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Medication-assisted treatment and HIV/AIDS:
aspects in treating HIV-infected drug users
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AIDS:
28 January 2010 - Volume 24 - Issue 3 - p 331-340
Bruce, R Douglas; Kresina, Thomas F; McCance-Katz, Elinore F
aYale University School of Medicine, New Haven, Connecticut, USA
bCenter for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration, Rockville, Maryland, USA
cDepartment of Psychiatry, University of California, San Francisco, USA.
"Patient-centered models of care that promote care and treatment of individuals who abuse or are dependent upon drugs/alcohol address those most disenfranchised in our society who most often receive a late diagnosis of HIV infection with a resultant poor clinical outcome. Model healthcare delivery programs are being developed and piloted and include an integrated model with onsite addiction/HIV treatment; a HIV primary care treatment model; a nonphysician healthcare model; and a community outreach model [72]. The implementation of such models of care and their incorporation of MAT will substantially impact the HIV epidemic in the United States that continues to affect racial and ethnic minorities at a disproportional level and is increasing among men who have sex with men [73]. These models of care will allow the medical community to provide comprehensive medical care for substance users and manage their other chronic diseases, most notably, cardiovascular disease, renal disease, diabetes, non-AIDS defining cancers and enhance their quality of life though preventive lifestyle changes including smoking cessation, weight loss, exercise programs and diet modifications."
Abstract
Drug use and HIV/AIDS remain serious public health issues in the US. The intersection of the twin epidemics of HIV and drug/alcohol use, results in difficult medical management issues for the healthcare providers who work in the HIV prevention and treatment fields. Access to care and treatment, medication adherence to multiple therapeutic regimens and concomitant drug-drug interactions of prescribed treatments are difficult barriers for drug users to overcome without directed interventions. Injection drug users are frequently disenfranchised from medical care and suffer stigma and discrimination creating additional barriers to care and treatment for their substance use disorders as well as HIV infection. Controlling the transmission of HIV will require access to care and treatment of individuals who abuse illicit drugs and alcohol. Improving health outcomes (e.g. access to and adherence to antiretroviral therapy) among HIV-infected substance users will also require access to evidenced-based pharmacological therapies for the treatment of drug abuse and dependence. The current review presents an overview of issues regarding the use of medication-assisted treatments for substance abuse and dependence among HIV-infected individuals, providing medical management paradigms for their care and treatment.
Introduction
The use of alcohol and illicit drugs can promote risk-related behaviors leading to the acquisition of HIV and, upon infection, can impede adherence to HIV therapy. Interruptions in antiretroviral therapy can result in significant morbidity and mortality including the development of HIV resistance. Alcohol consumption is associated with sexual behaviors that increase the risk of HIV acquisition [1]. In addition, almost half of HIV-infected individuals interviewed in a recent study reported they consumed alcohol within the last month, whereas over 1 in 10 reported hazardous drinking levels [2]. Illicit drug use can also enhance HIV risk behavior through the use of drugs during sex, sex trading and group sexual encounters [3]. In a recent survey, a majority of survival sex workers reported sharing illicit drugs, most commonly crack cocaine, with their clients [4]. Heroin use and needle sharing have occurred throughout the United States and have remained a significant cause of HIV transmission to this day [5]. It is therefore not surprising that many HIV-infected patients have drug abuse or dependence involved in the cause of their HIV infection that complicates the treatment of HIV in these individuals. Evidence-based treatment of substance use disorders (SUDs) in the form of medication-assisted treatment (MAT) is important to improving health outcomes in this population.
Substance use disorders
Substance use disorders (listed below) describe a patient's presenting symptoms that are best accounted for by the direct physiological effects of the drug or substance.
Substance use disorders as defined by DSM-IV-TR (SUDs are distinguished from nonpathological substance use, such as social drinking or prescription medication use, by the presence of tolerance, withdrawal, compulsive use, and/or substance related problems [6]):
1. Substance abuse: A maladaptive pattern of substance use manifested by recurrent and significant problems and consequences related to repeated substance use such as failure to fulfill major obligations, repeated drug use in physically hazardous situations, recurrent substance-related legal problems, social, or interpersonal problems over a 12-month period; symptoms do not meet the criteria for substance dependence.
