World Journal of AIDS, 2013, 3, 280-286 Published Online September 2013 (
Darunavir Resistance in HI V Infec ting Prote ase
Inhibitor-Experienced Mexican Patients*
Carlos A. Agudelo1, Luis E. Soto-Ramírez1, Abraham Katime-Zúñiga1, Lorena Cabrera-Ruíz2,
Hugo Lara-Sánchez3, Juan J. Calva3#
1Department of Infectious Diseases, “Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán”, Mexico City, Mexico;
2Department of Infectious Diseases, Hospital Médica Sur and GUIAR Group, Mexico City, Mexico; 3The Clinical Epidemiology
Unit, “Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán”, Mexico City, Mexico.
Received July 9th, 2013; revised August 9th, 2013; accepted August 19th, 2013
Copyright © 2013 Carlos A. Agudelo et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Darunavir (DRV) is a useful antiretroviral treatment in the salvage therapy of multiclass-resistant HIV-
infected patients. This study’s aim was to determine the frequency and risk factors for DRV resistance-associated muta-
tions (DRV-RAM) among DRV-naïve Mexican patients with virologic failure after extensive antiretroviral treatment
and exposure to at least one protease inhibitor (PI). Methods: HIV-infected patients with a history of at least 2 failed re-
gimes were included and their clinical histories and genotype resistance tests were analyzed. Major PI resistance-associ-
ated mutations (PI-RAM), DRV-RAM and resistance to DRV were defined according to the IAS-USA criteria. Previous
exposure to PI was compared between patients with DRV-resistant HIV and DRV-susceptible HIV-infected controls.
Results: The median number of major PI-RAM was 2 (IQR = 0 - 3). In 54.7% (95% CI = 50.0% - 59.4%) of 631 sub-
jects, no DRV-RAM were found on viral genotyping and 6.7% (95% CI = 4.8% - 8.6%) had 3 or more DRV-RAM. The
two most frequently found DRV-RAM were in codons I84V (in 22.7% of cases) and L33F (in 20% of cases) in the viral
protease gene. The number of major PI-RAM (as a surrogate marker of duration and number of PI used) and previous
exposure to (fos) amprenavir or tipranavir were independently associated with DRV-resistant HIV infection. Conclu-
sions: In this Mexican population, despite a high prior PI exposure, HIV-DRV resistance rate is relatively low and suc-
cessful viral control with DRV-containing combined salvage therapy is expected in most patients.
Keywords: Darunavir; Resistance; Risk Factors; Prevalence; Mexico
1. Introduction
Randomized clinical trials have shown that ritonavir-
boosted darunavir (DRV/r) as a component of salvage re-
gimens (and at least one other fully active drug), leads to
significantly higher rates of lasting virological control
when compared with conventional protease inhibitors (PI),
among patients infected with multidrug-resistant HIV and
an extensive treatment history [1-6].
Eleven specific darunavir resistance-associated muta-
tions (DRV-RAM) in the viral protease gene have been
linked to decrease in vitro HIV susceptibility as well as
sub-optimal clinical responses to darunavir [7]. A loss of
response begins to occur with one mutation but 3 or more
mutations and additional numerous protease inhibitor (PI)
resistance-associated mutations (PI-RAM) lead to a great-
ly diminished virologic suppression rate. Participants in
the POWER 1 and 2 trials (in the DRV/r arm) as well as
the DUET-1 and DUET-2 studies, had a baseline preva-
lence of 3 or more DRV-RAM of 22%, 41% and 44%,
respectively [2-5].
In routine clinical practice, the rate of occurrence of
these 11 DRV-RAM in PI-treated patients not participat-
ing in clinical trials, has been reported in some popula-
tions [8-10]. A low percentage (ranging between 4.1%
and 6.7%) of individuals with 3 or more DRV-RAM, has
consistently been found in these surveys. Furthermore,
these studies have shown an association between the
number of prior PI used, the total number of PI resistance
mutations, previous treatment with (fos) amprenavir, and
*Author Disclosure: L. E. S-R. has received payment for lectures from
MSD, Janssen-Cilag and ViiV. J. J. C. has served as a Board member o
the DSMB of the CADIRIS Study. None of the other authors had con-
flicts of interest or funding sources.
#Corresponding author.
Copyright © 2013 SciRes. WJA
Darunavir Resistance in HIV Infecting Protease Inhibitor-Experienced Mexican Patients 281
a greater risk of developing DRV-RAM.
