Substance Abuse and HIV: Treatment Challenges
Substance Abuse and HIV: Treatment Challenges
Alcohol and substance abuse are common in patients with HIV infection and often complicate treatment in a number of ways. Alcohol abuse, for example, is associated with poorer adherence to antiretroviral treatment, which in turn is associated with inadequate viral suppression and the development of antiviral drug resistance. Similarly, HIV-infected patients with opioid dependence are less likely to have access to HIV clinical care, less likely to receive and adhere to antiretroviral therapy, and more likely to have rapid disease progression. Appropriate treatment of both alcohol and substance abuse can result in improved adherence to antiretroviral therapy and decreased high-risk behaviors.
Substance abuse, especially injection drug abuse, is often associated with chronic infectious diseases, including HIV infection, hepatitis B, hepatitis C, and tuberculosis. Delivery of effective treatment for these chronic conditions can be very challenging in patients who continue to abuse substances. Studies have shown that untreated substance use disorders have a negative impact on access to HIV care, HIV treatment initiation, HIV outcomes and disease progression, and adherence.1-4 Here, we discuss the impact of ongoing alcohol, cocaine, and opioid abuse on HIV disease progression and discuss unique treatment challenges in patients with HIV and substance abuse.
Alcohol abuse and HIV
The spectrum of alcohol use ranges from occasional use to alcohol dependence. Moderate drinkers make up about 35% of the general population.5 Men who drink more than 4 drinks a day or 14 drinks per week and women who drink more than 3 drinks a day or 7 drinks per week are considered at-risk drinkers.6 At-risk drinkers and those meeting criteria for alcohol abuse make up about 20% of the population, while those meeting the criteria for alcohol dependence make up about 5% of the population.5 The prevalence of these disorders in patients with HIV infection is increased 2-4 fold compared with the general population.7-9
Alcohol abuse and dependence affect disease progression, treatment adherence, and comorbid disease severity in patients with HIV infection.10 In vitro studies have found increased viral replication in cells exposed to alcohol, suggesting that alcohol has a direct effect on disease progression.11 The association between alcohol and HIV disease progression in vivo, however, is variable. A cross-sectional study found that among patients receiving highly active antiretroviral therapy, log HIV RNA levels were significantly higher and CD4 counts were significantly lower in those with moderate and at-risk alcohol consumption compared with patients who abstained.12 However, among HIV-infected patients not receiving highly active antiretroviral therapy, there were no differences in HIV outcomes between any of the alcohol consumption groups.12
In a more recent, longitudinal study, CD4 counts were lower in HIV-infected patients who used alcohol and were not receiving HAART, but log HIV RNA levels were no different. There were no differences in CD4 counts or HIV RNA levels in patients receiving highly active antiretroviral therapy.13
The treatment of HIV infection in patients with alcohol use disorders can be challenging. Some studies suggest that alcohol abuse in treatment-nave patients who are initiating antiretroviral therapy slows the time to viral suppression, whereas other studies suggest little impact of alcohol abuse on HIV outcomes.14,15 The impact of alcohol abuse on HIV treatment outcomes is complex, but is at least partially mediated by medication adherence.15,16
Alcohol use disorders are associated with poorer adherence to antiretroviral treatment,17,18 which in turn is associated with inadequate viral suppression and the development of antiviral drug resistance. In addition to poorer disease outcomes and medication adherence, alcohol use may negatively affect comorbid conditions. HIV-infected patients who use alcohol, especially those meeting criteria for alcohol abuse or dependence, have more depressive symptoms than their abstaining counterparts.19 Patients co-infected with hepatitis C who use alcohol are more likely to have severe liver disease.20,21
The treatment of alcohol abuse and dependence ranges from brief interventions for at-risk drinkers to specialty referral and pharmacotherapy for patients with alcohol dependence. Brief interventions consist of 10-15 minutes of counseling focused on the negative effects of drinking. Individual studies and meta-analyses have shown that brief interventions effectively reduce alcohol use in patients who are at-risk drinkers.22,23 The efficacy of a brief intervention to reduce drinking in alcohol-dependent patients is limited.