2. Substance dependence: Clinically significant impairment or distress related to substance use that includes three or more of the following symptoms: repeated use results in tolerance (need for more of the substance to get desired effect or diminished effect with continued use of same amount of drug), withdrawal symptoms relieved when the substance is taken, the substance is taken for longer periods or in larger amounts than intended, persistent efforts to reduce or discontinue use fail, increasing time spent obtaining the substance and recovering from its effects, having daily social, occupational, or recreational activities reduced due to drug seeking and use, and continued use despite recognizing the role of substance use in psychological or physical problems, such as depressive symptoms or organ system damage. If this constellation occurs in a 12-month period, substance dependence should be diagnosed.
These diagnoses are not based on quantity of drug used, but on maladaptive patterns of drug use, cognitive, behavioral, and physiological symptoms as well as significant consequences related to drug use. Exposure to addictive substances is widespread in society, but vulnerability to abuse and dependence is behaviorally complex as a product of biological/genetic, psychological and environmental interactions and influences. SUDs are chronic, relapsing, but treatable diseases. Successful treatment of SUDs should include, when possible, both a behavioral therapy component and MAT. Successful treatment of HIV disease in drug users requires attention to and treatment of SUDs [7].
Substance abuse and dependence is a complex physiologic, social, and behavioral disorder that often coexists with psychiatric and comorbid medical illnesses. Appropriate screening of patients for SUDs and for co-occurring psychiatric and medical illnesses is a critical part of a comprehensive treatment program [8]. Although specific screens for these disorders is beyond the scope of this review, it is critical to understand that standardized assessment screens are required as self-report is often unreliable for these disorders (see TIPS discussed below). The medical treatment of SUDs is usually necessary to create sufficient patient stability prior to treating psychiatric illness and/or medical comorbidity. In addition, treatment for SUDs can be a helpful intervention as a HIV prevention strategy [9]. When possible, combining mental health services and substance abuse treatment can enhance the medical outcomes in those with HIV disease and co-occurring disorders. However, this is not always possible, therefore HIV clinicians should become familiar with community resources so that they can make appropriate referrals should they identify a SUD and/or mental illness requiring treatment. Substance abuse treatment for persons with co-occurring disorders, Treatment Improvement Protocol (TIP) 42 (CSAT/SAMHSA), provides current information about co-occurring substance use and mental disorders, as well best practices in the treatment of these disorders [10]. TIP 42 proposes an integrated approach to care and treatment at outpatient HIV clinic sessions combining medical and social services. In this model, the team works together to assess, engage and facilitate clinically appropriate services for clients with HIV, SUDs and co-occurring mental illness. The healthcare providers can, therefore, provide on-location services such as assistance with housing, medical withdrawal from substances, as well as inpatient or outpatient psychiatric care. The providers also develop joint assessment and treatment plans (see below).
Pharmacotherapies comprising MAT for substance dependence:
1. Pharmacotherapies for opioid dependence
2. Methadone: Federally regulated through opioid treatment programs (OTP); long-acting opioid receptor agonist for pharmacological therapy
3. Buprenorphine: Office-based opioid treatment or OTPs; federally regulated, long-acting opioid receptor partial agonist for pharmacological therapy
4. Naltrexone: Office-based and substance abuse treatment programs; opioid receptor antagonist for relapse prevention without abuse liability or reinforcing effects
5. Pharmacotherapies for alcohol dependence
6. Naltrexone: May reduce craving and reduce amount of alcohol consumed at relapse in some with alcohol dependence; opioid receptor antagonist; reduced reward effect with daily use; new, injectable, forms are long acting (1 month)
7. Acamprosate: May help to reduce craving, thought to normalize glutamatergic neurotransmission; slow acting, may attenuate relapse in some
8. Disulfiram: Requires motivated patient as it has potential to produce noxious response if alcohol is ingested; supports complete abstinence from alcohol
The Center for Substance Abuse Treatment (CSAT)/Substance Abuse and Mental Health Services Administration (SAMHSA) maintains a treatment locator website (www.csat.samhsa.gov) that can be helpful in finding patients a treatment program.
