The n e w e ng l a n d j o u r na l of
clinical therapeutics
From the Division of HIV/AIDS, Univer-
sity of California, San Francisco (UCSF),
San Francisco (M.G.); and the Division of
Infectious Diseases, Massachusetts Gener-
al 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.
*
Drs. Gandhi and Gandhi contributed
equally to this article.
N Engl J Med 2014;371:248-59.
DOI: 10.1056/NEJMct1215532
Copyright 2014 Massachusetts Medical Society.
248
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m e dic i n e
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.
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 pa-
tient is not taking any other medications; his renal function is normal. How should
he be evaluated and treated?
The Cl inic a l Probl em
Effective HIV treatment requires lifelong and daily consumption of multiple anti-
retroviral 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 pa-
tients 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 dra-
matic 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.
n engl j med 371;3nejm.orgjuly 17, 2014
The New England Journal of Medicine
 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 develop-
ing single-pill combinations to facilitate adher-
ence are based on the biologic features of the
virus (Fig. 1). Because of the high replication
and mutation rates of HIV-1, multiple antiretro-
viral agents (usually three) must be taken simul-
taneously 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 reser-
voirs found in specialized immune cells and tis-
sues.21 Because antiretroviral regimens typically
cannot eradicate infection, even when addition-
al agents are added,22,23 therapy must be contin-
ued over a lifetime to suppress viral replication
and prevent HIV-related complications.
Owing to the ability of HIV-1 to mutate rap-
idly, the effect of suboptimal adherence to ART
can be devastating (Fig. 2). Incomplete adher-
ence leads to ongoing HIV-1 replication, which,
in the presence of low-to-moderate levels of drug
exposure, can select for viral strains with muta-
tions 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, inconsis-
tent adherence can lead to drug resistance, per-
manently 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 drug-
resistant 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 combi-
nation regimen are inadvertently missed.
Cl inic a l E v idence
There are currently three single-pill combina-
tions marketed for HIV-1 treatment, each con-
taining 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, re-
spectively. The first agent (Atripla, Bristol-Myers
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Squibb and Gilead Sciences), released in 2006, is
a single pill that combines TDFFTC with 600 mg
of the nonnucleoside reverse-transcriptase inhib-
itor (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 strand-
transfer inhibitor (INSTI) elvitegravir (EVG) and
150 mg of the pharmacoenhancer cobicistat
(which boosts serum EVG levels). A fourth single-
pill 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 regi-
men simplification improves adherence. One meta-
analysis examined adherence among patients
with HIV-1 infection who received either once-
daily or twice-daily regimens in 19 randomized,
controlled studies (6321 patients).20 Modestly bet-
ter adherence, assessed by means of pill counts or
medication-event monitoring systems, was ob-
served 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 vi-
rologic suppression.20
The effect of single-pill combinations on adher-
ence and outcomes has been assessed by compar-
ing patients receiving the EFVTDFFTC single-pill
combination agent with those taking multipill
combinations. The only published randomized
trial to make this comparison enrolled 300 pa-
tients 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 re-
ceiving stable two- or three-drug EFV-based ART
were switched to the single-pill combination of
EFVTDFFTC27; the adherence rate increased from
249
 The n e w e ng l a n d j o u r na l of m e dic i n e

93.8% to 96.1% (P<0.01), with improvements in ready receiving a stable ART regimen, with viro-
self-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 pro-
combinations because most participants were al- spective analysis in a cohort of homeless and

Protease
CCR5 coreceptor antagonist inhibitors
HIV-1 Mature
(maraviroc) HIV-1

HIV
protease

8. Budding and
1. Virus Entry Maturation
CCR5 or CXCR4
Fusion inhibitor coreceptor
(enfuvirtide) gp120
gp41
CD4 receptor
Protease
inhibitors
Host cell

Viral
matrix
Nucleus
7. Assembly
Viral
2. Reverse Integrase strand-
capsid
Transcription transfer inhibitors
Viral (INSTIs)
RNA
Viral
Integrase 4. Transcription

Reverse 6. Cleavage
transcriptase Viral Genomic RNA
DNA
3. Integration
Provirus mRNA
Nonnucleoside reverse-
transcriptase inhibitors
(NNRTIs) Protease
Host-cell 5. Translation
DNA inhibitors
Nucleoside and nucleotide
reverse-transcriptase Viral
proteins
inhibitors (NRTIs)

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). Glyco-
protein 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.

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 clinical ther apeutics

marginally housed patients,28 have also shown

higher rates of adherence or improved outcomes 0%
with single-pill combinations.29-32 For example, a Individual level Community level
retrospective analysis compared rates of adher-
ence (measured on the basis of pharmacy refill Ongoing replication Minimal Ongoing transmission
data) among approximately 7000 patients receiv- of wildtype HIV or no of wildtype HIV
adherence
ing 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 Incomplete suppression Transmission
Intermediate
Similar findings were seen in observational stud- of viral replication;
adherence
of drugresistant
selection for drug- HIV
ies involving HIV-infected Medicaid enrollees,31 resistant HIV
U.S. veterans,32 and an Italian cohort,29 although
confounding by indication may play a role in all
these observational results. Suppression of viral Nearcomplete interruption
Near-perfect
replication; no of transmission
adherence
development of (treatment as prevention)
Cl inic a l Use drug resistance