Alcohol dependence requires a more aggressive treatment approach, with the goal being complete abstinence. Successful treatment of alcohol dependence generally uses a multimodal approach often consisting of behavioral interventions, pharmacotherapy, and participation in self-help programs (such as 12-step programs). Available pharmacotherapies for alcohol dependence include disulfiram, naltrexone, and acamprosate. Naltrexone has been shown to decrease alcohol-induced viral replication in in vitro studies.24 Acamprosate and disulfiram are both effective in treating alcohol dependence, but little data exist on their use in HIV-infected patients.
Cocaine abuse and HIV
According to the 2007 National Survey on Drug Use and Health, about 36 million Americans, 12 years or older, reported using cocaine and 9 million specifically reported using crack cocaine.25 More than 2 million (0.8%) Americans were current (past-month) users of cocaine and 610,000 (0.2%) were current users of crack. The prevalence of cocaine use in patients with HIV infection is approximately 25%.18 A cross-sectional study of 407 drug users in treatment facilities confirmed an association between HIV infection and use of crack cocaine.26
Injecting and smoking cocaine are both known risk factors for HIV acquisition.26,27 Cocaine use negatively affects access to HIV care.28 In addition, cocaine impairs human macrophage and CD4 cell activity and activates HIV-1 expression in these cell types.29,30 In a large multicenter cohort study of 1686 HIV-infected women, the use of crack cocaine predicted CD4 count and viral load markers of disease progression, development of opportunistic infections, and AIDS-related mortality.31
Another study showed that in HIV-infected patients, cocaine use or cocaine plus opioid use was associated with missed outpatient appointments, increased emergency department use, and lack of antiretroviral therapy.32 Cocaine use has also been shown to have a negative effect on medication adherence.33
HIV treatment in patients with cocaine use and combined cocaine and opioid use can be especially challenging. In a pilot study of HIV-infected patients receiving buprenorphine/naloxone for opioid dependence, 33% had cocaine use at baseline and throughout treatment.34 There is ongoing research investigating the complex relationship between HIV infection, cocaine abuse, and opioid dependence and how this relationship affects HIV treatment.35
There are no FDA-approved medications for the treatment of cocaine use. Behavioral interventions, primarily cognitive-behavioral therapy, are the mainstay of treatment and have been shown to decrease amount of use and prevent relapse.36,37 In a study of more than 1500 cocaine-dependent persons, community-based treatment decreased weekly cocaine use from 73% to 24% at 1-year follow up and to 25% at 5-year follow-up.38,39 Certain medications as well as a cocaine vaccine are being studied.39,40
Opioid abuse and HIV
Injection heroin use is a direct risk factor for HIV acquisition, and roughly one-third of all HIV cases are a result of injection drug use.34,41 Although the prevalence of heroin abuse in this country has been relatively stable over the past decade, the misuse of prescription opioids has markedly increased.42 According to the 2007 National Survey on Drug Use and Health, about 400,000 Americans used heroin in the past year, while 12 million misused prescription opioids.25
Patients with comorbid HIV infection and opioid dependence are less likely to have access to HIV clinical care, less likely to receive antiretroviral therapy, less likely to adhere to antiretroviral therapy, and more likely to have rapid disease progression.43-47 Often, treatment is delayed until active injection drug abuse has been treated, which may present a barrier to ever receiving antiretroviral therapy for many patients.2,43,44 AIDS-defining illnesses are more likely to develop in injection drug users, even those with access to care, than in non–injection drug-using counterparts.45
The most effective treatment approach for opioid dependence involves a combination of pharmacologic and psychosocial treatments.48-52 Opioid-agonist treatments are the most common pharmacologic options. These include methadone, a full opioid agonist, and buprenorphine, a partial agonist at the mu opioid receptor.51 Nonopioid treatments are available for detoxification, while the opioid antagonist naltrexone can be used for maintenance.
