| This article appeared as part of a CME module from the International AIDS Society-USA's "Cases on the Web" CME series, formerly hosted on HIV InSite. For current IAS-USA CME activities see the IAS-USA CME Programs page.
An increasing number and proportion of HIV-1 infected individuals are active or former drug users. In addition to the well-known complications of HIV disease, drug users have high rates of other medical illnesses that impact on HIV care. Among these are bacterial skin and respiratory infections, endocarditis, renal disease, and hepatitis B and C, for which prevalence rates of 70% to 80% are reported. This population is also characterized by a high rate of comorbid severe mental illness and unstable social and economic circumstances. Such patients form the basis of much of HIV clinical practice yet clinicians are often unprepared for the frequent and major challenges in treating these "triple-diagnosed" patients. Epidemiology and Comorbidity
Injection drug use (IDU) accounts for one third of cumulative AIDS cases in the United States, with a steady increase in proportion over time. The distribution of these cases varies by geographic region; IDU has accounted for the majority of newly diagnosed cases of AIDS in areas of the Northeast since the late 1980s. In addition, IDU has been indirectly associated with most cases of heterosexual and perinatal transmission of HIV in the United States. Ongoing transmission of HIV as well as HIV treatment benefits have resulted in a marked increase in the estimated number of injection drug users (IDUs) living with HIV disease and AIDS and eligible for or receiving HIV care. The importance of IDU in the HIV/AIDS pandemic is not confined to the United States. IDU is the major risk behavior associated with AIDS in southern and eastern European countries and in parts of Latin America and Asia. Noninjection drug use also facilitates sexual transmission of HIV infection. Drug use in both parenteral and oral form not only promotes HIV transmission but also may complicate and confound treatment of HIV infection.
The close association of drug use and mental illness contributes to these prevention and treatment difficulties. The epidemiology of overlapping mental illness and HIV infection is less well and broadly characterized, as there is no uniform collection of information for these 2 co-occurring illnesses. However, a number of surveys indicate that approximately 20% to 50% of individuals with HIV infection or AIDS have severe mental illness, principally mood and affective disorders (major depression; anxiety, panic disorder, or posttraumatic stress disorder; impulsivity or personality disorder). Studies among HIV-seropositive and -seronegative drug users who are not in drug treatment programs indicate frequencies of over 40% for depression, 10% for suicide attempt, 9% for posttraumatic stress disorder, and 7% for anxiety disorder. The rate of substance abuse among those receiving treatment for severe mental illness varies from 4% to 35% (3 to 25 times that in the general population) and there is an HIV-seroprevalence rate of close to 10% in this population (10 to 50 times that in the general population). Access to Care and Antiretroviral Therapy
Despite great health needs, clinical care for drug users with HIV disease both with and without comorbid mental illness is difficult and often inadequate. IDUs have had less access to and use of HIV therapies than other populations. Recent studies indicate that among drug users with known HIV disease who are clinically eligible for antiretroviral therapy, only a minority actually receives it. Factors associated with lack of use of antiretroviral therapy include active drug use, suboptimal health care, younger age, female gender, not being in a drug treatment program, limited health care provider expertise and recent incarceration. Drug users with longitudinal substance abuse care and an ongoing source of care that involves an HIV specialist or expert are 3 times more likely to receive highly active antiretroviral therapy (HAART).
