Antiretrovirals, Part II: Focus on Non-Protease Inhibitor Antiretrovirals (NRTIs, NNRTIs, and Fusion Inhibitors)

Med-Psych Drug-Drug Interactions Update Antiretrovirals, Part II: Focus on Non-Protease Inhibitor Antiretrovirals (NRTIs, NNRTIs, and Fusion Inhibitors) MICHAEL J. ZAPOR, M.D., PH.D., KELLY L. COZZA, M.D., F.A.P.M. GARY H. WYNN, M.D., GLENN W. WORTMANN, M.D. SCOTT C. ARMSTRONG, M.D.

The second in a series reviewing the HIV/AIDS antiretroviral drugs. This review summarizes the non-protease inhibitor antiretrovirals: nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs), the nonnucleoside reverse transcriptase inhibitors (NNRTIs), and cell membrane fusion inhibitors. In an overview format for primary care physicians and psychiatrists, this review presents the mechanism of action, side effects, toxicities, and drug interactions of these agents. (Psychosomatics 2004; 45:524–535)

T

he renowned 20th-century clinician Sir William Osler once remarked, “Know syphilis in all its manifestations and relations, and all other things clinical will be added unto you.”1 The same aphorism might aptly be applied today to HIV infection. As our understanding of HIV pathogenesis increases, so too does our knowledge in disciplines such as cell biology and immunology. Highly active antiretroviral therapy (HAART) became available in 1996 and generally includes at least three different antiretrovirals administered in combination (sometimes referred to as a “cocktail”), resulting in tremendous pill burdens, side effects, toxicities, and complicated drug interactions. From the Department of Medicine, Walter Reed Army Medical Center; and the Uniformed Services University of the Health Sciences F. Edward Hebert School of Medicine, Bethesda, Md. (Drs. Zapor, Cozza, Wynn, and Wortmann). Dr. Armstrong is the Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, Ore., and Associate Clinical Professor of Psychiatry, Oregon Health Sciences University, Portland, Ore. Drs. Armstrong and Cozza are co-authors, along with Dr. Jessica R. Oesterheld, of the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins, 2nd edition. (American Psychiatric Publishing, Inc., 2003). Address all correspondence to Dr. Cozza, Psychiatrist, Infectious Disease Service, Ward 63, Department of Medicine, Walter Reed Army Medical Center, 6900 Georgia Ave., Washington, DC 20307-5001; [email protected] (e-mail). The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Copyright 䉷 2004 The Academy of Psychosomatic Medicine.

524

http://psy.psychiatryonline.org

Strict adherence to the “cocktail” is imperative to limit the development of viral resistance to HAART. Noxious side effects, adverse drug reactions, and drug interactions may lead to nonadherence to or suboptimal HAART, placing the patient at risk for treatment failure. As the armamentarium of HIV medicines expands, so must our awareness of the myriad drug side effects and interactions. With this in mind, our colleagues at Walter Reed Army Medical Center’s Infectious Disease Service present this second of three installments reviewing the side effects and drug interactions associated with antiretroviral medications. This multipart synopsis is intended to provide succinct information regarding potential side effects, toxicities, and drug interactions of the medications commonly used in the management of HIV-infected patients. The protease inhibitors were presented in Part I (Psychosomatics 2004; 45:262–270 [May-June issue]). This segment reviews the rest of the antiretrovirals to date: the nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs), the nonnucleoside reverse transcriptase inhibitors (NNRTIs), and cell membrane fusion inhibitors. Part III will review drug-drug interactions between antiretrovirals and drugs of abuse. Up-to-the-minute information about these medications, including dosing strategies, may be found at web sites such as the Medscape HIV home page and http://hivinsite.ucsf.edu. Psychosomatics 45:6, November-December 2004

Med-Psych Drug-Drug Interactions NUCLEOSIDE AND NUCLEOTIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS The NRTI class of antiretroviral drugs consists of structural analogues of the nucleotide building blocks of RNA and DNA. When incorporated into the viral DNA, these defective nucleotide analogues prevent the formation of a new 3⬘r5⬘ phosphodiesterase bond with the next nucleotide, causing premature termination of strand synthesis and effectively inhibiting viral replication.2 Metabolism of these drugs depends on intracellular enzymes such as nucleoside kinases, 5⬘-nucleotidases, purine and pyrimidine nucleoside monophosphate kinases, and similar enzymes. They are generally not metabolized by hepatic cytochrome P450 enzymes.3 As a class, the NRTIs are generally safe and well tolerated, although there are several life-threatening toxicities attributed to these antiretroviral drugs. Most notable among these is mitochondrial toxicity. With the exception of lamivudine and abacavir, the NRTIs are competitive inhibitors of human mitochondrial DNA polymerase gamma, the sole enzyme responsible for the base excision repair of oxidative damage to mitochondrial DNA.4 The depletion of mitochondrial DNA associated with NRTI use disrupts oxidative phosphorylation, leading to the toxic accumulation of nonesterified fatty acids, dicarboxylic acids, and free radicals.5 NRTIs may also cause mitochondrial DNA mutations. Evidence that this decreased ability to repair oxidative damage leads to enduring mitochondrial DNA damage by altering mitochondrial genome sequencing is now being studied.6 As with inherited mitochondrial disorders, the clinical presentation of acquired mitochondrial toxicity is variable. This is due, in part, to the unequal distribution of mitochondria between cell lines, with metabolically active tissues more likely to be affected. These include nervous tissue (brain, retina, peripheral nerves), muscle (including cardiac) tissue, and endocrine, renal, gastrointestinal, hematologic, and hepatic tissue. Of these, the most common severe manifestations of NRTI-induced mitochondrial dysfunction include peripheral neuropathy,7,8 myopathy,9–12 lactic acidosis,13,14 hepatic steatosis, pancreatitis, and peripheral lipodystrophy.15–18 Although peripheral neuropathy, myopathy, lactic acidosis, and fat redistribution are the most commonly described complications of NRTI use, other adverse effects have also been reported. These include hematopoietic toxicity (culminating in anemia, neutropenia, or thrombocytopenia),19,20 ototoxicity,21 and myriad drug interactions. In general, NRTIs are not metabolized by the P450 system, Psychosomatics 45:6, November-December 2004

