Indications of Cross-resistance between Integrase Inhibitors Elvitegravir and Raltegravir

By Liz Highleyman

As it replicates, HIV can develop mutations that make it resistant to antiretroviral drugs. In some cases, the emergence of resistance to 1 drug also produces cross-resistance to other similar agents in the same class.

Drug resistance is an important barrier to successful long-term therapy, although simultaneous use of multiple drugs from different classes can delay the emergence of resistance.

Integrase inhibitors, which prevent HIV from inserting its genetic material into a host cell's DNA, are a new class of drugs that work by a different mechanism than any of the approved antiretroviral agents.

While these new drugs have been shown to work against HIV that has developed resistance to the 3 major older antiretroviral drug classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors), integrase inhibitors may exhibit cross-resistance within their own class, according to data presented at the recent 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Sydney, Australia (July 22-25, 2007).

Edwin DeJesus, MD, and colleagues presented the first data on patients who started taking Merck's integrase inhibitor raltegravir (MK-0518) after experiencing virological rebound on Gilead Sciences' elvitegravir (GS 9137).

After receiving Institutional Review Board approval and informed consent, 2 patients with triple-class drug resistance who were experiencing virological failure on elvitegravir were switched to raltegravir 400 mg twice daily for 7 days, while staying on the same background regimen. At day 8, their full regimens was re-optimized.

Data on anti-HIV activity, laboratory safety tests, Phenosense GT genotypic resistance testing, and sampling for integrase sequencing were performed at baseline (when the drugs were switched) and during 24 weeks of follow-up.

Results

• Patient 1, at baseline, had a viral load of 10,700 copies/mL, a CD4 count of 204 cells/mm3, and was taking elvitegravir, tenofovir/emtricitabine (Truvada), and enfuvirtide (Fuzeon, T-20).

- At week 1, after switching to raltegravir, viral load fell to 7254 copies/mL, or by about 0.16 logs.

- After the patient's regimen was optimized by adding darunavir (Prezista), viral load fell to 808 copies/mL by week 4.

- By week 8, however, the patient's viral load began to rise again, exceeding 12,000 copies/mL by week 24.

- The patient's CD4 cell count reached 357 cells/mm3 after optimization, but had fallen to 180 cells/mm3 when last measured at week 24.

• Patient 2, at baseline, had a baseline viral load of 840 copies/mL, a CD4 count of 459 cells/mm3, and was taking elvitegravir plus Truvada.

- At week 1, after switching to raltegravir, viral load fell to 427 copies/mL, or by about 0.29 logs.

- After this patient's regimen was also optimized by adding darunavir, viral load fell below 50 copies/mL by week 4 and remained undetectable through week 24.

- The patient's CD4 cell count rose to 639 cells/mm3 at week 8, but had fallen back to 432 cells/mm3 when last measured at week 24.

• In Patient 1, HIV integrase sequencing at baseline and week 1 revealed similar mutation patterns, including K7R, S17N, V31I, V72I, T124N, T125A, I151V, V201I, V234L, and A265A/V.

• This patient also had evidence of other mutations suspected to be associated with resistance to one or both of the integrase inhibitors, including E138E/K, G140G/C, S147S/G, and Q148R (the latter of which persisted after switching to raltegravir).

• In Patient 2, the elvitegravir-related resistance mutation N155H emerged after elvitegravir failure.

• The altered regimens were well tolerated, and no adverse effects more serious than grade 1 were reported.

Conclusion

The researchers halted further enrollment in the study given the lack of significant virological activity observed after switching from elvitegravir to raltegravir.
"These data support the possibility that at least some cross-resistance occurs between elvitegravir and raltegravir," they concluded. "Data with drug levels were not available to assess the possibility of a negative drug-drug interaction."

Orlando Immunology Center, Orlando, FL; CRI New England, Boston, MA; George Washington University, Washington DC; Monogram Biosciences, San Francisco, CA.

08/14/07

Reference
E DeJesus, C Cohen, R Elion, and others. First report of raltegravir (RAL, MK-0518) use after virologic rebound on elvitegravir (EVT, GS 9137). 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Sydney, Australia, July 22-25, 2007. Abstract TUPEB032.