Abacavir (Ziagen)

Abacavir is an anti-HIV drug that reduces the amount of virus in

the body. Anti-HIV drugs such as abacavir slow down or prevent
damage to the immune system and reduce the risk of developing
AIDS-related illnesses.
Abacavir belongs to a class of drugs known as nucleoside reverse
transcriptase inhibitors (NRTIs). When HIV infects a cell, the
enzyme reverse transcriptase copies the viral single-stranded
RNA genome into double-stranded viral DNA. This viral DNA is
then integrated into the CD4 chromosomal DNA and can go on to
reproduce in the body. Four natural nucleosides complete the
DNA synthesis: adenosine, cytidine, guanosine, and thymidine.
An NRTI drug substitutes a defective version of one of the
nucleosides, causing premature termination of the proviral DNA
chain.
In July 1999, abacavir was approved by the European Union
licensing body for use in combination with other anti-HIV drugs.
The drug was licensed in the United States in December 1998.
Once-daily abacavir was also approved in the European Union in
November 2004.
Abacavir was previously known by the codename 1592U89 and
has been registered under the trade name Ziagen. It is made by
GlaxoSmithKline, the company that also produces AZT
(zidovudine, Retrovir) and 3TC (lamivudine, Epivir).
A pill that combines 300mg abacavir, 150mg 3TC and 300mg
AZT called Trizivir, is also available from GlaxoSmithKline. It was
approved in the United States in November 2000 and in the
European Union in March 2001.
GlaxoSmithKline also produces a fixed-dose combination of
600mg abacavir with 300mg 3TC, which is suitable for once-daily
dosing. It is marketed as Kivexa in the European Union, where it
was licensed in December 2004. The same combination tablet is
called Epzicom in the United States, where it was approved for
use in August 2004.
Abacavir is recommended by WHO as an alternative NRTI in first-
line therapy, either as part of an NRTI backbone for use with a
non-nucleoside reverse transcriptase inhibitor or as part of a triple
nucleoside regimen.1
References
1. World Health Organization Antiretroviral therapy for HIV infection in
adults and adolescents: recommendations for a public health
approach, revised. World Health Organization, Geneva, available
online at www.who.int.hiv/pub/guidelines/artadultguidelines.pdf
[accessed 25 October 2008], 2006
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Effectiveness
Clinical studies have shown that abacavir (Ziagen) can reduce
HIV viral load and improve immune function in the majority of
people when taken in combination with at least two other anti-HIV
drugs. It is regarded as a highly potent nucleoside reverse
transcriptase inhibitor (NRTI) in people who have not taken
previous antiretroviral therapy, although it often retains an anti-
HIV effect in individuals who have previously taken treatment.
Abacavir is active against HIV-1 and HIV-2.
Abacavir was licensed after the results of the CNA 3003 study
showed that adding the drug to a combination of AZT
(zidovudine, Retrovir) and 3TC (lamivudine, Epivir) led to more
patients having suppressed viral loads in patients taking
antiretroviral therapy for the first time.1The CNAB 3005 study
extended this by comparing abacavir to the protease inhibitor
indinavir (Crixivan), in combination with AZT and 3TC, with both
groups having similar viral load reductions.2
Since its approval, studies have shown that abacavir is effective
when used as a part of a dual NRTI backbone. The CNA 30024
study showed that abacavir is just as effective in reducing viral
load as AZT when combined with 3TC and efavirenz (Sustiva).
However, people who received abacavir had a significantly better
CD4 cell count increase after 48 weeks.3
The ZODIAC study showed that once-daily dosing of abacavir
was just as safe and effective as the twice-daily separate doses in
patients starting antiretroviral therapy for the first time. The two
dosing schedules produced similar rates of side-effects.4
Like AZT and d4T (stavudine, Zerit), abacavir is able to cross the
blood-brain barrier and combat HIV in the central nervous system.
One study of treatment-experienced people with dementia found
that abacavir reduces the viral load in the cerebrospinal fluid that
surrounds the brain and spinal cord.5
References
1. Fischl M et al. Ziagen (abacavir) combined with 3TC and AZT is highly
effective and durable through 48 weeks in HIV-1 infected antiretroviral-
 naive subjects. Sixth Conference on Retroviruses and Opportunistic
Infections, Chicago, abstract 19, 1999
2. Staszewski S et al. Abacavir-lamivudine-zidovudine vs indinavir-
lamivudine-zidovudine in antiretroviral naive HIV-infected adults: a
randomized equivalence trial. JAMA 285: 1155-1163, 2001
3. de Jesus E et al. Efficacy and safety of abacavir versus zidovudine in
antiretroviral naive adults with HIV-1 infection. 43rd Interscience
Conference on Antimicrobial Agents and Chemotherapy, Chicago,
abstract H-446, 2003
4. Moyle G et al. Abacavir once or twice daily combined with once-daily
lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-
infected adults: results of the Ziagen Once Daily in Antiretroviral
Combination Study. J Acquir Immune Defic Syndr 38: 417-425, 2005
5. Lanier R et al. HIV-1 reverse transcriptase sequence in plasma and
cerebrospinal fluid of patients with AIDS dementia complex treated
with abacavir. AIDS 15: 747-751, 2001
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Taking it
The standard dose of abacavir (Ziagen) is one 300mg tablet twice
a day, twelve hours apart, or once a day at a dose of 600mg. It
can be taken with or without food. Abacavir is dosed once daily
when combined with 3TC in the tablet coformulation
(Kivexa / Epzicom).
A strawberry and banana-flavoured abacavir solution at a
concentration of 20mg/ml is also available for use in children and
adults who cannot take tablets. The oral solution of abacavir
contains 340mg/l sorbitol. This means that the product is
unsuitable for people with hereditary fructose intolerance. Sorbitol
can also cause stomach upset and diarrhoea.
Abacavir is generally not recommended for people with cirrhosis
or mild liver impairment because they are not able to process the
drug properly and high drug levels occur. One study has
recommended an abacavir dose of 150mg twice daily for people
with liver damage, although there are no definitive
recommendations on appropriate dose adjustments.1
Abacavir should not be taken by people with end-stage kidney
disease.
As with all anti-HIV drugs, it is important to take the drug as
prescribed in order to maintain the right level of the drug in the
blood. If blood levels of the drug fall too low, this will help the
development of resistance to abacavir and may affect future
treatment options.
References
1. Raffi F et al. Pharmacokinetics of, and tolerability to, a single, oral, 600
mg dosage of abacavir in HIV-positive subjects with or without liver
disease. 40th Interscience Conference on Antimicrobial Agents and
Chemotherapy, Toronto, abstract 1630, 2000
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Side-effects
The most common side-effects of abacavir (Ziagen) are nausea,
vomiting, lethargy, and fatigue. Other commonly reported side-
effects are fever, headache, diarrhoea, and loss of appetite. In
general, symptoms appear in the first few weeks of treatment, are
mild to moderate in severity, and tend to resolve on their own.
Abacavir seems to be less damaging to mitochondria than some
of the other nucleoside reverse transcriptase inhibitors (NRTIs),
such as d4T (stavudine, Zerit) and AZT (zidovudine, Retrovir).1 It
is therefore less likely than some of the other NRTIs, to cause
side-effects related to mitochondrial damage, such as fat loss
from under the skin.2 A number of studies have examined the
effects of switching from these drugs to abacavir, with most
showing modest improvements in fat levels.3 4 5
There is conflicting evidence as to whether abacavir increases the
risk of myocardial infarction. Recent data on this issue are
presented in the following section, Risk of cardiovascular disease.
Lactic acidosis is a rare, but serious side-effect of all NRTIs
including abacavir. Symptoms include an enlarged and tender
liver, nausea, and malaise. Lactic acidosis usually develops within
a few months of starting treatment with NRTIs. This side-effect
seems to occur more commonly in women and in individuals with
existing liver disease or who are obese.
Liver toxicity was reported in two women ten to 12 weeks after
switching to an abacavir-containing regimen. Neither had
underlying risk factors for liver disease and both tested HLA-
B*5701 negative before starting the drug. Laboratory values were
normal at six weeks, but alanine aminotransferase (ALT) were
well over five times the upper limit of normal a short time
later. The one biopsy done found severe inflammation in one
women. Hypersensitivity reaction and hepatitis were both ruled
out as causative agents. Lab values returned to normal and
Inflammation resolved after treatment with abacavir was
stopped. The authors point out that even minor symptoms after
starting therapy should be reported and investigated.6
Three case reports of changes in mental state in patients starting
abacavir have been reported. Although rare, symptoms include
depression, suicidal thoughts, auditory hallucinations, psychosis,
headaches and nightmares.7 8 9
References
1. Hoy JF et al. Changes in mitochondrial DNA in peripheral blood
mononuclear cells from HIV-infected patients with lipoatrophy
randomized to receive abacavir. J Infect Dis 190(4): 688-692, 2004
2. Podzamczer D et al. Less lipoatrophy and better lipid profile with
abacavir as compared to stavudine: 96-week results of a randomized
study. J Acquir Immune Defic Syndr 4(2):139-147, 2007
3. Martin A et al. Reversibility of lipoatrophy in HIV-infected patients 2
years after switching from a thymidine analogue to abacavir: the
MITOX Extension Study. AIDS 18: 1029-1036, 2004
4. Katlama C et al. Comparison of metabolic abnormalities 48 weeks
after switching from highly active antiretroviral therapy containing non-
nucleoside reverse transcriptase inhibitor to Trizivir versus continued
highly active antiretroviral therapy. AIDS 17: 1855-1856, 2003
5. Moyle G et al. A 48 week, randomized, open label comparison of three
abacavir-based substitution approaches in the management of
dyslipidemia and peripheral lipoatrophy. J Acquir Immune Defic Syndr
33: 22-28, 2003
6. Soni S et al. Abacavir-induced hepatotoxicity: a report of two
cases. AIDS 22(18): 2557-2258, 2008
7. Colebunders R et al. Neuropsychiatric reaction induced by
abacavir. Am J Med 113: 616, 2002
8. Foster R et al. Antiretroviral therapy-induced psychosis: case report
and brief review of the literature. HIV Med 4: 139-144, 2003
9. Foster R et al. More on abacavir-induced neuropsychiatric
reactions. AIDS 18: 2449, 2004
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Risk of cardiovascular disease
Jump to
Studies finding excess risk
Studies that did not find excess risk