In Mexico, scaling up of free access to antiretroviral
treatment started approximately 15 years ago; during the
first 4 years, about one third of total patient-months were
treated with a PI (predominantly unboosted indinavir and
unboosted saquinavir) [11]. Over the past few years,
close to 29% of combined therapy prescriptions have in-
cluded a PI with a broad range of agents, mostly: rito-
navir-boosted lopinavir, ritonavir-boosted atazanavir, ri-
tonavir-boosted saquinavir and ritonavir-boosted indina-
vir [12].
This study’s aim was to assess the impact of this long
and extensive use of diverse PI in our country, on the
number of DRV-RAM in HIV infected DRV-naïve pa-
tients and virologic failure with a long-standing history
of antiretroviral therapy with several regimens. Also, we
determined whether the presence of 3 or more DRV-
RAM was associated with surrogate markers of the level
of prior PI selective pressure.
2. Methods
2.1. Study Population
A retrospective, cross-sectional study was conducted to
estimate the prevalence of HIV DRV-RAM and by case-
control analysis, the association between certain charac-
teristics in study patients and DRV-resistant HIV was as-
To be eligible, patients required: 1) to be considered as
virologic failures (ongoing viral replication as defined by
an HIV viral load above 50 copies/ml in at least two con-
secutive measurements) and on antiretroviral therapy at
the time of this survey, 2) to have a history of at least two
antiretroviral failed regimes, 3) prior treatment with at
least one PI, 4) no previous use of DRV, 5) an HIV ge-
notype resistant test performed while receiving the last
drug scheme, 6) at least one PI resistance mutation (PI-
RAM) in this genotyping and 7) complete clinical data.
Between 2008 and 2010, patients were selected from two
populations of cases whose physician had requested and
received a recommendation to optimize the salvage re-
gimen of heavily-treated experienced patients, by one of
two national antiretroviral therapy peer-advisory commit-
tees. The Board for the rational use of antiretrovirals
(CORESAR) provides advice to physicians caring for in-
dividuals in the Mexican Ministry of Health system; the
Inter-institutional group for antiretroviral treatment
(GUIAR) provides help to practitioners caring for pa-
tients in this health system or in two of the largest na-
tional social security systems (IMSS and ISSSTE).
Demographic, virologic, prior specific drug exposure
and drug regimen at the time of last failure data were re-
corded in each case.
2.2. Drug Resistance Testing
Genetic sequencing of protease and reverse transcriptase
HIV genes was conducted in plasma, using the Viroseq®,
HIV-1 kit (Abbott Laboratories, Abbott Park, Illinois) in
samples from the cases in CORESAR, and the Trugene®,
HIV-1 kit (Siemens, Erlangen, Germany) in samples from
GUIAR. Drug resistance mutations within the pol gene
were interpreted following the 2011 International Anti-
viral Society-USA panel list. Accordingly, the following
11 resistance mutations were evaluated for darunavir:
V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V,
I84V and L89V [13]. Darunavir resistance was defined
as the presence of 3 or more of these mutations.
2.3. Statistical Analysis
All data are reported as absolute numbers and percent-
ages, as well as medians (Md) and interquartile ranges
(IQR). Comparisons between 2 independent groups were
established using the U-Mann-Whitney test for continu-
ous variables and the Pearson χ2 or the Fisher exact test
for categorical variables. Comparison of dimensional da-
ta distribution across more than 2 independent groups, was
analyzed with the Kruskal-Wallis non-parametric 1-way
ANOVA test. Univariate and multivariate logistic regres-
sion analysis were performed to assess factors associated
to the presence of each DRV-RAM and DRV resistance.
The magnitude of the association was expressed as the
odds ratio (OR) and its 95% confidence interval (95%
CI). Statistical significance was reflected by a P value <
0.05. Association between continuous variables was mea-
sured with the Pearson correlation coefficient (r). A re-
ceiver operating-characteristic (ROC) curve was plotted
to assess the diagnostic performance of the number of
major PI-RAM in the prediction of darunavir-resistance.
Statistical analysis was carried out using the SPSS®16.0
(IBM Corp. Armonk, NY).
2.4. Ethical Considerations
This study was approved by the Research Ethics Com-
mittee of the “Instituto Nacional de Ciencias Médicas y
Nutrición Salvador Zubirán” (Ref #62), and was conduc-
ted in accordance with The Declaration of Helsinki.
