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Drug-Drug Interactions Between ARV Agents, Medications Used in Substance Use Treatment, and Recreational Drugs

Updated March 2008

Click here to order the ‘Substance Use In Patients With HIV/AIDS: HIV Clinical Guidelines For The Primary Care Practitioner’ book

I. INTRODUCTION

RECOMMENDATION:
The clinician should conduct a thorough medication history at each visit that includes prescription medications, including those prescribed by other providers, over-the-counter medications, recreational drugs, and herbal/alternative therapies.

An increasing number of potential interactions between medications to treat substance use and ARV therapy have been systematically evaluated. Clinicians need to be alert to the possibility of such interactions, which can result in diminished efficacy of substance use treatment (e.g., methadone) or ARV treatment, medication toxicity, or both. Little is yet known regarding interactions between recreational drugs and ARV therapy. Although evidence is lacking that heroin, cocaine, or marijuana interact with ARV therapy, their use may decrease ARV effectiveness in some persons by diminishing adherence to prescribed regimens.

Current treatment guidelines recommend using a combination of at least three ARV drugs for the treatment of HIV-infected patients.1,2 Substance-using patients co-infected with HIV are often taking additional medications to treat their substance use, prevent opportunistic infections, and manage additional comorbid conditions that they may have. Herbal therapy or recreational drugs may further complicate drug interactions associated with ARV therapy because their use often goes unrecognized.

An overview of known and potential interactions between medications used in the treatment of substance use, recreational drugs, and ARV therapy is presented in this chapter. A more comprehensive review of drug-drug interactions among ARV drugs and other HIV-related medications can be found in the HIV Drug-Drug Interactions chapter, available at www.hivguidelines.org. Table 1 lists the generic and brand names of the drugs mentioned in this chapter.

Table 1: Generic and Brand Names of Drugs Commonly Used With ARV Medications
Generic Name Common Brand Names
Antimycobacterials
  • Rifabutin
  • Rifampin
  • Mycobutin
  • Rifadin, Rimactane
Antifungals
  • Fluconazole
  • Itraconazole
  • Ketoconazole
  • Voriconazole
  • Diflucan
  • Sporanox
  • Nizoral
  • Vfend
Anticonvulsants
  • Carbamazepine
  • Levetiracetam
  • Phenobarbital
  • Phenytoin
  • Valproic acid
  • Carbatrol, Tegretol
  • Keppra
  • Solfoton
  • Dilantin
  • Depakene, Depakote
Benzodiazepines
  • Alprazolam
  • Clonazepam
  • Midazolam
  • Triazolam
  • Xanax
  • Klonopin
  • Versed
  • Halcion

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II. DRUG INTERACTIONS RELATED TO THE METABOLISM OF HAART

Medications used in HAART, especially the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs), are metabolized via the cytochrome P450 enzyme system (CYP450). The isoenzyme responsible for the majority of this metabolism is CYP3A4, although 2C19 and 2D6 are also common and, to a lesser extent, CYP1A2.3-5 Medications that interact with the CYP450 system typically do so in one of three ways: 1) through inhibition, 2) through induction, or 3) by acting as a substrate.

Table 2 shows the potential for interactions among ARV agents and the most common medications used to treat substance use disorders according to how they are metabolized.

Table 2: Metabolism of Medications Used in the Treatment of Substance Abuse: Potential for Drug-Drug Interactions With HAART
Drug Metabolism Potential Interactions
Methadone
(used to treat opioid dependence)
CYP450 2B6
>CYP2C19> CYP3A4
Drug interactions when used concurrently with NNRTIs, EFV, NVP, and potentially LPV/r
Buprenorphine
(used to treat opioid dependence)
CYP3A4 Potential drug interactions when used concurrently with NNRTIs and PIs
Naltrexone
(used to treat narcotic and alcohol dependence)
Metabolized by the liver but not via the CYP450 system. Drug interactions with ARVs are unlikely
Disulfiram
(used to treat alcohol dependence)
Inhibits some CYP450 enzymes May interact with ARV agents6

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A. Inhibition

Drugs that inhibit the CYP450 enzyme system generally lead to decreased rates of metabolism of other drugs metabolized by the same enzyme, resulting in higher drug levels and increased potential for toxicity. Although inhibition is usually reversible, irreversible inhibition of CYP450 can occur, requiring new CYP450 enzyme to be synthesized to overcome the inhibition. Inhibition of drug metabolism tends to occur quickly (based on drug half-life), with maximal effect occurring when highest concentrations of the inhibitor are reached.7

EXAMPLE:
Ritonavir inhibition of midazolam metabolism resulting in increased sedation.

