Efficacy and safety of replacing lopinavir with atazanavir in HIV-infected patients with undetectable plasma viraemia: final results of the SLOAT trial.
ABSTRACT Atazanavir seems to be a protease inhibitor (PI) with a more favourable metabolic profile. Information regarding the potential benefit of replacing lopinavir/ritonavir by atazanavir in HIV-infected patients with prolonged viral suppression is scarce. If proved, this strategy could be particularly attractive for the subset of patients with greater cardiovascular risk.
SLOAT was a prospective, open, comparative trial in which patients receiving lopinavir/ritonavir-based regimens and having undetectable plasma HIV-RNA for longer than 24 weeks were randomized to continue on the same therapy or switch to atazanavir. Outcomes in viral rebound, CD4 counts, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides and glucose were compared in both groups of patients at 48 weeks of follow-up.
A total of 189 patients were recruited and took at least the first dose of the assigned treatment arm. Overall, 102 switched to atazanavir (49 on 400 mg once daily, and 53 on 300 mg plus 100 mg of ritonavir once daily due to concomitant tenofovir use) and 87 continued on lopinavir/ritonavir. All patients received the PI along with two nucleoside analogues. Virological failure occurred in 12 patients switched to atazanavir and 9 continuing on lopinavir/ritonavir. A reduction (P < 0.001) in median total cholesterol (-19 mg/dL) and triglycerides (-80 mg/dL) was observed after 48 weeks of atazanavir switching, whereas no significant changes occurred in the lopinavir/ritonavir arm. Greater reductions in total cholesterol and triglycerides were seen in patients switched to atazanavir without ritonavir boosting.
The replacement of lopinavir/ritonavir by atazanavir provides an overall significant reduction in total cholesterol and triglycerides, without increased risk of virological failure.
- [show abstract] [hide abstract]
ABSTRACT: Successful treatment of human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) with highly active antiretroviral therapy (HAART) requires that patients maintain nearly perfect adherence to the prescribed regimen. Suboptimal adherence to antiretroviral therapy is clearly the most common cause of virologic failure of HAART regimens. Given the critical role of adherence in successful antiretroviral therapy, it is essential that providers of care for patients with HIV infection have a strategy that proactively assists and supports their patients' efforts to adhere to medication regimens. This review endeavors to provide a clinically focused approach to optimizing adherence of patients to HAART.Clinical Infectious Diseases 10/2001; 33(6):865-72. · 9.37 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: There is an increasing uptake of TDM of antiretroviral drugs, particularly in Europe. There is consensus that current antiretroviral drugs meet most of the criteria of drugs that can be considered as candidates for a TDM strategy. This review examines the pharmacokinetic-pharmacodynamic relationship for protease inibitors and non nucleoside reverse transcriptase inhibitor, give an overview of the published randomised clinical trials and then summarises the scenarios for use of TDM. Finally the development of the inhibitory quotient (IQ) concept is discussed.Therapeutic Drug Monitoring 07/2006; 28(3):468-73. · 2.23 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Atazanavir is a once-daily protease inhibitor (PI) for the treatment of human immunodeficiency virus (HIV) infection that has previously been studied in cohorts of treatment-naive and treatment-experienced patients. Limited data are available on the usefulness of switching from a PI-based regimen to a regimen based on a different PI, such as atazanavir, in HIV-infected patients experiencing virologic suppression but seeking regimen simplification. The Switch to Another Protease Inhibitor (SWAN) study was a 48-week, open-label trial involving HIV-positive patients with virologic suppression who were receiving stable PI-based regimens (with or without ritonavir). Patients were randomized 