The chaotic lifestyle of drug users often makes use of existing facilities difficult and erratic. Providing care to HIV-infected IDUs is challenging and often stressful for clinicians and other health care workers. Inexperience in managing HIV disease is common at sites where drug users are cared for, such as drug treatment programs and prisons, and conversely, inexperience in managing substance abuse and mental illness issues is the rule at sites where HIV care is usually provided. The chronic relapsing nature of addiction as a medical disease is often not appreciated by clinicians, nor is the fact that drug users may be quite diverse and heterogeneous. Clinicians may have stereotypic views of drug users with and without mental illness and may have negative feelings about their social worth. Many physicians assume that drug users' antisocial behavior and drug use indicate a lifelong lack of concern for others and indifference to their own well-being, rather than a consequence of the disease of addiction. There is often mutual suspicion between drug users and health care providers. Drug-addicted patients are viewed as manipulative, unmotivated, and even undeserving of care. Conversely, drug users often are distrustful of the health care system and harbor expectations that they will be treated punitively. These views often crystallize around the treatment of pain and pain medication-seeking behavior. Substance abusers often have increased difficulties with adherence to medications. This may be compounded by their lack of information about HIV disease and its treatment, community beliefs about dangers of mixing HIV therapies and substances of abuse, underlying renal and hepatic disease, increased medication adverse effects, and drug interactions. Nevertheless, many drug users have benefited from current dramatic advances in HIV therapeutics, principally those receiving treatment or who have ceased or controlled their substance use and have had access to ongoing clinical care within drug treatment programs, prisons, and in flexible and comprehensive outpatient settings. Co-location of treatment for all 3 comorbid conditions is the most efficient and successful way of addressing the complex treatment needs of this population. Strategies for Providing Care for Substance Abusers
As with other medical illnesses, the establishment of mutual respect and trust is essential. Clinicians should obtain a thorough history of the patient's substance abuse, practices, needle and syringe source, drug abuse complications, and treatment history. As with any other medical problem, nonjudgmental, clinical assessment of this information is essential. It is important to acknowledge that addiction is a medical disease, compounded by psychological and social circumstances. Reducing or stopping drug use is difficult, as is sustaining abstinence. Success may require several attempts and relapse is common and should be anticipated and not seen as a treatment failure. Complete abstinence may not be a realistic goal for many substance-abusing patients. Rather, increasing the proportion of days, weeks, and months of drug-free or controlled sobriety is an acceptable goal. To provide care to active and former drug users, it is often necessary to work in community settings outside of the traditional health care system. Within the clinic setting, it is necessary to establish a team of clinicians, social workers and mental health workers and to work closely with a substance abuse treatment program. This requires that clinicians be familiar with local resources for substance abuse treatment. It is helpful to establish a formal treatment contract with the individual patient that specifies the services to be provided to the patient, the caregiver's expectations about the patient's behavior, and the consequences of behavior that violates the contract. These behaviors might include "loss" of prescriptions, misuse of prescription drugs, disruptive behavior in clinic or hospital, or use of illicit drugs during hospital stays. Patients with these behaviors often respond to the setting of appropriate limits and consistent response to behavior that violates those limits. In the hospital setting, it is useful to establish a system of graduated restrictions for violation of agreed upon behavior, eg, restrictions on unsupervised visits or visiting hours, closer supervision of visits, or confinement to room. These should be employed in a professional manner that reflects the aim of enhancing patients' well-being, and not in an atmosphere of blame or judgment. It is always important to consider acute substance use when evaluating behavior change and neurologic disease. Toxicologic testing is helpful in evaluating behavioral changes and discouraging illicit drug use during hospital stay.
Drug-addicted patients are concerned that they will not be given adequate pain medication. Conversely, clinicians often feel that drug users engage in manipulative pain medication-seeking behavior. This often results in contentious and confrontational interactions from which neither party benefits. It is important to remember that a person who is using opiates daily, including methadone, has developed a tolerance to the effects of these drugs, including the analgesic effects. However, his or her pain threshold may be the same as, or lower than, that of a drug-free person, and such patients will often require as much or more analgesic medication. Clarity, structure, and firmness in pain medication administration is often necessary. Providing adequate pain relief will contribute substantially to the development of a trusting patient-provider relationship, while failure to do so may contribute to drug-seeking behavior. Pain syndromes should be evaluated thoroughly. Let the patient know that you take the report of pain seriously, but be honest about your concerns and firm about treatment plans. For the patient on methadone maintenance, clinicians should continue the usual methadone dose and treat pain with other analgesics in standard or higher-than-usual doses. Methadone's analgesic effectiveness is quite limited in the tolerant individual and should not be used for analgesia. In addition, the methadone dose is part of the therapeutic plan developed by the drug treatment team and should not be altered without their participation.
