analysis of data from phase II and III trials showed that the 'Quad' single-tablet regimen
has antiviral efficacy at least as good as comparison regimens and is
associated with fewer adverse events than Atripla
or ritonavir-boosted atazanavir (Reyataz),
researchers reported on Monday at the 52nd Interscience Conference on
Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.
Gilead Science's four-in-one 'Quad' coformulation contains the next-generation integrase inhibitor elvitegravir, the novel
boosting agent cobicistat, and tenofovir DF/emtricitabine (FTC; the latter two are the drugs in Truvada). It was approved by the US Food
and Drug Administration in August 2012 for adults starting HIV treatment for
the first time and is marketed under the brand name Stribild in the US.
Approval was based on study data
showing that Stribild suppresses HIV
viral load as effectively as two widely used, guidelines-recommended
antiretroviral regimens. At ICAAC, David
Ward from Dupont Circle Physicians Group presented findings from a
pre-specified integrated analysis of safety and efficacy in three of these
102: a phase III head-to-head comparison of Stribild
(efavirenz/tenofovir/emtricitabine single-tablet regimen) in 700
103: a phase III comparison of Stribild
versus ritonavir-boosted atazanavir plus tenofovir DF/emtricitabine in 700
previously untreated patients.
104: a smaller phase II study comparing Stribild
versus Atripla in 75 treatment-naive
analysis included a total of 749 participants taking Stribild, 375 taking Atripla,
and 355 taking boosted atazanavir.
characteristics were similar across the three regimen groups. About 90% were
men, two-thirds were white, the median age was about 38 years and the median
CD4 T-cell count was approximately 380 cells/mm3.
The Quad pill
demonstrated a high rate of virological suppression in all studies, matching
that of comparison regimens. At 48 weeks, 89% of Stribild recipients, 84% of Atripla
recipients and 87% of atazanavir recipients achieved virological response, defined
as HIV RNA less than 50 copies/mL.
CD4 cell increases
at week 48 were also similar in all three regimen arms: 224, 203 and 211
cells/mm3, respectively. Virological suppression and CD4 cell gains
were consistent across subgroups stratified by demographic characteristics,
baseline HIV viral load and baseline CD4 count.
Stribild was generally safe and well tolerated,
with mostly mild-to-moderate side-effects. Overall rates of study
discontinuation were similar in all regimen arms at around 12%. Rates of serious
adverse events (9, 7 and 9%, respectively) and adverse events leading to drug
discontinuation (4, 5 and 5%) were also statistically equivalent. Mortality
was less than 1% in all groups.
However, Stribild recipients reported
significantly fewer neuropsychiatric side-effects such as abnormal dreams and dizziness
(43 vs 62%) and less skin rash (18 vs 28%) than those taking Atripla, and less bilirubin elevation
than those taking boosted atazanavir.
Stribild was associated with significantly
smaller increases in total, LDL and HDL cholesterol compared with Atripla, and smaller triglyceride
increases compared with boosted atazanavir.
Stribild recipients experienced an early
increase in serum creatinine –
a potential marker of impaired kidney function – but levels soon stabilised. At 48
weeks, the increase in the Stribild
arm was greater than that seen with Atripla,
but similar to that of atazanavir (median +0.13, +0.01 and +0.08 mg/dL,
respectively). Less than 1% of participants across arms discontinued therapy
due to kidney problems. People who stopped Stribild
for this reason showed improvement after discontinuation, but not necessarily
to baseline levels, according to Ward.
The researchers concluded that the Stribild single-tablet regimen
"demonstrated high rates of virologic suppression comparable to [Atripla] and [atazanavir/ritonavir +
tenofovir/emtricitabine] with potential to overcome toxicities, such as
neuropsychiatric symptoms, rash, and hyperlipidemia".
early small increase in creatinine that stabilizes is expected" with Stribild due to inhibition of renal
tubule secretion by cobicistat, they added.
While this is not thought to be problematic itself,
Ward explained that it raises the issue of how to differentiate cobicistat-related creatinine increases
from uncommon kidney toxicity associated with tenofovir. Stribild
prescribing information will include a threshold level indicating when the
regimen should be stopped.