3. Results
3.1. Study Population
From a total of 868 referred cases (476 patients in
CORESAR and 392 patients in GUIAR), 631 (73%) met
the inclusion criteria. Study patient features are depicted
in Table 1. Most had received various combinations of
antiretroviral therapies without optimal viral control, over
several years.
Copyright © 2013 SciRes. WJA
Darunavir Resistance in HIV Infecting Protease Inhibitor-Experienced Mexican Patients
Copyright © 2013 SciRes. WJA
Table 1. Characteristics of the 631 study subjects.
Age (years): Md (IQR) 40 (33 - 46)
Duration since HIV diagnosis (years): Md (IQR) 9 (6 - 11.6)
Nadir T-CD4+ cell count (cells/mm3): Md (IQR) 61 (23 - 155)
Patients with no documented HIV plasma viral load under the limit of detection at any time: n (%) 328 (52)
Duration with ARV therapy (years): Md (IQR) 8 (5 - 11)
Number of prior drug regimens: Md (IQR) 4 (3 - 5)
Number of PI previously used: Md (IQR) 2 (2 - 3)
Prior use of (fos) amprenavir: n (%) of cases 40 (6.3)
Prior use of tipranavir: n (%) of cases 98 (15.5)
Duration of prior use of any PI (years): Md (IQR) 5 (2.9 - 7.7)
Plasma HIV viral load prior to genotyping (log10 cop/ml): Md (IQR) 4.52 (3.95 - 5)
T-CD4+ cell count prior to genotyping (cells/mm3): Md (IQR) 192 (86.7 - 328.3)
ARV regimen at time of genotyping: n (%) of cases
NRTI + PI 429 (68%)
NRTI + NN 118 (19%)
NRTI + PI + NN 31 (5%)
Other 53 (8%)
Number of major PI-resistance associated mutations: Md (IQR) 2 (0 - 3)
NRTI = Nucleos (t) ide analogue reverse transcriptase inhibitor; PI = Protease inhibitor; NN = Non-nucleoside reverse transcriptase inhibitor.
3.2. Prevalence of Major PI-RAM and
Table 2 shows the distribution of the 631 study patients
according to the number of PI-RAM and DRV-RAM
found in their HIV genotype resistance test. Two or more
major PI-RAM and 4 or more major PI-RAM were iden-
tified in 60% and 18% of the patients, respectively. More
than half (54.7%, 95% CI = 49.5% - 59.9%) of patients
had no DRV-RAM; 20.9% (95% CI = 14% - 27.8%) had
more than one DRV-RAM and 6.7% (95% CI = 4.7% -
8.7%) were infected with HIV resistant to darunavir (ge-
notype with 3 or more DRV-RAM).
The two most frequently identified DRV-RAM in the
overall population were mutation I84V (22.7% of cases)
and mutation L33F (20% of cases). Other DRV-RAM
was present in less than 10% of the overall population.
Among the 42 patients with HIV resistant to DRV, the
relative frequency of all DRV-RAM was: I84V (76.2%
of cases), L33F (54.8% of cases) V32I (54.8% of cases),
I47V (47.6% of cases), L89V (31.0% of cases), I54L
(28.6% of cases), T74P (21.4% of cases), V11I (19.0%
of cases), I54M (16.7% of cases), L76V (7.1% of cases)
and I50V (2.4% of cases).
3.3. Association between DRV-RAM and Prior
Exposure to Other PI
An association between the presence of a particular
DRV-RAM and prior use of other specific PI was estab-
lished. There was a significant association between (fos)
amprenavir use (vs. no prior use of these PI) and the
identification of the following five DRV-RAM: I54M
(OR = 13.9; 95% CI = 4.1 - 47.8), I50V (OR = 6.2; 95%
CI = 1.1 - 32.8), V32I (OR = 3.2; 95% CI = 1.2 - 8),
I47V (OR = 3.1; 95% CI = 1.3 - 7.4) and L33F (OR = 2.3;
95% CI = 1.2 - 4.6). Moreover, there was also a signifi-
cant association between tipranavir use (vs. no prior use
of this PI) and the identification of the following five
DRV-RAM: I84V (OR = 4.9; 95% CI = 3.1 - 7.7), T74P
(OR = 4.0; 95% CI = 1.5 - 11), L33F (OR = 3.1; 95% CI
= 1.9 - 4.9), L32I (OR = 2.5; 95% CI = 1.2 - 5.2) and
I47V (OR = 2.4; 95% CI = 1.2 - 4.7).
