REVIEW

CURRENT
OPINION Bictegravir
Vincenzo Spagnuolo a,b, Antonella Castagna a,b, and Adriano Lazzarin b

Purpose of review
In this review, we will highlight and discuss the recent efficacy and safety data of bictegravir (BIC), a novel
second-generation integrase strand transfer inhibitor (INSTI) that has been recently approved, in
coformulation with emtricitabine and tenofovir alafenamide (B/F/TAF), for the treatment of HIV-1 infection
in antiretroviral naı̈ve subjects and in those with suppressed viremia.
Recent findings
Preclinical data showed that BIC has a genetic barrier that is higher than that of raltegravir and elvitegravir
but is similar to that of dolutegravir (DTG), with retained activity in vitro against isolates containing
substitutions associated with resistance against other INSTIs. Its pharmacokinetic interaction risks appear to
be low. Results of the phase 3 GS-US-380-1489 and GS-US-380-1490 clinical trials showed that the
coformulation B/F/TAF is not inferior to the recommended DTG-containing regimens in naı̈ve subjects.
Moreover, B/F/TAF exhibited excellent tolerability, and no treatment-emergent resistance to any
component of the coformulation was observed. In addition, preliminary data support switching from DTG
and emtricitabine/tenofovir alafenamide or boosted protease inhibitor-containing regimens to B/F/TAF in
subjects with undetectable viremia.
Summary
The coformulation bictegravir/emtricitabine/tenofovir alafenamide is set to become a new option in the
management of patients who are antiretroviral naı̈ve and in those with suppressed viremia.
Keywords
antiretroviral naı̈ve subjects, bictegravir, coformulation, genetic barrier, second-generation integrase strand
transfer inhibitor, switch strategies

INTRODUCTION concerns of increased risk of neuropsychiatric

Since their availability in clinical practice, integrase
strand transfer inhibitors (INSTIs) have revolution-
ized antiretroviral therapy as their efficacy and
safety profile are more favorable than those of other
drug classes [1–3]. Furthermore, INSTIs are the
standard of care for initial therapy in combination
with two nucleoside reverse transcriptase inhibitors
(NRTIs) in different guidelines [4,5].
In the last decade, three INSTIs were successively
approved: raltegravir (RAL), elvitegravir (EVG), and
dolutegravir (DTG). RAL is not coformulated with
NRTIs, whereas EVG requires pharmacological
boosting by cobicistat [a cytochrome P450 (CYP)
3A4 inhibitor], resulting in a potential for drug–
drug interactions [6]. Moreover, RAL and EVG have a
lower barrier to drug resistance and share a cross-
resistance profile [7].
DTG was the first approved second-generation
INSTI and differs from RAL and EVG in its higher
genetic barrier and improved resistance profile [8].
However, DTG is coformulated exclusively with the
abacavir (ABC)/lamivudine (3TC) combination and
adverse events with its use have been recently raised
[9,10]. Thus, the availability of novel INSTIs with
good tolerability and efficacy against INSTI-associ-
ated resistance, and coformulated with emtricita-
bine/tenofovir alafenamide (F/TAF), a newer, less
toxic NRTI backbone, would be useful in the man-
agement of subjects who are HIV-infected.
In this review, we will discuss and highlight the
recent efficacy and safety data of bictegravir (BIC),
a novel second-generation INSTI that has been recently
approved, in coformulation with F/TAF (B/F/TAF), for
the treatment of HIV-1 infected subjects who are treat-
ment-naı̈ve and in those with suppressed viremia.
a
Vita-Salute San Raffaele University and bInfectious Diseases, Istituto di
Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Hospital,
Milan, Italy
Correspondence to Vincenzo Spagnuolo, MD, Vita-Salute San Raffaele
University, via Stamira d’Ancona 20, Milan, Italy. Tel: +39 0226437907;
e-mail: spagnuolo.vincenzo@hsr.it
Curr Opin HIV AIDS 2018, 13:326–333
DOI:10.1097/COH.0000000000000468