Studies finding excess risk

Four major studies, D:A:D, SMART, ANRS CO4, and STEAL
have found that abacavir use increases the risk of myocardial
infarction (heart attack).
In 2009, D:A:D (Data Collection on Adverse Events of Anti-HIV
Drugs) investigators presented information collected from over
33,000 participants from 11 prospective cohorts. They found that
recent abacavir use (in the past six months) increased the risk
of MI by 68%; that risk rose with correspondingly longer time on
abacavir.1
Because there was no association between heart attack risk and
CD4 count or viral load, it was suggested that possibly an
inflammatory reaction affecting the blood vessel walls might be
involved.
Results from SMART (Strategies for Management of Anti-
Retroviral Therapy) study also found an excess risk of
cardiovascular disease (CVD) with abacavir use as compared to
other NRTIs. Events included myocardial infarction; stroke,
coronary artery disease, congestive heart failure, peripheral
vascular disease, and death. Researchers believe that abacavir
may cause vascular inflammation, increasing the risk of
cardiovascular events, particularly in those already highly
vulnerable.2
ANRS CO4 is a French study that looked at the effect of specific
ARVs on MI risk among more than 11,500 patients in the French
Hospital Database between 2000 and 2006, an analysis started
after release of the D:A:D report. A nested case-control study in
ANRS CO4 looked at 289 HIV patients in the database who
experienced a confirmed first MI in that period and matched them
with up to five control subjects (same gender and similar age)
who had never had an MI.
HIV disease status and pre-existing cardiovascular risk factors
were controlled for by the researchers. Patients with recent
abacavir exposure (in the past six months) had twice the risk of
heart attack of the control subjects. Past abacavir exposure of
less than one year resulted in a slight, but statistically insignificant
risk. There was no elevated risk of MI in patients with cumulative
exposure to abacavir.3
The Australian STEAL study looked at regimen simplification by
switching adults with suppressed viral load to regimens containing
either Kivexa (3TC/abacavir) or Truvada (emtricitabine/tenofovir).
Participants in the abacavir-containing arm had a higher rate of
cardiovascular disease events, including three MIs, one coronary
artery bypass, and one stroke. In the tenofovir-containing arm
there was just one event, but this difference was not statistically
significant as the numbers were too small.4