Medication-assisted treatment of opioid dependence
Evidence-based pharmacological therapy for opioid dependence in HIV-infected opioid-dependent patients should include MAT with either methadone or buprenorphine. MAT is extensively described in TIP 43 [11].
Methadone has demonstrated its efficacy over the last several decades in the treatment of opioid addiction; however, its use is limited to specialized treatment programs, called opioid treatment programs (OTPs) that are regulated by CSAT/SAMHSA. Primary care providers, therefore, are unable to provide this treatment to patients, but can refer patients needing methadone maintenance to an OTP if available in their region. CSAT/SAMHSA has recently published a state-by-state profile of OTPs for 2008 that will be updated yearly [12]. The Division of Pharmacologic Therapies at CSAT/SAMHSA also has an online OTP Directory that is available athttp://dpt2.samhsa.gov/treatment/directory.aspx.
Buprenorphine, unlike methadone, can be prescribed by any qualified and specially licensed physician. The Division of Pharmacologic Therapies at CSAT/SAMHSA provides an online physician and treatment program locator athttp://buprenorphine.samhsa.gov/bwns_locator/. In addition, CSAT/SAMHSA provides a state-by-state profile of the locations of physicians with waivers to prescribe buprenorphine. Buprenorphine treatment is reviewed in TIP 40 [13] and models to implement buprenorphine in HIV clinical settings have also been proposed [14]. The HIV/AIDS bureau of the Health Resources and Services Administration (HRSA) has developed and supported a Special Project of National Significance (SPNS) on the use of buprenorphine treatment in HIV primary care settings. The web site for this initiative can be found athttp://hab.hrsa.gov/special/%5CSPNS05RPT%5Cbup.htm.
These models of care and federal initiative are important because buprenorphine (Table 1) has fewer adverse events associated with its use in patients who have HIV disease and require treatment with antiretroviral therapy. Therefore, it may be preferable to utilize buprenorphine rather than methadone treatment for patients with HIV disease and opioid dependence. Because buprenorphine is available by prescription, HIV treatment providers and primary care providers could offer both medication treatment of opioid dependence and concurrent treatment of HIV disease. HIV clinical providers interested in obtaining a waiver to prescribe buprenorphine are directed to SAMHA's website for detailed information (http://buprenorphine.samhsa.gov/howto.html).
There are several important differences between methadone and buprenorphine. First, methadone is a full agonist at themu opioid receptor, whereas buprenorphine is a partial agonist. Therefore, buprenorphine has a ceiling effect at which higher doses provide no further opioid agonist effects. Given this ceiling effect, buprenorphine is safer in overdose than methadone. Methadone may be more helpful for those with high use patterns and high tolerance to opioids; however, patients should be evaluated to determine what opioid therapy might be the most appropriate treatment of their opioid dependence. The second important difference is that buprenorphine has a higher binding affinity and occupies more receptor sites than methadone [15,16]. This may result in more effective opioid blockade compared to methadone. Finally, an active metabolite (norbuprenorphine) and higher receptor binding affinity resulting in slower dissociation of buprenorphine from the mu receptor allows alternate day dosing, whereas methadone requires daily administration [7].
Naltrexone is a long-acting, opioid antagonist that blocks the euphoric effects of opioids binding the mu receptor. Unlike methadone, there is no negative reinforcement (opioid withdrawal) upon discontinuation. The effectiveness of naltrexone treatment, therefore, depends upon patient motivation and social support system [17,18]. Due to naltrexone's opioid antagonism, patients must abstain from opioids for a minimum of 7 days prior to starting treatment to avoid the precipitation of opioid withdrawal. Because of a lack of positive reinforcing effect with naltrexone and low motivation on the part of many patients, as well as poor clinician acceptability, it is not widely prescribed for the treatment of opioid dependence.
