Comment
The triumph of HIV treatment: another new antiretroviral
Since the approval of the first integrase strand inhibitor
(INSTI) raltegravir for the treatment of HIV 10 years ago,
INSTIs have become agents of choice in combination
with two nucleoside reverse transcriptase inhibitors
(NRTIs) in many international guidelines.1,2 This was
driven by the sound real-world experience of this
antiretroviral class, especially following the introduction
of the most recently licensed INSTI, dolutegravir.
Dolutegravir has shown superiority to other major
alternative third agents belonging to the classes of
protease inhibitors and non-NRTIs, and it has become
the gold standard against which other drugs need
to prove their efficacy. It is dosed once daily in most
patients, and it is coformulated with either abacavir
and lamivudine or tenofovir disoproxil fumarate
and lamivudine. Importantly, dolutegravir does not
require the coadministration of a pharmacoenhancer
and is characterised by a low potential for drug–drug
interactions, unlike elvitegravir. The high barrier to
the development of resistance3 might go some way
to address the recent concern over rising resistance to
efavirenz (the current primary recommendation for low-
income and middle-income countries), resulting in WHO
looking for alternative treatments, with dolutegravir
appearing to be the current leading cost-effective
candidate.4–6 The tide is changing and middle-income
countries like Brazil, Botswana, and South Africa are
starting to adopt INSTIs for first-line treatment.5
In The Lancet, a new INSTI, bictegravir, coformulated
with tenofovir alafenamide and emtricitabine, has
been compared with dolutegravir, either coformulated
with abacavir and lamivudine or administered with
tenofovir alafenamide and emtricitabine in two large
clinical trials.7,8 The first, by Joel Gallant and colleagues,7
was a randomised double-blind, multicentre,
phase 3, non-inferiority trial that showed that bictegravir,
emtricitabine, and tenofovir alafenamide (B/F/TAF) was
non-inferior to dolutegravir, abacavir, and lamivudine
(DTG/ABC/3TC), because at week 48 HIV-1 RNA below
50 copies per mL was achieved in 92·4% (290 of 314) of
participants in the B/F/TAF group versus 93% (293 of 315)
in the DTG/ABC/3TC group (difference –0·6%, 95·002% CI
–4·8 to 3·6). The second, by Paul Sax and colleagues,8 was
a randomised double-blind, multicentre, phase 3, non-
inferiority trial comparing bictegravir, emtricitabine,
www.thelancet.com Published online August 31, 2017 http://dx.doi.org/10.1016/S0140-6736(17)32297-3 1
and tenofovir alafenamide with dolutegravir plus Published Online
August 31, 2017
coformulated emtricitabine and tenofovir alafenamide, http://dx.doi.org/10.1016/
and showed 48-week response rates of 89·4% (286 of S0140-6736(17)32297-3
320 participants) in the bictegravir group versus 92·9% See Online/Articles
http://dx.doi.org/10.1016/
(302 of 325 participants) in the dolutegravir group S0140-6736(17)32299-7 and
(difference –3·5%, 95·002% CI –7·9 to 1·0), showing non- http://dx.doi.org/10.1016/
S0140-6736(17)32340-1
inferiority of the combination containing bictegravir
versus the one containing dolutegravir. All antiretroviral
combinations in the studies were well tolerated, with
strong safety profiles. A significant difference was
observed only for gastrointestinal adverse effects (mainly
nausea) in both trials but with a rate as high as 40% in
patients on abacavir in the trial by Gallant and colleagues,7
suggesting that the adverse event is mainly driven by the
nucleoside backbone containing abacavir. Importantly,
differences between study groups in grade 3 or 4 adverse
events or discontinuation rates were not observed in
either trial. Real-world data could unveil other potential
adverse events that might not be observed in these
phase 3 randomised clinical trials. Previous cohort studies
that followed the introduction of dolutegravir into clinical
practice reported treatment discontinuation rates for
sleep disturbances and psychiatric problems (16%), higher
than those measured by clinical trials (<3%);9 whereas
the trials by Gallant and Sax and their colleagues had not
reported such adverse effects in association with either
dolutegravir or bictegravir.