yet their exact route of metabolism has yet to be fully elucidated.22,23 Many are glucuronidated, and some are recovered without being metabolized in the urine and feces. Abacavir Abacavir (Ziagen威), a guanosine analogue that is phosphorylated intracellularly to carbovir triphosphate, has been approved for use in combination with other antiretroviral agents. Certain combinations produce especially potent, durable virologic suppression.24 In addition, abacavir-containing regimens have been associated with a lower incidence of lipodystrophy.25,26 Abacavir is generally well tolerated, with a side effect profile similar to that of the other drugs in its class. There is, however, one notable exception: a potentially fatal hypersensitivity reaction that occurs in approximately 5% of patients. Unfortunately, the presentation of abacavir hypersensitivity reaction is variable, making diagnosis challenging. Signs and symptoms commonly reported include fever, rash, pruritus, nausea, vomiting, diarrhea, mucosal lesions, and flulike symptoms. The onset of abacavir hypersensitivity reaction may occur at any time during the first year of therapy but usually manifests within 6 weeks of initiation, with a median of 11 days. Definitive therapy consists of discontinuation of the drug, and rechallenge is associated with profound worsening of symptoms and increased mortality.27 Abacavir is not metabolized by cytochrome P450 enzymes and has no effects on these enzymes. The manufacturer’s insert states that it is metabolized by alcohol dehydrogenase and glucuronyl transferase to inactive metabolites (Ziagen威 package insert, GlaxoSmithKline, Research Triangle Park, N.C., 2002). Didanosine Didanosine (ddI, Videx威) is generally well tolerated. However, two significant toxicities have been described: pancreatitis and peripheral neuropathy. The incidence of both is dose-related. Risk factors for pancreatitis include a previous history of pancreatitis, coinfection with cytomegalovirus or Mycobacterium avium-intracellulare, and concomitant use of stavudine, pentamidine, trimethoprim/ sulfamethoxazole (Septra威, Bactrim威),28 or tenofovir disoproxil fumarate.29 Concurrent use of either hydroxyurea or ethanol similarly increases the risk for pancreatitis.30 Neuropathy may present as an optic neuritis, sometimes with concomitant retinal depigmentation. Patients taking didanosine should undergo retinal examination every 6–12 months.31 http://psy.psychiatryonline.org

525

Med-Psych Drug-Drug Interactions As with other NRTIs, there are a number of significant drug interactions with didanosine. Didanosine is inactivated in an acidic environment, so it is formulated with a buffer (Videx威 package insert, Bristol-Myers Squibb Company, Princeton, N.J., 2003). Drugs that need an acidic pH for absorption (ketoconazole, itraconazole, dapsone, and pyrimethamine but not fluconazole) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine.32 Drugs that may potentiate the toxic effects of didanosine, especially mitochondrial toxicity, include other NRTIs, protease inhibitors, and ribavirin. Ribavirin is an antiviral medication used to treat hepatitis C. It also interferes with human DNA polymerase gamma and mitochondrial replication. There have been reports of pancreatitis and at least one case of fatal lactic acidosis with this combination.33 Tenofovir disoproxil fumarate, another NRTI, has been found to dramatically affect the metabolism of didanosine, with severe toxicity. Peripheral cell-based metabolism (erythrocytes, lymphocytes, granulocytes) of didanosine may be dependent upon purine nucleoside phosphorylase, which may be inhibited by allopurinol, ganciclovir, and tenofovir disoproxil fumarate.22,23 The combination of tenofovir disoproxil fumarate with didanosine, despite providing for adequate viral suppression, may actually reduce CD counts by increasing exposure to didanosine in plasma,4 leading to lymphocyte toxicity. These interactions are currently under further study.34

Lamivudine Lamivudine (3TC, Epivir威) has been approved by the U.S. Food and Drug Administration for the treatment of both HIV and HBV infection. Studies have demonstrated an unequivocal benefit to combination therapy with zidovudine (AZT) and lamivudine compared with monotherapy with either drug, thus ushering in the era of combination drug therapy for HIV.36 Lamivudine is generally well tolerated, with side effects similar to those commonly reported with other NRTIs. Like stavudine, lamivudine can be taken with food but should not be co-administered with either ribavirin or trimethoprim/sulfamethoxazole (Septra威, Bactrim威).32 Stavudine Stavudine (d4T, Zerit威), a thymidine analogue, is generally well tolerated, with side effects similar to those of zidovudine (AZT). The most significant adverse reaction is peripheral neuropathy, with an overall prevalence of about 14%. However, the prevalence increases with a declining CD4 count or coadministration with other potentially neurotoxic drugs.37 The combination of stavudine and zidovudine should be avoided. Both are thymidine analogues and compete for thymidine kinase for intracellular phosphorylation to their active forms. Stavudine should not be administered with either ribavirin or trimethoprim/sulfamethoxazole (Septra威, Bactrim威).38 Unlike some of the other NRTIs, stavudine absorption is unaffected by meals and can be taken with food.

Emtricitabine

Tenofovir Disoproxil Fumarate

Emtricitabine (Emtriva威), a cytosine analogue, is the newest of the NRTI drugs. A role as an antihepatitis B virus (HBV) drug is being studied after HIV/HBV co-infected patients were found to have exacerbation of their hepatitis following discontinuation of emtricitabine. Emtricitabine was well tolerated in clinical trials prior to its release. Most adverse events were consistent with the NRTI class and mild to moderate in intensity. Moreover, emtricitabinebased regimens were as well tolerated as those with lamivudine and better tolerated than those with stavudine.35 Emtricitabine has no currently known phase I (glucuronidation) or phase II (cytochrome P450 and others) interactions. There is a paucity of known significant drug interactions. Emtricitabine may be taken with or without food (Emtriva威 package insert, Gilead Sciences, Foster City, Calif., 2004).

