Clinically Significant Drug Interactions Associated With Highly Active Antiretroviral Therapy
One of the most challenging issues facing providers treating patients with human immunodeficiency virus-1 (HIV) infection is the complex problem of drug interactions associated with highly active antiretroviral therapy (HAART). Guidelines for the initial treatment of HIV infection recommend the use of at least three antiretroviral medications, each of which is associated with significant drug interactions.1 Further increasing the risk of drug interactions is the concurrent treatment of co-morbid disease states and therapies for prevention and/or treatment of opportunistic infections (OIs). This review focuses on the clinically significant drug interaction associated with the use of HAART.
Currently, there are 21 medications from four different classes licensed in the United States for the treatment of HIV infection. Drug interactions associated with HIV medications can be broadly classified into those that alter pharmacokinetics and those that alter pharmacodynamics.2 Pharmacokinetic drug interactions generally result in a change in pharmacokinetic parameters, such as the area under the curve (AUC), which is a common measure of drug exposure, peak concentration (Cmax), trough concentration, or half-life. Conversely, pharmacodynamic interactions result in alterations in the pharmacologic activity of the medication; generally not causing a change in pharmacokinetic parameters. The vast majority of drug interactions encountered in HIV medicine are pharmacokinetic in nature and occur as a result of a change in the absorption, distribution, metabolism or elimination of either the HIV medication itself or the concurrently administered medication.3
The cytochrome P450 (CYP450) enzyme system is responsible for the biotransformation of drugs from active to inactive metabolites that are readily excreted by the body. Given the effects of the protease inhibitor (PI) and non-nucleoside reverse transcriptase (NNRTI) class on the CYP450 system, metabolism drug interactions are most common and problematic when prescribing HAART. Though numerous isoenzymes of CYP450 have been identified, the enzymes responsible for the elimination of the majority of drugs used in HAART are CYP3A4, CYP1A2, and CYP2D6. Table 1 describes the route of elimination for HAART.
Drug interactions associated with the nucleoside (NRTI) and nucleotide (NtRTI) classes are minimal, as these medications are not metabolized by the CYP450 system. However, drug interactions may still occur within this class.
The currently available NRTIs and NtRTI include zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and tenofovir. Drug interactions with zidovudine are minimal; however, one of the few pharmacodynamic interactions encountered in HIV medicine occurs with co-administered zidovudine and stavudine. Since both of these NRTIs are thymidine analogues, they can compete for the same phosphorylation site in the growing chain of HIV DNA, resulting in an antagonistic, pharmacodynamic interaction.3 These two agents should therefore never be combined.
The use of didanosine (ddI) is often complicated by drug interactions. The buffered tablet formulation, which contains magnesium and calcium to improve systemic absorption, interacts with certain antibiotics.4 As a result of the buffer chelating the antibiotic, reduced ciprofloxacin, tetracycline or doxycycline absorption may occur. To minimize this interaction, ddI should be administered at least two hours after or six hours before the fluoroquinolone.5 Concurrent use of ddI-buffered tablet may also impair the absorption of the protease inhibitor (PI) atazanavir, since atazanavir requires an acidic environment for absorption.6 Patients should take a ddI-buffered tablet two hours after or one hour before taking atazanavir to minimize the interaction. Alternatively, use of the enteric-coated capsule formulation is an option; however, providers need to be sure that patients separate ddI and atazanavir since their dietary restrictions differ.6, 7
Probably the most significant ddI drug interaction reported occurs when didanosine is used concurrently with the NtRTI tenofovir. When enteric-coated ddI is co-administered with tenofovir, the ddI AUC increases by 60%.8 As a result, the recommendation for patients weighing >60kg who receive these medications concurrently is to reduce the ddI dosage to 250 mg once daily. For patients weighing <60kg, no specific guidelines are available for ddI dosing; however, reduction to 200 mg once daily is likely warranted. For severely underweight patients, providers may consider an even further ddI dosage reduction to 125 mg once daily. Due to the magnitude of this interaction, all patients receiving concurrent tenofovir and ddI should be monitored closely for ddI-related toxicities such as pancreatitis, hyperlactatemia, and lactic acidosis, regardless of ddI dosage adjustments.
