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OPINION PIECE
Clinical implications of fixed-dose coformulations of
antiretrovirals on the outcome of HIV-1 therapy
Josep M. Llibre
a
, Jose
´R. Arribas
b
, Pere Domingo
c
, Josep M. Gatell
d
,
Fernando Lozano
e
, Jose
´R. Santos
a
, Antonio Rivero
f
, Santiago Moreno
g
,
Bonaventura Clotet
a
, the Spanish Group for FDAC Evaluation
The substitution by generic equivalents of some of the drugs included in fixed-dose
antiretroviral coformulations (FDACs) poses the potential risk of disrupting these
combinations and administering the components separately in order to incorporate
the new generic drug, which offers a more competitive sales price. This may represent a
step backwards in the advances achieved in simplicity and adherence to therapy, posing
an increased risk of selective noncompliance of some of the separately administered
drug substances. Available antiretroviral drugs must be administered for life in the
affected individuals – both children and adults. The FDACs represent a significant
advance in the simplification of antiretroviral therapy, facilitating adherence to com-
plex and chronic treatments, and contributing to a quantifiable improvement in patient
quality of life. These drug coformulations reduce the risk of treatment error, are
associated with a lower risk of hospitalization, and can lessen the possibility of covert
monotherapy in situations of selective noncompliance. Thus, FDACs can reduce the risk
of selection of HIV-1 resistances, which not only adversely affect the treatment options
of the individual patient but also constitute a public health problem, and further
increase the cost and complexity of therapy. With the exception of those cases requiring
dose adjustments, the preferential use of FDACs should be recommended for the
treatment of HIV-1 infection in those situations when the agents included in the
coformulation are drugs of choice.
ß2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
AIDS 2011, 25:1683–1690
Keywords: AIDS, antiretroviral treatment, combined treatment, fixed-dose
combinations, human immunodeficiency virus infection, recommendation
Introduction
HIV-1 infection causes gradual destruction of host
cellular immunity, and persistent activation of the entire
immune system and associated nonspecific inflammatory
mechanisms. It is a world pandemic, one of the main
public health problems worldwide since the late 20th
century, and also probably the most significant success
a
Lluita Contra la SIDA Foundation, University Hospital Germans Trias i Pujol, Badalona,
b
Hospital Universitario La Paz, Madrid,
c
Hospital Sant Pau, Barcelona,
d
Hospital Clinic, IDIBAPS, Barcelona,
e
Hospital Universitario de Valme, Sevilla,
f
Hospital Reina
Sofı´a, Co
´rdoba, and
g
Hospital Ramo
´n y Cajal, Madrid, Spain.
Correspondence to Josep M. Llibre, Fundacio
´Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Ctra de Canyet s/n,
08916 Badalona, Spain.
Tel: +34 934978887; e-mail: jmllibre.fls.germanstrias@gencat.cat
Received: 2 February 2011; revised: 12 May 2011; accepted: 7 June 2011.
DOI:10.1097/QAD.0b013e3283499cd9
ISSN 0269-9370 Q2011 Wolters Kluwer Health | Lippincott Williams & Wilkins 1683
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
story in modern medicine [1 –5]. Antiretroviral drugs
administered in effective combinations persistently
suppress HIV-1 replication, allow gradual recovery of
the CD4
þ
T-lymphocyte counts, and reduce patient
morbidity and mortality [6 – 8]. In sum, these treatments
are able to revert the ominous prognosis of HIV-1 disease
and restore patient survival and quality of life to almost
normal longevity, with a radical change in the clinical
spectrum of the illness [2,9,10]. Likewise, the control of
HIV-1 replication drastically reduces the risk of
transmission to the general population, and avoids vertical
transmission to the offspring of infected mothers [11 –16].
Antiretroviral therapy (ART) represents one of the
strategies with favorable cost– efficacy ratios in the health-
care systems of the Western world [5,17–21]. The
consensus guides on ART developed in different countries
by government organizations and national and inter-
national scientific societies are continuously subjected to
revision – updating and optimizing the ideal timing for
starting therapy, the optimum first-choice combinations,
and many other aspects related to ART [22–27].
It presently can be firmly stated that in countries with
universal public healthcare coverage and free access to
ART, HIV-1 infection detected on time is a treatable
chronic disease allowing patients to lead lives similar in all
aspects to those of noninfected persons, including
occupational activity [1].
Individually replacing a drug with a usually less expensive
generic equivalent is a generally accepted practice when
drug protection by patent rights runs out. However, in
the Western world the introduction of generic equiva-
lents of some of the drugs included in fixed-dose
antiretroviral coformulations (FDACs), or of generic
equivalents presumed to have characteristics similar to
those of some of the drugs included in FDACs [like
emtricitabine (FTC) and lamivudine (3TC)], poses the
potential risk of disrupting these combinations and
administering the components separately in order to
incorporate the new generic drug which offers a more
competitive sales price. This may represent a step
backwards in the advances achieved in simplicity and
adherence to therapy, with an additional risk of selective
noncompliance of some of the separately administered
drugs, treatment failure, and selection of HIV-1 variants
resistant to antiretroviral agents [28–31].
On the contrary, local approval in certain centers or
countries of the possibility of disrupting FDACs may
imply significant healthcare disparities with access to
different levels of excellence in ART, administered on the
basis of economy-oriented criteria depending on the
geographical area of residency.
The present study reviews the existing knowledge on the
importance of FDACs in ART.
Implications of long-term antiretroviral
treatment
Whereas the cure is still seemingly impossible for a
retroviral infection, ART must be administered for life in
the affected individuals [32]. Success of ART requires
constant patient adherence to treatment regimens that are
often complex and with possible adverse effects over the
short and long term.