Patients infected with HIV and harboring 3 or more
DRV-RAM compared with those with less than 3 DRV-
RAM, had been treated with a significantly greater num-
ber of PI and had a longer cumulative time period of pro-
tease inhibitor exposure; moreover, these individuals were
significantly more likely to have used a regimen with two
Darunavir Resistance in HIV Infecting Protease Inhibitor-Experienced Mexican Patients 283
PI (independently of ritonavir use as a booster), (fos) am-
prenavir, lopinavir/ritonavir, and tipranavir (see Table 3).
The median number of major PI-RAM was significantly
greater in patients with 3 or more DRV-RAM.
A significant correlation between the number of major
PI-RAM and the previous amount and duration of PI ad-
ministration was also detected (Pearson correlation coef-
ficients = 0.30, p < 0.01 and 0.23, p < 0.01, respectively).
Hence, the number of major PI-RAM was used as a sur-
rogate marker of the level of prior PI pharmacologic se-
lective pressure. On multivariate analysis, prior use of (fos)
amprenavir, the use of tipranavir and the number of ma-
jor PI-RAM were independently associated with 3 or
more DRV-RAM (see Table 4). There is a 3.7 fold in-
crease in the risk of having a darunavir resistant HIV in-
fection per one extra major PI-RAM.
As Figure 1 shows, the median number of DRV-RAM
rose as the number of major PI-RAM increased (Pearson
correlation coefficient = 0.73; P < 0.001). The distribu-
tion of the number of DRV-RAM was significantly dif-
ferent across categories of the number of major PI-RAM
Table 2. Distribution of 631 cases according to the number
of major protease inhibitor-resistance associated (PI-RAM)
and darunavir-resistance associated mutations (DRV-RAM)
in genotype testing.
Number of RAM Number (%) of patient with
n (%) n (%)
0 185 (29.3) 345 (54.7)
1 72 (11.4) 154 (24.4)
2 115 (18.2) 90 (14.3)
3 148 (23.5) 28 (4.4)
4 70 (11.1) 5 (0.8)
5 29 (4.6) 7 (1.1)
6 9 (1.4) 2 (0.3)
7 3 (0.5) 0 (0)
631 (100) 631 (100)
Table 3. Comparison of prior exposure to other protease inhibitors (PI) between subjects infected with HIV harboring 3 or
more darunavir-resistance associated mutations (DRV-RAM) vs with less than 3 DRV-RAM.
Variable HIV with 3 or more DRV-RAM
(42 subjects)
HIV with less than 3 DRV-RAM
(589 subjects) P value
Number of PI used: median (IQR) 3 (2, 4) 2 (1, 3) <0.01
Duration of PI use (years): median (IQR) 7.1 (4.6, 8.4) 4.9 (2.8, 7.7) 0.02
(fos) amprenavir use: % of patients 24 5 <0.001
Tipranavir use: % of patients 40 14 <0.001
Lopinavir/ritonavir use: % of patients 81 65 0.03
Double PI use: % of patients 26 15 0.05
Number of major PI-RAM*: median (IQR) 5 (3, 6) 2 (0, 3) <0.001
*Protease inhibitor resistance-associated mutation.
Table 4. Association between infection by HIV harboring 3 or more darunavir-resistance associated mutations (DRV-RAM)
and prior exposure to other protease inhibitors (PI) in 631 subjects.
Variable Univariate Multivariate
Odds ratio95% CI p value Odds ratio 95% CI p value
Number of PI used, per one PI increase 1.9 1.4 - 2.5 <0.001
Duration of PI use, per one year increase 1.1 1.0 - 1.2 0.03
(fos) amprenavir use/no use 5.8 2.6 - 12.9 <0.001 7.3 2.4 - 22 <0.001
Tipranavir use/no use 4.3 2.2 -8.2 <0.001 2.4 1.0 - 5.7 0.04
Lopinavir/ritonavir use/no use 2.3 1.0 - 5.0 0.04 0.7 0.2 - 2.1 NS
Double PI use/no use 2 1.0 - 4.2 0.05 1.5 0.6 - 4.3 NS
Number of major PI-RAM*, per one mutation increase 4.3 3.0 - 6.2 <0.001 4.7 3.0 - 7.1 <0.001
*Protease inhibitor resistance-associated mutation.