Regardless of the specific pharmacotherapy, HIV-infected opioid-addicted patients must have as part of their drug treatment plan evidence-based approaches to both behavioral and pharmacological therapies. Whereas buprenorphine or naltrexone can be prescribed by the treating HIV or primary care physician, and methadone can only be administered through an OTP, all patients with opioid dependence should be referred to a substance abuse treatment provider for ongoing psychosocial therapy. In addition, mutual help programs such as Narcotics Anonymous can be very helpful to some patients and are available at no charge. Information about this program can be found at www.na.org. It is essential that those identified to have SUDs receive both MAT (when appropriate) and psychosocial interventions to assist with resolving the maladaptive behaviors associated with their drug abuse and dependence. To provide only MAT to such individuals would be less than the expected standard of care for treatment of SUDs.
Medication-assisted treatment of alcohol dependence
Treatment of alcohol use disorders (AUDs) is critically important for the patient with HIV infection [19]. Alcohol dependence compromises the effectiveness of HIV treatment by influencing access and adherence to antiretroviral therapy and, as noted earlier, self-report of alcohol use is prevalent in patients with HIV infection. A comprehensive approach to the treatment of alcohol dependence integrates psychosocial treatment with pharmacologic treatments [20]. Treatment paradigms for alcohol dependence that utilize pharmacotherapy focus clinical outcomes on stopping or at least reducing problematic drinking with relapse prevention therapy, motivational enhancement therapy, or a combination of these therapeutic techniques. Pharmacotherapies, approved by the FDA for alcohol dependence, are disulfiram, naltrexone and acamprosate. To promote the use of alcohol pharmacotherapies and integrated comprehensive treatment programs, a new TIP entitled 'Incorporating Alcohol Pharmacotherapies into Medical Practice' is being released [21]. This TIP discusses the medications currently FDA-approved for treating AUDs and provides basic information, evidence-based guidelines, tools, and resources to assist healthcare providers treat patients with AUDs. As for opioid dependence, the effective treatment of alcohol dependence will require psychosocial intervention, but in those physiologically dependent, medical withdrawal is also necessary and may need to occur on an inpatient unit specialized in the care of such patients, prior to considering medication treatment for the maintenance of abstinence. The latter can be provided by the primary care or HIV clinician should they wish to do so from their office or clinic-based practice.
Disulfiram, approved for the treatment of alcohol dependence, blocks the oxidation of alcohol with accumulation of acetaldehyde that is associated with many unpleasant symptoms (e.g. flushing, headache, nausea, vomiting) and therefore functions as means of discouraging alcohol use [22]. Disulfiram is not widely used for the treatment of alcohol dependence because of the possibility of an alcohol-disulfiram reaction. Adherence can be an issue as many dependent on alcohol are ambivalent about abstinence. However, if ingested as prescribed, disulfiram is associated with significantly higher rates of alcohol abstinence [23]. Further, disulfiram ingestion can be monitored by a treatment provider and/or significant other, which will enhance adherence and reduce alcohol consumption. The interactions of disulfiram with HIV medications are unknown, but are presently being studied. Disulfiram is bioactivated by cytochrome P450 3A4 to metabolites that inhibit the metabolism of alcohol [24]. Thus, the co-administration of medications that alter hepatic metabolizing enzyme function, such as some antiretroviral medications, could alter the effectiveness of disulfiram.
Naltrexone may assist in preventing relapse by attenuating the pleasure-response associated with alcohol ingestion [25]. Naltrexone is associated with a decrease in heavy drinking as well as a prolongation of abstinence [21]. Treatment effectiveness is a function of medication adherence. To address adherence issues, an injectable formulation is available which provides therapeutic plasma concentrations of naltrexone over a 30-day period. Because some patients with HIV disease suffer with medical disorders that may be associated with chronic pain, the use of naltrexone, an opioid antagonist that can complicate analgesia provision, should be carefully considered before prescribing to alcoholic patients with HIV disease.