ART is usually initiated as a regimen consisting of

two NRTIs (the backbone) combined with a third
100%
agent (the anchor), which consists of an NNRTI,
a protease inhibitor boosted with a pharmaco-
Figure 2. Effects on the Individual and Community of Various Levels
enhancer, or an INSTI. There are a number of con- of Antiretroviral Adherence.
siderations in the choice of a regimen, including Minimal or no adherence to treatment results in ongoing HIV replication
drug resistance (as assessed by means of HIV-1 with little to no selective pressure on the virus to develop mutations that
genotyping), potential adverse drug effects, drug confer drug resistance. Intermediate adherence results in low or moderate
drug interactions, food restrictions, convenience, drug exposure and, depending on the antiretroviral agent, selective pres-
and cost. sure 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
Selection of a Single-Pill Combination regimen clinical benefit in the individual, as well as a marked reduction in the risk of
Several additional factors must be weighed in de- transmission to HIV-uninfected partners and near-complete interruption
ciding on the use of a single-pill combination of transmission at the community level, is the goal of contemporary man-
(Fig. 3 and Table 1). These include determination agement of HIV infection.
of which NRTI combination (TDFFTC or ABC
formulations, but only TDFFTC is currently
3TC) is appropriate and whether a protease in-
available in single-pill combination regimens.
hibitor (not included in any of the currently avail-
Selection of the NRTI combination is mainly
able combinations) is preferable in the regimen.
driven by a choice between TDF and ABC because
Single-pill combinations should be avoided in
both FTC and 3TC have relatively few adverse ef-
patients with clinically significant renal disease
fects. TDFFTC has excellent potency and dura-
because TDF, 3TC, and FTC all require dose reduc-
ble effectiveness, but TDF can trigger proximal
tions or elimination when the estimated creati-
tubulopathy or frank renal insufficiency, particu-
nine clearance is less than 50 ml per minute. The
larly in patients with risk factors for kidney disease
inability to adjust the dose of individual drug com-
and those taking protease inhibitors.33,34 Patients
ponents in patients with renal insufficiency is an
receiving TDF-containing regimens also have a
important limitation of single-pill combinations.
larger drop in bone mineral density after ART
In addition, patients who have drug-resistant HIV-1
infection often require agents that are not included
initiation than those receiving ABC-containing
in single-pill combinations. 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 approxi-
tions 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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 The n e w e ng l a n d j o u r na l of m e dic i n e

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 cardio-
Is protease inhibitor
Yes
No current SPC available vascular disease because of a putative link be-
based regimen preferred? with a protease inhibitor
tween the drug and myocardial infarction, this
No
finding is controversial45 and has not been
confirmed in other studies, including a meta-
analysis conducted by the Food and Drug Ad-
Is estimated
Do not use SPC
ministration (FDA).46
creatinine clearance Yes
<50 ml/min?
Selection of an Anchor Drug
None of the current single-pill combinations
No
contain protease inhibitors, which should be
used in patients with known viral resistance to
Is patient positive for HLA B5701? Yes Do not use DTGABC3TC NNRTIs or INSTIs. In addition, because trans-
mitted resistance to protease inhibitors is un-
No common and resistance to this class emerges
relatively slowly, protease inhibitors are often
Is HIV-1 RNA level
Yes
SPC options favored when treatment decisions are required
>100,000 copies/ml? EFVTDFFTC (Atripla)
EVGcobicistatTDFFTC
before resistance-testing results are available
(Stribild), if creatinine for example, in the case of patients with acute
No clearance 70 ml/min
DTGABC3TC
HIV-1 infection19 or opportunistic infections.47
Protease inhibitors are also sometimes consid-
SPC options
EFVTDFFTC (Atripla)
ered in patients with inconsistent adherence be-
RPVTDFFTC (Complera) cause multiple viral mutations are required to
EVGcobicistatTDFFTC
(Stribild), if creatinine compromise the activity of these agents. Dis-
clearance 70 ml/min advantages of regimens containing protease in-
DTGABC3TC
hibitors include higher pill burdens (typically
three pills per day) and drug interactions due to
Figure 3. Factors to Consider in the Use of a Single-Pill Combination (SPC) inhibition of the cytochrome P-450 3A4 (CYP3A4)
for the Treatment of HIV Infection. enzyme system by these agents.
For patients who require a protease inhibitorbased regimen, no combination The anchor drug raltegravir does not inhibit
containing a protease inhibitor is currently available as a single pill. In addition,
CYP3A4 activity and has few drugdrug inter-
no combination formulated as a single pill is appropriate for patients with an
actions, with excellent virologic activity.48 Like
estimated creatinine clearance of less than 50 ml per minute, because the
NRTIs (lamivudine [3TC], emtricitabine [FTC], and tenofovir disoproxil fuma- other INSTIs, raltegravir should not be adminis-
rate [TDF]) that are incorporated into single-pill formulations require dose ad- tered with antacids that contain divalent cations;
justments in such patients. In the absence of these constraints, combination these agents can reduce INSTI absorption
therapy administered as a single-pill formulation may be a suitable option. For through chelation. However, unlike other rec-
patients who are positive for HLA B5701 (as determined by host genetic test- ommended anchors, all with once-daily dosing,
ing), the combination of dolutegravir (DTG), abacavir (ABC), and 3TC should raltegravir requires twice-daily dosing 49 and is
not be used. For patients with an HIV-1 RNA level of 100,000 copies per milli- therefore not available in a single-pill combination.
liter or less, any of the single-pill combination regimens may be used. For those
EFV, the anchor drug in EFVTDFFTC, is po-
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 rilpi-
tent and, in recent years, the drug to which every
virine (RPV), TDF, and FTC should not be used. For patients with a creatinine newly developed anchor antiretroviral agent has
clearance of less than 70 ml per minute, the combination of elvitegravir (EVG), been compared. EFV may cause neuropsychiatric
cobicistat, TDF, and FTC should not be initiated. The DTGABC3TC combina- effects (e.g., vivid dreams, insomnia, somnolence,
tion has not yet been approved as a single pill for clinical use. and depression) or rash, although symptoms
typically diminish over time. The FDA has cate-

