Drug-drug interactions are often a serious complication of taking multiple medications and account for 3% to 5% of all in-hospital medication errors.1 The consequences of drug interactions vary, ranging from drug toxicities to therapeutic failures. These consequences can result in suboptimal treatment of the targeted disease states, damage to vital organ systems, or death. Drug interactions are of particular concern in patients infected with HIV who are receiving highly active antiretroviral therapy (HAART). In a recent retrospective review of antiretroviral (ARV) drug therapy, logistic regression analysis revealed that age exceeding 42 years, greater than three comorbidities, and treatment with three or more ARVs or a protease inhibitor (PI) independently increased the risk of a clinically significant drug interaction.2 ARVs used in the treatment of HIV are often prone to drug interactions because many of them are metabolized through the CYP450 system. Of the CYP450 isoenzymes, CYP3A4, CYP2D, and CYP2C9/19 are considered the primary isoenzymes involved in the drugs' metabolism.3
There are six major classes of HIV ARVs available for use in HAART: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), PIs, fusion inhibitors, integrase inhibitors, and chemokine receptor (CCR5) antagonists. Since NRTIs, fusion inhibitors, and integrase inhibitors do not undergo hepatic metabolism through the CYP450 system, their drug interaction profile is minimal. Conversely, NNRTIs, PIs, and maraviroc (a CCR5 antagonist), are extensively metabolized by the CYP450 system; thus, they are highly susceptible to drug interactions. Furthermore, NNRTIs and PIs can inhibit and/or induce some of the CYP450 isoforms. For example, PIs are metabolized by, and are variable inhibitors of, the CYP3A4 isoform. Of the PIs, ritonavir is the most potent inhibitor, followed by indinavir, nelfinavir, amprenavir, and saquinavir, in decreasing order.4 Additionally, the PIs are substrates and inhibitors of P-glycoprotein, a major drug transmembrane efflux protein that transports PIs and other drugs out of the cell, which can lead to a decrease in the bioavailability of PIs.3 Of the four available NNRTIs, nevirapine and etravirine are substrates, as well as inducers of, CYP3A4, and delavirdine is a substrate and an inhibitor of CYP3A4.3,5 Etravirine is an inhibitor of CYP2C9/2C19.5 Efavirenz is considered both an inducer and inhibitor of the CYP3A4 isoform, with the inducing trait predominating.6 Maraviroc is metabolized by the CYP3A isoform and is likely to be affected by drugs that either inhibit or induce this CYP isoform; however, in vitro data indicate that maraviroc itself has minimal effect on the CYP450 system.7
Overall, the pharmacokinetic properties of NNRTIs and PIs can lead to sub- or supratherapeutic levels of concomitant drugs that are metabolized by the same CYP450 isoenzymes. Alternatively, if the concomitant drug acts as an inhibitor or inducer of the CYP450 isoenzymes that the NNRTIs, PIs, or maraviroc are metabolized through, the ARV levels will change accordingly, possibly resulting in a reduced antivirologic response or ARV-related toxicities to the patient. Understanding the mechanisms of the CYP450-systemÒmediated drug interactions between ARVs and commonly prescribed medications in the HIV patient population is important in order to determine if dosing modifications, close monitoring for adverse effects of drugs, or careful monitoring of a patient's viral load for virologic failure are necessary.
This review will discuss major drug interactions that occur with NNRTIs, PIs, and maraviroc and focus on the following classes of drugs: antiepileptic drugs (AEDs), statins, methadone, antidepressants, phosphodiesterase (PDE)-5 inhibitors, and acid-suppressive agents (TABLE 1).
