The FDA reviewed health-related information collected from 1,408 HIV-positive people who participated in two pivotal clinical trials.
In a trial called GS-US-236-0102 (we shorten this to trial '102), researchers compared the following regimens in a randomized, placebo-controlled design:
In trial GS-US-236-0103 (shortened to trial '103), researchers compared the following regimens also in a randomized, placebo-controlled design:
As both studies were of a similar design, the FDA reviewers often pooled or combined the data from these studies when conducting their analysis.
In total, 1,408 participants were recruited and distributed as follows:
In summary, the FDA found that the Quad is an effective therapy for HIV infection. The agency also found that the safety profile was "generally acceptable." The reviewers noted that a small but "disproportionate number of renal adverse events leading to [premature discontinuation from the studies] occurred in Quad [users] compared to [participants receiving other study regimens]."
So far, we do not have many details about participants. However, we do know that 90% were men and 10% were women. The average age was 38 years and prior to these studies participants had not previously taken treatment.
Gilead submitted data collected after participants had been in the studies for 48 weeks.
The main goal of the studies was to assess the proportion of participants whose viral load was less than 50 copies/ml at the 48th week. This result was distributed as follows:
Based on the statistics underpinning the study's design, these results suggest that the Quad is roughly equivalent (the technical term is "non-inferior") in potency to Atripla.
There were no major differences in efficacy when sub-group analyses were done examining gender, race, region, viral load at the start of the study, CD4+ counts and so on. However, only about 10% of participants were women. This gender imbalance will have other implications, which will be discussed at the end of this report on the Quad.
At week 48, increases in CD4+ cell counts, compared to their values at the start of the study, were not significantly different among all regimens in the study as the following shows:
This drug works in a similar way to the integrase inhibitor raltegravir (Isentress) -- by interfering with an enzyme called integrase. This interference by elvitegravir or raltegravir helps to block HIV's ability to take over a cell and turn it into a mini virus factory.
In laboratory experiments with cells, elvitegravir was tested against HIV collected from different regions of the world. This drug is active against different strains, or clades, of HIV, including clades A, B, C, D, E, F, G and O.
Strains of HIV that have become resistant to elvitegravir are also likely to be resistant to raltegravir (and vice versa).
The purpose of cobicistat is to boost the level of elvitegravir. Cobicistat does this by interfering with enzymes found in the intestine and liver -- places where elvitegravir is processed or broken down. These enzymes are called CYP3A4 and CYP2D6. By reducing the activity of these enzymes, cobicistat helps to delay the breakdown of elvitegravir, and so the concentration of elvitegravir in the blood remains elevated for about a day. This allows for once-daily dosing of the Quad.
Drugs such as cobicistat that are used to boost and maintain the level of other drugs in the body are called pharmacokinetic (PK) enhancers or boosters. An example of a commonly used PK booster is the protease inhibitor ritonavir.
When ritonavir was first introduced in the mid-1990s it was meant to be taken at a dose of 600 mg twice daily as part of potent combination anti-HIV therapy, commonly called ART or HAART. However, researchers in Ottawa quickly found that lower doses of ritonavir could be used to boost the level of other protease inhibitors. This made ritonavir more tolerable and resulted in greater efficacy. Today ritonavir is most commonly used at a dose of 100 or 200 mg once daily to boost these other protease inhibitors:
The FDA notes that cobicistat has a similar shape or structure (a "structural analogue") to ritonavir. In theory, cobicistat is not supposed to have anti-HIV activity. In lab experiments with cells and HIV, Gilead scientists could not detect anti-HIV activity from cobicistat.
Yet in analysing a limited number of blood samples from participants who took the Quad and whose regimen failed, Gilead made a surprising finding: 9 out of 14 people had HIV that had mutations in its protease gene. This would have been expected had they taken a protease inhibitor before. Moreover, in 3 of the 9 participants, the mutations in the protease gene allowed HIV to resist some protease inhibitors.
This finding is very surprising because prior to the study all participants who received the Quad had not previously been exposed to protease inhibitors or any other ART. Also, cobicistat is not supposed to have antiviral activity. The FDA is not certain why these resistance mutations occurred or what it may mean. The agency states that "this issue will require careful follow up."
As cobicistat is similar in shape and activity to the PK booster ritonavir, it should be expected that, like ritonavir, it will affect the body's processing of many drugs. This means that there is much potential for drug-drug interactions potentially enhancing existing drug side effects, causing new ones or altering the effectiveness of elvitegravir or another drug.
Due to this potential, the FDA recommends that Quad users do not take the antibiotic rifabutin (Mycobutin).
Cobicistat has a complex interaction with oral female contraceptives (commonly called "the Pill") and the FDA is studying how to advise doctors who wish to prescribe both the Quad and the Pill.
The full range of cobicistat-related drug interactions is not known and studies are underway or planned with opiate substitution therapies such as methadone and buprenorphine as well as the anti-HCV (hepatitis C virus) agents boceprevir (Victrelis) and telaprevir (Incevik).
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