i. Amphetamine (Benzedrine)

ii. Dextroamphetamine (Dexedrine)

iii. Dietylpropion (Tenuate)

iv. Benzphetamine (Didrex)

v. Methylphenidate (Ritalin)

vi. Methylendioxymethamphetamine (MDMA, “ecstasy”)

vii. Methamphetamine (Desoxyn)

b. Cocaine

i. Hydrochloride powder

ii. Freebase

iii. Crack (crystallized from) [15]

3. Alcohol

a. Ethyl alcohol (ethanol)- scientific name for beverage alcohol

b. Single drink: 12 grams of ethanol

i. 12 ounces of beer

ii. 4 ounces nonfortified wine

iii. 1-1.5 ounces of 80 proof liquor slide[12]

B. Substance Use Disorders

1. Misuse –category that describes substance use not meeting criteria for abuse /dependence

2. Diagnostic and Statistical Manual, 4^th edition (DSM-IV) definition of dependence and abuse

a. Substance dependence [16]

i. Maladaptive pattern of use

ii. Clinically significant impairment

iii. ≥3 within 12 months

(a) Tolerance

· Need more for same effect

· Decreased effect with same amount used

(b) Withdrawal

· Withdrawal syndrome (opposite of initial effects)

· Use substance to relieve/avoid withdrawal

(c) Larger amounts/longer period than intended

(d) Persistent desire/unsuccessful efforts to cut down

(e) Much time spent getting/using/recovering

(f) Give up/reduce important social/occupational/recreational activities

(g) Continued use despite physical/psychological problem

b. Substance abuse [16]

i. Maladaptive pattern of use

ii. Clinically significant impairment

iii. ≥1 within 12 month period

(a) Inability to fulfill major roles

(b) Use in physically hazardous situations

(c) Legal problems

(d) Continued use despite social/interpersonal problems

iv. Dependence criteria never met slide[13]

C. Prevalence of use and dependence for each drug category relevant to HIV

1. Opioids

a. Lifetime use: 1.3% Americans report using heroin in their lifetime [17]

b. Lifetime abuse or dependence of heroin: 0.7% [18]

2. Stimulants

i. Amphetamine

(a) Lifetime use: 7% [17]

(b) Lifetime abuse or dependence: 1.5% [18,19]

ii. Cocaine

(a) Lifetime use: 10%[17]

(b) Lifetime abuse or dependence: 2% [18,19]

3. Alcohol

a. Lifetime use: 80%

b. Lifetime rate of abuse or dependence: » 10-15% men, » 8-10% women [19,20] slide[14]

D. Relevant routes of administration for drugs

1. Injection: highest risk of transmission

a. Intravenous (injecting into veins; rapid effect; risk of overdose)

b. Intramuscular (injecting into muscle tissue; onset slower/less powerful)

c. Skin popping/subcutaneous (injecting under the surface of the skin)

2. Intranasal (sniffing powdered forms)

3. Smoking (heating drug and inhaling vapors; onset rapid)

4. Oral - lowest direct risk of HIV infection, (indirect risk for risky sexual behavior) less efficient oral high slide[15]

E. Key elements of treatment

1. Chronic disease model: like diabetes, asthma

a. Needs long term treatment

b. Patient has life-long disorder

c. No substance use safe

2. Treatment includes:

a. Individual or group psychotherapy

i. Motivational interviewing

(a) Therapy helps resolve ambivalence and build motivation for abstinence

(b) Clinician collaborates not confronts: listens to patient, highlights concerns

(c) Clinician moves patient through stages of change:

· precontemplation (no interest in quitting use)

· contemplation (considering behavior change),

· preparation (making some specific plans for quitting substance use).

