HIV AND ILLICIT DRUG USERS (IDUs) (Updated January 10, 2011)

Treatment Challenges of HIV-positive IDUs

Injection drug use is the second-most common mode of HIV transmission in the United States. In addition, noninjection illicit drug use may facilitate sexual transmission of HIV. Injection and noninjection illicit drugs include the following: heroin, cocaine, marijuana, and club drugs (i.e., methamphetamine, ketamine, gamma-hydroxybutyrate [GHB], and amyl nitrate). The most commonly used illicit drugs associated with HIV infection are heroin and stimulants (e.g., cocaine and amphetamines); however, the use of club drugs has increased substantially in the past several years and is common among those who have HIV infection or who are at risk of HIV infection.

Methamphetamine and amyl nitrate (i.e., poppers) have been the most strongly associated with high-risk sexual behavior in men who have sex with men (MSM), and the association is less consistent with the other club drugs [1].

All illicit drugs have been associated with depression and anxiety, either as part of the withdrawal process or as a consequence of repeated use. This is particularly relevant in the treatment of HIV infection because depression is one of the strongest predictors of poor adherence and poor treatment outcomes [2]. Although treatment of HIV disease in this population can be successful, IDUs who have HIV disease present special treatment challenges. These may include the following: (1) an array of complicating comorbid medical and mental health conditions; (2) limited access to HIV care; (3) inadequate adherence to therapy; (4) medication side effects and toxicities; (5) the need for substance abuse treatment; and (6) drug interactions that can complicate HIV treatment [3].

Underlying health problems among injection and noninjection drug users result in increased morbidity and mortality, either independent of or accentuated by HIV disease. Many of these problems are the consequence of prior exposures to infectious pathogens from nonsterile needle and syringe use. Such problems can include hepatitis B or C virus infection, tuberculosis, skin and soft tissue infections, recurrent bacterial pneumonia, and endocarditis. Other morbidities such as alteration in levels of consciousness and neurologic and renal disease are not uncommon. Furthermore, these comorbidities are associated with a higher risk of drug overdoses in IDUs with HIV disease, due in part to respiratory, hepatic, and neurological impairments [4]. Successful HIV therapy for IDUs often rests upon acquiring familiarity with and providing care for these comorbid conditions and overdose prevention support.

IDUs have less access to HIV care and are less likely to receive antiretroviral therapy (ART) than other populations [5-6]. Factors associated with low rates of ART among IDUs include active drug use, younger age, female gender, suboptimal health care, recent incarceration, lack of access to rehabilitation programs, and lack of expertise among health care providers [5-6]. The typically unstable, chaotic life patterns of many IDUs; the powerful pull of addictive substances; and common misperceptions about the dangers, impact, and benefits of ART all contribute to decreased adherence [7]. The chronic and relapsing nature of substance abuse as a biologic and medical disease, compounded by the high rate of mental illness that antedates and/or is exacerbated by illicit substance use, additionally complicate the relationship between health care workers and IDUs [8-9]. The first step in provision of care and treatment for these individuals is to recognise the existence of a substance abuse problem. Whereas this is often open and obvious, patients may hide such behaviors from clinicians. Assessment of a patient for substance abuse should be part of routine medical history taking and should be done in a clinical, straightforward, and nonjudgmental manner.

Treatment efficacy in HIV-positive illicit drug use populations

Although IDUs are underrepresented in HIV therapy clinical trials, available data indicate that—when they are not actively using drugs—efficacy of ART in IDUs is similar to that seen in other populations [10]. Furthermore, therapeutic failure in this population generally correlates with the degree that drug use disrupts daily activities rather than with drug use per se [11]. Providers need to remain attentive to the possible impact these factors have upon the patient before and during prescription of ART. Although many IDUs can sufficiently control their drug use over long enough periods of time to benefit from care, substance abuse treatment is often necessary for successful HIV management.

Close collaboration with substance abuse treatment programs and proper support and attention to this population’s special multidisciplinary needs are critical components of successful HIV treatment. Essential to this end are accommodating and flexible, community-based HIV care sites that are characterised by familiarity with and nonjudgmental expertise in management of drug users’ wide array of needs and in development of effective strategies to promote medication adherence [9], including, if available, the use of adherence support mechanisms such as modified directly observed therapy, which has shown promise in this population [12].