Studies that did not find excess risk

Five studies, the US Veterans Study, BICOMBO, ALLRT,
MACS/WIHS, and HEAT have found that abacavir use does not
increase the risk of adverse cardiovascular events.
Investigators searched the US Veterans Administrations Clinical
Case Registry to identify patients who had experienced heart
attacks or cerebrovascular events such as strokes. Over 19,000
HIV-infected veterans were followed for an average of four
years. An unadjusted analysis found that cumulative exposure to
abacavir was associated with a modest, non-statistically
significant increase in acute myocardial infarction (heart attack)
and cerebrovascular events (stroke). After controlling for
recognised heart disease risk factors and co-existing conditions,
the association between abacavir and heart attack or stroke was
weak and no longer close to being statistically significant.
Researchers noted that people with kidney disease were
significantly more likely to have heart attacks and significantly
more likely to be prescribed abacavir, indicating that kidney
dysfunction may be an important confounding factor. In fact,
kidney disease was associated with a significantly higher risk of
heart attacks and strokes even when no other risk factors were
considered.5
The Spanish BICOMBO study was a randomised comparison of
abacavir plus 3TC (Epivir) versus tenofovir plus FTC (Emtriva).
The investigators measured several blood biomarkers associated
with an increased risk of cardiovascular disease. These included
C-reactive protein, monocyte chemoattractant protein-1,
osteoprotegrin, adiponectin, IL-6, IL-10, tumour necrosis factor-
alpha, ICAM-1, VCAM-1, selectin E and P, D-dimer, and insulin.6
There were no significant differences in baseline biomarker levels
between the abacavir-treated patients and those taking tenofovir.
After a year of treatment, changes in all biomarker levels were
relatively minor and comparable for each study arm. The
researchers concluded that among otherwise healthy HIV patients
with suppressed viral load, starting abacavir did not lead to
significant changes in biomarkers of inflammation, coagulation,
blood vessel dysfunction, or insulin resistance.
The AIDS Clinical Trials Group ALLRT study (ACTG Longitudinal
Linked Randomized Trials/ACTG 5001) also conducted an
analysis of cardiovascular events in their database following the
2008 D:A:D report. Almost a quarter of the more than 3200 HIV
patients from five clinical trials initiated ART with regimens that
included abacavir. Researchers found 63 severe cardiovascular
events, including 27 MIs. They did not find a significant
association between recent abacavir use and MI or severe
cardiovascular disease risk.7
In looking for inflammatory markers amongst participants in the
Women's Interagency HIV Study (WIHS) and the Multicenter
AIDS Cohort Study (MACS), abacavir-experienced participants
were compared 1:1 to patients without abacavir experience.
Researchers found that abacavir use was not independently
associated with elevated plasma levels of high-sensitivity C-
reactive protein (hsCRP), interleukin 6 (IL-6), and D-dimer at
baseline at the first visit after baseline (usually occurring six
months later). This study included just over 325 women and
men.8
A 48-week interim study analysis of HEAT (Head-to-
Head Epzicom and Truvada) failed to find excess CVD risk in
the Epzicom (Kivexa) arm. Comparing the two NRTI
backbones, each paired with Kaletra, Kivexa was found to be non-
inferior to Truvada and lacking in any excess toxicity. HEAT is
a prospective, randomised trial sponsored by GlaxoSmithKline.9
In a later analysis of biomarkers of inflammation and endothelial
activation among 476 treatment-naive participants in the HEAT
study, researchers measured blood levels of hsCRP, IL-6, and
vascular cell adhesion molecule-1 (sVCAM-1) at baseline and
again at weeks 48 and 96. Levels of hsCRP, IL-6, and sVCAM-1
decreased after starting therapy in both groups, and reductions
were not significantly different between the two arms for any of
the biomarkers. There were not enough cardiovascular events to
meaningfully compare rates in the two arms.10
References
1. Lundgren J et al. Risk of myocardial infarction with exposure to
specific ARV from the PI, NNRTI, and NRTI drug classes: The D:A:D
Study. 16th Conference on Retroviruses and Opportunistic Infections,
Montreal, abstract 44LB, 2009
2. Strategies for Management of Anti-Retroviral Therapy/INSIGHT; D:A:D
Study Groups. Use of nucleoside reverse transcriptase inhibitors and
risk of myocardial infarction in HIV-infected patients. AIDS 22(14):
F17-24, 2008
3. Lang S et al. Impact of specific nNRTI and PI exposure on the risk of
myocardial infarction: a case-control study nested within FHDH ANRS
CO4. 16th Conference on Retroviruses and Opportunistic Infections,
Montreal, abstract 43LB, 2009
4. Martin A et al. Simplification of antiretroviral therapy with tenofovir-
emtricitabine or abacavir-lamivudine: a randomized, 96-week trial. Clin
Infect Dis 49(10):1591-1601, 2009
5. Bedimo R et al. Abacavir use and risk of acute myocardial infarction
and cerebrovascular disease in the HAART era. 5th IAS Conference
on HIV Pathogenesis, Treatment and Prevention, Cape Town, abstract
MoAb202, 2009
6. Martinez E et al. No evidence for recent abacavir/lamivudine use in
promoting inflammation, endothelial dysfunction, hypercoagulability, or
insulin resistance in virologically suppressed HIV-infected patients: a
substudy of the BICOMBO randomized clinical trial (ISRCTN6189). 5th
IAS Conference on HIV Pathogenesis, Treatment and Prevention,
Cape Town, abstract MoAb203, 2009
7. Benson C et al. No association of abacavir use with risk of myocardial
infarction or severe cardiovascular disease events: Results from
ACTG A5001. 16th Conference on Retroviruses and Opportunistic
Infections, Montreal, abstract 721, 2009
8. Palella F et al. Inflammatory markers among abacavir and non-
abacavir recipients in the Womens Interagency HIV Study and the
 Multicenter AIDS Cohort Study. 16th Conference on Retroviruses and
Opportunistic Infections, Abst 150LB, 2009
9. Smith KY et al. Randomized, double-blind, placebo-matched,
multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with
lopinavir/ritonavir for initial HIV treatment. AIDS 23(12):1547-556,
2009
10. McComsey G et al. Similar Reductions in Markers of Inflammation
and Endothelial Activation after initiation of Abacavir/Lamivudine or
Tenofovir/Emtricitabine: the HEAT Study. 16th Conference on
Retroviruses and Opportunistic Infections, Montreal, abstract 732,
2009
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Atazanavir (Reyataz)
Atazanavir (Reyataz, Zrivada) is an antiretroviral drug from the
class known as protease inhibitors. Protease inhibitors block the
activity of the HIV protease (or proteinase) enzyme that HIV uses
to break up large viral proteins so that new HIV particles can be
formed. Inhibiting this action slows HIV replication and delays
damage to the immune system. For more information on how
protease inhibitors work, see Protease inhibitors in the
section Ways of attacking HIV.
Atazanavir was developed by Bristol-Myers Squibb, the makers of
d4T (stavudine, Zerit) and ddI (didanosine, Videx / VidexEC). It
was formerly identified as BM-232632.
In the European Union, atazanavir was approved for use in
treatment-experienced patients in 2004, at a dose of 300mg,
boosted with 100mg ritonavir (Norvir) once a day. It was approved
for use in treatment-naive patients at the same dose in 2008.
In the United States, atazanavir was approved as an HIV
treatment in 2003 without restrictions on its use. The
licensed dosing is 400mg once daily for treatment-naive patients
and 300mg plus 100 mg ritonavir once daily for treatment-
experienced patients. It is recommended that this drug be taken
with food. It has also been approved for use in children six years
of age and older.
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Effectiveness
Atazanavir (Reyataz) is an effective antiretroviral agent with
comparable efficacy to other protease inhibitors and to non-
nucleoside reverse transcriptase inhibitors (NNRTIs). It should be
given in combination with other antiretroviral drugs, except in
certain limited circumstances.
In 2007, the 96-week results of the AI424-089 trial showed that
atazanavir taken alone or boosted with ritonavir (atazanavir/r)
once-daily as part of an antiretroviral regimen is safe and effective
in treatment-naive, HIV-infected individuals, including those with
advanced HIV disease.1
The trial compared atazanavir/ritonavir 300/100mg once daily with
atazanavir 400mg once daily in treatment-naive participants. In
both study arms, once-daily lamivudine (3TC), and extended