The evaluation of different controlled treatment inter-
ruption strategies failed to demonstrate clinical benefits,
and treatment interruption moreover was found to be
associated with an increase in opportunistic diseases and
other disorders associated with the proinflammatory state
derived from uncontrolled HIV-1 replication [4,33– 35].
Therefore, it is likewise not possible to reduce the
economical cost or toxicity of ART by administering it
intermittently [36,37].
Unlike other treatable chronic conditions (e.g. arterial
hypertension, type 2 diabetes mellitus or hypercholester-
olemia), in which the ultimate control achieved after
several years depends on the total period of time for which
the patient has undergone correct treatment, irregular
adherence to ART for only a few weeks may lead to
definitive loss of efficacy of the treatment provided,
selection of resistance to the drugs administered, and even
cross-resistance to other drugs which the patient has not
received [13,38]. For this reason, the long-term morbidity
and mortality of HIV-1 infection does not only depend on
‘average’ adherence over the entire course of ART, but on
the resistance selected during the periods of patient
noncompliance [39]. This represents one of the most
difficult aspects to control in the chronic management of
this disease.
Antiretroviral drug resistance implies loss of treatment
options, requires more complex, expensive and toxic
rescue therapies, and can be transmitted [38,40]. At
present, 10– 14% of the treated population in Europe is
infected with HIV-1 strains resistant to some antiretroviral
agents [41–43].
Optimized virological control of the HIV-1-infected
population therefore ultimately results in a lesser risk of
transmission of resistant strains, and thus better response
rates in recently infected individuals who start ART [40].
For this reason, once effective ART is made freely
available and at no cost, sustained patient adherence to
such treatment is the key factor for preventing failure.
Factors related to adherence to
antiretroviral therapy
Long-term adherence to ART is of utmost importance
for long-term outcomes and has been extensively
1684 AIDS 2011, Vol 25 No 14
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
investigated for years. The presence of psychiatric
problems, active substance abuse, poverty, low edu-
cational level, comorbidities, frequency of doses, number
of tablets, and short-term or long-term toxicity of ART
are all significantly related to inadequate adherence
[23,25,44]. Not surprisingly, adherence and type of
treatment were the modifiable factors most strongly
associated with survival [45,46].
It should be stressed that not only the percentage of
missed doses is important, but also the suboptimal
adherence patterns involved. In effect, treatment inter-
ruptions (defined as more than 2 days without taking any
drug) have a greater impact upon virological response
than occasional failure to take a dose, depending on the
regimen involved [39,47]. On the contrary, improved
adherence results in lower associated global economical
costs, and is also significantly associated with a lower risk
of hospitalization [19].
For this reason, all HIV units worldwide have focused on
improving adherence to ART, with implication of the
nursing personnel, psychologists and pharmacists of the
different centers in the effort. Likewise, in the different
consensus documents on ART, the chapter addressing the
optimization of treatment compliance has become
particularly important [23 – 25].
The use of fixed-dose drug combinations:
the model represented by other treatable
chronic diseases
A reduction in the number of different containers and
medicines which the patient must control, and in the
number of daily doses and tablets, results in improved
adherence to therapy in chronic diseases requiring
combined treatments [48]. Such reduction lessens the
risk of error and the possibility of incomplete adherence
to the regimen due to selective noncompliance.
As an example, most patients with arterial hypertension
require combined treatments involving several drugs.
Consequently, the American Society of Hypertension
favors the use of fixed-dose drug combinations (FDCs) as
a practical need to improve adherence in chronic
treatments, reducing the risk of error in following
therapy [48].
An infectious disease requiring prolonged treatment is an
example much more similar to HIV-1 infection, and in
this sense tuberculosis has been the closest model. The use
of FDC not only affords convenience and improves
adherence but also prevents the patient from self-
administering monotherapy with any of the individual
drugs – thereby avoiding the selection of resistance [49].
For many years, the scientific societies working on the
treatment of tuberculosis have actively promoted the use
of FDCs of antituberculous drugs, and have requested the
authorities and even stimulated the drug companies to
increase their production and diffusion [50,51]. Even in
those situations when dose adjustments may be required,
the use of a FDC is recommended, associated with the
drug supplement needed for dose adjustment, with a view
to avoiding covert monotherapy and the selection of
resistance, which represent a genuine public healthcare
problem. The WHO and the International Union
Against Tuberculosis and Lung Disease presently recom-
mend the use of FDCs as an additional measure to
guarantee optimum treatment and avoid the selection and
spread of drug-resistant strains of Mycobacterium tuberculosis
[52] – designing specific programs to ensure that these
FDCs are of high quality in their manufacture.
A recent meta-analysis has evaluated the efficacy of FDCs
in nine randomized studies on the treatment of
different diseases, such as hypertension (n¼4), tubercu-
losis (n¼2), diabetes mellitus (n¼2) and HIV-1 infection
(n¼1). Lastly, the use of FDCs afforded a 26% reduction
in the risk of treatment noncompliance with respect to
administration of the same drugs separately [relative risk
(RR) 0.74; 95% confidence interval (CI) 0.69–0.80,
P<0.0001] [53]. There is therefore no doubt that FDCs
improve adherence to therapy in chronic illnesses that
require combined treatments – though there is still
uncertainty regarding the magnitude of such improve-
ment and its impact upon therapeutic efficacy [54].