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KEY POINTS
 BIC shows a high genetic barrier and demonstrates
antiviral activity in vitro against INSTI-resistant isolates
and non-B subtypes.
 BIC is the first unboosted INSTI coformulated with F/TAF.
 Phase III trials demonstrated virological efficacy similar
to that of DTG in naive subjects.
 Preliminary data indicate that BIC might be a valuable
option for regimen switching in patients on
antiretroviral therapy with undetectable viremia.
MECHANISM OF ACTION AND
PRECLINICAL DATA
The integrase enzyme of the HIV is essential for viral
replication and persistence in human cells and
exerts its effects by the catalyzing two consecutive
reactions: 30 processing and strand transfer [11].
In preclinical studies, BIC was shown to be a
potent inhibitor of the strand transfer activity with
an activity comparable with that of EVG and DTG
&&
[8,12 ,13]. However, as reported for all other
INSTIs, inhibition of the 30 -processing activity was
&&
considerably weaker [12 ].
Importantly, BIC differs structurally from other
INSTIs and is in fact characterized by the presence of
a bridged bicyclic ring and a distinct benzyl tail
consisting of a tri-substituted 2,4,6-trifluorobenzyl
&&
moiety [12 ]. These characteristics are associated
with an increased plasma protein binding and
decreased activation of the pregnane X receptor,
with a consequent reduction of the risk of drug–
&&
drug interactions [12 ].
Moreover, the structure of BIC may also explain
its long-dissociation half-life from wild-type and
mutant G140S/Q148H HIV integrase-DNA com-
plexes [14]. The long residence time of BIC on the
integrase-DNA complex mediates its potent antivi-
ral activity and high genetic barrier in vitro
&&
[12 ,14,15]. In addition, BIC showed an improved
resistance profile compared with those of EVG and
RAL and retained activity against patient-derived
isolates containing substitutions associated with
resistance against other INSTIs, including T66I,
E92G/Q, T97A, Y143R, Q148H/K/R, N155H, and
&&
R263K [12 ,15].
Moreover, BIC, similar to other second-genera-
tion INSTIs, showed a higher antiretroviral potency
against non-B subtypes than that of RAL and
EVG [16], which might make it suitable for use
in countries with a higher prevalence of non-B
subtypes.
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Bictegravir Spagnuolo et al.
An extensive Phase I pharmacology study pro-
gram evaluated BIC doses from 5 to 600 mg in
healthy volunteers [17].
The results showed that BIC was well absorbed
(>70%), highly bound to plasma proteins (>99%),
and metabolized with a similar contribution of oxida-
tion (CYP3A4) and glucuronidation [UDP glucurono-
syltransferase family 1 member A1 (UGT1A1)]. The
drug was only minimally excreted in the urine (1% of
unchanged parent drug), and, therefore, no clinically
significant effect of severe renal impairment [esti-
mated glomerular filtration rate (eGFR) 15–30 ml/
min) on BIC pharmacokinetics has been observed.
BIC is a substrate of CYP3A4 and UGT1A1, and
inhibition of both enzymes is necessary for a sub-
stantial increase in exposure (341% when coadmi-
nistered with atazanavir), whereas potent induction
of CYP3A4 and UGT1A1 reduces the exposure sig-
nificantly (71% with rifampin coadministration).
STUDIES IN NAIVE SUBJECTS
The virological efficacy, pharmacokinetics, and
safety of a 10-day BIC monotherapy were evaluated
in a Phase Ib study of 20 HIV-infected subjects (16
&
treated with BIC and four with placebo) [18 ]. The
study included subjects with detectable HIV-RNA
who were either treatment naı̈ve or antiretroviral
experienced but INSTI-naı̈ve. The study was
designed with two sequential parts. In the first part,
10 subjects were randomized 1 : 1 to cohorts 1 or 2
(BIC 25 or 100 mg, respectively). Successively,
within each cohort, participants were assigned to
receive BIC or the placebo in a 4 : 1 ratio.
In the second part, 10 additional participants
were randomized 1 : 1 to cohorts 3 or 4 [BIC 5 or
50 mg, respectively, and again assigned to receive
BIC or the matching placebo (4 : 1 ratio)]. Adminis-
tration of BIC was associated with a dose-dependent
reduction in viral load. The mean decrease (SD) in
plasma HIV-RNA on day 11 was 1.45 (0.10) and
2.43 (0.39) log10cp/ml with 5 and 100 mg BIC,
respectively. The posttreatment viral load decline
continued through day 14 and 17 in the 50 and 100-
mg dose groups, respectively. No primary resistance
mutations emerged during the study.
Pharmacokinetic determinations showed that
BIC was rapidly absorbed with a time to reach the
maximum concentration (Tmax) between 1.3 and
2.7 h on Day 10. The cohort median half-life (t1/2)
ranged from 15.9 to 20.9 h across dose groups.
Phase II
The randomized, double-blind Phase 2 trial
&
NCT02397694 [19 ] was the first comparative study
www.co-hivandaids.com 327
New HIV drugs
of second-generation INSTIs, BIC vs. DTG, in naı̈ve