2 : 1 to switch to atazanavir (400 mg per day)--or, if they were receiving tenofovir, to atazanavir-ritonavir (300/100 mg per day)--or to continue to receive their existing PI. The proportion of patients who experienced virologic rebound (defined as an HIV RNA load >or=50 copies/mL) was compared through study week 48. Patients either received an atazanavir-containing regimen (278 patients) or continued to receive a comparator PI-containing regimen (141 patients). The proportion of patients who experienced virologic rebound was significantly lower among those who switched to an atazanavir-containing regimen (19 [7%] of 278) than it was among those who continued to receive a comparator PI regimen (22 [16%] of 141; P=.004). Patients who switched to atazanavir therapy experienced significantly fewer total cholesterol, fasting triglyceride, and non-high density lipoprotein cholesterol elevations than did patients in the comparator PI group (P<.001); patients receiving atazanavir had comparable rates of adverse event-related discontinuation and serious adverse events. In patients with virologic suppression who were receiving other PIs, switching to a once-per-day regimen containing atazanavir provided better maintenance of virologic suppression (as demonstrated by significantly lower rates of virologic rebound and treatment failure than those observed with continued unmodified therapy), a comparable safety profile, and improved lipid parameters, compared with those for patients who continued their prior PI-based regimen through 48 weeks.Clinical Infectious Diseases 07/2007; 44(11):1484-92. · 9.37 Impact Factor
Efficacy and safety of replacing lopinavir with atazanavir
in HIV-infected patients with undetectable plasma viraemia: final
results of the SLOAT trial
Vincent Soriano1*, Pilar Garcı ´a-Gasco1, Eugenia Vispo1, Andre ´s Ruiz-Sancho1, Francisco Blanco1,
Luz Martı ´n-Carbonero1, Sonia Rodrı ´guez-Novoa2, Judit Morello2, Carmen de Mendoza3,
Pablo Rivas1, Pablo Barreiro1and Juan Gonza ´lez-Lahoz1
1Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain;
2Pharmacokinetic Unit, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain;3Laboratory
of Virology, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain
Received 23 June 2007; returned 27 August 2007; revised 13 September 2007; accepted 8 October 2007
Background: Atazanavir seems to be a protease inhibitor (PI) with a more favourable metabolic profile.
Information regarding the potential benefit of replacing lopinavir/ritonavir by atazanavir in HIV-infected
patients with prolonged viral suppression is scarce. If proved, this strategy could be particularly attrac-
tive for the subset of patients with greater cardiovascular risk.
Methods: SLOAT was a prospective, open, comparative trial in which patients receiving lopinavir/rito-
navir-based regimens and having undetectable plasma HIV-RNA for longer than 24 weeks were ran-
domized to continue on the same therapy or switch to atazanavir. Outcomes in viral rebound, CD4
counts, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, tri-
glycerides and glucose were compared in both groups of patients at 48 weeks of follow-up.
Results: A total of 189 patients were recruited and took at least the first dose of the assigned treatment
arm. Overall, 102 switched to atazanavir (49 on 400 mg once daily, and 53 on 300 mg plus 100 mg of
ritonavir once daily due to concomitant tenofovir use) and 87 continued on lopinavir/ritonavir. All
patients received the PI along with two nucleoside analogues. Virological failure occurred in 12
patients switched to atazanavir and 9 continuing on lopinavir/ritonavir. A reduction (P < 0.001) in
median total cholesterol (219 mg/dL) and triglycerides (280 mg/dL) was observed after 48 weeks of
atazanavir switching, whereas no significant changes occurred in the lopinavir/ritonavir arm. Greater
reductions in total cholesterol and triglycerides were seen in patients switched to atazanavir without
Conclusions: The replacement of lopinavir/ritonavir by atazanavir provides an overall significant
reduction in total cholesterol and triglycerides, without increased risk of virological failure.