The use of fixed-dose antiretroviral
coformulations in HIV-1 infection
Research by the pharmaceutical industry has contributed
to improve adherence to ART, by lowering the daily pill
count, and developing drugs with pharmacokinetic/
dynamic characteristics that allow once-daily adminis-
tration, as well as dosing in FDACs.
Different studies have demonstrated patient preference
for treatments involving a single daily dose and as few
tablets as possible [30,55]. A recent meta-analysis of 11
controlled clinical trials (involving a total of 3029 patients)
has confirmed that adherence is greater with single daily
dosing regimens than with two daily doses (P¼0.003)
[30]. Likewise, many studies have reported improved
overall quality of life and better adherence to therapy in
patients who are able to simplify their ART to a single
daily tablet – retaining the same virological and
immunological efficacy [30,31,56,57]. This improvement
has been documented independently of whether the
patients were receiving treatment based on non-nucleo-
side reverse transcriptase inhibitors (NNRTIs) or protease
inhibitors [31]. Such findings have been documented in
patients receiving efavirenz (EFV), tenofovir (TDF), and
Antiretroviral coformulations in HIV treatment Llibre et al. 1685
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
FTC or 3TC in a single dose but administered separately,
and who changed to a single FDAC with the same
compounds [56]. On the contrary, adherence to ARTand
percentage of virological response were also greater with a
regimen involving a single tablet once daily, in a cohort of
marginally housed patients with baseline factors that
made adherence particularly problematic [29]. Indeed,
patients receiving TDF, FTC and EFV as one pill daily are
more likely to maintain the regimen after 1 year than
patients receiving the same regimen as two pills a day [58].
Thus, simplicity importantly affects outcomes of chronic
therapies. The risk factors associated in multivariate
analysis with ART modification during the first year of
treatment were months since HIV-1 diagnosis, existence
of prior AIDS-defining conditions, and not receiving a
coformulated ART [58,59].
In fact, the massive use of FDACs has been correlated to
an increase in regimen persistence and a decrease in the
prevalence of antiretroviral drug resistance mutations in
the period 2003 – 2008, and even to a decrease in those
mutations specifically related to the drugs included in
such combinations (K65R and M184V/I), although a
causal relationship has not been established [59,60]. Thus,
FDACs, by preventing partial noncompliance and hidden
monotherapy, could reduce the risk of development of
HIV-1 drug resistance.
Moreover, patients who received their ART as a once-
daily single-tablet regimen were significantly more likely
to be highly adherent to therapy and were associated with
a lower risk of hospitalization compared to patients on
two or more pills per day regimens, even though the study
could not assess causality [61].
Pairs of nucleoside reverse transcriptase
inhibitors coformulated in fixed-dose
antiretroviral coformulations: importance
of pharmacokinetic homogeneity of the
included drugs
When a FDAC is designed, it must meet a series of
criteria in order to ensure its long-term efficacy. The
coformulated drugs must not present similar or additive
toxicities or require individual dose adjustments, and their
pharmacokinetic profile must be concordant. This latter
condition refers not only to frequency of administration
but also to the elimination half-life (t
1/2
), which is a
pivotal factor when the patient fails to take some doses or
interrupts ART. Nucleoside reverse transcriptase inhibi-
tor (NRTI) efficacy is correlated to the intracellular levels
of the drug (Table 1) [23,25,62–64]. The plasma and
intracellular t
1/2
values of FTC are significantly longer
than those of 3TC, and more concordant with those of
TDF and EFV in the existing coformulation. This point is
extremely important for avoiding the selection of resistant
mutants in every ART interruption, since the t
1/2
values
of the three drugs are overlapped, thus avoiding sequential
terminal monotherapy when the concentrations of them
drop to below the IC
50
of HIV-1, when resistant mutants
are easily selected.
Emtricitabine and 3TC have similar chemical structures,
are administered once a day, act on the same target, select
the same resistance pathways, and offer similar efficacy in
treatment-naı
¨ve patients. As a result, both drugs are
considered to be interchangeable in some ART guides
[23,24]. Thus, even though the table of preferred
antiretroviral regimens lists the exact combination used
in pivotal trials in which efficacy has been demonstrated, a
footnote states that 3TC may substitute for FTC or vice
versa [23]. Nevertheless, there are some differences
between 3TC and FTC that should be taken into
consideration. The IC
50
of HIV-1 is usually about 11
times greater for 3TC than for FTC, though the clinical
relevance of this fact has not been confirmed, since the
plasma or intracellular levels of the drug remain far above
the mentioned concentration [65,66]. On the contrary,
FTC-triphosphate offers greater (about nine times)
efficacy than 3TC-triphosphate in incorporation during
RNA-dependent viral DNA synthesis catalyzed by
reverse transcriptase [67]. All this would result in a
greater maximum polymerization rate and greater affinity
for FTC. In fact, in vitro, appearance of the M184V/I
mutant occurs earlier in cultures with 3TC than with
FTC [68].
Assessing the clinical relevance of these minor differences
in vivo in the context of triple regimens is not simple.
Nevertheless, in a randomized, double-blind trial
comparing 3TC with FTC together with nevirapine
1686 AIDS 2011, Vol 25 No 14
Table 1. Plasma and intracellular elimination half-lives (t
1/2
) of the
HIV-1 nucleoside and non-nucleoside reverse transcriptase
inhibitors, integrase inhibitors, and protease inhibitors used in fixed-
dose coformulations.