The first-generation AEDs (i.e., carbamazepine, phenytoin, phenobarbital) are substrates as well as inducers of the CYP450 system.8 Since PIs, NNRTIs, and maraviroc are metabolized through the same pathways, the potential exists for significant drug interactions.7,9,10 Several case reports and reviews have demonstrated that there is a decreased metabolism and subsequent toxicity of carbamazepine when concomitantly administered with PIs, particularly ritonavir (including low doses of ritonavir utilized for boosting other PIs).8,11-15 One study reported an increase in carbamazepine concentrations from 9.5 mcg/mL to 17.8 mcg/mL within 12 hours of a single dose of ritonavir 200 mg.12 Therefore, in patients receiving carbamazepine concurrently with a ritonavir-containing HAART regimen, careful monitoring of carbamazepine levels is essential. Additionally, it may be appropriate to initiate a conservative carbamazepine dose in these patients or choose an alternative AED.12,13,15
Induction of certain CYP450 isoenzymes (i.e., 2C9/19 by lopinavir/ritonavir and nelfinavir) has been reported and can lead to an increase in the metabolism of AEDs like phenytoin, a narrow therapeutic index drug. Consequently, this reduction in the anticonvulsant serum concentrations can lead to seizures.16,17 Likewise, ritonavir-based HAART regimens have been shown to decrease valproic acid concentrations. One case report demonstrated a 48% decrease in valproic acid levels after a patient was started on a lopinavir/ritonavir-based regimen. 18 This interaction is likely due to ritonavir's ability to induce valproic acid metabolism via glucuronidation.18 Both NNRTIs (efavirenz and nevirapine) have been shown to decrease carbamazepine levels. The area under the curve (AUC) decreased by 27% when efavirenz was coadministered with carbamazepine.19,20 This reduction in carbamazepine levels occurred as a result of the induction of the CYP3A4 isoenzyme by efavirenz and nevirapine.3
Furthermore, carbamazepine, phenytoin, and phenobarbital all have the potential to induce PI, maraviroc, delavirdine, efavirenz, and etravirine metabolism and thus reduce serum concentrations of these drugs, which can lead to ARV resistance and drug failure.5,7,8,17,21 Recommendations regarding the use of maraviroc with these AEDs suggest that the dose of maraviroc should be increased to 600 mg twice a day; however, formal recommendations regarding dosing adjustments of PIs, delavirdine, efavirenz, or etravirine are lacking.5,7 Therefore, careful monitoring for virologic resistance and failure is essential.
Some of the newer, second-generation AEDs may have pharmacokinetic advantages over traditional agents, including decreased drug interactions. However, there are limited clinical data to support their use in combination with ARVs. Gabapentin, levetiracetam, and lamotrigine are minimally metabolized by the CYP450 system and may be considered when the potential for significant drug interactions limits the use of first-generation AEDs.8,22 Use of other second-generation AEDs (e.g., topiramate, tiagabine, oxcarbazepine, felbamate) may be limited due to their induction/inhibition of CYP450 isoenzymes and/or their adverse-effect profiles.8
Due to the difficulty in predicting the potential interactions between first-generation AEDs and ARVs, strict monitoring of serum concentrations of these AEDs are necessary in order to avoid drug toxicity or inadequate control of seizures/disease states. Dosing adjustments should be made according to serum AED concentrations, control of the patient's disease state, and adverse effects. Moreover, it is important to also monitor the patient's virologic response to HAART since some AEDs have the potential to accelerate the clearance of some ARVs, resulting in a likely decrease in efficacy.8,15,17,23,24 Alternatively, other second-generation AEDs that are minimally metabolized by the CYP450 system may be suitable alternatives if deemed appropriate for the patient.8,22
Although HAART has decreased the morbidity and mortality rates among HIV patients, these drugs have also been associated with long-term metabolic complications (e.g., lipodystrophy, dyslipidemia, diabetes mellitus).25,26 The PIs in particular have been associated with causing dyslipidemia, with a prevalence as high as 74%.27 In addition, dyslipidemia can also be caused by HIV infection itself.28 Similarly to non-HIV-infected individuals, HIV patients will often require treatment of their dyslipidemia with lipid-lowering therapy such as HMG-CoA reductase inhibitors (statins), fibrates, niacin, or ezetimibe.29 Many statins are metabolized by the CYP450 system, specifically the CYP3A4 isoenzyme.30 Exceptions to this are pravastatin, fluvastatin, and rosuvastatin, which are eliminated through varying pathways.31,32