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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. guide-
lines, 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, double-
dummy trials comparing it with EFV, each in
combination with TDFFTC56 or investigator-
selected 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 muta-
tions emerged more frequently in patients re-
ceiving 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 pre-
therapy 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 vi-
ral 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 recom-
mended 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 con-
comitant use of proton-pump inhibitors. In addi-
tion to its use in initial therapy, RPVTDFFTC
may have a role in patients with virologic suppres-
sion 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 cobi-
cistat, is the anchor drug in the single-pill combina-
tion 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 suppres-
sion.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 cre-
atinine clearance. As a result, patients may have
a mild increase in the serum creatinine level, typi-
cally less than 0.4 mg per deciliter (35 mol per
liter), with this medication initially; if a higher
elevation occurs, evaluation for TDF-induced dam-
age is warranted. The studies that led to drug
approval involved patients with an estimated
creatinine clearance of more than 70 ml per min-
ute, so use should be limited to this group.19
Cobicistat is a potent CYP3A4 inhibitor with po-
tential drugdrug interactions.
DTG is a recently approved INSTI; the recom-
mended 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 dis-
continuations with EFV. In the FLAMINGO study,
DTG was superior to ritonavir-boosted darunavir
with either TDFFTC or ABC3TC,44 in part be-
cause 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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 The n e w e ng l a n d j o u r na l of m e dic i n e

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 pharmacokineti-
cally bioequivalent to the individual compo-
nents of DTG plus ABC3TC,72 and an applica-
tion for approval of the single-pill formulation
is under review at the FDA.73 DTG, like prote-
ase 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 Average Wholesale

Combination Pros
Approved for HIV-1 infection
EFVTDFFTC This combination has the longest record of
(Atripla) safety and effectiveness. TDF and FTC have
activity against HBV; regimens containing
both drugs are recommended for patients
with HIVHBV coinfection.
RPVTDFFTC As compared with EFV, RPV is associated with
(Complera) 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; regi-
mens containing both drugs are recommend-
ed for patients with HIVHBV coinfection.
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 suppres-
sion during treatment with a protease in-
hibitorbased 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.
Cons and Other Considerations Price per Month
EFV is potentially teratogenic; avoid in women try- $2,402.04
ing to conceive, although it can be continued
in pregnant women with virologic suppres-
sion who present for antenatal care in the
first trimester. EFV may cause neuropsychi-
atric 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.
This combination is not recommended if pretherapy $2,463.37
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.
Cobicistat inhibits tubular secretion of creatinine, $2,948.70
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 in-
sufficiency. (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 second-
line regimens). As a CYP3A4 inhibitor, cobi-
cistat 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 inhib-
itors (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, aluminum-
containing, or calcium carbonate antacids.

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 clinical ther apeutics

Table 1. (Continued.)

Single-Pill Average Wholesale

Combination Pros
Pending FDA approval
DTGABC3TC In phase 3 trials involving previously untreated
patients, DTG-based regimens were supe-
rior to EFV-based regimens and ritonavir-
boosted, darunavir-based regimens and
were noninferior to raltegravir-based regi-
mens. In previously treated patients with-
out 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 (esti-
mated creatinine clearance >50 ml/min).
DTG has had a high genetic barrier to re-
sistance in trials to date. DTG is not
known to be teratogenic in humans (preg-
nancy class B).
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.
Cons and Other Considerations Price per Month
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 ABC-
containing regimens requires genetic testing
for HLA B5701, an allele that predicts hyper-
sensitivity to this drug. DTG should be taken at
least 2 hr before or 6 hr after oral administra-
tion of sucralfate or cation-containing antacids
or laxatives with magnesium or aluminum; cal-
cium 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 supple-
ment is taken). Double the dose with concomi-
tant rifampin or EFV; do not use with etravirine
unless boosted protease inhibitors are being
administered. No dose adjustments are need-
ed 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.
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
Tenofovir alafenamide (TAF), a prodrug of teno-
fovir that is converted to the active form in lym-
phocytes, 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 esti-
mated 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 com-
bination regimen of darunavircobicistatTAF
FTC is being studied in clinical trials.
A r e a s of Uncer ta in t y
The potential benefits of single-pill combina-
tions must be weighed against the higher costs
of these branded combinations as compared
with multipill regimens containing generic anti-
retroviral 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 treat-
ment efficacy.79 A study from Denmark showed
that switching patients from a branded single-
pill combination to a cheaper multipill regimen
did not compromise virologic efficacy.80 In pa-
tients who struggle with adherence, however, the
decreased pill burden of a single-pill combina-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

