The

n e w e ng l a n d j o u r na l

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m e dic i n e

clinical therapeutics
John A. Jarcho, M.D., Editor

Single-Pill Combination Regimens

for Treatment of HIV-1 Infection
Monica Gandhi, M.D., M.P.H., and Rajesh T. Gandhi, M.D.
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the authors clinical recommendations.
From the Division of HIV/AIDS, University of California, San Francisco (UCSF),
San Francisco (M.G.); and the Division of
Infectious Diseases, Massachusetts General Hospital (MGH), Boston, and the Ragon
Institute of MGH, Massachusetts Institute
of Technology, and Harvard, Cambridge,
MA (R.T.G.). Address reprint requests to
Dr. Monica Gandhi at UCSF, 995 Potrero
Ave., 4th Fl., San Francisco, CA 94110, or at
monica.gandhi@ucsf.edu; or to Dr. Rajesh
T. Gandhi at MGH, GRB 504, Infectious
Diseases, 55 Fruit St., Boston, MA 02114,
or at rgandhi@partners.org.

A 52-year-old man with a history of homelessness, depression, and polysubstance

use received a diagnosis of human immunodeficiency virus type 1 (HIV-1) infection
in 2005 but has declined antiretroviral therapy (ART) in the past. His CD4+ T-cell
count is now 257 per cubic millimeter, and his plasma HIV-1 RNA level is 17,000 copies
per milliliter. The patient was prescribed a multipill antiretroviral regimen 2 months
ago but has not followed this regimen regularly because taking out lots of pills in the
shelter just announces to the world that I have AIDS [the acquired immunodeficiency
syndrome]. The patient desires to keep his HIV status private and states that he
would take medications regularly if he could take just one pill once a day. The patient is not taking any other medications; his renal function is normal. How should
he be evaluated and treated?

*
Drs. Gandhi and Gandhi contributed
equally to this article.

The Cl inic a l Probl em

N Engl J Med 2014;371:248-59.

DOI: 10.1056/NEJMct1215532
Copyright 2014 Massachusetts Medical Society.

248

Effective HIV treatment requires lifelong and daily consumption of multiple antiretroviral medications. With the advent and refinement of combination ART, the
life expectancy of HIV-infected patients has risen dramatically.1,2 In addition to
benefiting infected persons, ART almost completely blocks HIV-1 transmission to
uninfected sexual partners.3 If we were able to treat most or all HIV-infected patients and thereby prevent new infections, the beginning of the end of AIDS
would be in sight.4,5
For the benefits of ART to be realized at the individual and population levels,
patients must maintain high levels of adherence to all components of the regimen.
A number of factors are associated with lower levels of adherence,6 including the
stigma associated with HIV infection,7 membership in a minority racial or ethnic
group,8-11 depression,9,12,13 alcohol or drug use,14 cognitive impairment,15 young
age,10 and medication side effects.16 Moreover, rates of adherence to ART may
decline over time,10,12,17-20 even when antiretroviral agents are provided at no cost.
There is therefore a compelling need for strategies that can help patients sustain
lifelong adherence to treatment.
When effective ART was first developed almost two decades ago, adherence
was particularly challenging because patients had to consume handfuls of pills,
often with substantial toxicity, multiple times per day. With the introduction of
coformulated drugs that are less toxic and more potent, there have been dramatic reductions in the pill burden. This trend has culminated in single-pill
combinations, in which all components of an ART regimen, typically three or
more medications from two different drug classes, are formulated into one pill
taken once daily.
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clinical ther apeutics