release stavudine were also given. At baseline, roughly half the
participants had an average CD4 cell count around 200
cells/mm3 and a viral load above 100,000 copies/ml.
At 96 weeks, boosted atazanavir showed a trend toward a higher
rate of viral suppression, fewer virological rebounds, and less
protease inhibitor or nucleoside analogue resistance. There was
no statistically significant difference in the number of study
participants achieving a viral load less than 50 copies/ml by
intent-to-treat analysis. There were fewer virologic failures among
people taking boosted atazanavir.
Five patients taking boosted atazanavir stopped treatment due to
hyperbilirubinaemia, compared to none in the unboosted arm and
there was a much higher rate of grade 3/4 bilirubin elevation in
the boosted atazanavir group (66 vs 24%).
Although participants taking boosted atazanavir experienced lipid
elevations at a greater frequency (20 vs 7%), none
required intervention.
The AI424-008 study has shown that atazanavir is of similar
efficacy to the protease inhibitor nelfinavir (Viracept) in patients
who are ARV-naive. After 48 weeks, similar numbers of patients
had undetectable viral loads, with similar CD4 cell count
increases.2 The A1424-007 study came to similar conclusions.3
In the United States, atazanavir, alone or boosted, is already
licensed for first-line ART in therapy-naive or experienced patients
and it is listed as a preferred regimen in the treatment guidelines.
In Europe, it must be boosted with ritonavir.
The CASTLE study is a randomised, open-label,
multicentre, study for ART-naive participants, assessing the non-
inferiority of once-daily atazanavir (300mg) boosted with 100mg
ritonavir compared to lopinavir/ritonavir (Kaletra) taken twice daily.
Participants also receive once-daily Truvada (tenofovir +
emtricitabine). In early 2008, the 48-week results were
presented.4
Although designed as a 96-week trial, the studys primary
endpoint was the proportion of study participants with a viral load
less than 50 copies/ml at week 48. That goal was met by 78% of
participants in the atazanavir/r arm as compared to 76% in the
lopinavir/r arm, a statistically insignificant difference.
The study enrolled over 800 participants who were evenly
matched at baseline. The median CD4 count was just over 200
cells/mm3 and all patients had a baseline viral load greater than or
equal to 5000 copies/ml. Thirty-one percent of the participants in
both arms were female.
Responses in the two arms were also similar in participants who
began with higher and with lower viral loads. Of the 435
participants with HIV RNA levels 100,000 copies/ml at baseline,
82% in the atazanavir/r arm and 81% in the lopinavir/r arm
achieved suppression. Of the 448 with viral load <100,000, 74%
and 72% achieved suppression respectively.
Mean CD4 increases from baseline were 203 cells/mm3for
atazanavir/ritonavir and 219 cells/mm3 for Kaletra.
The investigators conclude that once-daily atazanavir/r is non-
inferior to twice-daily lopinavir/r in treatment-naive individuals,
with comparable antiviral efficacy, when combined with tenofovir
and FTC. Boosted atazanavir appears to be better tolerated with
a favourable lipid profile.
Seven percent of patients in the atazanavir/r arm vs 18% of
patients in the lopinavir/r arm had total cholesterol greater than or
equal to 240 mg/dL. In the atazanavir/r arm, 26% of
patients experienced any grade 2-4 treatment-related adverse
events as compared to 30% of patients in the other arm.
Participants in the atazanivir/r arm also experienced fewer cases
of diarrhoea and nausea.
Data on atazanavir in treatment-experienced patients are also
available. Unsurprisingly, the AI424-043 study showed that
atazanavir alone is not as potent as ritonavir-boosted lopinavir.5
However, study AI424-045 showed that once-daily, atazanavir/r
was as effective as twice-daily lopinavir/r at suppressing viral load
over two years when combined with tenofovir (Viread) and an
NRTI in treatment-experienced patients. That study also
suggested that atazanavir was better tolerated than Kaletra and
resulted in a better lipid profile. More patients in the Kaletra arm
experienced severe gastrointestinal side-effects, such as
diarrhoea. The relative effects of the drugs in this study were
unaffected by the number of baseline mutations.6 7
There is also evidence that dual boosted protease inhibitor drug
combinations including atazanavir with Kaletra, ritonavir-boosted
saquinavir (Invirase) are effective and safe in patients with
substantial treatment experience.8 9
Recent evidence has suggested that ritonavir-boosted atazanavir-
based therapy is safe and well tolerated in patients infected with
hepatitis B or hepatitis C viruses. Similar rates of liver enzyme
elevations were seen in a group of 180 hepatitis-co-infected
patients and 124 patients who were not co-infected, with similar
withdrawal rates in the two groups.10
Atazanavir is also safe and effective in HIV-positive patients with
liver cirrhosis, according to a retrospective Spanish study
presented in 2006. The investigators found that patients with
cirrhosis who received atazanavir had both an immunological and
virological response to the drug, but did not experience any
clinically significant liver-related side-effects.11
Ritonavir-boosted atazanavir without any other anti-HIV drugs
may also be a suitable 'maintenance' treatment for patients who
have suppressed viral loads on combination therapy. One study
of 36 patients found that 31 maintained viral suppression for at
least 24 weeks. However, larger, randomised studies are required
before this strategy can be recommended.12
References
1. Malen N et al. Efficacy and safety of atazanavir-based therapy in
antiretroviral nave HIV-1 infected subjects both with and without
ritonavir: 96-week results from AI424-089. 4th International AIDS
Society Conference on HIV Pathogenesis, Treatment and Prevention,
Sydney, abstract WEPEB024, 2007
2. Murphy R et al. Dose-ranging, randomized, clinical trial of atazanavir
with lamivudine and stavudine in antiretroviral-naive subjects: 48-week
results. AIDS 17: 2603-2614, 2003
3. Sanne I et al. Results of a phase 2 clinical trial at 48 weeks (A1424-
007): a dose-ranging, safety, and efficacy comparative trial of
atazanavir at three doses in combination with didanosine and
stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr
32: 18-29, 2003
4. Molina J-M et al. Efficacy and safety of once-daily atazanavir/ritonavir
compared to twice-daily lopinavir/ritonavir, each in combination with
tenofovir and emtricitabine in ARV-nave HIV-1-infected subjects: the
CASTLE study, 48-week results. Fifteenth Conference on Retroviruses
and Opportunistic Infections, Boston, Abstract 37, 2008
5. Nieto-Cisneros L et al. Antiviral efficacy, metabolic changes and safety
of atazanavir versus lopinavir / ritonavir in combination with NRTIs in
patients who have experienced virological failure with prior PI-
containing regimen(s): 24-week results from BMX A1424-043. Second
International AIDS Society Conference on HIV Pathogenesis and
Treatment, Paris, abstract 117, 2003
6. Johnson M et al. Atazanavir plus ritonavir or saquinavir, and lopinavir /
ritonavir in patients experiencing multiple virological failures. AIDS 19:
685-694, 2005
7. Johnson M et al. The influence of baseline protease inhibitor mutations
on the efficacy of ritonavir-boosted atazanavir, atazanavir plus
saquinavir, and lopinavir / ritonavir in patients who have experienced
 virologic failure on multiple HAART regimens. Twelfth Conference on
Retroviruses and Opportunistic Infections, Boston, abstract 711, 2005
8. Duvivier C et al. Dual boosted atazanavir / lopinavir / ritonavir
containing regimen in HIV-1 infected pretreated patients: plasma
trough concentration and efficacy results. Third International AIDS
Society Conference on HIV Pathogenesis and Treatment, Rio de
Janeiro, abstract WePe3.2C10, 2005
9. Boffito M et al. Atazanavir enhances saquinavir hard gel
concentrations in a ritonavir-boosted once daily regimen. AIDS 18:
1291-1297, 2004
10. Perez-Elias MJ et al. Effect of ritonavir-boosted atazanavir (Atv / R)
in experienced HIV-infected patients regarding chronic hepatitis B / C
status. Third International AIDS Society Conference on HIV
Pathogenesis and Treatment, Rio de Janeiro, abstract TuPe1.1C25,
2005
11. Hermida JM et al. Efficacy and safety of atazanavir in HIV-infected
patients with liver cirrhosis. Fourth International AIDS Society
Conference on HIV Pathogenesis, Treatment and Prevention, Sydney,
abstract MOPEB060, 2007
12. Swindells S et al. Regimen simplification to atazanavir-ritonavir
alone as maintenance antiretroviral therapy after sustained virologic
suppression. JAMA 296: 806-814, 2006
PreviousNext