· 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)

ii. Cognitive behavioral therapy

(a) Lifestyle change ( health: sleep, diet, exercise, and identification of sources of distress; seek sober social support network; healthy activities/hobbies)

(b) Relapse prevention

· Identify high-risk situations and problem-solve with patient how to avoid them

· Learn that cravings and urges to use are feelings that will pass with time; teach use of coping skills

b. Pharmacotherapy

i. Opioid dependence

(a) Methadone

· Oral opioid with long half-life, given once daily

· ¯s cravings and withdrawal;¯ relapse

(b) Buprenorphine –similar maintenance to methadone

ii. Alcohol dependence:

(a) Disulfiram –aversive agent for alcohol ingestion

(b) Naltrexone- blocks reinforcing effects

(c) Acamprosate- blocks reinforcing effects and reduces craving

c. Self help groups

i. 12-step (AA and NA) meetings - free and widely available

ii. Group support

3. Treatment compliance important in controlling illness

a. Outcomes poorest if patient noncompliant

b. Relapse rates relatively high in substance use disorders

c. Compliance helps patient avoid triggers and increases coping [21]

slide[16]

IV. SUBSTANCE USE DISORDERS AND HIV

A. What is connection? slide[17]

1. High prevalence of HIV in patients with substance use disorders

a. 35% of cocaine users HIV positive [22]

b. 22% opioid users HIV positive [7]

2. High prevalence of substance use disorders in patients with HIV

a. 25% rate of alcohol dependence [23]

b. 25% rate of use of opioids

c. 33% rate of cocaine use [24] slide[18]

B. Drug use and transmission of HIV

1. Risk with injection, intranasal and other routes of use

a. Highest: intravenous use

b. Increased: intranasal use

c. Increased if:

i. Number of sexual partners

ii. Unsafe sex practices

(a) Anal sex

(b) ¯ Use of condoms

iii. Associated with concurrent alcohol use

(a) Higher impulsivity

(b) Poor judgment [25] slide[19]

C. Effects of drugs/alcohol on natural history of HIV

1. Opioids

a. Cause immunosuppression

i. ¯ functioning of T & B lymphocyte

ii. ¯ production of antibodies

iii. ¯effect of natural killer cells

iv. 20 % decrease of CD4 count

b. Induce apoptosis (programmed cell death) of macrophages

c. viral replication

d. Injection drug use results in coinfection of HIV and blood borne pathogens (i.e hepatitis B, hepatitis C) [25-31] slide[20]

2. Cocaine

a. Cause suppression on T cell

b. Degree of immunosupression related to the amount used (two-three fold higher)

c. Viral replication throughout the body

d. Increases permeability of the blood-brain barrier to viral strains

e. Brain cells infected: macrophage and microglia

f. Viral products released by HIV infected cells result in immunosuppression and neurotoxicity (dopaminergic brain sites affected cause cognitive and motor impairment)[26,31,32,33,34]

3. Amphetamine

a. Not much data: assume similar to cocaine

b. Research beginning to accumulate

c. Use results in immunosuppression - decreasedCD4 count [31] slide[21]

4. Alcohol

a. Crosses cell membranes:¯ immune responsiveness (i.e ¯ lymphocyte response to HIV infection)

b. Suppresses lymphocyte response to HIV infection

c. Viral replication

d. Promotes progression from asymptomatic to symptomatic illness

e. Permeability of the blood brain barrier to infectious agents [35,36]

slide [22]

D. Effects of drugs/alcohol on antiretroviral medications slide [23]

1. Opioids

a. Associated with high risk behavior and noncompliance with therapy (» 40% active users noncompliant)

b. Methadone reduces blood levels of didanosine, zidovudine and stavudine

c. Methadone concentrations are decreased by efavirenz, nevirapine (50%) nelfinavir (40%), lopinavir and ritonavir (32%)

i. Opioid withdrawal symptoms can occur

ii. Adjustment of methadone dose may be necessary [37] slide[24]

2. Cocaine

a. Associated with high risk behavior

b. Increased resistance to antiretroviral medications in 30% as consequence of noncompliance [38] slide[25]

3. Alcohol

a. Associated with high risk behavior and noncompliance with therapy

b. Alters immune responses

c. ¯ response to antiretroviral therapy as alcohol HIV replication

d. Heavy HIV drinkers less likely to achieve suppression of viral replication and CD4 count >500

e. Alcohol :¯ drug absorption, protein binding and rate of drug clearance

f. Induces/ inhibits the metabolizing enzymes of antiretroviral medication medications [39,40] slide[26]