Biol o gic Fe at ur e s
of HI V-1 infec t ion
The rationale for lifelong combination therapy
for HIV-1 infection and the interest in developing single-pill combinations to facilitate adherence are based on the biologic features of the
virus (Fig. 1). Because of the high replication
and mutation rates of HIV-1, multiple antiretroviral agents (usually three) must be taken simultaneously to suppress replication and prevent
the development of viral resistance. ART can
reduce HIV-1 RNA to extremely low levels in the
blood, although the virus still persists in reservoirs found in specialized immune cells and tissues.21 Because antiretroviral regimens typically
cannot eradicate infection, even when additional agents are added,22,23 therapy must be continued over a lifetime to suppress viral replication
and prevent HIV-related complications.
Owing to the ability of HIV-1 to mutate rapidly, the effect of suboptimal adherence to ART
can be devastating (Fig. 2). Incomplete adherence leads to ongoing HIV-1 replication, which,
in the presence of low-to-moderate levels of drug
exposure, can select for viral strains with mutations conferring resistance to those agents. The
rapidity with which drug-resistant strains emerge
and the subsequent immunologic and clinical
consequences vary according to the HIV-1 RNA
level, the antiretroviral class, and the fitness of
the mutant virus. At the individual level, inconsistent adherence can lead to drug resistance, permanently rendering particular agents or classes
of drugs ineffective.24 At the population level,
inconsistent use of antiretroviral agents can lead
to ongoing transmission and the spread of drugresistant viral strains. Regimens with a low pill
burden, such as single-pill combinations, may both
facilitate adherence over a prolonged period and
ensure that none of the components of a combination regimen are inadvertently missed.

Cl inic a l E v idence
There are currently three single-pill combinations marketed for HIV-1 treatment, each containing the same combination of one nucleotide
reverse-transcriptase inhibitor and one nucleoside
reverse-transcriptase inhibitor (NRTIs): tenofovir
disoproxil fumarate (TDF) at a dose of 300 mg
and emtricitabine (FTC) at a dose of 200 mg, respectively. The first agent (Atripla, Bristol-Myers

Squibb and Gilead Sciences), released in 2006, is

a single pill that combines TDFFTC with 600 mg
of the nonnucleoside reverse-transcriptase inhibitor (NNRTI) efavirenz (EFV). The second agent
(Complera, Gilead Sciences), approved in 2011,
combines TDFFTC with 25 mg of the NNRTI
rilpivirine (RPV). The third agent (Stribild, Gilead
Sciences), released in 2012, consists of TDFFTC
combined with 150 mg of the integrase strandtransfer inhibitor (INSTI) elvitegravir (EVG) and
150 mg of the pharmacoenhancer cobicistat
(which boosts serum EVG levels). A fourth singlepill combination is in development and has not
yet been approved for clinical use. This agent
would combine two NRTIs abacavir (ABC) at
a dose of 600 mg and lamivudine (3TC) at a dose
of 300 mg with 50 mg of the recently approved
INSTI dolutegravir (DTG).
Studies of once-daily dosing of antiretroviral
agents provide support for the concept that regimen simplification improves adherence. One metaanalysis examined adherence among patients
with HIV-1 infection who received either oncedaily or twice-daily regimens in 19 randomized,
controlled studies (6321 patients).20 Modestly better adherence, assessed by means of pill counts or
medication-event monitoring systems, was observed among recipients of once-daily regimens
(an increase of 2.55 percentage points, P<0.001),
although there were no overall differences in
the virologic-suppression rate between the two
groups.20 Regimens involving fewer numbers of
pills improved both rates of adherence and virologic suppression.20
The effect of single-pill combinations on adherence and outcomes has been assessed by comparing patients receiving the EFVTDFFTC single-pill
combination agent with those taking multipill
combinations. The only published randomized
trial to make this comparison enrolled 300 patients receiving stable ART and assigned them
either to continue their previous regimen or to
switch to EFVTDFFTC as a single pill.25,26 At
48 weeks, patient-reported treatment adherence
was 96% or higher in both groups, and the rate of
virologic suppression did not differ significantly
between the two groups25; 91% of participants,
however, stated their preference for the EFVTDF
FTC regimen.26 In an open-label prospective study
using within-patient analyses, 202 patients receiving stable two- or three-drug EFV-based ART
were switched to the single-pill combination of
EFVTDFFTC27; the adherence rate increased from

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249

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93.8% to 96.1% (P<0.01), with improvements in ready receiving a stable ART regimen, with viroself-reported quality of life. These two studies logic suppression, before making the switch.25,27
probably underestimate the benefit of single-pill
Several observational studies, including a procombinations because most participants were al- spective analysis in a cohort of homeless and

CCR5 coreceptor antagonist

(maraviroc)