tion could be crucial for successful treatment. R ec om mendat ions

Moreover, if a multipill regimen requires multi-
ple copayments, the cumulative cost may be pro-
hibitive 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 avail-
able, EFVTDFFTC is recommended in guide-
lines from the U.S. Department of Health and
Human Services (DHHS),19 the International
Antiviral SocietyUSA,45 and the British HIV As-
sociation.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 untreat-
ed patients in the DHHS and British guidelines.19,81
RPVTDFFTC is recommended by the DHHS
only for patients with pretherapy HIV-1 RNA lev-
els 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 evi-
dence, IIIB)83 in a statement by an International
Association of Physicians in AIDS Care panel.84
However, the panel called for future research com-
paring single-pill combinations with their individ-
ual drug components, including analyses of cost.
The first step in evaluating the patient described in
the vignette would be to check the HIV-1 genotype
to determine whether prior inconsistent use of ART
has selected for drug resistance. If not, a single-
pill combination is an attractive option owing to
the low pill burden and the patients stated prefer-
ence. TDFFTC, the only NRTI backbone in cur-
rently available single-pill combinations, would be
reasonable for this patient, given his normal renal
function. Although a regimen containing a prote-
ase inhibitor as the anchor is sometimes selected
if adherence is uncertain, the patient indicates that
he is more likely to adhere to a single-pill combina-
tion. Each of the anchor drugs in currently available
single-pill combinations would be suitable because
of his normal renal function and relatively low
HIV-1 RNA level and because he is not taking other
medications. The selection of a regimen should be
based on potential side effects, food requirements,
dosing schedule, and, possibly, anticipated adher-
ence; cost may also be a consideration. Regardless
of which regimen is chosen, careful clinical, viro-
logic, and immunologic monitoring, along with
regular adherence assessment and counseling, will
be key contributors to treatment success.
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
the full text of this article at NEJM.org.
We thank Drs. Diane Havlir, David Bangsberg, Rochelle
Walensky, Harry Lampiris, Joseph Eron, and Rakesh Mishra for
helpful input in reviewing the content, Kelsey Han for her as-
sistance, and our patients at Ward 86 and Massachusetts Gen-
eral Hospital for providing the inspiration.

References
1. May MT, Gompels M, Delpech V, et al.
Impact on life expectancy of HIV-1 posi-
tive individuals of CD4+ cell count and
viral load response to antiretroviral ther-
apy: UK cohort study. AIDS 2014 February
19 (Epub ahead of print).
2. Bor J, Herbst AJ, Newell ML, Brnig
hausen T. Increases in adult life expec-
tancy in rural South Africa: valuing the
scale-up of HIV treatment. Science 2013;
339:961-5.
3. Cohen MS, Chen YQ, McCauley M, et al.
Prevention of HIV-1 infection with early
antiretroviral therapy. N Engl J Med 2011;
365:493-505.
4. Havlir D, Beyrer C. The beginning of
the end of AIDS? N Engl J Med 2012;367:
685-7.
5. Granich RM, Gilks CF, Dye C, De Cock
KM, Williams BG. Universal voluntary
HIV testing with immediate antiretroviral
therapy as a strategy for elimination of
HIV transmission: a mathematical model.
Lancet 2009;373:48-57.
6. Bangsberg DR, Mills EJ. Long-term
adherence to antiretroviral therapy in
resource-limited settings: a bitter pill to
swallow. Antivir Ther 2013;18:25-8.
7. Earnshaw VA, Smith LR, Chaudoir SR,
Amico KR, Copenhaver MM. HIV stigma
mechanisms and well-being among PLWH:
a test of the HIV stigma framework. AIDS
Behav 2013;17:1785-95.
8. OConnor JL, Gardner EM, Mannheimer
SB, et al. Factors associated with adherence
amongst 5295 people receiving antiretro
viral therapy as part of an international
trial. J Infect Dis 2013;208:40-9.
9. Kong MC, Nahata MC, Lacombe VA,
Seiber EE, Balkrishnan R. Association be-
tween race, depression, and antiretroviral
therapy adherence in a low-income popu-
lation with HIV infection. J Gen Intern
Med 2012;27:1159-64.
10. Mannheimer S, Friedland G, Matts J,
Child C, Chesney M. The consistency of
adherence to antiretroviral therapy pre-
dicts biologic outcomes for human im-
munodeficiency virus-infected persons in
clinical trials. Clin Infect Dis 2002;34:
1115-21.
11. Simoni JM, Huh D, Wilson IB, et al.
Racial/ethnic disparities in ART adher-
ence in the United States: findings from

256 n engl j med 371;3nejm.orgjuly 17, 2014

The New England Journal of Medicine

Downloaded from nejm.org at MEMORIAL UNIV OF NEWFOUNDLAND on July 16, 2014. For personal use only. No other uses without permission.
Copyright 2014 Massachusetts Medical Society. All rights reserved.