Antiretroviral agents and opioid substitution therapy

IDUs are more likely to experience an increased frequency of side effects and toxicities of ART. Although not systematically studied, this is likely because underlying hepatic, renal, neurologic, psychiatric, gastrointestinal, and hematologic disorders are highly prevalent among IDUs. Selection of ARV agents in this population should be made with consideration of these comorbid conditions. Opioid substitution therapies such as methadone and buprenorphine/naloxone and extended release naltrexone are commonly used for management of opioid dependence in HIV positive-patients.

Methadone and ART. Methadone, an orally administered, long-acting opioid agonist, is the most common pharmacologic treatment for opioid addiction. Its use is associated with decreased heroin use, decreased needle sharing, and improved quality of life. Because of its opioid-induced effects on gastric emptying and the metabolism of cytochrome P (CYP) 450 isoenzymes 2B6, 3A4, and 2D6, pharmacologic effects and interactions with ARV agents may commonly occur [13]. These may diminish the effectiveness of either or both therapies by causing opioid withdrawal or overdose, increased methadone toxicity, and/or decreased ARV efficacy. Efavirenz (EFV), nevirapine (NVP), and lopinavir/ritonavir (LPV/r) have been associated with significant decreases in methadone levels. It is necessary to inform patients and substance abuse treatment facilities of the likelihood of this interaction. The clinical effect is usually seen after 7 days of coadministration and may be managed by increasing the methadone dosage, usually in 5-mg to10-mg increments daily until the desired effect is achieved.

Buprenorphine and ART. Buprenorphine, a patial μ-opioid agonist, is administrated sublingually and is often coformulated with naloxone. It is being increasingly used for opioid dependence treatment. The lower risk of respiratory depression and overdose compared with methadone allows it to be prescribed by physicians in primary care for the treatment of opioid dependency. This flexible treatment setting could be of significant value to opioid-addicted HIV-positive patients who require ART because it enables one physician or program to provide both medical and substance abuse services.

Limited information is currently available about interactions between buprenorphine and antiretroviral agents [13-14]. Findings from available studies show a more favorable drug interaction profile than that of methadone.

Naltrexone and ART. A once monthly extended-release intramuscular formulation of naltrexone was recently approved for prevention of relapse in patients who have undergone an opioid detoxification program. Naltrexone is also indicated for treatment of alcohol dependency. Naltrexone is not metabolised via the CYP 450 enzyme system and is not expected to interact with protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs) [15].

Table 11 provides the currently available pharmacokinetic interaction data that clinicians can use as a guide for managing patients receiving ART and methadone or buprenorphine. Particular attention is needed concerning communication between HIV care providers and drug treatment programs regarding additive drug toxicities and drug interactions resulting in opiate withdrawal or excess.
Methylenedioxymethamphetamine (MDMA), GHB, ketamine, and methamphetamine all have the potential to interact with ARV agents because all are metabolised, at least in part, by the CYP 450 system. Overdoses secondary to interactions between the party drugs (i.e., MDMA or GHB) and PI-based ART have been reported [16].

Summary

It is usually possible over time to support most active drug users such that acceptable adherence levels with ARV agents can be achieved [17-18]. Providers must work to combine all available resources to stabilize an active drug user in preparation for ART. This should include identification of concurrent medical and psychiatric illnesses, drug treatment, needle and syringe exchange, reduction in high-risk sexual behavior, and harm reduction strategies. A history of drug use alone is insufficient reason to withhold ART because individuals with a history of prior drug use have adherence rates similar to individuals who do not abuse drugs. Important considerations in the selection of successful regimens and the provision of appropriate patient monitoring in this population include supportive clinical sites; linkage to substance abuse treatment; and awareness of the interactions between illicit drugs and ARV agents, including the increased risk of side effects and toxicities. Simple regimens should be considered to enhance medication adherence. Preference should be given to ARV agents that have a lower risk of hepatic and neuropsychiatric side effects, simple dosing schedules, and minimal interaction with methadone.

