Elvitegravir in Treatment-Experienced People

Elvitegravir is an emerging integrase inhibitor. When elvitegravir is taken with a low dose of the drug ritonavir (Norvir), the concentration of elvitegravir in the blood rises and remains elevated for about a day. The manufacturer of elvitegravir, Gilead Sciences, is also developing another pharmacokinetic (PK) booster called cobicistat, which will be co-formulated with elvitegravir in the future.

Presently, raltegravir (Isentress) is the only integrase inhibitor approved by regulatory authorities. Raltegravir is active against strains of HIV that are resistant to several classes of anti-HIV drugs, such as:

• nukes (nucleoside analogues)
• non-nukes (NNRTIs)
• protease inhibitors

Elvitegravir is also effective against such drug-resistant strains of HIV. In a Phase II study that ran for 48 weeks, elvitegravir when taken as part of combination therapy was effective in significantly reducing viral load in treatment-experienced patients.

Researchers have also conducted a randomized placebo-controlled study comparing elvitegravir to raltegravir in treatment-experienced people. After one year, elvitegravir was found to be roughly equivalent to raltegravir in its effectiveness.

Study Details

Clinics in Canada, Australia and the U.S. screened 1,335 HIV-positive volunteers to find potential participants for this clinical trial. Eligible volunteers were randomly assigned to one of the following study groups:

• elvitegravir 150 mg and ritonavir 100 mg, both drugs once daily + background regimen
• raltegravir 400 mg twice daily + background regimen

All participants had blood samples drawn so that their virus' resistance to therapy could be analysed. Based on this testing, doctors selected a protease inhibitor that was "fully active" against their HIV. A third anti-HIV drug was also included. This third drug, which may or may not have had anti-HIV activity (depending on the person's resistance profile), was one of the following:

• a nuke
• maraviroc (Celsentri)
• etravirine (Intelence)

Overall, 351 volunteers were assigned to receive elvitegravir and 351 others to receive raltegravir.

All participants received placebos to help disguise who received which integrase inhibitor. Some placebos had to be taken twice daily.

The average profile of participants at the start of the study was as follows:

• 82% men, 18% women
• age -- 45 years
• hepatitis B virus co-infection -- 4%
• hepatitis C virus (HCV) co-infection -- 15%
• viral load -- 24,000 copies/ml
• 26% of participants had a viral load greater than 100,000 copies/ml
• 36% of participants had been diagnosed with AIDS

Commonly used protease inhibitors were darunavir (Prezista), followed by lopinavir-ritonavir (Kaletra) and atazanavir (Reyataz). Less-commonly used protease inhibitors were fosamprenavir (Telzir) and tipranavir (Aptivus).

The study is scheduled to last for two years and results from the first year have been made available.

Results -- Effectiveness

After one year, the proportion of participants with a viral load less than 50 copies/ml were distributed as follows:

• elvitegravir -- 59%
• raltegravir -- 58%

Changes in CD4+ cell counts after one year were as follows:

• elvitegravir -- 119 more CD4+ cells
• raltegravir -- 127 more CD4+ cells

As the differences in viral load and CD4+ count between regimens were minor, elvitegravir can be considered to be no worse than raltegravir (the statistical term for this is "non-inferior").

Similar proportions of participants in each group were able to quickly suppress HIV. This effect is unique to integrase inhibitors.

Effectiveness Within Sub-Groups of People

The data were also analysed according to the composition of different groups of participants. For instance, in some previous studies of other drugs, participants with high viral loads (more than 100,000 copies/ml) did not always respond as quickly and as well to therapy as people with lower viral loads.

Rates of virologic failure among people with high viral loads in this study were not significantly different between the study groups:

• elvitegravir -- 27 of 90 participants
• raltegravir -- 28 of 90 participants

The pattern of resistance mutations that developed among participants in this study suggests that, in general, HIV that is resistant to elvitegravir will likely also be resistant to raltegravir and vice versa.

Both integrase inhibitors worked well with the protease inhibitors used in this study.

Complications and Side Effects

Here are potential side effects that occurred that were at least moderate in intensity:

Diarrhea

• elvitegravir -- 12%
• raltegravir -- 7%

Depression

• elvitegravir -- 5%
• raltegravir -- 4%

Bone and/or Joint Pain

• elvitegravir -- 4%
• raltegravir -- 2%

Although elvitegravir users experienced more diarrhea than raltegravir users, this decreased somewhat after the first month of use. No one left the study because of diarrhea.

Overall, 23% of participants taking elvitegravir and 20% taking raltegravir reported side effects. Serious side effects occurred in 1% of elvitegravir users and 2% of raltegravir users.

Two participants taking elvitegravir and eight taking raltegravir died during the study. However, given the causes of their death -- complications of HCV co-infection, sudden heart failure, heroin overdose, car accidents and so on -- it seems unlikely that either elvitegravir or raltegravir was the cause of their deaths.