J Antimicrob Chemother 2016; 71: 856 – 861
doi:10.1093/jac/dkv429 Advance Access publication 7 January 2016
Backbones versus core agents in initial ART regimens:
one game, two players
Josep M. Llibre1,2*, Sharon Walmsley3 and Josep M. Gatell4
1
HIV Unit and ‘Lluita contra la SIDA’ Foundation, University Hospital Germans Trias I Pujol, Badalona, Spain; 2Universitat Autònoma
de Barcelona, Barcelona, Spain; 3Infectious Diseases, University Health Network, University of Toronto, Toronto, Canada; 4Infectious
Diseases & AIDS Units, Hospital Clinic/IDIBAPS, University of Barcelona, Barcelona, Spain
*Corresponding author. HIV Unit, Hospital Universitari Germans Trias i Pujol, Ctra de Canyet, s/n, 08916 Badalona (Barcelona), Spain.
Tel: +34-934978887; E-mail: [email protected]
The advances seen in ART during the last 30 years have been outstanding. Treatment has evolved from the initial
use of single agents as monotherapy. The ability to use HIV RNA as a surrogate marker for clinical outcomes
allowed the more rapid evaluation of new therapies. This led to the understanding that triple-drug regimens,
including a core agent (an NNRTI or a boosted PI) and two NRTIs, are optimal. These combinations have demonstrated continued improvements in their efficacy and toxicity as initial therapy. However, the need for pharmacokinetic boosting, with potential drug–drug interactions, or residual issues of efficacy or toxicity have persisted
for some agents. Most recently, integrase strand transfer inhibitors, particularly dolutegravir, have shown unparalleled safety and efficacy and are currently the core agents of choice. Regimens that included only core agents or
only backbone agents have not been as successful as combined therapy in antiretroviral-naive patients. It
appears that at least one NRTI is needed for optimal performance and lamivudine and emtricitabine may be
the ideal candidates. Several studies are ongoing of agents with longer dosing intervals, lower cost and new
NRTI-saving strategies to address unmet needs.
Introduction
Over the past 30 years, there has been considerable evolution of
the agents and strategies used as initial ART. Its origin began in
1986 with the proof-of-concept study of zidovudine (azidothymidine) as monotherapy. This was a drug developed in the
1960s for cancer and rescued from the shelf because of observations of its potential activity against the HIV-1 reverse transcriptase.1 Since then, the field has witnessed improvements in the
numbers and classes of agents and the understanding of the
need for combination therapy to obtain maximal viral suppression
and prevention of the emergence of resistance. Current tripledrug ART in antiretroviral-naive patients is generally well tolerated
and fully suppressive treatments can be administered once daily,
preferably as single tablet regimens, with response rates ≥90% at
48 weeks.
ART with only backbones
The so-called ‘backbone’ in a regimen is a combination of generally two NRTIs. In antiretroviral history, the initial weak mono or
dual NRTI regimens had to demonstrate their efficacy in pivotal
studies with decreases in clinical endpoints (progression to new
AIDS events or death). Despite its modest antiviral activity, zidovudine monotherapy was associated with a statistically significant reduction in clinical HIV-1 progression or death, but only
over the short term (24 weeks) and with some serious adverse
events. 2 – 4 A few years later this monotherapy was demonstrated to cause a significant reduction (approximately
two-thirds) in materno-fetal HIV-1 transmission (ACTG 076
study), with minimal short-term toxicity for mothers and
their offspring. This remarkable clinical achievement paved
the way for the evaluation of further regimens to eradicate
mother-to-child HIV-1 transmission. 5 It took 8 years for the
next major advance in HIV therapy. This was the demonstration
in the Delta, ACTG 175 and other studies that a combination of
two NRTIs (zidovudine plus didanosine or zalcitabine or lamivudine) improved the efficacy compared with zidovudine alone for
subjects with CD4+ cell counts of ,500 cells/mm3. This dual ART
prolonged life and delayed disease progression, but again only
relatively short term, limited mainly by early loss of efficacy
with the selection of resistance mutations.6 – 8 Despite these significant advances, death rates from HIV were high in that dark
period, as demonstrated by the fact that 699 of 3207 Delta
study participants died over a median follow-up of 30 months.
