Drugs 2009; 69 (8): 1107-1140

ADIS DRUG EVALUATION 0012-6667/09/0008-1107/$55.55/0

ª 2009 Adis Data Information BV. All rights reserved.

Atazanavir
A Review of its Use in the Management of HIV-1 Infection
Katherine F. Croom, Sohita Dhillon and Susan J. Keam
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Philadelphia, Pennsylvania, USA

Various sections of the manuscript reviewed by:

F. Cainelli, School of Medicine, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana;
F. Gutiérrez, Infectious Diseases & HIV-1 Unit, Hospital General Universitario de Elche, Elche, Spain;
K.A. Lichtenstein, School of Medicine, Division of Infectious Diseases, University of Colorado Health
Sciences Center, Denver, Colorado, USA; J.D. Scott, Pharmacy Practice and Administration, Western
University of Health Sciences, Pomona, California, USA; E. Seminari, Clinical Epidemiology and Biometric
Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Pavia, Pavia, Italy;
R. ter Heine, Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands.

Data Selection
Sources: Medical literature published in any language since 1980 on ‘atazanavir’, identified using MEDLINE and EMBASE, supplemented
by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of
published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing
the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘atazanavir’ and ‘HIV-1 infections’. Searches were last updated 22
May 2009.
Selection: Studies in patients with HIV-1 infection who received atazanavir. Inclusion of studies was based mainly on the methods section
of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant
pharmacodynamic and pharmacokinetic data are also included.
Index terms: Atazanavir, HIV-1 infection, protease inhibitors, antiretroviral therapy, pharmacodynamics, pharmacokinetics, therapeutic
use, tolerability.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
2.1 In vitro Activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
2.2 Resistance and Cross-Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
2.3 Predictors of Virological Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
2.4 Metabolic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
3. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113
3.1 Absorption and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113
3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114
3.3 Use in Special Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1114
3.4 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1118
4.1 Antiretroviral Therapy-Naive Patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1118
4.1.1 Unboosted Atazanavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1119
4.1.2 Ritonavir-Boosted Atazanavir. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121
1108 Croom et al.

4.2 Antiretroviral Therapy-Experienced Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1122

4.2.1 Patients with Past Virological Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123
4.2.2 Patients with Prolonged Virological Suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1123
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
5.1 General Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1125
5.2 Metabolic Profile. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127
6. Pharmacoeconomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
7. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
8. Place of Atazanavir in the Management of HIV-1 Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132

Summary
Abstract Atazanavir (Reyataz), a protease inhibitor (PI), is approved in many coun-
tries for use as a component of antiretroviral therapy (ART) regimens for
the treatment of adult, and in some countries in paediatric, patients with HIV-1
infection. ART regimens containing ritonavir-boosted atazanavir improved
virological and immunological markers in adult patients with HIV-1 infec-
tion, and had similar efficacy to regimens containing lopinavir/ritonavir in
treatment-naive and treatment-experienced patients. In addition, unboosted
atazanavir was noninferior to ritonavir-boosted atazanavir in treatment-naive
patients. Atazanavir is administered once daily and has a low capsule burden.
Atazanavir, whether unboosted or boosted, was generally well tolerated and
appeared to be associated with less marked metabolic effects, including less
alteration of lipid levels, than other PIs. These properties mean that boosted
atazanavir, and unboosted atazanavir in patients unable to tolerate ritonavir,
continues to have a role as a component of ART regimens in patients with HIV-1
infection.
Pharmacological Atazanavir is a potent, HIV-1-specific PI that prevents the formation of mature
Properties virions in HIV-1-infected cells by inhibiting the cleavage of gag and gag-pol
polyproteins. At the highest concentrations evaluated, there was no antagonistic
antiretroviral activity, or enhanced cytotoxicity, in two-drug combinations of
atazanavir with several nucleoside/nucleotide reverse transcriptase inhibitors
(NRTIs), PIs, non-nucleoside reverse transcriptase inhibitors, an HIV-1 fusion
inhibitor, or agents used for the treatment of viral hepatitis.
The signature resistance mutation for atazanavir has been identified as an
isoleucine to leucine substitution at residue 50 (I50L). This mutation conferred
resistance to atazanavir, but increased susceptibility to other PIs. Nonetheless,
when the I50L substitution developed in isolates with other PI-associated muta-
tions already present, these isolates were cross-resistant to other PIs. Virological
response to atazanavir in ART-experienced patients was affected by the type and
number of PI mutations present at baseline.

The absorption parameters of orally administered atazanavir were nonlinear

after multiple doses. Steady-state was reached after approximately 6 days.
Boosting with low-dose ritonavir increased plasma concentrations of atazanavir.
Atazanavir was metabolized by cytochrome P450 isozyme 3A4 to inactive meta-
bolites, and eliminated primarily via the biliary route. The elimination profile of
atazanavir allows for once-daily administration. Pharmacokinetic drug interac-
tions have been demonstrated between atazanavir and several drugs. For example,

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection 1109

in treatment-experienced patients, concomitant administration with efavirenz is

not recommended and proton-pump inhibitors should not be used.
Therapeutic Efficacy The efficacy of ART regimens containing unboosted or boosted atazanavir has
been assessed in a number of well designed trials in ART-naive and ART-
experienced adults with HIV-1 infection. Patients also received dual-NRTI ther-
apy, and virological efficacy was generally assessed using the mean change in viral
load and/or the proportion of patients with viral load below the limit of quanti-
fication after 48–96 weeks of treatment.
In ART-naive patients receiving dual-NRTI backbone therapy, the virological
efficacy of unboosted atazanavir 400 mg once daily was similar to that of un-
boosted nelfinavir and was noninferior to that of efavirenz in three 48-week trials.
A 24-week extension of one study showed that viral suppression was maintained
at 72 weeks with unboosted atazanavir. Similarly, the virological efficacy of once-
daily atazanavir 300 mg boosted with ritonavir 100 mg was noninferior to that of
lopinavir/ritonavir in ART-naive patients receiving dual-NRTI backbone ther-
apy in a 96-week trial. In these studies, outcomes were similar for immunological
response, as assessed by change in CD4+ cell count.
In ART-experienced patients with a history of virological failure on PI-
containing regimens, the efficacy of boosted atazanavir was noninferior to that of
lopinavir/ritonavir in terms of viral suppression, when both regimens were
coadministered with dual-NRTI therapy for 48 weeks. The effect with boosted
atazanavir was maintained in the longer term, with noninferiority to lopinavir/
ritonavir also demonstrated after 96 weeks. However, unboosted atazanavir
provided less viral suppression than a regimen containing lopinavir/ritonavir in
similar patients.
In ART-experienced patients with prolonged virological suppression on a PI-
containing ART regimen, a switch to an atazanavir-based regimen was non-
inferior or similar to remaining on the original regimen in terms of maintaining
suppression in three 48-week trials. In one of these trials (SWAN), the rate of
virological failure was significantly reduced and the time to virological failure
significantly increased in patients switching to atazanavir-based regimens, com-
pared with patients who continued with the original PI-containing regimens.
Tolerability In clinical trials, the most common adverse events reported with atazanavir
(administered in combination with NRTI therapy) were nausea, jaundice and
diarrhoea. The most common laboratory abnormality was elevated total bili-
rubin, which was generally due to elevated indirect (unconjugated) bilirubin,
related to inhibition of uridine-glucuronosyl transferase 1A1. The tolerability
profiles of unboosted and boosted atazanavir were generally similar, with the
exception that jaundice and hyperbilirubinaemia were more common with boos-
ted atazanavir. The overall incidence of adverse events was generally similar
for atazanavir-based therapy and comparators, but jaundice and elevated bili-
rubin levels were more common with atazanavir than with nelfinavir, lopinavir/
ritonavir, fosamprenavir plus ritonavir and efavirenz, and diarrhoea was less
common with atazanavir than with nelfinavir, lopinavir/ritonavir and fosampre-
navir plus ritonavir. Rash, mostly mild to moderate in severity, was reported in
»20% of atazanavir recipients in clinical trials. PR interval prolongation may
occur in some patients receiving atazanavir, and patients with chronic hepatitis B
or C may be at risk of increased transaminases or hepatic decompensation during
atazanavir therapy.
In clinical trials, unboosted atazanavir had a lower propensity to alter total
cholesterol, low-density lipoprotein cholesterol and triglyceride levels than

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
1110 Croom et al.

nelfinavir, lopinavir/ritonavir or efavirenz in antiretroviral-naive patients,

and boosted atazanavir had a lower propensity to alter total cholesterol,
non-high-density lipoprotein cholesterol and triglyceride levels compared with
lopinavir/ritonavir in ART-naive or -experienced patients. Like other anti-
retroviral regimens, atazanavir-based regimens can be associated with fat accu-
mulation, generally around the trunk, and some limb fat loss in the longer term,
but there were no differences in fat accumulation or distribution for atazanavir
compared with efavirenz or lopinavir/ritonavir. Atazanavir had no significant
effect on blood glucose or insulin levels.

1. Introduction resistance and tolerability profiles that can be

HIV-1 infection affects more than 30 million
people worldwide and is one of the leading causes
of death.[1] Each year, 2.7 million new infections
develop,[1] including more than 50 000 in the US.[2]
The efficacy of highly active antiretroviral therapy
(HAART) in the treatment of HIV-1 infection
is well established.[3,4] According to US[5] and
European[6] guidelines, HAART regimens usually
contain at least three drugs from two different
classes of antiretroviral agents, and are generally
composed of two nucleoside/nucleotide reverse
transcriptase inhibitors (NRTIs) plus either one
non-nucleoside reverse transcriptase inhibitor
(NNRTI) or a protease inhibitor (PI). HAART
reduces viral load, improves immune function and
increases life expectancy.[7] However, these regi-
mens also have some disadvantages, such as
tolerability issues, poor adherence to complex
regimens and drug resistance.[4,7]
PIs are one of the main classes of antiretroviral
drugs recommended for the initial treatment of
HIV-1-infected patients; they have been shown to
improve morbidity and mortality[8] and have a
high threshold for the development of resistance.[9]
Certain PIs are often boosted with a low dose of
ritonavir, which can increase systemic exposure,
reduce the risk of resistance and decrease the dose
administration frequency of the main PI.[8,10]
However, they can be associated with a number of
adverse effects, such as gastrointestinal distur-
bances, liver toxicity and metabolic disorders, in-
cluding alteration of lipid levels, insulin resistance
and lipodystrophy.[9] There remains a need for
effective antiretroviral drugs with favourable
administered using a simple dose administration
regimen.
Atazanavir (Reyataz) is a well established PI
with a distinct resistance and metabolic profile,
which has been reviewed previously.[11] This article
reviews the pharmacological properties, efficacy
and tolerability of oral atazanavir (unboosted and
ritonavir-boosted) in the treatment of patients with
HIV-1 infection, focussing on new clinical data.
2. Pharmacodynamic Properties
The pharmacological properties of atazanavir
have been reviewed in detail previously;[11] there-
fore, this section provides only a brief overview.
2.1 In vitro Activity
Atazanavir prevents HIV-1 protease-mediated
cleaving of viral gag and gag-pol polyproteins in
HIV-1 infected cells, preventing the formation of
mature virions.[12] It selectively and potently
inhibits the HIV-1 protease enzyme, with an
inhibition constant of 66 nmol/L.[12] The 50%
effective concentration (inhibition of 50% of
viral replication; EC50) of atazanavir was
2.6–5.3 nmol/L and the EC90 (inhibition of 90%
of viral replication) was 9–15 nmol/L.[12] Its anti-
retroviral potency was generally greater than that
of indinavir (5.00–28.7 nmol/L), nelfinavir
(6.14–25.9 nmol/L), ritonavir (35.5–129 nmol/L),
saquinavir (5.28–24.8 nmol/L) and amprenavir
(16.6–54.3 nmol/L) in a variety of HIV strains
from clinical and laboratory isolates.[12] Further-
more, in vitro cytotoxic activity with atazanavir