subjects. The study design involved the random
assignment of patients (2 : 1 ratio) to receive BIC
(75 mg) or DTG (50 mg) each administered with a
fixed-dose combination of emtricitabine (200 mg)
and tenofovir alafenamide (25 mg) in naı̈ve subjects.
The primary outcome was the proportion of
subjects with HIV-RNA less than 50 copies/ml
at week 24, according to the US Food and
Drug Administration (FDA) Snapshot algorithm.
Secondary outcomes included the proportion of
subjects with HIV-RNA less than 20 copies/ml at
week 48 (FDA Snapshot), safety and tolerability,
and pharmacokinetics.
Efficacy, resistance, and safety
Ninety-eight subjects received at least one dose of
drug (65 and 33 in the BIC and DTG arms, respec-
tively). At week 24, according to the Snapshot algo-
rithm, 97% in the BIC group had HIV-1 RNA less
than 50 copies/ml vs. 94% in the DTG group [differ-
ence 2.9%, 95% confidence interval (CI) –8.5
to 14.2; P ¼ 0 50]. When the low-level HIV-RNA
threshold (<20 copies/ml) was considered, 90.8
and 87.9% in BIC and DTG groups, respectively,
had virological suppression (difference 2.8%, –
11.9 to 17.5%; P ¼ 0 67).
Three participants met the criteria to perform
HIV resistance testing: one and two in the BIC and
DTG groups, respectively. No resistance mutations
for INSTIs and NRTIs were detected in two subjects.
The third subject (on DTG) had genotypic resistance
analysis that revealed the evolution of integrase
mutation T97A at week 48 (not detected at baseline
or a subsequent timepoint after week 48) and no
resistance to NRTIs.
Treatment-emergent adverse events were
reported by 55 of 65 participants (85%) in the BIC
arm vs. 22 of 33 (67%) in the DTG arm. The most
common treatment-related adverse event was diar-
rhea. No treatment-related serious adverse events or
deaths occurred.
Phase III: study GS-US-380-1489
&&
The current study [20 ] was the first clinical trial to
compare the fixed-dose combination of BIC/emtri-
citabine/tenofovir alafenamide (B/F/TAF, 50/200/
25 mg) with coformulated DTG/abacavir/lamivu-
dine (DTG/ABC/3TC, 50/600/300 mg) among treat-
ment-naı̈ve, HIV-infected subjects. GS-US-380-1489
was a double-blind, multicentric, randomized,
phase 3, noninferiority trial (with a prespecified
noninferiority margin of 12%), designed to ran-
domly assign (1 : 1) subjects to B/F/TAF or DTG/
ABC/3TC.
328 www.co-hivandaids.com
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The primary outcome was the proportion of
subjects with plasma HIV-1 RNA less than 50
copies/ml at week 48 (according to FDA Snapshot
algorithm). Secondary outcomes included the pro-
portion of participants with plasma HIV-1 RNA less
than 50 copies/ml at week 48 after imputation of
missing-as-failure and missing-as-excluded values;
participants with HIV-1 RNA less than 20 copies/
ml at week 48 by the Snapshot algorithm and
change in HIV-1 RNA and CD4 cell count from
baseline to week 48.
Other secondary outcomes included the per-
centage changes from baseline in hip and lumbar
spine bone mineral density at week 48, change from
baseline in serum creatinine and eGFR at week 48.
Efficacy and resistance
B/F/TAF (n ¼ 316) was noninferior to DTG/ABC/3TC
(n ¼ 315) for the primary outcome: 92.4 vs. 93.0%
(difference 0.6%, 95% CI: 4.8 to 3.6; P ¼ 0.78) of
subjects had HIV-RNA less than 50 copies/ml at
week 48 in the BIC and DTG groups, respectively.
The results of the missing-as-failure and missing-
as-excluded analyses were consistent with those of
the primary analysis.
The proportion of subjects with HIV-RNA less
than 20 copies/ml was 87.6 vs. 87.3% (difference
0.4%; 95% CI: 4.8 to 5.6; P ¼ 0.87) and a similar
increase in the CD4 cell count was observed in both
groups (þ233 vs. þ299 cells/ml in the BIC and DTG
groups, respectively; P ¼ 0.81).
Viral genotypic analysis was performed on five
subjects who met the protocol-defined criteria for
resistance testing (n ¼ 1 and 4 in the BIC and DTG
groups, respectively). No treatment-emergent resis-
tance to any component of either treatment regi-
men was observed.
Safety and tolerability
Both treatments were generally well tolerated, and
most adverse events reported were mild or moderate
in severity. Nausea was more frequent in the DTG/
ABC/3TC group than it was in the B/F/TAF group (23
vs. 10%, P < 0.001; Table 1). Adverse events leading
to discontinuation were not common (0 vs. 4 in the
BIC and DTG groups, respectively). No differences
in overall neuropsychiatric adverse events were
observed between groups.
Changes in hip and lumbar spine bone mass
density from baseline were similar between the
groups [0.78% (SD 2.22) vs. 1.02% (2.31) for
the hip, P ¼ 0.23; 0.83 (3.19) vs. 0.6 (3.1) for
the spine; P ¼ 0.39].
A small increase in serum creatinine [0.11 mg/dl
(0.03–0.17) vs. 0.11 mg/dl (0.03–0.18); P ¼ 0.78]
and a secondary decrease in eGFR [10.5 ml/min
Volume 13  Number 4  July 2018
 && &&
Table 1. Main results of the phase 3 GS-US-380-1489 [20 ] and 1490 [21 ] trials

