Once-daily elvitegravir matches raltegravir

Jean-Michel Molina from Hôpital Saint Louis, Paris. ©IAS/Marcus Rose/Worker's Photos
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The experimental HIV integrase inhibitor elvitegravir works as well as raltegravir (Isentress) for treatment-experienced people with extensive drug resistance, and was well tolerated overall, according to data presented at the sixth International AIDS Society conference (IAS 2011) this week in Rome.

Integrase inhibitors prevent HIV from integrating its genetic material into the chromosomes of a host cell, a requirement for viral replication. The sole approved drug in this class, raltegravir, has enabled many highly treatment-experienced patients to bring their viral load under control, but resistance can develop if it is used without enough other active drugs.

Elvitegravir is a next-generation integrase inhibitor that can be taken once daily, whilst raltegravir is taken twice daily. But it must be used with a boosting agent, either ritonavir (Norvir) or the new pharmacoenhancer cobicistat. Elvitegravir and cobicistat are part of a single-tablet regimen known as the Quad pill (along with tenofovir/emtricitabine) that is being tested in treatment-naive people.

Glossary

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

treatment-experienced

A person who has previously taken treatment for a condition. Treatment-experienced people may have taken several different regimens before and may have a strain of HIV that is resistant to multiple drug classes.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

phase III

The third and most definitive stage in the clinical evaluation of a new drug or intervention, typically a randomised control trial with the new intervention compared to an existing therapy or a placebo, in large numbers of participants (typically hundreds or thousands). Trial results are used to evaluate the overall risks and benefits of the drug and provide the information needed for regulatory approval.

nucleotide

A building block of DNA or RNA, chemical structures that store genetic information. 

At the IAS conference, Jean-Michel Molina from Hôpital Saint Louis in Paris reported findings from Study 183-0145, the first randomized, head-to-head study of elvitegravir vs raltegravir for treatment-experienced people.

This international Phase 3 study included 702 participants. Most were men and the average age was 45 years. The mean CD4 cell count was approximately 260 cells/mm3, nearly half had CD4 counts less than 200 cells/mm3, and one-quarter had high viral load (> 100,000 copies/ml).

About two-thirds had virus resistant to two or more antiretroviral drug classes. However they were able to construct viable regimens that included a fully active ritonavir-boosted protease inhibitor (the ritonavir acts as a booster for elvitegravir as well) and an active third agent such as etravirine (Intelence), maraviroc (Celsentri) or a nucleoside/nucleotide reverse transcriptase inhibitor. Boosted darunavir (Prezista) and tenofovir (Viread) were the most commonly used other drugs.

Participants were randomly assigned to receive either 150mg elvitegravir once daily (dose adjusted if used with certain drugs) or 400mg raltegravir twice-daily. The researchers looked at proportions of patients achieving viral load suppression at 48 weeks; the study is continuing to follow patients to the 96 week point.

Elvitegravir and raltegravir were found to be equally effective, with 59% and 58%, respectively, achieving HIV RNA < 50 copies/mL. About 20% in both arms experienced virological failure. CD4 cell gains were also similar at around 140 cells/mm3 in both groups.

Both study drugs were well-tolerated overall and few people discontinued due to side effects (3% vs 4%, respectively). Adverse events and laboratory abnormalities were generally similar, though more elvitegravir recipients reported diarrhoea (12% vs 7%). About 20% of patients who experienced virological failure developed integrase resistance mutations.

The researchers concluded, on this basis, that elvitegravir was non-inferior to raltegravir when given with an active boosted protease inhibitor.

References

Molina J-M et al. Elvitegravir once-daily is non inferior to raltegravir twice-daily in treatment experienced patients: 48 week results from a phase 3 multicenter, randomized, double blind study. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, abstract WELBB05, 2011.

View abstract WELBB05 on the conference website

This news report is also available in French