Drug Interactions Among the Antiretroviral Agents
While further study is needed, data are accumulating regarding pharmacokinetic interactions among the various antiretroviral agents, especially those involving the HIV protease inhibitors and NNRTIs, and the need for dosage adjustments as a result of these interactions. While some pharmacokinetic interactions between antiretroviral agents can be used for therapeutic advantage (e.g., use of low-dose ritonavir to boost plasma concentrations of some other HIV protease inhibitors), other interactions can result in suboptimal drug concentrations and reduced therapeutic effects and should be avoided.
The pharmacokinetic interaction between ritonavir and other HIV protease inhibitors is now used for therapeutic advantage in various antiretroviral regimens. Low-dose ritonavir (100-400 mg daily) inhibits metabolism of other HIV protease inhibitors and increases plasma concentrations and prolongs the plasma half-lives of the drugs. Use of low-dose ritonavir in conjunction with another HIV protease inhibitor has been referred to as ritonavir pharmacokinetic enhancement or ritonavir-boosted therapy and some of these regimens (e.g., low-dose ritonavir with amprenavir, indinavir, lopinavir, saquinavir) are now considered preferred or alternative regimens for initial antiretroviral therapy (see Table 1).
Addition of low-dose ritonavir also is recommended to intensify HIV protease inhibitor-based regimens used in previously treated adults experiencing virologic failure. The antiretroviral activity of these regimens is due to the other HIV protease inhibitor since the dosage of ritonavir used (100-400 mg daily) is not considered a therapeutic dosage. A fixed-combination preparation of lopinavir and low-dose ritonavir is commercially available (Kaletra®); other ritonavir-boosted regimens involve administration of specified low doses of ritonavir and the other HIV protease inhibitor (e.g., amprenavir, atazanavir, indinavir, saquinavir).
Antimycobacterial Agents
The fact that pharmacokinetic interactions between some antimycobacterial agents (e.g., rifabutin, rifampin) and some antiretroviral agents (e.g., HIV protease inhibitors, NNRTIs) have been reported or are expected to occur must be considered when antimycobacterial therapy is indicated for the treatment of active tuberculosis or latent tuberculosis infection or for the prophylaxis or treatment of Mycobacterium avium complex (MAC) infections in HIV-infected patients who are receiving or are being considered for antiretroviral therapy. Because the management of these patients is complex and must be individualized, experts in the management of mycobacterial infections in HIV-infected patients should be consulted.
Illicit Drugs
Because HIV protease inhibitors and NNRTIs affect a wide range of enzymes in the cytochrome P-450 (CYP) enzyme system, the potential exists for interactions with many classes of recreational (illicit) drugs that are metabolized by these enzymes. Life-threatening reactions and at least one fatality have been reported secondary to interactions between methylenedioxymethamphetamine (MDMA, ecstasy) or γ-hydroxybutyrate (GHB, liquid ecstasy) and HIV protease inhibitors.
MDMA undergoes demethylenation principally by CYP2D6 but also is metabolized by CYP1A2, CYP2B6, and CYP3A4; concomitant use with inhibitors of these enzymes (e.g., HIV protease inhibitors, efavirenz) can result in substantial increases in MDMA exposure. Other amphetamines (e.g., methamphetamine; crystal meth, speed) also are metabolized by CYP2D6. In addition, metabolism of ketamine (special K) appears to be mediated principally by CYP2B6 and to a lesser extent by CYP3A4 and CYP2C9 and metabolism of PCP (angel dust, rocket fuel, killer weed) appears to be mediated by CYP3A4 and possibly by CYP2C11. Although metabolism of GHB has not been characterized, the drug may undergo first-pass metabolism mediated by the CYP isoenzyme system.
CYP3A4 appears to play only a small role in metabolism of cocaine and interactions between antiretroviral agents and cocaine have not been described. However, further study is needed to more fully evaluate possible interactions between cocaine and antiretroviral agents. Limited data suggest that CYP3A and CYP2C9 isoenzymes are involved in microsomal oxidation of tetrahydrocannabinol (THC), but the effects of THC are unlikely to be substantially attenuated by drugs that inhibit these enzymes. There is evidence that THC can decrease plasma concentrations of indinavir and concentrations of the active metabolite of nelfinavir (M8), but these effects are not likely to have a clinically important effect on efficacy of the antiretrovirals.
Because the margin of safety for many illicit drugs is narrow or poorly defined and the known or potential interactions between some of these drugs and antiretroviral agents is complex and potentially life-threatening, patients should be advised of the risk of serious consequences if they use these drugs while receiving antiretroviral therapy. In addition, pharmacokinetic interactions between methadone and HIV protease inhibitors (amprenavir, lopinavir, nelfinavir, ritonavir), NRTIs (abacavir), and NNRTIs (efavirenz, nevirapine) can occur and may result in decreased methadone concentrations; this possibility should be considered in HIV-infected individuals being treated for opiate addiction who are stabilized on methadone maintenance therapy since symptoms of opiate withdrawal can occur and modification of methadone dosage may be necessary.