Since all of the PIs and delavirdine inhibit CYP3A4, drug interactions with statins are inevitable for those metabolized by the same enzyme. This interaction results in increased levels of statins, which could increase the patient's risk for adverse effects such as myalgias, rhabdomyolysis, elevated creatinine phosphokinase (CPK), and hepatic dysfunction.29,31 One study demonstrated that the 24-hour area under the curve (AUC0-24) for simvastatin increased by more than 3,000% when it was coadministered with saquinavir/ritonavir.30 Another study demonstrated that the AUC0-24 for atorvastatin increased more than 800% and the maximum concentration (Cmax) increased more than 760% when coadministered with tipranavir/ritonavir.33 Two recent studies demonstrated an unexpected drug-drug interaction involving rosuvastatin and the PIs, lopinavir/ritonavir, and tipranavir/ritonavir. 34,35 When rosuvastatin was concurrently administered with lopinavir/ritonavir, rosuvastatin's AUC was increased by 2.1-fold and the C max was increased by 4.7-fold. There were four patients who experienced elevated CPKs as a result of this increase in rosuvastatin concentrations. 34 Furthermore, the combination of tipranavir/ritonavir and rosuvastatin 10 mg resulted in an increase of 37% in rosuvastatin's AUC, and the Cmax was increased by 123%.35 The mechanisms of these drugÒdrug interactions are currently unclear.34,35
Interactions with the NNRTIs have also been established. In one study, volunteers receiving concomitant efavirenz with either simvastatin, atorvastatin, or pravastatin revealed that the AUC0-24 decreased by 58%, 43%, and 40%, respectively.36 This study suggests that patients taking a drug considered to be an inducer of the CYP450 system will probably require higher doses of interacting statins in order to achieve optimal lipid-lowering effects.36 Since etravirine is also an inducer of CYP450 3A4, atorvastatin, simvastatin, and lovastatin concentrations will likely be decreased when coadministered with etravirine. Additionally, since fluvastatin is metabolized by CYP2C9 and etravirine is an inhibitor of this isoenzyme, fluvastatin concentrations will be increased when it is taken concurrently with etravirine.5
Presently, the statins recommended for use in HIV patients on a PI-based regimen are atorvastatin, fluvastatin, and pravastatin.29,37-39 Both simvastatin and lovastatin should not be used with a PI or delavirdine-containing HAART regimen due to elevations in serum concentrations of the statin.28,38-42 The concurrent use of rosuvastatin and PIs should be used with caution until additional studies have been performed with other PIs besides lopinavir/ritonavir and tipranavir/ritonavir. When initiating statin therapy in an HIV patient, it is advisable to start with the lowest dose available and titrate up gradually in order to achieve the necessary lipid-lowering effect. Another option may be to consider alternative lipid-lowering drugs such as fibrates, ezetimibe, or niacin. All of these bypass the hepatic P450 system and undergo different routes of metabolism, thus eliminating the potential for major drug interactions with ARVs.29,40-44
Methadone, commonly prescribed for HIV patients for the treatment of pain or drug addiction, interacts with most PIs and NNRTIs through several complex mechanisms. These include induction of the CYP450 system and glucuronyltransferase, changes in plasma protein binding, induction of P-glycoprotein, and unequal stereoselective metabolism of the active R-isomer and inactive S-isomer of methadone.45-47 Methadone is metabolized primarily by CYP3A4 and, to a lesser degree, by CYP2D6, 2B6, and 1A2 isoenyzmes.45,48-50 Numerous studies have demonstrated that when most PIs, efavirenz, and nevirapine are administered concurrently with methadone, an unexpected decrease in methadone concentration results, which can potentially lead to opiate withdrawal symptoms; however, there seems to be a discordance between the degree of decrease in methadone concentrations and the risk of opioid withdrawal.45,46,51,52 It has been hypothesized that this discordance may be due to an increase in the metabolism of the inactive S-isomer of methadone or to alterations in methadone protein binding.45
Of the PIs, this drug-drug interaction with methadone is more pronounced with lopinavir/ritonavir and nelfinavir, with decreases in methadone AUCs of 53% and 47%, respectively. 53,54 Efavirenz and nevirapine, both NNRTIs and known inducers of CYP3A4, have also been shown to cause significant decreases in methadone concentrations when coadministered.55 Concentrations of methadone were reduced up to 60% when taken with efavirenz and by 46% with nevirapine. 19,46,56,57 Managing these drug interactions can be challenging due to the unpredictable changes in serum methadone concentrations and correspondence to patient response; however, changes in methadone doses should be guided by patient opioid response and signs and symptoms of opioid withdrawal. If methadone doses need to be increased, it is recommended that the doses be augmented 10 mg at a time and all changes be accompanied by careful monitoring. 51 If opioid withdrawal symptoms are present, a dose increase of 20 mg may also be acceptable.51