Table 11. Drug interactions between antiretroviral agents and drugs used to treat opioid addiction

*Norbuprenorphine is an active metabolite of buprenorphine.   † R-methadone is the active form of methadone.
Acronyms:
3TC = lamivudine,  d4T = stavudine,  ddI = didanosine,  AZT = zidovudine,

FTC = emtricitabine, TDF = tenofovir,  ABC = abacavir, RAL = raltegravir,

NVP = nevirapine,  EFV = efavirenz,  ETR = etravirine,  MVC = maraviroc,  T20 = enfuvirtide,

APV = amprenavir,  FPV = fosamprenavir,    FPV/r = fosamprenavir/ritonavir,
RTV = ritonavir,  NFV = nelfinavir,  ATV = atazanavir,  ATV/r = atazanavir/ritonavair,
IDV = indinavir,  IDV/r = indinavir/ritonavir,  LPV/r = lopinavir/ritonavir,

TPV = tipranavir,     TPV/r = tipranavir/ritonavir    DRV/r = darunavir/ritonavir, SQV/r = sacquinavir/ritonavir.

References:
1.     Colfax G, Guzman R. Club drugs and HIV infection: a review. Clin Infect Dis. May 15 2006;42(10):1463-1469.
2.     Tucker JS, Burnam MA, Sherbourne CD, Kung FY, Gifford AL. Substance use and mental health correlates of nonadherence to antiretroviral medications in a sample of patients with human immunodeficiency virus infection. Am J Med. May 2003;114(7):573-580.
3.     Bruce RD, Altice FL, Gourevitch MN, Friedland GH. Pharmacokinetic drug interactions between opioid agonist therapy and antiretroviral medications: implications and management for clinical practice. J Acquir Immune Defic Syndr. Apr 15 2006;41(5):563-572.
4.     Wang C, Vlahov D, Galai N, et al. The effect of HIV infection on overdose mortality. AIDS. Jun 10 2005;19(9):935-942.
5.     Strathdee SA, Palepu A, Cornelisse PG, et al. Barriers to use of free antiretroviral therapy in injection drug users. JAMA. Aug 12 1998;280(6):547-549.
6.     Celentano DD, Vlahov D, Cohn S, Shadle VM, Obasanjo O, Moore RD. Self-reported antiretroviral therapy in injection drug users. JAMA. Aug 12 1998;280(6):544-546.
7.     Altice FL, Mostashari F, Friedland GH. Trust and the acceptance of and adherence to antiretroviral therapy. J Acquir Immune Defic Syndr. Sep 1 2001;28(1):47-58.
8.     Altice FL, Kamarulzaman A, Soriano VV, Schechter M, Friedland GH. Treatment of medical, psychiatric, and substance-use comorbidities in people infected with HIV who use drugs. Lancet. Jul 31 2010;376(9738):367-387.
9.     Bruce RD, Altice FL, Friedland GH, Volberding P. HIV Disease Among Substance Misusers: Treatment Issues. Global AIDS/HIV Medicine. San Diego, CA: Elsevier Inc; 2007:513-526.
10.     Morris JD, Golub ET, Mehta SH, Jacobson LP, Gange SJ. Injection drug use and patterns of highly active antiretroviral therapy use: an analysis of ALIVE, WIHS, and MACS cohorts. AIDS Res Ther. 2007;4:12.
11.     Bouhnik AD, Chesney M, Carrieri P, et al. Nonadherence among HIV-infected injecting drug users: the impact of social instability. J Acquir Immune Defic Syndr. Dec 15 2002;31 Suppl 3:S149-153.
12.     Altice FL, Maru DS, Bruce RD, Springer SA, Friedland GH. Superiority of directly administered antiretroviral therapy over self-administered therapy among HIV-infected drug users: a prospective, randomized, controlled trial. Clin Infect Dis. Sep 15 2007;45(6):770-778.
13.     Gruber VA, McCance-Katz EF. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. Curr HIV/AIDS Rep. Aug 2010;7(3):152-160.
14.     Bruce RD, McCance-Katz E, Kharasch ED, Moody DE, Morse GD. Pharmacokinetic interactions between buprenorphine and antiretroviral medications. Clin Infect Dis. Dec 15 2006;43 Suppl 4:S216-223.
15.    Food and Drug Administration (FDA). Vivitrol (package insert). October 2010.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021897s015lbl.pdf.
16.     Bruce RD AFaFG. A review of pharmacokinetic drug interactions between drugs of abuse and antiretroviral medications: Implications and management for clinical practice. Exp Rev of Clin Pharmacol. 2008;1(1):115-127.
17.     Hicks PL, Mulvey KP, Chander G, et al. The impact of illicit drug use and substance abuse treatment on adherence to HAART. AIDS Care. Oct 2007;19(9):1134-1140.
18.     Cofrancesco J, Jr., Scherzer R, Tien PC, et al. Illicit drug use and HIV treatment outcomes in a US cohort. AIDS. Jan 30 2008;22(3):357-365.