Copyright © 2013 SciRes. WJA
Darunavir Resistance in HIV Infecting Protease Inhibitor-Experienced Mexican Patients
Figure 1. Distribution of the number of darunavir resis-
tance-associated mutations (DRV-RAM) according to the
number of major protease inhibitor resistance-associated
mutations (PI-RAM) in genotype testing of 631 study sub-
jects (Kruskal-Wallis test: p < 0.001).
(Kruskal-Wallis test: p < 0.001). The area under the
curve of the ROC curve plotting the number of major
PI-RAM as predictors of DRV-resistance was 0.90. With
a cut-off point of 6 or more major PI-RAM, we found a
positive predictive value of 100% (95% CI = 73% -
100%) and a negative predictive value of 95% (95% CI=
93.3% - 96.7%) in the diagnosis or DRV-resistance. Four
non-DRV major PI-RAM were found to be significantly
associated with darunavir resistance: M46I (OR = 2.5
95% CI = 1.3 - 4.7; p < 0.01), Q58E (OR = 3.1 95% CI =
1.5 - 6.4; p < 0.01), V82T (OR = 2.7 95% CI = 1.1 - 6.4;
p = 0.03) and L90M (OR = 3.0 95% CI = 1.5 - 6.0; p <
3.4. Other Factors Associated with Genotypic
Resistance to Darunavir
Comparison of demographic and clinical characteristics
between patients infected with darunavir-resistant HIV
versus darunavir-susceptible HIV, showed that the for-
mer had a higher viral load at the time of resistance test-
ing (median HIV-RNA = 93,253 [4.97 log10] copies/ml
vs. 30,150 [4.48 log10] copies/ml, respectively; p = 0.02)
and a longer-lasting virological failure with the last ad-
ministered regimen (median of 41.8 months vs. 30.3
months, respectively; p = 0.02).
4. Discussion
Darunavir, a second-generation PI with a strong affinity
for the HIV-1 protease and a relatively very high genetic
barrier to resistance development, has become the stan-
dard-of-care PI in advanced salvage regimens [14]. Indi-
viduals in whom previous various PI-containing antiret-
roviral regimens have failed, are generally infected with
HIV bearing multiple resistance mutations induced by
conventional first generation PI and with potential cross-
resistance with the new extended-activity PI, such as da-
runavir and/or tipranavir. In these circumstances, resis-
tance testing is mandatory, particularly in populations
where long-lasting and failing inappropriate combina-
tions, including unboosted PI, have been used as has oc-
curred in certain health facilities in Mexico [11,12]. A fun-
damental issue in the rational approach to patients in-
fected with multidrug resistant HIV, is the knowledge of
the pre-resistance test likelihood of finding DRV-RAM;
this requires continuous monitoring of the rate of occur-
rence of these viral genetic determinants at the popula-
tion level. Moreover, it is important to have the ability to
predict who is at higher risk of infection with HIV with 3
or more DRV-RAM and therefore, have a lower probabi-
lity of reaching lasting viral control with darunavir-based
combined salvage therapy.
In our survey, the sample point estimate of the preva-
lence rate of patients infected with HIV with 3 or more
DRV-RAM was 6.7%. Interestingly, the frequency of da-
runavir resistance was significantly higher in our study
population when compared with a rate of 4.1% (a value
which is not within the boundaries of the 95% confidence
interval of our estimate) reported in a population of PI-
treated patients in 16 clinics of the Kaiser-Permanente
Medical Care Program in Northern California [10], de-
spite an equal median number of PIs administered in both
The determinants of successful DRV/r-based therapy
in highly antiretroviral-experienced HIV-infected patients,
have been identified. In these patients, virologic success
is independently associated with fewer major PI muta-
tions and the use of new drug classes and/or fully active
drugs in the salvage regimen [15]. Moreover, the analysis
of pooled 24-week data from POWER 1, 2 and 3 showed
that the virologic response was significantly diminished
with 3 or more baseline DRV-RAM in the context of a
high number of PI-RAM [7].
In comparison to the baseline features of participants
in randomized clinical trials testing the efficacy of DRV/
r-containing salvage regimens in treatment-experienced
HIV patients (POWER 1 and 2 and DUET 1 and 2) [2,
4,5] subjects in our study were characterized by a rela-
tively lower prior exposure to PI (median of 2 drugs, me-
dian cumulative time of PI usage of 5 years), a lower re-
sistance profile to PIs (median of 2 major PI-RAM) and a
significantly lower prevalence of DRV-resistant HIV.