Drug Plasma t
1/2
(h) Intracellular t
1/2
(h)
a
Zidovudine 1.1 7
Lamivudine (3TC) 5– 7 16– 22
Emtricitabine (FTC) 8.2– 10 39
Abacavir 1.5 – 2.5 12–26
Tenofovir (TDF) 17 >60
Efavirenz 40– 55 –
Nevirapine 25– 30 –
Elvitegravir/ritonavir 11.2 –
Elvitegravir/cobicistat
b
5.9– 9.1 –
Lopinavir/ritonavir 5– 6 –
Atazanavir/ritonavir
c
15.7 –
Atazanavir/cobicistat
d
16.7 –
Data from [23,25,62,63].
a
Intracellular t
1/2
usually refers to the active metabolites of the drug.
b
Depending on the use of 100 or 150 mg of cobicistat, respectively.
c
Administered as a 300 mg/100 mg dosing; unboosted atazanavir has
a serum t
1/2
of 7 h.
d
Using an atazanavir/cobicistat dosing of 300/150 mg.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
(or EFV) and stavudine, and which included 468 naive
patients, the M184V/I mutation rate (associated to high
resistance to both drugs) was lower with FTC than with
3TC (30 vs. 65% of the virological failures with available
genotype, P¼0.01) [66] – though in contrast the
virological failure rate was greater with FTC than with
3TC (12.8 vs. 7.3%, P¼0.046) [69].
An in-vitro study involving HIV-1 strains resistant to
antiretrovirals without the M184V/I mutation but with
thymidine-analog mutations (TAMs), K65R, Q151M or
L74I/V, showed cross-resistance to both drugs to be
similar in the presence of the K65R, Q151M or L74I/V
mutations, though in the presence of TAMs the impact
upon phenotypic resistance of FTC was greater than on
3TC (P<0.001) [70]. However, it is not common in
clinical practice to find these mutations without having
selected M184V/I.
On the contrary, retrospective analysis of episodes of
virological failure revealed a significantly higher resistance
rate in regimens with TDF/3TC than with TDF/FTC
[71,72]. Interestingly the K65R mutation has been
reported in trials in which TDF was combined with 3TC
[73], but not with FTC (both used with EFV) [74].
Replacing 3TC with FTC has been shown not to be
inferior in a clinical trial, whereas the opposite situation,
that is, replacing FTC with 3TC, has not been evaluated
[75].
Therefore, although the molecules are similar, 3TC and
FTC have differential pharmacokinetic characteristics
that do not allow us to rule out the possibility of different
resistance rates in the event of virological failure, and
the efficacy of replacing FTC with 3TC (particularly in
the context of FDAC) remains uncertain. Thus, until
adequate studies are carried out, such replacement should
be avoided in view of the potential risk involved.
Positioning of the scientific societies and
official organisms in consensus documents
regarding the use of fixed-dose
antiretroviral coformulations
The following FDACs are now available: zidovudine/
3TC, zidovudine/3TC/ABC, ABC/3TC, TDF/FTC,
EFV/TDF/FTC, and lopinavir/ritonavir. New cofor-
mulations are in the pipeline [74,75].
The North American guides on ART, the CDC, the
FDA, and the NIH consider that fixed-dose coformula-
tions offer an important advantage, and that among other
factors, the number of tablets and the frequency of dosing
are elements on which the choice of ART is to be based
[23]. They likewise specifically recommend the use of
pairs of coformulated NRTIs (TDF/FTC or ABC/3TC).
In turn, the European AIDS Clinical Society specifically
recommends the use of these coformulations [24], in the
same way as the British guides [26]. The Spanish guides
include an important chapter on the simplification of
ART [25], recommending the adoption of once-daily
regimens whenever possible (level A, maximum level of
evidence from randomized studies). Likewise, whenever
possible, nucleosides should be coformulated as prefer-
ential treatment regimen (level A). The IAS – USA also
recommends pairs of NRTIs in coformulation (TDF/
FTC or ABC/3TC) in starting therapy [27].
Conclusion
Fixed-dose antiretroviral coformulations represent a
significant advance in the simplification of ART,
facilitating adherence to chronic treatments, and con-
tributing to a quantifiable improvement in patient quality
of life. The drug coformulations may reduce the risk of
treatment error and consequently the possibility of
functional monotherapy in situations of selective non-
compliance. They therefore may reduce the risk of
developing HIV-1 resistance to antiretrovirals. Resistance
not only adversely affects the treatment options of the
individual patient as well as its cost and complexity, but is
transmissible and constitutes a public health concern.
Patients receiving ART as a once-daily single-tablet
regimen are significantly more likely to be highly
adherent to therapy and have a lower risk of hospital-
ization. With the exception of those cases in which dose
adjustment is required, the preferential use of FDACs
should be recommended for the treatment of HIV-1
infection in those situations in which the agents
included in the coformulation are drugs of choice.
Thus, both the authorities and the drug industry must
maximize efforts to preserve the use of FDACs when the
introduction of a generic equivalent to any of the drugs
in the coformulation poses the risk of disrupting the
fixed combination and separate administration. How-
ever, for the sake of the ART budget, as soon as all
components of currently available FDACs become
available as generics, FDACs built with them should
be pursued.
Acknowledgements
Members of the Spanish Group for FDAC Evaluation also
include Antonio Antela (Complejo Hospitalario Uni-
versitario, Santiago de Compostela, Spain), Jose
´Lo
´pez-
Aldeguer (Hosp Univ La Fe, Valencia, Spain), Jose
´Molto
´
(Lluita contra la SIDA Fndn, Univ Hosp Germans Trias i
Pujol, Badalona, Spain), Celia Miralles (Hosp Xeral,
Vigo, Spain), Enrique Ortega (Hosp General Univ,
Antiretroviral coformulations in HIV treatment Llibre et al. 1687
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Valencia, Spain), Piedad Arazo (Hosp. Univ. Miguel
Servet, Zaragoza, Spain), and Melcior Riera and
Concepcio
´n Villalonga (Hosp Son Dureta, Palma de
Mallorca, Spain).