Discuss pain management plans with the drug abuse treatment program staff or others involved in the care of the patient. For outpatients, clinicians should prescribe small quantities of medications, no more than 2 weeks at a time if possible. Patients should be informed that prescriptions will not be refilled earlier. Careful recording of both the pain management plan and the actual medications, number prescribed, and date of prescriptions will help avoid subsequent disagreements about medication amount and frequency. The patient should receive medication from only 1 source, preferably prescribed in long-acting generic formulations, such as morphine sustained release tablets or fentanyl transdermal patch. Only small quantities of shorter acting generic preparations, such as oxycodone, should be provided, with the goal of decreasing reliance on these over time. For inpatients with acute medical problems, it is useful to set up a reasonable around-the-clock dosage schedule, using long-acting agents. Prior discussion with the patient and clarity about amount prescribed and dosing schedule is important. This will help avoid non-scheduled requests and administration. Medication need should be reassessed every 24 to 48 hours.
When control of opiate withdrawal symptoms is needed, administer a daily oral dose of 25 to 30 mg of methadone. Decreasing the methadone dose by 20% a day after the abstinence syndrome is suppressed and the acute medical problem has subsided should maintain patient comfort. It is best to do this during acute medical admissions so as not to confuse medical problems with opiate withdrawal. Specific Drugs of Abuse
The illicit drugs most closely associated with HIV infection in the United States are heroin and cocaine. More recently, the abuse of methamphetamine has raised great concerns as well. It is important to be aware of local patterns of drug availability and use.
Heroin is a short-acting, semisynthetic opioid produced from opium poppies. It may be smoked, inhaled, or injected into a vein or soft tissue. Heroin has a moderately long half-life. Peak heroin euphoria begins shortly after injection and lasts approximately 1 hour, followed by 1 to 4 hours of sedation. Withdrawal symptoms commence several hours later. As a consequence, most individuals addicted to heroin inject 2 to 4 times per day. Many heroin users will mediate the sedating effects of heroin by injecting a small amount of cocaine with heroin, a mixture known as a "speedball." Heroin metabolites can be measured in the urine for up to 24 hours after administration. Apart from overdose risk, heroin itself is not a dangerous drug. Rather, the unsterile method of use, unpredictable concentrations in street samples, adulterants in the injection mixture, and the lifestyle necessary to procure drugs are responsible for most heroin-associated medical complications.
Cocaine is an alkaloid extracted from the leaves of the coca plant. It is available as a water-soluble hydrochloride salt, which is injected or taken by nasal inhalation ("snorted"). Cocaine hydrochloride powder is destroyed by heat and therefore cannot be smoked. However, it may be chemically converted to a free-base "rock" or "crack" cocaine, which can be smoked. Pulmonary absorption of "crack" is as rapid as intravenous injection. Cocaine's half-life is short, resulting in the need for frequent administration. Active cocaine users may inject or inhale cocaine as many as 20 times a day. Cocaine can be detected in the urine for about 12 hours after administration. Cocaine induces feelings of elation, omnipotence and invincibility and is rapidly addicting. Cocaine may induce vascular spasm or constriction with resultant cardiac, neurologic, or other end organ dysfunction. The multiple psychological and physical effects of cocaine can completely disrupt clinical care of HIV-infected men and women and their families.
Methamphetamine is similar in chemical structure to amphetamine but has more profound effects on the central nervous system. It is easily manufactured and can be used intravenously, by smoking, or by snorting. Methamphetamine use produces stimulation and feelings of euphoria. In contrast to cocaine, it has a longer duration of action and a larger percentage of the drug remains unchanged in the body. Thus, stimulant effects can be quite prolonged, lasting from 6 to 8 hours after a single dose. However, tolerance develops rapidly and escalation of dose and frequency is required. Substance Abuse Treatment
Addiction is a chronic, relapsing, and treatable disease, characterized by compulsive drug seeking and drug use. The provision of substance abuse and mental health treatment is central and often precedes HIV treatment. Indeed, for many, HIV treatment is not likely to be successful without first addressing these issues. The relative lack of effective drug treatment programs in the United States influences both antiretroviral use and continued transmission of HIV infection among injection drug users. Resources are limited in many communities, substantially limiting options for referral. Treatment of Opioid Dependence
The treatment of choice for the patient who is opioid-dependent and has HIV disease is maintenance with a long-acting opiate agonist such as methadone or buprenorphine. Methadone is one of the most successful chronic disease therapies. Its use is associated with decreased heroin use, improved quality of life, and decreased needle sharing and HIV transmission. It is estimated that only 15% to 20% of individuals currently eligible for opiate addiction treatment are receiving treatment in the United States. Methadone