Keywords: antiretroviral therapy, simplification strategies, drug resistance, metabolic syndrome, dyslipidaemia
Lopinavir/ritonavir has been the preferred and most widely used
protease inhibitor (PI) until recent times.1Its efficacy has been
well established for up to 8 years, although metabolic abnormali-
ties, including hyperlipidaemia and insulin resistance, are fre-
quent side effects of this medication.2Since cardiovascular risk
has emerged as a leading cause of morbidity and mortality in
HIV-infected individuals in developed countries3,4and it has
been significantly associated with PI exposure,5the use of
PI-sparing regimens has been eagerly explored and advised,6
particularly for individuals with high cardiovascular risk. For
patients with no more options than PI, the use of atazanavir
could be a good alternative, since it seems to have a more
favourable metabolic profile.7,8Moreover, the drug can be pro-
vided once daily as only two pills making for easier treatment
*Corresponding author. Tel: þ34-91-4532500; Fax: þ34-91-7336614; E-mail: firstname.lastname@example.org
# The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: email@example.com
Journal of Antimicrobial Chemotherapy (2008) 61, 200–205
Advance Access publication 13 November 2007
by guest on June 5, 2013
adherence, which is one of the main challenges of therapy with
other PIs, which often have to be provided twice a day and/or
taking more pills daily.9
Information regarding the potential benefit of replacing lopi-
navir/ritonavir by atazanavir in HIV-infected patients with pro-
longed virus suppression is scarce and mainly derived from the
SWAN trial,10in which several PIs besides lopinavir/ritonavir
were replaced by atazanavir and the main end-point of the study
was virological failure. If substitution of atazanavir for lopina-
vir/ritonavir proves to improve the metabolic profile without
compromising the antiviral activity, this strategy could be par-
ticularly attractive for the subset of patients with greater cardio-
vascular riskwho havefailed
non-nucleoside reverse transcriptase inhibitors.
and/or did nottolerate
Patients and methods
The Simplification LOpinavir to ATazanavir (SLOAT) trial was a
prospective, randomized, open, comparative trial in which patients
receiving lopinavir/ritonavir-containing regimens and having plasma
HIV-RNA ,50 copies/mL for longer than 24 weeks were allocated
to continue on the same therapy or switch to atazanavir. The study
began to recruit patients in March 2005. All patients assigned to the
atazanavir arm received 400 mg once daily; however, when tenofovir
was taken concomitantly, ritonavir-boosted atazanavir (300/100 mg
once daily) was prescribed. The study was conducted at a single
HIV reference institution located in Madrid and was approved by
the corresponding Ethics Committee.
Recruitment started in March 2004 and all patients included in
the study were followed for at least 1 year. Outcomes in viral
rebound, CD4 counts, total cholesterol, low-density lipoprotein
(LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, tri-
glycerides and glucose were compared in both groups of patients at
48 weeks of follow-up. All metabolic parameters were examined in
blood samples taken on a fasting stomach.
Drug resistance testing was examined in samples obtained at the
time of viral rebound in patients experiencing virological failure.
Plasma trough concentrations of lopinavir or atazanavir were
measured using a modified ultraviolet HPLC method described
elsewhere.11Effective minimal concentrations were considered as
4 mg/L for lopinavir and 0.15 mg/L for atazanvir, following the
latest recommendations.12Drug adherence was measured using a
modified validated questionnaire,13in which pills missed during the
last week and over the past 3 months were recorded. Poor adherence
was considered when three or more pills were missed during the last
week or when 3 or more days of therapy were missed during the last
trimester. The accuracy of these specific questions to recognize poor
treatment adherent patients is the highest reported so far in several
The calculation of the size of the study population was of 105
patients per arm, based on the need to obtain a 90% power to
demonstrate non-inferiority of the atazanavir regimen compared
with the lopinavir/ritonavir arm. This calculation assumed a two-
sided 95% confidence interval with an upper confidence limit of
90% and a rate of virological rebound of 5% in the lopinavir/ritona-
The virological response was defined as the proportion of
patients with plasma HIV-RNA ,50 copies/mL at 48 weeks. The
virological data are reported on an intention-to-treat basis. With
respect to changes in lipids, the results are provided only for sub-
jects who were receiving the assigned study medication. The virolo-
gical response was compared among treatment arms using the x2
test. Treatment failure was defined on the basis of virological failure
(plasma HIV-RNA .50 copies/mL) or discontinuation due to side
effects. All efficacy analyses were made on an intent-to-treat basis,
whereas metabolic comparisons were made in patients on-treatment
at the end of the 48 week follow-up study period. Qualitative and
quantitative baseline characteristics were compared using the x2test
(with Yates and Fisher’s corrections when necessary) and the
Mann–Whitney U-test, respectively. Changes in continuous vari-
ables between both treatment arms were compared using non-
parametric tests. All statistical analyses were performed using the
SPSS software (version 13.0).