Opioid-agonist treatment has been shown to be effective in HIV prevention. In a study by Metzger and associates,53 155 HIV-seronegative injection drug users were followed for 18 months. Of the 152 patients receiving methadone, 3.5% became seropositive, compared with 22% of the 103 patients not in treatment. Similarly, buprenorphine has been shown to decrease behaviors that may lead to HIV infection. In a study of 166 patients receiving buprenorphine in primary care, injection drug use decreased from 37% at baseline to 7% at 24 weeks, and having sex while high decreased from 64% to 15%.54
Methadone maintenance clinics provide a unique opportunity to enhance antiretroviral adherence and decrease risk behavior.55 One model that enhances these endpoints is directly observed therapy. Many patients who are enrolled in methadone maintenance present to the clinic daily or several times per week. Therefore, a protocol in which antiretroviral therapy is administered with methadone can improve HIV outcomes.56,57
Co-location of HIV treatment within a methadone maintenance treatment program improves HIV outcomes. However, with the approval of buprenorphine for treatment of opioid dependence in office-based settings, co-location of treatment for opioid dependence within an HIV clinic is now possible.50,58 Buprenorphine has been shown to improve treatment adherence and HIV outcomes in HIV-infected, opioid-dependent patients.59,60 In one study, the feasibility of integrating buprenorphine into HIV clinical care was established. In this 3-month trial, CD4 counts remained stable, HIV RNA levels decreased, and opioid-positive urine toxicology decreased.34
Drug-drug interactions are an important consideration when treating comorbid HIV and opioid dependence. The pharmacokinetic interactions between methadone and antiretroviral drugs have been investigated. Methadone increases the area under the concentration-time curve (AUC) of zidovudine.61,62 The clinical significance of this interaction is not entirely clear, but physicians should be aware of the increased risk of zidovudine toxicity in patients receiving methadone maintenance.
The nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are known to decrease methadone blood concentrations and, therefore, may promote opioid withdrawal in patients.63,64 Interactions between methadone and some protease inhibitors have also been noted. Nelfinavir decreases the AUC of methadone; however, this interaction does not appear to be clinically significant.65 Similar interactions have been noted with lopinavir/ritonavir, although some studies have noted opioid withdrawal.66
Clinically significant interactions between buprenorphine and antiretroviral drugs have also been identified. Treatment with the protease inhibitor atazanavir (or atazanavir boosted with ritonavir) has been found to increase levels of buprenorphine, a cytochrome P450-3A4 substrate, and cause sedation. However, clinically significant interactions between buprenorphine and other protease inhibitors or NNRTIs have not been noted.67,68
Substance abuse is commonly associated with chronic infectious diseases, including HIV. Ongoing substance abuse has a negative impact on access to HIV care, antiretroviral therapy initiation, HIV disease progression, treatment outcomes, and adherence to antiretroviral treatment. Treatment of comorbid HIV infection and active substance use can be especially challenging. Effective treatment for opioid dependence has been established in HIV-infected patients, while treatments for cocaine dependence and alcohol abuse and dependence are still under investigation. Linkage and co-location of treatment for substance use and HIV is feasible and may be a useful strategy for some patients and providers.
1. Bassetti S, Battegay M, Furrer H, et al. Why is highly active antiretroviral therapy (HAART) not prescribed or discontinued? Swiss HIV Cohort Study. J Acquir Immune Defic Syndr. 1999;21(2):114-119.
2. Turner BJ, Fleishman JA, Wenger N, et al. Effects of drug abuse and mental disorders on use and type of antiretroviral therapy in HIV-infected persons. J Gen Intern Med. 2001;16(9):625-633.
3. Dronda F, Zamora J, Morena S, et al. CD4 cell recovery during successful antiretroviral therapy in naive HIV-infected patients: the role of intravenous drug use. AIDS. 2004;18(16):2210-2212.
4. Sullivan LE, Fiellin DA. Hepatitis C and HIV infections: implications for clinical care in injection drug users. Am J Addictions. 2004;13(1):1-20.
5. Fiellin DA, Reid MC, O’Connor PG. Outpatient management of patients with alcohol problems. Ann Intern Med. 2000;133(10):815-827.