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B. Induction

Induction of the CYP450 system results in the increased clearance of concomitant medications metabolized by the same enzyme. When drugs that induce CYP450 enzymes are administered to a patient, the body responds by increasing the production of specific enzymes of the CYP450 system. The increased enzyme production can lead to increased metabolism and decreased concentrations of drugs metabolized via the same pathway.

Induction can be problematic during ARV therapy due to concerns for virologic failure when PI and/or NNRTI drug concentrations are reduced. In most cases, the maximal effect of enzyme induction is apparent within 7 to 14 days.

EXAMPLE:
Efavirenz induction of methadone metabolism resulting in withdrawal symptoms.

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C. Substrates

A medication may act as a substrate by occupying the active site of a specific CYP450 enzyme. The medication’s metabolism is then affected by other medications that either induce or inhibit the CYP450 enzyme system.

EXAMPLE:
NNRTIs and PIs are substrates at CYP3A4 and are therefore prone to drug interactions. Inducers will lower NNRTI and PI levels. Inhibitors will increase NNRTI and PI levels.

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III. DRUG INTERACTIONS WITH METHADONE

RECOMMENDATIONS:
Clinicians should discuss potential drug interactions with patients receiving methadone before initiating ARV therapy.

Clinicians should report all prescribed ARV drug-related drug changes for patients receiving methadone to the patient’s methadone maintenance program.

Clinicians should monitor HIV-infected substance users receiving concurrent methadone and ARV therapy for symptoms of withdrawal and/or excess sedation when ARV therapy is initiated or changed.

An overview of interactions among HIV-related medications and medications used for the treatment of heroin addiction is presented in Appendix XI.

Key Point:
Interactions between ARV therapy and methadone may precipitate symptoms of oversedation or withdrawal.

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A. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

RECOMMENDATIONS:
When using didanosine in patients receiving methadone, clinicians should consider using the enteric-coated capsule formulation because it does not lead to a clinically significant interaction when given concurrently with methadone.

Clinicians should monitor patients for symptoms of zidovudine toxicity, such as anemia, nausea, and headaches, when zidovudine and methadone are used concurrently.

Clinically significant interactions between methadone and most NRTIs are unlikely. Specific interactions that the clinician should be aware of are listed below:

SPECIFIC INTERACTIONS:

1. Abacavir
One study showed an increase of 22% in oral methadone clearance but did not require a change in methadone dose because there were no withdrawal symptoms.8 A dose modification is not likely in most patients; however, some patients receiving methadone and abacavir concomitantly may require a dose alteration.

2. Didanosine
Drug interactions between methadone and didanosine have been documented.9 When used concurrently with methadone, the AUC of buffered didanosine was reduced by 63%. Specific dosing guidelines for concurrent use of buffered didanosine and methadone have not been established. Therefore, in place of the buffered tablet formulation, clinicians can use the didanosine enteric coated capsule because this formulation does not lead to a clinically significant interaction when given concurrently with methadone.10

3. Lamivudine
A study of 16 non-HIV-infected patients receiving methadone maintenance therapy demonstrated that administration of Combivir (lamivudine 150 mg + zidovudine 300 mg) resulted in no significant differences in the mean AUC or Cmax. These results suggest that a methadone dose adjustment is likely not needed for patients treated with lamivudine/zidovudine combination pharmacotherapy.11

4. Stavudine
Drug interactions between methadone and stavudine have been documented.9 When used concurrently with methadone, the measured AUC of stavudine was reduced by 25%, which may not be clinically significant and most likely does not require dose adjustment.9

5. Tenofovir
Tenofovir pharmacokinetics were not affected by methadone in 13 non-HIV-infected patients who received tenofovir 300 mg daily for 14 days. Concurrent use of methadone and tenofovir did not alter the pharmacokinetics or pharmacodynamics of total, R-, or S-methadone, and no patients demonstrated withdrawal symptoms. Therefore, tenofovir may be given as part of a once-daily ARV regimen in patients receiving methadone maintenance therapy.12

6. Zidovudine
Methadone has been shown to increase the AUC of zidovudine by 43%,13 and acute methadone treatment has been associated with a 41% increase in the AUC of zidovudine.14 Although the clinical implications of this interaction are unknown, patients should be monitored for symptoms of zidovudine toxicity, such as anemia, nausea, myalgia, and headaches, when these agents are used concurrently.