HIV-1

Protease
inhibitors

Mature
HIV-1
HIV
protease

8. Budding and
Maturation

1. Virus Entry
Fusion inhibitor
(enfuvirtide)

gp120
gp41

CCR5 or CXCR4
coreceptor

CD4 receptor

Protease
inhibitors

Host cell

Viral
matrix
Nucleus
Viral
capsid
Viral
RNA

2. Reverse
Transcription

Integrase strandtransfer inhibitors

(INSTIs)
Viral
Integrase

Reverse
transcriptase

Viral
DNA

Nonnucleoside reversetranscriptase inhibitors

(NNRTIs)
Nucleoside and nucleotide
reverse-transcriptase
inhibitors (NRTIs)

7. Assembly

4. Transcription
Genomic RNA

3. Integration

Provirus

6. Cleavage

mRNA

Host-cell
DNA

5. Translation

Protease
inhibitors

Viral
proteins

Figure 1. Reproductive Cycle of Human Immunodeficiency Virus Type 1 (HIV-1) and Sites of Action of the Major Classes of Antiretroviral Medications.
Step 1 represents HIV-1 entry into the host cell, which involves the binding of the viral envelope protein, glycoprotein 120 (gp120), to the CD4
molecule, followed by a conformational change in gp120 that allows binding to the chemokine host-cell receptor (e.g., CCR5 or CXCR4). Glycoprotein 41 (gp41), also part of the virus envelope, then mediates HIV-cell fusion to permit viral entry. The fusion inhibitor, enfuvirtide, blocks
fusion between the virus (through gp41) and the CD4 molecule, and the CCR5 coreceptor antagonist, maraviroc, blocks viral binding (through
gp120) to CCR5. Step 2 is reverse transcription, in which the single-stranded HIV-1 RNA is transcribed into double-stranded DNA by the HIV
enzyme (polymerase) called reverse transcriptase. This step is the site of action of nucleoside and nucleotide reverse-transcriptase inhibitors
(NRTIs) and nonnucleoside reverse-transcriptase inhibitors (NNRTIs). Step 3 is the migration of HIV DNA into the nucleus and its integration
into the DNA of the host cell, a process catalyzed by the viral enzyme integrase. Integrase strand-transfer inhibitors (INSTIs) target this step.
Step 4 is the transcription of the HIV-1 DNA into HIV messenger RNA (mRNA) and HIV genomic RNA. Step 5 is the transport of the HIV-1
RNA out of the nucleus and the translation of HIV-1 mRNA into viral polyproteins. To be functional, the transcribed proteins must be cleaved
into smaller component proteins, a process that occurs in step 6 through the action of the HIV-1 enzyme protease. This is the site of action of
protease inhibitors. Step 7 is the assembly of viral genomic RNA and viral enzymes (reverse transcriptase, integrase, and protease) into viral
particles. Step 8 is the budding and maturation of new viral particles, which then go on to infect other host cells.

250

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clinical ther apeutics

marginally housed patients,28 have also shown

higher rates of adherence or improved outcomes
with single-pill combinations.29-32 For example, a
retrospective analysis compared rates of adherence (measured on the basis of pharmacy refill
data) among approximately 7000 patients receiving ART composed of one, two, or three or more
pills per day.30 Adherence of 95% or higher was
more likely with a single-pill combination than
with a regimen of three or more pills per day.30
Similar findings were seen in observational studies involving HIV-infected Medicaid enrollees,31
U.S. veterans,32 and an Italian cohort,29 although
confounding by indication may play a role in all
these observational results.

0%
Individual level

Ongoing replication
of wildtype HIV

Incomplete suppression
of viral replication;
selection for drugresistant HIV

Suppression of viral
replication; no
development of
drug resistance

Cl inic a l Use
ART is usually initiated as a regimen consisting of
two NRTIs (the backbone) combined with a third
agent (the anchor), which consists of an NNRTI,
a protease inhibitor boosted with a pharmacoenhancer, or an INSTI. There are a number of considerations in the choice of a regimen, including
drug resistance (as assessed by means of HIV-1
genotyping), potential adverse drug effects, drug
drug interactions, food restrictions, convenience,
and cost.
Selection of a Single-Pill Combination regimen

Several additional factors must be weighed in deciding on the use of a single-pill combination
(Fig. 3 and Table 1). These include determination
of which NRTI combination (TDFFTC or ABC
3TC) is appropriate and whether a protease inhibitor (not included in any of the currently available combinations) is preferable in the regimen.
Single-pill combinations should be avoided in
patients with clinically significant renal disease
because TDF, 3TC, and FTC all require dose reductions or elimination when the estimated creatinine clearance is less than 50 ml per minute. The
inability to adjust the dose of individual drug components in patients with renal insufficiency is an
important limitation of single-pill combinations.
In addition, patients who have drug-resistant HIV-1
infection often require agents that are not included
in single-pill combinations.

