Integrase Strand Transfer Inhibitors

INTEGRASE STRAND TRANSFER INHIBITORS

RALTEGRAVIR

Raltegravir is a pyrimidinone analog that binds integrase, a viral enzyme essential to the replication of both HIV-1 and HIV-2. By doing so, it inhibits strand transfer, the third and final step of provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells (Figure 49–4). It was initially licensed for use in treatment-experi-enced adult patients infected with strains of HIV-1 resistant to multiple other agents, but more recently has received approval for use in initial therapy as well. However, clinical experience is lim-ited in treatment-naïve patients.

Absolute bioavailability of raltegravir has not been established but does not appear to be food-dependent. The drug is metabo-lized by glucuronidation and does not interact with the cyto-chrome P450 system; therefore, it is expected to have fewer drug-drug interactions than many of the other antiretroviral agents. However, in combination with rifampin, a strong inducer of UDP-glucuronosyl transferase 1A1 (UGT1A1), the dose of raltegravir should be increased from 400 mg twice daily to 800 mg twice daily. Since polyvalent cations (eg, magnesium, calcium, and iron) may bind integrase inhibitors and interfere with their activ-ity, antacids should be used cautiously and taken separately from raltegravir.

Although virologic failure has been uncommon in clinical trials of raltegravir to date, in vitro resistance requires only a single point mutation (eg, at codons 148 or 155). The low genetic barrier to resistance emphasizes the importance of combination therapies and of adherence. Integrase mutations are not expected to affect sensitivity to other classes of antiretroviral agents.

Potential adverse effects of raltegravir include insomnia, headache, diarrhea, nausea, dizziness, and fatigue. Increases in cre-atine kinase may occur, with potential myopathy or rhabdomyolysis; there is minimal effect on serum lipids.