E. Substance use disorders and compliance with HIV medications slide[27]

1. Inconsistent outpatient medical care (> 50% of patients)

2. Noncompliance with medication regimen

a. 44% of active drug users noncompliant compared to 22% of non drug users

b. Suboptimal virologic and immunologic responses associated with noncompliance

3. Substance dependent often lack of medical insurance

4. Poor social support

5. Methadone and buprenorphine maintenance programs

a. Associated with better adherence to HIV/AIDS medical treatments

b. Methadone programs require daily follow up

c. Associated with less active drug use [25, 46-52] slide[28]

F. Effects of substance use disorders in HIV patients in relation to psychiatric disorders: Drugs/ alcohol can cause/exacerbate most psychiatric symptoms

1. Psychiatric symptoms more common among substance users

2. HIV+ more sensitive to illicit drugs [41,42,43,44,45] slide[29]

V. GUIDELINES FOR TREATMENT slide[30]

A. Treatment for substance use disorders and HIV/AIDS should consider both

1. Case management model: patient should have a single clinician who coordinates treatment plan

2. Establish and maintain treatment plan that supports patient’s complete set of needs

B. Maximize care for HIV/AIDS and substance use disorders

1. Medical treatment

a. Varies depending on stage of infection

i. Asymptomatic infection

(a) Treat with antiretroviral therapy

· Risk of disease progression (assessed by CD4 count and viral load)

· Willingness to begin therapy and remain adherent

(b) Patients with good adherence have ¯ morbidity, mortality

ii. Symptomatic infection

(a) Treat opportunistic infections

(b) Prophylactic treatment for Pneumocystis carrini and cytomegalovirus

iii. Treat acute and chronic pain

(a) Local measures as first line therapy

(b) Use of narcotics for a limited time and as a last resort

slide[31]

2. Substance use disorder treatment

a. Abstinence is the goal

b. Reduce HIV risk behavior:

i. Safe sex practices

ii. Use of clean needles should any injection drug use occur, but emphasize that abstinence is the ultimate and best goal

c. Harm reduction approaches may be appropriate

i. Methadone maintenance programs more available (associated with normalization of immune function, ¯ spread of HIV infection, ¯ use of medical services, ¯ spread of HIV infection)

ii. Syringe exchange programs provide information about safer injection techniques (e.g., use of clean needles, use of disinfectant) and reduce spread of HIV and other infectious diseases

3. Mental health treatment

a. High comorbidity in HIV+ patients with substance use disorders

b. Assessment and diagnosis challenging

c. Patients at increased risk of suicide (20% increased risk compared to general population)

d. Standard pharmacologic approaches may be used to treat psychiatric disorders [53] slide[32]

C. Vignette:

1. What next:

a. Treat with antiretroviral meds: educate re management of pills,

b. Substance use disorder treatment:

i. Consider methadone maintenance program to¯ reduce risk of reinfection and needle sharing; consider need dose of antiretroviral regimen when determining methadone dose

ii. Encourage self-help meetings re both for HIV and opioid dependence

c. Mental health treatment:

i. Evaluate possible need for treatment

ii. Use meds (e.g. antidepressants) if an independent disorder is indicated

iii. Initiate cognitive behavioral therapy re: coping skills and positive behaviors to promote improvement of mood

d. Monitor compliance 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

1. Hollander H., Katz HM: HIV Infection, chapter 31, Edited by Tierney LM, McPhee SJ, Papadakis MA, Lange Medical Books/McGraw-Hill 2003, pp 1272-1302.

2. Centers for disease control. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR 1993; 41(RR-17): 1-20.

3. UNAIDS/WHO-2004, joint United Nations programme on HIV/AIDS (UNAIDS), World Health Organization, UNAIDS/04.45E, Dec 2004.

4. Glynn M, Rhodes P: Estimated HIV prevalence in the United States at the end of 2003. National HIV Prevention Conference; June 2005; Atlanta. Abstract 595.

5. CDC, HIV/Aids Surveillance Report, 2003 (Vol.15) Atlanta: US Department of Health and Human Services, CDC; 2004:1-46. Available at http//www.cdc.gov/hiv/stats/2003 surveillance report.pdf.pdf Accessed March 16, 2005.

6.