Tenofovir disoproxil fumarate (Viread威) is an analogue of adenosine 5⬘-monophosphate, which is phosphorylated to the active tenofovir diphosphate. It has a longer serum half-life than most other NRTIs, so it has a oncedaily dosing. Tenofovir disoproxil fumarate is not a substrate, inhibitor, or inducer of the P450 system, and is renally excreted. Adverse reactions are relatively uncommon, and nausea is the most often reported symptom (Viread威 package insert, Gilead Sciences, Foster City, Calif., Oct. 26, 2001). It has the aforementioned interactions with didanosine and also has potential interactions with atazanavir.39,40 Since the kidneys primarily eliminate tenofovir, coadministration with nephrotoxic drugs (e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, and valganciclovir) may increase serum tenofovir disoproxil fumarate concentra-

526

http://psy.psychiatryonline.org

Psychosomatics 45:6, November-December 2004

Med-Psych Drug-Drug Interactions tions as well as serum levels of the coadministered drugs. There have been case reports of renal tubular injury with the use of tenofovir, perhaps most prevalent in patients with low body weight.41 The bioavailability of tenofovir disoproxil fumarate is increased in the presence of a high fat (40%–50%) diet, and the drug should be taken with food. Again, studies demonstrate a high rate of virologic nonresponse with a regimen consisting of abacavir, lamivudine, and tenofovir, and the manufacturer recommends avoiding this combination.39 Zalcitabine Like didanosine, the major toxicities associated with zalcitabine (ddC, Hivid威) are pancreatitis and peripheral neuropathy, and as with didanosine, peak plasma concentrations of zalcitabine are decreased if taken with food. The side effects are similar to those of the other NRTI drugs. However, transient stomatitis occurs in up to 70% of patients taking zalcitabine.42 Relative to other NRTIs, there are few clinically significant drug interactions with zalcitabine. Antacids and metoclopramide (Reglan威) may reduce absorption, whereas doxorubicin and lamivudine impair in vitro phosphorylation from zalcitabine to the active metabolite ddCTP.2 Additionally, ribavirin may increase the risk of lactic acidosis. Zalcitabine is excreted relatively unchanged by the kidneys, and coadministration with nephrotoxic drugs (e.g., amphotericin and aminoglycoside antibiotics) may interfere with renal excretion. Neurotoxic drugs (e.g., isoniazid, phenytoin, cisplatin) should also be avoided to minimize the risk of peripheral neuropathy. Finally, it is recommended not to combine zalcitabine with didanosine, stavudine, or lamivudine because of overlapping toxicities. Zidovudine Zidovudine (AZT, Retrovir威), or 3⬘-azido-3⬘-deoxythymidine, was the first antiretroviral drug approved for the treatment of HIV infection. Its effectiveness has been hampered by rapid acquisition of viral resistance. Presently, the two indicated uses of AZT are 1) management of HIV infection in combination with at least two other antiretroviral drugs, and 2) monotherapy in the prevention of maternal-fetal HIV transmission. AZT is generally well tolerated. The most commonly reported side effects include headache, fever, rash, and gastrointestinal complaints (usually nausea). In addition to the toxicities found with all the aforementioned NRTIs, the use of AZT may lead to hematologic toxicity (granulocytopenia, anemia, pancytoPsychosomatics 45:6, November-December 2004

penia). It is estimated that 60%–80% of AZT is eliminated via glucuronidation, primarily by UDP-glucuronosyltransferase (UGT) 2B7 to AZT-glucuronide43,44—also called 5⬘glucuronosyl zidovudine—and to a lesser degree to the myelotoxic 3⬘-amino-3⬘deoxythymidine (AMT) by reduction of the azide to an amide.45 Zidovudine is so specific to UGT 2B7 that it is now used as a drug probe for this enzyme.46 AZT metabolism may be inhibited (have its activity reduced) by drugs that inhibit glucuronidation, which may increase the serum concentration of AZT and lead to increased risk of side effects and toxicity. Antoniou et al.47 reported that a patient on a stable HAART regimen that included AZT developed severe anemia after introduction of valproic acid for complex partial seizures (valproic acid is a known inhibitor of several UGT enzymes48). In a within-subject study of recently detoxified heroin-addicted patients with HIV disease, McCance-Katz et al.49 confirmed that methadone treatment increased oral and intravenous serum levels of AZT, placing patients on both drugs at increased risk of zidovudine toxicity. Other UGT inhibitors, such as fluconazole and atovaquone, have been found to increase plasma levels of zidovudine.50–52 In vitro studies using human liver microsomes have determined that many drugs may inhibit the production of myelotoxic AMT, and that ethacrynic acid, dipyridamole, and indomethacin may increase the formation of AMT, possibly at cytochrome b5, a minor human cytochrome. These findings have not been reproduced in vivo or reported clinically.44,45,53 Gallicano et al.54 studied rifampin induction of AZT metabolism in eight asymptomatic HIVinfected patients. Fourteen days of coadministration with rifampin significantly increased or induced AZT glucuronidation and amination pathways, resulting in decreased plasma and urine exposures to AZT. Of interest is that AMT plasma exposure decreased. The authors report that induction was greater for the major metabolite 5⬘glucuronosyl zidovudine than for AMT. NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS There are currently three approved NNRTIs: delavirdine, nevirapine, and efavirenz. Like NRTIs, NNRTIs target HIV reverse transcriptase. However, the mechanism of action is different.55 Whereas the NRTIs are nucleotide analogues competing for incorporation into the HIV genome, the NNRTIs block complementary DNA elongation by binding directly and noncompetitively to the enzyme. This effects a conformational change in the protein at its active site, http://psy.psychiatryonline.org

527

Med-Psych Drug-Drug Interactions decreasing affinity for nucleoside binding. NNRTIs do not require intracellular phosphorylation to become active and inhibit HIV-1. Their antiviral potency and tolerability make the NNRTIs a favorable component of HAART regimens, and toxicities and viral cross-resistance do not overlap with the NRTIs.3 The most frequently reported adverse effects are mild rash,56,57 asymptomatic elevation of liver enzymes58, and fat redistribution.59 Despite different chemical structures and pharmacokinetics, NNRTIs share a similar mechanism of action, and all are metabolized to some degree by cytochrome P450 enzymes. In addition, they act as either inhibitors or inducers of cytochrome P450 enzymes, thus affecting the metabolism of other drugs. For a fully detailed status report on the NNRTIs including effectiveness, structural and viral mechanisms, dosing schedules, and viral resistance patterns (with excellent tables), please refer to Balzarini.3 Delavirdine Delavirdine (Rescriptor威) is associated with a maculopapular rash but rarely as severe or frequent as with nevirapine. Headache, gastrointestinal difficulties, and elevations in liver-associated enzymes also occur. Delavirdine is metabolized by CYP450 3A4 in vivo, with in vitro data for CYP2D6. Delavirdine potently inhibits CYP450 3A4, thus inhibiting the metabolism of other drugs metabolized there (e.g., clarithromycin [Biaxin威], protease inhibitors, HMG-CoA reductase inhibitors [“statins”], sildenafil [Viagra威], triazolobenzodiazepines56,60) and raises the serum levels of these drugs. In vitro studies show that delavirdine also inhibits CYP2C9 and CYP2C19.61 The metabolism of delavirdine can be inhibited as well, leading to greater serum concentrations of the drug as well as potentially intensifying noxious side effects such as nausea, vomiting, and diarrhea. Ketoconazole is a potent CYP3A4 inhibitor and has increased concentrations of delavirdine.62 Most protease inhibitors are potent inhibitors of CYP3A4 and may also raise levels of delavirdine when coadministered.63 Conversely, medications such as rifabutin and rifampin, St. John’s wort, ritonavir (Norvir威), and modafinil (Provigil威) all induce CYP3A4, which may result in greater metabolic efficiency and lower serum levels of delavirdine.64 Finally, it should be noted that antacids decrease delavirdine absorption, so dosing of NNRTIs and antacids should be at least an hour apart.60 Efavirenz Efavirenz (Sustiva威) is associated with greater side effects and toxicities than the other NNRTIs and has a more 528