It was soon recognized that to enable more rapid evaluation of
new therapies and new strategies, surrogate markers for clinical
endpoints were required. The ACTG 175 investigators were able
to demonstrate that among potential available markers of
HIV-1 replication, including infectious HIV-1 titre from PBMCs,
serum HIV-1 p24 antigen, plasma HIV-1 RNA and viral
syncytium-inducing phenotype, the correct one was plasma
HIV-1 RNA copies/mL. This marker was then used in future trials
and in care.9
# The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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Coincident with identification of the surrogate markers was the
emerging understanding of the importance of the use of fixeddose combination tablets (zidovudine plus lamivudine being the
first) for simplifying regimens and supporting adherence.10
The use of surrogate markers and their acceptance by the FDA
and other licensing authorities paved the way for more rapid
evaluation of new strategies and the demonstration of the need
for triple combination therapy to suppress viral replication more
completely. This initially included the study of the triple NRTI combination of abacavir, zidovudine and lamivudine. Although effective, the combination was found to be inferior to efavirenz plus two
NRTIs in the ACTG 5095 study. These results closed the search for
an NRTI-only or a backbone-only ART. This study also demonstrated that adding a third NRTI (abacavir in this case) as a fourth
drug in the regimen containing efavirenz as the anchor drug provided no additional benefit to the gold standard of the time
(zidovudine, lamivudine and efavirenz).11 With ongoing concerns
regarding toxicity of the NRTIs (zidovudine and stavudine), studies
during this era also showed the improved tolerability of a combination of tenofovir disoproxil fumarate plus emtricitabine or abacavir plus lamivudine. These co-formulated NRTIs have remained as
preferred backbone regimens so far. However, there is need for
improvement as both have issues, bone and renal toxicity for
tenofovir disoproxil fumarate and hypersensitivity reactions,
lower efficacy in subjects with high viral load and concerns of
cardiovascular risk for abacavir.12 – 14
ART regimens with a backbone of two NRTIs
plus a third or core agent: the case for NNRTIs
The ability to achieve a sustained virological response with
undetectable plasma HIV-1 RNA was first demonstrated in 1996
in the INCAS and 075 studies when a backbone of two NRTIs was
combined with an agent of a different class of drugs (nevirapine –
an NNRTI or indinavir – a PI), highlighting the importance of
so-called core agents in the combination.15,16 For the first time,
achieving prolonged virological suppression could at least forestall
the emergence of resistance. Since then core agents to be combined with the dual NRTI backbone have included an NNRTI, an
unboosted PI or a ritonavir- or cobicistat-boosted PI (PI/ritonavir/cobicistat), a CCR5 antagonist and, more recently, an integrase
strand transfer inhibitor (INSTI).
Despite early success, among the NNRTIs, nevirapine is currently considered too toxic for use particularly in antiretroviralnaive women with high CD4+ cell counts. It is therefore
designated at best an alternative agent or simply no longer
recommended. 12 – 14 The efficacy of efavirenz was initially
demonstrated in the 006 study and subsequently confirmed in
multiple studies in a variety of patient populations. Since then it
has evolved as the gold standard and a preferred agent in guidelines for 15 years.17 However, in practice and clinical trials, efavirenz was associated with a relatively frequent and persistent
CNS toxicity that often led to premature discontinuation. 18,19
Concerningly, a recent meta-analysis of several ACTG trials in
which efavirenz was a comparator core agent has found an
association with an increased risk of suicidality, which may be
related to host genetics and increased drug levels.20 Together
with these drawbacks, the more recent demonstration of a
lower efficacy and safety when compared with the newer
INSTIs (dolutegravir in the primary study endpoint, and raltegravir in a mid – long term in sensitivity analyses) have eventually
forced the demotion of this giant to the alternative group in initial ART recommendations in 2015. 21 – 25 Rilpivirine, despite
some limitations including drug – drug interactions, the need
for administration with a medium to high calorie meal and
higher risk of virological failure and selection of resistance mutations with poor adherence or if baseline viral load is above
100 000 copies/mL, has become the reference core agent
in the NNRTI family. 26 – 28 The drug demonstrated superior
outcomes to efavirenz in subjects with baseline viral load
,100 000 HIV-1 RNA copies/mL in the pooled analysis of the
ECHO/THRIVE studies, and in the STaR study. Its approval as
first-line therapy is limited to those with low baseline viral
loads.28,29 The newest agent under investigation in the NNRTI
class, doravirine, looks promising. This potent drug may have
activity against resistant mutants selected by rilpivirine and efavirenz and lower rates of CNS side effects. However, Phase III
trials are still ongoing to determine its place in HIV therapy.30
The boosted PI era
The early unboosted PIs were not very effective (saquinavir), toxic
(ritonavir and indinavir) and all had a low barrier to the emergence
of resistance.31 – 34 None of them, including nelfinavir, was very
convenient, with the need for specific food and fluid requirements
and for multiple pills and frequent dosing, issues that compromised adherence.35
The demonstration of the role of low-dose ritonavir as a boosting agent for another PI through the inhibition of the hepatic
enzyme cytochrome p450 was a major advance. This led to the
ability to use lower doses, fewer pills and longer dosing intervals.