Community level
Minimal
or no
adherence

Ongoing transmission
of wildtype HIV

Intermediate
adherence

Transmission
of drugresistant
HIV

Near-perfect
adherence

Nearcomplete interruption
of transmission
(treatment as prevention)

100%
Figure 2. Effects on the Individual and Community of Various Levels
of Antiretroviral Adherence.
Minimal or no adherence to treatment results in ongoing HIV replication
with little to no selective pressure on the virus to develop mutations that
confer drug resistance. Intermediate adherence results in low or moderate
drug exposure and, depending on the antiretroviral agent, selective pressure on the virus to develop resistance. Incomplete suppression of viral
replication in an individual allows for ongoing transmission to partners.
High-level adherence, which leads to virologic suppression and maximal
clinical benefit in the individual, as well as a marked reduction in the risk of
transmission to HIV-uninfected partners and near-complete interruption
of transmission at the community level, is the goal of contemporary management of HIV infection.

formulations, but only TDFFTC is currently

available in single-pill combination regimens.
Selection of the NRTI combination is mainly
driven by a choice between TDF and ABC because
both FTC and 3TC have relatively few adverse effects. TDFFTC has excellent potency and durable effectiveness, but TDF can trigger proximal
tubulopathy or frank renal insufficiency, particularly in patients with risk factors for kidney disease
and those taking protease inhibitors.33,34 Patients
receiving TDF-containing regimens also have a
larger drop in bone mineral density after ART
initiation than those receiving ABC-containing
regimens,35,36 although changes in bone density
subsequently stabilize. Use of ABC3TC requires
Selection of an NRTI backbone
initial testing of the patient for HLA B5701, a
The two most commonly used NRTI combina- genetic polymorphism that is present in approxitions in the United States are TDFFTC and mately 8% of whites and 2.5% of blacks in the
ABC3TC. Both are available as fixed-dose- United States37 and that predicts ABC-related
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hypersensitivity.38 When combined with EFV or responses observed with TDFFTC in patients with
ritonavir-boosted atazanavir, ABC3TC resulted pretherapy HIV-1 RNA levels of 100,000 copies
in inferior virologic responses as compared with per milliliter or higher39,40; this difference was not
observed when the HIV-1 RNA level was less than
100,000 copies per milliliter or when ABC3TC
Use of an SPC for HIV
was combined with other agents (e.g., DTG).41-44
Although some clinicians avoid the use of ABC
in patients who are at high risk for cardioIs protease inhibitor
No current SPC available
vascular disease because of a putative link beYes
based regimen preferred?
with a protease inhibitor
tween the drug and myocardial infarction, this
finding is controversial45 and has not been
No
confirmed in other studies, including a metaanalysis conducted by the Food and Drug AdIs estimated
ministration (FDA).46
Do not use SPC
creatinine clearance
<50 ml/min?

Yes

Selection of an Anchor Drug

No

Is patient positive for HLA B5701?

Yes

Do not use DTGABC3TC

No
Is HIV-1 RNA level
>100,000 copies/ml?
No

Yes

SPC options
EFVTDFFTC (Atripla)
EVGcobicistatTDFFTC
(Stribild), if creatinine
clearance 70 ml/min
DTGABC3TC

SPC options
EFVTDFFTC (Atripla)
RPVTDFFTC (Complera)
EVGcobicistatTDFFTC
(Stribild), if creatinine
clearance 70 ml/min
DTGABC3TC