6. National Institute of Alcohol Abuse and Alcoholism. Helping Patients Who Drink Too Much: A Clinicians Guide. US Department of Health and Human Services, 2005.
7. Lefevre F, O’Leary B, Moran M, et al. Alcohol consumption among HIV-infected patients. J Gen Intern Med. 1995;10(8):458-460.
8. Petry NM. Alcohol use in HIV patients: what we don’t know may hurt us. Int J STDs & AIDS. 1999;10:561-570.
9. Fiellin DA. Substance use of disorders in HIV-infected patients: impact and new treatment strategies. Topics in HIV Medicine. 2004;12(3):77-82.
10. Conigliaro J, Gordon J, McGinnis KA, et al. How harmful is hazardous alcohol use and abuse in HIV infection: do health care providers know who is at risk? J Acquir Immune Defic Syndr. 2003;33(4):521-525.
11. Bagasra O, Kajdacsy-Balla A, Lischner HW, et al. Effects of alcohol ingestion on in vitro susceptibility of peripheral blood mononuclear cells to infection with HIV and of selected T-cell functions. Alcoholism: Clinical & Experimental Research. 1989;13(5):636-643.
12. Samet JH, Horton NJ, Traphagen ET, et al. Alcohol consumption and HIV disease progression: are they related? Alcoholism: Clinical & Experimental Research. 2003;27(5):862-867.
13. Samet JH, Cheng DM, Libman H, et al. Alcohol consumption and HIV disease progression. J Acquir Immune Defic Syndr. 2007;46(2):194-199.
14. Pence BW, Miller WC, Gaynes BN, Eron JJ, Jr. Psychiatric illness and virologic response in patients initiating highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2007;44(2):159-166.
15. Henrich TJ, Lauder N, et al. Association of alcohol abuse and injection drug use with immunologic and virologic responses to HAART in HIV-positive patients from urban community health clinics. J Community Health. 2008;33(2):69-77.
16. Parsons JT, Rosof E, et al. Medication adherence mediates the relationship between adherence self-efficacy and biological assessments of HIV health among those with alcohol use disorders. AIDS & Behavior. 2008;12(1):95-103.
17. Cook RL, Sereika SM, et al. Problem drinking and medication adherence among persons with HIV infection.[see comment]. J Gen Intern Med. 2001;16(2):83-88.
18. Samet JH, Horton NJ, et al. Alcohol consumption and antiretroviral adherence among HIV-infected persons with alcohol problems. Alcoholism: Clinical & Experimental Research. 2004;28(4):572-577.
19. Sullivan LE, Saitz R, et al. The impact of alcohol use on depressive symptoms in human immunodeficiency virus-infected patients. Addiction. 2008;103(9):1461-1167.
20. Romeo R, Rumi MG, et al. Hepatitis C is more severe in drug users with human immunodeficiency virus infection. J Viral Hepatitis. 2000;7(4):297-301.
21. Cheng DM, Nunes D, et al. Impact of hepatitis C on HIV progression in adults with alcohol problems. Alcoholism: Clinical & Experimental Research. 2007;31(5):829-836.
22. Fleming MF, Barry KL, et al. Brief physician advice for problem alcohol drinkers. A randomized controlled trial in community-based primary care practices.[see comment]. JAMA. 1997;277(13):1039-1045.
23. Kaner EFS, Beyer F, et al. Effectiveness of brief alcohol interventions in primary care populations.[see comment]. Cochrane Database of Systematic Reviews. 2007;2:CD004148.
24. Wang X, Douglas SD, et al. Naltrexone inhibits alcohol-mediated enhancement of HIV infection of T lymphocytes. J Leukocyte Biology. 2006;79(6):1166-1172.
25. Substance Abuse and Mental Health Services Administration, Office of Applied Studies (2008). Results From the 2007 National Survey on Drug Use and Health: National Findings. (NSDUH Series H-34, DHHS Publication No. SMA 08-4343.) Rockville, MD. http://www.oas.samhsa.gov/NSDUH/2k7NSDUH/2k7results.cfm
26. Hwang LY, Ross MW, et al. Prevalence of sexually transmitted infections and associated risk factors among populations of drug abusers. Clin Infect Dis. 2000;31(4): 920-926.