Participants
with HIV-1 Treatment Treatment
RNA < 50 difference Participants difference:
copies/ml at (experimental– with HIV-1 (experimental–
Week 48a comparator RNA < 20 comparator Drug- AEs occurring with
primary arm) (95% CI; copies/ml at arm) (95% CI; related AEs leading to study drug 10% incidence in
outcome P value) Week 48a P value) AEs discontinuation either group

GS-US-380-1489
B/F/TAF 50/200/25 mg, 92.4%, n ¼ 290 0.6% (4.8 to 87.6%, 0.4% (4.8 to 26%, 0 Diarrhea (13%);
n ¼ 314; Experimental 3.6; P ¼ 0.78) n ¼ 275 5.6; P ¼ 0.87) n ¼ 82 Headache (11%);
arm Nausea (10%)
DTG/ABC/3TC 50/600/ 93.0%, n ¼ 293 87.3%, 40%, 1%, n ¼ 4: chronic pancreatitis Nausea (23%);
300 mg, n ¼ 315; n ¼ 275 n ¼ 127 and steatorrhea, n ¼ 1; nausea Headache (14%);
Comparator arm and generalized rash, n ¼ 1; Diarrhea (13%);
depression, n ¼ 1; Upper RTI (11%)
thrombocytopenia, n ¼ 1

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GS-US-380-1490
B/F/TAF 50/200/25 mg, 89.4%, n ¼ 286 3.5% (7.9 to 82.2%, 3.9% (9.4 to 18%, 2%, n ¼ 5: cardiac arrest, n ¼ 1; Headache (13%);
n ¼ 320); Experimental 1.0; P ¼ 0.12) n ¼ 263 1.5; P ¼ 0.16) n ¼ 57 paranoia, n ¼ 1; chest pain, Diarrhea (12%)
arm n ¼ 1; abdominal distension,
n ¼ 1; sleep disorder,
dyspepsia, tension headache,
depressed mood, insomnia,
n¼1
DTG þ F/TAF 50 þ 200/ 92.9%, n ¼ 302 87.1%, 26%, <1%, n ¼ 1: erythema and Headache (12%);
25 mg, n ¼ 325; n ¼ 283 n ¼ 83 pruritus Diarrhea (12%);
Comparator arm Nasopharyngitis
(10%)

ABC/3TC, abacavir/lamivudine; AE, adverse event; B/F/TAF, bictegravir/emtricitabine/tenofovir alafenamide; CI, confidence interval; DTG, dolutegravir; FDA, Food and Drug Administration; F/TAF, emtricitabine/
tenofovir alafenamide; RTI, respiratory tract infections.

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a
FDA-defined Snapshot algorithm.

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Bictegravir Spagnuolo et al.