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
was observed at concentrations 6500- to 23 800-
fold higher than those required for antiretroviral
activity.[12]
At the highest concentrations evaluated, there
was no antagonistic antiretroviral activity, or en-
hanced cytotoxicity, in two-drug combinations of
atazanavir with NNRTIs (delavirdine, efavirenz
and nevirapine), PIs (amprenavir, indinavir, lo-
pinavir, nelfinavir, ritonavir and saquinavir),
NRTIs (abacavir, didanosine, emtricitabine, la-
mivudine, stavudine, tenofovir disoproxil fuma-
rate [tenofovir DF], zalcitabine and zidovudine)
or the HIV-1 fusion inhibitor enfuvirtide, as well
as with adefovir or ribavirin used for the treat-
ment of viral hepatitis.[12-14] Instead, additive
or moderately synergistic antiretroviral effects
were observed in combinations of atazanavir
with stavudine, didanosine, lamivudine, zidovu-
dine, nelfinavir, indinavir, ritonavir, saquinavir
or amprenavir at the highest concentrations
evaluated.[12]
2.2 Resistance and Cross-Resistance
The signature resistance mutation for ataza-
navir is an isoleucine to leucine substitution at
amino acid residue 50 (I50L) of the HIV-1 pro-
tease gene.[15] This substitution appears to confer
a unique phenotype on affected viruses, namely
resistance to atazanavir, but increased in vitro
susceptibility to other PIs.[15,16] This substitution
was the sole primary mutation in 100% of ataza-
navir-resistant isolates (n = 23 isolates) from anti-
retroviral therapy (ART)-naive patients who did
not respond to treatment with atazanavir
in clinical trials.[15] Additional mutations seen in
13–53% of isolates with the I50L substitution in
ART-naive patients included A71V, K45R/Q/N,
G73S, I64V, M46I/L and V82A.[15] In general, ad-
ditional substitutions did not accumulate rapidly
after the I50L substitution emerged.[15] In ART-
naive patients treated with boosted atazanavir,
primary PI mutations tended not to occur.[17,18]
In PI-naive patients who experienced virological
failure while receiving atazanavir-containing re-
gimens, isolates containing the I50L substitution,
showed unchanged or increased susceptibility
to amprenavir, indinavir, lopinavir, nelfinavir,
ª 2009 Adis Data Information BV. All rights reserved.
1111
ritonavir and saquinavir.[15] The I50L substitu-
tion occurred in a variety of genetic backgrounds,
with nearly seven protease substitutions in base-
line isolates, including L10F/I/V, K20R, M36I/L
and L63P substitutions.[15]
In ART-experienced patients with virological
failure, the most common substitutions seen in clin-
ical isolates included V321, L33F/V/I, E35D/G,
M46I/L, I50L, F53L/V, 154V, A71V/T/I, G73S/T/I,
V82A/T/L, I85V and L89V/Q/M/T.[13] The I50L
substitution was present in »30% of isolates from
ART-experienced patients with virological fail-
ure.[19] The most common additional mutations co-
emerging in isolates with I50L included A71V,
G73S, K45R, E34X and L33F.[19] Where atazana-
vir-resistant isolates did not have the I50L sub-
stitution, several mutations for resistance to other
protease inhibitors were seen.[20]
Isolates with cross-resistance to multiple other
PIs, including amprenavir, indinavir, lopinavir,
nelfinavir, ritonavir and saquinavir, tended to be
resistant to atazanavir.[13,20-23] Cross-resistance
to atazanavir increased as the number of PIs an
isolate was resistant to increased.[20] Compared
with a reference strain, the median reduction in
susceptibility to atazanavir was 1.6-, 2.1-, 4.0-,
6.2- and 22-fold for isolates resistant to one, two,
three, four or five PIs, respectively.[20] In a study
using an in vitro panel of clinical isolates with
3.5-fold reduction in susceptibility to indinavir,
saquinavir, ritonavir and nelfinavir compared
with wild-type, cross-resistance to atazanavir
was higher than cross-resistance to amprenavir
or lopinavir (statistical data not available).[21]
If the I50L substitution developed in isolates
where other PI-associated mutations were al-
ready present, the isolates were cross-resistant to
other PIs.[13]
2.3 Predictors of Virological Response
In ART-experienced patients, the virological
response was affected by both the type and
number of PI mutations at baseline.[24] In study
045 in ART-experienced patients (section 4),[25]
response rates (based on viral load <400 copies/
mL) in recipients of boosted atazanavir were
lower if at least three PI substitutions were
Drugs 2009; 69 (8)
1112
present at baseline than if two or fewer substitu-
tions were present (41% [14 of 34 patients] vs 75%
[50 of 67]; no statistical data available).[24] In the
presence of at least five mutations, the response
rate was 0. These results were consistent with the
outcome for a comparator lopinavir/ritonavir
group, with the exception that the response rate
in patients with at least five mutations in the lat-
ter group was 28%. Less than 30% of recipients of
boosted atazanavir were classified as responders
if substitutions were present at M46 (5 of 20 pa-
tients were responders), G73 (2 of 7), I84 (1 of 8)
or L90 (7 of 23).[24] When analysed according to
baseline phenotype (change in susceptibility
compared with wild-type reference), response
rates in the boosted atazanavir group were 71%
(55 of 58 patients), 53% (8 of 15), 13% (1 of 8) and
10% (1 of 10) in patients with a shift of <2-fold,
2- to 5-fold, 6- to 10-fold and >10-fold, respec-
tively (compared with 69% [56 of 81], 44% [4 of 9],
33% [3 of 9] and 23% [3 of 13] for lopinavir/
ritonavir).[24]
Based on a post hoc analysis of data from
study 045[25] and another trial, study 043[26] (sec-
tion 4), the ‘clinical’ cut-off for phenotypic re-
sistance (i.e. the cut-off beyond which a change in
susceptibility leads to a decrease in virological
response) for atazanavir was determined to be
<2.2 (fold change in EC50 vs wild type) for iso-
lates from recipients of unboosted atazanavir and
<5.2 for boosted atazanavir.[27]
The minimum plasma concentration (Cmin; see
section 3) or trough concentration of atazanavir
correlated with virological response in some,[28-30]
but not all,[31] studies that evaluated this rela-
tionship. The optimal range for atazanavir trough
concentration was determined to be 150–850 ng/
mL in one study[28] and 300–650 ng/mL at 24
hours in another.[29] In other studies, high ataza-
navir trough concentrations correlated with ele-
vated serum bilirubin levels in patients receiving
boosted atazanavir.[32,33]
The relationship between the genotypic in-
hibitory quotient (GIQ; ratio of Cmin to number
of resistance mutations) and response has been
evaluated for atazanavir in a number of small
studies (n <100).[28,31,34,35] Atazanavir GIQ was
predictive of virological response in ART-
ª 2009 Adis Data Information BV. All rights reserved.
Croom et al.
experienced patients treated with unboosted[31] or
either unboosted or boosted[28,34,35] atazanavir.
For example, in one study, the median atazanavir
GIQ was 365 (range 50–1172) in responders
compared with 126 (23–1126) in nonresponders
(p = 0.05).[34] After 6 months, virological response
was achieved in 74% (17 of 23) of patients with
a GIQ >183 versus 26% (6 of 23) of those with
a GIQ <183 (p = 0.02).[34] In two of these
studies,[31,34] the number of baseline mutations
was not predictive of virological response (ac-
cording to multivariate analysis in one study[31]),
whereas in the third study, there was significant
association between baseline mutations and the
decrease in viral load after 12 weeks,[35] but not
24 weeks of treatment.[28] Another study found
that GIQ was predictive of virological failure in
patients with, but not those without, PI muta-
tions at baseline.[33]
2.4 Metabolic Effects
In randomized clinical trials in HIV-1-infected
patients, atazanavir generally had a lower pro-
pensity to alter lipid levels than comparator PIs;
this is discussed in detail in section 5.2. In vitro,
atazanavir did not alter adipocyte differentiation,
whereas ritonavir significantly reduced the dif-
ferentiation of human subcutaneous and omental
adipocytes.[36] In the same study, ritonavir, but
not atazanavir, led to a reduction in adiponectin
secretion in subcutaneous (but not omental) adi-
pocytes. Both atazanavir and ritonavir increased
leptin secretion in subcutaneous cells; ritonavir
decreased leptin levels in omental cells, whereas
atazanavir had little effect.[36]
In in vitro studies, atazanavir did not inhibit the
insulin responsive glucose transporter 4.[37,38] In
addition, atazanavir did not have any significant
effects on glucose levels and insulin resistance in
studies in healthy volunteers[39-41] or short-term
studies in HIV-1-infected patients.[42] For
example, in a study in 22 ART-naive patients
without metabolic disorders, a median increase
of 2.3% (range -26.4% to +103.7%) in glucose
disposal rate (during hyperinsulinaemic euglyc-
emic clamp) was seen after 4 weeks’ treatment
with atazanavir 300 mg plus ritonavir 100 mg
Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
(compared with a decrease of 10.8% [-33.6% to
+32%] in recipients of saquinavir/ritonavir
2000 mg/100 mg).[42] Data from longer-term clin-
ical trials in HIV-1-infected patients are discussed
in section 5.2.
Atazanavir did not induce endothelial dysfunc-
tion in healthy volunteers.[43] In a small study in
39 HIV-1-infected patients with viral suppression
on a PI-containing regimen and low-density lipo-
protein-cholesterol (LDL-C) >3 mmol/L, switch-
ing to unboosted atazanavir for 24 weeks did not
improve endothelial function compared with con-
tinuing to receive the current regimen, despite im-
proving serum lipid levels.[44]
Elevated bilirubin levels can occur in patients
receiving atazanavir (section 5.1), and this is pri-
marily related to the inhibition of the uridine-
glucuronosyl transferase (UGT) 1A1 enzyme
(which is involved in bilirubin conjugation) by
atazanavir.[45] There is a correlation between
elevated atazanavir plasma levels and hyperbili-
rubinaemia; plasma levels can be affected by
polymorphisms of the multidrug resistance 1
gene,[45,46] and the presence of UGT1A1 polymor-
phisms can exacerbate hyperbilirubinaemia.[45,47]
3. Pharmacokinetic Properties
The pharmacokinetic properties of atazanavir
have been reviewed in detail previously;[11,48]
therefore, this section provides a brief overview
of the properties in healthy volunteers and HIV-
1-infected adult and paediatric patients, with the
main focus on pharmacokinetic properties re-
levant to the clinical setting, including multiple-
dose pharmacokinetics, and drug interactions.
Atazanavir may be administered alone[13] or in
combination[13,14] with ritonavir (leading to in-
creased exposure to atazanavir), and the phar-
macokinetics of both unboosted and boosted
atazanavir are discussed where relevant.
3.1 Absorption and Distribution
Atazanavir was rapidly absorbed after oral
administration, reaching peak plasma concentra-
tions (Cmax) after 2–3 hours (table I).[13] Steady
state was reached by around day 6.[49] The phar-
ª 2009 Adis Data Information BV. All rights reserved.
1113
macokinetics of atazanavir after multiple doses
are nonlinear. A greater than dose-proportional
increase in the area under the plasma concentra-
tion-time curve (AUC) was observed in healthy
volunteers receiving atazanavir 400 or 800 mg
once daily for 6 days,[49] while in ART-naive HIV-
1-infected patients, the increase in AUC tended to
be less than dose proportional with atazanavir
200, 400 or 500 mg once daily (monotherapy for
2 weeks, followed by combination therapy with
two nucleosides) on days 1 and 29.[50] In addition,
there was considerable inter- and intra-patient
pharmacokinetic variability.[51,52]
Atazanavir exposure appeared to be lower in
HIV-1-infected patients than in healthy volun-
teers (table I), although the reason for this is not
clear.[13,48] Despite this, Cmin concentrations in
patients treated with atazanavir 400 mg or ata-
zanavir 300 mg plus ritonavir 100 mg once daily
tended to be several-fold higher than the protein-
binding corrected EC50 for wild-type virus.[48]
Coadministration with ritonavir results in
increased exposure to atazanavir compared
with unboosted atazanavir (table I).[13,48,53] This
occurs because ritonavir inhibits the cytochrome
P450 (CYP) 3A enzyme, leading to reduced me-
tabolism of atazanavir.[53] When multiple doses
of atazanavir 300 mg plus ritonavir 100 mg were
administered to healthy volunteers, steady-state
Cmax and AUC across the dose administration
interval increased 1.86- and 3.38-fold compared
with unboosted atazanavir 300 mg.[53]
Following high- and low-fat meals, the AUC
of unboosted atazanavir 400 mg increased by
35% and 70%.[54] After a high-fat meal, the
24-hour concentration of atazanavir increased by
33% because of delayed absorption, as indicated
by Cmax being reached after 5 hours.[13] When
atazanavir was administered with food, the
coefficient of variation for AUC and Cmax de-
creased compared with the fasting state[13,54] (e.g.
by 25% for boosted atazanavir[14]). Atazanavir
should be taken with food to improve bioavail-
ability and reduce variability.[14]
Atazanavir is ‡86% protein bound (86% to
albumin and 89% to a1-acid glycoprotein).[13]
Population pharmacokinetic studies in HIV-1-
infected patients estimated the steady-state
Drugs 2009; 69 (8)
1114
Table I. Steady-state pharmacokinetic parameters of oral once-daily (od) atazanavir (ATV) administered alone or boosted with ritonavir
(RTV) od in healthy adult volunteers or patients (pts) with HIV-1 infection. Drugs were taken with food (adapted from the manufacturer’s
prescribing information)[13]
Regimen Cmax (ng/mL)a
[CV%]
Unboosted ATV 400 mg od
Pts with HIV-1 infection (n = 13) 2298 [71]
Healthy volunteers (n = 14) 5199 [26]
ATV 300 mg od plus RTV 100 mg od
Pts with HIV-1 infection (n = 10) 4422 [58]
Healthy volunteers (n = 28) 6129 [31]
a Geometric mean.
b n = 26.
AUC = area under the plasma concentration-time curve; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration;
CV = coefficient of variation; SD = standard deviation; t1/2 = elimination half-life; tmax = time to reach Cmax.
volume of distribution of atazanavir to be
80.8 L[52] or 88.3 L.[51] Atazanavir concentration
in seminal plasma ranged from 0.02 to 0.99 mg/L
in a study in 15 patients receiving unboosted ata-
zanavir 400 mg once daily (n = 2) or atazanavir
300 mg (n = 9) or 400 mg (n = 4) boosted with ri-
tonavir 100 mg (n = 9 and 4/group); the median
seminal : blood plasma ratio was 0.10.[55] Cerebro-
spinal fluid (CSF) concentrations of atazanavir
were highly variable in 117 patients receiving un-
boosted or boosted atazanavir 300 or 400 mg,
with a median of 7.9 (range <5 to 40) ng/mL and
10.3 (<5 to 38 ng/mL) ng/mL in the two groups.[56]
The concentrations in CSF were approximately
100-fold lower than plasma concentrations, with
median CSF : plasma ratios of 0.0112 and 0.009
with unboosted or boosted atazanavir.[56] The
CSF concentrations of atazanavir were in the
same range as the 50% inhibitory concentration
(IC50) of atazanavir against wild-type HIV
(1–11 ng/mL; IC50 measured in human serum
containing drug-binding proteins is »11 ng/mL
and the IC50 measured in the absence of protein is
1 ng/mL); 54% of CSF samples had atazanavir
concentrations <11 ng/mL and 24% had concen-
trations <5 ng/mL.[56]
3.2 Metabolism and Elimination
Atazanavir is extensively metabolized in the
liver, principally by CYP3A4 to oxygenated me-
tabolites, of which two minor, pharmacologically
ª 2009 Adis Data Information BV. All rights reserved.
Croom et al.
[CV%]


AUC (ng h/mL)a Cmin (ng/mL)a
[CV%]
Median tmax (h) Mean t1/2 (h) [SD]
14 874 [91] 120 [109] 2.0 6.5 [2.6]
28 132 [28] 159 [68] 2.5 7.9 [2.9]
46 073 [66] 636 [97] 3.0 8.6 [2.3]
57 039 [37] 1227 [53] 2.7 18.1 [6.2]b
inactive metabolites have been characterized.[13]
Elimination is mainly via the biliary route, with
only minor elimination via the kidneys; after a
single 400 mg dose, 79% was eliminated in the
faeces and 13% in the urine.[13] Unchanged drug
accounted for 20% and 7% of these quantities.[13]
Population pharmacokinetic analyses in HIV-
1-infected patients estimated the oral clearance of
atazanavir to be 7.6 L/h (boosted atazanavir[52])
and 12.9 L/h (pooled data for unboosted and
boosted; 78% of patients received boosted ataza-
navir).[51] The mean steady-state elimination half-
life (t1/2) of atazanavir in HIV-1-infected patients
was 6.5 hours for unboosted atazanavir 400 mg
and 8.6 hours for atazanavir 300 mg boosted with
ritonavir 100 mg (table I).[13] In population phar-
macokinetic analyses, the t1/2 for boosted ataza-
navir was 7.5 hours[52] and 8.8 hours.[51]
3.3 Use in Special Populations
Age and sex had no clinically significant effect
on the pharmacokinetics of atazanavir in adults.[57]
The pharmacokinetics of atazanavir have been
evaluated in HIV-1-infected paediatric patients
administered atazanavir 205 mg/m2 plus ritonavir
100 mg/m2 in the fed state.[13,58] In children
aged ‡6–13 years receiving a median dose of
atazanavir 200 mg, geometric mean values for
Cmax, Cmin and AUC were 4451 ng/mL,