Underlying health problems among this population result in increased morbidity and mortality, either independent of or accentuated by HIV disease. Many of these problems are the consequence of prior poverty-related infectious disease exposures and the added effects of non-sterile needle and syringe use.

These include tuberculosis, skin and soft tissue infections, recurrent bacterial pneumonia, endocarditis, hepatitis B and C, and neurologic and renal disease. Furthermore, the high prevalence of underlying mental illness in this population, antedating and/or exacerbated by substance use, results in both morbidity and difficulties in provision of clinical care and treatment [311-313]. Successful HIV therapy for injection drug users often rests upon acquiring familiarity with and providing care for these comorbid conditions.

IDUs often have decreased access to HIV care and are less likely to receive antiretroviral therapy than other populations [314, 315]. Factors associated with lack of use of antiretroviral therapy among drug users have included active drug use, younger age, female gender, suboptimal health care, not being in a drug treatment program, recent incarceration, and lack of health care provider expertise [314, 315]. The chaotic lifestyle ofmany drug users, the powerful pull of addictive substances and a series of beliefs about the dangers of antiretroviral therapy among this population impact on and blunt the benefit of antiretroviral therapy and contribute to decreased adherence to antiretroviral therapy [316]. The chronic and relapsing nature of substance abuse and lack of appreciation of substance abuse as a biologic and medical disease, compounded by the high rate of coexisting mental illness, further complicates the relationship between health care workers and IDUs.

Efficacy of HIV treatment in IDUs

Although underrepresented in clinical trials of HIV therapies, available data indicate that, when not actively using drugs, efficacy of antiretroviral therapies among IDUs is similar to other populations.

Further, therapeutic failure in this population is generally the degree to which drug use results in disruption of organized daily activities, rather than drug use per se. Whereas many drug users can control their drug use sufficiently and over sustained periods of time to engage in care successfully, treatment of substance abuse is often a prerequisite for successful antiretroviral therapy. Close collaboration with substance abuse treatment programs, and proper support and attention to the special needs of this population, is often a critical component of successful treatment for HIV disease. Essential to this end as well are flexible, community-based HIV care sites characterized by familiarity with, and non-judgmental expertise in, managing the wide array of needs of substance abusers, and the development and use of effective strategies for promoting medication adherence [312, 313]. Foremost among these is the provision of substance abuse treatment. In addition, other support mechanisms for adherence are of value, and the use of drug treatment and community-based outreach sites for modified directly observed therapy has shown promise in this population [317].

IDU/HIV drug toxicities and interactions

IDUs are more likely to experience an increased frequency of side effects and toxicities of antiretroviral therapies. Although not systematically studied, this is likely because of the high prevalence of underlying hepatic, renal, neurologic, psychiatric, gastrointestinal, and hematologic disease among IDUs. The selection of initial and continuing antiretroviral agents in this population should be made based upon the presence of these conditions and risks.

Methadone and antiretroviral therapy

Methadone, an orally administered long-acting opiate agonist, is the most common pharmacologic treatment for opiate addiction. Its use is associated with decreased heroin use, improved quality of life, and decreased needle sharing. Methadone exists in two racemic forms, R (active) and S (inactive). As a consequence of its opiate-induced effects on gastric emptying and metabolism by cytochrome P450 (CYP) isoenzymes 3A4 and 2D6, pharmacologic effects and interactions with antiretrovirals may commonly occur [318]. These may diminish the effectiveness of either or both therapies by causing opiate withdrawal, opiate overdose, or increased toxicity or decreased efficacy of antiretrovirals.