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B. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

RECOMMENDATIONS:
Clinicians initiating an ARV regimen consisting of efavirenz or nevirapine in patients receiving methadone should contact the methadone maintenance program clinicians to ensure that the onset of withdrawal symptoms, if they occur, is promptly addressed by increasing the patient’s methadone dose.

Clinicians prescribing methadone maintenance therapy should closely monitor patients when adding efavirenz or nevirapine to their ARV regimens.

The NNRTIs nevirapine and efavirenz are of particular concern when used concurrently with methadone because they strongly induce the metabolism of methadone in many patients, thereby reducing methadone blood levels and precipitating symptoms of opioid withdrawal.

SPECIFIC INTERACTIONS:

1. Delavirdine
The manufacturer reports that an increase in the concentration of methadone may occur when given concomitantly with delavirdine; however, there is no indication that such dose reductions are actually required in practice.15

2. Efavirenz
When efavirenz was used concurrently with methadone, the methadone AUC decreased 57% due to CYP450 induction. Narcotic withdrawal has been reported when efavirenz is added to stable methadone treatment.16-20 Nine of 11 patients described symptoms of methadone withdrawal and required a mean increase in methadone dose of 22% (range 15-30 mg).21 Because CYP450 enzyme induction associated with efavirenz may take up to 14 days to occur and because of the long half-life of methadone, symptoms of withdrawal may be delayed for up to 2 to 3 weeks. To offset this interaction, patients often require an increase in their methadone maintenance dose. One study reported that 68% of patients initiating efavirenz while receiving concurrent methadone required an average 50% increase in their methadone maintenance dose.21,22 Clinicians initiating an ARV regimen containing efavirenz in patients receiving methadone should contact the methadone maintenance program to ensure that the onset of withdrawal symptoms is addressed by promptly increasing the patient’s methadone dose when clinically indicated (i.e., when opiate withdrawal is detected). Clinicians prescribing methadone maintenance therapy should develop plans for close monitoring of patients when adding efavirenz to their ARV regimens.

3. Etravirine (TMC 125)
Unlike the currently available FDA-approved NNRTIs, there appears to be no significant change in S-methadone and R-methadone AUC with etravirine and methadone in healthy, non-HIV-infected volunteers receiving methadone therapy. In a 14-day study of 16 individuals, no significant symptoms of methadone withdrawal were observed. Therefore, there is no methadone dose adjustment necessary in patients taking etravirine.23

4. Nevirapine
When nevirapine was used concurrently with methadone, the methadone AUC decreased 46% due to CYP450 induction.20 Narcotic withdrawal has been reported when nevirapine was added to stable methadone treatment.16-20 Because CYP450 enzyme induction associated with nevirapine may take up to 14 days to occur and because of the long half-life of methadone, symptoms of withdrawal may be delayed for up to 2 to 3 weeks. To offset this interaction, patients often require an increase in their methadone maintenance dose. One study reported that 75% of patients started on nevirapine while receiving concurrent methadone required an average 16% increase in their methadone maintenance dose.20 Clinicians initiating an ARV regimen consisting of nevirapine should contact methadone maintenance clinicians to ensure that the onset of withdrawal symptoms is promptly addressed by increasing the patient’s methadone dose. Clinicians prescribing methadone maintenance therapy should develop plans for close monitoring of patients when adding nevirapine to their ARV regimens.20,22

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C. Protease Inhibitors (PIs)

PIs are inducers and inhibitors of the CYP450 system, as is methadone; therefore, drug interactions with concurrent use of these drugs may occur but clinically significant interactions have only been reported in some but not all studies of lopinavir/ritonavir and of nelfinavir.24-30

SPECIFIC INTERACTIONS:

1. Amprenavir
Active methadone levels are reduced 13% in patients receiving amprenavir. Amprenavir concentrations are decreased 25%.24 One study of five patients demonstrated that when abacavir and amprenavir were used in patients receiving stable methadone doses, methadone levels were reduced an average 35% (28% to 87%).31 The authors believed that this interaction was most likely due to amprenavir. However, withdrawal symptoms have not been observed when amprenavir and methadone are co-administered; therefore, dose adjustments are unlikely.

