Page 185 - HIV/AIDS Guidelines

RNA, with or without ARV dosage adjustment and therapeutic drug monitoring (TDM), may be warranted.
For example, the rifamycins (i.e., rifampin and, to a lesser extent, rifabutin) are CYP3A4 inducers that can
significantly reduce plasma concentrations of most PIs and NNRTIs. 4-5 Because rifabutin is a less potent
inducer, it is generally considered a reasonable alternative to rifampin for the treatment of tuberculosis (TB)
6
when it is used with a PI-based regimen, despite wider experience with rifampin use. Tables 15a and 15b list
dosage recommendations for concomitant use of rifamycins and other CYP3A4 inducers with PIs and
NNRTIs.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Unlike PIs and NNRTIs, NRTIs do not undergo hepatic transformation through the CYP metabolic pathway.
Some, however, do have other routes of hepatic metabolism. Significant pharmacodynamic interactions of
NRTIs and other drugs have been reported. They include increases in intracellular drug levels and toxicities
9
when didanosine (ddI) is used in combination with hydroxyurea 7-8 or ribavirin, additive bone marrow
10
suppressive effects of zidovudine (ZDV) and ganciclovir, and antagonism of intracellular phosphorylation
11
with the combination of ZDV and stavudine (d4T). Pharmacokinetic interactions have also been reported.
However, the mechanisms of some of these interactions are still unclear. Examples of such interactions
12
include increases of ddI concentration in the presence of tenofovir (TDF) and decreases in ATV
13
concentration when ATV is coadministered with TDF. Table 15c lists significant interactions with NRTIs.
CCR5 Antagonist

Maraviroc (MVC), the first Food and Drug Administration (FDA)-approved CCR5 antagonist, is a substrate
of CYP3A enzymes and P-glycoprotein. As a consequence, the concentrations of MVC can be significantly
increased in the presence of strong CYP3A inhibitors (such as RTV and other PIs, except for TPV/r) and are
reduced when used with CYP3A inducers (such as EFV or rifampin). Dose adjustment is necessary when
MVC is used in combination with these agents. (See Table 16b or Appendix B, Table 6 for dosage
recommendations.) MVC is neither an inducer nor an inhibitor of the CYP3A system and does not alter the
pharmacokinetics of the drugs evaluated in interaction studies to date.

Integrase Inhibitor

Raltegravir (RAL), an HIV integrase strand transfer inhibitor, is primarily eliminated by glucuronidation that
is mediated by the uridine diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 enzymes. Strong inducers
of UGT1A1 enzymes (e.g., rifampin) can significantly reduce the concentration of RAL. (See Table 15e for
14
dosage recommendations.) Other inducers of UGT1A1, such as EFV and TPV/r, can also reduce RAL
concentration. A pharmacokinetic interaction should be considered if optimal virologic response is not
achieved when these drugs are used in combination.

Fusion Inhibitor

The fusion inhibitor enfuvirtide (T-20) is a 36–amino acid peptide that does not enter human cells. It is
expected to undergo catabolism to its constituent amino acids with subsequent recycling of the amino acids
in the body pool. No clinically significant drug-drug interaction has been identified with T-20 to date.

References

1. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med.
2001;344(13):984-996.
2. Acosta EP. Pharmacokinetic enhancement of protease inhibitors. J Acquir Immune Defic Syndr. 2002;29 Suppl 1:S11-18.
3. Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency
virus protease by coadministration with ritonavir. Antimicrob Agents Chemother. 1997;41(3):654-660.

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents K-15

Downloaded from http://aidsinfo.nih.gov/guidelines on 12/8/2012 EST.