Methadone is a semisynthetic, long-acting opioid analgesic used for opiate detoxification and for long-term treatment of opiate abuse. It is well absorbed, reaching peak plasma levels in 1 or 2 hours. It has a long half-life of 24 to 36 hours and a single daily dose is given to maintain stable plasma levels. Methadone is a very safe drug. Persistent adverse effects include drowsiness, diaphoresis, constipation, and amenorrhea. Methadone users do not experience euphoria and the highs and lows of the heroin cycle. Drug-seeking behavior decreases, creating the possibility for the development of more constructive behaviors and relationships. There is no optimal dose of methadone. Patients must be assessed individually for treatment response. Generally, doses of 30 to 60 mg daily will block opioid withdrawal symptoms, but higher doses in the 70 to 80 mg daily range are needed to block opioid craving and decrease illicit drug use. LAAM, a derivative of methadone, has also become available for the treatment of opioid dependence. LAAM is usually prescribed in doses of 20 to 140 mg with an average dose being 60 mg. Buprenorphine, a partial µ-opiate agonist, also has a long duration of action, allowing for a once-a-day or alternate-day schedule of administration. Mild withdrawal symptoms make detoxification from buprenorphine maintenance easier than that of methadone. It has less risk of respiratory depression than methadone and therefore diminished overdose risk. Cocaine Abuse Treatment
Unfortunately, treatment modalities for cocaine addiction are much more limited than those for opiate dependence. There is no specific drug therapy but group programs and support can be effective. HIV care providers may feel helpless and frustrated when confronted with a patient who is actively using cocaine. Referral to a cocaine treatment program, if available, is essential. As a provider, although you may be unable to help a patient immediately, it is important to let the patient know that you are concerned about his or her health, and will be available for the time when the addictive disease is in remission and he or she is ready to engage in care. Drug Interactions with HIV Therapies
Provision of drug abuse treatment is often key to successful treatment of HIV disease. Drug interactions between agents used for the treatment of substance-related disorders and those used for the treatment of HIV disease and mental illness may influence efficacy and toxicity of each. Although many studies of interactions between antiretroviral agents and other HIV therapies and other classes of drugs have been performed, interactions between HIV therapeutics and substances of abuse and their treatments have been very limited until recently.
Methadone is metabolized by hepatic demethylation and activity of the cytochrome P450 3A4 isoenzyme system and, possibly, other CYP450 isoenzyme systems (1A2, 2C9, 2D6). The methadone derivative LAAM has similar pharmacokinetics. See the Table for a summary of interactions between HIV-related drugs and methadone.
Table: Interactions Between HIV-Related Drugs and Methadone
|Drug||Formally Studied?||Effect on Methadone||Effect on HIV-related Drug|
|Zidovudine||Yes||None||Increase in zidovudine AUC by 40%|
|Didanosine (tablet formulation)||Yes||None||Decrease in didanosine AUC by 60%|
|Zalcitabine||No||Not studied or reported||Not studied or reported|
|Stavudine||Yes||None||Decrease in stavudine AUC by 18%|
|Abacavir||Yes||Increase in methadone clearance||Increase in time to peak concentration, |
Decrease in peak concentration
|Nevirapine||Yes||Withdrawal symptoms increase, methadone levels decrease by 46%, need for
increase in methadone dose
||Not studied or reported|
|Delavirdine||No||Increase in methadone levels predicted||Not studied or reported|
|Efavirenz||Yes||Decrease in methadone levels by 48%, need for increase in methadone dose, heroin use relapse||Not studied or reported|
|Indinavir||No||Not reported||Not reported|
|Ritonavir||Yes||Decrease in methadone levels reported (study design limits clinical utility of data), decrease of meperidine levels||No effect reported|
(study design limits clinical utility of data)
|Nelfinavir||Yes||Decrease in methadone levels, but no withdrawal symptoms observed||No|
|Saquinavir||No||Not studied or reported||Not studied or reported|
|Amprenavir||In progress||Not yet available||Not yet available|
|Other Drugs Used in the Treatment of HIV-infected Persons|
|Rifampin||Yes||Decrease in methadone levels, often sharply,|
severe narcotic withdrawal
|Rifabutin||Yes||No change in methadone levels, mild narcotic withdrawal||None reported|
|Fluconazole||Yes||Increase in methadone levels by approximately 30%, clinical significance unknown||None reported|
|Phenytoin||Yes||Decrease in methadone levels, often sharply||None reported|
|Phenobarbital||Yes||Decrease in methadone levels, often sharply||None reported|
|Carbamazepine||Yes||Decrease in methadone levels||None reported|
(case series only)
|Increase in methadone levels by 20-100%||None reported|
(case series only)
|Minimal increase in methadone levels||None reported|
|Sertraline||Yes||Transient mild increase in methadone levels||None reported|
|nRTI indicates nucleoside reverse transcriptase inhibitor;|
NNRTI indicates nonnucleoside reverse transcriptase inhibitor;
AUC indicates area under curve.