the MACH14 study. J Acquir Immune
Defic Syndr 2012;60:466-72.
12. Byakika-Tusiime J, Crane J, Oyugi JH,
et al. Longitudinal antiretroviral adherence
in HIV+ Ugandan parents and their chil-
dren initiating HAART in the MTCT-Plus
family treatment model: role of depression
in declining adherence over time. AIDS
Behav 2009;13:Suppl 1:82-91.
13. Sullivan PS, Campsmith ML, Nakamura
GV, Begley EB, Schulden J, Nakashima AK.
Patient and regimen characteristics asso-
ciated with self-reported nonadherence to
antiretroviral therapy. PLoS One 2007;2(6):
e552.
14. Cohn SE, Jiang H, McCutchan JA, et al.
Association of ongoing drug and alcohol
use with non-adherence to antiretroviral
therapy and higher risk of AIDS and
death: results from ACTG 362. AIDS Care
2011;23:775-85.
15. Applebaum AJ, Reilly LC, Gonzalez JS,
Richardson MA, Leveroni CL, Safren SA.
The impact of neuropsychological func-
tioning on adherence to HAART in HIV-
infected substance abuse patients. AIDS
Patient Care STDS 2009;23:455-62.
16. Al-Dakkak I, Patel S, McCann E, Gad-
kari A, Prajapati G, Maiese EM. The im-
pact of specific HIV treatment-related ad-
verse events on adherence to antiretroviral
therapy: a systematic review and meta-
analysis. AIDS Care 2013;25:400-14.
17. Horne R, Cooper V, Gellaitry G, Date
HL, Fisher M. Patients perceptions of high-
ly active antiretroviral therapy in relation to
treatment uptake and adherence: the utility
of the necessity-concerns framework. J Ac-
quir Immune Defic Syndr 2007;45:334-41.
18. Liu H, Miller LG, Hays RD, et al. Re-
peated measures longitudinal analyses of
HIV virologic response as a function of
percent adherence, dose timing, geno-
typic sensitivity, and other factors. J Ac-
quir Immune Defic Syndr 2006;41:315-22.
19. Panel on Antiretroviral Guidelines for
Adults and Adolescents. Guidelines for
the use of antiretroviral agents in HIV-1-
infected adults and adolescents. Rock-
ville, MD: AIDSinfo, May 1, 2014 (http://
aidsinfo.nih.gov/contentfiles/lvguidelines/
AdultandAdolescentGL.pdf).
20. Nachega JB, Parienti JJ, Uthman OA,
et al. Lower pill burden and once-daily
antiretroviral treatment regimens for HIV
infection: a meta-analysis of randomized
controlled trials. Clin Infect Dis 2014;58:
1297-307.
21. Eisele E, Siliciano RF. Redefining the
viral reservoirs that prevent HIV-1 eradi-
cation. Immunity 2012;37:377-88.
22. Gandhi RT, Zheng L, Bosch RJ, et al.
The effect of raltegravir intensification on
low-level residual viremia in HIV-infected
patients on antiretroviral therapy: a ran-
domized controlled trial. PLoS Med 2010;
7(8):pii:e1000321.
23. Hatano H, Hayes TL, Dahl V, et al.
Arandomized, controlled trial of raltegra
vir intensification in antiretroviral-treated,
n engl j med 371;3nejm.orgjuly 17, 2014
The New England Journal of Medicine
Downloaded from nejm.org at MEMORIAL UNIV OF NEWFOUNDLAND on July 16, 2014. For personal use only. No other uses without permission.
Copyright 2014 Massachusetts Medical Society. All rights reserved.
clinical ther apeutics
HIV-infected patients with a suboptimal
CD4+ T cell response. J Infect Dis 2011;
203:960-8.
24. Gardner EM, Hullsiek KH, Telzak EE,
et al. Antiretroviral medication adherence
and class-specific resistance in a large pro-
spective clinical trial. AIDS 2010;24:395-403.
25. Dejesus E, Young B, Morales-Ramirez
JO, et al. Simplification of antiretroviral
therapy to a single-tablet regimen con-
sisting of efavirenz, emtricitabine, and
tenofovir disoproxil fumarate versus un-
modified antiretroviral therapy in viro-
logically suppressed HIV-1-infected pa-
tients. J Acquir Immune Defic Syndr 2009;
51:163-74.
26. Hodder SL, Mounzer K, Dejesus E, et
al. Patient-reported outcomes in virologi-
cally suppressed, HIV-1-infected subjects
after switching to a simplified, single-
tablet regimen of efavirenz, emtricitabine,
and tenofovir DF. AIDS Patient Care STDS
2010;24:87-96.
27. Airoldi M, Zaccarelli M, Bisi L, et al.
One-pill once-a-day HAART: a simplifica-
tion strategy that improves adherence and
quality of life of HIV-infected subjects.
Patient Prefer Adherence 2010;4:115-25.
28. Bangsberg DR, Ragland K, Monk A,
Deeks SG. A single tablet regimen is as-
sociated with higher adherence and viral
suppression than multiple tablet regimens
in HIV+ homeless and marginally housed
people. AIDS 2010;24:2835-40.
29. Antinori A, Angeletti C, Ammassari A,
et al. Adherence in HIV-positive patients
treated with single-tablet regiments and
multi-pill regimens: findings from the
COMPACT study. J Int AIDS Soc 2012;15:
Suppl 4:18098. abstract.
30. Sax PE, Meyers JL, Mugavero M, Davis
KL. Adherence to antiretroviral treatment
and correlation with risk of hospitaliza-
tion among commercially insured HIV
patients in the United States. PLoS One
2012;7(2):e31591.
31. Cohen CJ, Meyers JL, Davis KL. Asso-
ciation between daily antiretroviral pill
burden and treatment adherence, hospi-
talisation risk, and other healthcare utili-
sation and costs in a US Medicaid popula-
tion with HIV. BMJ Open 2013;3(8):pii:
e003028.
32. Rao GA, Sutton SS, Hardin J, Bennett
CL. Impact of highly active antiretroviral
therapy regimen on adherence and risk of
hospitalization in veterans with HIV/AIDS.
Presented at the 53rd Interscience Confer-
ence on Antimicrobial Agents and Chemo-
therapy, Denver, September 1013, 2013.
abstract.
33. Scherzer R, Estrella M, Li Y, et al.
Association of tenofovir exposure with
kidney disease risk in HIV infection.
AIDS 2012;26:867-75.
34. Young J, Schfer J, Fux CA, et al. Renal
function in patients with HIV starting ther-
apy with tenofovir and either efavirenz, lo
pinavir or atazanavir. AIDS 2012;26:567-75.