2. Atazanavir
Atazanavir is an inhibitor of CYP3A4. Concurrent administration of atazanavir and methadone showed no clinically relevant pharmacokinetic interactions32 or opiate withdrawal or excess33; thus, dosage adjustments are unlikely.

3. Darunavir/ritonavir
Darunavir, ritonavir, and methadone are substrates of the CYP3A4 enzyme. Additional metabolism of methadone occurs via CYP2B6, which is induced by ritonavir. A study evaluated 16 non-HIV-infected opioid-dependent patients receiving once-daily methadone maintenance therapy at a stable individualized dose. When darunavir/ritonavir (600 mg/100 mg) bid was added, mean Cmin, Cmax, and AUC values of the biologically active methadone R-isomer were decreased by 15%, 24%, and 16%, respectively. Mean Cmin, Cmax, and AUC values of the methadone S-isomer were also decreased by 40%, 44%, and 36%, respectively. Four (25%) patients potentially experienced symptoms associated with opiate withdrawal. Although an increase in methadone dose is not routinely recommended, patients should be monitored for withdrawal symptoms and methadone titrated to effect.34

4. Fosamprenavir
Administration of fosamprenavir and ritonavir in non-HIV-infected patients receiving methadone therapy showed that the AUC and Cmax of active (R-) methadone decreased 18% and 21%, respectively, while the AUC and Cmax of inactive (S-) methadone decreased 42% and 43%, respectively. However, no significant decrease in unbound (R-) methadone was observed and no patient reported symptoms of opiate withdrawal. Methadone dose adjustments are unlikely when co-administered with fosamprenavir/ritonavir.35

5. Indinavir
Data from the manufacturer indicate that there was little or no change in indinavir or methadone AUC when taken concurrently for 1 week.26

6. Lopinavir/ritonavir
A study assessing the possible interaction between lopinavir/ritonavir and methadone showed that the AUC of methadone was reduced 26% to 36%. However, no patient reported experiencing signs or symptoms of opioid withdrawal or required increases in methadone maintenance doses.36

Another study, however, showed that when lopinavir/ritonavir and methadone were co-administered, the methadone AUC, Cmax, and Cmin were reduced significantly and opiate withdrawal symptoms were increased. Thus, some patients may require an increase in methadone dose.37

7. Nelfinavir
Results from studies on the effects of concurrent administration of nelfinavir and methadone are conflicting. One study reported that significant decreases in methadone were observed, but without accompanying significant opiate withdrawal.15 Other studies have resulted in withdrawal symptoms and dose increase. However, the manufacturer states the nelfinavir reduces the AUC, Cmax, and Cmin of methadone and that the dosage of methadone may need to be increased when co-administered with nelfinavir.30 As with all of these interactions, clinical observation and tailoring of the methadone dose to the patient’s symptoms of opioid craving and withdrawal is the guiding principle.

8. Ritonavir
Ritonavir is an inhibitor of CYP3A4 and modestly increases methadone concentrations37; thus, no adjustments to methadone are generally required.

9. Saquinavir/ritonavir
AIDS Clinical Trials Group (ACTG) 401 evaluated the effects of saquinavir/ritonavir (400 mg/400 mg) on the pharmacokinetics of methadone in 12 HIV-infected methadone-using patients. Saquinavir/ritonavir reduced the R-isomer of methadone 32%; however, no study participant experienced withdrawal symptoms and no methadone dosage changes were required.38 Another study evaluating the effects of daily saquinavir/ritonavir (1600 mg/100 mg) on unbound methadone identified that methadone concentrations were unchanged. Researchers also reported reductions in saquinavir drug exposure; however, the majority of patients (83%) maintained saquinavir minimum concentrations above the EC50 for this drug. Therefore, there appears to be a clinically insignificant interaction for most patients receiving concurrent saquinavir and methadone.