Three NNRTIs are currently licensed for use in the U.S.: nevirapine, delavirdine, and efavirenz. Drugs in this class are prone to drug interactions, given the fact that they are extensively metabolized via CYP3A4 and can act as either inducers or inhibitors of CYP3A4. Nevirapine and efavirenz are, in general, inducers of CYP3A4, while delavirdine is an inhibitor of CYP3A4. When one of these agents is combined with a medication that is also metabolized by CYP3A4, a drug interaction is likely to occur.
Numerous drug interactions with nevirapine have been identified. Nevirapine is a CYP3A4 inducer, therefore most drug interactions associated with it lead to an increase in metabolism and reduced concentration of the co-administered drug. For example, when nevirapine is given concurrently with methadone, withdrawal symptoms may occur as a result of reduced methadone levels.9-12 When using methadone and nevirapine concurrently, patients should be monitored closely for signs and symptoms of methadone withdrawal. Since the full effects of CYP3A4 induction may take time, signs of withdrawal may occur one to two weeks (or longer) after nevirapine is added to methadone. An increase in methadone dosage may be necessary after the addition of nevirapine.
Concurrent nevirapine and oral contraceptive use may lead to contraceptive failure; therefore providers should recommend alternate methods of birth control.13 Rifabutin and rifampin are also potent CYP3A4 inducers and have been shown to reduce nevirapine trough concentrations by 16% and 37%, respectively. Therefore, patients on nevirapine who require anti-mycobacterial therapy should be given rifabutin to minimize the reduction in nevirapine drug levels.
Efavirenz is a potent inducer of CYP3A4 in vivo. As with nevirapine, CYP3A4 induction properties of efavirenz can result in reduced concentrations of concurrently administered drugs that are also metabolized by CYP3A4. In vitro data also suggest that efavirenz can inhibit CYP3A4. Efavirenz is therefore contraindicated with midazolam, triazolam, and ergotamine derivatives since there is a potential for increased drug concentrations of these medications and associated toxicity.14 Despite the inclusion of these contraindicated medications in the product labeling, no published case reports to date have either proven or refuted the validity of these interactions. Concurrent use of the macrolide antibiotic clarithromycin should be avoided in patients receiving concurrent efavirenz. When used together, the clarithromycin AUC and Cmax decreased by 39% and 26%, respectively.14 Therefore, clinicians may consider using azithromycin instead, as CYP450 drug interactions are unlikely with this medication.
Similar to nevirapine, methadone withdrawal has also been reported with concurrent use of efavirenz and methadone. This is more likely to occur when adding efavirenz to a stable methadone regimen.12 Providers should be aware that the full effect of methadone withdrawal may take one to two weeks. Any change to antiretroviral therapy (ART) regimens should be communicated to methadone maintenance providers so that potential drug interactions may be anticipated and avoided.
Concurrent use of efavirenz with rifampin has been shown to reduce the AUC and Cmax of efavirenz by 26% and 20%, respectively. Although the clinical significance of this interaction is unknown, providers should increase the efavirenz dosage to 800 mg daily to offset this interaction when using rifampin to treat tuberculosis.15 Another alternative would be to use rifabutin instead of rifampin; current guidelines suggest that the rifabutin dose be increased to 450 mg daily and the dosage of efavirenz should remain at 600 mg once daily.
Unlike efavirenz and nevirapine, delavirdine is a potent inhibitor of CYP3A4. As a result, concurrent administration of drugs metabolized by the same isoenzyme are likely to cause increased drug levels and potential drug toxicity. Drugs that are likely to have increased serum levels when used concurrently with delavirdine include alprazolam, midazolam, triazolam, sildenafil, ergot alkaloid derivatives, nifedipine, and the HMGCoA-reductase inhibitors simvastatin and lovastatin.16 Concurrent use of these medications should be avoided in patients receiving delavirdine.