http://psy.psychiatryonline.org

complicated drug interaction profile. Fontas et al.65 reported that their patients receiving NNRTIs had higher levels of total cholesterol and low-density lipoprotein cholesterol than did antiretroviral-naive patients. The patients receiving efavirenz had higher levels of total cholesterol and triglycerides than those receiving nevirapine. Neuropsychiatric side effects have also been seen with efavirenz. Lochet et al.66 evaluated neuropsychiatric symptoms in subjects taking efavirenz in a prospective, multicenter survey study. They found that sleep disturbances were the most common complaint in their 174 subjects. Neuropsychiatric complaints also included impaired concentration and memory, anxiety, sadness (19.3%), and suicidal ideations (9.2%). Twenty-three percent of patients rated their global neuropsychiatric discomfort as moderate to severe after 3 months of treatment. Fumaz et al.67 in a randomized, prospective, two-arm controlled study compared quality of life and neuropsychiatric side effects in patients receiving an efavirenz-containing regimen versus a group whose treatment did not include efavirenz. They found that the group receiving an efavirenz-containing regimen reported a better quality of life, particularly because their regimen was easier. They found, however, that 13% of their patients reported “character change” (mood swings, melancholy, and irritability) at week 48. In our clinic, patients with a previous history of mood disorders often have a worsening of their symptoms at the onset of efavirenz treatment, a minority of them unable to tolerate the medication because of neuropsychiatric side effects. We provide a psychiatric assessment of all patients with a previous history of psychiatric disorder before initiation of efavirenz, and most efavirenz-treated patients are followed for at least 6 months after initiation of efavirenz to monitor for neuropsychiatric symptoms that might worsen their adherence and quality of life. Patients with a previous history of mood disorder are informed of the risk of recurrence with efavirenz and often are cotreated with therapy and antidepressants if efavirenz is absolutely warranted. Efavirenz is metabolized at CYP3A4 and CYP2B6. Whereas in vivo, efavirenz is an inducer of CYP3A4, it also inhibits CYP3A4, 2C9, 2C19, 2D6, and 1A2 in vitro (the latter two only weakly) (Sustiva威 package insert, BristolMyers Squibb Company, Princeton, N.J., 2002).61 Concomitant use with CYP3A4-dependent drugs with narrow therapeutic windows warrants caution. Drugs such as tricyclic antidepressants, antiarrhythmics, or triazolobenzodiazepines may initially require lower dosing when taken with efavirenz because of efavirenz’s inhibition of CYP3A4. Induction may then lead to decreased levels of Psychosomatics 45:6, November-December 2004

Med-Psych Drug-Drug Interactions the CYP 3A4-dependent medications, requiring increased dosages of them at a later date. In one study it was demonstrated that CYP 3A4 induction by efavirenz reached full magnitude on day 10 of administration.68 Efavirenz is often used in combination with protease inhibitors and can induce or increase their metabolism, bringing plasma levels below therapeutic ranges. Efavirenz can decrease amprenavir levels 1–2 weeks after efavirenz initiation.69 It is fortunate that this effect can be reversed with the addition of protease inhibitors that inhibit 3A4. Efavirenz induces metabolism of all protease inhibitors except nelfinavir and ritonavir. In a study of 11 patients receiving methadone therapy, efavirenz resulted in an over 50% decrease in methadone area under the curve after only 24 hours of efavirenz administration. This led to nine patients complaining of withdrawal symptoms beginning on day 8 of efavirenz treatment.70 Efavirenz can also be induced by the usual potent CYP 3A4 inducers: phenytoin, carbamazepine, alcohol, rifamycins, St. John’s wort, and barbiturates. Rifampin and rifapentine induce the metabolism of protease inhibitors and NNRTIs and can decrease serum concentrations, leading to viral resistance (decreased sensitivity of the virus). Nevirapine Seventeen percent (17%) of patients treated with nevirapine (Viramune威) develop a maculopapular rash within the first 6 weeks, and several cases of Stevens-Johnson syndrome have been reported.3 Other, less frequently reported side effects include hepatitis, gastrointestinal complaints, fatigue, depression, and headache.71 Nevirapine is an inducer of CYP3A4 as well. Because this enzyme metabolizes the protease inhibitors, the concomitant use of nevirapine and protease inhibitors typically requires dose modification. For example, studies show significant reductions of plasma saquinavir and indinavir concentrations when coadministered with nevirapine.72,73 However, this induction is compensated for by coadministration of ritonavir.74 Some other commonly prescribed CYP3A4 substrates that have the potential for drug-drug interactions with nevirapine include methadone (nevirapine effects a decreased plasma concentration of methadone75), certain HMG-CoA reductase inhibitors (excluding pravastatin and fluvastatin, which are metabolized by alternate cytochrome enzymes76), and oral contraceptives (oral contraceptive concentrations are reduced in the presence of nevirapine77). Because nevirapine is also a substrate of CYP3A4, it induces its own metabolism as well. Therefore, nevirapine Psychosomatics 45:6, November-December 2004