Thus, assuming that patients in our survey will be highly
adherent to the prescribed DRV/r-based salvage therapy,
combined with at least 2 other novel and/or fully active
drugs, a higher rate (compared to that of those trials) of a
lasting plasma viral load under the limit of detection is to
be expected. In contrast, patients with at least one major
PI-RAM (which occurred in 70% of our patients) would
be less likely to achieve this goal with lopinavir/ritona-
Copyright © 2013 SciRes. WJA
Darunavir Resistance in HIV Infecting Protease Inhibitor-Experienced Mexican Patients 285
vir-containing salvage combined therapy [16].
Our data show that the number of major PI-RAM de-
tected by genotype testing is an accurate proxy of the
magnitude of prior PI exposure/failure and of pharmaco-
logic PI selective pressure during long periods of treat-
ment with PI-containing failing regimens. Our findings
provide further support to the concept that the risk of in-
fection with darunavir-resistant HIV is directly related to
the level and duration of previous PI exposure; there is a
3.7 fold increase in this risk per each additional major PI-
RAM identified by genotype testing. We also found that
specific non-darunavir PI-RAM (such as M46I, Q58E,
V82T and L90M) were associated with darunavir resis-
tance, as was also shown by Mitsuya et al. [10].
By multivariate analysis, we were able to establish that
previous use of (fos) amprenavir and/or tipranavir sig-
nificantly increases the risk of darunavir resistance, inde-
pendently of the number of major PI-RAM (as an indica-
tor of the prior overall load of PI selective pressure). Both
molecules, (fos) amprenavir and darunavir, are structur-
ally related and hence, share some specific resistance mu-
tations [17]. In our study sample, this effect of (fos) am-
prenavir might be mediated through the selection of mu-
tations I50V and I54M which were more common in in-
dividuals who had received these agents versus other PI.
Interestingly, to our knowledge this is the first report
of the previous use of tipranavir as an independent risk
factor for the loss of viral susceptibility to darunavir. A
possible explanation of this finding is that a failing ti-
pranavir-containing regimen increases the likelihood of
selecting certain PI-RAM conferring cross-resistance with
darunavir (such as mutations L33F, I47V, T74P and I84V).
During the last six years, the prescription of this PI in
Mexico has been unrestricted and commonly used inap-
propriately since it has been added to other antiretroviral
agents without full antiviral activity (functional monothe-
rapy); we are now seeing the deleterious effect of this er-
roneous clinical practice on darunavir-viral susceptibili-
A potential methodological drawback of this study is
the possible lack of representativeness of our study sam-
ple (sample selection bias) which may limit the extrapo-
lation of our results to other multi-drug exposed patients
but with a different degree of previous PI use. The preva-
lence of DRV-RAM-bearing HIV needs to be determined
in other populations with a diverse history of PI selective
5. Conclusion
In summary, in this sample of heavily antiretroviral
treated patients, despite the fact that most had a history of
several years under selective pressure by PI-including
failing regimens, the emergence of HIV variants with
DRV-RAM was of relatively low magnitude. DRV/r-
based salvage therapy with at least 2 other novel and/or
fully active drugs is likely to be successful in a signifi-
cant proportion of these patients, with expected higher
rates of virologic control compared to those found in cli-
nical trial participants. Future similar surveys are neces-
sary in order to continuously monitor this dynamic phe-
nomenon; a rise in the incidence of darunavir-resistant
HIV infections is likely to occur with longer patient sur-
vival and an increase in overall PI (including tipranavir
and darunavir) exposure.
6. Source of Research Funds
The Inter-institutional group for antiretroviral treatment
(GUIAR) group was funded with a grant provided by
Merck Sharp & Dohme and The Board for the rational
use of antiretrovirals (CORESAR), with subsidies provi-
ded by the Centro Nacional para la Prevención y el Con-
trol del VIH/SIDA (CENSIDA-México).
7. Acknowledgements
We thank Dr. Wendy K. Moncada, Dr. Yukie García-
Kishi, Dr. Elsa Vidal-Laurencio and Luis Fuentes-Rome-
ro, BSc, from the Department of Infectious Diseases, Ins-
tituto Nacional de Ciencias Médicas y Nutrición Salva-
dor Zubirán, Mexico City, Mexico, for their technical as-
sistance. We are particularly grateful to the physicians
who referred clinical cases for peer-advising on salvage
antiretroviral therapy.
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