The medications rifampin and rifabutin have also been shown to reduce the AUC of delavirdine by 96% and 80%, respectively. Current guidelines for ART recommend that these medications be avoided in patients receiving concurrent delavirdine due to the high risk for development of resistance and virologic failure.15, 16
Other potential drug interactions with the entire NNRTI class include the anticonvulsants phenytoin, carbamazepine, and phenobarbital. Since these medications induce the CYP450 system, reduced drug levels of delavirdine, efavirenz, and nevirapine may occur and should be avoided if possible. A potential alternative is the medication levetiracetam and may be considered with concurrent ARV treatment, as it does not have significant CYP450 interactions. When prescribing levetiracetam, the patient should have close follow-up with a neurologist.
In treating patients who have failed their first regimen, or are in deeper salvage therapy, providers may be forced to use NNRTIs and PIs together. Providers need to be cognizant of dosage changes required when using these two classes concurrently, given the effect of both classes on the CYP3A4 system. As the NNRTIs efavirenz and nevirapine are known inducers of the CYP3A4 system, significant reductions in PI levels may occur when using these drugs concurrently. For example, when using efavirenz or nevirapine with indinavir or lopinavir/ritonavir, the AUC of the PIs are reduced by about 33%. To offset this interaction, providers need to increase the PI dosage: for indinavir the dosage needs to be increased to 1000 mg every eight hours, and for lopinavir/ritonavir, the dosage needs to be increased to four capsules (533 mg/133 mg) twice daily.17, 18 Conversely, as delavirdine is a potent inhibitor of CYP3A4, concurrent use with indinavir requires a dosage reduction to 600 mg every eight hours.17 No data exist that describe the pharmacokinetic interaction between lopinavir/ritonavir and delavirdine.
Concurrent use of the two new PIs atazanavir and fosamprenavir with either efavirenz or nevirapine also result in reduction in PI levels. However, instead of dosage adjustments, data suggest that the addition of ritonavir to these PIs is a viable option to offset the reductions in PI drug level. For example, during concurrent use of atazanavir and efavirenz, atazanavir AUC was reduced by about 74%.19 To offset the interaction, providers need to reduce the atazanavir dosage to 300 mg once daily and also add ritonavir 100 mg once daily. When boosted fosamprenavir once daily is used concurrently with efavirenz, fosamprenavir should be given 1,400 mg with 300 mg of ritonavir once daily or fosamprenavir 700 mg with ritonavir 100 mg both twice daily.20 Though data evaluating the drug interaction between nevirapine and either atazanavir or fosamprenavir are unavailable, expert opinion suggests that the same dosage adjustments should be made, given the similarity in efavirenz and nevirapine metabolism. Data combining these medications with delavirdine is not available. See Table 2 for a summary of dosage recommendations with select PI and NNRTI combinations.
All PIs are potent inhibitors of CYP3A4, and as a result, drug interactions are often very complex. As a result of CYP3A4 inhibition, medication levels of agents also metabolized by the same izoenzyme have the potential to be markedly increased by the PI, potentially leading to an increased incidence of adverse effects. PIs have differing affinities for the CYP3A4 isoenzyme. The most potent inhibitor of CYP3A4 is ritonavir, whereas the least potent is saquinavir; CYP3A4 inhibition associated with indinavir, nelfinavir, and amprenavir, and atazanavir tends to be intermediate.21 Ritonavir is often the most likely medication in the PI class to cause drug interactions because in addition to its CYP3A4 inhibition, it also inhibits CYP2D6 and induces CYP1A2 and CYP2C9. However, ritonavir is often used to enhance the pharmacokinetic parameters of co-administered PIs due to its potent inhibition of their metabolism by CYP3A4.