The absence of any resistance development with
virological failure with either INSTI reported in these
Manjunath Kiran/Stringer/Getty
 Comment
two trials is an important finding. This makes the
commercial competitors bictegravir and dolutegravir
combinations likely to dominate the market going
forward in higher income countries.
Two important clinical aspects might favour the use
of the bictegravir combination (containing tenofovir
alafenamide), because this combination does not require
testing for potential hypersensitivity to abacavir before
use, and it can be given as an effective treatment to
patients with active hepatitis B virus infection. However,
the combination of tenofovir disoproxil fumarate,
lamivudine, and dolutegravir is being developed by
generic manufacturers under licensing agreements with
ViiV Healthcare making dolutegravir, and will be available
in low-income and middle-income countries, preserving
these advantages.5 Tenofovir alafenamide, which is also
likely to be licensed to generic companies, might replace
tenofovir disoproxil fumarate in this combination, if drug
interactions with rifampicin are addressed in ongoing
clinical trials, allowing for a safer, smaller, cheaper, and
robust daily antiretroviral therapy tablet.
Although both dolutegravir and bictegravir are
characterised by a low potential for drug–drug
interactions, differences exist as dolutegravir is
metabolised by cytochrome P450 3A4 (CYP3A4)
poorly (by 7·9%) and undergoes mainly phase 2
enzyme metabolism,3 and bictegravir is metabolised
with similar contribution by CYP3A4 and UDP-
glucuronosyltransferase.10 Although dolutegravir can
be coadministered with the strong inducer rifampicin
at a doubled dose of 50 mg twice daily, bictegravir dose
adjustment data are unavailable and non-coformulated
bictegravir to promote such dose adjustments might
not be available.3,10 Furthermore, although there are
accumulating data regarding safety in pregnancy
for dolutegravir,11,12 both bictegravir and tenofovir
alafenamide need to show safety in pregnant women
and neonates.
Is there a place for bictegravir in low-income and
middle-income countries? The high resistance barrier
and safety of both dolutegravir and bictegravir
are compelling in countries with limited access to
genotyping, toxicity monitoring, and subsequent
line therapies. However, most patients treated in
low-income and middle-income countries are women
of childbearing potential, and tuberculosis is a common
comorbidity. There are accumulating data suggesting
2 www.thelancet.com Published online August 31, 2017 http://dx.doi.org/10.1016/S0140-6736(17)32297-3
that dolutegravir is safe in pregnancy, and current
recommendations for tuberculosis allow for rifampicin
coadministration after dose adjustments. For bictegravir
to be recommended over dolutegravir, a similar case
showing safety and efficacy in pregnancy will be
required to reassure programme implementers that the
drug can be used in low-income and middle-income
countries, where outcomes of antiretroviral therapy are
often poorly monitored.
Currently, the difference between dolutegravir and
bictegravir is difficult to discern; they both have good
and similar safety profiles, similar chemical structure,
and the same milligram dosing, presumably leading
to similar manufacturing costs. Dolutegravir seems
likely to be taken forward, simply because more data
are available within low-income and middle-income
countries (neither of these trials was done in
Africa or Asia). Multiple studies comparing various
combinations of dolutegravir in low-income and
middle-income countries are being done in response to
the lack of randomised trial evidence of combinations
of tenofovir prodrugs and dolutegravir flagged by
WHO, which did not recommend INSTI-containing
regimens as preferred combinations. It appears
bictegravir will need to show cost or safety benefits
over dolutegravir in low-income and middle-income
countries, because these countries will soon be able to
source generics in combination with WHO-preferred
NRTIs combined with dolutegravir in fixed-dose
formulations.