Conflicts of interest
J.M.L. has received funding for research or payment for
conferences or participation on advisory boards from
Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb,
Gilead Sciences, GlaxoSmithKline, Jansen-Cilag, Merck
Sharp & Dohme, Pfizer, Roche, Tibotec and ViiV
Healthcare.
J.R.A. has received consulting fees, speaker fees or grant
support from Merck, Abbott, Tibotec, Janssen, Gilead,
GSK, Pfizer, Biogen, Avexa, BMS.
P.D. has received funding for research or payment for
conferences or participation on advisory boards from
Abbott Laboratories, Bristol-Myers Squibb, Boehringer
Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen
Cilag, Merck Sharp & Dohme, Pfizer, Roche and
ViiV Healthcare.
J.M.G. has received funding for research or payment
for conferences or participation on advisory boards
from Boehringer-Ingelheim, Merck Sharp & Dohme,
Janssen, Tibotec, Abbott, Tobira, Gilead and ViiV
Healthcare.
F.L. has received funding for research or payment for
conferences or participation on advisory boards from
Abbott Laboratories, Bristol-Myers Squibb, Boehringer
Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen
Cilag, Merck Sharp & Dohme, Pfizer, Roche and ViiV
Healthcare.
J.R.S. has received funding for research or payment for
conferences or participation on advisory boards from
Abbott, Bristol-Myers Squibb, Gilead Sciences, Glaxo-
SmithKline, and Jansen.
J.L.-A. has received funding for research or payment for
conferences or participation on advisory boards from
Abbott, Boehringer-Ingelheim, Gilead Sciences, Glaxo-
SmithKline, Merck Sharp & Dohme, Pfizer, Roche,
Tibotec and ViiV Healthcare.
C.M. has received funding for research or payment for
conferences or participation on advisory boards from
Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim,
Gilead Sciences, GlaxoSmithKline, Merck Sharp &
Dohme, Pfizer, Roche, Tibotec and ViiV Healthcare.
E.O. has received funding for research or payment for
conferences or participation on advisory boards from
Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim,
Gilead Sciences, GlaxoSmithKline, Merck Sharp &
Dohme, Pfizer, Roche, Tibotec and ViiV Healthcare.
P.A. has received funding for research or payment for
conferences or participation on advisory boards from
Abbott, Bristol-Myers Squibb, Boehringer-Ingelheim,
Gilead Sciences, GlaxoSmithKline, Pfizer, Jansen and
ViiV Healthcare.
S.M. has received funding for research or payment for
conferences or participation on advisory boards from
Abbott, Boehringer-Ingelheim, Bristol-Myers Squibb,
Gilead Sciences, GlaxoSmithKline, Jansen-Cilag, Merck
Sharp & Dohme, Pfizer, Roche, Tibotec and ViiV
Healthcare.
B.C. has served during the past 2 years as a consultant on
advisory boards or participated in speakers’ bureaus or
conducted clinical trials with Boehringer-Ingelheim,
Abbott, GlaxoSmithKline, Gilead, Janssen, Merck,
Shionogi and ViiV.
J.M.L. ideated and drafted the manuscript. All authors
reviewed and approved the final document.
References
1. van Sighem AI, Gras LA, Reiss P, Brinkman K, de WF. Life
expectancy of recently diagnosed asymptomatic HIV-infected
patients approaches that of uninfected individuals. AIDS 2010;
24:1527–1535.
2. Hamers FF, Downs AM. The changing face of the HIV epidemic
in western Europe: what are the implications for public health
policies? Lancet 2004; 364:83–94.
3. Tien PC, Choi AI, Zolopa AR, Benson C,Tracy R, Scherzer R,etal.
Inflammation and mortality in HIV-infected adults: analysis of
the FRAM study cohort. J Acquir Immune Defic Syndr 2010;
55:316– 322.
4. Kuller LH, Tracy R, Belloso W, De WS, Drummond F, Lane HC,
et al.Inflammatory and coagulation biomarkers and mortality
in patients with HIV infection. PLoS Med 2008; 5:e203.
5. Beck EJ, Harling G, Gerbase S, DeLay P. The cost of treatment
and care for people living with HIV infection: implications of
published studies. Curr Opin HIV AIDS 2010; 5:215–224.
6. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J,
Satten GA, et al.Declining morbidity and mortality among
patients with advanced human immunodeficiency virus infec-
tion. HIV Outpatient Study Investigators. N Engl J Med 1998;
338:853–860.
7. Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC,
Brooks JT, et al.Mortality in the highly active antiretroviral
therapy era: changing causes of death and disease in the
HIV outpatient study. J Acquir Immune Defic Syndr 2006;
43:27–34.
8. Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J,
Sorensen HT, et al.Survival of persons with and without
HIV infection in Denmark. Ann Intern Med 2007; 146:87–95.
9. Llibre JM, Falco V, Tural C, Negredo E, Pineda JA, Munoz J, et al.
The changing face of HIV/AIDS in treated patients. Curr HIV
Res 2009; 7:365–377.
10. Palella FJ Jr, oria-Knoll M, Chmiel JS, Moorman AC, Wood KC,
Greenberg AE, et al.Survival benefit of initiating antiretroviral
therapy in HIV-infected persons in different CD4Rcell strata.
Ann Intern Med 2003; 138:620–626.