Methadone and NRTIs.

Most of the currently available antiretrovirals have been examined in terms of potential pharmacokinetic interactions of significance with methadone. (See Table 21.)

Among the NRTIs, none appear to have a clinically significant effect on methadone metabolism. Conversely, important effects of methadone on NRTIs have been well documented. Methadone is known to increase the area under the curve of zidovudine by 40% [318], with a possible increase in zidovudine-related side effects. Methadone decreases levels of stavudine and the buffered tablet didanosine formulation (no longer available) by 18% and 63%, respectively [319]. This marked reduction in didanosine levels is not observed with the EC formulation. Recent data indicate lack of significant interaction between abacavir and tenofovir and methadone.

Methadone and NNRTIs.

Pharmacokinetic interactions between NNRTIs and methadone are well known and clinically problematic [320]. Both efavirenz and nevirapine, potent inducers of CYP isoenzymes, have been associated with significant decreases in methadone levels. Methadone levels are decreased by 43% and 46% in those receiving efavirenz and nevirapine, respectively, with corresponding clinical opiate withdrawal. It is necessary to inform patients and substance abuse treatment facilities of the likelihood of occurrence of this interaction if either drug is prescribed to those receiving methadone. The clinical effect is usually seen after 7 days of coadministration and is treated with increase in methadone dosage, usually at 5-10mg daily until the patient is comfortable.

Delavirdine, an inhibitor of CYP isoenzymes, increases methadone levels moderately and without clinical significance.

Methadone and PIs.

Limited information indicates that PI levels are generally not affected by methadone, except for amprenavir, which appears to be reduced by 30%. However, many PIs have significant effects on methadone metabolism.

Saquinavir does not affect free, unbound methadone levels. However, amprenavir, nelfinavir, and lopinavir administration each results in a significant decrease in methadone levels [321, 322]. Whereas fosamprenavir may result in mild opiate withdrawal, decrease in methadone concentration from nelfinavir was not associated with opiate withdrawal. This is likely because of lack of effect on free, rather than total, methadone levels.

Lopinavir/ritonavir combination has been associated with significant reductions in methadone levels and opiate withdrawal symptoms. This is because of the lopinavir, not ritonavir, component [323]. Another study indicates a lack of pharmacokinetic interaction among atazanavir and methadone [324].

Buprenorphine

Buprenorphine, a partial μ-opiate agonist, is increasingly being used for opiate abuse treatment. Its decreased risk of respiratory depression and overdose enables use in physician’s offices for the treatment of opioid dependence. This flexible treatment setting could be of significant value to drug-abusing opiateaddicted HIV-infected patients requiring antiretroviral therapy, as it would enable one physician or program to provide needed medical and substance abuse services.

Only limited information is currently available about interactions between buprenorphine and antiretroviral agents. In contrast to methadone, buprenorphine does not appear to raise zidovudine levels. Pilot data indicate that buprenorphine levels do not appear to be reduced and opiate withdrawal does not occur during coadministration with efavirenz.

Summary

Provision of successful antiretroviral therapy for injection drug users is possible. It is enhanced by supportive clinical care sites and provision of drug treatment, awareness of interactions with methadone, and the increased risk of side effects and toxicities and the need for simple regimens to enhance medication adherence. These are important considerations in selection of regimens and provision of appropriate patient monitoring in this population. Preference should be given to antiretroviral agents with lower risk for hepatic and neuropsychiatric side effects, simple dosing schedules, and lack of interaction with methadone.

Extract from US Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, January 2008.