Taking it
In the European Union, boosted atazanavir (Reyataz) is taken
once daily as one 300mg capsule with a 100mg dose of ritonavir.
It can also be dosed with two 150mg capsules plus one 100mg
ritonavir (Norvir) capsule once a day. Atazanavir is approved for
use by treatment-naive and treatment-experienced patients in the
United States and the European Union.
In the United States, the approved dosing for treatment-naive
patients is 300mg atazanavir/100mg ritonavir once daily with food
or atazanavir 400mg once daily with food. If taken in combination
with efavirenz or tenofovir, both of those drugs are dosed
normally, but the recommendation is to use
boosted atazanavir (300mg/r 100mg once daily).
If using unboosted atazanavir, ARV-naive patients should avoid
the combination of enteric-coated didanosine with tenofovir.1
Treatment-experienced patients should take 300mg
atazanavir/100mg ritonavir daily with food. Unboosted atazanavir
is not recommended.
Experimental doses of 300 or 400mg atazanavir plus 200mg
ritonavir have been shown to improve atazanavir exposure in
patients with suboptimal levels on the standard boosted dose.2
A dosing study in HIV-negative volunteers found that taking
400mg atazanavir with food increased drug concentrations by 35
to 70%, so taking the drug without food could result in failing to
meet the necessary pharmacokinetic targets for efficacy.
Atazanavir should also not be taken with proton pump inhibitors or
antacids as the AUC of atazanavir is decreased with co-
administration.
Atazanavir should not be used in patients with severe liver
damage. A dose reduction to 300mg once daily should be made
for someone with moderate liver damage (Child-Pugh Class B). In
cases of mild liver damage, it should be used with caution.
Treatment-naive patients with end-stage renal disease managed
with haemodialysis should receive 300mg of atazanavir with
100mg of ritonavir. Atazanavir should not be given to treatment-
experienced patients with end-stage renal disease managed with
haemodialysis.3
References
1. National Institute of Allergy and Infectious Disease Monitoring Board
recommends stopping experimental treatment regimen in international
study of patients new to HIV treatment. NIAID Bulletin, available online
at www3.niaid.nih.gov/news/newsreleases/2008/ACTG_5175
[accessed 28 October 2008], 2008
2. Harris M et al. Effect on atazanavir (ATZ) and ritonavir (rtv) plasma
levels of increasing ATZ / rtv daily dosing from 300 / 100 mg to 300 /
200 mg and 400 / 200 mg. Third International AIDS Society
Conference on HIV Pathogenesis and Treatment, Rio de Janeiro,
abstract WePe3.2C07, 2005
3. Bristol-Myers Squibb Company Reyataz (atazanavir sulfate) capsules
[prescribing
information]. www.fda.gov/cder/foi/label/2007/021567s0141bl.pdf,
2007
PreviousNext