535 ng/mL and 42 503 ng h/mL, respectively. In
adolescents aged ‡13–18 years receiving a median
Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
dose of 400 mg, values for these parameters were
3711 ng/mL, 1090 ng/mL and 44 970 ng h/mL
(see section 7 for dosage recommendations).[13]

metabolized by these enzymes may lead to in-
In patients with moderate to severe hepatic im-
pairment (Child-Pugh class B and C) administered
a single dose of atazanavir 400 mg, the mean AUC
increased by 42% compared with healthy volun-
teers and the t1/2 increased to 12.1 hours (vs 6.4
hours in healthy volunteers).[13] Therefore, ataza-
navir should not be administered to patients with
moderate or severe hepatic impairment, and
should be used with caution in patients with mild
to moderate impairment, as dosage adjustments
may be necessary (see section 7 for dosage re-
commendations).[13,14] In patients with HIV-1 and
hepatitis C co-infection, the extent of liver fibrosis
(measured as liver stiffness) did not affect the Cmax,
Cmin or AUC of atazanavir significantly.[59,60]
In adults with severe renal impairment (not
further specified), including those on haemo-
dialysis, receiving multiple doses of atazanavir
400 mg once daily, Cmax was reduced by 9% and
AUC and Cmin increased by 19% and 96% com-
pared with values in healthy volunteers. However,
no dosage adjustments are needed for patients
with severe renal disease not managed by haemo-
dialysis according to the US prescribing infor-
mation[13] and no dosage adjustments are required
in patients with renal impairment according to the
European summary of product characteristics.[14]
Atazanavir is not appreciably cleared during
haemodialysis. When administered during hae-
modialysis, the Cmax, Cmin and AUC of ataza-
navir were 25–43% lower than in individuals with
normal renal function, the mechanism for which
is unknown. The drug should not be administered
to treatment-experienced patients with end-stage
renal disease (ESRD) managed with haemodia-
lysis, while treatment-naive patients with ESRD
managed by haemodialysis can receive atazanavir
300 mg plus ritonavir 100 mg.[13]
3.4 Drug Interactions
Atazanavir is a substrate of CYP3A4[13,14] and
drugs that induce CYP3A4 may lead to reduced
plasma concentrations of atazanavir.[13] Ataza-
navir is an inhibitor of CYP3A and UGT1A1
ª 2009 Adis Data Information BV. All rights reserved.
1115
and coadministration of atazanavir with drugs
creased plasma concentrations of these drugs.[13]
Atazanavir is also a weak inhibitor of CYP2C8,
and unboosted atazanavir should only be co-
administered with caution with drugs depen-
dent on CYP2C8 that have a narrow therapeutic
index (e.g. repaglinide or paclitaxel).[13] Inter-
actions with CYP2C8 substrates are unlikely
with boosted atazanavir.[13] Clinically significant
drug interactions are discussed briefly in this
section; the manufacturer’s prescribing informa-
tion should be consulted for specific pharmaco-
kinetic data on drug interactions and dosage
adjustments.
Ritonavir is also a CYP3A4 inhibitor and is
used to boost the systemic exposure of atazanavir.
The magnitude of drug interactions associated
with this enzyme may be altered by coadminis-
tration of atazanavir and ritonavir, particularly
since ritonavir is an inducer of UGT1A1[61] and a
more potent inhibitor of CYP3A4 than atazana-
vir.[13,14,48] When atazanavir is boosted with rito-
navir, the prescribing information for ritonavir
should also be consulted for information on drug
interactions.
Potential interactions between unboosted or
boosted atazanavir and other HIV-1 antiviral
drugs are summarized in table II. In general,
coadministration of boosted atazanavir with
other PIs is not recommended as it would be
expected to increase the exposure to the other
PIs.[13] However, some double-boosted PI regi-
mens (i.e. two PIs plus low-dose ritonavir) have
been evaluated as possible therapeutic options in
treatment-experienced patients with limited
treatment options (e.g. because of resistance or
toxicity associated with NRTIs) and atazanavir
has been included in some of these regimens. The
combination of atazanavir plus saquinavir plus
ritonavir led to significantly (p < 0.05) increased
saquinavir plasma concentrations compared with
saquinavir/ritonavir,[81-83] but, where assessed,
did not significantly increase atazanavir concen-
trations compared with boosted atazanavir.[81]
There were no significant pharmacokinetic
interactions between atazanavir and darunavir
when administered together with ritonavir
Drugs 2009; 69 (8)
1116
boosting, compared with either boosted drug
alone.[84] Studies evaluating the pharmacokinetic
properties of the combination of atazanavir plus
lopinavir plus ritonavir produced conflicting re-
sults and additional studies are needed before
conclusions can be drawn.[85-88]
Coadministration of atazanavir with other
drugs that are highly dependent on CYP3A or
UGT1A1 for clearance is also contraindicated,
since elevated concentrations of these drugs may
be associated with serious and/or life-threatening
events.[13] These include irinotecan (UGT1A1
may be inhibited by atazanavir, thereby inhibit-
ing irinotecan metabolism and resulting in in-
creased irinotecan toxicities);[13,14] rifampicin
(a strong CYP3A4 inducer substantially [72%]
decreases plasma concentrations of atazana-
vir);[13,14] indinavir (both atazanavir and indina-
vir are UGT inhibitors and are associated with
indirect [unconjugated] hyperbilirubinaemia);[13,14]
triazolam and oral midazolam (coadministration
with atazanavir may cause large increases in the
concentration of these drugs, with the potential
for serious and/or life-threatening events);[13,14]
and quinidine in the EU,[14] caution and mon-
itoring of drug concentration are recommended
in the US when quinidine is coadministered with
atazanavir.[13]
Other drugs that are contraindicated for con-
comitant use with atazanavir are: ergot derivatives
(including dihydroergotamine and ergotamine)
[potential for serious and/or life-threatening
events]; cisapride, pimozide, lovastatin and sim-
vastatin (potential for serious reactions); and St
John’s wort (coadministration may significantly
reduce plasma concentrations of atazanavir).[13,14]
According to the European summary of product
characteristics, atazanavir should not be used with
fluticasone because of significant increase in fluti-
casone concentrations and »86% decrease in the
intrinsic cortisol levels.[14] Coadministration of
fluticasone with boosted atazanavir is not recom-
mended in the US;[13] systemic corticosteroid ef-
fects, such as Cushing’s syndrome and adrenal
suppression, have been reported in patients re-
ceiving inhaled or intranasal fluticasone with
boosted atazanavir.[13] Caution is also advised in
the US when fluticasone is coadministered with
ª 2009 Adis Data Information BV. All rights reserved.
Croom et al.
unboosted atazanavir.[13] Current US guidelines
recommend that astemizole, terfenadine and
bepridil should not be used with atazanavir[5] and
the US prescribing information recommends cau-
tion and monitoring of drug concentrations when
bepridil is coadministered with atazanavir.[13]
The solubility of atazanavir decreases as pH
increases, and plasma concentrations of atazanavir
may be reduced if it is coadministered with proton
pump inhibitors (e.g. omeprazole and lansopra-
zole), H2-receptor antagonists (e.g. famotidine),
antacids or buffered drugs.[13,89,90] Coadministra-
tion of ritonavir partially attenuates the effect.[90]
Temporal separation of drug administration can
help reduce the effect.[90] Atazanavir plus ritonavir
should be administered simultaneously with an-
d/or at least 10 hours after the dose of H2-receptor
antagonists,[13,14] and in patients unable to tolerate
ritonavir, atazanavir should be administered at
least 2 hours before and 10 hours after H2-receptor
antagonists (see local prescribing information for
full details).[13] Proton pump inhibitors are not
recommended in Europe,[14] and are not recom-
mended in treatment-experienced patients in the
US.[13] However, in the US,[13] proton-pump inhi-
bitors may be administered concomitantly with
atazanavir in treatment-naive patients and in the
EU,[14] they may be administered concomitantly in
these patients when unavoidable (local prescribing
should be consulted for full details).
Coadministration of unboosted and/or boos-
ted atazanavir with the following drugs may
increase plasma concentrations of these drugs
because of CYP3A4 inhibition, and caution and
monitoring of patients is advised as dosage re-
ductions may be required: clarithromycin (94%
increase in the exposure to clarithromycin,[5]
which may cause corrected QT [QTc] interval
prolongations[13]); ketoconazole and itraconazole
(increased concentrations of these drugs is ex-
pected);[5,13,14] voriconazole (coadministration
with ritonavir 100 mg twice daily decreased ex-
posure to voriconazole by 39%, and exposure to
ritonavir by 14%);[5,14] rifabutin (2.5-fold increase
in the exposure to rifabutin);[5] trazodone, cy-
closporin, sirolimus and tacrolimus (may in-
crease concentrations of these drugs);[13,14]
amiodarone and systemic lidocaine (lignocaine)
Drugs 2009; 69 (8)
ª 2009 Adis Data Information BV. All rights reserved.

Atazanavir in HIV-1 Infection

Table II. Drug interactions between atazanavir (ATV) or ATV boosted with ritonavir (RTV) and other HIV-1 antiviral drugs. Apart from data for amprenavir (APV) and nevirapine
(NVP) [both from HIV-1-infected patients (pts)] and darunavir (DRV) [population details not available], all data are from healthy volunteers
Concomitant Dosage ATV dosages (mg) Effect on AUC Mechanism Comment
treatment drug (mg) [with or without [ratio or %
RTV] change]
Protease inhibitors
APV[62] 1200 d ATV 400 od ATV fl [0.69a] CYP3A4 Dose administration recommendations not established
induction
FPV[63] 1400 od ATV 400 od ATV fl [33%*] Unknown Dose administration recommendations not established
FPV › [78%*]
Indinavir[13,14] Both inhibit Risk of hyperbilirubinaemia; coadministration contraindicated in US[13] and not
UGT recommended in the EU[14]
Lopinavir + RTV 400 + ATV 300 od ATV 2 Unknown Dose administration recommendations not established
100 bid
RTV[13,14] 100 od ATV 300 od ATV › [3.38a] CYP3A4 Used to boost ATV plasma concentrations
inhibition
SQV[5,13,54,64] 1600 od ATV 300 + RTV SQV › [60%] CYP3A4 Dose administration recommendations not established. In addition,
100 od inhibition SQV concentrations were higher when coadministered with ritonavir than when
coadministered with ATV[65]
DRV + RTV[5,66] 400 + ATV 300 od 2 ATV 2 DRV Unknown No dosage adjustments required for either drug
100 bid
Other antiretroviral agents
ddI buffered 200 + 40 ATV 400 (1 dose) ATV fl [0.13a] Reduced Stagger administration of ATV and ddI
tablet + d4T[13,14,67] (1 dose) solubility of
ATV
ddI EC with 400 ATV 300 + RTV ddI fl [0.66b] Unknown
food[13,14,67] (1 dose) 100 od
TDF[13,14,68-72] 300 od ATV 400 od ATV fl [0.75a] Unknown Do not coadminister with unboosted ATV; monitor pts on boosted ATV
TDF › [1.24b]
300 od ATV 300 + RTV ATV fl [0.75a]
100 od TDF › [1.37b]
EFV[13,14,73-75] 600 od ATV 400 od ATV fl [0.26a] CYP3A4 Do not coadminister with unboosted ATV. In the US, an adjusted dose of boosted
induction ATV may be coadministered with EFV in treatment-naive pts, but coadministration is not
recommended in treatment-experienced pts.[13] In the EU, coadministration with boosted
ATV is also not recommended[14]
600 od ATV 300 + RTV ATV 2 [1.0a]
100 od
Drugs 2009; 69 (8)

NVP[13,14,75,76] 200 bid ATV 400 + RTV ATV fl [0.81a] CYP3A4 Coadministration not recommended
100 od NVP › [1.26b] induction

Continued next page

1117
1118 Croom et al.

[exposure to these drugs may be increased, and

AUC = area under the concentration-time curve; bid = twice daily; CYP = cytochrome P450; d4T = stavudine; ddl = didanosine; EC = enteric-coated; EFV = efavirenz; ETR = etravirine;
FPV = fosamprenavir; MAR = maraviroc; od = once daily; RAL = raltegravir; SQV = saquinavir; TDF = tenofovir disoproxil fumarate; UGT = uridine-glucuronosyl transferase;
may produce serious and/or life-threatening
adverse events];[13,14] diltiazem (»2-fold increase
In the US, boosted ATV should not be coadministered with ETR.[77] In the EU,

in the exposure to diltiazem);[14] and verapamil,

ETR can be administered with boosted ATV without dosage adjustment[78]

sildenafil and tadalafil (may increase the ex-

posure to these drugs resulting in an increase in
associated adverse events).[13,14]
UGT inhibition by atazanavir may lead to
increased plasma concentrations of hormonal
Dose administration recommendations not established

Dose administration recommendations not established

contraceptives (concentration of ethinyl estra-

diol decreased and progestin increased with
boosted atazanavir, and exposure to ethinyl
estradiol and norethindrone increased by 48%
and 110% with unboosted atazanavir).[5]
Buprenorphine is metabolized by both CYP3A4
and UGT1A1, and plasma concentrations may
increase during coadministration with atazana-
vir.[13,14] Warfarin coadministered with boosted
atazanavir may potentially decrease or, less
often, increase international normalized ratio,[14]
and may lead to serious and/or life-threatening
Comment

bleeding events.[13]
› indicates increased; fl indicates decreased; 2 indicates no change; * p < 0.05 vs comparator.
ATV was administered for 9 days and RAL was administered as a single dose on day 7.