329
New HIV drugs
(19.5 to 0.2) vs. 10.8 (21.6 to 2.4)] were
observed in BIC and DTG group, respectively. This
findings were associated with the inhibition of the
tubular secretion of creatinine via organic cation
transporter 2 and multidrug and toxin extrusion
transporter-1 by BIC and DTG [22,23] and does
not represent a nephrotoxic effect.
Phase III: study GS-US-380-1490
The current Phase III, randomized, multicenter,
&&
double-blind trial (GS-US-380-1490) [21 ] com-
pared the fixed-dose combination of B/F/TAF 50/
200/25 mg to DTG and coformulated F/TAF (200/
25 mg) in antiretroviral treatment naı̈ve subjects.
The primary outcome of the study was the propor-
tion of subjects with a plasma HIV viremia less than
50 copies/ml at week 48 (FDA Snapshot algorithm).
This was a noninferiority trial with a prespecified
noninferiority margin of 12%.
The secondary outcomes were the proportion of
participants with plasma HIV-1 RNA less than 50
copies/ml at week 48 after imputation of missing-as-
failure and missing-as-excluded values and partici-
pants with HIV-1 RNA less than 20 copies/ml at
week 48 based on the Snapshot algorithm. The
safety outcomes were the changes in fasting glucose,
lipid panels, serum creatinine, and eGFR at week 48
compared with baseline values.
Efficacy and resistance
The BIC and DTG groups consisted of 327 and 330
randomized patients, respectively. The BIC regimen
was noninferior to the DTG regimen in the primary
outcome (89.4 vs. 92.9%; difference 3.5%, 95% CI
7.9 to 1.0; P ¼ 0.12).
The results of the missing-as-failure and miss-
ing-as-excluded analyses were similar to those of the
primary analysis. The proportion of subjects with
HIV-RNA less than 20 copies/ml at week 48 (FDA
Snapshot) was numerically lower in the BIC group
than it was in the DTG group (82.2 vs. 87.1%;
difference 3.9%, 95% CI 9.4 to 1.5; P ¼ 0.16).
Furthermore, most subjects in each group achieved
virological suppression within the 1st month of
therapy: 75.2% in the BIC group and 79.4% in the
DTG group; P ¼ 0.43.
Twelve subjects fulfilled the criteria for viral
resistance testing (seven and five in the BIC and
DTG groups, respectively). No treatment-emergent
resistance to the components of either treatment
regimen was identified.
Safety and tolerability
The most frequent adverse events were headache
and diarrhea in both groups (Table 1).
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Adverse events leading to study drug discontin-
uations were uncommon and occurred in five sub-
jects (2%) in the BIC group and one (<1%) in the
DTG group.
Subjects in the BIC arm had a lower incidence of
drug-related adverse events than those in the DTG
arm did (18 vs. 26%, P ¼ 0.022).
At week 48, both groups showed a similar
increase in fasting lipid parameters, whereas a
smaller decrease in eGFR was observed in BIC arm
[7.3 (17.3 to 0.1) ml/min vs. 10.8 (20.0 to
1.7) ml/min in BIC and DTG group, respectively;
P ¼ 0.02].
STUDIES IN VIROLOGICALLY
SUPPRESSED SUBJECTS
Preliminary data from two ongoing studies that
investigated the efficacy of a switch from
DTG þ F/TAF or from boosted protease inhibitor
regimens to B/F/TAF in virologically suppressed sub-
jects have recently become available.
The first study is the continuation of the previ-
ously described Phase II trial NCT 02397694 [19 ].
&
All subjects who completed the first phase (double-
blinded) of the study were provided the opportu-
nity to continue in the open-label B/F/TAF at
week 60. The efficacy and safety were evaluated
through week 72 in subjects who continued the
study [24].
In the open-label phase, the virological suppres-
sion was maintained in 98% of subjects who con-
tinued B/F/TAF and 100% who switched from DTG.
In subjects who changed regimen, there were no
discontinuations or serious adverse events after
the switch.
The second study (NCT02603107) was a phase
III trial that assessed the efficacy and safety of
switching to B/F/TAF from boosted atazanavir or
darunavir and ABC/3TC or FTC/TDF in virologically
&
suppressed subjects [25 ].
The primary endpoint was the proportion of
subjects with plasma viremia at least 50 copies/ml
(snapshot analysis) at week 48 with a prespecified
noninferiority margin of 4%.
Participants were randomized (1 : 1) to continue
the boosted protease inhibitor regimens (n ¼ 287)
or switch to B/F/TAF (n ¼ 290). At week 48, the
treatment switch to B/F/TAF was not inferior
to the continuation of the boosted protease
inhibitor regimens (1.7% in both groups with
HIV-1 RNA > 50 copies/ml, P ¼ 1.00). No develop-
ment of resistance was observed in the BIC group,
whereas one subject on darunavir/ritonavir þ
ABC/3TC developed a treatment-emergent L74V
mutation.
Volume 13  Number 4  July 2018
 Table 2. Ongoing studiesa on bictegravir, as reported in ClinicalTrials.gov (assessed on 22 January 2018)

ClinicalTrials.- Recruitment Enrollment,

gov identifier status Phase Population Design n Primary objective(s) Primary outcome(s)