References
311. Tindall B, Cooper DA. Primary HIV infection: host responses and intervention strategies. AIDS, 1991. 5(1):1-14.
312. Niu MT, Stein DS, Schnittman SM. Primary human immunodeficiency virus type 1 infection: review of pathogenesis and early treatment intervention in humans and animal retrovirus infections. J Infect Dis, 1993. 168(6):1490-501.
313. Kinloch-De Loes S et al. Symptomatic primary infection due to human immunodeficiency virus type 1: Review of 31 cases. Clin Infect Dis, 1993. 17(1):59-65.
314. Schacker T et al. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med, 1996. 125(4):257-64.
315. Daar ES et al. Diagnosis of primary HIV-1 infection. Los Angeles County Primary HIV Infection Recruitment Network. Ann Intern Med, 2001. 134(1):25-9.
316. Hecht FM et al. Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS, 2002. 16(8):1119-29.
318. Hoen B et al. Highly active antiretroviral treatment initiated early in the course of symptomatic primary HIV-1 infection: Results of the ANRS 053 trial. J Infect Dis, 1999. 180(4):1342-6.
319. Lafeuillade A et al. Effects of a combination of zidovudine, didanosine, and lamivudine on primary human immunodeficiency virus type 1 infection. J Infect Dis, 1997, 175(5).1051-5.
320. Lillo FB et al. Viral load and burden modification following early antiretroviral therapy of primary HIV-1 infection. AIDS, 1999. 13(7):791-6.
321. Malhotra U et al. Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. J Infect Dis, 2000. 181(1):121-31.
322. Smith DE et al. Is antiretroviral treatment of primary HIV infection clinically justified on the basis of current evidence? AIDS, 2004. 18(5):709-18.
323. Mehandru S et al. Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med, 2004. 200(6):761-70.
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Taken together, the updates included the following changes

• Resistance testing on diagnosis and before starting treatment
• Starting treatment when CD4 count is <350 cells/mm3
• Use of HLA B*5701 testing prior to using abacavir
• Starting HIV treatment for people coinfected with HBV who need to treat their hepatitis
• Preferred first line dual nukes: tenofovir/FTC or abacavir/3TC; this is the first time that the guidelines have even mentioned lipoatrophy, and although they recognise it occurred more frequently with AZT compared to tenofovir, AZT is no longer a preferred first line choice.
• Preferred NNRTI is efavirenz; aternative is nevirapine
• Preferred boosted PIs for first-line therapy are atazanavir/r, fosamprenavir/r, lopinaivr/r, Alternative PI-regimens are unboosted atazanavir (but not with tenofovir), saquinavir/r, fosamprenavir twice daily, boosted fosamprenavir once-daily and lopinavir/r once-daily. Lowest recommendations are for nelfinavir, and boosted saquinavir.
• Nelfinavir is now contraindicated in pregnancy because of the unknown risk of small amounts of a byproduct (ethyl methanesulfonate or EMS)
• Changes to management of treatment experienced patients stress for the need for at least two or preferably three active drugs and includes recently developed drugs (maraviroc, raltegravir, etravirine), but also recognises that there is no consensus on the optimal time to switch a failing regimen
• A new discussion on immunological failure that quantifies chances of reaching over 500 cells/mm3.

“The proportion of patients experiencing immunologic failure depends on how failure is defined, the observation period, and the CD4 T-cell count when treatment was started. In the longest study conducted to date, the percentage of patients with suppressed viremia who reached a CD4 T-cell count >500 cells/mm3 through 6 years of treatment was 42% (starting treatment with a CD4 <200 cells/mm3), 66% (starting with CD4 200–350 cells/mm3) and 85% (starting with CD4 >350 cells/mm3) increases in CD4 T-cell counts in treatment-naïve patients with initial antiretroviral regimens are approximately 150 cells/mm3 over the first year. A CD4 T-cell count plateau may occur after 4–6 years of treatment with suppressed viremia.

A persistently low CD4 T-cell count while on suppressive antiretroviral therapy is associated with a small, but appreciable, risk of AIDS- and non– AIDS-related morbidity and mortality. For example, in the FIRST study, a low CD4 T-cell count on therapy was associated with an increased risk for AIDS-related complications (adjusted hazard ratio of 0.57 for CD4 T-cell count 100 cells/mm3 higher). Similarly, a low CD4 T-cell count was associated with an increased risk for non-AIDS events, including cardiovascular, hepatic, renal and cancer events. Other studies support these associations.”

Unlike French guidelines, use of IL-2 to boost CD4 counts to above 200 cells/mm3 in immunological non-responders is only recommended within a clinical trial setting.