doses are escalated upon initiation of therapy (the current recommended schedule is 200 mg/day for 14 days then 200 mg twice per day). Nevirapine serum levels may also be reduced by other medications that induce CYP3A4, including St. John’s wort, the rifamycins, and troglitazone.78,79 CELL MEMBRANE FUSION INHIBITORS Fusion inhibitors such as enfuvirtide (Fuzeon威) are the newest class of antiretroviral drugs. Fusion inhibitors prevent the conformational changes that are necessary for the fusion of virions to host cells.80,81 It is a synthetic peptide derived from a naturally occurring amino acid sequence in viral membrane proteins. Because of the complicated production, cost, and need for subcutaneous injections, it is currently used in treatment-experienced patients, generally those who have failed traditional antiretroviral combinations. The most frequent and disturbing complication with this treatment is injection-site reactions, most of which resolve on their own and do not interfere with continuation for most patients. Patients are encouraged to rotate injection sites, but the need for injections may affect adherence.82 It is expected that since it is a peptide, it is metabolized in the liver and kidneys by peptidases, with recycling of the amino acids. In vitro studies indicate that there are no cytochrome P450 interactions, and clinical trials with potent P450 inhibitors and inducers such as the protease inhibitors, NNRTIs like efavirenz and nevirapine, and rifampin revealed no clinically significant interactions.80 Zhang et al.83 conducted an open-label, onesequence crossover study in 12 HIV-infected patients. They assessed clinical interactions between five probe drugs and enfuvirtide and found no clinically significant P450 interactions. SUMMARY Antiretroviral drugs have dramatically changed the survival rate for patients with HIV/AIDS. They are also a complicated group of medications with significant side effects, toxicities, and drug interactions. NRTIs have no CYP 450 interactions. NRTIs are subject to interactions of absorption and glucuronidation. NRTIs have serious side effects and toxicities, which are additive with other similar drugs. NNRTIs are metabolized by P450 enzymes and are subject to P450 interactions, being substrates as well as inhibitors and inducers of those metabolic enzymes themselves. NNRTIs have their own significant side effect and http://psy.psychiatryonline.org

529

Med-Psych Drug-Drug Interactions toxicity profiles. Table 1 and Table 2 summarize the metabolism and significant side effect/toxicities of the NRTIs and NNRTIs. Non-HIV specialists will encounter patients TABLE 1.

receiving antiretrovirals and will be faced with assisting with the life-changing complications these drugs cause in HIV/AIDS patients.

Metabolism of Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs) and Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Drug Name NRTIs Abacavir (Ziagen威) Didanosine (ddI, Videx威) Emtricitabine (Emtriva威) Lamivudine (3TC, Epivir威) Stavudine (d4T, Zerit威) Tenofovir disoproxil fumarate (Viread威) Zalcitabine (ddC, Hivid威) Zidovudine (AZT, Retrovir威) NNRTIs Delavirdine (Rescriptor威) Efavirenz (Sustiva威) Nevirapine

Metabolism Site

Enzymes Inhibited

Enzymes Induced

Alcohol dehydrogenase, glucuronyl transferase Purine nucleoside phosphorylase Full recovery in urine and feces Minimal metabolism Not yet known Renal Renal UGT 2B7, CYP450 b5

None known Unknown None known None known None known 1A2a

None known Unknown None known None known None known None known

3A4, 2D6a, 2C9b, 2C19b 3A4, 2B6 3A4, 2B6

None known 3A4c, 2C9a, 2D6a, 2C19a 3A4c, 2C9a, 2C19a, 2D6a, 1A2a None known

None known 3A4d, 2B6e 3A4d, 2B6d

a

Inhibited in vitro. Minor Pathway. c Potent. d Moderate. e Mild. b

530

http://psy.psychiatryonline.org

Psychosomatics 45:6, November-December 2004

Psychosomatics 45:6, November-December 2004

TABLE 2.

Side Effects, Toxicities, and Potential Drug Interactions of Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs) and Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Drug Name

Typical Dosing Regimen

Food and Drink Considerations

NRTIs In general

300 mg b.i.d.

With or without food

Didanosine (ddI, Videx威, Videx EC威 [enteric coated])

200 mg b.i.d. if ⱖ 60 kg Take on an empty stomach 125 mg b.i.d. if ⬍ 60 kg Do not crush or chew EC tablets EC: 400 mg/day if ⱖ 60 kg EC: 250 mg/day if ⬍ 60 kg

Emtricitabine (Emtriva威)

200 mg/day

None

Lamivudine (3TC, Epivir威)

300 mg/day 150 mg b.i.d.

With or without food

Stavudine (d4T, Zerit威)

40 mg b.i.d. if ⱖ 60 kg 30 mg b.i.d. if ⬍ 60 kg

With or without food

Hepatomegaly with steatosis Lactic acidosis Lipodystrophy Myopathy Pancreatitis Peripheral neuropathy Abacavir hypersensitivity reaction (rechallenge is contraindicated) Optic neuritis and retinal depigmentation Pancreatitis Peripheral neuropathy

Allopurinol Dapsonea Delavirdine Ganciclovir Itraconazolea Ketoconazolea Methadone Pyrimethaminea Quinolonesb Ribavirin Stavudine Tenofovir Tetracyclinesb Trimethoprim/sulfamethoxazole

Discontinuation in hepatitis B virus infected persons may exacerbate hepatitis Generally well tolerated Ribavirin Trimethoprim/sulfamethoxazole Zalcitabinec Peripheral neuropathy (increased risk with Didanosine didanosine) Ribavirin Trimethoprim/sulfamethoxazole Zidovudined

Tenofovir disoproxil fumarate (Viread威) 300 mg/day

High fat meals increase bioavailability Nausea

Zalcitabine (ddC, Hivid威)

Do not take with antacids

0.750 mg/8 hours

Potential Interactions

Pancreatitis Peripheral neuropathy Stomatitis

Atazanavir Didansosinee Antacidsf Didanosine Doxorubicin Lamivudine Metoclopramidef Ribavirin Stavudine

531

Med-Psych Drug-Drug Interactions

http://psy.psychiatryonline.org

Abacavir (Ziagen威)

Major Side Effects/Toxicities

Side Effects, Toxicities, and Potential Drug Interactions of Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs) and Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) (continued )

Zidovudine (AZT, Retrovir威)

http://psy.psychiatryonline.org

200 mg t.i.d. 300 mg b.i.d.

With or without food

NNRTIs In general

Anemia Granulocytopenia Headache Gastrointestinal complaints Pancytopenia

Rash Asymptomatic elevation of liver associated enzymes Fat redistribution See ‘‘in general’’

Psychosomatics 45:6, November-December 2004

Delavirdine (Rescriptor威)

400 mg t.i.d.

With or without food

Efavirenz (Sustiva威)

600 mg/day

Take on an empty stomach, preferably at bedtime

CNS (insomnia, vivid dreams, depression, euphoria, confusion, agitation, amnesia, hallucinations, stupor, altered cognition)

Nevirapine (Viramune威)

200 mg/day initially, then 200 mg b.i.d.