10. Tipranavir/ritonavir
In clinical studies, methadone serum concentrations decreased 50% when tipranavir/ritonavir was co-administered. Patients taking tipranavir/ritonavir and methadone should be monitored for withdrawal signs and symptoms and co-administration may require a methadone dose increase.39

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D. Fusion Inhibitors

Enfuvirtide
Data regarding the concurrent use of methadone and enfuvirtide have not been reported. Data from the manufacturer state that enfuvirtide is unlikely to have significant drug interactions with concomitantly administered drugs metabolized by CYP450 enzymes.40

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E. CCR5 Co-receptor Antagonists

Maraviroc
Data regarding the concurrent use of methadone and maraviroc have not been reported. Maraviroc is unlikely to interact with methadone because it does not inhibit or induce CYP2B6, CYP2C19, and CYP3A in vitro.41

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F. Integrase Inhibitors

Raltegravir
Data regarding the concurrent use of methadone and raltegravir have not been reported; however, because raltegravir is neither a substrate, inhibitor, nor inducer of CYP450 enzymes, raltegravir is not expected to exhibit metabolic drug interactions with methadone.42

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G. Antimycobacterials (Rifampin/Rifabutin)

Many HIV-infected individuals are co-infected with tuberculosis and may require rifampin, a potent inducer of CYP3A4. Rifampin has been reported to induce methadone withdrawal in patients receiving these agents concurrently, with a 33% to 68% decrease in plasma methadone concentrations.43 Therefore, additional methadone will likely be needed to avert narcotic withdrawal symptoms. Rifabutin may be a potential alternative because it is known to induce CYP3A4 to a lesser degree than rifampin and has not been shown to alter methadone levels when these drugs are used concurrently.44

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H. Antifungals

Antifungal therapy is often prescribed to HIV-infected patients to treat fungal opportunistic infections such as oral candidiasis and cryptococcal meningitis. Because these agents have been shown to inhibit CYP3A4, potential drug interactions are possible when used concurrently with methadone. In one study, patients receiving fluconazole and methadone experienced an average 35% increase in the AUC of methadone, although no signs of methadone toxicity were reported.45 Although these reports involve fluconazole, clinicians should be alert for symptoms of opioid toxicity when other azole antifungals such as itraconazole, ketoconazole, or voriconazole are used concurrently with methadone.

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I. Anticonvulsants

Due to their ability to induce the CYP450 system, anticonvulsants often reduce methadone concentrations. Studies evaluating this interaction found that phenytoin, phenobarbital, and carbamazepine induced methadone withdrawal; thus, clinicians should consider the potential for withdrawal when used concomitantly.46-48 Valproic acid and levetiracetam, however, do not typically precipitate the need for alterations in methadone dose requirements.48

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IV. DRUG INTERACTIONS WITH BUPRENORPHINE

Buprenorphine drug interaction data are limited at this time.

A. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

One study suggested that no significant drug interaction occurs when buprenorphine is given concurrently with zidovudine.49

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B. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Efavirenz has been shown to reduce buprenorphine plasma concentrations without precipitating symptoms of opiate withdrawal. Buprenorphine does not significantly alter efavirenz levels, indicating that no dose adjustments of buprenorphine or efavirenz are likely to be required when these medications are used concomitantly.50

Nevirapine may also decrease buprenorphine serum concentrations.

Delavirdine increased buprenorphine concentrations approximately 3-fold; however, no clinically significant consequence of this interaction was observed. Buprenorphine did not alter ARV pharmacokinetics; therefore, no dose adjustments of buprenorphine or delavirdine are likely to be required when these medications are used concomitantly.51

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C. Protease Inhibitors (PIs)

The in vitro effects of ritonavir, indinavir, and saquinavir on human liver microsomes when used concurrently with buprenorphine or methadone have been evaluated. Buprenorphine metabolism, for which CYP3A4 is primarily responsible, was inhibited by the PIs in the following order: ritonavir>indinavir>saquinavir.52

Atazanavir and atazanavir/ritonavir have been shown to increase buprenorphine AUC by 93% and 67%, respectively. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. However, three patients reported increased sedation with atazanavir/ritonavir. Therefore, patients receiving atazanavir or atazanavir/ritonavir may require a decreased buprenorphine dose.53

Buprenorphine AUC was increased 36% when used concomitantly with ritonavir 100 mg bid. Lopinavir/ritonavir and nelfinavir did not significantly affect the serum concentration of buprenorphine. Co-administration of ritonavir, lopinavir/ritonavir, or nelfinavir with buprenorphine did not result in an increased level of sedation.50

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V. DISULFIRAM/NALTREXONE AND HAART MEDICATION INTERACTIONS

Published data regarding interactions between ARV medications and disulfiram or naltrexone are limited. Drug interactions between naltrexone and most ARV medications are not expected because naltrexone is not metabolized via CYP450. One study demonstrated that the use of naltrexone in patients receiving concurrent zidovudine resulted in no change in zidovudine pharmacokinetics.49

However, co-administration of tipranavir/ritonavir with disulfiram may result in severe reaction (intense headache, flushing, vomiting, and chest pain) because tipranavir capsules contain alcohol. Furthermore, inhibition of aldehyde dehydrogenase by disulfiram will increase the risk of toxicity with amprenavir oral solution due to propylene glycol-induced toxicity (acidosis, central nervous system depression).