35. McComsey GA, Kitch D, Daar ES, et
al. Bone mineral density and fractures in
antiretroviral-naive persons randomized to
receive abacavir-lamivudine or tenofovir
disoproxil fumarate-emtricitabine along
with efavirenz or atazanavir-ritonavir:
AIDS Clinical Trials Group A5224s, a sub-
study of ACTG A5202. J Infect Dis 2011;
203:1791-801.
36. Bedimo R, Maalouf NM, Zhang S,
Drechsler H, Tebas P. Osteoporotic frac-
ture risk associated with cumulative ex-
posure to tenofovir and other antiretrovi-
ral agents. AIDS 2012;26:825-31.
37. Phillips EJ. Genetic screening to pre-
vent abacavir hypersensitivity reaction:
are we there yet? Clin Infect Dis 2006;43:
103-5.
38. Mallal S, Phillips E, Carosi G, et al.
HLA-B*5701 screening for hypersensitivity
to abacavir. N Engl J Med 2008;358:568-79.
39. Sax PE, Tierney C, Collier AC, et al.
Abacavir/lamivudine versus tenofovir DF/
emtricitabine as part of combination regi-
mens for initial treatment of HIV: final
results. J Infect Dis 2011;204:1191-201.
40. Post FA, Moyle GJ, Stellbrink HJ, et
al. Randomized comparison of renal ef-
fects, efficacy, and safety with once-daily
abacavir/lamivudine versus tenofovir/
emtricitabine, administered with efavirenz,
in antiretroviral-naive, HIV-1-infected
adults: 48-week results from the ASSERT
study. JAcquir Immune Defic Syndr
2010;55:49-57.
41. Smith KY, Patel P, Fine D, et al. Ran-
domized, double-blind, placebo-matched,
multicenter trial of abacavir/lamivudine
or tenofovir/emtricitabine with lopinavir/
ritonavir for initial HIV treatment. AIDS
2009;23:1547-56.
42. Raffi F, Jaeger H, Quiros-Roldan E, et
al. Once-daily dolutegravir versus twice-
daily raltegravir in antiretroviral-naive
adults with HIV-1 infection (SPRING-2
study): 96 week results from a randomised,
double-blind, non-inferiority trial. Lancet
Infect Dis 2013;13:927-35.
43. Raffi F, Rachlis A, Stellbrink HJ, et al.
Once-daily dolutegravir versus raltegravir
in antiretroviral-naive adults with HIV-1
infection: 48 week results from the
randomised, double-blind, non-inferiority
SPRING-2 study. Lancet 2013;381:735-43.
44. Clotet B, Feinberg J, van Lunzen J, et al.
Once-daily dolutegravir versus darunavir
plus ritonavir in antiretroviral-naive adults
with HIV-1 infection (FLAMINGO): 48 week
results from the randomised open-label
phase 3b study. Lancet 2014;383:2222-31.
45. Thompson MA, Aberg JA, Hoy JF, et
al. Antiretroviral treatment of adult HIV
infection: 2012 recommendations of the
International Antiviral Society-USA panel.
JAMA 2012;308:387-402.
46. Ding X, Andraca-Carrera E, Cooper C,
et al. No association of abacavir use with
myocardial infarction: findings of an FDA
meta-analysis. J Acquir Immune Defic
Syndr 2012;61:441-7.
47. Zolopa A, Andersen J, Powderly W, et al.
257
 The n e w e ng l a n d j o u r na l
Early antiretroviral therapy reduces AIDS
progression/death in individuals with
acute opportunistic infections: a multi-
center randomized strategy trial. PLoS
One 2009;4(5):e5575.
48. Rockstroh JK, DeJesus E, Lennox JL,
et al. Durable efficacy and safety of ral
tegravir versus efavirenz when combined
with tenofovir/emtricitabine in treatment-
naive HIV-1-infected patients: final 5-year
results from STARTMRK. J Acquir Im-
mune Defic Syndr 2013;63:77-85.
49. Eron JJ Jr, Rockstroh JK, Reynes J, et
al. Raltegravir once daily or twice daily in
previously untreated patients with HIV-1:
a randomised, active-controlled, phase 3
non-inferiority trial. Lancet Infect Dis
2011;11:907-15. [Erratum, Lancet Infect
Dis 2011;11:895.]
50. Ford N, Calmy A, Mofenson L. Safety
of efavirenz in the first trimester of preg-
nancy: an updated systematic review and
meta-analysis. AIDS 2011;25:2301-4.
51. Ford N, Mofenson L, Kranzer K, et al.
Safety of efavirenz in first-trimester of
pregnancy: a systematic review and meta-
analysis of outcomes from observational
cohorts. AIDS 2010;24:1461-70.
52. Ford N, Calmy A. Efavirenz is not a
known teratogen. Pediatr Infect Dis J 2012;
31:999-1000.
53. Panel on Treatment of HIV-Infected
Pregnant Women and Prevention of Peri-
natal Transmission. Recommendations
for use of antiretroviral drugs in pregnant
HIV-1-infected women for maternal health
and interventions to reduce perinatal HIV
transmission in the United States. Rock-
ville, MD: AIDSinfo, March 28, 2014 (http://
aidsinfo.nih.gov/contentfiles/lvguidelines/
PerinatalGL.pdf).
54. Consolidated guidelines on the use
of antiretroviral drugs for treating and
preventing HIV infection. Geneva: World
Health Organization, June 30, 2013 (http://
www.who.int/hiv/pub/guidelines/arv2013/
download/en/index.html).
55. Worm SW, Sabin C, Weber R, et al.
Risk of myocardial infarction in patients
with HIV infection exposed to specific
individual antiretroviral drugs from the
3major drug classes: the Data Collection
on Adverse Events of Anti-HIV Drugs
(D:A:D) study. J Infect Dis 2010;201:318-30.
56. Molina JM, Cahn P, Grinsztejn B, et
al. Rilpivirine versus efavirenz with teno-
fovir and emtricitabine in treatment-naive
adults infected with HIV-1 (ECHO): a
phase 3 randomised double-blind active-
controlled trial. Lancet 2011;378:238-46.
57. Cohen CJ, Andrade-Villanueva J, Clo-
tet B, et al. Rilpivirine versus efavirenz
with two background nucleoside or nucle-
otide reverse transcriptase inhibitors in
treatment-naive adults infected with HIV-1
(THRIVE): a phase 3, randomised, non-
inferiority trial. Lancet 2011;378:229-37.
58. Cohen CJ, Molina JM, Cassetti I, et al.
Week 96 efficacy and safety of rilpivirine
in treatment-naive, HIV-1 patients in two
258
The New England Journal of Medicine
Downloaded from nejm.org at MEMORIAL UNIV OF NEWFOUNDLAND on July 16, 2014. For personal use only. No other uses without permission.