High fat foods increase bioavailability

Hepatotoxicity

a

Drug that requires an acidic pH for absorption and thus should not be coadministered with didanosine, which is buffered with an antacid. Antibiotic that would be chelated by didanosine’s buffered formulation. c Lamivudine and zalcitabine may inhibit each other’s intracellular phosphorylation, worsening toxicity, and should not be coadministered. d Zidovudine may inhibit the intracellular phosphorylation of stavudine, worsening toxicity, and should not be coadministered. e Take tenofovir 2 hours before or 1 hour after didanosine. f Decrease absorption of zalcitabine. g Increase zidovudine levels and toxicity. h Decrease zidovudine levels. i Increase hematologic toxicity. b

Atovaquoneg Fluconazoleg Gancicloviri Methadone Rifampinh Ritonavirh Valproic acidg

Atorvastatin Calcium channel blockers Ergots Lovastatin Pimozide Triazolobenzodiazepines St. John’s wort Phenobarbital Phenytoin Rifampin Atorvastatin Carbamazepine Ergots Lovastatin Pimozide Phenobarbital Phenytoin Rifampin St. John’s wort Antiarrhythmics Beta-blockers Cyclosporine Protease inhibitors St. John’s wort Tacrolimus

Med-Psych Drug-Drug Interactions

532

TABLE 2.

Med-Psych Drug-Drug Interactions

References

1. Sir William Osler: Aphorisms From His Bedside Teachings and Writings. Collected by Bean RB; edited by Bean WB. New York, Henry Schuman, 1950 2. Hoggard PG, Sales SD, Kewn S, Sunderland D, Khoo SH, Hart CA, Back DJ: Correlation between intracellular pharmacological activation of nucleoside analogues and HIV suppression in vitro. Antivir Chem Chemother 2000; 11:353–358 3. Balzarini J: Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1. Curr Top Med Chem 2004; 4:921–944 4. Moyle G: Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther 2000; 22:911–939 5. Fromenty B, Pessayre D: Impaired mitochondrial function in microvesicular steatosis: effects of drugs, ethanol, hormones and cytokines. J Hepatol 1997; 26(suppl 2):43–53 6. Martin AM, Hammond E, Nolan D, Pace C, Den Boer M, Taylor L, Moore H, Martinez OP, Christiansen FT, Mallal S: Accumulation of mitochondrial DNA mutations in human immunodeficiency virus-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. Am J Hum Genet 2003; 72:549– 560; correction, 72:1358 7. Moyle GJ, Sadler M: Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Drug Saf 1998; 6:481–494 8. Simpson DM, Tagliati M: Nucleoside analogue-associated peripheral neuropathy in human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 9:153–161 9. Gold R, Meurers B, Reichmann H: Mitochondrial myopathy caused by long-term zidovudine therapy (letter). N Engl J Med 1990; 323:994 10. d’Amati G, Kwan W, Lewis W: Dilated cardiomyopathy in a zidovudine-treated AIDS patient. Cardiovasc Pathol 1992; 1:317–320 11. Simpson DM, Citak KA, Godfrey E, Godbold J, Wolfe DE: Myopathies associated with human immunodeficiency virus and zidovudine: can their effects be distinguished? Neurology 1993; 43:971–976 12. de la Asuncion JG, del Olmo ML, Sastre J, Millan A, Pellin A, Pallardo FV, Vina J: AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria: prevention by antioxidant vitamins. J Clin Invest 1998; 102:4–9 13. Carr A: Lactic acidemia in infection with human immunodeficiency virus. Clin Infect Dis 2003; 36(suppl 2):S96–S100 14. Claessens YE, Cariou A, Monchi M, Soufir L, Azoulay E, Rouges P, Goldgran-Toledano D, Branche F, Dhainaut JF: Detecting lifethreatening lactic acidosis related to nucleoside-analog treatment of human immunodeficiency virus-infected patients, and treatment with L-carnitine. Crit Care Med 2003; 31:1042–1047 15. Kakuda TN: Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000; 22:685–708 16. Carr A, Miller J, Law M, Cooper DA: A syndrome of lipoatrophy, lactic acidemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 2000; 14:F25–F32 17. Brinkman K, Smeitink JA, Romijn JA, Reiss P: Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapyrelated lipodystrophy. Lancet 1999; 354:1112–1115 18. Ammassari A, Antinori A, Cozzi-Lepri A, Trotta MP, Nasti G,

Psychosomatics 45:6, November-December 2004

Ridolfo AL, Mazzotta F, Wu AW, d’Arminio Monforte A, Galli M (AdICoNA Study Group): Relationship between HAART adherence and adipose tissue alterations. J Acquir Immune Defic Syndr 2002; 31(suppl 3):S140–S144 19. Gallicchio VS, Hughes NK, Tse KF: Comparison of dideoxynucleoside (DDI and zidovudine) and induction of hematopoietic toxicity using normal human bone marrow cells in vitro. Int J Immunopharmacol 1993; 15:263–268 20. Freund YR, Dabbs J, Creek MR, Phillips SJ, Tyson CA, MacGregor JT: Synergistic bone marrow toxicity of pyrimethamine and zidovudine in murine in vivo and in vitro models: mechanism of toxicity. Toxicol Appl Pharmacol 2002; 181:16–26 21. Simdon J, Watters D, Bartlett S, Connick E: Ototoxicity associated with use of nucleoside analog reverse transcriptase inhibitors: a report of 3 possible cases and review of the literature. Clin Infect Dis 2001; 32:1623–1627 22. Ray AS, Olson L, Fridland A: Role of purine nucleoside phosphorylase in interactions between 2⬘3⬘-dideoxyinosine and allopurinol, gancyclovir, or tenofovir. Antimicron Agents Chemother 2004; 48:1089–1095 23. Boelaert JR, Dom GM, Huitema AD, Beijnen JH, Lange JM: The boosting of didanosine by allopurinol permits a halving of the didanosine dosage (letter). AIDS 2002; 16:2221–2223 24. Ruane PJ, Parenti DM, Margolis DM, Shepp DH, Babinchak TJ, Van Kempen AS, Kauf TL, Danehower SA, Yau L, Hessenthaler SM, Goodwin D, Hernandez JE (COL30336 Study Team): Compact quadruple therapy with the lamivudine/zidovudine combination tablet plus abacavir and efavirenz, followed by the lamivudine/zidovudine/abacavir triple nucleoside tablet plus efavirenz in treatment-naive HIV-infected adults. HIV Clin Trials 2003; 4:231–243 25. Moyle GJ, Baldwin C, Langroudi B, Mandalia S, Gazzard BG: A 48-week, randomized, open-label comparison of three abacavirbased substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. J Acquir Immune Defic Syndr 2003; 33:22–28 26. John M, McKinnon EJ, James IR: Randomized, controlled, 48-week study of switching stavudine and/or protease inhibitors to Combivir/ abacavir to prevent or reverse lipoatrophy in HIV-infected patients. J Acquir Immune Defic Syndr 2003; 33:29–33 27. Clay PG: The abacavir hypersensitivity reaction: a review. Clin Ther 2002; 24:1502–1514 28. Grasela TH, Walawander CA, Beltangady M, Knupp CA, Martin RR, Dunkle LM, Barbhaiya RH, Pittman KA, Dolin R, Valentine FT, et al: Analysis of potential risk factors associated with the development of pancreatitis in phase I patients with AIDS or AIDS-related complex receiving didanosine. J Infect Dis 1994; 169:1250–1255 29. Blanchard JN, Wohlfeiler M, Canas A, King K, Lonergan JT: Pancreatitis with didanosine and tenofovir disoproxil fumarate. Clin Infect Dis 2003; 37:e57–e62; correction, 37:995 30. Rossero R, Asmuth DM, Grady JJ, McKinsey DS, Green S, Andron L, Pollard RB: Hydroxyurea in combination with didanosine and stavudine in antiretroviral-experienced HIV-infected subjects with a review of the literature. Int J STD AIDS 2003; 14:350–355 31. Cobo J, Ruiz MF, Figueroa MS, Antela A, Quereda C, Perez-Elias MJ, Corral I, Guerrero A: Retinal toxicity associated with didanosine in HIV-infected adults (letter). AIDS 1996; 10:1297–3000 32. Taburet AM, Singlas E: Drug interactions with antiretroviral drugs. Clin Pharmacokinet 1996; 30:385–401

