Use of Raltegravir in Pediatric HIV-1 Infection

Marcia L. Buck, Pharm.D., FCCP, FPPAG; Kristi N. Hofer, Pharm.D; Michelle W. McCarthy, Pharm.D.; FASHP Susan B. Cogut, Pharm.D

Disclosures

Pediatr Pharm. 2012;18(1) 

In This Article

Mechanism of Action

Raltegravir inhibits the catalytic activity of HIV-1 integrase and blocks the strand transfer step in the integration of linear HIV-1 DNA into the host cell genome. As a result, raltegravir prevents formation of the HIV-1 provirus that is necessary for propagation of the viral infection. Raltegravir has demonstrated potent activity against HIV-1, including a wide range of isolates resistant to other antiretroviral therapies. In adults, a raltegravir dose of 400 mg twice daily as monotherapy produced a mean reduction in viral load of 1.66 log10copies/mL by day 10. Additive or synergistic activity has been demonstrated when raltegravir is administered along with nucleoside analog reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI).[2–5]

As with other antiretrovirals, raltegravir may induce viral mutation resulting in resistance to its effects. Resistance was identified in four of the 10 cases of treatment failure among the 563 treatment-naïve adult subjects enrolled in the STARTMRK trial. In the two BENCHMRK trials conducted in a total of 699 treatment-experienced adults, mutations were found in 76 of the 112 subjects with treatment failure.[3] More than 30 mutations in the integrase enzyme have been identified in cell culture and in treated patients.[4,6] The primary mutations include Y143C/H/R, Q148H/K/R, and N155H and result in a significant increase in viral replication capacity. Secondary mutations include E92Q, associated with the N155H mutation, and G140S, found with the Q148H mutation. These secondary mutations amplify resistance of the HIV-1 virus to raltegravir and return integrase activity back to that seen without the drug.

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