Acamprosate is a structural analog of the gamma-aminobutyric acid (GABA) neurotransmitter [26]. Some clinical trials show a modest advantage over placebo in maintaining abstinence from alcohol; however, a recent large trial demonstrated no benefit over placebo [27,28]. Medication adherence is an issue in these trials with dosing of two capsules, three times a day. This pill burden, compared to naltrexone and disulfiram, may adversely impact adherence, particularly in patients with HIV disease, who may already be taking large numbers of medications daily.
Medication-assisted treatment for nicotine dependence
Cigarette smoking is prevalent among HIV-infected patients and substance users. Understanding the negative health consequences of smoking in general, and particularly for HIV-infected patients, clinicians should advise all smokers to quit smoking. For those patients who are interested in quitting, the clinician should discuss pharmacotherapy, set a quit date agreeable to the patient, refer to a counseling program for smoking cessation, and educate patients about the symptoms of nicotine withdrawal. The pharmacotherapy of nicotine dependence is divided into two categories: non-nicotinic receptor-mediated: buproprion, or nicotinic receptor-mediated: nicotine replacement or varenicline. A detailed discussion of the clinical use of each medication is beyond the scope of this review. The reader is directed to an updated guide on treating nicotine dependence published by The Office of the Surgeon General (http://www.surgeongeneral.gov/tobacco/treating_tobacco_use08.pdf).
Other substances
There are no FDA-approved medication treatments for other stimulant use disorders (e.g. cocaine, methamphetamine), cannabis, or sedative/hypnotic use disorders. Effective pharmacotherapies for these SUDs are an ongoing focus of research.
Medication-assisted treatment and antiretroviral therapy: drug-drug interactions
Drug users are frequently the least considered for treatment of their HIV infection. HIV-infected drug users, particularly injection drug users, suffer additional comorbidities and co-occurring conditions and experience poorer outcomes for HIV disease. Injection drug users also experience unmet health service needs, suboptimal ambulatory care, missed medical appointments and poor medication adherence [29]. These factors complicate their access to antiretroviral therapy. Thus, it is important for the healthcare provider to understand and manage the complex drug interactions that are clinically significant, among pharmacotherapies for the treatment of SUDs and antiretroviral medications. Extensive interaction guidelines are published for other medications often prescribed with antiretroviral medications (www.aidsinfo.nih.gov/Guidelines/).
Interactions between methadone and antiretroviral medications
The metabolism of methadone occurs in the liver via cytochrome P450 isoenzymes [30,31]. The first-line regimen nucleoside reverse transcriptase inhibitors (NRTIs) do not affect methadone metabolism in a clinically significant manner [32]. However, methadone metabolism affects the pharmacokinetics of several of the NRTIs (Table 1). Specifically, studies show that methadone increases zidovudine (ZDV) levels by approximately 40% [33]. This increase is clinically important for methadone-treated patients, since it may result in ZDV side effects that mimic opioid withdrawal. Importantly, this increase in ZDV concentrations is not observed in buprenorphine, L-acetyl-methadol or naltrexone-treated patients [34]. Results from studies with stavudine (d4T) show that, whereas stavudine does not modify methadone levels, methadone metabolism alters the disposition of d4T [35]. However, the degree of decrease in d4T plasma concentrations is not thought to require a dosage change for this medication to be effective [36]. Didanosine (ddI) concentrations in the original tablet formulation were significantly decreased in methadone-maintained individuals. However, the enteric-coated formulation provides therapeutic ddI concentrations in methadone-maintained individuals [37].
Nevirapine and efavirenz induce methadone metabolism with resultant opioid withdrawal [38-42]. Thus, the co-medication of methadone with these frequently utilized medications often requires rapid elevations in methadone dosages. Therefore, patients taking methadone who initiate regimens containing these medications should be monitored for signs of opioid withdrawal.
With the exception of tipranavir, protease inhibitors in second-line HIV treatment regimens appear to lack significant interactions with methadone [32]. Tipranavir's package insert states that co-administration of ritonavir boosted tipranavir (TPV/r) and methadone could result in a 50% decrease in the methadone concentration which may require increases in methadone in some patients [43]. Other HIV medications, namely the CCR5 antagonist, maraviroc, and integrase inhibitor, raltegravir, need to be studied for drug interactions with methadone. A detailed discussion of HIV medications and their known interactions with methadone and buprenorphine is available (see Table 1) [33,44-46].