A total of 224 patients were identified at our institution as fulfill-
ing the study entry criteria. However, 9 declined to participate in
the study before randomization and 26 did not accept the treat-
ment allocation arm (the latter were mainly subjects assigned to
continue on lopinavir/ritonavir). Of the 189 patients recruited in
the study who received at least one dose of the assigned medi-
cation, 87 continued on lopinavir/ritonavir and 102 were
switched to atazanavir (49 on 400 mg once daily and 53 on ata-
zanavir/ritonavir 300/100 mg once daily, since they were taking
tenofovir concomitantly). Another three patients did not com-
plete the planned 48 week study period. One in the lopinavir/
ritonavir arm was lost to follow-up and two in the atazanavir
arm developed severe jaundice and withdrew from the study.
Both were receiving ritonavir-boosted atazanavir along with
tenofovir. In both cases, atazanavir was replaced by fosamprena-
vir/ritonavir and patients continued with undetectable viraemia.
Figure 1 summarizes the allocation of patients during the study
All patients received the PI along with two nucleos(t)ide ana-
logues. The most common was tenofovir, which was prescribed
along with emtricitabine in most cases, as it is co-formulated as
Truvadaw. Other nucleoside analogues used in order of fre-
quency were lamivudine, zidovudine, didanosine and abacavir.
Stavudine was only used by two patients in the whole study
Figure 1. Patient’s disposition in the SLOAT trial.
The SLOAT trial
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population. All these drugs were used at standard doses. There
were no significant differences in the use of these drugs when
comparing the two treatment arms. Moreover, all patients had
been on their regimen for longer than 3 months and none had
changed the nucleoside backbone at the time of study entry.
Finally, it should be noted that most individuals (177/186;
95.1%) in the SLOAT trial had received other antiretroviral regi-
mens before their current lopinavir/ritonavir-based combination.
Nearly half had been exposed to other PIs, mainly indinavir and
to a lower extent nelfinavir; and failures on prior PIs had
occurred in two-thirds of PI-experienced patients.
Table 1 shows the main characteristics of the study popu-
lation. There were no significant differences in median age, risk
category nor in hepatitis B or C serostatus between groups. It
should be highlighted that ?40% of patients in each arm had
chronic hepatitis B and/or C. All but five patients (two in the
lopinavir/ritonavir arm and three in the atazanavir arm) were
Caucasians. There were more males in the atazanavir arm than
in the lopinavir/ritonavir arm (84% versus 59%; P , 0.001). The
median CD4 count was higher in the subset of patients who
switched to atazanavir in comparison to those who continued on
Finally, total cholesterol and fasting triglycerides were signifi-
cantly more elevated at baseline in patients who switched to ata-
zanavir than in those who continued on lopinavir/ritonavir. The
reasons for these differences in gender, CD4 counts and lipids at
baseline between treatment arms might have been determined by
the fact that 26 patients did not accept to stay on lopinavir/rito-
navir upon randomization. Although patients with lower CD4
counts having been on prior antiretroviral therapy for a shorter
time might have not been prone to change a successful antiviral
therapy, those experiencing lipid abnormalities that were
403 cells/mm3;P, 0.001).
difficult to be controlled under longer antiretroviral therapy
could have been more in favour of being recruited into a trial in
which a potentially safer metabolic PI was evaluated. They
expected to receive atazanavir and did not agree to stay on lopi-
navir/ritonavir for a longer period of time.
Virological failure occurred in 12 patients switched to ataza-
navir and 9 on lopinavir/ritonavir (Table 2). Interestingly, eight
out of nine patients who failed on lopinavir/ritonavir had no rel-
evant protease resistance mutations. The only patient who failed
with resistance changes at the protease gene had previously
failed to nelfinavir. Among the 12 patients who failed on ataza-
navir, 5 were on atazanavir 400 mg once daily and 7 on atazana-
vir/ritonavir 300/100 mg once daily. Five of these patients
harboured primary resistance mutations. All of them had pre-
viously failed other PIs, generally indinavir and/or nelfinavir.