Side-effects
Jump to
Hyperbilirubinaemia
Lipodystrophy
Other side-effects
The commonest side-effects associated with atazanavir (Reyataz)
are headache, nausea, rash, diarrhoea and vomiting. However,
the 045 study concluded that gastrointestinal side-effects are less
common in patients taking ritonavir (Norvir)-boosted atazanavir
than those taking ritonavir-boosted lopinavir (Kaletra).1

Hyperbilirubinaemia
The major side-effect associated with atazanavir treatment is
hyperbilirubinaemia, an elevation of bilirubin levels in the blood.
Bilirubin is a waste product from the breakdown of red blood cells.
Although it is not clinically harmful, trials have shown that up to
45% of people who take atazanavir can develop
hyperbilirubinaemia. Elevated bilirubin levels can cause jaundice,
a yellowing of the skin and the whites of the eyes.
Hyperbilirubinaemia tends to emerge within the first week of
starting atazanavir treatment, but does not always cause
jaundice. In one large study of patients initiating ART, 33% of the
nearly 400 patients developed severe hyperbilirubinaemia, but
less than 1% discontinued treatment due to bilirubin elevations,
and only 5% developed jaundice.2
In a study of protease inhibitor-experienced patients, two-thirds
exhibited elevations in bilirubin, of whom 10% experienced very
severe elevations.1 Reversible hyperbilirubinaemia, rated grade 3
and 4 occur in 35 to 47% of patients. This does not mean therapy
should be discontinued or that there is actual liver disease. It is
usually a benign development.
The risk of bilirubin elevations in individuals receiving atazanavir
is dose-related, being most prevalent at higher drug
concentrations.3 4 Data have also shown that it is more common
in patients taking ritonavir-boosted atazanavir than those taking
the drug without boosted atazanavir.5
It has been shown that those with a particular version of the gene
for an enzyme involved in bilirubin metabolism are at an elevated
risk of developing hyperbilirubinaemia when taking atazanavir.6 A
variant of the multidrug resistance gene 1 is also linked to
atazanavir levels and the risk of
hyperbilirubinaemia.7 Polymorphisms at MDR1-3435 significantly
influence atazanavir plasma concentrations, as do other factors.
The risk of severe hyperbilirubinaemia is further increased in the
presence of the UGT1A1-TA7 allele.

Lipodystrophy
Several comparative studies have suggested that atazanavir may
not disrupt lipids to the same extent as other protease inhibitors.
In a study comparing atazanavir and nelfinavir (Viracept),
atazanavir was not associated with any significant increases in
cholesterol or triglyceride levels. In contrast, significant lipid
elevations occurred in the nelfinavir arm.8 This was confirmed in a
similar, second study comparing the two drugs.9 Studies 043 and
045 also showed that atazanavir had a superior lipid profile to
lopinavir, even when each drug is combined with ritonavir.10 1
There is also some evidence that atazanavir can reverse lipid
increases caused by other protease inhibitors. In one study,
switching from nelfinavir to atazanavir-based therapy returned
lipids to pre-treatment levels after three months, while maintaining
viral suppression for at least 36 weeks after the switch.11 These
findings have been confirmed in at least three other
studies.12 13 14 A case series of three protease inhibitor-
experienced patients with buffalo hump fat accumulation also
provided evidence that switching to atazanavir can reverse fat
redistribution, at least in part. All three patients experienced a
decrease in these fat deposits and falls in blood lipids after
switching to atazanavir, without significantly changing their diet or
exercise regimens.15
Atazanavir also has fewer effects on blood lipid levels than the
non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz
(Sustiva). For example, one large study comparing efavirenz and
atazanavir found that efavirenz recipients were significantly more
likely to experience increases in low-density lipoprotein (LDL or
bad) cholesterol and triglycerides. However, the rate of
discontinuation was similar in the two arms of the study.2
The two groups of patients also had similar increases in the levels
of fat under the skin and around the organs, suggesting that both
atazanavir and efavirenz may reduce the risk of fat loss due to
nucleoside reverse transcriptase inhibitor (NRTI)
treatment.16 However, this conclusion may be premature, since
the study only lasted 48 weeks, and there are uncertainties
surrounding the fat levels and CD4 cell counts of the patients at
the start of the study.17