Figure 3. Factors to Consider in the Use of a Single-Pill Combination (SPC)

for the Treatment of HIV Infection.
For patients who require a protease inhibitorbased regimen, no combination
containing a protease inhibitor is currently available as a single pill. In addition,
no combination formulated as a single pill is appropriate for patients with an
estimated creatinine clearance of less than 50 ml per minute, because the
NRTIs (lamivudine [3TC], emtricitabine [FTC], and tenofovir disoproxil fumarate [TDF]) that are incorporated into single-pill formulations require dose adjustments in such patients. In the absence of these constraints, combination
therapy administered as a single-pill formulation may be a suitable option. For
patients who are positive for HLA B5701 (as determined by host genetic testing), the combination of dolutegravir (DTG), abacavir (ABC), and 3TC should
not be used. For patients with an HIV-1 RNA level of 100,000 copies per milliliter or less, any of the single-pill combination regimens may be used. For those
with an HIV-1 RNA level of more than 100,000 copies per milliliter or with a
CD4+ T-cell count of 200 per cubic millimeter or less, the combination of rilpivirine (RPV), TDF, and FTC should not be used. For patients with a creatinine
clearance of less than 70 ml per minute, the combination of elvitegravir (EVG),
cobicistat, TDF, and FTC should not be initiated. The DTGABC3TC combination has not yet been approved as a single pill for clinical use.

252

n engl j med 371;3

None of the current single-pill combinations

contain protease inhibitors, which should be
used in patients with known viral resistance to
NNRTIs or INSTIs. In addition, because transmitted resistance to protease inhibitors is uncommon and resistance to this class emerges
relatively slowly, protease inhibitors are often
favored when treatment decisions are required
before resistance-testing results are available
for example, in the case of patients with acute
HIV-1 infection19 or opportunistic infections.47
Protease inhibitors are also sometimes considered in patients with inconsistent adherence because multiple viral mutations are required to
compromise the activity of these agents. Disadvantages of regimens containing protease inhibitors include higher pill burdens (typically
three pills per day) and drug interactions due to
inhibition of the cytochrome P-450 3A4 (CYP3A4)
enzyme system by these agents.
The anchor drug raltegravir does not inhibit
CYP3A4 activity and has few drugdrug interactions, with excellent virologic activity.48 Like
other INSTIs, raltegravir should not be administered with antacids that contain divalent cations;
these agents can reduce INSTI absorption
through chelation. However, unlike other recommended anchors, all with once-daily dosing,
raltegravir requires twice-daily dosing 49 and is
therefore not available in a single-pill combination.
EFV, the anchor drug in EFVTDFFTC, is potent and, in recent years, the drug to which every
newly developed anchor antiretroviral agent has
been compared. EFV may cause neuropsychiatric
effects (e.g., vivid dreams, insomnia, somnolence,
and depression) or rash, although symptoms
typically diminish over time. The FDA has catenejm.org

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clinical ther apeutics

gorized EFV as a class D agent with respect to

pregnancy risk on the basis of data from primate
models, although the extent of teratogenicity in
humans is unclear.50-52 According to U.S. guidelines, EFV should be avoided in sexually active
women of reproductive potential who are not
using contraception, although discontinuing EFV
if pregnancy occurs is not recommended and
EFV is the preferred NNRTI during pregnancy,
when initiated 8 weeks after conception.53 The
World Health Organization (WHO) recommends
EFV as a first-line agent for women regardless of
reproductive potential or pregnancy.54 Finally,
EFV can cause dyslipidemia, although it has not
been linked to an increased rate of myocardial
infarction.55
RPV, the anchor drug in RPVTDFFTC, was
approved on the basis of double-blind, doubledummy trials comparing it with EFV, each in
combination with TDFFTC56 or investigatorselected NRTIs.57 The pooled 96-week analysis
of these studies showed equal rates of virologic
suppression in the RPV and EFV groups.58 The
RPV group had fewer treatment discontinuations
due to adverse events and lower rates of rash,
central nervous system effects, and adverse lipid
effects than the EFV group. Among patients
whose pretherapy HIV-1 RNA level was more
than 100,000 copies per milliliter or whose
CD4+ T-cell count was less than 200 per cubic
millimeter, however, virologic-failure rates were
higher with RPV. Moreover, among patients with
virologic failure, HIV-1 drug resistance mutations emerged more frequently in patients receiving RPV. In an open-label, randomized study
comparing RPVTDFFTC with EFVTDFFTC,
each administered as a single-pill combination,59
RPV was superior to EFV in patients with pretherapy HIV-1 RNA levels of 100,000 copies per
milliliter or less and was noninferior to EFV in
patients with HIV-1 RNA levels of more than
100,000 copies per milliliter; in patients with viral loads of more than 500,000 copies per milli
liter, the rate of virologic failure in the RPV group
was higher. RPV-based regimens are not recommended for patients whose pretherapy HIV-1 RNA
level is more than 100,000 copies per milliliter or
whose CD4+ T-cell count is 200 per cubic milli
meter or less.19 RPV must be taken with a solid
meal (390 kcal)60 and requires stomach acid
for adequate absorption, precluding the concomitant use of proton-pump inhibitors. In addition to its use in initial therapy, RPVTDFFTC

