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Learning from drug changes in antiretroviral therapy
Julia ` Blancoaand Bonaventura Cloteta,b
AIDS 2013, 27:833–834
In middle 1990s, the availability of nucleoside analog and
non-nucleoside analog inhibitors of the HIV reverse
transcriptase (NRTI and NNRTI, respectively) and
inhibitors of viral protease (PIs) allowed for the
introduction of treatments combining different families
of antiretrovirals. This approach was defined as HAART
and is currently known as Combined Antiretroviral
Therapy (cART). Initial cART combinations included
three drugs (two NRTI and a PI or NNRTI) and
achieved a durable reduction of HIV replication in HIV-
infected patients, resulting in a sharp reduction in AIDS-
related deaths and opening a new era in HIV treatment.
problems emerged. Resistance to cART resulting in
virological failure was rapidly reported, mostly in
fraction of patients showed short-term drug toxicity or a
range of long-term side-effects associated with different
drugs or combinations. This fact added complexity to the
management of dangerous inflammatory sequels of viral
replication . Moreover, the requirement of a lifelong
to treatment, which was rapidly identified as a source for
the appearance of resistances and increased risk of
comorbidities. Several attempts to lessen these problems
were explored, including proactive treatment switch ,
treatment simplifications , structured treatment inter-
ruptions (STIs)  and development of new drugs.
Although the former strategies are still under debate, the
use of STI was ruled out by the compelling data of the
Strategies for Management of Anti-Retroviral Therapy
study . The availability of new drugs (more than 20
antiretrovirals are currently available in developed
countries) has broaden drug choice and has improved
as safety profile of new regimens. However, the definition
of thebest available starting cART ishampered by thelack
of data on the exact impact of long-term durability of
different regimens. Under the premise ‘never change a
regimen is changed can be a good surrogate marker of its
success. Moreover, the analysis of the reasons leading to
drug change may point up the main limitations of cART
regimens, andtherefore may helptobring regimenscloser
to the best achievable setting.
A study published by Abgrall et al. (pp. 803–813) in the
current issue of AIDS addresses some of these issues and
provides a wide picture of the stability of cART
combinations over the period 2002–2009 in developed
countries. The authors interrogate 18 cohorts (more than
20000 patients) from seven European countries, Canada
and the USA for the durability of first cART regimens.
The results are clear and indicate a high rate of cART
modifications that affects roughly one-third of patients
after 1 year of treatment. This proportion increases over
respectively. Although numbers are similar to those
idea that we are (at least, we were in the last decade) far
from an optimized cART treatment.
Importantly, the work goes beyond the global cART
modification rates and explores the nature of changes
(death, treatment interruption or simplification, change
between or within drug families) and their relationship
with other factors such as (among others) age, CD4 T-cell
aAIDS Research Institute, IrsiCaixa-HIVACAT, Institut d’Investigacio ´ en Cie `ncies de la Salut Germans Trias i Pujol, Universitat
Auto `noma de Barcelona, andbFundacio ´ Lluita contra la SIDA, Badalona, Catalonia, Spain.
CorrespondencetoJulia ` Blanco,RetrovirologyLaboratory,Fundacio ´ irsiCaixa,HospitalUniversitariGermansTriasiPujol,08916
Badalona, Catalonia, Spain.
Tel: +34 93 465 6374; fax: +34 93 465 3968; e-mail: firstname.lastname@example.org
Received: 26 September 2012; accepted: 30 October 2012.
ISSN 0269-9370 Q 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Download full-text
counts at baseline, infection route, and importantly first
PI/NNRTI or first NRTI background. This vast analysis
shows several pieces of information that fit with major
recurring issues of cART: when to start? And which
regimen to start with?
Two ‘usual suspects’ seem to be clearly correlated with
increased rates of death and drug changes: advanced age
and lower baseline CD4 T-cell counts. Indeed, early
cARTadministration is not only associated with a better
immune recovery  but also seems to allow for a more
stable, and therefore easier treatment. However, the
reported data also indicate that starting cARTat younger
age or with higher CD4 T-cell counts are risk factors for a
interruptions). Thus, we will probably need a better
adherence follow-up for a completely successful early
introduction of treatment.
Also relevant is the analysis of stability of first cART
regimens. Although differences are faint in some cases,
one drug stands out in each familyas the more stable first-
line option: efavirenz among NNRTIs, atazanavir among
PIs and emtricitabine/tenofovir among NRTI combi-
nations. It cannot be a coincidence that these combi-
nations are the drugs recommended some months ago by
the ‘International Antiviral Society-USA panel’ for
antiretroviral treatment of adult HIV infection .
The interpretation of these data is completed with an
analysis of the reasons leading to cART changes.
Although this analysis has been performed in a subset
of 5000 patients, in which the potential bias is unknown,
it is clear that the main force driving drug change is
toxicity, whereas virological failure has a lower impact.
This observation is consistent with other studies, and
strongly suggests that individual responses to treatment
are the main limitation to cART durability. Hypersensi-
tivity to abacavir opened the door for an individualized
approaches could be needed to predict the toxic effect
of other antiretrovirals and its implementation could be
compromised even in developed countries.
Finally, the study of Abgrall et al. (pp. 803–813) cannot
drugs, but opens a methodological path to assess them
in the near future. In addition, the reported data
may help in the definition of strategies for cART
implementation in developing countries, in which the
analysis of drug availability, resistance development and
toxicity has to drive the main decisions on regimen
Conflicts of interest
J.B. has received research funding, consultancy fees or
lecture sponsorships from Glaxo Smith Kline, ViiV and
Merck. B.C. has served as a consultant on advisory boards
or participated in speakers’ bureaus or conducted clinical
trials with Boehringer-Ingelheim, Glaxo Smith Kline,
Gilead, Janssen, Merck, Pfizer and ViiV.
1. Wensing AM, van Maarseveen NM, Nijhuis M. Fifteen years of
HIV Protease Inhibitors: raising the barrier to resistance. Anti-
viral Res 2010; 85:59–74.
Deeks SG. HIV infection, inflammation, immunosenescence,
and aging. Annu Rev Med 2011; 62:141–155.
Martinez-Picado J, Negredo E, Ruiz L, Shintani A, Fumaz CR,
Zala C, et al. Alternation of antiretroviral drug regimens for HIV
infection. A randomized, controlled trial. Ann Intern Med 2003;
Mathis S, Khanlari B, Pulido F, Schechter M, Negredo E, Nelson
M, et al. Effectiveness of protease inhibitor monotherapy versus
combination antiretroviral maintenance therapy: a meta-analy-
sis. PLoS One 2011; 6:e22003.
El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D,
Arduino RC, et al., Strategies for Management of Antiretroviral
Therapy (SMART) Study Group. CD4R count-guided interrup-
tion of antiretroviral treatment. N Engl J Med 2006; 355:2283–
Negredo E, Massanella M, Puig J, Pe ´rez-Alvarez N, Gallego-
Escuredo JM, Villarroya J, et al. Nadir CD4 T cell count as
predictor and high CD4 T cell intrinsic apoptosis as final me-
chanism of poor CD4 T cell recovery in virologically suppressed
Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P,
et al. Antiretroviral treatment of adult HIV infection: 2012
recommendations of the International Antiviral Society-USA
panel. JAMA 2012; 308:387–402.
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