Other side-effects
A small number of patients treated with atazanavir have
developed cardiac disturbances. Electrocardiogram monitoring is
recommended for people with existing heart conditions or who are
taking medication known to affect heart function. However, a
panel of experts who assessed atazanavir for approval found that
it did not provide any greater cause for concern than other
protease inhibitors.
Liver damage due to atazanavir treatment has only been reported
in a single case. This involved a 56-year-old HIV-positive woman
with no other risk factors for liver-related side-effects.18
Around 6% of patients taking atazanavir also develop a rash,
which may require treatment to be discontinued in a few cases.19
Atazanavir is not known to be associated with the development of
insulin resistance. A test tube study has shown that this is unlikely
to be affected by co-administration of atazanavir with ritonavir.20
References
1. Johnson M et al. Atazanavir plus ritonavir or saquinavir, and lopinavir /
ritonavir in patients experiencing multiple virological failures. AIDS 19:
685-694, 2005
2. Squires K et al. Comparison of once-daily atazanavir with efavirenz,
each in combination with fixed-dose zidovudine and lamivudine, as
initial therapy for patients infected with HIV. J Acquir Immune Defic
Syndr 36: 1011-1019, 2004
3. Gonzalez de Requena D et al. Atazanavir trough is associated with
efficacy and safety: definition of therapeutic range. Twelfth Conference
on Retroviruses and Opportunistic Infections, Boston, abstract 645,
2005
4. Rendon A et al. Safety profile of atazanavir and correlation with
plasma levels. 15th International AIDS Conference, Bangkok, abstract
TuPeB4624, 2004
5. Ward D et al. Hyperbilirubinemia among patients in the HIV outpatient
study (HOPS) receiving atazanavir. Third International AIDS Society
Conference on HIV Pathogenesis and Treatment, Rio de Janeiro,
abstract TuPe2.1B02, 2005
6. O'Mara E et al. Population pharmacodynamic assessment of
atazanavir exposure, uridine diphosphatase-glucoronosyl transferase
(UGT) 1A1 genotype and safety in healthy human subjects. 42nd
Interscience Conference on Antimicrobial Agents and Chemotherapy,
San Diego, abstract A-1253, 2002
7. Rodrguez-Nvoa S et al. Genetic factors influencing atazanavir
plasma concentrations and the risk of severe
hyperbilirubinemia. AIDS; 21(1): 41-46, 2007
8. Murphy R et al. Dose-ranging, randomized, clinical trial of atazanavir
with lamivudine and stavudine in antiretroviral-naive subjects: 48-week
results. AIDS 17: 2603-2614, 2003
9. Sanne I et al. Results of a phase 2 clinical trial at 48 weeks (A1424-
007): a dose-ranging, safety, and efficacy comparative trial of
atazanavir at three doses in combination with didanosine and
 stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr
32: 18-29, 2003
10. Nieto-Cisneros L et al. Antiviral efficacy, metabolic changes and
safety of atazanavir versus lopinavir / ritonavir in combination with
NRTIs in patients who have experienced virological failure with prior
PI-containing regimen(s): 24-week results from BMX A1424-
043. Second International AIDS Society Conference on HIV
Pathogenesis and Treatment, Paris, abstract 117, 2003
11. Wood R et al. Long-term efficacy and safety of atazanavir with
stavudine and lamivudine in patients previously treated with nelfinavir
or atazanavir. J Acquir Immune Defic Syndr 36: 684-692, 2004
12. Markowitz M et al. 48-week results of an atazanavir-based QD
regimen in patients switching from BID-based HAART. Antivir Ther 8:
S329, 2003
13. Martinez E et al. Effects of switching to ritonavir-boosted atazanavir
on HIV-infected patients receiving antiretroviral therapy with
hyperlipidemia. Twelfth Conference on Retroviruses and Opportunistic
Infections, Boston, abstract 850, 2005
14. Gatell JM et al. Efficacy of atazanavir (ATV) based HAART in
patients switched from a stable PI or boosted PI (PI/r) treatment.
Planned week 24 analysis of a phase IIIb 48 week multicenter, open-
label, randomized, prospective trial. The SWAN study. Third
International AIDS Society Conference on HIV Pathogenesis and
Treatment, Rio de Janeiro, abstract WePe6.3C15, 2005
15. Haerter G et al. Regression of lipodystrophy in HIV-infected
patients under therapy with the new protease inhibitor
atazanavir. AIDS 18: 952-955, 2004
16. Jemsek JG et al. Body fat and other metabolic effects of atazanavir
and efavirenz, each administered in combination with zidovudine plus
lamivudine, in antiretroviral-naive, HIV-infected patients. Clin Infect Dis
42: 273-280, 2006
17. Dube MP HIV-associated lipoatrophy: what are the kinder, gentler
agents? Clin Infect Dis 42: 281-282, 2006
18. Eholie SP et al. Acute hepatic cytolysis in an HIV-infected patient
taking atazanavir. AIDS 18: 1610-1611, 2004
19. Ouagari Z et al. Skin rash associated with atazanavir: report of
three cases. AIDS 20: 1207-1208, 2006
20. Noor MA et al. Maintenance of favorable in vitro metabolic profile of
atazanavir when combined with low dose ritonavir. 15th International
AIDS Conference, Bangkok, abstract ThOrB1356, 2004
PreviousNext

Resistance
As with all other anti-HIV drugs, strains of HIV that are resistant to
atazanavir (Reyataz) may emerge after a period of treatment. The
emergence of drug-resistant strains coincides with a fall in the
effectiveness of the drug .
Early resistance data suggested that atazanavir would usually be
active against HIV in people who have failed another protease
inhibitor. For example, only 5% of virus isolates with reduced
sensitivity to one protease inhibitor showed a similar reduction in
sensitivity to atazanavir. In contrast, only 30% of 63 virus isolates
with reduced sensitivity to three protease inhibitors and 67% with
reduced sensitivity to four or more protease inhibitors also
showed reduced sensitivity to atazanavir. Unsurprisingly, a
greater number of mutations was associated with reduced
sensitivity to atazanavir.1
More recent studies have suggested that atazanavir may not be
as active against protease inhibitor-resistant virus as previously
thought. In one study, 40% of people who had taken one protease
inhibitor had reduced sensitivity to atazanavir. Furthermore,
resistance testing showed that 3.5-fold resistance to other
 protease inhibitors reduced sensitivity to atazanavir in
approximately 80% of viral isolates.2 In addition, patients with
more protease inhibitor resistance mutations had a worse
outcome.3 4
Mutations in the protease gene that have been linked to
atazanavir resistance include:
L10I/V/F/R.
16E.

K20I/M/R.

L24I.

L33I/F/V.

M46I/L.

I54L/M/T/V.

Q58E.

60E.

L64P.

A71I/L/V/T.

G73A/C/F/T.

V77I.

V821/F/S/T.

I84V.