4. Therapeutic Efficacy
Mechanism

Unknown

Unknown

inhibition

This section reviews randomized controlled

CYP3A

trials that enrolled ‡100 patients with HIV-1

infection who were ART-naive (section 4.1)
or ART-experienced (section 4.2). Where
MAR › [3.57b]

MAR › [4.88b]
ATV fl [0.83a]

ATV fl [0.86a]

RAL › [1.72b]
Effect on AUC

ETR › [1.5b]

ETR › [1.3b]

stated, patients were generally aged ‡18 years,

[ratio or %

although some studies enrolled patients aged

change]

‡16 years.[25,26,91] In most trials, the primary

endpoint was assessed at 48 weeks, although
some studies continued assessments for up to
ATV dosages (mg)

96 weeks.[25,92-95] Where combinations of drugs

ATV 300 + RTV

ATV 300 + RTV

[with or without

are administered as a co-formulated tablet/

ATV 400 od

ATV 400 od

ATV 400 od

capsule, this will be indicated as ‘drug x/drug y’;

100 od

100 od
RTV]

when combinations are administered as separate

tablets/capsules this will be indicated as ‘drug x
plus drug y’.
Ratio of comparator : ATV.
Ratio of ATV : comparator.
Dosage

200 bid

200 bid

300 bid
100 (1
dose)
(mg)

4.1 Antiretroviral Therapy-Naive Patients

Randomized controlled trials with atazanavir

Table II. Contd

treatment drug

in ART-naive patients included two dose-ranging

Concomitant

studies using unboosted atazanavir (studies 007

ETR[77,78]

RAL[79]c

MAR[80]

and 008),[94,96] a double-blind comparison of

unboosted atazanavir with efavirenz (study
a
b
c

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
034),[91] and open-label comparisons of boosted
atazanavir with unboosted atazanavir (study
089),[92,97] boosted lopinavir (CASTLE)[98,99] or
boosted fosamprenavir (ALERT) [see table III
for definition of acronyms, where available];[100]
of these, three were noninferiority trials.[91,97,98]
The dose-ranging studies, which were blinded
to atazanavir dose, included an open-label com-
parison of atazanavir with nelfinavir.[94,96] One
of these studies[94] was followed by a 24-week
extension study.[95] All patients in these trials also
received dual-NRTI therapy.[91,92,94,96,98,100,101]
In addition, two other open-label trials com-
pared different combinations of antiretroviral
drugs: dual-NRTI therapy plus unboosted ata-
zanavir versus triple-NRTI therapy (ACTION;
noninferiority study),[101] and dual-NRTI
therapy plus unboosted atazanavir versus two
different regimens incorporating dual-NRTI
therapy plus a NNRTI (reported as an
abstract).[102] Although ART-naive patients in
study ACTG 5202 (four-arm study in patients
receiving double-blind abacavir/lamivudine or te-
nofovir DF/emtricitabine with open-label efavir-
enz or atazanavir plus ritonavir)[103] and the
ARIES (one arm study in patients receiving aba-
cavir/lamivudine with atazanavir plus ritona-
vir)[104] trials also received boosted atazanavir,
these trials are not discussed here because results
for the efficacy of the atazanavir regimens are not
available.
To be enrolled in the trials, patients generally
had to have HIV-1 RNA levels ‡2000 copies/mL
and CD4+ cell counts ‡100 cells/mm3 (or ‡75
cells/mm3 in the absence of an AIDS-defining
illness),[91,94,96] or HIV-1 RNA levels of ‡2000
copies/mL[92] or ‡5000 copies/mL[98] with no
CD4+ cell count restrictions. In most studies,
patients were considered to be ART-naive if they
had received £4 weeks therapy with an NRTI and
£1 week with an NNRTI or PI,[91,92,94,96] but
some studies used a definition of <1 week[98] or
<2 weeks[100] of ART therapy.
The primary endpoint was antiretroviral effi-
cacy, as assessed by the change in plasma viral
load (HIV-1 RNA level; log10 copies/mL) from
baseline[94,96] or the proportion of patients with
HIV-1 RNA <400 copies/mL[91,92] or <50 copies/
ª 2009 Adis Data Information BV. All rights reserved.
1119
mL[98,100,101] at endpoint. One trial evaluated
time to treatment failure or death.[102]
4.1.1 Unboosted Atazanavir
Dose-ranging studies in ART-naive patients
found that the mean change in viral load after 48
weeks of treatment was similar across the differ-
ent atazanavir dosages evaluated (200, 400 and
500 mg once daily,[96] and 400 or 600 mg once
daily[94]).
Based on these studies and a phase III trial
(study 034, a noninferiority trial), the efficacy
of unboosted atazanavir 400 mg once daily was
similar to that of unboosted nelfinavir 750 mg
three times daily[96] or 1250 mg twice daily[94] and
was noninferior to that of the NNRTI efavirenz
600 mg once daily[91] (all administered in combi-
nation with dual NRTI therapy) in terms of mean
reduction in viral load, the proportion of patients
achieving a viral load below the limit of quanti-
fication, and mean increase in CD4+ cell count
(table III). In the comparison with efavirenz,
the time-averaged difference between groups in
the change in CD4+ cell count reached statistical
significance in favour of atazanavir (p < 0.001);
however, it did not meet the predefined crite-
rion for clinical significance (a difference of
50 cells/mL).[91]
Reductions in viral load of approximately 2.5
log10 copies/mL were achieved by week 12,[91]
16[96] or 24[94] and sustained for the remainder of
the 48-week study period. The proportion of
patients whose viral load was reduced to <400
copies/mL after 48 weeks was 64–70% with ata-
zanavir and 53–64% with comparators (table III).
Using a lower limit of quantification of 50 copies/
mL, these percentages were 32–36% with ataza-
navir and 34–39% with comparators
(table III).[91,94,96] Viral suppression with un-
boosted atazanavir continued in the longer term,
based on a 24-week extension study[95] that fol-
lowed one of the dose-ranging studies.[94] At the
end of the extension phase, 83% of patients trea-
ted with atazanavir 400 mg once daily throughout
both studies had a viral load of <400 copies/mL
(compared with 76% at the end of the original
48-week study).[95] Patients treated with nelfinavir
in the original study were switched to atazanavir
Drugs 2009; 69 (8)
1120 Croom et al.

Table III. Efficacy of oral atazanavir (ATV) in the treatment of antiretroviral-naive adult patients (pts) aged ‡16 y with HIV-1 infection. Sum-
mary of randomized, double-blind[91] or open-label[92,94,96,98,100] 48-wk trials (three were noninferiority trials[91,92,98]) comparing unboosted with
ritonavir (RTV), boosted ATV, or ATV (unboosted or boosted) with other protease inhibitors (unboosted or boosted) or non-nucleoside reverse
transcriptase inhibitors. Pts also received dual nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) therapy
Study Treatment regimen No. of Median plasma viral Mean increase in CD4+ Pts with plasma viral load <LOQ
(mg) pts load (log10 copies/mL) cell count (cells/mL) (%) [ITT]
baseline change at baseline change at <50 copies/mL <400 copies/mL
study end study end
[OT] [OT]
Unboosted vs boosted ATV
Malan et al.[92] ATV 400 oda 105 5.1 194 213 70b 85b
b
(study 089) ATV 300 od + RTV 95 4.8 201 174 75 86b
100a

Unboosted ATV vs comparators

Murphy et al.[94] ATV 400 181 4.74e -2.51f 294 234 35 64
(study 008)c od + 3TC + d4Td
NFV 1250 91 4.73e -2.31f 283 211 34 53
bid + 3TC + d4Td
Sanne et al.[96] ATV 400 103 4.60e -2.42f 357 221 36 64
(study 007)c od + ddI + d4Tg
NFV 750 103 4.81e -2.33f 341 185 39 56
tid + ddI + d4Tg
Squires et al.[91] ATV 400 404 4.87 -2.7 286i 176*i,j 32 70f,b
(study 034) od + AZT/3TCh
EFV 600 401 4.91 -2.7 280i 160i 37 64f,b
od + AZT/3TCh

Boosted ATV vs comparators

Molina et al.[98] ATV 300 od + RTV 440 5.01l 205i 203 78f,b
(CASTLE) 100 od + TDF/FTCk
LPV/RTV 400/100 443 4.96l 204i 219 76f,b
bid + TDF/FTCk
Smith et al.[100] ATV 300 + RTV 100 53 4.89l 188 183 83f 87
(ALERT) od + TDF/FTCk
FPV 1400 od + RTV 53 4.92l 161 170 75f 79
100 od + TDF/FTCk
a NRTI dosages were 3TC 300 mg od and an investigational extended-release formulation of d4T od (dosage depending on weight; not
commercially available).
b Noninferiority was indicated if the lower limit of the 95% confidence interval (CI) for the difference between treatment groups (boosted ATV –
unboosted ATV, atazanavir – efavirenz or atazanavir plus ritonavir – lopinavir/ritonavir) in the proportion of patients with HIV-1 RNA levels
<50[92,98] or <400[91,92] copies/mL exceeded -10%. The difference estimates for HIV-1 RNA loads of <50 copies/mL were 5.0% [95% CI
-7.0, 17.0][92] and 1.7% [95% CI -3.8, 7.1],[98] and for HIV-1 RNA loads <400 copies/mL were 1.5% [95% CI -8.2, 11.1][92] and 5.2% [95% CI
-1.2, 11.7].[91]
c Dose-ranging study; however, only data for the US-approved dosage for unboosted ATV (400 mg) are shown.
d NRTI dosages were 3TC 150 mg bid and d4T 30 or 40 mg bid (depending on weight).
e Mean value.
f Primary endpoint.
g NRTI dosages were ddI 250 or 400 mg and d4T 30 or 40 mg bid (depending on weight).
h NRTI dosage was AZT/3TC 300/150 bid (fixed-dose combination tablet). Continued next page

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection 1121

Table III. Contd.

i Median value.
j The time-averaged difference between groups reached statistical significance, but did not meet the predefined criterion for clinical
significance (a difference of 50 cells/mL).
k NRTI dosage was TDF/FTC 300 mg/200 mg od (fixed-dose combination tablet).
l It was reported that there was no difference between the groups for reduction in viral load at week 48, but specific data were not reported.
3TC = lamivudine; ALERT = Atazanavir or LEXIVA with Ritonavir and Truvada (study COL103952); AZT = zidovudine; bid = twice daily;
CASTLE = study 138 (acronym not defined); d4T = stavudine; ddI = didanosine; EFV = efavirenz; FTC = emtricitabine; ITT = intent to treat;
LOQ = limit of quantification; LPV = lopinavir; NFV = nelfinavir; od = once daily; OT = on-treatment; TDF = tenofovir disoproxil fumarate;
tid = three times daily. * p < 0.001 vs comparator.

400 mg once daily for the extension phase, at the
end of which 87% achieved a viral load <400
copies/mL (compared with 63% at the end of nel-
finavir treatment).[95]
Two open-label studies, of which one
(ACTION)[101] was a noninferiority trial, have
evaluated different combinations of anti-
retroviral drugs incorporating unboosted ataza-
navir.[101,102] In ACTION, which involved 279
ART-naive patients, atazanavir 400 mg once
daily plus dual-NRTI therapy (zidovudine/
lamivudine twice daily) regimen was noninferior
to triple-NRTI therapy (abacavir/lamivudine/
zidovudine twice daily) in terms of the proportion
of patients achieving viral load <50 copies/mL
after 48 weeks (59% vs 62%). Noniferiority
was established as the lower limit of the
95% confidence interval (-5.9, 10.4) for the dif-
ference in proportions between the triple-NRTI
group and atazanavir 400 mg once daily plus
dual-NRTI group was more than -12%.[101]
In the other study (presented as an abstract),
the relative hazard of a combination of viro-
logical failure, disease progression or death was
1.67 (99.8% CI 1.02, 2.75) for dual-NRTI therapy
(didanosine plus emtricitabine) plus unboosted
atazanavir (all once daily) compared with dual
NRTI therapy plus an NNRTI (zidovudi-
ne/lamivudine twice daily plus efavirenz once
daily).[102]
4.1.2 Ritonavir-Boosted Atazanavir
Once-daily atazanavir 300 mg boosted with ri-
tonavir 100 mg was noninferior to unboosted ata-
zanavir 400 mg in an open-label, noninferiority
trial (study 089) in which both regimens were
administered with lamivudine and stavudine in
ART-naive patients.[92] After 48 weeks, the pro-
portion of patients with a viral load <400
copies/mL (primary endpoint) was 86% with
atazanavir plus ritonavir and 85% with un-
boosted atazanavir, meeting the criteria for non-
inferiority (table III). There was no difference in
outcome between the groups when patients were
stratified by baseline viral load; however, in both
groups, the response rate was higher among pa-
tients with a baseline HIV-1 RNA level
<100 000 copies/mL than among those with a
higher viral load.[92] Efficacy was sustained in the
longer term, such that after 96 weeks ‡70% of
patients in both groups had <400 copies/mL
(reported in an abstract).[97] By this timepoint,
virological failure (not defined further) had oc-
curred in 5 recipients of atazanavir plus riton-
avir compared with 20 recipients of unboosted
atazanavir.[97]
A noninferiority study (CASTLE), in which
all patients received backbone dual-NRTI
therapy (tenofovir DF/emtricitabine), showed
that the virological efficacy of once daily ataza-
navir 300 mg plus ritonavir 100 mg in ART-naive
patients was noninferior to that of lopina-
vir/ritonavir 400 mg/100 mg twice daily,[98] as
assessed by the proportion of patients with a viral
load <50 copies/mL after 48 weeks of treatment
(table III).[100] The outcome was similar when
immunological response (change in CD4+ cell
count) was considered (table III). In addition,
virological failure occurred in a similar number
of patients in both treatment groups (6% in both
the atazanavir plus ritonavir and the lopinavir/
ritonavir groups).[98]