Adapted from Gourevitch et al, Mt Sinai J Med, 2001.
Important and unanticipated interactions occur between methadone and nucleoside reverse transcriptase inhibitors (nRTIs). Data from within- and between-subject studies indicate that the zidovudine area under the curve (AUC) concentration is increased by approximately 40% with co-administered methadone, with no change in methadone disposition observed. The increase in zidovudine levels appears to have resulted primarily from inhibition of zidovudine glucuronidation, but also from decreased renal clearance. Methadone-maintained patients receiving standard zidovudine doses may experience greater zidovudine exposure and consequently, increased zidovudine adverse effects and toxicity. Methadone-maintained patients may complain of malaise, insomnia, headache, and dysphoria upon initiating zidovudine therapy. Although related to increased exposure to zidovudine, these symptoms are often attributed to opiate withdrawal, resulting in the common belief that "zidovudine eats your methadone." Rather than increasing methadone doses, increased toxicity surveillance and possibly reduction in zidovudine dose are indicated when these 2 agents are given concomitantly.
A crossover study of coadministered methadone and the tablet formulation of didanosine has shown a decrease in didanosine AUC of 60%, presumably the result of delayed gastric emptying and decreased bioavailability. Whether other formulations of didanosine will be similarly affected is currently under study. A similar, but less dramatic decrease in stavudine AUC of 18% when coadministered with methadone has been reported. Coadministration of abacavir and methadone has produced a small but statistically significant increase in methadone clearance, resulting in a decrease in methadone levels. In addition, a small but significant decrease in maximum abacavir concentration and a delay in abacavir maximum time concentration have been seen. The latter is likely the result of the methadone effect of slowing gastrointestinal motility. Methadone levels are not affected by lamivudine, but the effect of methadone on lamivudine levels has not been studied. The clinical significance of these interactions is not known.
Interactions with methadone are more problematic with the nonnucleoside reverse transcriptase inhibitors (NNRTIs). Both nevirapine and efavirenz induce the metabolism of methadone and result in significantly lowered methadone levels and opiate withdrawal. In a recently reported case series, 7 patients had opiate withdrawal symptoms within 8 days of starting nevirapine. Three of these had methadone levels measured and all were low at the onset of symptoms. All patients required substantial increases in methadone dose and several refused additional antiretroviral therapy. A recent study supports this observation of induction of increased metabolism of methadone by nevirapine and extends the findings to efavirenz. In a group of 22 stable-dose methadone patients started on nevirapine or efavirenz, measurement of drug levels at baseline and after 2 and 3 weeks showed that the methadone AUC was decreased by 43% in subjects receiving efavirenz and by 46% in those receiving nevirapine. Patients had opiate withdrawal symptoms after 8 days and required a mean methadone dose increase of 22%. The effect of methadone/delavirdine coadministration has not been studied; however, based on what is known of delavirdine pharmacokinetics, it is hypothesized that coadministration would result in an increase in methadone levels.
Less is known about the effects of methadone on protease inhibitor pharmacokinetics. Coadministration appears to be associated with some delay in indinavir absorption, but there are as yet no published reports on interactions with other protease inhibitors. No effect on methadone levels has been reported with indinavir. Ritonavir has been reported to decrease methadone levels, although this information is based on use of very low doses of methadone. Interestingly, ritonavir appears to decrease meperidine levels and increase fentanyl levels. Nelfinavir has been reported to decrease methadone levels by 30% to 50% without resulting in clinical symptoms. It is hypothesized that nelfinavir may largely affect protein-bound methadone rather than the active free drug. Available preliminary information indicates that saquinavir and amprenavir have minimal effects on methadone levels and information about lopinavir and methadone is lacking.