NCT03110380 Active, not 3 HIV-1 infected participants
recruiting with suppressed viremia
and without resistance to
INSTIs
NCT03348163 Not yet recruiting 4 Transgender woman on
effective ART (HIV-
RNA < 50 copies/ml) as
24 weeks prior entry
NCT03405935 Not yet recruiting 3b HIV-1 infected participants
aged 65 years and with
suppressed viremia
NCT02881320 Recruiting 2/3 HIV-1 infected children and
adolescents with
suppressed viremia and
no resistance to FTC, TFV,
or INSTIs
Randomized, double- 567 To evaluate the efficacy of switching Proportion of participants
blind, multicenter from a regimen of either DTG and with HIV-1 RNA  50
F/TAF or DTG and F/TDF to B/F/ copies/ml at Week 48
TAF vs. DTG þ F/TAF
Randomized, 48 (estimated) To determine the safety and tolerability Number of participants who
monocenter, open- of switching from current ART to B/ maintain <50 copies/ml
label F/TAF, in HIV-infected transgender HIV-1 RNA for 48 weeks
women
Number of participants who
discontinue study drug
because of study-drug
related adverse events
Single arm, open- 80 (estimated) To characterize the virologic efficacy of Proportion of participants
label, multicenter switching from E/C/F/TAF or a TDF- with HIV-1 RNA < 50
containing regimen to B/F/TAF copies/ml at week 24
(FDA Snapshot algorithm)
Single arm, open- 100 To evaluate the steady state AUCtau of bictegravir, Ctau
label, multicenter (estimated) pharmacokinetics for bictegravir and of bictegravir
confirm the dose of B/F/TAF fixed-
dose combination.

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To evaluate the safety and tolerability Incidence of treatment-
of B/F/TAF emergent adverse events
through week 24,
incidence of treatment-
emergent laboratory
abnormalities through
Week 24
NCT02603120 Active, not 3 HIV-1 infected participants Randomized, double- 567 To evaluate the efficacy of switching Proportion of participants
recruiting with suppressed viremia blind, multicenter from a regimen of DTG and ABC/ with virologic failure
and no resistance to FTC, 3TC or a fixed-dose combination of (HIV-1 RNA  50 copies/
TFV, DTG, ABC, or 3TC ABC/DTG/3TC to B/F/TAF vs. ml) at week 48 (FDA-
continuing DTG and ABC/3TC as defined snapshot
ABC/DTG/3TC algorithm)
NCT02652624 Active, not 3 HIV-1 infected women with Randomized, open- 471 To evaluate the efficacy of switching to Proportion of participants
recruiting suppressed viremia label, multicenter B/F/TAF vs. continuing on a with HIV-1 RNA  50
regimen consisting of E/C/F/TAF, copies/ml at Week 48

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E/C/F/TDF, or ATV/r þ FTC/TDF (FDA-defined snapshot
algorithm)

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3TC, lamivudine; ABC, abacavir; ABC/3TC, abacavir/lamivudine; ABC/3TC/DTG, abacavir/lamivudine/dolutegravir; ATV, atazanavir; AUCtau, concentration of drug over time (the area under the concentration verses
time curve over the dosing interval); B/F/TAF, bictegravir/emtricitabine/tenofovir alafenamide; Ctau, observed drug concentration at the end of the dosing interval; DRV, darunavir; DTG, dolutegravir; F/TAF,
emtricitabine/tenofovir alafenamide; F/TDF, emtricitabine/tenofovir disoproxil fumarate; FTC, emtricitabine; INSTIs, integrase strand transfer inihbitors; r, ritonavir; TFV, tenofovir.
a & && && &
Studies [19 ,20 ,21 ,25 ] were not included in the Table as they are detailed in the text.
Bictegravir Spagnuolo et al.

