Phase II data positive for HIV drug

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The Pharmaceutical Journal
Vol 278 No 7448 p450
21 April 2007

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Phase II data positive for HIV drug

The first in a new class of drugs to treat HIV has shown promise in a phase II trial of patients with few remaining treatment options. Published last week in The Lancet (2007;369:1261), the study demonstrated superior viral control of raltegravir — a HIV-1 integrase inhibitor, formerly MK-0518 — over placebo at three different doses (see Panel below).

Study subjects

Investigators recruited 179 adult patients with:

• HIV-1 RNA viral load over 5,000 copies per ml

• CD4 cell counts over 50 cells per µl

• Documented resistance to at least one nucleoside reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor and one protease inhibitor

All patients were given an optimised background regimen based on individual antiretroviral treatment history and were randomised to receive 200mg, 400mg or 600mg of raltegravir or placebo orally twice a day.

The primary endpoints of the study were change in patients’ viral load after 24 weeks and treatment safety. Compared with placebo, significant reductions in viral load (from baseline at week 24) were seen for patients receiving raltegravir 200mg (difference –1.45 log10 copies per ml, 95 per cent confidence interval –1.84 to –1.06; P<0.0001), raltegravir 400mg (–1.52, CI –1.90 to –1.14; P<0.0001) and raltegravir 600mg (–1.49, CI –1.85 to –1.13; P<0.0001).

The authors say that the safety of raltegravir was similar to that of placebo, and no dose-related toxicities were identified.

They conclude: “The promising efficacy and tolerability profile of raltegravir suggests that this drug has the potential to become an important component of combination treatment regimens used to treat heavily pretreated patients failing current therapies with multidrug-resistant virus and limited treatment options.”

[Phase III investigations of the drug are already under way — early data were reported at a recent conference (PJ, 17 March, p303).]

Sebastian Kaulitzki/Dreamstime.com

HIV virion

HIV virion, three-dimensional model

Writing about the drug’s pharmacology and clearance in an accompanying comment (ibid, p1235), Pedro Cahn and Omar Sued from the Department of Clinical Research, Fundación Huésped, Buenos Aires, say: “The integrase inhibitors target an essential enzyme for the HIV-1 virus that catalyses the insertion of HIV-1 DNA into the host’s cellular genome. This process is required for expression and high-level HIV-1 replication. Integrase also affects retrotranscription and viral assembly. Host cells lack this enzyme, hence toxicity at this level is not expected.”

They go on: “The major mechanism of clearance of raltegravir in human beings is UGT1A1-mediated glucuronidation. Raltegravir does not inhibit or induce cytochrome P450 enzymes, nor is it a substrate there, which implies that interactions with ritonavir and other drugs metabolised via this system are unlikely.”