The NNRTI delavirdine is a CYP3A4 inhibitor, and coadministration of this medication results in increased methadone concentrations. Based on a pharmacokinetic study, the AUC was increased by 19%.58 When methadone therapy is needed in conjunction to a delavirdine-containing HAART regimen, patient response to methadone should be closely monitored, and it may be necessary to decrease the dose of methadone.58
Depression is a frequent disorder among HIV patients, with a reported incidence of up to 47.8% in some studies.59,60 Patients are often treated with a variety of antidepressants, including selective serotonin reuptake inhibitors (SSRIs). The majority of ARVs (PIs and NNRTIs) and antidepressants are substrates for, and can inhibit or induce, the CYP450 system, and they have the potential to cause clinically significant drug interactions including serotonin syndrome, a potentially fatal complication.61-63 Most of these drugÒdrug interactions are mediated through CYP450 2D6 and 3A4 isoenzymes.61
Ritonavir has been shown to augment levels of a variety of SSRIs, including fluoxetine, citalopram, paroxetine, and sertraline.63,64 One study reported cases of serotonin syndrome in patients taking concurrent fluoxetine with either ritonavir-, saquinavir/ritonavir-, or efavirenz-based regimens.63 These cases were managed by either decreasing the daily dose of fluoxetine by half or discontinuing ritonavir. Monitoring for antidepressant side effects when initiating ritonavir in patients receiving concurrent SSRI therapy is recommended.65 Other ARVs are anticipated to affect SSRIs to a lesser extent, and initial dose adjustments may not be necessary.61
Fluvoxamine, a potent inhibitor of CYP1A2 along with fluoxetine and paroxetine (both potent inhibitors of CYP2D6), may also cause PI toxicity by increasing their concentrations.61,64,66,67 A statistically significant increase of 19% in the AUC for ritonavir was seen with concomitant fluoxetine administration.67 However, considering the magnitude of the change, no ritonavir dose adjustment was recommended. Sertraline, citalopram, and escitalopram appear to have little effect on the major CYP isoforms and are not expected to affect levels of the ARVs.66
Alternatives to SSRIs, including bupropion, mirtazapine, nefazodone, and venlafaxine, have also been shown to be effective in treating depression in HIV-infected patients. 65,66,68,69 These drugs, together with trazodone, are metabolized by the CYP isoenzymes, leaving the potential for interactions with PIs (especially ritonavir) and NNRTIs.61,70 In a blinded study, ritonavir decreased the clearance of trazodone (metabolized by CYP3A4 and 2D6), resulting in increased levels of trazodone, which can cause nausea, dizziness, and hypotension.71 The AUC for trazodone has been shown to increase 2.4-fold when coadministered with ritonavir.72 However, when bupropion was coadministered with ritonavir, no adverse effects (i.e., seizures) were reported.73 At this time, there are very limited data on the effects of these alternative antidepressants on the PIs and NNRTIs. Therefore, when coadministering antidepressants and either a PI- or NNRTI-based HAART regimen, antidepressants should be initiated at a low dose and titrated over several weeks. Patients should also be closely monitored for adverse effects.74
Erectile dysfunction is a common occurrence among HIV-infected men, with some studies demonstrating an incidence as high as 61.4%.75 PDE-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) are the cornerstone of therapy for erectile dysfunction and are considered to be an effective treatment for this disorder.76
PDE-5 inhibitors are metabolized through the CYP450 3A4 isoenzyme. Therefore, concentrations of PDE-5 inhibitors are increased in the presence of PIs and delavirdine. 19,77,78 When saquinavir (the least potent CYP3A4 inhibitor) and ritonavir (the most potent CYP3A4 inhibitor) were coadministered with sildenafil, a 3.1-fold and an 11-fold increase in the AUC occurred, respectively. The Cmax was also increased by 2.4-fold with saquinavir and 3.9-fold with ritonavir.77 These increases in the AUC and Cmax of sildenafil suggest that a lower starting dose of sildenafil should be utilized when initiating therapy in a patient receiving concurrent therapy with PIs or delavirdine. Limited data exist involving vardenafil and tadalafil interactions with PIs and delavirdine; however, since both of these drugs are metabolized primarily through the CYP3A4 isoenzyme, it can also be expected that the drug concentrations of these PDE-5 inhibitors will also be increased in the presence of these ARVs.