The most significant advantage of ‘boosted-PIs’ was their high
barrier to the development of resistance.34,36,37 Lopinavir/ritonavir
was demonstrated to be superior to nelfinavir (a gold standard of
the time) but non-inferior to saquinavir/ritonavir and fosamprenavir/ritonavir. After years of use, no resistance mutations are
typically selected in the protease gene among patients on initial
ART developing an episode of virological failure with a PI/ritonavir.38 – 40 Although the era of PI/ritonavir as core agents was inaugurated, and embraced widely in the field, they were not without
problems. The gastrointestinal tolerance of lopinavir/ritonavir was
far from optimal and abnormalities in the plasma lipid profile—
especially hypertriglyceridaemia—were frequently detected.41
In the Castle study, atazanavir/ritonavir outperformed lopinavir/
ritonavir mainly in advanced patients due to a better tolerance
but continued to have lipid issues when boosted with ritonavir.42,43 In the Artemis study darunavir/ritonavir also outperformed lopinavir/ritonavir not only because of better tolerance
but also because of a superior virological response, particularly
in advanced patients.44,45 The high barrier to resistance of a
ritonavir-boosted PI was confirmed.34,46 Darunavir/ritonavir
became the reference core agent in the PI/ritonavir family for
patients at all stages of HIV disease (including early and advanced
salvage) but continued to be suboptimal due to the need for
boosting (ritonavir and more recently cobicistat), which is associated with potential drug – drug interactions, abnormalities in
the plasma lipid profile and still some degree of gastrointestinal
intolerance.47 Although a direct comparison of darunavir/ritonavir
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with atazanavir/ritonavir showed similar virological activity, the
better tolerability of darunavir/ritonavir has led to its inclusion as
a preferred initial option in both US guidelines and the most
recent version of the EACS guideline. It is often selected because
of the high barrier to resistance, its demonstration of activity in
those presenting with advanced disease, and the fact that it may
be more forgiving to patients with adherence challenges.13,48,49
Despite a favourable safety profile, the CCR5 inhibitors have not
performed adequately as core agents. Maraviroc was not found to
be non-inferior to efavirenz as the core agent in the Merit study
and non-inferiority could only be demonstrated in a post-hoc
re-analysis using a more sensitive assay to determine the tropism
of the infecting virus. Other barriers to its use include the need for
prior screening for CCR5 tropism, twice-daily administration and
relatively higher cost at least in some countries.50
The INSTI era
We are now in the era of the INSTI. The INSTIs were initially
evaluated in patients with multidrug resistance and clearly
demonstrated an ability to rescue those with few treatment
options. 51,52 Given their efficacy and tolerability profiles they
were subsequently evaluated in ART-naive subjects. Three
agents are currently available. Elvitegravir needs pharmacokinetic boosting with cobicistat, and thus is associated with
almost the same issues as ritonavir with respect to drug interactions but has a low barrier to resistance (similar to that of
efavirenz) despite this. As a core agent it has demonstrated
non-inferiority to atazanavir/ritonavir or efavirenz in the pivotal
QUAD studies, 53,54 and superiority to atazanavir/ritonavir in
the women-only WAVES study. 55 Unlike the observation of
emergence of integrase resistance mutations in those with failure in the QUAD studies, in the WAVES trial none of the seven
patients who developed virological failure on elvitegravir and
were included in the resistance analysis population had emergent resistance mutations compared with 3 of the 12 in the
atazanavir/ritonavir arm (all the M184V/I).