Numerous medications should be avoided when using PI-based therapy. The benzodiazapines midazolam and triazolam are contraindicated, as these medications are metabolized by CYP3A4 and their concentrations can be markedly increased, resulting in prolonged sedation. Though the benzodiazapine alprazolam may also be increased by concurrent PI therapy, low doses may be acceptable to use. Other potential alternatives to these agents include lorazepam, oxazepam, or temazepam, as these medications are not metabolized by CYP450.21
Hyperlipidemia is a common occurrence with PI therapy, though it may also be associated with stavudine and efavirenz. As a result, providers often treat hyperlipidemia with either fibric acid derivatives or with HMG-CoA reductase inhibitors, also referred to as statins. Although drug interactions with the fibric acid derivatives have not been identified, the use of certain statins is contraindicated with the use of a PI. The two most problematic statins are simvastatin and lovastatin, as these agents are extensively metabolized via CYP3A4.22 When used concurrently with PIs, these statin levels are markedly increased, placing the patient at risk for myopathy, rhabdomyolysis, and possibly renal failure and death. Statins that are considered safe include pravastatin or fluvastatin, as they have minimal effect on CYP450, therefore reducing the risk of drug interactions. Another potential option is atorvastatin, however CYP3A4 is involved with its metabolism. Use of atorvastatin with PI therapy should be done only with the lowest available dosages and with close follow-up for potential hepatotoxicity and muscle toxicity. The newest statin, rosuvastatin, cannot be recommended as no drug interaction studies exist evaluating concurrent PI use.
The use of PIs (and NNRTIs) often complicates the treatment of mycobacterial infections such as tuberculosis and MAC because rifampin and rifabutin are potent inducers of CYP3A4, leading to significant reductions in PI levels. However, rifampin is much more problematic, as it is a more potent inducer of CYP3A4 compared to rifabutin. Therefore, concurrent use of rifampin with PI regimens that do not include ritonavir is generally contraindicated due to risks of subtherapeutic levels of PIs that can result in either virologic failure or resistance.
Herbal therapy is common in the setting of HIV infection.23 Oftentimes, herbal therapies have not been studied with concurrent HAART, and therefore their use should be discouraged unless data evaluating their effect on HAART are available. St. John's wort and garlic supplementation significantly reduce the levels of the PIs indinavir and saquinavir soft gel capsule, respectively.24, 25 Since other PIs and NNRTIs are also metabolized by CYP3A4, similar interactions with other medications in these classes would be expected. Therefore, patients should be encouraged to avoid St. John's wort, garlic supplements, and other herbal therapies that have not been formally studied with PIs. The herbal therapy milk thistle, often used as a hepatoprotectant, has been shown to have minimal effects on the PI indinavir.26 Providers choosing to offer milk thistle to patients may be able to do so safely with PI- and NNRTI-based therapies; however, data demonstrating its effect on PIs exist only for indinavir.
Drugs for erectile dysfunction, such as sildenafil, vardenafil and the recently approved tadalafil, can also have their levels increased significantly by concurrent PI use.27-29 Specifically, sildenafil levels can be increased from two to eleven-fold when used concurrently with PI therapy. Therefore, clinicians should prescribe, at most, 25 mg every 48 hours initially. For patients who do not respond to 25 mg, consideration for using higher doses should only be done with extreme caution. PIs can also increase vardenafil concentrations.
Current guidelines from the product labeling suggest that for patients on a PI-based regimen that does not include ritonavir, the maximum initial dose of vardenafil should be 2.5 mg, without repeating the dose for 24 hours.29 For patients receiving ritonavir even at low doses, the maximum initial vardenafil dose should be 2.5 mg and should not be repeated for 72 hours.29 Tadalafil was also recently approved; maximum doses used should not exceed 10 mg every 72 hours for patients receiving concurrent PI therapy.30 Possible toxicities from these drugs include priapism, hypotension, and visual color changes.