27. Chaisson RE, Bacchetti P, et al. Cocaine use and HIV infection in intravenous drug users in San Francisco. JAMA. 1989;261(4):561-565.
28. Cunningham CO, Sohler NL, et al. Type of substance use and access to HIV-related health care. AIDS Patient Care & Stds. 2006;20(6):399-407.
29. Tashkin DP. Evidence implicating cocaine as a possible risk factor for HIV infection. J Neuroimmunol. 2004;147(1-2): 26-27.
30. Dhillon NK, Williams R, et al. Cocaine-mediated enhancement of virus replication in macrophages: implications for human immunodeficiency virus-associated dementia. J Neurovirol. 2007;13(6): 483-495.
31. Cook JA, Burke-Miller JK, et al. Crack cocaine, disease progression, and mortality in a multicenter cohort of HIV-1 positive women.[erratum appears in AIDS. 2008 Sep 12;22(14):i Note: Levine, Andrea [corrected to Levine, Alexandra M]]. AIDS. 2008;22(11):1355-1363.
32. Sohler NL, Wong MD, et al. Type and pattern of illicit drug use and access to health care services for HIV-infected people. AIDS Patient Care & Stds. 2007;21(suppl 1):S68-S76.
33. Hinkin CH, Barclay TR, et al. Drug use and medication adherence among HIV-1 infected individuals. AIDS & Behavior. 200711(2):185-94.
34. Sullivan LE, Barry D, et al. A trial of integrated buprenorphine/naloxone and HIV clinical care. Clin Infect Dis. 2006;43(suppl 4):S184-S190.
35. Kresina TF, Bruce RD, McCance-Katz EF. Medication assisted treatment in the treatment of drug abuse and dependence in HIV/AIDS infected drug users. Current HIV Research. 2009;7(4):354-364.
36. Crits-Christoph P, Siqueland L, et al. Psychosocial treatments for cocaine dependence: National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Arch Gen Psychiatry. 1999;56(6):493-502.
37. Simpson DD, Joe GW, et al. A national evaluation of treatment outcomes for cocaine dependence. Arch Gen Psychiatry. 1999;56(6):507-514.
38. Simpson DD, Joe GW, et al. A national 5-year follow-up of treatment outcomes for cocaine dependence. Arch Gen Psychiatry. 2002;59(6):538-544.
39. Martell BA, Mitchell E, et al. Vaccine pharmacotherapy for the treatment of cocaine dependence. Biological Psychiatry. 2005;58(2):158-64.
40. Sofuoglu M, Kosten TR. Emerging pharmacological strategies in the fight against cocaine addiction. Expert Opinion on Emerging Drugs. 2006;11(1):91-98.
41. Centers for Disease Control and Prevention. HIV/AIDS Fact Sheets. 2002. Retrieved July 15, 2009, from http://www.cdc.gov/hiv/resources/Factsheets/idu.htm.
42. Compton WM, Volkow ND. Abuse of prescription drugs and the risk of addiction. Drug & Alcohol Dependence. 2006;83(suppl 1): S4-S7.
43. Celentano D, Vlahov D, et al. Self-reported antiretroviral therapy in injection drug users. JAMA. 1998;280(6):544-546.
44. Strathdee SA, Palepu A, et al. Barriers to use of free antiretroviral therapy in injection drug users. JAMA. 1998;280(6):547-549.
45. Moore RD, Keruly JC, et al. Differences in HIV disease progression by injecting drug use in HIV-infected persons in care. J Acquir Immune Defic Syndr. 2004;35(1):46-51.
46. Poundstone KE, Chaisson RE, et al. Differences in HIV disease progression by injection drug use and by sex in the era of highly active antiretroviral therapy. AIDS. 2001;15(9):1115-1123.
47. Malta M, Strathdee SA, et al. Adherence to antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome among drug users: a systematic review. Addiction. 2008;103(8):1242-1257.