A retrospective review of the clinical charts revealed that poor
drug compliance was the most likely reason for virological
failure in this subset of patients, either on lopinavir/ritonavir or
atazanavir. However, three out of the five individuals who failed
on atazanavir with PI-resistant viruses were compliant with their
medication and had atazanavir plasma trough concentrations
above the Cmin.
The median atazanavir plasma trough concentrations were
0.822 (0.042–1.278) mg/mL in patients taking atazanavir/ritona-
vir 300/100 mg/day and 0.234 (0.034–0.456) mg/mL in subjects
taking atazanavir 400 mg/day. The minimum efficacious plasma
concentration for the drug has been established in 0.150 mg/
Changes in CD4 cell counts from baseline were comparable
between treatment arms at week 48, with median increases of
42 cells/mm3for patients continuing on lopinavir/ritonavir and
46 cells/mm3for patients switched to atazanavir.
Table 1. Main baseline characteristics of the study population
Lopinavir/ritonavirAtazanavir totalAtazanavir 400 Atazanavir/ritonavir 300/100P*
No. of patients
Median age (years)
Median CD4 count (cells/mm3)
Median exposure to prior antiretroviral
Chronic hepatitis C
Chronic hepatitis B
Median AST (IU/L)
Median ALT (IU/L)
Median triglycerides (mg/dL)
Median total cholesterol (mg/dL)
Median LDL-cholesterol (mg/dL)
Median HDL-cholesterol (mg/dL)
Median glucose (mg/dL)
IDU, injecting drug user; MSM, men who have sex with men; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
*Comparisons between lopinavir/r and total atazanavir arms.
Soriano et al.
by guest on June 5, 2013
A significant reduction in median fasting total cholesterol
(219 mg/dL) and triglycerides (280 mg/dL) (P, 0.001) was
observed after 48 weeks of atazanavir switching, although lipids
(Table 3). Greater reductions in fasting total cholesterol and tri-
glycerides were seen in patients on ritonavir-unboosted atazana-
vir in comparison with those switched to atazanavir/ritonavir
300/100 mg once daily. The benefits in the lipid profile did not
differ significantly comparing patients with or without underlying
chronic viral hepatitis (data not shown). The proportion of
patients who achieved lipid levels below the threshold for thera-
peutic interventions with either life style, exercise and/or
lipid-lowering drugs was greater in the atazanavir arm in com-
parison with the lopinavir/ritonavir arm. At week 48, the pro-
portion of patients with LDL-cholesterol levels above the distinct
cardiovascular risk categories was significantly lower in the ata-
zanavir arm compared with the lopinavir/ritonavir arm (Figure 2).
This difference could be appreciated despite a more frequent use
of lipid-lowering drugs in the lopinavir/ritonavir arm compared
with the atazanavir arm (17% versus 5%; P ¼ 0.006).
No significant changes in fasting serum glucose were seen in
any of the treatment arms during the 48 week follow-up.
Likewise, changes in HDL- and LDL-cholesterol did not differ
significantly when comparing treatment arms, although a trend
Table 2. Main characteristics of patients who experienced virological failure
CD4 count at
PI plasma trough
adherence Protease resistance mutations
Atazanavir 400 arm
3 78 939
4 29 404
Atazanavir/r 300/100 arm
2 90 758
4 52 917
6 243 318
7 75 579
D30N, L63PS, A71V, V77I, N88ND, L90ML
V32I, I47V, L63P, A71T, V82A
L10I, M46I, L63P, A71I, G73S, V77I, L90M
L10I, K20V, M36I, G48I, F53L, I54V, L63P, V82A
L10I, M46I, L63A, G73S, V77I, L90M
L10I, I54V, L63P, A71V, V77I, V82A, L90M
Table 3. Median changes in metabolic parameters from baseline up to week 48
(n ¼ 87)
(n ¼ 102)P
(n ¼ 49)P
(n ¼ 53)P
All changes in lipids and glucose values are expressed as mg/dL.
The SLOAT trial
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towards reduced LDL-cholesterol was seen in the subset of
patients on ritonavir-unboosted atazanavir.
