"Quad" Single-tablet Regimen Shows Continued HIV Suppression
at 48 Weeks
Gilead Science's experimental "Quad" pill -- a once-daily
single-tablet coformulation containing the new integrase inhibitor
the novel boosting agent cobicistat (GS 9350), and tenofovir
plus emtricitabine (the drugs in the Truvada
pill) -- continued to demonstrate potent antiviral activity
and good tolerability at 48 weeks, according to data presented
this week at the 50th Interscience Conference on Antimicrobial
Agents and Chemotherapy (ICAAC 2010).
In a second comparison, cobicistat worked as well as ritonavir
as a booster for atazanavir, with similar changes in kidney
approved, elvitegravir will be the second integrase inhibitor to enter
the market. Unlike raltegravir, it requires a pharmacoenhancer, or boosting
agent, to reach optimal levels in the body. Cobicistat interferes with
liver enzymes that process other drugs, thereby raising the latter drug's
concentration in the blood. In contrast with ritonavir
(Norvir), the only currently approved booster, cobicistat has no
anti-HIV activity of is own.
Results at week 24 from studies of the Quad pill and of cobicistat
as a booster for the protease inhibitor atazanavir were presented this
past February at the Conference on Retroviruses and Opportunistic Infections
At ICAAC, Rick Elion from the Whitman Walker Clinic and colleagues presented
48 week findings from Study 236-0104, a Phase 2 trial comparing the
elvitegravir/cobicistat/tenofovir/emtricitabine Quad coformulation versus
in previously untreated HIV patients. They also presented data from
a comparison of atazanavir boosted with either cobicistat or ritonavir.
Quad vs Atripla
Study 236-0104 included 71 treatment-naive participants who were randomly
assigned (2:1) to take the Quad pill or Atripla once-daily for 48 weeks.
Most participants (about 90%) were men, the average age was about 35
years, and about 75% were white. All had a baseline viral load of >
5000 copies/mL (mean of about 40,000 copies/mL) and no resistance to
NRTIs, NNRTIs, or protease inhibitors. The average CD4 count was approximately
an intent-to-treat (missing = failure) analysis at 48 weeks, 90%
of participants in the Quad group achieved viral load < 50 copies/mL,
compared with 83% in the Atripla group, showing that the Quad pill
was non-inferior to Atripla.
an analysis with missing patients excluded, 96% in the Quad group
and 95% in the Atripla group achieved undetectable viral load.
CD4 count gains (which had been similar at week 24) were now greater
in the Quad arm compared with the Atripla arm (240 vs 162 cells/mm3,
participants in each arm discontinued their study drug early due;
none in the Quad arm and 1 in the Atripla arm did so due to adverse
patients in the Quad arm experienced drug-related adverse events
of any severity, compared with 57% in the Atripla arm.
difference was largely attributable to fewer central nervous system
(CNS) side effects in the Quad arm.
estimated glomerular filtration rate (eGFR, a calculation of kidney
function) was worse in the Quad arm than in the Atripla arm at 48
weeks (change of -20 mL/min or -14% vs -6 mL/min or -4%, respectively).
findings led the investigators to conclude that the Quad pill "was
well tolerated and maintained a high rate of virologic suppression (90%)
that was non-inferior to [Atripla] (83%)."
Study 102, a large 96-week Phase 3 trial of the Quad pill versus Atripla,
is currently underway at more than 130 study sites in the United States
and Puerto Rico.
Cobicistat vs Ritonavir
The second trial, Study 216-0105, included 79 treatment-naive participants
who were randomly assigned (again 2:1) to receive 150 mg cobicistat
or 100 mg ritonavir, all with once-daily atazanavir plus tenofovir/emtricitabine
for 48 weeks. Patient characteristics were similar to those in the previous
study, except this trial included a higher proportion of people of color.
an intent-to-treat (missing = failure) analysis at 48 weeks, 82%
of participants in the cobicistat arm and 86% in the ritonavir arm
achieved HIV RNA < 50 copies/mL, not a significant difference.
an analysis with missing patients excluded, viral suppression rates
were 91% vs 96%, respectively.
taking cobicistat experienced a median CD4 cell gain of 230 cells/mm3
vs 206 cells/mm in the ritonavir arm, again not significantly different.
people in the cobicistat arm and 1 in the ritonavir arm discontinued
early due to adverse events.
of patients in the cobicistat arm and 48% in the ritonavir group
experienced any drug-related adverse events (mostly elevated bilirubin
associated with atazanavir).
48 weeks, mean eGFR decreased by about the same amount in the cobicistat
and Atripla arms (-13 mL/min or -12% vs -14 mL/min or -11%, respectively).
on these findings, the researchers concluded that cobicistat-boosted
atazanavir plus tenofovir/emtricitabine was safe and had efficacy similar
to ritonavir-boosted atazanavir plus tenofovir/emtricitabine through
Elevated serum creatinine and reduced eGFR observed at week 24 in people
taking cobicistat raised concern about potential kidney toxicity. Prior
studies of HIV negative volunteers showed that cobicistat may inhibit
kidney tubular secretion -- leading to elevated creatinine -- but does
not seem to cause significant nephrotoxicity. Caution is warranted,
however, especially when combining cobicistat with tenofovir, which
has been linked to kidney
Since creatinine is one of the factors in the equation used to compute
eGFR, researchers at CROI said that cobicistat alters estimated but
not actual GFR. At 48 weeks, the early changes in eGFR seen through
week 24 were stable, and in the booster comparison, eGFR decreases were
similar in the cobicistat and ritonavir arms.
Investigator affiliations: Whitman Walker Clinic, Washington, DC;
Therapeutic Concepts, P.A., Houston, TX; Capital Med. Associates, PC,
Washington, DC; Peter Shalit, MD, Seattle, WA; Southwest CARE Ctr.,
Santa Fe, NM; Gilead Sciences, Inc, Foster City, CA.
R Elion, J Gathe, B Rashbaum, and others. The
Single-Tablet Regimen of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir
Disoproxil Fumarate (EVG/COBI/FTC/TDF; Quad) Maintains a High Rate of
Virologic Suppression, and Cobicistat (COBI) is an Effective Pharmacoenhancer
Through 48 Weeks. 50th Interscience Conference on Antimicrobial
Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010.
Sciences. Gilead's Single-Tablet "Quad" HIV Regimen Maintains
High Viral Suppression Through 48 Weeks in Phase II Study. Press release.
September 13, 2010.