Interactions between methadone and medications for opportunistic infections
HIV-infected drug users, particularly injection drug users, suffer comorbidities and co-occurring conditions, including opportunistic infections, and frequently access treatment for SUD presenting with opportunistic infections. Some medications used to treat co-occurring conditions (e.g. tuberculosis) and opportunistic infections modify methadone metabolism. Rifampin, a potent inducer of cytochrome P450 3A4, produces rapid and profound reductions in methadone levels and development of opioid withdrawal. Rifampin should be substituted with rifabutin or, if rifabutin is unavailable, methadone doses will likely need to be increased to avoid opioid withdrawal in methadone-maintained patients requiring treatment for tuberculosis [47]. Fluconazole, a known inhibitor of cytochrome P4503A4 metabolism, increases methadone exposure, and methadone dosage may need to be reduced [48]. Although interferon, which is utilized in the treatment of hepatitis B and C, has extensive symptom overlap with opioid withdrawal (e.g. flu-like symptoms), studies have not demonstrated a pharmacokinetic interaction [49]. In our experience, however, many patients will request increases in methadone dose due to these symptoms.
Interactions between buprenorphine and antiretroviral medications
Several recent reviews have delineated the antiretroviral medications studied to-date with buprenorphine [33,44-46,50]. In summary, compounds that lower buprenorphine concentrations appear not to affect the pharmacodynamic properties of buprenorphine. This is seen in efavirenz's ability to lower buprenorphine concentrations without precipitating withdrawal [45]. In addition, recent data demonstrates that no dosage adjustment of buprenorphine is required when taken in combination with nevirapine [51]. Compounds that elevate buprenorphine concentrations, such as ritonavir and delavirdine, do not substantially alter buprenorphine's pharmacodynamic profile and do not produce opioid excess [45,46]. An exception to this lack of pharmacodynamic interaction with antiretroviral medications is with atazanavir/ritonavir. Atazanavir shares a glucuronidation pathway with buprenorphine that may contribute to higher buprenorphine concentrations when both medications are taken together [52,53]. With surveillance for opioid excess, atazanavir and buprenorphine can be safely co-administered. Finally, recent data have suggested that buprenorphine may decrease tipranavir blood levels [54]. The clinical significance of this remains unknown; however, HIV providers should carefully monitor patients who may be receiving both therapies. Despite these recent findings, the combination of buprenorphine's long elimination half-life and its high binding affinity at the mu opioid receptor suggest that precipitated opioid withdrawal will be less likely with antiretroviral medications and buprenorphine than has been observed for methadone.
Interactions between alcohol and antiretroviral medications
Alcohol and prescription medication interactions are important, particularly in the case of prescribed antiretroviral medications [55]. Alcohol can modify the pharmacokinetics of drugs by multiple mechanisms including altering gastric emptying, changing liver P450 metabolism or reducing liver function through fibrosis/cirrhosis. Drugs may affect the pharmacokinetics of alcohol by altering gastric emptying and inhibiting gastric alcohol dehydrogenase (ADH). ADH converts alcohol to acetaldehyde, then acetaldehyde dehydrogenase converts acetaldehyde to acetate [56]. Beverages that contain a mixture of alcohols that induce P450 3A4 can reduce the serum concentrations of protease inhibitors and NNRTIs [57]. The implication for individuals who consume alcohol-containing beverages is that antiretroviral therapy may be less effective due to enhanced drug metabolism and reduced therapeutic drug levels. In addition, consumption of alcohol can lead to nonadherence that would result in subtherapeutic drug levels resulting in virologic failure and the potential for developing viral resistance. Alcohol dependence, however, is not a contraindication to the prescription of antiretroviral drugs and therefore the medical provider should be aware of important interactions between alcohol and antiretrovirals, and should consider providing MAT for alcohol dependence when indicated.