http://psy.psychiatryonline.org

533

Med-Psych Drug-Drug Interactions 33. Butt AA: Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine therapy. AIDS Read 2003; 13:344–348 34. Negredo E, Molto J, Burger D, Viciana P, Ribera E, Paredes R, Juan M, Ruiz L, Puig J, Pruvost A, Grassi J, Masmitja E, Clotet B: Unexpected CD4 count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load. AIDS 2004; 18:459–463 35. Bang LM, Scott LJ: Emtricitabine: an antiretroviral agent for HIV infection. Drugs 2003; 63:2413–2424 36. Eron J, Benoit S, Jemsek J, MacArthur RD, Santana J, Quinn JB, Kuritzkes DR, Fallon MA, Rubin M (North American HIV Working Party): Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4Ⳮ cells per cubic millimeter. N Engl J Med 1995; 333:1662–1669 37. Spruance SL, Pavia AT, Mellors JW, Murphy R, Gathe J Jr, Stool E, Jemsek JG, Dellamonica P, Cross A, Dunkle L (Bristol-Myers Squibb Stavudine 019 Study Group): Clinical efficacy of monotherapy with stavudine compared with zidovudine in HIV-infected, zidovudine experienced patients: a randomized, double-blind, controlled trial. Ann Intern Med 1997; 126:355–363 38. Lea AP, Faulds D: Stavudine: a review of its pharmacodynamic and pharmacokinetic properties and clinical potential in HIV infection. Drugs 1996; 51:846–864 39. Kearney BP, Flaherty JF, Shah J: Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet 2004; 43:595–612 40. Grim SA, Romanelli F: Tenofovir disoproxil fumarate. Ann Pharmacother 2003; 37:849–859 41. Peyriere H, Reynes J, Rouanet I, Daniel N, de Boever CM, Mauboussin JM, Leray H, Moachon L, Vincent D, Salmon-Ceron D: Renal tubular dysfunction associated with tenofovir therapy: report of 7 cases. J Acquir Immune Defic Syndr 2004; 35:269–273 42. McNeely MC, Yarchoan R, Broder S, Lawley TJ: Dermatologic complications associated with administration of 2⬘,3⬘-dideoxycytidine in patients with human immunodeficiency virus infection. J Am Acad Dermatol 1989; 21:1213–1217 43. Barbier O, Turgeon D, Girard C, Green MD, Tephly TR, Hum DW, Belanger A: 3⬘-Azido-3⬘deoxythymidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7). Drug Metab Dispos 2000; 28:497–502 44. Placidi L, Cretton EM, Placidi M, Sommadossi JP: Reduction of 3⬘-azido-3⬘deoxythymidine to 3⬘-amino-3⬘deoxythymidine in human liver microsomes and its relationship to cytochrome P450. Clin Pharmacol Ther 1993; 54:168–176 45. Fayz S, Inaba T: Zidovudine azido-reductase in human liver microsomes: activation by ethacrynic acid, dipyridamole, and indomethacin and inhibition by human immunodeficiency virus protease inhibitors. Antimicrob Agents Chemother 1998; 42:1654– 1648 46. Court MH, Krishnaswamy S, Hao Q, Duan SX, Patten CJ, Von Moltke LL, Greenblatt DJ: Evaluation of 3⬘-azido-3⬘deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: specificity and influence of the UGT2B7*2 polymorphism. Drug Metab Dispos 2003; 31:1125–1133 47. Antoniou T, Gough K, Yoong D, Arbess G: Severe anemia secondary to a probable drug interaction between zidovudine and valproic acid. Clin Infect Dis 2004; 38:e38–e40 48. Ethell BT, Anderson GD, Burchell B: The effect of valproic acid on drug and steroid glucuronidation by expressed human UDPglucuronosyltransferases. Biochem Pharmacol 2003; 65:1441– 1449 49. McCance-Katz EF, Rainey PM, Jatlow P, Friedland G (AIDS