11. Wilson DP, Law MG, Grulich AE, Cooper DA, Kaldor JM.
Relation between HIV viral load and infectiousness: a mod-
el-based analysis. Lancet 2008; 372:314–320.
1688 AIDS 2011, Vol 25 No 14
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
12. Sperling RS, Shapiro DE, Coombs RW, Todd JA, Herman SA,
McSherry GD, et al.Maternal viral load, zidovudine treatment,
and the risk of transmission of human immunodeficiency virus
type 1 from mother to infant. Pediatric AIDS Clinical Trials
Group Protocol 076 Study Group. N Engl J Med 1996;
335:1621–1629.
13. Bartlett JA, Buda JJ, von SB, Mauskopf JA, Davis EA, Elston R,
et al.Minimizing resistance consequences after virologic
failure on initial combination therapy: a systematic overview.
J Acquir Immune Defic Syndr 2006; 41:323–331.
14. Townsend CL, Cortina-Borja M, Peckham CS, de RA, Lyall H,
Tookey PA. Low rates of mother-to-child transmission of HIV
following effective pregnancy interventions in the United King-
dom and Ireland. AIDS 2008; 22:973–981.
15. Russo G, Lichtner M, Traditi F, Vullo V. Is the time for an AIDS-
free new generation different in resource-limited and indus-
trialized countries? AIDS 2009; 23:293–296.
16. Attia S, Egger M, Muller M, Zwahlen M, Low N. Sexual trans-
mission of HIV according to viral load and antiretroviral
therapy: systematic review and meta-analysis. AIDS 2009;
23:1397–1404.
17. Bender MA, Kumarasamy N, Mayer KH, Wang B, Walensky RP,
Flanigan T, et al.Cost-effectiveness of tenofovir as first-line
antiretroviral therapy in India. Clin Infect Dis 2010; 50:416–
425.
18. Freedberg KA, Kumarasamy N, Losina E, Cecelia AJ, Scott CA,
Divi N, et al.Clinical impact and cost-effectiveness of anti-
retroviral therapy in India: starting criteria and second-line
therapy. AIDS 2007; 21 (Suppl 4):S117–S128.
19. Nachega JB, Leisegang R, Bishai D, Nguyen H, Hislop M, Cleary
S, et al.Association of antiretroviral therapy adherence and
healthcare costs. Ann Intern Med 2010; 152:18–25.
20. Simpson KN. Economic modeling of HIV treatments. Curr Opin
HIV AIDS 2010; 5:242–248.
21. Freedberg KA, Losina E, Weinstein MC, Paltiel AD, Cohen CJ,
Seage GR, et al.The cost effectiveness of combination anti-
retroviral therapy for HIV disease. N Engl J Med 2001;
344:824–831.
22. Kitahata MM, Gange SJ, Abraham AG, Merriman B, Saag MS,
Justice AC, et al.Effect of early versus deferred antiretroviral
therapy for HIV on survival. N Engl J Med 2009; 360:1815–
1826.
23. Panel on Antiretroviral Guidelines for Adults and Adolescents.
Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Department of Health and Human
Services. January 10, 2011; 1-166. Available at http://www.
aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
Accessed January 16, 2011.
24. EACS Guidelines. Clinical management and treatment of HIV
infected adults in Europe. Version 5-2. November 2009. http://
europeanaidsclinicalsociety.org/. [Accessed 16 January 2011]
25. Panel de expertos de GESIDA y Plan Nacional del SIDA.
Documento de consenso de Gesida/Plan Nacional sobre el
Sida respecto al tratamiento antirretroviral en adultos infectados
por el virus de la inmunodeficiencia humana (Actualizacio
´n
enero 2011). http://www.gesida.seimc.org.
26. Gazzard BG, Anderson J, Babiker A, Boffito M, Brook G, Brough
G, et al.British HIV Association Guidelines for the treatment of
HIV-1-infected adults with antiretroviral therapy 2008. HIV
Med 2008; 9:563–608.
27. Thompson MA, Aberg JA, Cahn P, Montaner JS, Rizzardini G,
Telenti A, et al.Antiretroviral treatment of adult HIV infection:
2010 recommendations of the International AIDS Society-USA
panel. JAMA 2010; 304:321–333.
28. Llibre JM, Antela A, Arribas JR, Domingo P, Gatell JM, Lopez-
Aldeguer J, et al.Role of fixed-dose combinations of antire-
trovirals in HIV-1 therapy. Enferm Infecc Microbiol Clin 2010;
28:615–620.
29. Bangsberg DR, Ragland K, Monk A, Deeks S. A one-pill, once
daily fixed dose combination (FDC) of efavirenz, emtricita-
bine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) regi-
men is associated with higher unannounced pill count
adherence than nonone pill, once-daily therapy. In 17th
Conference on Retroviruses and Opportunistic Infections.
San Francisco, CA, USA, February 16–19, 2010. Abstract 510.
30. Parienti JJ, Bangsberg DR, Verdon R, Gardner EM. Better
adherence with once-daily antiretroviral regimens: a meta-
analysis. Clin Infect Dis 2009; 48:484–488.
31. Dejesus E, Young B, Morales-Ramirez JO, Sloan L, Ward DJ,
Flaherty JF, et al.Simplification of antiretroviral therapy
to a single-tablet regimen consisting of efavirenz, emtricita-
bine, and tenofovir disoproxil fumarate versus unmodified
antiretroviral therapy in virologically suppressed HIV-1-
infected patients. J Acquir Immune Defic Syndr 2009; 51:
163–174.