Other potential clinically significant interactions between disulfiram and ARV medications have not been defined.55

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VI. RECREATIONAL DRUGS AND HAART

RECOMMENDATION:
Clinicians should assess adherence and be alert for signs of hepatotoxicity in HIV-infected patients receiving ARV therapy who are concurrently using recreational drugs (see Appendix XII).

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A. Alcohol

Alcohol use, which is common among persons with HIV infection, can reduce the effectiveness of ARV therapy by reducing adherence and by leading to hepatotoxicity (either directly or indirectly by increasing the risk of drug-induced hepatotoxicity).56-58 Alcohol use has also been linked to ARV-related hepatotoxicity in patients with HIV/HCV co-infection.59,60 Pharmacokinetic studies evaluating interactions between alcohol and ARV therapy are limited.

Ethanol and abacavir are both metabolized by alcohol dehydrogenase; an evaluation of their concurrent use identified that the pharmacokinetics of ethanol were unchanged while the AUC of abacavir increased 41% and the half-life increased 26%.61 The investigators concluded that these changes in abacavir pharmacokinetics were likely to be clinically insignificant, because abacavir has been well tolerated in daily doses up to 1800 mg. Adjustment of abacavir dose to 150 mg twice daily has been suggested in patients with mild hepatic impairment but clinical data are limited.

Co-administration of ethanol and amprenavir oral solution is contraindicated. Amprenavir oral solution contains the excipient propylene glycol. Alcohol consumption may increase propylene glycol toxicity due to competitive inhibition of alcohol and aldehyde dehydrogenase enzyme pathway by ethanol.24

Alcohol may lead to cirrhosis, which would affect ARV dosing. Although clinical data are limited, reductions in ARV dosage in patients with hepatic impairment are currently recommended for abacavir, amprenavir, fosamprenavir, atazanavir, and indinavir, based on Child-Pugh liver disease severity scores (see Appendix VII).24,26 Clinicians should be vigilant for potential hepatotoxicity from ARV therapy (especially with nevirapine and high-dose ritonavir) in patients with significant hepatic dysfunction or cirrhosis of any cause.58,59

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B. Amphetamines

RECOMMENDATION:
Clinicians should not prescribe ritonavir, even in low doses for boosting, if patients report using amphetamines.

CYP2D6 has been identified as the enzyme responsible for metabolism of the amphetamines methamphetamine and methoxyphenamine.62 Because the PIs ritonavir and lopinavir/ritonavir may inhibit CYP2D6, there is a concern regarding increased amphetamine concentrations when used concurrently. Life-threatening interactions have been observed in patients receiving ritonavir who used ecstasy, which is chemically related to amphetamine. As with other drug use, crystal meth and other amphetamine use may disrupt adherence to ARV regimens.

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C. Barbiturates

RECOMMENDATION:
Clinicians treating HIV-infected patients misusing barbiturates should:

  • Avoid co-administration of NNRTIs and phenobarbital
  • Use caution if maraviroc and phenobarbital are used concomitantly
  • Consider doubling the raltegravir dose when co-administered with phenobarbital

Barbiturates such as phenobarbital are potent inducers of CYP3A4. Clinicians should avoid concurrent administration of other potent inducers (e.g., efavirenz, nevirapine) in patients misusing barbiturates.

Maraviroc is a substrate of CYP3A4 and concurrent administration of phenobarbital may increase maraviroc metabolism, leading to loss of virologic response, and possible resistance to maraviroc. Clinicians should use caution if maraviroc and phenobarbital are used concomitantly (without a strong CYP3A inhibitor). The maraviroc dose should be increased to 600 mg twice daily.41

Raltegravir AUC and Cmax values decreased by 40% and 38% when co-administered with rifampin; therefore, the raltegravir dose should be doubled when co-administered with a potent enzyme inducer like rifampin. On the basis of the results with rifampin, doubling the raltegravir dose should be considered when co-administered with phenobarbital.63

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D. Benzodiazepines

RECOMMENDATION:
Clinicians should avoid concurrent use of alprazolam, midazolam, and triazolam with all PIs, delavirdine, and efavirenz.