may have a role in patients with virologic suppression during treatment with a protease inhibitor
containing regimen who have a reason to change
medications: in a recent trial, switching such
patients to RPVTDFFTC maintained high rates
of virologic suppression and improved lipid
levels.61
EVG, together with the pharmacoenhancer cobicistat, is the anchor drug in the single-pill combination EVGcobicistatTDFFTC. This combination
was noninferior to two other first-line regimens,
TDFFTC with either EFV 62-64 or ritonavir-boosted
atazanavir.65 In the STRATEGY trials, patients
with virologic suppression who were switched
from an NNRTI-containing or protease inhibitor
containing regimen to EVGcobicistatTDFFTC
continued to have high rates of virologic suppression.66,67 Cobicistat-boosted EVG does not have
neuropsychiatric effects and does not commonly
cause rash. However, cobicistat inhibits tubular
secretion of creatinine without reducing the creatinine clearance. As a result, patients may have
a mild increase in the serum creatinine level, typically less than 0.4 mg per deciliter (35 mol per
liter), with this medication initially; if a higher
elevation occurs, evaluation for TDF-induced damage is warranted. The studies that led to drug
approval involved patients with an estimated
creatinine clearance of more than 70 ml per minute, so use should be limited to this group.19
Cobicistat is a potent CYP3A4 inhibitor with potential drugdrug interactions.
DTG is a recently approved INSTI; the recommended dose in previously untreated patients
and in previously treated patients who did not
receive an INSTI is 50 mg once daily, allowing
its potential use in a single-pill combination.
Three randomized, phase 3 trials have compared
DTG with other first-line agents in previously
untreated patients. In the SPRING-2 study, DTG
was noninferior to raltegravir when combined with
either TDFFTC or ABC3TC.42,43 In the SINGLE
study, DTG was superior to EFVTDFFTC,68
largely because of more treatment-related discontinuations with EFV. In the FLAMINGO study,
DTG was superior to ritonavir-boosted darunavir
with either TDFFTC or ABC3TC,44 in part because of higher rates of study withdrawal in the
darunavir group and lower rates of virologic
nonresponse among patients in the DTG group
who had high viral loads at baseline. DTG was
also superior to raltegravir, each given with other
agents, in previously treated patients who had

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not received an INSTI,69 and it retains activity

against some raltegravir-resistant viruses when
given twice daily.70,71 A single-pill combination
containing DTGABC3TC is pharmacokinetically bioequivalent to the individual components of DTG plus ABC3TC,72 and an application for approval of the single-pill formulation

of

m e dic i n e

is under review at the FDA.73 DTG, like protease inhibitors, appears to have a high genetic
barrier to resistance, which could help prevent
the development of resistance in patients with
inconsistent adherence; however, more clinical
experience is needed to assess the role of DTG
in this context.

Table 1. Considerations for the Use of Particular Single-Pill Combinations in the Management of HIV-1 Infection.*
Single-Pill
Combination

Average Wholesale
Price per Month

Pros

Cons and Other Considerations

EFVTDFFTC
(Atripla)

This combination has the longest record of

safety and effectiveness. TDF and FTC have
activity against HBV; regimens containing
both drugs are recommended for patients
with HIVHBV coinfection.

EFV is potentially teratogenic; avoid in women trying to conceive, although it can be continued
in pregnant women with virologic suppression who present for antenatal care in the
first trimester. EFV may cause neuropsychiatric effects; avoid in patients with psychosis
or depression. EFV raises lipid levels, and it
may cause rash, typically mild to moderate in
severity and rarely requiring discontinuation.
To ameliorate neuropsychiatric effects, the
combination is often given at bedtime. It
should be taken on an empty stomach, since
food increases absorption, which may increase
the risk of adverse effects.