32. Trono D, Van Lint C, Rouzioux C, Verdin E, Barre-Sinoussi F,
Chun TW, et al.HIV persistence and the prospect of long-term
drug-free remissions for HIV-infected individuals. Science
2010; 329:174–180.
33. El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D,
Arduino RC, et al.CD4Rcount-guided interruption of
antiretroviral treatment. N Engl J Med 2006; 355:2283–
2296.
34. Phillips AN, Carr A, Neuhaus J, Visnegarwala F, Prineas R,
Burman WJ, et al.Interruption of antiretroviral therapy and risk
of cardiovascular disease in persons with HIV-1 infection:
exploratory analyses from the SMART trial. Antivir Ther
2008; 13:177–187.
35. Neuhaus J, Jacobs DR Jr, Baker JV, Calmy A, Duprez D, La RA,
et al.Markers of inflammation, coagulation, and renal function
are elevated in adults with HIV infection. J Infect Dis 2010;
201:1788–1795.
36. Hirschel B, Flanigan T. Is it smart to continue to study treat-
ment interruptions? AIDS 2009; 23:757–759.
37. Ruiz L, Paredes R, Gomez G, Romeu J, Domingo P, Perez-
Alvarez N, et al.Antiretroviral therapy interruption guided by
CD4 cell counts and plasma HIV-1 RNA levels in chronically
HIV-1-infected patients. AIDS 2007; 21:169–178.
38. Llibre JM, Schapiro JM, Clotet B. Clinical implications of geno-
typic resistance to the newer antiretroviral drugs in HIV-1-
infected patients with virological failure. Clin Infect Dis 2010;
50:872–881.
39. Parienti JJ, Ragland K, Lucht F, de la BA, Dargere S, Yazdanpa-
nah Y, et al.Average adherence to boosted protease inhibitor
therapy, rather than the pattern of missed doses, as a predictor
of HIV RNA replication. Clin Infect Dis 2010; 50:1192–
1197.
40. Gill VS, Lima VD, Zhang W, Wynhoven B, Yip B, Hogg RS, et al.
Improved virological outcomes in British Columbia concomi-
tant with decreasing incidence of HIV type 1 drug resistance
detection. Clin Infect Dis 2010; 50:98–105.
41. Bannister WP, Cozzi-Lepri A, Clotet B, Mocroft A, Kjaer J, Reiss
P, et al.Transmitted drug resistant HIV-1 and association with
virologic and CD4 cell count response to combination anti-
retroviral therapy in the EuroSIDA Study. J Acquir Immune
Defic Syndr 2008; 48:324–333.
42. Cozzi-Lepri A, Phillips AN, Clotet B, Mocroft A, Ruiz L, Kirk O,
et al.Detection of HIV drug resistance during antiretroviral
treatment and clinical progression in a large European cohort
study. AIDS 2008; 22:2187–2198.
43. Wensing AM, van d V, Angarano G, Asjo B, Balotta C, Boeri E,
et al.Prevalence of drug-resistant HIV-1 variants in untreated
individuals in Europe: implications for clinical management.
J Infect Dis 2005; 192:958–966.
44. Atkinson MJ, Petrozzino JJ. An evidence-based review of treat-
ment-related determinants of patients’ nonadherence to HIV
medications. AIDS Patient Care STDS 2009; 23:903–914.
45. Wood E, Hogg RS, Yip B, Harrigan PR, O’Shaughnessy MV,
Montaner JS. Effect of medication adherence on survival
of HIV-infected adults who start highly active antiretroviral
therapy when the CD4Rcell count is 0.200 to 0.350 T10(9)
cells/L. Ann Intern Med 2003; 139:810–816.
46. Garcia de OP, Knobel H, Carmona A, Guelar A, Lopez-Colomes
JL, Cayla JA. Impact of adherence and highly active antiretro-
viral therapy on survival in HIV-infected patients. J Acquir
Immune Defic Syndr 2002; 30:105–110.
47. Nachega JB, Hislop M, Dowdy DW, Chaisson RE, Regensberg L,
Maartens G. Adherence to nonnucleoside reverse transcriptase
inhibitor-based HIV therapy and virologic outcomes. Ann
Intern Med 2007; 146:564–573.
48. Gradman AH, Basile JN, Carter BL, Bakris GL, Materson BJ,
Black HR, et al.Combination therapy in hypertension. J Am Soc
Hypertens 2010; 4:90–98.
49. Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations
of antituberculous medications to prevent drug resistance. Ann
Intern Med 1995; 122:951–954.
Antiretroviral coformulations in HIV treatment Llibre et al. 1689
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
50. Norval PY, Blomberg B, Kitler ME, Dye C, Spinaci S. Estimate of
the global market for rifampicin-containing fixed-dose combi-
nation tablets. Int J Tuberc Lung Dis 1999; 3 (11 Suppl 3):S292–
S300.
51. Aguado JM, Rufi G, Garcı´a Rodrı´guez J, Solera J, Moreno S.
Tuberculosis. Protocolos Clı
´nicos de la Sociedad Espan˜ola de
Infecciones y Microbiologia Clı
´nica (SEIMC). Protocolo VII. In
Disponible en www.seimc.org Consultado el 28 de junio de;
2010.
52. Blomberg B, Spinaci S, Fourie B, Laing R. The rationale
for recommending fixed-dose combination tablets for treatment
of tuberculosis. Bull World Health Organ 2001; 79:61–68.
53. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-
dose combinations improve medication compliance: a meta-
analysis. Am J Med 2007; 120:713–719.