HIV-infected patients may either have a seizure disorder or may require seizure prophylaxis due to OIs that involve the central nervous system. This often becomes problematic in the setting of HAART due to very limited data on concurrent use of anticonvulsants and PIs. Use of the anticonvulsants phenytoin, phenobarbital, and carbamazepine is of particular concern as they induce CYP450 enzymes that may lead to reduced PI or NNRTI levels.21 In fact, one case report in the literature describes ART failure possibly related to carbamazepine therapy in a patient receiving a PI.31 In this case, 200 mg of carbamazepine was taken with 800 mg of indinavir every eight hours, which led to subsequent virologic failure. Therefore, concurrent use of these drugs with PIs should be avoided, and a different anticonvulsant should be considered. More recently, a drug interaction study was reported between lopinavir/ritonavir and phenytoin.32 When used together, a dual interaction occurred, such that the levels of both lopinavir and phenytoin were markedly reduced. Therefore, providers should avoid this combination and select an alternative HAART regimen or an alternative anticonvulsant. One potential option is the use of levetiracetam, an anticonvulsant that has minimal drug interactions. Use of this medication in HIV-infected patients has not been studied, and therefore its use for treatment or prevention of seizures should only be done with close consultation with a neurologist. Whenever possible, patients who require concurrent HAART and anticonvulsant therapy should undergo periodic monitoring of anticonvulsant drug levels. For some PIs, therapeutic drug monitoring may also be an option to ensure that adequate levels are being attained. Consensus trough concentrations have been established and are available in the most recent revision of the federal Department of Health and Human Services Guidelines.1
Patients infected with HIV-1 may require antifungal therapy for such infections as cryptococcal meningitis, or candidiasis. With regard to PI drug interactions, the safest of the oral medications is fluconazole, as drug interactions are minimal.33, 34 However, the azole antifungal ketoconazole is a potent CYP3A4 inhibitor and increases the level of drug exposure to saquinavir and amprenavir by 190% and 31%, respectively.35, 36 Conversely, ritonavir and lopinavir/ritonavir have demonstrated a three-fold increase in ketoconazole levels when used concurrently. Therefore doses >200 mg/day of ketoconazole are not recommended when using these medications concurrently.18 In general, ketoconazole should be avoided with concurrent HAART. The newest azole antifungal, voriconazole, has significant activity against aspergillosis and candida albicans. Its use for treatment of candidiasis in HIV-infected patients has been established; however, drug interaction data only exist for concurrent use of indinavir, where no clinically significant interaction occurred.1 Although extrapolation to other PIs may be possible, until data are available, use of this azole with other PI-containing regimens (especially those that contain ritonavir) should be undertaken when an alternative azole cannot be used, and with close monitoring for voriconazole toxicity, such as elevated transaminases and visual toxicity.
One of the recently approved PIs for use in the U.S. is atazanavir.19 Drug interactions with atazanavir are very similar to the other PIs; however, some differences do exist. In particular, atazanavir is a pH-dependent medication, requiring an acidic environment for absorption. As a result, the use of drugs that may alter the gastric pH are likely to be problematic. Since antacids may reduce atazanavir absorption, atazanavir should be administered two hours before or one hour after antacids. Proton pump inhibitors (PPIs) such as lansoprazole and omeprazole significantly alter the gastric pH for prolonged periods of time (often lasting longer than 24 hours), the atazanavir product labeling recommends that PPIs should not be used concurrently with atazanavir. As an alternative, providers may consider the use of a once daily histamine-2 (H-2) receptor antagonist separated by 12 hours from atazanavir. The current thought is that H2 blockers provide less prolonged suppression of acid, and, if separated, the interaction should be minimized. However, no data exist to prove or refute this theory.19
Other significant drug interactions may also occur with concurrent PI use. Table 3 summarizes medications that should generally be avoided with concurrent PI therapy.
Drug interactions are often complex and may be difficult to predict due to limited studies. Providers should be diligent in educating themselves about routes of metabolism for HAART and commonly prescribed medications to help recognize potential medications that may be problematic. As therapy for HIV changes very rapidly, providers may utilize internet resources to help screen for potential drug interactions and to identify new treatment options and issues surrounding HIV infection (See "Resources" in this issue). With such interventions, toxicity or adverse events associated with drug interactions may be prevented.
John J. Faragon, Pharm.D. is Assistant Professor of Pharmacy Practice at Albany College of Pharmacy and Clinical Pharmacist at Albany Medical College. Disclosures: Speakers fees -- Abbott, Agouron (Pfizer), and GlaxoSmithKline; consultant fees -- Roche and Gilead.
Peter J. Piliero, M.D. is Associate Professor of Medicine at Albany Medical College and Clinical Consultant at the New York State Department of Corrections. Honoraria: BMS, Abbott, GSK, Roche, Merck and Gilead. Research: GSK, Roche, Trimeris, Pfizer, Boehringer-Ingelheim and Gilead.
This article was provided by Brown Medical School. It is a part of the publication HEPP Report.