Raltegravir is a generally well-tolerated twice-daily drug with a
low barrier to resistance but with a low potential for drug interactions. It was non-inferior at the primary endpoint to efavirenz in the
STARTMRK study but demonstrated superiority in longer follow-up
primarily due to better tolerability.22 – 25 Recently it was shown to be
superior to darunavir/ritonavir and atazanavir/ritonavir in the ACTG
5257 study (again mostly due to better tolerability), and noninferior to dolutegravir in the Spring-2 study.48,56
The newest agent in the class, dolutegravir, has the same
advantages as the other INSTIs and demonstrated superiority
to efavirenz and darunavir/ritonavir in the Single and Flamingo
studies, respectively, and non-inferiority to raltegravir in the
Spring-2 study.21,56,57 Indeed, it has been the first drug in antiretroviral history to beat efavirenz in the primary endpoint in a
fully powered randomized study. In addition, it is a once-daily
drug without a requirement for boosting, available in a coformulated
single tablet regimen (with abacavir and lamivudine), and has a high
barrier to resistance.58 – 60 Indeed, no dolutegravir-associated resistance mutations have been selected in antiretroviral-naive patients
recruited in the dolutegravir Phase III clinical trials through
96 weeks. Its activity is confirmed when combined with a backbone
of abacavir/lamivudine (or tenofovir and emtricitabine) irrespective
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of the baseline viral load. The efficacy of abacavir/lamivudine in
individuals with high baseline viral load has not raised issues with
either raltegravir or lopinavir/ritonavir but seems lower with efavirenz or atazanavir/ritonavir.61 – 63 Because of the confirmed efficacy,
the high barrier to resistance and formulation characteristics,
dolutegravir has become the reference agent in the INSTI class.
Antacids (containing aluminium, calcium or magnesium) and
iron supplements reduce the absorption and systemic exposure of
all three current HIV INSTIs, which should therefore be taken separately (2 h after or 6 h before) to avoid absorption interactions.
Regimens with less than two NRTIs in the
backbone or with only core agents
Although triple therapy has emerged and remains the gold standard ART, some core agents might not need two drugs as a backbone in initial ART. The Gardel study (testing lopinavir/ritonavir
and lamivudine in treatment-naive subjects) was the first proofof-concept study, demonstrating non-inferiority at 48 and
96 weeks to a standard triple therapy with lopinavir/ritonavir
plus two NRTIs (half of patients receiving zidovudine) irrespective
of baseline viral load.64,65 There was uncommon emergent HIV-1
resistance (and none in the protease) among those with virological failure. Two additional switch studies in virologically suppressed patients further supported this concept of a third/core
agent (a boosted PI) plus lamivudine only.66,67
Conversely, regimens initiating therapy with only core agents
have not been as successful as triple ART in treatment-naive subjects. Monotherapy with lopinavir/ritonavir in the Monark study
was clearly suboptimal.68 A meta-analysis of PI monotherapy
has demonstrated suboptimal activity compared with triple
therapy although this can be considered a strategy for selected
patients with toxicity and limited options.