This study demonstrates that the replacement of lopinavir/ritona-
vir by atazanavir may provide an overall significant reduction in
fasting total cholesterol and triglycerides, without an increased
risk of virological failure throughout 48 weeks in patients with
undetectable plasma viraemia under a stable lopinavir/ritonavir-
based regimen. These data confirm what has recently been
suggested in the SWAN trial for patients with virological control
using different PI-based regimens.10In contrast to the SWAN
trial, in which patients switched to atazanavir experienced fewer
viral rebound episodes than patients continuing on their prior
PIs (7% versus 16%, respectively), in our study the rate of viro-
logical failure was 10% on average and similar between patients
continuing on lopinavir/ritonavir and those switched to atazana-
vir. It should be noted, however, that patients who had experi-
enced previous virological failure under other PIs were excluded
from the SWAN trial but not from our study. Thus, the lower
genetic barrier for resistance to atazanavir compared with lopi-
navir/ritonavir could explain at least in part the differences
between virological outcomes in the two studies. In any case, it
should be highlighted that poor drug compliance was the most
likely reason for virological failure in our study population,
regardless of treatment arm allocation, as demonstrated by
looking at plasma drug trough concentrations. Measurement of
plasma PI concentrations confirmed pharmacy records and a
modified validated self-reported questionnaire for low drug
adherence.13As expected and not surprisingly, PI-associated
resistance mutations were not seen in the majority of our
patients experiencing viral rebound, although this was particu-
larly true for lopinavir/ritonavir failures and less common for
At week 48, patients in the atazanavir arm experienced sig-
nificant improvements in fasting total cholesterol and triglyceri-
des compared with patients who continued on lopinavir/
ritonavir. More patients who switched to atazanavir than patients
who received lopinavir/ritonavir achieved lipid levels below the
National Cholesterol Education
pharmacologic intervention,15even when lipid-lowering agents
had been more frequently used in the lopinavir/ritonavir arm
than in the atazanavir arm during the study period. These results
are in agreement with those obtained in the SWAN trial10and
other studies that have assessed the metabolic profile of atazana-
vir.16–19It should be noted, however, that our findings extend
the improvement in the lipid profile to patients with fewer
severe lipid abnormalities at baseline in whom theoretically it
might have been more difficult to recognize any further benefit
in the lipid profile.
Around 40% of patients in the SLOAT trial suffered from
chronic hepatitis C. While insulin resistance and hyperglycaemia
have beenreported tobe
HCV-coinfected individuals, particularly following exposure to
antiretroviral therapy,20a paradoxical lower incidence of lipid
abnormalities, especially hypercholesterolaemia,
reported in HCV/HIV-coinfected versus HIV-monoinfected
patients.21In our study, the benefit in the lipid profile after
switching from lopinavir/ritonavir to atazanavir was equally
noticed regardless of the presence of underlying chronic hepa-
The implications of our results are clear in an era in which
more than 20 antiretrovirals exist and achievement of complete
virus suppression is the rule for most patients in need of antire-
troviral therapy. Undesirable metabolic consequences have
become a relevant aspect of HIV care6–8and for the already
relatively large number of individuals who have failed non-
nucleoside reverse transcriptase inhibitors and/or do not tolerate
them, it is very welcome that active antiviral drugs with a clean
lipid profile such as atazanavir have become available.
We would like to thank German Ramirez-Olivencia for his
excellent assistance in the collection and analysis of data.
This work was supported in part by grants from Fundacio ´n
Investigacio ´n y Educacio ´n en SIDA (IES), the European NEAT
project, and the Spanish Red de Investigacio ´n en SIDA (RIS,
V. S. has received research grants and has been member of advi-
sory boards and speaker’s bureau from BMS, Gilead, GSK and
MSD during the past 2 years. All other authors have none to
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Figure 2. Proportion of patients with LDL-cholesterol levels stratified
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*Patients with LDL-cholesterol levels .160 mg/dL should be treated with
lipid-lowering agents regardless of the presence of other cardiovascular risk
factors. These were 4% on atazanavir and 14% on lopinavir/r in the SLOAT
trial (P ¼ 0.008).
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The SLOAT trial
by guest on June 5, 2013