The evolution of combination antiretroviral therapy
over the past 20 years has been astonishing, and the
INSTI-era marks another leap forward for countries of all
income levels. Whether dolutegravir or bictegravir offers
an advantage of one over the other (other than through
their coformulated drugs) has yet to be seen.
*Marta Boffito, Francois Venter
St Stephen’s AIDS Trust, Chelsea and Westminster Hospital,
London SW10 9NH, UK (MB); Division of Medicine, Imperial
College London, London, UK (MB); and WITS Reproductive Health
and HIV Institute, University of the Witwatersrand, Johannesburg,
South Africa (FV)
marta.boffito@chelwest.nhs.uk
MB reports grants and personal fees from Gilead, ViiV, Mylan, Janssen, Merck,
and Teva; grants from Bristol-Myers Squibb; and personal fees from Cipla.
MB has also discussed the results of the studies by Gallant et al and Sax et al
with one of the coauthors, Anton Pozniak. FV reports personal fees and non-
financial support from Gilead and ViiV and grants from USAID and UNITAID.

1 Günthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment
and prevention of HIV infection in adults: 2016 recommendations of the
International Antiviral Society–USA Panel. JAMA 2016; 316: 191–210.
2 Department of Health and Human Services Panel on Antiretroviral
Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. 2016.
http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.
pdf (accessed Aug 15, 2017).
3 Elliot E, Chirwa M, Boffito M. How recent findings on the pharmacokinetics
and pharmacodynamics of integrase inhibitors can inform clinical use.
Curr Opin Infect Dis 2017; 30: 58–73.
4 WHO. Guidelines: HIV. 2017. http://www.who.int/hiv/pub/guidelines/en
(accessed Aug 15, 2017).
5 Clinton Health Access Initiative. Chai HIV mid-year market memo.
2017. https://clintonhealthaccess.org/content/uploads/2017/06/2017-
CHAI-HIV-Mid-Year-Market-Memo_FINAL-3.pdf (accessed Aug 15, 2017).
6 WHO. Guidelines on the public health response to pretreatment HIV drug
resistance. July, 2017. Geneva: World Health Organization, 2017.
7 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 non-inferiority trial.
Lancet 2017; published online Aug 31. http://dx.doi.org/10.1016/
S0140-6736(17)32299-7.
www.thelancet.com Published online August 31, 2017 http://dx.doi.org/10.1016/S0140-6736(17)32297-3 3
Comment
8 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 randomised, double-blind, multicentre,
phase 3, non-inferiority trial. Lancet 2017; published online Aug 31.
http://dx.doi.org/10.1016/S0140-6736(17)32340-1.
9 van den Berk G, Oryszczyn J, Blok W, et al. Unexpectedly high rate of
intolerance for dolutegravir in real-life setting. Conference on Retroviruses
and Opportunistic Infections; Feb 22–25, 2016; Boston, MA, USA. Abstr 948.
10 Zhang H, Custodio JM, Wei X, et al. Clinical pharmacology of the HIV
integrase strand transfer inhibitor bictegravir. Conference on Retroviruses
and Opportunistic Infections; Feb 13–16, 2017; Seattle, WA, USA. Abstr 40.
11 Zash R, Jacobson D, Mayondi G, et al. Dolutegravir/tenofovir/emtricitabine
(DTG/TDF/FTC) started in pregnancy is as safe as efavirenz/tenofovir/
emtricitabine (EFV/TDF/FTC) in nationwide birth outcomes surveillance in
Botswana. 9th IAS Conference on HIV Science; July 23–26, 2017; Paris,
France. Abstr MOAX02.
12 Thorne C, Favarato G, Peters H, et al, for the European Pregnancy and
Paediatric Cohort Collaboration (EPPICC). Pregnancy and neonatal
outcomes following prenatal exposure to dolutegravir. 9th IAS Conference
on HIV Science; July 23–26, 2017; Paris, France. Abstr MOPEC0609.