Metabolic interactions can occur if abacavir, didanosine, or nevirapine are part of multidrug regimens in patients drinking alcohol. Abacavir and ethanol share ADH in their metabolic pathway. Studies show pharmacokinetic interaction between abacavir and ethanol and an increased drug half-life for abacavir [58]. The combination of alcohol consumption and a treatment regimen containing didanosine places the patient at an increased risk of pancreatitis [59]. Alcohol consumption with nevirapine may enhance the hepatotoxic properties of nevirapine thereby enhancing liver disease particularly in patients with HIV and hepatitis coinfection [60,61].
Interactions between other drugs of abuse and antiretroviral medications
Antiretroviral medications interact with numerous drugs of abuse including benzodiazepines, ecstasy, opiates and marijuana and full details of these interactions have been reviewed elsewhere [62,63]. Benzodiazepine interactions must be emphasized due to their widespread use both therapeutically and as substances of abuse. The benzodiazepines midazolam, triazolam, alprazolam and flunitrazepam, are dependent upon CYP 3A4 metabolism [63,64]. Therefore, compounds that inhibit CYP 3A4 can also decrease clearance and potentiate the pharmacodynamic effect of these specific benzodiazepines. Patients prescribed these benzodiazepines should not receive inhibitors of CYP 3A4 metabolism such as delavirdine, ritonavir, ketoconazole, clarithromycin, or atazanavir [63,65-68]. As an alternative, such patients should be offered lorazepam or oxazepam, both metabolized via glucuronidation and not likely to interact with these antiretrovirals. Raltegravir is metabolized via UGT 1A1 which is a separate glucuronidation pathway and not likely to interact with lorazepam (UGT2B7) or oxazepam (UGT2B15) [69,70]. Conversely, inducers of CYP 3A4 could lead to reductions in some benzodiazepine drug levels and consequent reductions in therapeutic effect with possible withdrawal symptoms.
Management of pharmacological interactions in medication-assisted treatment
The time course of symptom development due to medication interactions is highly variable. An important distinction is between inhibition and induction. Inhibition can occur shortly after a medication is started as in the case of fluconazole inhibition of methadone metabolism and resultant symptoms of opioid excess. Induction, however, requires the synthesis of new enzymes. Therefore, a prolonged period, between 7 and 21 days, is required to synthesize new enzymes resulting in reduction in drug levels and resultant side effects. For example, opioid withdrawal may occur within 1 week after starting efavirenz, a potent inducer of hepatic metabolism. In the setting of a perceived medication interaction, medical causes should also be considered as a possible cause (e.g. thyroid dysfunction or pregnancy) before assuming symptoms are related to a pharmacological interaction.
Interactions between medications and methadone require rapid consultation with the medical staff of the methadone program. It is best for the HIV care provider to establish lines of communication with the OTP before a medication interaction occurs because the OTP is in control of the methadone dose and must be included in the treatment plans regarding the HIV care of the patient.
Buprenorphine is predominantly utilized in primary care settings by physicians with waivers from SAMHSA and registration with the Drug Enforcement Agency [71]. Thus, the evaluation and treatment of buprenorphine and antiretroviral drug interactions may be more likely to be managed primarily by HIV practitioners.
Conclusion
Patient-centered models of care that promote care and treatment of individuals who abuse or are dependent upon drugs/alcohol address those most disenfranchised in our society who most often receive a late diagnosis of HIV infection with a resultant poor clinical outcome. Model healthcare delivery programs are being developed and piloted and include an integrated model with onsite addiction/HIV treatment; a HIV primary care treatment model; a nonphysician healthcare model; and a community outreach model [72]. The implementation of such models of care and their incorporation of MAT will substantially impact the HIV epidemic in the United States that continues to affect racial and ethnic minorities at a disproportional level and is increasing among men who have sex with men [73]. These models of care will allow the medical community to provide comprehensive medical care for substance users and manage their other chronic diseases, most notably, cardiovascular disease, renal disease, diabetes, non-AIDS defining cancers and enhance their quality of life though preventive lifestyle changes including smoking cessation, weight loss, exercise programs and diet modifications.
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