48. O’Connor PG, Oliveto AH, et al. A randomized trial of buprenorphine maintenance for heroin dependence in a primary care clinic for substance users versus a methadone clinic. Am J Med. 1998;105(2):100-105.
49. O’Connor PG, Fiellin DA. Pharmacologic treatment of heroin-dependent patients. Ann Intern Med. 2000;133(1):40-54.
50. Fiellin DA, O’Connor PG. New federal initiatives to enhance the medical treatment of opioid dependence. Ann Intern Med. 2002;137(8):688-692.
51. Fiellin DA, Friedland GH, et al. Opioid dependence: rationale for and efficacy of existing and new treatments. Clin Infect Dis. 2006;43(suppl 4): S173-S177.
52. Tetrault JM, O’Connor PG. Opioid intoxication and withdrawal. Principles of Substance Abuse, 4th ed. I. Philadelphia: Lippincott Williams & Wilkins, 2009; 589-603.
53. Metzger DS, Woody GE, et al. Human immunodeficiency virus seroconversion among intravenous drug users in- and out-of-treatment: an 18-month prospective follow-up. J Acquir Immune Defic Syndr. 1993;6(9):1049-1056.
54. Sullivan LE, Moore BA, et al. Buprenorphine/naloxone treatment in primary care is associated with decreased human immunodeficiency virus risk behaviors. J Substance Abuse Treatment. 2008;35(1):87-92.
55. Selwyn PA, Budner NS, et al. Utilization of on-site primary care services by HIV-seropositive and seronegative drug users in a methadone maintenance program. Public Health Reports. 1993;108(4):492-500.
56. McCance-Katz EF, Gourevitch MN, et al. Modified directly observed therapy (MDOT) for injection drug users with HIV disease. Am J Addictions. 2002;11(4):271-278.
57. Lucas GM, Weidle PJ, et al. Directly administered antiretroviral therapy in an urban methadone maintenance clinic: a nonrandomized comparative study. Clin Infect Dis. 2004;38(suppl 5):S409-S413.
58. Ling W, Charuvastra C, et al. Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction. 1998;93(4):475-486.
59. Moatti JP, Carrieri MP, et al. Adherence to HAART in French HIV-infected injecting drug users: the contribution of buprenorphine drug maintenance treatment. The Manif 2000 study group. AIDS. 2000;14(2):151-155.
60. Carrieri MP, Rey D, et al. Evaluation of buprenorphine maintenance treatment in a French cohort of HIV-infected injecting drug users. Drug & Alcohol Dependence. 2003;72(1):13-21.
61. McCance-Katz EF, Rainey PM, Jatlow P, Friedland G. Methadone effects on zidovudine disposition (AIDS Clinical Trials Group 262). J Acquired Immune Deficiency Syndromes & Human Retrovirology. 1998;18(5):435-443.
62. McCance-Katz EF, Rainey PM, Friedland G, et al. Effect of opioid dependence pharmacotherapies on zidovudine disposition. Am J Addictions. 2001;10(4): 296-307.
63. Marzolini C, Troillet N, Talenti A, et al. Efavirenz decreases methadone blood concentrations. AIDS. 2000;14(9):1291-1292.
64. Clarke SM, Mulcahy FM, Tjia J, et al. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clin Infect Dis. 2001;33(9):1595-1597.
65. McCance-Katz EF, Rainey PM, Smith P, et al. Drug interactions between opioids and antiretroviral medications: interaction between methadone, LAAM, and nelfinavir. Am J Addictions. 2004;13(2):163-180.
66. McCance-Katz EF, Rainey PM, Friedland G, Jatlow P. The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained patients. Clin Infect Dis. 2003;37(4):476-82.
67. McCance-Katz EF, Moody DE, Morse GD, et al. Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine. Clin Infect Dis. 2006;43(suppl 4):S224-S234.
68. McCance-Katz EF, Moody DE, Smith PF, et al. Interactions between buprenorphine and antiretrovirals. II. The protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir. Clin Infect Dis. 2006;43(suppl 4):S235-S246.