With regard to therapies for opportunistic infections, most problematic is the long-known rifampin induction of methadone metabolism, with resultant rapid opiate withdrawal. Fluconazole acts as an inhibitor of methadone metabolism, with a mean increase of 35% in serum methadone AUC. Other clinically significant interactions with therapies for opportunistic infections have not been reported.
There is considerable likelihood of pharmacokinetic interactions between HIV therapies metabolized by the CYP450 system and commonly abused substances, such as heroin, marijuana, benzodiazapines and alcohol. However, virtually nothing is known of the clinical effects of such interactions. The need for concern is highlighted by a recent case report in which a patient taking the amphetamine methylene dioxymethamphetamine (MDMA) experienced a prolonged amphetamine-like reaction after switching from one protease inhibitor to ritonavir. After taking the nonsedating antihistamine g-hydroxybutyrate (GBH), the patient became comatose.
There is also minimal to no supporting published literature on potential pharmacokinetic interactions between psychiatric drug therapies and antiretroviral drugs. It is suspected that interactions occur between protease inhibitors and tricyclics, selective serotonin reuptake inhibitors (metabolized via CYP450 2D6), and bupropion among the antidepressants. With antidepressants, the most severe interactions are likely with ritonavir. Those taking ritonavir and tricyclic antidepressants (TCAs) should have the TCA dosage cut by one half to two thirds initially, with blood levels checked to establish a safe and effective dose. Bupropion is contraindicated with ritonavir.
It is also suspected that interactions occur between protease inhibitors and benzodiazepines (metabolized by CYP450 3A4) among the anxiolytics (particularly midazolam and triazolam). Benzodiazepines that appear safe to administer with ritonavir include lorazepam, temazepam, and oxazepam. Patients taking ritonavir and other benzodiazepines should be switched to one of these 3 agents. Insufficient information exists about other protease inhibitors, but they appear to be safe to use in combination with benzodiazepines.
No information is available on potential interactions between protease inhibitors and antipsychotics (metabolized via CYP450 1A2, 2D6), nor on potential interactions between nRTIs and NNRTIs and psychiatric drugs. Indinavir, saquinavir, and nelfinavir appear to have much less effect on psychotropic drug levels compared with ritonavir, but still may inhibit cytochrome P450 3A4. Selective serotonin reuptake inhibitors and nefazodone may increase protease inhibitor blood levels, particularly through CYP 3A4 inhibition. The clinical significance is unknown. Carbamazepine, venlafaxine and St. John's Wart can lower protease inhibitor levels. The mood stabilizer gabapentin does not undergo hepatic metabolism and has no inhibitor-inducing effects of the CYP450 system. These characteristics make it an ideal agent for mood stabilization and treatment of neuropathic pain in patients on HAART.
Several recent reports in small numbers of patients demonstrated increases in methadone levels when coadministered with fluvoxamine and sertraline, and less effect with fluoxetine. Although clinical indications for administration of therapies for HIV, substance abuse, and mental illness should be followed, prudence dictates that caution be taken when these drugs are administered concomitantly and that heightened awareness of possible interactions be maintained. All patients on psychiatric medications should carry an updated medication list to share with their psychiatrist and other health care providers.
Interactions between antiretrovirals and substance abuse therapies are common, and interactions between antiretrovirals and psychiatric medications may also be common but have not been well studied. The most important currently identified interactions are the effect of methadone on nRTIs and the effect of NNRTIs on methadone (and to a lesser extent the effect of protease inhibitors on methadone). Conclusions
HIV disease, substance abuse, and mental illness frequently coexist and complicate and confound HIV treatment efforts. More limited access to HIV care, decreased provision, acceptance, and adherence to therapy, lack of substance abuse and mental health treatment and complex and poorly studied drug interactions all contribute to limiting the benefits of potent antiretroviral therapy in populations with these comorbid conditions. HIV clinicians need to increase their expertise in the management of these comorbid conditions and help develop systems of care that better address the special needs of this population. Suggested Reading General
Drugs and Drug Interactions
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