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
1122
When patients in CASTLE were stratified
according to the baseline HIV-1 RNA levels
(prespecified analysis), a decrease in virological
response with increasing baseline HIV-1 RNA
levels was observed in both atazanavir plus rito-
navir and lopinavir plus ritonavir treatment
groups (abstract plus poster presentation).[105]
Response rates in patients with baseline HIV-1
RNA levels of <100 000, 100 000 to <500 000 and
‡500 000 copies/mL were 83%, 76% and 64%, re-
spectively, in the atazanavir plus ritonavir group,
compared with 80%, 74% and 61%, respectively,
in the lopinavir plus ritonavir group (intent-
to-treat [ITT] analysis; no statistical data avail-
able). In another prespecifed subgroup analysis
in which patients were stratified into four groups
according to baseline CD+ cell counts (<50, 50 to
<100, 100 to <200 and ‡200 cells/mL), consistent
virological response rates were observed with
atazanavir plus ritonavir across the groups (78%,
76%, 75% and 80%, respectively). However, in
the lopinavir plus ritonavir group lower baseline
CD4+ cell counts were associated with lower
(p = 0.085) response rates (63%, 69%, 78% and
80% for baseline cell counts of <50, 50 to <100,
100 to <200 and ‡200 cells/mL, respectively; ITT
analysis).[14,105] In addition, in patients with
baseline CD4+ count of <100 cells/mL and HIV-1
RNA level of ‡100 000 copies/mL, 72% of ataza-
navir plus ritonavir recipients versus 63% of lo-
pinavir plus ritonavir recipients achieved HIV-1
RNA levels of <50 copies/mL (ITT analysis).[105]
The virological efficacy of atazanavir plus ri-
tonavir remained noninferior to that of lopina-
vir/ritonavir until week 96 in the CASTLE trial,
with the between-group difference estimate of
6.1% (95% CI 0.3, 12.0) in the proportion of pa-
tients with a viral load <50 copies/mL meeting the
predefined criterion of noninferiority (lower limit
of the 95% confidence interval exceeded -10%)
[reported in an abstract].[99] Response rates (74%
vs 68%) in the ITT population were significantly
(p < 0.05) higher with atazanavir plus ritonavir
than lopinavir/ritonavir, largely owing to fewer
discontinutations (16% vs 21%) with the former
than latter treatment; response rates in the ob-
served-case population were 89% and 88% in the
two treatment groups. Virological failure in both
ª 2009 Adis Data Information BV. All rights reserved.
Croom et al.
treatment groups was low (7%) and the mean
change from baseline in the CD4+ cells with
atazanavir plus ritonavir was not significantly
different from that with lopinavir/ritonavir
(268 vs 290 cells/mm3).[99]
In a pilot open-label study (ALERT) in which
patients received backbone dual-NRTI therapy
(tenofovir DF/emtricitabine), the virological effi-
cacy of once daily atazanavir 300 mg plus ritonavir
100 mg in ART-naive patients was similar to that of
once-daily fosamprenavir 1400 mg plus ritonavir
100 mg after 48 weeks of treatment, as assessed by
the proportion of patients with a viral load
<50 copies/mL (table III).[100] A similar outcome
was observed when the immunological response
to therapy (change in CD4+ cell count) was con-
sidered (table III). In addition, virological failure
occurred in a similar number of patients in both
treatment groups (3 of 53 [6%] patients treated
with boosted atazanavir vs 4 of 53 [8%] patients
treated with fosamprenavir plus ritonavir). It
should be noted that no power calculations were
made to determine the sample size for this study
and it may be underpowered to detect differences
between the two treatment groups.[100]
4.2 Antiretroviral
Therapy-Experienced Patients
Randomized controlled trials of atazanavir in
ART-experienced patients with a history of vir-
ological failure (on PI-containing regimens)
included open-label comparisons of boosted ata-
zanavir versus boosted lopinavir versus atazana-
vir plus saquinavir (study 045, a noninferioirity
study),[25,93] and of unboosted atazanavir versus
boosted lopinavir (study 043, a superiority
study).[26] It should be noted that unboosted
atazanavir is not approved for use in ART-
experienced patients;[13] study 043 is included
here because it provides background evidence for
this labelling decision.
In addition, several open-label trials in ART-
experienced patients who had prolonged viro-
logical suppression on a PI-containing regimen
(SWAN,[106] SLOAT[107] and ATAZIP[108] stu-
dies) compared switching to atazanavir (boos-
ted[108] or unboosted[106,107]) versus continuing on
Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
their current PI (boosted[106-108] or unboosted[106])
[see table V for definition of study acronyms,
where available]. Two of these trials (SWAN[106]
and ATAZIP[108]) were noninferiority studies.
For enrolment into studies 043 and 045, pa-
tients had to have not responded to treatment
with at least one[26] or at least two[25] PI-
containing ART regimens (but have a history of
response to at least one ART regimen in the past),
and have a plasma HIV-1 RNA viral load
‡1000 copies/mL and a CD4+ count ‡50 cells/
mm3.[25,26] Patients were excluded from these
studies if they had prior exposure to the medica-
tions being evaluated (up to 30 days exposure was
allowed in study 045[25]),[25,26] or if they had >10-
fold phenotypic resistance to study medications
at baseline (study 043).[26] The primary endpoint
in both trials was the mean change in viral load at
week 48.[25,26] Study 045 was amended (prior to
the week 48 analysis) to allow for continued
evaluation up to 96 weeks.[93]
For the ‘switch’ studies, patients had to have
virological suppression (defined as <50[106,107]
or <200 copies/mL[108] for ‡3[106] or ‡6[107,108]
months) receiving a PI-containing regimen. For
SWAN, this could be any PI with or with-
out ritonavir,[106] whereas in SLOAT and
ATAZIP, patients had to be receiving lopinavir/
ritonavir.[107,108] Patients with a history of vir-
ological failure during PI-based ART therapy
were excluded from SWAN[106] and SLOAT,[107]
whereas in ATAZIP patients with more than two
virological failures were excluded.[108] The pri-
mary endpoint in these trials was virological
failure (defined as HIV-1 RNA load ‡50
copies/mL)[106,107] or treatment failure (defined as
HIV-1 RNA load ‡200 copies/mL in two conse-
cutive determinations at least 2 weeks apart)[108]
at 48 weeks, although ATAZIP continued for a
total of 96 weeks.[108]
4.2.1 Patients with Past Virological Failure
When administered in combination with dual
NRTI therapy, the virological efficacy (measured
as decrease in viral load) of atazanavir 300 mg
plus ritonavir 100 mg once daily was found to
be noninferior to that of lopinavir/ritonavir
400 mg/100 mg twice daily in ART-experienced
ª 2009 Adis Data Information BV. All rights reserved.
1123
patients with a history of virological failure in
study 045 [table IV].[25] An extension of the trial
to 96 weeks demonstrated that the viral suppres-
sion was sustained in the longer term (figure 1),
with the time-averaged difference in reduction
of HIV-1 RNA of 0.14 log10 copies/mL (97.5%
CI -0.13, 0.41) at this timepoint meeting the
predefined criterion for noninferiority (upper
CI limit <0.5 log10 copies/mL).[93] This outcome
was supported by secondary endpoints at
96 weeks: the proportions of patients with <400
or <50 copies/mL were 44% and 33% with boos-
ted atazanavir versus 46% and 36% with lopina-
vir/ritonavir, and CD4+ counts increased by a
median of 160 and 142 cells/mL, respectively.[93]
In this study, noninferiority of atazanavir
coadministered with saquinavir was not esta-
blished compared with lopinavir/ritonavir
(table IV) and this arm was discontinued at
48 weeks.[93]
In another trial (study 043), a regimen including
unboosted atazanavir provided less viral suppres-
sion than a regimen containing lopinavir/ritonavir
(table IV).[26] Secondary endpoints, including the
proportion of patients with viral load below the
limit of quantification, and increases in CD4+
cell count, also favoured lopinavir/ritonavir
(table IV).[26] Consequently, unboosted atazanavir
is not approved for use in ART-experienced
patients.[13]
4.2.2 Patients with Prolonged
Virological Suppression
In patients who had virological suppression
while receiving a stable PI-based ART regimen, a
switch to atazanavir-based regimens was non-
inferior[106,108] or similar[107] to original regimens
in maintaining suppression, regardless of whether
patients did[107,108] or did not[106] have a history of
virological failure on past PI-based regimens
(table V).
Two studies (SLOAT[107] and ATAZIP[108])
allowed patients with a history of virological
failure on past PI-based regimens to be enrolled.
For example, almost half of the SLOAT popu-
lation had in the past received PIs other than lo-
pinavir/ritonavir, and two-thirds of these patients
had experienced virological failure.[107] ATAZIP
Drugs 2009; 69 (8)
1124 Croom et al.

Table IV. Efficacy of oral atazanavir (ATV) in the treatment of antiretroviral therapy (ART)-experienced adult patients (pts) aged ‡16 y with
HIV-1 infection and a history of virological failure on protease inhibitor-containing ART. Summary of randomized, open-label, noninferiority[25]
or superiority,[26] 48-wk trials comparing ATV (unboosted or ritonavir-boosted) with lopinavir/ritonavir (LPV/RTV) is presented. Pts also
received dual nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) therapy
Study Treatment regimen (mg) No. of pts Mean plasma viral load Mean increase in CD4+ Pts with plasma viral load
(log10 copies/mL) cell count (cells/mL) <LOQ (%) [ITT]
baseline change at baseline change at <50 copies/ <400 copies/
study end study end mL mL
[ITT] [ITT]
Unboosted ATV
Cohen et al.[26] ATV 400 od + two NRTIa 150 4.18 -1.59b,c 288 112 37 48
(study 043)
LPV/RTV 400/100 150 4.25 -2.02**b,c,d 256 169*d 53d 68d
bid + two NRTIa
Boosted ATV
Johnson et ATV 300 od + RTV 100 120 4.44 -1.93b,f 317 110f 38g 56g
al.[25] (study od + TDF 300 od + NRTIe
045)
ATV 400 od + SQV 1200 115 4.42 -1.55b,h 286 72 26 38
od + TDF 300 od + NRTIe
LPV/RTV 400/100 123 4.47 -1.87b 283 121 46 58
bid + TDF 300
od + NRTIe
a AZT plus 3TC, d4T plus 3TC, AZT plus ddI, d4T plus ddI, or ABC plus either ddI, d4T or 3TC (dosages not stated). TDF was excluded
throughout the study because it was not approved for use at study start.
b Primary endpoint.
c Based on observed values.
d TAD estimate for change in viral load (ATV – LPV/RTV) was 0.38 log10 copies/mL (97.5% CI 0.16, 0.60; p < 0.001) and for change in CD4+
count was -35.7 cells/mm3 (95% CI -58.9, -12.6; p = 0.0025). Superiority criterion was not met, where superiority was indicated if the upper
limit of the 97.5% CI for the difference between treatment groups (atazanavir – lopinavir/ritonavir) in the change from baseline in HIV-1 RNA
levels (log10 copies/mL) was <0. The differences in % of pts with viral load <400 and <50 copies/mL (for ATV – LPV/RTV) were -20.2 (95%
CI -31.5, -8.9) and -16.0 (95% CI -27.4, -4.5).
e Pts were switched from their previous NRTI therapy to TDF plus one of the following at study week 2: ddI 400 mg od, d4T 40 mg bid, ABC
300 mg bid, AZT 300 mg bid or 3TC 150 mg bid.
f TAD estimate for change in viral load (ATV – LPV/RTV) was 0.13 log10 copies/mL (97.5% CI -0.12, 0.39), meeting the predefined criterion
for noninferiority (upper limit of the 97.5% CI <0.5 log10 copies/mL). The TAD estimate for change in CD4+ count (vs LPV/RTV) was -17.5
cells/mL (95% CI -45.6, 10.6).
g The difference estimate (ATV/RTV vs LPV/RTV) for viral load <400 copies/mL was -1.9 (95% CI -14.3, 10.6) and for <50 copies/mL was
-8.0 (95% CI -20.4, 4.4).
h TAD estimate for change in viral load (for ATV + SQV – LPV/RTV) was (0.33 log10 copies/mL (97.5% CI 0.07, 0.60), which did not meet the
criterion for noninferiority versus LPV/RTV as defined in footnote f. TAD estimate for change in CD4+ count was -47.6 cells/mL (95% CI
-79.2, -16.1).
3TC = lamivudine; ABC = abacavir; AZT = zidovudine; bid = twice daily; d4T = stavudine; ddI = didanosine; ITT = intent to treat; LOQ = limit of
quantification; od = once daily; SQV = saquinavir; TAD = time-averaged difference; TDF = tenofovir disoproxil fumarate. * p = 0.0025,
**
p < 0.001 vs comparator.

evaluated boosted atazanavir only,[108] while in
SLOAT, approximately half of the atazanavir
group received boosted, and half unboosted,
atazanavir.[107]
In SLOAT, the efficacy of atazanavir-based
regimens was similar to that of lopinavir/
ritonavir[107] (table V). The rate of virological
failure was 11.7% with atazanavir-based therapy
compared with 10.3% with lopinavir/ritonavir
(table V).[107] Statistical results were not reported
for this study; however, it was stated that the
virological failure rates for the two groups were

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
ATV+RTV LPV/RTV
0
Mean change from baseline in HIV-1 RNA
−0.5
−1.0
(log10 copies/mL)
−1.5
−2.0
−2.08
−2.5 −2.29
−3.0
Fig. 1. Efficacy of ritonavir-boosted atazanavir (ATV + RTV) in pa-
tients (pts) with multiple virological failures. Data from a 96-wk, ran-
domized, open-label, noninferiority trial comparing once-daily ATV
300 mg plus RTV 100 mg with twice-daily lopinavir/RTV (LPV/RTV)
400 mg/100 mg in pts with a history of virological failure on more than
one previous antiretroviral therapy regimens.[93] All pts also received
tenofovir disoproxil fumarate 300 mg once daily and one other nu-
cleoside reverse transcriptase inhibitor. Mean change from baseline
in plasma HIV-1 RNA (primary endpoint) is shown. The time-aver-
aged difference of 0.14 log10 copies/mL (97.5% CI -0.13, 0.41) met
the predefined criterion for noninferiority (upper CI limit <0.5 log10
copies/mL).
similar. Among the virological failures in the
atazanavir group, five were receiving unboosted
and seven boosted atazanavir; five of these pa-
tients had primary resistance mutations and all
had failed on other PIs in the past. One of the
nine virological failures in the lopinavir/ritonavir
group had a protease resistance mutation.[107]
In ATAZIP, the efficacy of atazanavir plus
ritonavir was noninferior to that of lopinavir/
ritonavir.[108] The difference between atazanavir
plus ritonavir and lopinavir/ritonavir for the rate
of treatment failure (primary endpoint) was
-3.1% (95% CI -13.6, 8) and for the rate of vir-
ological failure was -1.3% (95% CI -7.7, 4.8)
[table V].[108] Among the subgroup of patients at
high risk of failure (at least one previous PI fail-
ure or history of at least three prior PI resistance
mutations) treatment and virological failure rates
were 18% and 11% in the atazanavir plus ritona-
vir group compared with 18% and 13% in the
lopinavir/ritonavir group.[109]
In the SWAN noninferiority study, which ex-
cluded patients who had a history of virological
ª 2009 Adis Data Information BV. All rights reserved.
1125
failure on previous PI-based regimens, switching to
atazanavir 400 mg once daily (or boosted atazana-
vir in the 9% of patients who were also receiving
tenofovir DF) significantly reduced the rate of vir-
ological failure (table V) and increased the time to
virological failure (hazard ratio 0.42; 95% CI 0.22,
0.79; p = 0.007) compared with patients who con-
tinued on their original boosted or unboosted
PI-based regimen[106] A post hoc analysis showed
that atazanavir was also associated with a signi-
ficant reduction in the rate of treatment failure
(table V) and an increase in the time to treatment
failure (hazard ratio 0.59; 95% CI 0.40, 0.87,
p = 0.008).[106]
5. Tolerability
5.1 General Profile
Most tolerability and safety data for atazanavir
come from clinical trials in which it was adminis-
tered in combination with NRTI therapy. Accord-
ing to pooled data (available from the European
summary of product characteristics) from controlled
clinical trials in 1806 patients treated with atazanavir
400 mg once daily (n = 1151) or atazanavir 300 mg
plus ritonavir 100 mg once daily (n = 655) in clinical
trials, the most common adverse events were nausea
(20%), jaundice (12%) and diarrhoea (10%).[14]
Other adverse events reported commonly (incidence
‡1% but <10%) included ocular icterus, lipodystro-
phy syndrome, rash, vomiting, abdominal pain,
dyspepsia, headache and fatigue.[14]
Rash of any severity occurred in »20% of pa-
tients receiving atazanavir in clinical trials.[13]
Rashes were generally mild to moderate maculo-
papular skin eruptions, with a median time to
onset of 7.1 weeks and a median duration of 1.3
weeks.[13] In four clinical trials in treatment-naive
patients,[91,94,96,98] treatment-emergent rash of
moderate to severe intensity was reported in 5–7%
of atazanavir (vs 1–10% of patients receiving
comparators) and 3% of boosted atazanavir
(vs 2% of patients receiving lopinavir/ritonavir)
recipients.[13] Rash-related discontinuation
rates were <1% in clinical trials; there have been
reports of Stevens-Johnson syndrome, erythema
Drugs 2009; 69 (8)
1126 Croom et al.