331
New HIV drugs
The switch to B/F/TAF was well tolerated with a
similar incidence of grade 3 or 4 adverse events in
both groups (4 vs. 6%).
FURTHER CLINICAL NEEDS
Switching to B/F/TAF by the virologically sup-
pressed patient on antiretroviral therapy is cur-
rently under evaluation in five other Phase 3
studies (Table 2) with a particular focus on the
HIV fragile populations: children and adolescents,
elderly, women.
In addition, B/F/TAF has specific characteristics
(high genetic barrier, activity against hepatitis B
virus and HIV-1 non-B subtypes, no need for pre-
treatment HLAB5701 testing) that make it a suit-
able candidate for use in low-income and middle-
income countries [26].
However, differently from DTG (ongoing
INSPIRING study; NCT02178592, and [27]), B/F/
TAF has not yet been studied in subjects with tuber-
culosis coinfection or in pregnant women, two HIV
populations largely represented in low-income and
middle-income countries, and, thus, further studies
are required to support the use of B/F/TAF in these
settings.
To date, registrational studies on BIC used the
coformulation B/F/TAF in naı̈ve and suppressed sub-
jects; it remains uncertain if BIC will be available as a
single agent.
However, availability of BIC as a single drug may
allow investigation of its efficacy in failing and
multiexperienced subjects and in dual-therapy strat-
egies, situations in which BIC may play an impor-
tant role.
BIC demonstrates antiviral activity in vitro
against INSTI-resistant isolates. However, no data
on the antiviral activity in vivo of BIC, in subjects
failing RAL or EVG and harboring INSTIs resistance
mutations, are currently available.
CONCLUSION
BIC is an unboosted, second-generation INSTI with
a high genetic barrier and excellent tolerability. The
ongoing phase III trials GS-US-380-1489 and GS-US-
380-1490 have shown that the B/F/TAF coformula-
tion is not inferior to the recommended DTG-con-
taining regimens in naı̈ve subjects. In addition,
preliminary data support switching from DTG
and emtricitabine/tenofovir alafenamide or
boosted protease inhibitor-containing regimens
to B/F/TAF in subjects with undetectable viremia.
According to these findings, BIC coformulated
with F/TAF is currently positioned to become a new
first-line option for the initial therapy of HIV-1
332 www.co-hivandaids.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
infection and a valuable option for regimen switch-
ing in subjects with suppressed viremia.
Acknowledgements
We would like to thank Editage (https://www.edita-
ge.com/) for editing and reviewing this article for
English language.
Financial support and sponsorship
None.
Conflicts of interest
V.S. received consulting fees from Gilead Sciences, ViiV
Healthcare, Janssen-Cilag, and Merck Sharp & Dohme;
A.C. received consulting fees from Gilead Sciences, ViiV
Healthcare, and Janssen-Cilag and Merck Sharp &
Dohme; A.L. received consulting fees from Gilead Scien-
ces, ViiV Healthcare, and Janssen-Cilag and Merck
Sharp & Dohme.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability 3 non-
nucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for
treatment-naive volunteers infected with HIV-1: a randomized, controlled
equivalence trial. Ann Intern Med 2014; 161:461–471.
2. Walmsley SL, Antela A, Clumeck N. Dolutegravir plus abacavir–lamivudine for
the treatment of HIV-1 infection. N Engl J Med 2013; 369:1807–1818.
3. Squires K, Kityo C, Hodder S, et al. Integrase inhibitor versus protease
inhibitor-based regimen for HIV-1 infected women (WAVES): a randomised,
controlled, double-blind, phase 3 study. Lancet HIV 2016; 3:e410–e420.
4. European AIDS Clinical Society. Guidelines. Milan: European AIDS Clinical
Society; 2017; Available at: http://www.eacsociety.org/files/guidelines_9.0-
english.pdf. [Accessed 15 January 2018]
5. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for
the use of antiretroviral agents in adults and adolescents living with HIV.
Department of Health and Human Services, 2017. Available at: http://
www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. [Accessed
15 January 2018]
6. Shimura K, Kodama EN. Elvitegravir: a new HIV integrase inhibitor. Antivir
Chemother 2009; 20:79–85.
7. Mesplede T, Quashie PK, Wainberg MA. Resistance to HIV integrase
inhibitors. Curr Opin HIV AIDS 2017; 7:401–408.
8. Min S, Song I, Borland J, et al. Pharmacokinetics and safety of S/
GSK1349572, a next-generation HIV integrase inhibitor, in healthy volun-
teers. Antimicrob Agents Chemother 2010; 54:254–258.
9. de Boer MG, van den Ber GE, van Holten N, et al. Intolerance of dolutegravir-
containing combination antiretroviral therapy regimens in real-life clinical
practice. AIDS 2016; 30:2831–2834.
10. Fettiplace A, Stainsby C, Winston A, et al. Psychiatric symptoms in patients
receiving dolutegravir. J Acquir Defic Syndr 2017; 74:423–431.
11. Maertens GN, Hare S, Cherepanov P. The mechanism of retroviral integration
from X-ray structures of its key intermediates. Nature 2010; 468:326–329.
12. Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (Gs-9883)
a novel potent HIV-1 integrase strand transfer inhibitor with an improved
&&
resistance profile. Antimicrob Agents Chemother 2016; 60:7086–7097.
The study describes the structure, mechanism of action, and resistance of
bictegravir (BIC). This article provides the reader with an overview of the virologic
profile of BIC.
13. Shimura K, Kodama E, Sakagami Y, et al. Broad antiretroviral activity and
resistance profile of the novel human immunodeficiency virus integrase
inhibitor elvitegravir (JTK-303/GS-9137). J Virol 2008; 82:764–774.
14. White K, Niedziela-Majka A, Novikov N, et al. Bictegravir dissociation half-life
from HIV-1G140S/Q148H integrase-DNA complexes. Conference on retro-
viruses and opportunistic infections (CROI), 13–16 February 2017, Seattle,
WA. Poster 497.
Volume 13  Number 4  July 2018