534

http://psy.psychiatryonline.org

Clinical Trials Group 262): Methadone effects on zidovudine disposition. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18:435–443 50. Brockmeyer NH, Tillmann I, Mertins L, Barthel B, Goos M: Pharmacokinetic interaction of fluconazole and zidovudine in HIVpositive patients. Eur J Med Res 1997; 2:377–383 51. Sahai J, Gallicano K, Pakuts A, Cameron DW: Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus. J Infect Dis 1994; 169:1103–1107 52. Trapnell CB, Klecker RW, Jamis-Dow C, Collins JM: Glucuronidation of 3⬘-azido-3⬘-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. Antimicrob Agents Chemother 1998; 42:1592–1596 53. Pan-Zhou XR, Cretton-Scott E, Zhou ZJ, Yang MX, Lasker JM, Sommadossi JP: Role of human liver P450s and cytochrome b5 in the reductive metabolism of 3⬘-azido-3⬘deoxythymidine (AZT) to 3⬘-amino-3⬘deoxythymidine. Biochem Pharmacol 1998; 55: 757–766 54. Gallicano KD, Sahai J, Shukla VK, Seguin I, Pakuts A, Kwok D, Foster BC, Cameron DW: Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV-infected patients. Br J Clin Pharmacol 1999; 48:168–179 55. De Clercq E: The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res 1998; 38:153–179 56. Scott LJ, Perry CM: Delavirdine: a review of its use in HIV infection. Drugs 2000; 60:1411–1444 57. Bardsley-Elliot A, Perry CM: Nevirapine: a review of its use in the prevention and treatment of paediatric HIV infection. Paediatr Drugs 2000; 2:373–407 58. Dieterich DT, Robinson PA, Love J, Stern JO: Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. Clin Infect Dis 2004; 38(suppl 2):S80–S89 59. Adkins JC, Noble S: Efavirenz. Drugs 1998; 56:1055–1066 60. Tran JQ, Gerber JG, Kerr BM: Delavirdine: clinical pharmacokinetics and drug interactions. Clin Pharmacokinet 2001; 40:207– 226 61. Von Moltke LL, Greenblatt DJ, Granda BW, Giancarlo GM, Duan SX, Daily JP, Harmatz JS, Shader RI: Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol 2001; 41:85–91 62. Tseng AL, Foisy MM: Management of drug interactions in patients with HIV. Ann Pharmacother 1997; 31:1040–1058 63. Smith PF, DiCenzo R, Morse GD: Clinical pharmacokinetics of non-nucleoside reverse transcriptase inhibitors. Clin Pharmacokinet 2001; 40:893–905 64. Cozza KL, Armstrong SC, Oesterheld J: Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-Glycoproteins, 2nd ed. Arlington, Va, American Psychiatric Publishing, 2003, pp 107, 234 65. Fontas E, van Leth F, Sabin CA, Friis-Moller N, Rickenbach M, d’Arminio Monforte A, Kirk O, Dupon M, Morfeldt L, Mateu S, Petoumenos K, El-Sadr W, de Wit S, Lundgren JD, Pradier C, Reiss P (D:A:D Study Group): Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles? J Infect Dis 2004; 189:1056–1074 66. Lochet P, Peyriere H, Lotthe A, Mauboussin JM, Delmas B, Reynes J: Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Med 2003; 4:62–66 67. Fumaz CR, Tuldra A, Ferrer MJ, Paredes R, Bonjoch A, Jou T, Negredo E, Romeu J, Sirera G, Tural C, Clotet B: Quality of life,

Psychosomatics 45:6, November-December 2004

Med-Psych Drug-Drug Interactions emotional status, and adherence of HIV-1-infected patients treated with efavirenz versus protease inhibitor-containing regimens. J Acquir Immune Defic Syndr 2002; 29:244–253 68. Mouly S, Lown KS, Kornhauser D, Joseph JL, Fiske WD, Benedek IH, Watkins PB: Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans. Clin Pharmacol Ther 2001; 72:1–9 69. Duval X, Le Moing V, Longuet C, Leport C, Vilde JL, Lamotte C, Peytavin G, Farinotti R: Efavirenz-induced decrease in plasma amprenavir levels in human immunodeficiency virus-infected patients and correction by ritonavir (letter). Antimicrob Agents Chemother 2000; 44:2593 70. Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbons SE, Barry MG, Back DJ: The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001; 51:213–217 71. Vandamme AM, Van Vaerenbergh K, DeClercq E: Anti-human immunodeficiency virus drug combination strategies. Chem Chemother 1998; 9:187–203 72. Sahai J, Cameron W, Salgo M, Stewart F, Myers M, Lamson M, Gagnier P: Drug interactions study between saquinavir (SQV) and nevirapine (NVP), in Abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, Chicago, February 1997, abstract 496. http://www.retroconference.org/retrovirus97/abstracts/ a496_abstract.htm 73. Murphy RL, Sommadossi JP, Lamson M, Hall DB, Myers M, Dusek A: Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1. J Infect Dis 1999; 179:1116–1123 74. Skowron G, Leoung G, Kerr B, Dusek A, Anderson R, Beebe S, Grosso R: Lack of pharmacokinetic interaction between nelfinavir and nevirapine (editorial). AIDS 1998; 12:1243–1244 75. Altice FL, Friedland GH, Cooney EL: Nevirapine induced opiate

Psychosomatics 45:6, November-December 2004

withdrawal among injection drug users with HIV infection receiving methadone. AIDS 1999; 13:957–962 76. Hsyu PH, Schultz-Smith MD, Lillibridge JH, Lewis RH, Kerr BM: Pharmacokinetic interactions between nelfinavir and 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001; 45:3445–3450 77. Back D, Gibbons S, Khoo S: Pharmacokinetic drug interactions with nevirapine. J Acquir Immune Defic Syndr 2003; 34(suppl 1): S8–S14 78. Maldonado S, Lamson M, Gigliotti M, et al: Pharmacokinetic interaction between nevirapine and rifabutin, in Abstracts of the 39th International Conference on Antimicrobial Agents and Chemotherapy. Washington, DC, American Society for Microbiology, 1999, abstract 341 79. de Maat MMR, Mathot R, Hoetelmans R, et al: A population pharmacokinetic model of nevirapine reveals drug interaction with St John’s wort in a cohort of HIV-1 infected patients, in Abstracts of the Second International Workshop on Clinical Pharmacology of HIV Therapy, Nordwijk, the Netherlands, April 2001, abstract 1.2 80. Hardy H, Skolnick PR: Enfuvirtide, a new fusion inhibitor for therapy of human immunodeficiency virus infection. Pharmacotherapy 2004; 24:198–211 81. Cervia JS, Smith MA: Enfuvirtide (T-20): a novel human immunodeficiency virus type 1 fusion inhibitor. Clin Infect Dis 2003; 37:1102–1106 82. Maggi P, Ladisa N, Cinori E, Altobella A, Pastore G, Filotico R: Cutaneous injection site reactions to long-term therapy with enfuvirtide. J Antimicrob Chemother 2004; 53:678–681 83. Zhang X, Lalezari JP, Badley AD, Dorr A, Kolis SJ, Kinchelow T, Patel IH: Assessment of drug-drug interaction potential of enfuvirtide in human immunodeficiency virus type 1-infected patients. Clin Pharmacol Ther 2004; 75:558–568

http://psy.psychiatryonline.org

535