Table V. Efficacy of oral atazanavir (ATV) in the treatment of antiretroviral therapy (ART)-experienced HIV-1-infected adult patients (pts)
aged ‡18 y with virological suppression. Summary of open-label 48-wk, trials (two of which were noninferiority studies[106,108]) in which pts
receiving a stable protease inhibitor (PI)-based ART regimen (any PI with or without ritonavir [RTV][106] or lopinavir/RTV [LPV/RTV][107,108])
were randomized to switch to an ATV-based regimen (unboosted[106,107] or RTV-boosted[107,108]) or to remain on their current regimen. Pts
continued receiving nucleoside/nucleotide (NRTI) backbone therapy. Analyses were performed on an intent-to-treat basis
Study Treatment regimen No. of Baseline values (median) Pts (%) with Median
(mg) pts plasma viral load CD4+ cell count virological treatment increase in CD4+ cell
(log10 copies/mL) (cells/mm3) failure failure (%)a count (cells/mm3)
Gatell et al.[106] ATV 400 odb 278 1.69 490 7*c,d 21* 47e
f c,d
(SWAN) PI or PI/RTV 141 1.69 489 16 34 48e
g *c *h,d
Mallolas ATV + RTV 121 5 17 27
et al.[108]
(ATAZIP)i LPV/RTVg 127 7c 20d 48
[107]
Soriano et al. ATV 400 od or ATV 102 403 11.7 46
(SLOAT) 300 + RTV 100j
LPV/RTVk 87 548 10.3 42
a Where stated, defined as virological failure, study therapy not initiated or study therapy discontinued.[106]
b Pts receiving TDF as part of their NRTI backbone therapy received ATV 300 mg boosted with RTV 100 mg; this affected 26 pts (9%) in the
ATV group.
c HIV-1 RNA load ‡50 copies/mL[106,107] or two consecutive loads >200 copies/mL.[108] Noninferiority of the ATV-based regimen vs the
comparator regimens was indicated if the upper limit of the 95% CI of estimated difference between the treatment groups was <12%; the
difference estimate between the two regimens was -8.8% (95% CI -14.8, -2.7).
d Primary endpoint.
e Mean.
f Pts in the comparator group could receive any unboosted or boosted PI (except ATV); 46% received unboosted NFV, IDV, or SQV and 54%
received LPV/RTV, IDV/RTV or SQV/RTV.
g Doses not stated.
h Noninferiority of the ATV-based regimen versus the comparator regimens was indicated if the upper limit of the 95% CI of estimated
difference between the treatment groups was <12.5%; the difference estimate the two regimens was -2.3% (95% CI -12.0, 8.0).
i Study acronym not defined.
j Pts receiving TDF as part of their NRTI backbone therapy received ATV 300 mg boosted with RTV 100 mg; 49 pts (48%) received ATV
400 mg od and 53 pts (52%) received ATV 300 mg plus RTV 100 mg.
k Dose not stated.
IDV = indinavir; NFV = nelfinavir; od = once daily; SLOAT = Simplification LOpinavir to ATazanavir; SQV = saquinavir; SWAN = Switch to
Another Protease Inhibitor (study 097); TDF = tenofovir disoproxil fumarate; * p < 0.005 vs comparator.

multiforme and toxic skin eruptions in atazanavir
recipients.[13]
The most common laboratory abnormality
was elevated total bilirubin, which occurred in
84% of patients, mostly as elevated indirect (un-
conjugated) bilirubin, thought to relate to in-
hibition of the UGT1A1 enzyme.[14] Grade 3 or 4
elevations of bilirubin occurred in 35% of pa-
tients.[14] However, grade 3 or 4 elevations in
ALT and AST occurred in only 4% and 3%
of patients, respectively. Other grade 3 or 4
laboratory abnormalities occurring in ‡2% of
patients included elevated creatine kinase (7%),
low neutrophil count (4%) and elevated lipase
level (2%).[14]
The tolerability profile was generally similar
between unboosted and boosted atazanavir, with
the exception that jaundice and elevated total
bilirubin were more common with boosted ata-
zanavir (no statistical data reported).[14,92]
Treatment-related grade 2–4 jaundice was re-
ported in 3% of patients receiving boosted ata-
zanavir and <1% of patients receiving unboosted
therapy.[92]

ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
In clinical trials of ART-naive or -experienced
patients, where reported, the overall incidence of
adverse events and the proportion of patients
who discontinued treatment because of adverse
events were generally similar for atazanavir and
comparator regimens.[25,26,91,94,96,98,106] Jaundice
was generally more common with atazanavir
than with comparators; grade 2–4 jaundi-
ce/scleral icterus occurred in 3–9% of recipients of
atazanavir-based regimens but was not reported
with comparators including nelfinavir, lopinavir/
ritonavir, fosamprenavir/ritonavir and efavir-
enz.[13,25,26,91,94,96,98,100] Elevated bilirubin levels
were also generally more common with atazana-
vir than with comparators.[25,26,91,94,96,100] For
example, grade 3–4 elevations of bilirubin
(‡2.6 the upper limit of normal) occurred in 34%[98]
and 49%[25] of patients treated with atazanavir plus
ritonavir compared with <1% of recipients of
lopinavir/ritonavir. In contrast, diarrhoea was gen-
erally less frequent with boosted or unboosted ata-
zanavir than with nelfinavir, lopinavir/ritonavir
or fosamprenavir/ritonavir.[13,25,26,94,96,98,100] For
example, grade 2–4 diarrhoea was reported for
3%[25] and 5%[98] of recipients of atazanavir plus
ritonavir compared with 11%[25] and 15%[98] of
lopinavir/ritonavir recipients. Rash and dizziness
were less frequent with atazanavir than with efa-
virenz (p < 0.05).[91]
Viral hepatitis co-infection is common among
patients with HIV-1 infection.[110] In clinical
trials of atazanavir, there was no difference in the
incidence of elevated bilirubin levels between
patients with or without chronic hepatitis B or C
co-infection.[14,111] Among patients with co-infec-
tion, the incidence of treatment-emergent hepatitis
or elevated transaminases was similar among
recipients of atazanavir or comparators.[14] How-
ever, in CASTLE the incidence of grade 2–4
treatment-related hyperbilirubinaemia (15% vs
0%) and jaundice (3% vs 0%) was generally higher
in patients receiving atazanavir plus ritonavir than
those receiving lopinavir/ritonavir in patients with
HIV-1 infection and chronic hepatitis B or C co-
infection. Generally, more atazanavir plus ritona-
vir than lopinavir/ritonavir recipients experienced
grade 3–4 elevations in ALT (8% vs 6%), AST (8%
vs 0%) and total bilirubin (38% vs 0%) in patients
ª 2009 Adis Data Information BV. All rights reserved.
1127
with HIV-1 infection and chronic hepatitis B or C
co-infection.[112] In study 045, elevated transami-
nases were more common in patients with a history
of hepatitic B or C than in those who had HIV-1
infection alone (data not available).[25] Another
trial in 72 patients co-infected with hepatitis C
and HIV-1 showed a significant (p = 0.003) in-
crease in serum bilirubin levels with atazanavir
regimens than comparator regimens 4 weeks after
the initiation of hepatitis therapy (pegylated-
interferon and ribavirin) [median increase 0.80 vs
0.15 mg/dL].[113] In addition, in the atazanavir
treatment group, the proportion of patients with
hyperbilirubinaemia grade 3–4 increased 2.5-fold
(from 9% [2/22] to 45% [10/22]; p = 0.021) after
beginning hepatitis therapy; none of the patients
receiving comparator regimens developed hyper-
bilirubinaemia grade 3–4.[113] In another study,
the degree of hepatic fibrosis present in patients
co-infected with viral hepatitis did not affect the
risk of severe adverse events during atazanavir
treatment.[110]
Among less common adverse events, atazana-
vir may cause prolongation of the PR interval in
some patients.[13,114] Atazanavir treatment in
healthy volunteers and patients was also asso-
ciated with atrioventricular (AV) conduction
abnormalities, which were asymptomatic and
generally limited to first-degree AV block.[13] In
clinical trials that included ECG evaluations, the
incidence of asymptomatic first-degree AV block
in patients treated with atazanavir was 5.9%,
compared with 5.2% among recipients of lopina-
vir/ritonavir, 10.4% with nelfinavir and 3.0% with
efavirenz.[13] However, there have been reports of
second- and third-degree AV block, and other
conduction abnormalities (left-bundle branch
block and QTc interval prolongation) during
postmarketing experience.[13]
5.2 Metabolic Profile
Some PIs are associated with metabolic effects
including alteration of lipid levels, lipodystrophy
and insulin resistance.[115,116] However, generally,
in randomized comparative clinical trials (dis-
cussed in section 4), the magnitude of lipid level
changes with atazanavir were less than with other
Drugs 2009; 69 (8)
1128
PIs, effects on body fat composition were similar
to those seen with other ART drugs, and ataza-
navir was not associated with adverse effects on
glucose or insulin levels.
After 48 weeks’ treatment, unboosted ataza-
navir was associated with generally smaller in-
creases (or a reduction) in total cholesterol, LDL-
C and triglyceride levels compared with nelfina-
vir, lopinavir/ritonavir or efavirenz (table VI).
However, the increase in high-density lipopro-
tein-cholesterol (HDL-C) level seen with ataza-
navir was lower than with efavirenz (table VI).[91]
At baseline in the comparison with nelfinavir,
79–83% of patients had total cholesterol levels
within the desirable level according to The Na-
tional Cholesterol Education Programs Adult
Treatment Panel (NCEP ATP) III guidelines
(<200 mg/dL), and at week 48, 75% of recipients
of atazanavir 400 mg still had total cholesterol
levels below this level, whereas the proportion in
the nelfinavir group had decreased to 49% (sta-
tistical comparison not reported).[94]
The addition of ritonavir to atazanavir, in
study 089, was associated with numerically
greater increases in total cholesterol and LDL-C
levels than seen with unboosted atazanavir, and
triglyceride levels increased only with boosted
atazanavir (table VI).[92] At week 48, the pro-
portions of patients with a one NCEP ATP III
category increase in total cholesterol were 16%
versus 11%, LDL-C were 46% versus 48%, and
fasting triglycerides were 30% and 18% in boos-
ted and unboosted atazanavir treatment groups.
The proportion of patients with HDL-C levels
‡40 mg/dL in the boosted and unboosted ataza-
navir groups were 41% versus 35% at baseline,
and 71% versus 71% at week 48; corresponding
values for the proportion of patients with total :
HDL cholesterol ratios >5 were 35% versus 38%
at baseline and 24% versus 14% at week 48. Ad-
ditionally, 4% of boosted atazanavir compared
with 3% of unboosted atazanavir recipients re-
ceived lipid-lowering therapy.[92]
In CASTLE and study 045, lipid profiles as-
sociated with boosted atazanavir were favourable
compared with lopinavir/ritonavir (table VI).
After 48 weeks of treatment, atazanavir plus ri-
tonavir was associated with significantly smaller
ª 2009 Adis Data Information BV. All rights reserved.
Croom et al.
increases (or a reduction) in total cholesterol,
non-HDL-C (reported for one study only[98])
and triglyceride levels compared with lopina-
vir/ritonavir (table VI).[25,98] In CASTLE, fewer
atazanavir plus ritonavir than lopinavir/ritonavir
recipients required lipid lowering therapy during
48 weeks of therapy.[98] In study 045, the propor-
tions of individuals in the atazanavir plus ritona-
vir group with total cholesterol level within the
NCEP ATP III desirable level (<200 mg/dL) and
LDL-C level within the optimal range (<130
mg/dL) were 83% and 84% (60% and 73% at
baseline); corresponding proportions of in-
dividuals in the lopinavir/ritonavir group were
62% and 74% (69% and 84% at baseline).[25]
Longer term data have been reported for the same
trial, and changes in lipid parameters after 96
weeks were consistent with the 48-week data.[93]
In ALERT, compared with fosamprenavir
plus ritonavir, the median change from baseline
in lipid levels were generally similar for atazana-
vir plus ritonavir (no statistical data reported)
[table VI], although median fasting triglyceride
level was lower with atazanavir than fosampre-
navir after 48 weeks (131 vs 150 mg/dL; base-
line values 124 and 116 mg/dL; p-value not
reported).[100]
The favourable effects of atazanavir on lipid
profiles compared with most other PIs was sup-
ported by the studies in which patients with viral
suppression on another PI-containing regimen
were switched to an atazanavir-based regi-
men.[106-108,117] For example, significant reduc-
tions were seen in total cholesterol, triglyceride
and (where reported[106]) non-HDL-C levels in
patients switched to boosted or unboosted ata-
zanavir compared with patients remaining on
their current boosted or unboosted PI regimen
(p < 0.001 where reported).[106,107] Data from a
large observational cohort of 8100 patients who
were started on atazanavir-based therapy after
failing other ART regimens also showed that
after 48 weeks of treatment with unboosted or
boosted atazanavir, mean percentage changes in
lipid levels from baseline were -10.3% and -3.6%
for total cholesterol, -6.0% and +2.8% for LDL-
C, +6.1% and +9.1% for HDL-C and -27.1% and
-19.1% for triglycerides, respectively.[118]
Drugs 2009; 69 (8)
 Table VI. Effects of atazanavir (ATV) on lipid parameters. Summary of data from randomized, open-label (or double-blind[91]) trials in antiretroviral therapy (ART)-naive[91,94,98,100] or
ª 2009 Adis Data Information BV. All rights reserved.