Copyright 2014 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
phase III randomized trials. AIDS 2013;
27:939-50.
59. Cohen C, Wohl D, Arribas JR, et al.
Week 48 results from a randomized
clinical trial of rilpivirine/emtricitabine/
tenofovir disoproxil fumarate vs. efavirenz/
emtricitabine/tenofovir disoproxil fuma-
rate in treatment-naive HIV-1-infected
adults. AIDS 2014;28:989-97.
60. Custodio JM, Yin X, Hepner M, et al.
Effect of food on rilpivirine/emtricitabine/
tenofovir disoproxil fumarate, an anti
retroviral single-tablet regimen for the
treatment of HIV infection. J Clin Phar-
macol 2014;54:378-85.
61. Palella FJ Jr, Fisher M, Tebas P, et al.
Simplification to rilpivirine/emtricitabine/
tenofovir disoproxil fumarate from ritonavir-
boosted protease inhibitor antiretroviral
therapy in a randomized trial of HIV-1
RNA-suppressed participants. AIDS 2014;
28:335-44.
62. Sax PE, DeJesus E, Mills A, et al. Co-
formulated elvitegravir, cobicistat, emtricit
abine, and tenofovir versus co-formulated
efavirenz, emtricitabine, and tenofovir for
initial treatment of HIV-1 infection: a ran-
domised, double-blind, phase 3 trial, analy-
sis of results after 48 weeks. Lancet 2012;
379:2439-48. [Erratum, Lancet 2012;380:
730.]
63. Zolopa A, Sax PE, DeJesus E, et al.
Arandomized double-blind comparison
of coformulated elvitegravir/cobicistat/
emtricitabine/tenofovir disoproxil fumarate
versus efavirenz/emtricitabine/tenofovir dis
oproxil fumarate for initial treatment of
HIV-1 infection: analysis of week 96 results.
J Acquir Immune Defic Syndr 2013;63:96-
100.
64. Wohl DA, Cohen C, Gallant JE, et al.
Arandomized, double-blind comparison of
single-tablet regimen elvitegravir/cobicistat/
emtricitabine/tenofovir DF versus single-
tablet regimen efavirenz/emtricitabine/
tenofovir DF for initial treatment of HIV-1
infection: analysis of week 144 results.
JAcquir Immune Defic Syndr 2014;65(3):
e118-e120.
65. DeJesus E, Rockstroh JK, Henry K,
etal. Co-formulated elvitegravir, cobicistat,
emtricitabine, and tenofovir disoproxil fu-
marate versus ritonavir-boosted atazanavir
plus co-formulated emtricitabine and teno-
fovir disoproxil fumarate for initial treat-
ment of HIV-1 infection: a randomised,
double-blind, phase 3, non-inferiority trial.
Lancet 2012;379:2429-38.
66. Pozniak A, Markowitz M, Mills A, et al.
Switching to coformulated elvitegravir,
cobicistat, emtricitabine, and tenofovir
versus continuation of non-nucleoside re-
verse transcriptase inhibitor with emtri
cita bine and tenofovir in virologically
suppressed adults with HIV (STRATEGY-
NNRTI): 48 week results of a randomised,
open-label, phase 3b non-inferiority trial.
Lancet Infect Dis 2014;14:590-9.
67. Arribas JR, Pialoux G, Gathe J, et al.
Simplification to coformulated elvitegra-
n engl j med 371;3nejm.orgjuly 17, 2014
vir, cobicistat, emtricitabine, and tenofovir
versus continuation of ritonavir-boosted
protease inhibitor with emtricitabine and
tenofovir in adults with virologically sup-
pressed HIV (STRATEGY-PI): 48 week re-
sults of a randomised, open-label, phase
3b, non-inferiority trial. Lancet Infect Dis
2014;14:581-9.
68. Walmsley SL, Antela A, Clumeck N, et
al. Dolutegravir plus abacavirlamivudine
for the treatment of HIV-1 infection. N Engl
J Med 2013;369:1807-18.
69. Cahn P, Pozniak AL, Mingrone H, et
al. Dolutegravir versus raltegravir in anti-
retroviral-experienced, integrase-inhibitor-
naive adults with HIV: week 48 results
from the randomised, double-blind, non-
inferiority SAILING study. Lancet 2013;
382:700-8. [Erratum, Lancet 2014;383:30.]
70. Eron JJ, Clotet B, Durant J, et al. Safety
and efficacy of dolutegravir in treatment-
experienced subjects with raltegravir-
resistant HIV type 1 infection: 24-week
results of the VIKING Study. J Infect Dis
2013;207:740-8.
71. Castagna A, Maggiolo F, Penco G, et al.
Dolutegravir in antiretroviral-experienced
patients with raltegravir- and/or elvitegravir-
resistant HIV-1: 24-week results of the phase
III VIKING-3 Study. J Infect Dis 2014 Feb-
ruary 23 (Epub ahead of print).
72. Weller S, Chen S, Borland J, Savina P,
Wynne B, Piscitelli S. Bioequivalence of a
dolutegravir, abacavir and lamivudine
fixed-dose combination tablet and the ef-
fect of food. J Acquir Immune Defic Syndr
2014;66:393-8.
73. ViiV Healthcare announces US regu-
latory submission for a single-tablet regi-
men combining dolutegravir with abacavir
and lamivudine for people living with HIV.
Press release of ViiV Healthcare, October
22, 2013 (http://www.viivhealthcare.com/
media/press-releases/2013/october/viiv
-healthcare-announces-us-regulatory
-submission-for-a-single-tablet-regimen
-combining-dolutegravir-with-abacavir
-and-lamivudine-for-people-living-with
-hiv.aspx).
74. Sax PE, Zolopa A, Brar I, et al. Tenofo-
vir alafenamide vs. tenofovir disoproxil
fumarate in single tablet regimens for ini-
tial HIV-1 therapy: a randomized phase 2
study. J Acquir Immune Defic Syndr 2014
May 27 (Epub ahead of print).
75. Gallant JE, Koenig E, Andrade-
Villanueva J, et al. Cobicistat versus
r i
t onavir as a pharmacoenhancer of
atazan avir plus emtricitabine/tenofovir
dis oproxil fumarate in treatment-naive
HIV type 1 -infected patients: week 48
results. J Infect Dis 2013;208:32-9.
76. Bristol-Myers Squibb submits new
drug application to U.S. FDA for a fixed-
dose combination tablet of atazanavir sul-
fate with cobicistat for people living with
HIV-1. Press release of Bristol-Myers Squibb,
April 14, 2014 (http://news.bms.com/press
-release/bristol-myers-squibb-submits
-new-drug-application-us-fda-fixed-dose
 clinical ther apeutics

