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New integrase inhibitor bictegravir works well for first-line HIV treatment
Liz Highleyman, 2017-07-25 06:30:00
A single-tablet regimen
containing the experimental integrase inhibitor bictegravir was as effective as
two widely used approved regimens for first-line therapy in a pair of phase 3
clinical trials, according to presentations at the 9th International AIDS
Society Conference on HIV Science (IAS 2017) this week in Paris, France.
strand transfer inhibitors are an effective and well-tolerated class of
antiretroviral drugs that are recommended in European and US HIV treatment
guidelines. Preclinical studies showed that Gilead
Sciences' next-generation integrase inhibitor bictegravir is potent, has a high
barrier to resistance and has a low potential for interactions with other medications.
At this year's
Conference on Retroviruses and Opportunistic Infections (CROI), Paul Sax of Brigham
and Women's Hospital in Boston presented results from a phase 2 clinical trial comparing
bictegravir to ViiV Healthcare's potent and popular dolutegravir (Tivicay), both taken with emtricitabine
and tenofovir alafenamide or TAF, Gilead's newer tenofovir formulation with
less kidney and bone toxicity.
bictegravir and dolutegravir were highly effective (97 vs 91% with
undetectable HIV RNA at week 48) and well tolerated, setting the stage for
larger phase 3 studies. These studies tested a once-daily combination pill
containing bictegravir, emtricitabine (FTC) and TAF – dubbed B/F/TAF until it
gets a brand name.
At this week's IAS
meeting, Sax presented data from a follow-up phase 3 trial (Study 1490) comparing
essentially the same regimens, but using the B/F/TAF coformulation instead of
separate pills. Participants in this blinded study received matching placebos
so that everyone took the same number of pills.
study enrolled 645 adults in Europe, North America, Latin America and Australia. About 80% were men and the
median age was 34 years. The median CD4 count was 440 cells/mm3,
about 10% had a low CD4 count below 200 cells/mm3 and about 20% had
a high viral load above 100,00 copies/ml. They had normal kidney function at baseline, with an estimated glomerular
filtration rate (eGFR) of at least 30 ml/min.
After 48 weeks of treatment,
B/F/TAF was shown to be non-inferior to the dolutegravir regimen, with 89 and
93% of participants in the respective study arms achieving undetectable viral
load (HIV RNA below 50 copies/ml). Virological failure was rare (4 and 1%,
respectively) and no one developed resistance to any of the study drugs.
Treatment was generally safe
and well tolerated in both study arms. More people stopped treatment early in
the B/F/TAF arm (3 vs <1%), but this was usually for reasons unrelated to
lack of efficacy or poor tolerability. The most common adverse events were
headache and diarrhoea, reported by about 12% of participants in both groups.
Few participants stopped treatment early due to adverse events (2 and 1%,
respectively). Estimated GFR declined less in the B/F/TAF group, and no one
discontinued due to kidney side-effects in either study arm. Blood lipid changes were
similar in both arms.
Joel Gallant of
the Southwest CARE Center in Santa Fe, New Mexico, reported results from another
phase 3 trial (Study 1489) that more closely reflects current clinical practice
for initial HIV treatment. This was a head-to-head comparison of two
single-tablet regimens: the B/F/TAF coformulation and the Triumeq combination pill containing dolutegravir, abacavir and
enrolled 629 participants in Europe and North America. Again, most (90%) were
men and the median age was approximately 32 years. The median CD4 count was
about 450 cells/mm3, about 10% had less than 200 cells/mm3
and 17% had a high viral load. Because they
could be randomised to either regimen, they had to be HLA B*5701 negative to
guard against abacavir hypersensitivity, and they could not have hepatitis B
virus (HBV), as none of the drugs in Triumeq are active against HBV, unlike tenofovir
At week 48,
virological response rates were 92% in the B/F/TAF group and 93% in the Triumeq group, again demonstrating
non-inferiority. Here, too, virological failure was rare (1 and <3%,
respectively). Among the five people who met criteria for resistance testing,
no integrase or NRTI (nucleoside reverse transcriptase inhibitor) resistance mutations were detected.
was well tolerated. There were no early discontinuations due to adverse events
in the B/F/TAF arm and four in the
Triumeq arm. Diarrhoea and headache were both reported by approximately 12%
of participants in both arms, but nausea was about twice as common with Triumeq (10 vs 23%). There were no notable
differences in markers of kidney and bone toxicity. Lipid levels rose modestly,
but were similar in both treatment arms.
looked at patient-reported outcomes, a metric commonly used in cancer trials
that is starting to be applied to HIV. Several outcomes differed significantly in
favour of B/F/TAF, including gastrointestinal symptoms, loss of appetite,
fatigue, fever, dizziness, anxiety and depression. Based on a sleep quality
index, more people on Triumeq
reported sleep disturbances or use of sleep medications. Researchers have
previously reported increased central nervous system side-effects with
Dr Gallant said
that two studies looking at B/F/TAF for treatment-experienced people switching
therapy are now fully enrolled. A study of B/T/TAF for women is expected to report
results in early 2018, and a study for adolescents and children is underway.
Gilead has submitted B/F/TAF for regulatory review by the European Medicines Agency
and the US Food and Drug Administration.
continue to look for treatment regimens with simple, convenient dosing that can
sustain virologic suppression with a safety profile that is appropriate for
most HIV patients,” Dr Gallant said in a Gilead press release. “In clinical
trials, the investigational regimen of [B/F/TAF] has been well tolerated with
low rates of discontinuations due to adverse events, a high barrier to
resistance and few drug interactions.”