[NATAP] Integrase Inhibitors in Trials

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Integrase Inhibitor in Phase II

Reported by Jules Levin

14th Intl HIV Drug resistance Workshop

June 7-11, 2005

Quebec City, Canada

The Merck integrase inhibitor is in phase II studies in patients. The drug appears promising. Another integrase inhibitor is being developed by Gilead and the initial study of this drug is screening for enrollment now.

“Context dependent effects of mutations associated with resistance to inhibitors of HIV-1 integrase strand transferâ€

--the data from this study suggest the possibility that integrase inhibitors may be able to be used sequentially as they may limited cross resistance. The gilead integrase has started in clinical study, recruitment for the study has started

DJ Hazuda and the MRL HIV-1 Drug Discovery

Team

Merck Research Laboratories, West Point, PA, USA

Integrase strand transfer inhibitors (InSTIs) have been shown to be effective inhibitors of integration and HIV-1 replication in vitro and in vivo. Compounds belonging to the diketo acid and naphthyridine structural series are among the most well studied InSTIs as the first integrase inhibitors to have demonstrated efficacy in vitro and in SIV-1 infected rhesus and HIV-1 infected patients, respectively.

Although structurally distinct, these compounds have identical mechanisms of action and compete for binding to the same site on the integrase strand transfer complex. We are interested in understanding the potential for cross-resistance between structurally diverse InSTIs and have selected viral variants resistant

to InSTIs in vitro and in vivo.

With a variety of diketo acids and napthyridines we have observed that resistance is generally associated with multiple mutations in integrase that accumulate progressively during the course of selection and result in impaired replication capacity in vitro. We have recently noted a similar effect in rhesus macaques infected with SIVmac239 treated with L-870812 monotherapy over the course of 9 months.

By analysing a series of site directed HIV-1 mutants containing one or more mutations in a various combinations we now show that resistance to a given

InSTI is dominated by a specific primary mutation which engenders measurable albeit generally low level resistance and that secondary mutations which have no

effect alone strikingly augment the level of resistance when combined but only in the context of a specific primary mutation. These results are consistent with the observation that distinct secondary mutations appear to be selected in the context of different primary mutations. A striking example of these phenomena was observed with two different primary mutations at residue155: N155S selected in vitro and N155H observed in rhesus macaques. The secondary mutation A91R selected after prolonged administration of L-870812 in rhesus macaques was shown to enhance resistance when combined with N155H while having little or no affect in the context of N155S.

These analyses provide further evidence to support previous studies suggesting it is possible to identify InSTIs which exhibit distinct resistance profiles and limited cross resistance.