Other studies have evaluated combinations of other classes of
antiretrovirals without NRTIs (NRTI-sparing strategies) in the hope
of reducing the toxicity of the NRTI while maintaining the efficacy
of triple ART. The combination of darunavir/ritonavir plus raltegravir was non-inferior to standard treatment of darunavir/ritonavir
plus two NRTIs in the overall NEAT 001 study but had some efficacy limitations in subjects with high baseline viral load or low
CD4+ cell counts.69 Lopinavir/ritonavir plus raltegravir also underperformed relative to the standard triple-drug arm in subjects
with low CD4+ cells, and integrase resistance emerged in some
subjects at failure.70 Several other combinations of two core
agents (atazanavir/ritonavir plus raltegravir, darunavir/ritonavir
plus maraviroc among others) simply failed with respect to efficacy, provided no advantages or the experience is very limited,
and are typically more costly.13 A regimen with darunavir/ritonavir
plus maraviroc plus emtricitabine was non-inferior to a standard
triple regimen of darunavir/ritonavir plus two NRTIs and had
toxicity advantages in the ACTG 5303 study.71
Collectively these studies suggest that for reasons that remain
unclear at least one NRTI may be needed as a backbone agent in
the combination. Lamivudine and emtricitabine may turn out to
be the ideal candidates. The addition of these agents has been
shown to prevent the increased incidence of blips or low-level viraemia seen with boosted PI monotherapies, and the emergence
of resistance to these drugs is uncommon when used in these
dual therapies. This success is most likely related to the high
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efficacy and genetic barrier of resistance to the boosted PI irrespective of baseline viral load, key advantages of the core agent
in contrast to other situations where other dual therapies have
typically failed.45,64 – 67 Therefore, despite their low genetic barrier
to resistance, lamivudine and emtricitabine are potent NRTIs
associated with 1.5 – 1.7 log10 mean reduction in HIV-1 RNA in
10 day monotherapy studies and have proven potent enough to
suppress durably the viral load in dual regimens without adding
toxicity, pharmacokinetic interactions or regimen complexity.72
The best NRTI-free regimens thus far are actually NRTI-sparing
regimens, as including at least one NRTI in the regimen seems to
be a key for success. Given the high barrier to resistance demonstrated to date with dolutegravir, investigators are speculating
whether dolutegravir together with a single NRTI will prove to
be adequate therapy.
Actually, a proof-of-concept pilot study has recently reported
that 20 selected treatment-naive subjects treated with dolutegravir and lamivudine in a dual PI-sparing regimen achieved an
undetectable (,50 copies/mL) HIV-1 RNA as soon as week 8,
and all remained undetectable at 24 weeks.73 If true in fully
powered clinical trials, this could offer an effective and safe combination for those in whom toxicity issues compromise the use of
the currently recommended NRTI backbones, and constitute a
cost-effective initial ART.
New agents in the NRTI backbone
Tenofovir alafenamide—a novel tenofovir prodrug—has been
demonstrated to be non-inferior to tenofovir disoproxil fumarate
both coformulated with elvitegravir/cobicistat/emtricitabine, with
similar clinical toxicity as initial ART.74 Moreover, it may be able to
overcome some of the kidney and bone problems (proteinuria and
bone mineral density) of tenofovir disoproxil fumarate but obviously not those associated with the need of boosting core agents
(cobicistat in this coformulation with elvitegravir). Actually, superiority could be demonstrated in a recently reported study in virologically suppressed patients receiving a triple regimen including
tenofovir disoproxil fumarate/emtricitabine plus efavirenz, atazanavir/ritonavir or elvitegravir/cobicistat who were switched
to coformulated elvitegravir/cobicistat/emtricitabine/tenofovir
alafenamide.75 Longer follow-up studies will show if the benefits
demonstrated so far in kidney tubular markers or bone densitometry translate into clinical benefits.
Conclusions
In summary, advances seen in ART during the past 30 years have
been outstanding. A backbone of at least one (in general two)
NRTI together with a third or core agent appears to be necessary
and complementary to adequately control viral replication and
neither performs adequately without the other. Although INSTIs
and particularly dolutegravir have emerged as effective and low
toxicity core agents, they do need to be supported and there continues to be toxicity concerns with current NRTI backbones.
Further research in the arena of ART to develop agents with
lower toxicity, longer dosing intervals, lower cost and alternative
routes of administration or to evaluate new NRTI-saving strategies are ongoing.
Transparency declarations
J. M. L. has been a member of the speakers’ bureaus of and received
fees from lectures from Janssen-Cilag, Merck, Sharp & Dohme, ViiV
Healthcare, Gilead Sciences and Bristol-Myers Squibb. S. W. has served
on advisory boards and spoken at CME events for Abbvie, ViiV, Gilead,
Merck, Bristol-Myers Squibb and Janssen. J. M. G. has been a member of
the speakers’ bureaus of and received fees from lectures or for participating in advisory boards from Janssen-Cilag, Merck, Sharp & Dohme, ViiV
Healthcare, Gilead Sciences, Bristol-Myers Squibb and Abbvie, and his institution has received research grants from Janssen-Cilag, Merck, Sharp &
Dohme, ViiV Healthcare, Gilead Sciences, Bristol-Myers Squibb and Abbvie.
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