Potential consequences of increased concentrations of PDE-5 inhibitors include hypotension, dizziness, and priapism.79 Therefore, if PDE-5 inhibitor therapy is needed in a patient receiving a PI- or delavirdine-based HAART regimen, conservative dosing of these drugs is essential and careful monitoring for adverse effects of PDE-5 inhibitors is warranted. Recommendations for concurrent therapy with PIs or delavirdine indicate that sildenafil dosing should not exceed 25 mg every 48 hours, the starting dose of tadalafil should be 5 mg and not exceed 10 mg within a 72-hour period, and vardenafil should be initiated at 2.5 mg in a 24-hour period. However, if the HAART regimen contains ritonavir, then the vardenafil dose should not exceed 2.5 mg within a 72-hour period.19,79
Acid-suppressive therapy with histamine-2 (H2) blockers, proton pump inhibitors (PPIs), or antacids can cause a decrease in the absorption of some PIs and delavirdine due to changes in the pH of the gastrointestinal tract.80,81 Some PIs (e.g., indinavir) are able to overcome this alteration in absorption through boosting with ritonavir.82 However, other PIs (e.g., atazanavir, fosamprenavir, tipranavir) have been found to have significant interactions with acid-suppressive therapy that requires intervention due to the potential for virologic failure from inadequate ARV concentrations.80 Atazanavir/ritonavir's AUC and minimum concentration (Cmin) were decreased by up to 76% and 71%, respectively, when coadministered with omeprazole.83 Additionally, fosamprenavir's AUC was decreased by 30% when coadministered with ranitidine (an H2 blocker), and tipranavir/ritonavir's AUC and Cmin were reduced by 27% and 29%, correspondingly, when given with antacids.84,85 Of the NNRTIs, delavirdine can also be affected by antacids, with a 44% reduction in the AUC when coadministered.86
Recommendations for managing these interactions vary, but when fosamprenavir, tipranavir/ritonavir, or delavirdine are used in combination with antacids, it is recommended that the ARV be given either one to two hours before or one hour after the administration of the antacid. Fosamprenavir should be boosted with ritonavir when concurrently administered with H2 blockers.19,57,80,81,87 Atazanavir 300 mg in combination with ritonavir 100 mg should be administered concurrently with or at least 10 hours after the H2 blocker; additionally, depending on whether the patient is treatment-naëve or treatment-experienced, the H2-blocker dose should not surpass 40 mg or 20 mg twice daily equivalent of famotidine, respectively.88 Atazanavir should not be administered with PPI therapy in individuals who are treatment-experienced due to the significant reductions in ARV concentrations. In treatment-naëve patients, however, the PPI dose should not be greater than 20 mg equivalent of omeprazole. Additionally, the PPI must be taken 12 hours before the atazanavir 300-mg/ritonavir 100-mg dose.88 Data are lacking in regards to the administration of fosamprenavir or tipranavir with PPIs, but patients should be closely monitored while receiving concurrent therapy.19,57,80,81,8
Drug-drug interactions with HAART, particularly PI- and NNRTI-based regimens, often complicate the management of patients with HIV. Many of these drug interactions are mediated through the CYP450 system, particularly the CYP3A4 isoenzyme. PIs, NNRTIs, and maraviroc are metabolized through this same system; therefore, any drugs that alter the CYP450 system through inhibition or induction can cause changes in serum concentrations of these ARVs. Additionally, PIs and NNRTIs can also inhibit or induce CYP450 isoenzymes and affect concentrations of other drugs that are coadministered with them. As a clinician, it is imperative to understand these drug interactions in order to prevent drug toxicities, virologic failure, or death in patients with HIV. Various resources such as Web sites, databases, and HIV guidelines are routinely updated and are helpful sources of information that should be utilized when reviewing HIV patients' medication profiles, especially as this area continues to expand and more drug interactions are discovered.
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