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Nucleoside Reverse Transcriptase Inhibitors
Protease Inhibitors
Non-nucleoside Reverse Transcriptase Inhibitors

Within the past decade, numerous agents have been marketed to treat patients with HIV/AIDS. Antiretrovirals include nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Other classes of agents are soon to be marketed. In addition to virus-specific drugs, agents to prevent or treat opportunistic infections, wasting, depression and anxiety, or neoplasia are often given to patients with HIV/AIDS. As a result, it is common for these patients to be maintained on polypharmacy that often involves five to nine medications. Many of these are known to interact with other drugs or food, such that the effects of the medications involved may be either enhanced or negated. This problem is exacerbated by the current inability to determine drug levels for most of these agents. The incidence of drug interactions in patients taking few agents has been estimated at about 5%. With polypharmacy, this can be expected at least to quadruple. Selected interactions may be life-threatening. The clinician managing the care of patients with HIV/AIDS must be aware of the potential for drug interactions, and in many cases an inordinate amount of time may be spent in determining appropriate management. Before new medications are prescribed for a patient with HIV/AIDS, both prescription and nonprescription agents being taken by the patient must be assessed. The following discussion focuses on mechanisms of drug interactions and depicts many of the most common. It is not meant to be inclusive. A caveat, however, is that with the large number of drugs that many patients ingest, interactions not heretofore known may be uncovered.
The mechanisms for drug-drug and drug-food interactions are multiple. For an agent to perform therapeutically, it must be successfully ingested and absorbed from the gastrointestinal tract. Many products are transported through the circulation by plasma proteins. Then, depending on mechanism of excretion, a drug will be metabolized and excreted by either the kidney or liver. The majority of antiretrovirals are metabolized by the liver, and it is within the liver that most problems with interactions occur. However, such problems may develop at any location along the metabolic pathway. As an example, selected agents require a specific pH for absorption, and agents that cause a change in pH (e.g., antacids, histamine2 antagonists) may significantly interfere with absorption. Many antiretrovirals and other AIDS-related medications are excreted through the liver. Most are metabolized by the cytochrome P-450 system, for which there are several gene families and subfamilies. Three of these (CYP1, CYP2, and CYP3) are associated with the metabolism of most medications. Table 91-1 depicts substrates, inducers, and inhibitors for each of these.

Table 91-1. Major cytochrome P-450 enzymes

Drug interactions may be either “pharmacokinetic” or “pharmacodynamic.” Pharmacokinetic interactions alter blood levels of specific agents (and thus have the potential to render the product either toxic or clinically ineffective). Such alterations may be based on changes in absorption or excretion. Phamacodynamic interactions are related to toxicity or activity. Examples would include the simultaneous use of several nephrotoxic agents, or the use of products that bind to the same site (and thus may prove antagonistic).
Nucleoside Reverse Transcriptase Inhibitors
Table 91-2 summarizes the major interactions for products within this class, which are more limited than those for other classes of antiretrovirals. Only in the case of didanosine is absorption affected by gastric pH or by other products metabolized in the liver. All antiretrovirals within this class must be absorbed and metabolized by cells (intracellular phosphorylation).