Atazanavir in HIV-1 Infection

-experienced[25,26] patients (pts) aged ‡16 y comparing ATV (unboosted or ritonavir [RTV]-boosted) with other protease inhibitors (unboosted or boosted) or a non-nucleoside reverse
transcriptase inhibitor. Pts also received dual nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) therapy. See table III for definition of study acronyms, where available
Study Treatment regimen (mg) No. of ptsa Mean percentage change from baseline at wk 48 [baseline values (mg/dL)]
TC LDL-C non-HDL-C HDL-C TG
Unboosted vs boosted ATV
Malan et al.[92] (study 089) ATV 400 odb 104 6 [159]c 14 [99]c 2 [121]c 20 [36]c -13 [129]c
ATV 300 mg od + RTV 100 mgb 95 14 [152]c 19 [92]c 9 [115]c 20 [37]c 10 [123]c
Unboosted ATV vs comparators
Cohen et al.[26] (study 043) ATV 400 od + two NRTId 144 -2* -6* 9 1*
d
LPV/RTV 400/100 bid + two NRTI 146 12 3 10 53
Murphy et al.[94] (study 008) ATV 400 od + 3TC + d4Te 178 5* [168] 5*f[99] 7* [128]
NFV 1250 bid + 3TC + d4Te 91 25 [164] 23 f[97] 50 [108]
Squires et al.[91] (study 034) ATV 400 od + AZT/3TCg 404 2*** [165h] 1*** [100h] 13 [40h] -9*** [135h]
g h h h
EFV 600 od + AZT/3TC 401 21 [160 ] 18 [100 ] 24 ***
[40 ] 23 [125h]
Boosted ATV vs comparators
Molina et al.[98] (CASTLE) ATV 300 od + RTV 100 od + TDF/FTCi 441 12*** [147c] 12 [91c] 7*** [108c] 27 [36c] 13*** [110c]
LPV/RTV 400/100 bid + TDF/FTCi 437 24 [147c] 15 [91c] 21 [112c] 32 [35c] 51 [110c]
j c c c
Johnson et al. [25]
(study 045) ATV 300 od + RTV 100 od + TDF 300 od + NRTI 119 -8 **
[183 ] -10 [100 ] -7 [38 ] -4** [164c]
j c c c
LPV/RTV 400/100 bid + TDF 300 od + NRTI 118 6 [178 ] 1 [103 ] 2 [37 ] 30 [163c]
Smith et al.[100] (ALERT) ATV 300 + RTV 100 od + TDF/FTCi 53 10k -6k 14k
FPV 1400 + RTV 100 od + TDF/FTCi 53 13k 2k 11k
[25,26,92,94,98] [91,100]
a Evaluable or intent-to-treat population.
b NRTI dosages were 3TC 300 mg od and an investigational extended-release formulation of d4T od (dosage depending on weight; not commercially available).
c Median values.
d AZT plus 3TC, d4T plus 3TC, AZT plus ddI, d4T plus ddI, or ABC plus either ddI, d4T or 3TC (dosages not stated).
e NRTI dosages were 3TC 150 mg bid and d4T 30 or 40 mg bid (depending on weight).
f Value at 56 weeks.
g NRTI dosage was AZT/3TC 300/150 bid (fixed-dose combination tablet).
h Estimated from a graph.
i NRTI dosage was TDF/FTC 300/200 od (fixed-dose combination tablet).
j Patients were switched from their previous NRTI therapy to TDF plus one of the following at study week 2: ddI 400 mg od, d4T 40 mg bid, ABC 300 mg bid, AZT 300 mg bid or 3TC
150 mg bid.
k Median change from baseline at week 48 (mg/dL). In the ATV + RTV group, median values at baseline and week 48 for TC were 153 nd 180 mg/dL, for LDL-C were 97 and
Drugs 2009; 69 (8)

101 mg/dL, for HDL-C were 37 and 48 mg/dL, and for TG were 124 and 131 mg/dL; corresponding values for the FPV + RTV were 160 and 171 for TC, 95 and 99 for LDL-C, 38 and
43 for HDL-C, and 116 and 150 for TG.
3TC = lamivudine; ABC = abacavir; AZT = zidovudine; bid = twice daily; d4T = stavudine; ddI = didanosine; EFV = efavirenz; FPV= fosamprenavir; FTC = emtricitabine; HDL-C = high-
density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; LPV = lopinavir; NFV = nelfinavir; od = once daily; TC = total cholesterol; TDF = tenofovir disoproxil

