CROI: Experimental 'salvage' integrase inhibitor, elvitegravir (GS-9137) appears potent at higher doses

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Intermediate results from an ongoing phase II study in treatment-experienced patients of Gilead’s experimental once-daily, ritonavir-boosted integrase inhibitor, suggest that it is potent when used in higher doses and durable when it is combined with at least one other active drug, according to data presented as a late breaker to last week’s Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles. The drug now has a generic name, elvitegravir (el-vy-tegra-veer), but was previously known as GS-9137 and JTK-303.

Last year, a study presented to the same conference suggested that once daily 50mg elvitegravir boosted with 100mg ritonavir (Norvir) was potent following ten days of monotherapy, and resulted in a 2 log10 drop in viral load in all six participants on that dose.

However, longer-term data reported this year suggest that this potency is short-lived if elvitegravir is used as effective monotherapy – as was the case in 50% of this study’s participants whose HIV was genotypically resistant to all of their backbone drugs – and that virological rebound following resistance to elvitegravir appears within about two weeks. This is in contrast to the Merck integrase inhibitor, raltegravir, which has shown impressive results as functional monotherapy: 61% of participants in the BENCHMRK 1 & 2 studies of raltegravir achieved a viral load below 400 copies/ml at week 16 despite showing phenotypic sensitivity to no other antiretroviral drugs.


protease inhibitor (PI)

Family of antiretrovirals which target the protease enzyme. Includes amprenavir, indinavir, lopinavir, ritonavir, saquinavir, nelfinavir, and atazanavir.


Taking a drug on its own, rather than in combination with other drugs.

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.


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.

On the other hand, no resistance appeared to emerge in the participants who were also able to find at least one other active drug to combine with the integrase inhibitor. And the 47 participants on the highest elvitegravir dose who could combine it with at least one or more additional active drug(s) experienced median 2.1 log10 viral load declines sustained to 24 weeks.

Andrew Zolopa from California’s Stanford University presented 16- and 24-week data from this 48 week noninferiority study of 278 heavily treatment-experienced partipicants. At baseline, study participants – the majority of whom were white males, with an average age of 45 – had a mean viral load of 4.59 log10 copies/mL, a mean CD4 cell count of 185 cells/mm3 and their HIV had a median of eleven protease resistance mutations.

Originally, there were four arms to this study. Three groups of participants were randomised to receive once-daily elvitegravir 20mg (n=71), 50mg (n=71) or 125mg (n=73) boosted with 100mg ritonavir. Participants in the fourth arm (n=63) received a ritonavir-boosted protease inhibitor (PI) of their choice; primarily darunavir (Prezista) (49%) or tipranavir (Aptivus (27%). All four arms combined these drugs with two or more nucleoside/tide reverse transcriptase inhibitors (NRTIs) and about 20% in each arm also added T-20 (enfuvirtide, Fuzeon).

At week eight, however, after a high rate of virologic failure was observed in the 20mg elvitegravir arm, the study’s data safety monitoring board (DSMB) closed that arm. Of the 71 participants subsequently offered open-label 125mg elvitegravir, 85% took up the offer.

Around the same time, drug-drug interaction studies that had not been completed at the start of the trial suggested that there were no significant interactions between elvitegravir and either darunavir or tipranavir. Subsequently, participants in the two remaining elvitegravir dosing arms were allowed to add one of these PIs to their regimens.

Given these changes, Dr Zolopa presented both 16 week and 24 week data, since only four participants had added one of the allowed PIs prior to week 16, but by week 24 this had increased to 15% of all participants taking elvitegravir.

In intent to treat (ITT) analysis where missing equals failure, by week 16 the mean reduction in viral load was 1.2 logs10 in the comparison PI arm, 1.5 logs10 in the elvitegravir 50mg arm and 1.7 logs10 in the elvitegravir 125mg arm. Dr Zolopa noted that both doses of elvitegravir were noninferior to the comparison PI arm, and that the 125mg elvitegravir arm was statistically superior to the comparison PI arm (p=0.01). Very similar results were seen at week 24.

At week 16, a viral load below 50 copies/ml was seen in 38% and 40% of participants receiving 50mg and 125mg elvitegravir, respectively, compared to 30% in the comparison PI arm. This reduced to 32%, 36% and 27% by week 24, respectively, however. None of the differences were statistically significant.

Mean CD4 cell count increases at week 16 were 52, 61 and 28 cells/mm3 in the participants receiving 50mg or 125mg elvitegravir or a comparison PI, respectively. By 24 weeks, the increase in CD4 cells was similar in all three arms, at 53, 57 and 53 cells/mm3, respectively. Neither 16- nor 24-week differences were considered statistically significant, however.

At all doses, elvitegravir appeared to be as well-tolerated as the comparison PIs. No dose relationship was observed in either grade 3 or 4 adverse events or laboratory abnormalities, and similar, small numbers (3% or fewer) of participants in all four treatment arms discontinued due to adverse events.

"The story here,” Dr Zolopa said during his summing up, “[is that] we have a potent drug, but it is only good if there are other companion drugs available to use with it.”

During the question and answer session that followed, Dr Zolopa noted that there appear to be two separate mutation pathways by which HIV may become resistant to elvitegravir, and that this may lead to cross resistance with Merck’s raltegravir (MK-0518). He also suggested that elvitegravir’s genetic barrier to resistance “looks somewhere between NNRTIs and PIs.”

He noted said that phase III studies in treatment-experienced patients are now planned, utilising a 150mg tablet that is “bioequivalent to 125mg in this trial”.

Following some criticism of this study’s design – which resulted in half the participants receiving effective monotherapy – Gilead’s vice president of clinical research subsequently told Medscape that participants in the phase III study will receive “a minimum of two active agents in background therapy. That means, if you get placebo, you still have two active agents." He added that in order for this ideal to realised, Gilead is in discussions with other drug companies in order to allow participants to use a combination of different experimental agents in the study.


Zolopa AR. The HIV integrase inhibitor GS-9137 demonstrates potent antiretroviral activity in treatment-experienced patients. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 143LB, 2007.