Table 91-2. Major interactions for nucleoside reverse transcriptase inhibitors

Intracellular phosphorylation of zidovudine is inhibited by ribavirin, whereas both zidovudine and stavudine compete for the same intracellular enzymes (and thus inhibit each other). Didanosine is unstable in gastric acid and is therefore manufactured with buffers. Medications that are acidic (indinavir) may alter the bioavailability of didanosine, and those that require acid for absorption (ketoconazole, itraconazole) should not be administered at the same time. The buffering agents in didanosine interfere with the absorption of tetracycline and fluoroquinolones. Stavudine may cause peripheral neuropathy and should be cautiously employed with other agents capable of inducing this adverse reaction. Nevertheless, the combination of stavudine and didanosine appears to be well tolerated.
Protease Inhibitors
PIs are major components of most intensive regimens for the management of HIV/AIDS, but they can be associated with major, life-threatening drug interactions. Agents to avoid with most PIs include astemizole (Hismanal), cisapride (Propulsid), and terfenadine (Seldane). Others to use with extreme caution with at least some of these (especially ritonovir) include amiodarone, clozapine, diazepam, flurazepam, meperidine, midazolam, ergot alkaloids, quinidine, rifabutin, triazolam, and zolpidem. Table 91-3 provides data on some of the most important of these but is not meant to be inclusive. In general, medications that enhance by-products that inhibit the cytochrome system, especially CYP 3A4, must be avoided or else utilized with extreme caution. Such a product is ketoconazole; effects of itraconazole have not been well studied. Alternatively, agents that increase the metabolic rates of PIs (rifampin, barbiturates, phenytoin) may substantially lower the effective concentrations of PIs. Rifampin is the most potent of these and generally should not be coadministered with PIs. Potentially fatal interactions between PIs and terfenadine or astemizole may occur because of enhanced levels of these histamine receptor antagonists. Quinidine and cisapride may be rendered esssentially inert when coadminsitered with PIs.

Table 91-3. Major interactions with protease inhibitors

The bioavailability of saquinavir, even in its newer soft-gel form (Fortovase), is tenuous in comparison with that of other PIs. Agents associated with CYP 3A4 induction may decrease saquinavir levels to the extent that the drug is rendered impotent. In contrast, agents such as ritonavir, which are potent inhibitors of CYP 3A4, enhance the bioavailability of saquinavir by about 50 to 100 times, making this dual PI combination therapeutically viable.
Ritonavir causes numerous and conflicting interactions within the cytochrome systems. Thus, it is difficult to understand intellectually how it interfaces with other agents, and it should be used with caution when other products with hepatic metabolism are coadministered. In addition to being the most potent inhibitor of CYP 3A4, it has the capacity either to inhibit or to induce other isoenzymes within the system. It is also likely that interactions may exist that have yet to be fully investigated. Examples of agents to be used with great caution include serotonin reuptake inhibitors, tricyclic antidepressants, anticonvulsants, antiarrhythmics, lovastatin and simvastatin, and rifabutin.
Nelfinavir and indinavir are less potent inhibitors of CYP 3A4 than is ritonavir. Selected agents that include terfenadine, astemizole, and cisapride are contraindicated. Indinavir requires acid for absorption and cannot be taken on a full stomach. Nor can it be coadministered with didanosine.
Non-nucleoside Reverse Transcriptase Inhibitors
Like the PIs, these agents are metabolized by the cytochrome P-450 system. Delavirdine is an enzyme inhibitor, whereas nivirapine is an inducer. Interactions with other agents are complex and incompletely studied. In general, astemizole, terfenadine, cisapride, midazolam, triazolam, rifampin, ergot alkaloids, and phenytoin should be used with caution. Levels of agents that include quinidine, warfarin, dapsone, and clarithromycin will be enhanced if they are administered with delavirdine. Delavradine will enhance the levels of selected PIs that include indivavir and saquinavir. Table 91-4 summarizes selected available data. (R.B.B.)

Table 91-4. Interactions with non-nucleoside reverse transcriptase inhibitors

Cretton-Scott E, Commadossi JP. Drug interactions in HIV therapy. Northwestern University Reports on HIV/AIDS 1998;2:1–9.
This article is concise and readable. Charts are clear and not intended to be encyclopedic. The authors counsel care givers of AIDS patients to be thorough in obtaining drug histories and to be alert to drug interactions not yet reported.
McDonald CK, Gerber JG. Avoiding drug interactions with antiretroviral agents [Parts 1 and 2]. J Respir Dis 1998;19:24–25,103–113.
An extensive two-part review of drug interactions in HIV-infected patients. The authors provide contemporary information concerning mechanisms of potential interactions and depict interactions by class of antiretroviral.
Piscitelli SC, et al. Drug interactions in patients infected with human immunodeficiency virus. Clin Infect Dis 1996;23:685–693.
One of several excellent recent overviews detailing problems with drug interactions in patients with HIV/AIDS. The authors assess mechanisms of drug interactions and provide several tables outlining important examples of significant interactions. Some of the tables provide information about the potential severity of selected interactions.

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