-combination-tablet#sthash.CKqvvBOS
.dpuf ).
77. Kakuda TN, Opsomer M, Timmers M,
et al. Pharmacokinetics of darunavir in
fixed-dose combination with cobicistat
compared with coadministration of daruna
vir and ritonavir as single agents in healthy
volunteers. J Clin Pharmacol 2014 March 19
(Epub ahead of print).
78. Janssen submits new drug application
to U.S. FDA for a fixed-dose combination
tablet of HIV-1 medicine darunavir with
cobicistat as part of combination HIV ther-
apy. Press release of Johnson & Johnson,
April 1, 2014 (http://www.investor.jnj.com/
releasedetail.cfm?ReleaseID=836924).
79. Walensky RP, Sax PE, Nakamura YM,
et al. Economic savings versus health
losses: the cost-effectiveness of generic
antiretroviral therapy in the United States.
Ann Intern Med 2013;158:84-92.
80. Engsig F, Gerstoft J, Helleberg M,
Kronborg G, Mathiesen L, Obel N. Viro-
logical response in patients, who for eco-
nomic reasons were changed from Atripla
to a multitablet cART regimen. Presented
at the 20th Conference on Retroviruses
and Opportunistic Infections, Atlanta,
March 36, 2013. abstract.
81. Williams I, Churchill D, Anderson J,
et al. British HIV Association guidelines
for the treatment of HIV-1-positive adults
with antiretroviral therapy 2012 (updated
November 2013: all changed text is cast in
yellow highlight). HIV Med 2014;15:Suppl
1:1-85.
82. European AIDS Clinical Society guide-
lines: version 7.02, updated June 2014 (http://
www.eacsociety.org/guidelines.aspx).
83. Oxford Centre for Evidence-Based Med-
icine Levels of Evidence Working Group. The
Oxford levels of evidence 2, updated 2011
(http://www.cebm.net/index.aspx?o=5653).
84. Thompson MA, Mugavero MJ, Amico
KR, et al. Guidelines for improving entry
into and retention in care and antiretroviral
adherence for persons with HIV: evidence-
based recommendations from an Interna-
tional Association of Physicians in AIDS
Care panel. Ann Intern Med 2012;156:
817-33.
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