15. Hassounah SA, Alikhani A, Oliveira M, et al. Antiviral activity of bictegravir and
cabotegravir against integrase inhibitor-resistant SIVmac239 and HIV-1.
Antimicrob Agents Chemother 2017; 61: e01695–17.
16. Neogi U, Singh K, Aralaguppe SG, et al. Ex vivo antiretroviral potency of newer
integrase strand transfer inhibitors cabotegravir and bictegravir in HIV-1 non-
B subtypes. AIDS 2018; 32:469–476.
17. Zhang H, Custodio JM, Wei X, et al. Clinical pharmacology of the HIV
integrase strand transfer inhibitor bictegravir. Conference on retroviruses
and opportunistic infections (CROI), 13–16 February 2017, Seattle, WA.
Abstract 40.
18. Gallant FE, Thompson M, DeJesus E, et al. Antiviral activity, safety and
& pharmacokinetics of bictegravir as 10-day monotherapy in HIV-1-infected
adults. J Acquir Immune Defic Syndr 2017; 75:61–66.
The phase 1b study reports data on the efficacy and pharmacokinetics of BIC
monotherapy in a cohort of subjects who are HIV-infected, both naı̈ve and
antiretroviral experienced.
19. Sax PE, DeJesus E, Crofoot G, et al. Bictegravir versus dolutegravir, each
& with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1
infection: a randomized, double-blind, phase 2 trial. Lancet HIV 2017;
4:e154–e160.
The phase 2 study reports on the first trial that directly compared the
antiretroviral activity of two second-generation integrase strand transfer
inhibitors.
20. Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir
&& alafenamide versus dolutegravir, abacavir, and lamivudine for initial
treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre,
phase 3, randomised controlled noninferiority trial. Lancet 2017; 390:
2063–2072.
A phase 3 registrational trial assessing the virologic efficacy of bictegravir/
emtricitabine/tenofovir alafenamide (B/F/TAF) compared with dolutegravir
(DTG)/abacavir/lamivudine. The demonstration of noninferiority probably provided
evidence to support and initiate the use of B/F/TAF for initial therapy of HIV-1
infection.
1746-630X Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Bictegravir Spagnuolo et al.
21. Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine,
&& and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir
alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a
randomized, double-blind, multicenter, phase 3, noninferiority trial. Lancet
2017; 390:2073–2082.
A phase 3 registrational trial assessing the virologic efficacy of B/F/TAF compared
with DTG and F/TAF. The demonstration of noninferiority probably provided evidence
to support and initiate the use of B/F/TAF for the initial therapy of HIV-1 infection.
22. Custodio J, West S, Yu A, et al. Lack of clinically relevant effect of bictegravir
(BIC, B) on metformin (MET) pharmacokinetics (PK) and pharmacodynamics
(PD). Open Forum Infect Dis 2017; 4(Suppl 1):S429.
23. European Medicines Agency. Tivicay: EPAR - Product information. Available
at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_
Information/human/002753/WC500160680.pdf. [Assessed on 15 February
2018]
24. Sax PE, DeJesus E, Crofoot G, et al. A randomized trial of bictegravir or
dolutegravir with emtricitabine and tenofovir alafenamide (F/TAF) followed by
an open-label switch to bictegravir F/TAF fixed dose combination. IDWeek
2017, 4–8 October 2017, San Diego, CA. Poster 1380.
25. Daar E, DeJesus E, Ruane P, et al. Phase-3 Randomized, controlled trial of
& switching to fixed-dose bictegravir/emtricitabine/tenofovir alafenamide (B/F/
TAF) from boosted protease inhibitor-based regimens in virologically sup-
pressed adults: week 48 results. IDWeek 2017, 4–8 October 2017, San
Diego, CA. Abstract LB-4.
The preliminary data from a Phase III trial on the use of B/F/TAF in a switching strategy
in virologically suppressed patients on a protease inhibitor-containing regimen.
26. Boffito M, Venter F. The triumph of HIV treatment: another new antiretroviral.
Lancet 2017; 390:2019–2021.
27. Zash R, Jacobson D, Mayondi G, et al. Dolutegravir/tenofovir/emtricitabine
(DTG/TDF/FTC) started in pregnancy is as safe as efavirenz/tenofovir/em-
tricitabine (EFV/TDF/FTC) in nationwide birth outcomes surveillance in Bots-
wana. 9th IAS Conference on HIV Science; 23–26 July 2017; Paris, France.
Abstr MOAX02.
www.co-hivandaids.com 333