54. Connor J, Rafter N, Rodgers A. Do fixed-dose combination pills
or unit-of-use packaging improve adherence? A systematic
review. Bull World Health Organ 2004; 82:935–939.
55. Laurent C, Kouanfack C, Koulla-Shiro S, Nkoue N, Bourgeois A,
Calmy A, et al.Effectiveness and safety of a generic fixed-dose
combination of nevirapine, stavudine, and lamivudine in HIV-
1-infected adults in Cameroon: open-label multicentre trial.
Lancet 2004; 364:29–34.
56. Airoldi M, Zaccarelli M, Bisi L, Bini T, Antinori A, Mussini C,
et al.One-pill once-a-day HAART: a simplification strategy that
improves adherence and quality of life of HIV-infected sub-
jects. Patient Prefer Adherence 2010; 4:115–125.
57. Hodder SL, Mounzer K, Dejesus E, Ebrahimi R, Grimm K, Esker
S, et al.Patient-reported outcomes in virologically 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.
58. Perez-Valero I, Martin N, San Jose B, Mora M, Bernardino-Serra
J, Gonzalez J, et al.Naı¨ve patients receiving TDF/FTC REFV (2
pills) are more likely to modify regimen components than
patients receiving TDF/FTC/EFV (1 pill). J Intl AIDS Soc
2010; 13 (Suppl 4):122.
59. Bae JW, Guyer W, Grimm K, Altice FL. Medication persistence
in the treatment of HIV infection: a review of the literature and
implications for future clinical care and research. AIDS 2011;
25:279–290.
60. Guyer B, Miller M, Ho J, HaddadM, Coakley E, McColl D. Trends
in HIV-1 resistance mutations and antiretroviral prescription
data from 2003–2008. J Managed Care Pharmacy 2010; 16:165.
61. Sax P, Meyers J, Mugavero M, Davis K. Adherence to anti-
retroviral treatment regimens and correlation with risk of
hospitalization among commercially insured HIV patients in
the United States. J Intl AIDS Assoc 2010; 13 (Suppl 4):O3.
62. Rousseau FS, Kahn JO, Thompson M, Mildvan D, Shepp D,
Sommadossi JP, et al.Prototype trial design for rapid dose
selection of antiretroviral drugs: an example using emtricita-
bine (Coviracil). J Antimicrob Chemother 2001; 48:507–513.
63. Schinazi RF. Assessment of the relative potency of emtricita-
bine and lamivudine. J Acquir Immune Defic Syndr 2003;
34:243–245.
64. Modrzejewski KA, Herman RA. Emtricitabine: a once-daily
nucleoside reverse transcriptase inhibitor. Ann Pharmacother
2004; 38:1006–1014.
65. Feng JY, Anderson KS. Mechanistic studies comparing the
incorporation of (R) and (S) isomers of 3TCTP by HIV-1
reverse transcriptase. Biochemistry 1999; 38:55–63.
66. Schinazi RF, Lloyd RM Jr, Nguyen MH, Cannon DL, McMillan
A, Ilksoy N, et al.Characterization of human immunodefi-
ciency viruses resistant to oxathiolane-cytosine nucleosides.
Antimicrob Agents Chemother 1993; 37:875–881.
67. Hazen R, Lanier ER. Assessment of the relative potency of
emtricitabine and lamivudine. J Acquir Immune Defic Syndr
2003; 34:245–246.
68. Ross LL, Parkin N, Gerondelis P, Chappey C, Underwood MR, St
Clair MH, et al.Differential impact of thymidine analogue
mutations on emtricitabine and lamivudine susceptibility.
J Acquir Immune Defic Syndr 2006; 43:567–570.
69. Maserati R, De SA, Uglietti A, Colao G, Di BA, Bruzzone B, et al.
Emerging mutations at virological failure of HAART combina-
tions containing tenofovir and lamivudine or emtricitabine.
AIDS 2010; 24:1013–1018.
70. Svicher V, Alteri C, Artese A, Forbici F, Santoro MM, Schols D,
et al.Different evolution of genotypic resistance profiles to
emtricitabine versus lamivudine in tenofovir-containing regi-
mens. J Acquir Immune Defic Syndr 2010; 55:336–344.
71. Gallant JE, Staszewski S, Pozniak AL, Dejesus E, Suleiman JM,
Miller MD, et al.Efficacy and safety of tenofovir DF vs.
stavudine in combination therapy in antiretroviral-naive
patients: a 3-year randomized trial. JAMA 2004; 292:191–
201.
72. Gallant JE, Dejesus E, Arribas JR, Pozniak AL, Gazzard B,
Campo RE, et al.Tenofovir DF, emtricitabine, and efavirenz
vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J
Med 2006; 354:251–260.
73. Benson CA, van der HC, Lamarca A, Haas DW, McDonald CK,
Steinhart CR, et al.A randomized study of emtricitabine and
lamivudine in stably suppressed patients with HIV. AIDS 2004;
18:2269–2276.
74. German P, Warren D, West S, Hui J, Kearney BP. Pharmaco-
kinetics and bioavailability of an integrase and novel pharma-
coenhancer-containing single-tablet fixed-dose combination
regimen for the treatment of HIV. J Acquir Immune Defic Syndr
2010; 55:323– 329.
75. Ramanathan S, Warren D, Wei L, Kearney BP. Pharmacokinetic
boosting of atazanavir with the pharmacoenhancer GS-9350
versus ritonavir. In 43rd Interscience Conference on Antimi-
crobial Agents and Chemotherapy (ICAAC). September 12– 15,
2009. A1-1301.
1690 AIDS 2011, Vol 25 No 14