$2,402.04

RPVTDFFTC
(Complera)

As compared with EFV, RPV is associated with

lower rates of neuropsychiatric events and
rash and has more favorable lipid effects.
Patients with virologic suppression during
treatment with a protease inhibitorbased
regimen who switch to RPVTDFFTC have a
high rate of continued virologic suppression and
improved lipid levels. RPV is not known to be
teratogenic in humans (pregnancy class B).
TDF and FTC have activity against HBV; regimens containing both drugs are recommended for patients with HIVHBV coinfection.

This combination is not recommended if pretherapy

HIV-1 RNA level is >100,000 copies/ml or if
CD4+ T-cell count is 200/mm3. RPV must be
taken with a meal (390 kcal); administration
with a protein shake decreases absorption.
RPV requires acid for absorption. Donot use
proton-pump inhibitors; use antacids and
H2-receptor antagonists with caution. Use
caution if patient is taking another drug that
has been associated with prolongation of the
QTc interval.

$2,463.37

Cobicistat inhibits tubular secretion of creatinine,

leading to an early modest increase in the
serum creatinine level in some patients
(average increase, 0.14 mg/dl; increase is
usually <0.4 mg/dl). The increase is usually
reversible with treatment discontinuation.
This combination is not currently recommended
for patients with mild or moderate renal insufficiency. (Studies to date involved patients
with an estimated creatinine clearance of
>70ml/min.) EVG is not active against viral
strains that are resistant to raltegravir (an
important consideration for use in secondline regimens). As a CYP3A4 inhibitor, cobicistat can affect the metabolism of commonly
used medications, such as statins (lovastatin
and simvastatin are contraindicated), rifampin
(particularly important in HIVtuberculosis
coinfection), phosphodiesterase type 5 inhibitors (e.g., sildenafil), and fluticasone. This
combination should be taken with food and
should be administered at least 2 hr before
or after magnesium-containing, aluminumcontaining, or calcium carbonate antacids.

$2,948.70

Approved for HIV-1 infection

EVGcobicistat EVGcobicistat does not cause the neuro

TDFFTC
psychiatric effects or rash observed with
(Stribild)
EFV, and it has more favorable lipid effects
than EFV. Patients with virologic suppression during treatment with a protease inhibitorbased or NNRTI-based regimen
who switch to EVGcobicistatTDFFTC
have a high rate of continued virologic
suppression. EVGcobicistat is not known
to be teratogenic in humans (pregnancy
class B). TDF and FTC have activity against
HBV; regimens containing both drugs are
recommended for patients with HIVHBV
coinfection.

254

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clinical ther apeutics

Table 1. (Continued.)
Single-Pill
Combination

Pros

Cons and Other Considerations

Average Wholesale
Price per Month

Pending FDA approval

DTGABC3TC

In phase 3 trials involving previously untreated

patients, DTG-based regimens were superior to EFV-based regimens and ritonavirboosted, darunavir-based regimens and
were noninferior to raltegravir-based regimens. In previously treated patients without INSTI resistance, DTG was superior
to raltegravir with respect to virologic
activity. DTG has few drug interactions.
DTG can be taken with or without food.
The ABC3TC backbone can be used in
patients with mild renal insufficiency (estimated creatinine clearance >50 ml/min).
DTG has had a high genetic barrier to resistance in trials to date. DTG is not
known to be teratogenic in humans (pregnancy class B).

DTG inhibits creatinine secretion, leading to a

small rise in the serum creatinine level in some
patients (mean increase at 48 wk, 0.1 mg/dl
[range, 0.6 to 0.6]) an increase similar to
that observed with cobicistat. Use of ABCcontaining regimens requires genetic testing
for HLA B5701, an allele that predicts hypersensitivity to this drug. DTG should be taken at
least 2 hr before or 6 hr after oral administration of sucralfate or cation-containing antacids
or laxatives with magnesium or aluminum; calcium or iron supplements can be administered
with DTG with food (otherwise, DTG should be
taken at least 2 hr before or 6 hr after the supplement is taken). Double the dose with concomitant rifampin or EFV; do not use with etravirine
unless boosted protease inhibitors are being
administered. No dose adjustments are needed with RPV. There is limited clinical experience
with DTG to date (approved in August 2013).
Some studies have shown a link between ABC
and myocardial infarction, but there was no
such relationship in other studies and an FDA
meta-analysis.