1129
fumarate; TG = triglycerides; * p < 0.01, ** p £ 0.005, *** p < 0.0001 vs comparator.
1130
In addition, a 48-week, open-label, rando-
mized study (067) in 246 virologically suppressed
(viral load of <50 copies/mL) and hyperlipi-
daemic (fasting LDL-C >130 mg/dL [>3.4
mmol/L]) HIV-1 patients showed that switching
to atazanavir 400 mg once daily, either on day 1
(immediate switch; n = 126) or after 24 weeks of
treatment with prior PI-based regimens (delayed
switch; n = 244), was associated with improve-
ments in plasma lipid parameters.[117] At week
12, patients in the immediate-switch group ex-
perienced greater reductions in their fasting
LDL-cholesterol levels than patients in the de-
layed-switch group (mean change from baseline
-15% vs 1%; p < 0.001; primary endpoint). At
week 48 (24 weeks after the delayed-switch group
started receiving unboosted atazanavir therapy),
the mean changes from baseline in LDL-C were
-18% in the immediate-switch group and -16%
in the delayed-switch group. Furthermore, the
reduction in LDL-C levels in the immediate-
switch group was sustained up to 48 weeks (mean
change from baseline -17.5%; estimated from
a graph).[117]
In a 48-week trial, grade 2–4 lipodystrophy (as
assessed by the investigator) was reported as an
adverse event in 4% and 4% of ART-naive pa-
tients receiving unboosted atazanavir 400 or
600 mg compared with 2% of those treated with
nelfinavir.[94] Similarly, the incidence of grade
2–4 lipodystrophy (investigator reported) in two
48-week trials in ART-experienced patients was
5% versus 4%[25] and 6% versus 1%[26] in boosted
atazanavir or lopinavir/ritonavir recipients.
In two trials in ART-naive patients,[91,92] sub-
sets of patients had fat distribution measure-
ments performed using CT scans and dual-energy
x-ray absorptiometry.[116,119] One analysis found
that adipose tissue parameters increased signifi-
cantly from baseline after 96 weeks with both un-
boosted atazanavir and boosted atazanavir, but
there were no significant differences between the
groups.[119] Visceral adipose tissue, total adipose
tissue and trunk fat increased by 32%, 11%
and 14%, respectively, with atazanavir 400 mg
and by 33%, 17% and 16%, respectively, with
atazanavir 300 mg plus ritonavir 100 mg (mean
values; all p < 0.05), whereas limb fat decreased
ª 2009 Adis Data Information BV. All rights reserved.
Croom et al.
by a mean of 17% (p < 0.001 vs baseline) with
unboosted and by a mean of 9% with boosted
atazanavir.[119] Most of the changes in visceral
adipose tissue and total adipose tissue occurred
within the first 48 weeks of therapy, with mean
increases from baseline of 34% and 19% with
atazanavir 400 mg, and 28% and 18% with ata-
zanavir 300 mg plus ritonavir 100 mg.[119] The
mean increase from baseline to week 48 in
subcutaneous adipose tissue was 12% for both
atazanavir 400 mg and atazanavir 300 mg plus
ritonavir 100 mg treatment groups, and 8%
and 2% in the two groups at week 96, indi-
cating that some of the subcutaneous abdominal
fat acquired during the first year of therapy was
lost during the second year of therapy.[119] Total
body fat did not increase significantly from
baseline to week 96 in either treatment group
(decrease of 1% with atazanavir 400 mg and
an increase of 4% with atazanavir 300 mg plus
ritonavir 100 mg).[119] The incidence of lipoa-
trophy was lower with the atazanavir 300 mg
plus ritonavir 100 mg regimen than the atazana-
vir 400 mg regimen, with fewer patients in the
former treatment group experiencing a ‡20%
limb fat loss at 96 weeks (29% vs 49%; p
< 0.05).[119] The proportion of patients with ‡20%
limb fat loss at 48 weeks was 21% in the ataza-
navir 300 mg plus ritonavir 100 mg and 30% in
the atazanavir 400 mg treatment groups.[119]
Based on a subanalysis of another trial (n = 211),
there were no significant differences between
unboosted atazanavir and efavirenz in terms of
fat accumulation or distribution after 48 weeks
treatment.[116]
In a study in 201 HIV-1-infected patients with
lipohypertrophy (waist circumference >90 cm),
there was no significant difference in mean per-
cent change in trunk : limb fat ratio (0.02 vs
-0.02) from baseline to week 48 between patients
switching to atazanavir plus ritonavir and those
continuing on their previous twice-daily boosted
PI (lopinavir/ritonavir for 72% of patients).[120]
In the same study, mean percent reduction in to-
tal, LDL-C and non-HDL-C and triglyceride
levels were significantly greater in the atazanavir
than the comparator group (p £ 0.04 for each
parameter).[120]
Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
Atazanavir did not alter fasting glucose[91,107]
or insulin[91] levels significantly during 48 weeks of
treatment in HIV-1-infected patients. In a small,
uncontrolled study in 21 ART-experienced pa-
tients who had metabolic disturbances (insulin
resistance and/or alteration of lipid levels) while
receiving a protease inhibitor regimen, switching
to unboosted atazanavir for 24 weeks led to a
significant improvement in glucose tolerance
compared with baseline, as indicated by a decrease
of 13 mg/dL in the 120-minute glucose level
(p = 0.021).[121] In addition, fasting glucose, insulin
and C-peptide levels did not differ significantly
from baseline; consequently, there was no change
in fasting homeostasis model assessment indices of
insulin sensitivity and b-cell function.[121]
6. Pharmacoeconomic Considerations
Pharmacoeconomic analyses that used clinical
data from a direct comparison of the drugs have
compared atazanavir plus ritonavir with co-for-
mulated lopinavir/ritonavir in ART-experienced
patients in the US,[122,123] and the UK, France,
Italy and Spain.[124] These analyses estimated the
combined effect of HIV-1 disease, ART benefits
and ART-related risk for coronary heart disease
(CHD). A Markov model that incorporated both
HIV-1 data and the Framingham CHD risk
equation was used. Patients started treatment with
either boosted atazanavir or lopinavir/ritonavir,
and progression through the three-stage model
was based on health status, viral load/viral sup-
pression and CD4+ cell count. Clinical trial data
came from study 045[25] and the CASTLE
study.[123] Local costs were used and the year of
costing was 2005,[122] 2006[124] or 2007.[123] The
perspective was that of the healthcare system for
each country and therefore excluded indirect costs.
The main time horizon was the patient’s lifetime,
but 5- and 10-year horizons were also examined.
In ART-experienced patients, lopinavir/
ritonavir was associated with an increase of
4.6 quality-adjusted life months compared with
boosted atazanavir.[122,124] In one study in the
US, lopinavir/ritonavir was associated with per-
patient cost savings compared with atazanavir
plus ritonavir of $US17 995 over 5 years and
ª 2009 Adis Data Information BV. All rights reserved.
1131
$US21 298 over 10 years for the lopinavir/
ritonavir capsule formulation, and $US19 598
and $US23 126 for the tablet formulation (2005
costs).[122] In another study in the US, lopina-
vir/ritonavir was associated with per-patient cost
savings compared with atazanavir plus ritonavir
of $US24 518 over 5 years and $US36 651 over 10
years (2007 costs).[123] The atazanavir plus rito-
navir regimen was associated with an increase in
life expectancy of 0.031 quality-adjusted life years
(QALYs) [11 days], with an incremental cost-ef-
fectiveness ratio (ICER) of US$1 409 734/QALY
gained relative to lopinavir/ritonavir, which was
higher than the generally accepted range of
US$50 000–100 000.[123] In a senstivity analysis,
when all patients were assumed to be smokers and to
have an elevated systolic blood pressure con-
trolled by medication (mean level 140 mmHg),
the predicted ICER of atazanavir plus ritonavir
relative to lopinavir/ritonavir therapy decreased
to US$520 861/QALY gained, but remained
higher than the generally accepted range, and the
life expectancy increased by 31 quality-adjusted
days.[123] For nonsmokers with low CHD risk
at baseline, the predicted ICER was >2 000 000/
QALY gained and life expectancy increased by 1
quality-adjusted day.[123]
In the four European countries, lopinavir/
ritonavir was associated with per-patient cost sav-
ings of h947–6594 after 5 years (2006 costs).[124]
After 10 years, lopinavir/ritonavir was associated
with cost savings of h1572–7388 compared with
boosted atazanavir in Italy, the UK and Spain, but
in France it was associated with a higher cost than
atazanavir (by h308). Lifetime ICERs for lopina-
vir/ritonavir versus atazanavir plus ritonavir ran-
ged from dominant in Spain to h11 856 per QALY
in Italy.[124] Sensitivity analyses confirmed the
results were robust.[122,124] One of the main drivers
for cost differences was the higher acquisition
cost of atazanavir plus ritonavir compared with
co-formulated lopinavir/ritonavir.[122,124]
7. Dosage and Administration
Atazanavir is approved for use in combination
with other antiretroviral drugs for the treatment
Drugs 2009; 69 (8)
1132
of adults with HIV-1 infection in numerous
countries worldwide, and in paediatric patients
with HIV-1 infection in some countries, including
the US. In the US[13] and EU,[14] it is re-
commended that both treatment-naive and
-experienced adults receive boosted atazanavir
(atazanavir 300 mg plus ritonavir 100 mg, taken
together once daily). In the US, treatment-naive
patients who cannot tolerate ritonavir can be
prescribed unboosted atazanavir 400 mg once
daily.[13] Atazanavir (boosted or unboosted)
should be taken with food. In paediatric patients
in the US, the recommended dosage of atazanavir
is based on bodyweight and should not exceed the
recommended adult dosage.[13] In treatment
naive pediatric patients ‡13 years of age and
‡39 kg, the recommended atazanavir dosage is
400 mg once daily (see local prescribing in-
formation for full dosage details).[13] There are no
dosage recommendations for pediatric patients in
the EU because of lack of sufficient safety and
efficacy data.[14]
Atazanavir should not be administered to pa-
tients with severe (Child-Pugh class B) hepatic
impairment, and should be used with caution
in patients with mild to moderate impairment
according to the US prescribing information.[13]
A dosage reduction to 300 mg once daily should
be considered for patients with moderate hepa-
tic impairment (Child-Pugh class B) who have
experienced prior virological failure.[13] The
European summary of product characteristics
recommends that atazanavir should be used with
caution in patients with mild hepatic impairment
and should not be used in patients with moderate
to severe hepatic impairment.[14]
As PR interval prolongation may occur in
some patients receiving atazanavir (section 5.1),
caution is recommended when administered to
patients with pre-existing conduction abnormal-
ities or when administered with other drugs that
prolong the PR interval.[13,14] Atazanavir therapy
should be discontinued in patients with severe
rash (section 5.1) and temporary interruption
of therapy should be considered in patients
with nephrolithiasis.[13,14] Since patients with he-
patitis B or C may be at risk of increased transa-
minases or hepatic decompensation (section 5.1),
ª 2009 Adis Data Information BV. All rights reserved.
Croom et al.
monitoring of liver function prior to and during
therapy is recommended.[13,14] Adjustments to
atazanavir dosages and/or the timing of admin-
istration are required when a number of different
medications are administered concomitantly, in-
cluding some other antiretroviral drugs (section
3.4). In addition, coadministration with a num-
ber of drugs is contraindicated (section 3.4). Lo-
cal prescribing information should be consulted
for full details of dosage recommendations, con-
traindications, precautions, drug interactions
and use in special patient populations.
8. Place of Atazanavir in the
Management of HIV-1 Infection
Where it is available, the use of HAART has
improved the prognosis for patients with HIV-1
infection.[4] Notably, the introduction of PIs led
to a reduction in morbidity and mortality.[4,9]
However, treatment can be complex. The selec-
tion of the initial treatment regimen depends on a
number of factors, including viral susceptibility,
the potential for resistance, tolerability, co-mor-
bidity, concomitant medications, pill burden and
inconvenient dose administration regimens.[3,5]
Subsequently, regimens may need to be modified
because of virological failure or adverse events,
or to simplify them to improve adherence to
treatment.[3,5] The primary goal of treatment, for
both treatment-naive and -experienced patients,
is to achieve viral suppression with a plasma
HIV-1 RNA load <50 copies/mL.[3,6,8] Other
goals include improving immune function, clin-
ical status and health-related quality of life, and
avoiding the development of viral resistance.[6]
Current US guidelines recommend the combina-
tion of two NRTIs plus either an NNRTI or a
boosted PI as initial therapy.[3,5] European
guidelines include similar recommendations,[6]
but the British HIV-1 Association recommends
two NRTIs plus efavirenz as first-line therapy,
with boosted PIs reserved for specific patients
groups, such as those with NRTI or NNRTI re-
sistance, women wanting to become pregnant
and some patients with psychiatric disorders.[8]
All of these guidelines recommend that PIs
are boosted with low-dose ritonavir. Boosting
Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
increases systemic exposure to the concurrent PI
and prolongs its half-life.[8] As a consequence, the
dose administration frequency, and therefore the
pill burden, can be reduced for some PIs.[8,10] In
addition, the higher blood concentrations of the
drug reduces the likelihood of resistance develop-
ing.[8,10] However, the addition of ritonavir can
increase the incidence of some adverse events as-
sociated with PIs, such as altered lipid levels and
diarrhoea, and also the likelihood of certain drug
interactions.[10]
Boosted atazanavir is one of the preferred[5] PIs
recommended for use in initial HAART regimens
by US guidelines.[3,5] It is also included as an op-
tion in the European guidelines.[6,8] In treatment-
experienced patients, choice of therapy is de-
termined by the patients’ previous drug history
and resistance testing profile, and boosted ataza-
navir may be an option in these patients.[3,5,6,8]
In clinical trials in ART-naive patients who
received dual-NRTI background therapy, boos-
ted atazanavir was noninferior to lopina-
vir/ritonavir in a large study and was similar to
fosamprenavir plus ritonavir in a small, pilot
study (section 4.1.2). Similarly, in ART-experi-
enced patients with a history of virological failure
who received dual-NRTI background therapy,
atazanavir plus ritonavir was noninferior to
lopinavir/ritonavir (section 4.2.1). Futhermore,
the virological efficacy of atazanavir was main-
tained in studies lasting up to 96 weeks (section
4). In both the US[13] and EU,[14] boosted ataza-
navir is approved for use in treatment-naive and
treatment-experienced patients.
Despite the preference for boosted PIs, guide-
lines do indicate a few circumstances when an
unboosted PI may be used. For example, ataza-
navir or fosamprenavir are suggested in a US
guideline for patients who are not suitable for
NNRTI-based therapy or have contraindications
to ritonavir.[3] Unboosted atazanavir is also sug-
gested as an option for patients with established
cardiovascular disease risk factors who need to
take a PI in both US[5] and British[8] guidelines.
However, some of these uses would be off-label;
in the US, unboosted atazanavir is only approved
for use in treatment-naive patients who cannot
tolerate ritonavir,[13] while only boosted ataza-
ª 2009 Adis Data Information BV. All rights reserved.
1133
navir is approved for use in the EU.[14] The viro-
logical efficacy of unboosted atazanavir was
noninferior to that of boosted atazanavir in
ART-naive patients who also received dual-
NRTI background therapy (section 4.1.2). In
addition, the virological efficacy of unboosted
atazanavir was noninferior to that of efavirenz,
and was similar to that of nelfinavir, in ART-
naive patients (section 4.1.1). In contrast, in
ART-experienced patients, noninferiority was
not established for unboosted atazanavir com-
pared with boosted lopinavir in study 045
(section 4.2.1), and the use of unboosted ataza-
navir in treatment-experienced patients is not
recommended. Interestingly, in ART-experienced
patients without a history of virological failure,
who achieved virological suppression on a PI-
based regimen, switching to unboosted atazana-
vir was associated with better maintenance of
virological suppression than remaining on their
previous regimen (section 4.2.2).[106]
Ritonavir-boosted darunavir, together with
ritonavir-boosted tipranavir, are the newest PIs
to be introduced (reviewed by Fenton and
Perry[125] and Orman and Perry[126]); they are
approved for use in highly treatment-experienced
patients,[10] with darunavir also indicated for use
in treatment-naive patients in the US.[127] Com-
parisons of boosted atazanavir with these agents
would be of interest.
Atazanavir is a substrate of CYP3A4, and drugs
that induce or inhibit CYP3A4 may affect the
plasma concentrations of atazanavir.[13] For ex-
ample, coadministration with efavirenz or nevir-
apine is not recommended,[13,14] since these
CYP3A4 inducers reduce drug concentrations of
atazanavir (section 3.4). However, in the US, a
modified dose of boosted atazanavir (400 mg plus
ritonavir 100 mg) may be used with efavirenz in
treatment-naive patients.[13] High gastric pH re-
duces the solubility, and therefore absorption, of
atazanavir, resulting in reduced drug concentra-
tions when coadministered with certain drugs, in-
cluding H2-receptor antagonists (e.g. famotidine)
and proton pump inhibitors (e.g. omeprazole and
lansoprazole) [section 3.4]. Recommendations
for concomitant administration of H2-receptor
antagonists and proton pump inhibitors vary, and
Drugs 2009; 69 (8)
1134
local prescribing information should be consulted
for full details.
Atazanavir-based therapy was generally well
tolerated (section 5). The incidence of diarrhoea
was lower with atazanavir-based regimens than
with other PIs, but atazanavir was associated
with a higher incidence of elevated total bilirubin
levels and jaundice than other PIs. Bilirubin ele-
vations were mainly from unconjugated bili-
rubin, related to the inhibition of UGT1A1 by
atazanavir, and were not associated with elevated
levels of hepatic enzymes (section 5). PR interval
prolongation may occur in some patients (section 5)
and caution is advised in patients with pre-
existing conduction system disease, or when ad-
ministered with other drugs that may prolong the
PR interval (section 7).[13,14] Rash of any severity
occurred in »20% of patients receiving atazanavir
in clinical trials.[13] Although generally mild,
treatment-emergent rash of moderate to severe
intensity was reported in 5–7% of atazanavir
and 3% of boosted atazanavir recipients in
some clinical trials.[13] Treatment discontinuation
is recommended in patients with severe rash
(section 7).[13]
ART, and in particular PI-based therapy, may
be associated with adverse metabolic effects such
as disturbances of lipid metabolism, insulin re-
sistance and changes in body fat partitioning,
and with an increased risk of cardiovascular
disease.[128,129] Altered lipid levels, insulin
resistance and cardiovascular risk have the
strongest association with PIs,[115,129] whereas
lipodystrophy is most common with NRTIs.[129]
Although increases in lipids may be partly attri-
butable to a correction of lipid abnormalities as-
sociated with HIV-1 progression, the total and
LDL-C levels usually increase beyond premorbid
levels.[128]
Altered lipid levels, in turn, may result in a
higher risk of experiencing cardiovascular dis-
ease.[128] The DAD (Data collection on adverse
events of Anti-HIV-1 Drugs) study, a prospective,
observational study in 23 468 patients with HIV-1,
showed a significant (p < 0.001) increase in the risk
of myocardial infarction (adjusted relative rate per
year of exposure 1.26 [95% CI 1.12, 1.41]) with
longer exposure to ART therapy.[130] However,
ª 2009 Adis Data Information BV. All rights reserved.
Croom et al.
the association between ART therapy and an in-
creased risk of cardiovascular disease is not clear-
cut. The randomized SMART (Strategies for
Management of AntiRetroviral Therapy) study,
which enrolled 5472 HIV-1 patients, showed that
risk of fatal or nonfatal cardiovascular disease
(hazard ratio 1.6 [95% CI 1.0, 2.5]) tended to in-
crease (p = 0.05) with episodic ART therapy versus
continuous ART therapy, suggesting that episo-
dic ART therapy may not reduce the risk of ex-
periencing cardiovascular events.[131] Nonetheless,
a retrospective analysis of data from a phase II
trial suggested that minimizing dyslipidaemic
changes associated with ART may be associated
with increased life expectancy;[132] however, pro-
spective trials are needed to confirm any effect on
cardiovascular outcomes.
Diet, life-style interventions, the addition of
lipid-lowering agents, drug selection and a switch
to treatments with less impact on metabolic ef-
fects may reduce the cardiovascular or metabolic
risk in patients with HIV-1 infection receiving
ART therapy.[128] The addition of lipid-lowering
agents to PI therapy was shown to be more ef-
fective than switching from PI to NNRTI therapy
in a randomized, open-label study in 130 HIV-1-
infected patients.[133] Significant reductions from
baseline in mean plasma total cholesterol, LDL-
C and triglyceride were observed following the
addition of pravastatin and bezafibrate to PI
therapy compared with switching from PI to
NNRTI therapy.[133] However, the addition of
lipid-lowering agents may not be sufficient to
achieve NCEP lipid standards.[128]
Switching to ART agents with less propensity
for causing lipid level changes is another option
for correcting lipid levels.[5,8] Within the PI class,
currently available data suggests that atazanavir
is associated with the smallest effect on lipid le-
vels.[128,129] In clinical trials, boosted atazanavir
was associated with generally better lipid profiles
than ritonavir-boosted lopinavir, and more
patients receiving boosted atazanavir reached
recommended lipid levels (section 5.2). In addi-
tion, atazanavir did not cause insulin resistance
or affect glucose metabolism.
Modelled pharmacoeconomic analyses compa-
ring atazanavir plus ritonavir with co-formulated
Drugs 2009; 69 (8)
Atazanavir in HIV-1 Infection
lopinavir/ritonavir in ART-experienced patients
favoured the latter combination, mainly because
of the lower drug acquisition cost of the co-
formulation (section 6). In addition to the effect
of HIV-1 disease, these analyses took into ac-
count CHD risk associated with ART, but found
that the additional costs of treatment for CHD
were outweighed by the overall costs savings with
lopinavir/ritonavir.[122,124] Pharmacoeconomic
data from comparisons of atazanavir with other
drugs would be of interest.
Adherence to ART regimens can be poor be-
cause of the number of different drugs that must be
taken, the high overall pill burden, complex dose
administration regimens and the need for lifelong
therapy.[5,134] Poor adherence to treatment is one of
the main causes of viral resistance, so it is important
to encourage patients to comply with dose admin-
istration requirements.[5,134] Simpler regimens,
including once-daily regimens, are becoming in-
creasingly available.[134] Atazanavir is administered
once daily and therefore is suitable as a component
of such regimens. In addition, atazanavir has a low
total daily capsule burden (two capsules for
unboosted and one capsule when boosted with ri-
tonavir). This compares with a total of 4–10 tablets/
capsules per day for other PIs, with the exception of
ritonavir-boosted fosamprenavir or ritonavir-
boosted darunavir, which also use three tablets
when administered once daily for naive patients.[5]
In conclusion, ART regimens containing
boosted atazanavir improved virological and im-
munological markers in adult patients with HIV-1
infection, and had similar efficacy to regimens
containing lopinavir/ritonavir in treatment-naive
and treatment-experienced patients. In addition,
unboosted atazanavir was noninferior to ritano-
vir-boosted atazanavir in treatment-naive pa-
tients. Atazanavir is administered once daily and
has a low capsule burden. Atazanavir, whether
unboosted or boosted, was generally well toler-
ated and appeared to be associated with less
marked metabolic effects, including less alteration
of lipid levels, than other PIs. These properties
mean that boosted atazanavir, and unboosted
atazanavir in patients unable to tolerate ritonavir,
continues to have a role as a component of ART
regimens in patients with HIV-1 infection.
ª 2009 Adis Data Information BV. All rights reserved.
1135
Disclosure
The preparation of this review was not supported by any
external funding. During the peer review process, the manu-
facturer of the agent under review was offered an opportunity
to comment on this article. Changes resulting from comments
received were made on the basis of scientific and editorial
merit.
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