Some benzodiazepines (alprazolam, clonazepam, midazolam, and triazolam) are metabolized by the CYP3A4 system. Interactions with ARV therapy should be considered if excessive sedation is observed clinically.

If patients are receiving CYP3A4 inhibitors (PIs or delavirdine) and require a benzodiazepine, lorazepam, oxazepam, and temazepam may be considered because they are not metabolized via the CYP3A4 pathway.

There are no clinically significant interactions between benzodiazepines and maraviroc or raltegravir.

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E. Cocaine

Cocaine is metabolized via ester hydrolysis to an inactive metabolite. Data suggest that CYP3A4 is a minor pathway involved in the metabolism of cocaine into a hepatotoxic metabolite.64 With a CYP3A4 inducer (e.g., nevirapine, efavirenz), it is theoretically possible that drug interactions may result in increased hepatotoxicity. To date, no case reports have described toxicity related to pharmacologic interactions between cocaine and ARV therapy.

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F. Ecstasy (MDMA)

Clinicians should not prescribe PIs, even in low doses for boosting, if patients report using ecstasy or GHB.

CYP2D6 has been identified as the isoenzyme responsible for the metabolism of ecstasy (N-methyl-3,4-methylenedioxyamphetamine, MDMA).65 Because the ARV agent ritonavir can inhibit the CYP2D6 isoenzyme, there is concern for increased concentrations of MDMA when this drug is used concurrently with ARV therapy. This combination can be lethal: one case report described a fatal interaction between ritonavir and ecstasy, while a second described a near-fatal reaction in a patient taking saquinavir/ritonavir and using small doses of ecstasy.66,67 In the fatal case, the patient was receiving a full dose of ritonavir; the near-fatal case demonstrates that this reaction is of concern even in patients receiving low-dose ritonavir for pharmacokinetic enhancement. Patients using ecstasy or suspected of using ecstasy should be warned about the potential enhanced effects of ecstasy when taking concurrent ritonavir therapy.

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G. Heroin

Although several mechanisms of potential medication interactions between heroin and ARV medications have been hypothesized,68 no documented studies or cases have suggested the existence of clinically significant interactions between heroin and ARV medications.

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H. Marijuana

The effects of marijuana, either smoked or taken orally, on the pharmacokinetics of indinavir and nelfinavir were assessed in 67 patients.69 When marijuana was smoked, it reduced both the AUC and Cmax of nelfinavir by 10% and 17%, respectively, and by 14% and 14%, respectively, for indinavir. However, marijuana, smoked or taken orally, had no negative effect on viral load. Although the results of this study raise concern about marijuana and reduced PI concentrations, the clinical significance of reductions of this magnitude are unlikely to be significant.

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I. Psychotropics

RECOMMENDATION:
Clinicians should consider medication interactions as a potential cause of mental status changes in persons receiving psychotropic medications and ARV therapy.

The prevalence of comorbid substance use and psychiatric disorders is high among the HIV-infected population. Although most patients tolerate psychiatric pharmacotherapy while receiving concurrent ARV therapy, some patients may experience either a change in mental status or increased psychiatric symptomatology when either an ARV therapy regimen or psychotropic medications have been changed. Clinicians are encouraged to refer to the prescribing information of all agents that the patient is receiving if a change in mental status or the onset of psychiatric symptoms seems to be linked chronologically to changes in medications. See Appendix XIII for more information on significant interactions between ARV therapy and psychotropic medications.

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VII. RESOURCES FOR CONSULTATION

Clinicians who need additional information concerning ARV drug interactions can refer to the following websites:
www.aidsinfo.nih.gov
www.hiv-druginteractions.org

Antiretroviral Package Inserts:

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REFERENCES

1. New York State Department of Health AIDS Institute. Antiretroviral Therapy. 2007. Available at: www.hivguidelines.org

2. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2008. Available at: http://aidsinfo.nih.gov

3. Gerber JG, Rosenkranz S, Segal Y, et al. Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: Results of AIDS Clinical Trials Group (ACTG) 401. J Acquir Immune Defic Syndr 2001;27:153-160. [PubMed]

4. Iribarne C, Berthou F, Baird S, et al. Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol 1996;9:365-373. [PubMed]

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