In development for HIV-1 infection

EVGcobicistat Data to 48 wk suggest TAF may be associated
TAFFTC
with smaller reductions in bone density and
estimated creatinine clearance than TDF.

Available data are from a phase 2 study; no data

beyond 48 wk are available. More information
is needed.

* ABC denotes abacavir, DTG dolutegravir, EFV efavirenz, EVG elvitegravir, FDA Food and Drug Administration, FTC emtricitabine, HBV hepatitis B
virus, HIV human immunodeficiency virus, INSTI integrase strand-transfer inhibitor, NNRTI nonnucleoside reverse-transcriptase inhibitor,
QTccorrected QT, RPV rilpivirine, TAF tenofovir alafenamide, TDF tenofovir disoproxil fumarate, and 3TC lamivudine. To convert the values
forcreatinine to micromoles per liter, multiply by 88.4.

Agents in Development for Use in Single-Pill

Combinations

A r e a s of Uncer ta in t y

Tenofovir alafenamide (TAF), a prodrug of tenofovir that is converted to the active form in lymphocytes, is an agent being developed for use in
single-pill combinations. The virologic activity of
TAF was similar to that of TDF when each was
coformulated with cobicistatEVGFTC and taken
for 48 weeks.74 The TAF-containing regimen caused
a smaller decline in bone mineral density and estimated creatinine clearance than the TDF-containing
combination. Further studies of TAF-containing
single-pill combinations, including ones that include
protease inhibitors, are under way. Applications
for the fixed-dose combinations of atazanavir
cobicistat75,76 and darunavircobicistat77,78 are
under review at the FDA, and a single-pill combination regimen of darunavircobicistatTAF
FTC is being studied in clinical trials.

The potential benefits of single-pill combinations must be weighed against the higher costs
of these branded combinations as compared
with multipill regimens containing generic antiretroviral agents. One analysis projected that
switching patients with HIV-1 infection from the
branded EFVTDFFTC single-pill combination
to a three-pill regimen of generic EFV (not yet
available), branded TDF, and generic 3TC would
save almost $1 billion per year in the United
States, with a relatively small reduction in treatment efficacy.79 A study from Denmark showed
that switching patients from a branded singlepill combination to a cheaper multipill regimen
did not compromise virologic efficacy.80 In patients who struggle with adherence, however, the
decreased pill burden of a single-pill combina-

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255

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n e w e ng l a n d j o u r na l

tion could be crucial for successful treatment.

Moreover, if a multipill regimen requires multiple copayments, the cumulative cost may be prohibitive for some patients. On a global scale,
country- and region-specific pharmacoeconomic
analyses are needed for single-pill combinations
and other formulations (e.g., long-acting agents)
designed to improve adherence.

Guidel ine s
Of the single-pill combinations currently available, EFVTDFFTC is recommended in guidelines from the U.S. Department of Health and
Human Services (DHHS),19 the International
Antiviral SocietyUSA,45 and the British HIV Association.81 The WHO recommends EFVTDF
FTC or EFVTDF3TC, formulated as a single-pill
combination, as first-line agents.54 EVGcobicistat
TDFFTC is recommended for previously untreated patients in the DHHS and British guidelines.19,81
RPVTDFFTC is recommended by the DHHS
only for patients with pretherapy HIV-1 RNA levels of less than 100,000 copies per milliliter and
CD4+ T-cell counts of more than 200 per cubic
millimeter.19 The European AIDS Clinical Society
recommends the following single-pill combination
regimens: EFVTDFFTC, EVGcobicistatTDF
FTC, and, if the HIV-1 RNA level is less than
100,000 copies per milliliter, RPVTDFFTC.82
The use of fixed-dose combinations was listed
as an adherence-boosting strategy (level of evidence, IIIB)83 in a statement by an International
Association of Physicians in AIDS Care panel.84
However, the panel called for future research comparing single-pill combinations with their individual drug components, including analyses of cost.
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The first step in evaluating the patient described in
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Dr. Rajesh Gandhi reports receiving grant support through
his institution from ViiV Healthcare, Abbott Laboratories, and
Janssen Pharmaceuticals. No other potential conflict of interest
relevant to this article was reported.
Disclosure forms provided by the authors are available with
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