85V.
5
L90M.
The presence of more than five of these mutations reduces
susceptibility to atazanavir by threefold.6 7 A study of viral isolates
found that viruses resistant only to nelfinavir and ritonavir were
more likely to be susceptible to atazanavir than viruses resistant
to three or more protease inhibitors, suggesting that atazanavir
may be used in people who have experienced failure of nelfinavir
(Viracept) with a good chance of success.
On a positive note, the I50L mutation, which confers resistance to
atazanavir, may increase susceptibility to other protease
inhibitors. This unique mutation commonly emerges in people
who develop resistance to atazanavir taken as first-line therapy.
I50L significantly improves susceptibility to indinavir (Crixivan),
saquinavir (Invirase), lopinavir and ritonavir, and possibly
nelfinavir.8 9 10
References
1. Colonno RJ et al. Identification of amino acid substitutions correlated
with reduced atazanavir susceptibility in patients treated with
atazanavir-containing regimens. Antivir Ther 7: S4, 2002
2. Schnell T et al. Distinct cross-resistance profiles of the new protease
inhibitors amprenavir, lopinavir and atazanavir in a panel of clinical
samples. AIDS 17: 1258-1260, 2003
3. Barrios A et al. Atazanavir plasma levels associated with efficacy and
safety in protease inhibitor-experienced HIV-infected
patients. Eleventh Conference on Retroviruses and Opportunistic
Infections, San Francisco, abstract 606, 2004
4. Zala C et al. Virologic determinants of 24 week efficacy of atazanavir
with or without ritonavir in patients with prior failure on a protease
inhibitor. Ninth European AIDS Conference, Warsaw, abstract F7/2,
2003
5. Vora S et al. Clinical validation of atazanavir / ritonavir genotypic
resistance score in protease inhibitor-experienced patients. AIDS 20:
35-40, 2006
6. Naeger LK et al. Effect of baseline protease genotype and phenotype
on HIV response to atazanavir / ritonavir in treatment-experienced
patients. AIDS 20: 847-853, 2006
7. Pellegrin I et al. Virological responses to atazanavir-ritonavir-based
regimens: resistance-substitutions score amd pharmacokinetic
parameters (Reyaphar study). Antivir Ther 11: 421-429, 2006
8. Colonno R et al. Activities of atazanavir (BMS-232632) against a large
panel of human immunodeficiency virus type 1 clinical isolates
resistant to one or more approved protease inhibitors. Antimicrob
Agents Chemother 47: 1324-1333, 2003
9. Colonno R et al. Pathways to atazanavir resistance in treatment-
experienced patients and impact of residue 50 substitutions. Eleventh
 Conference on Retroviruses and Opportunistic Infections, San
Francisco, abstract 656, 2004
10. Weinheimer S et al. Recombinant HIV gag-pol proteins display
unique I50L phenotype of selective atazanavir resistance and
increased susceptibility to other PI. Eleventh Conference on
Retroviruses and Opportunistic Infections, San Francisco, abstract
625, 2004
PreviousNext

Drug interactions
Like other protease inhibitors, atazanavir (Reyataz) is
metabolised through the cytochrome P450 system, and is a
specific inhibitor of the CYP3A4 enzyme. This means that it may
interact with a wide variety of drugs also metabolised through this
pathway .
Many other drugs using the CYP3A4 enzyme should not be given
with atazanavir, as their levels may be increased in the body.
These include:
Alfuzosin
Astemizole
Bepridil
Cisapride
Colchicine in patients with renal or hepatic impairment
 Ergotamine tartrate (Cafergot/Migril)
Flecainide acetate (Tambocor)
Fluticasone propionate (Flixotide)
Halofantrine

Hypericin (St Johns wort)

Lovastatin

Lumefantrine

Midazolam (Hypnovel)
Pimozide (Orap)
Propafenone (Arythmol)
Quinidine (Kinidin Durules)
Rifampicin (Rifadin / Rimactane)
Simvastatin (Zocor)
Terfenadine

Triazolam

Voriconazole (Vfend).
Atazanavir also inhibits P-glycoprotein and the multidrug
resistance-associated protein, which pump foreign substances,
including some drugs, out of cells. This could explain the
observation that the blood disorders caused by many
chemotherapy drugs are more severe in patients taking protease
inhibitors.
When atazanavir is taken with drugs to treat acid reflux disease
and related symptoms, the AUC of atazanavir decreases
significantly. Studies have shown that taking atazanavir with
proton-pump inhibitors such as omeprazole (Losec) and
esomeprazole (Nexium) or H2-receptor blockers (e.g.
ranitidine/Zantac and cimetidine/Dyspamet, Tagamet)) results in
lowered blood atazanavir concentrations in HIV-negative patients.
Proton-pump inhibitors should not be used in treatment-
experienced patients receiving atazanavir. In treatment-naive
patients, the proton-pump inhibitor dose should not exceed a
dose comparable to omeprazole 20mg and must be taken
approximately 12 hours prior to the atazanavir/ritonavir
300/100mg dose.
According to the Bristol-Myers Squibb package insert, ARV-naive
patients taking omeprazole (or other proton pump inhibitor drugs)
with an atazanavir-containing regimen decrease atazanavir
exposure by 30 to 65%. When use of the two drugs is
unavoidable, the drugs should be taken 12 hours apart, close
clinical monitoring is recommended, and an increase in
the atazanavir dose to 400mg boosted with 100mg ritonavir is
recommended.
In ARV-experienced patients on an atazanavir-containing
regimen, the H2-receptor antagonist dose should not exceed the
dose-equivalent of 20mg famotidine taken twice daily. Atazanavir
and ritonavir should be administered simultaneously with, or at
least 10 hours after, the H2-receptor antagonist.
This advisory was issued despite an earlier study carried out in
HIV-positive patients that failed to show reduced atazanavir levels
when combined with low-dose ritonavir.1 In that study, PPIs did
not have a significant effect on the outcomes of antiretroviral
therapy containing ritonavir-boosted atazanavir.2 The study
investigators claim that the effects of omeprazole may be less
important in patients with HIV because of possible reduced
stomach acid levels. Differences in study design and variability in
drug levels may have also led to confusion over the relationship
between these drugs.3 [ref Regardless, current (as of July 2008)
directives on co-administration of atazanavir with acid-reducing
medications have now been made clear.
Atazanavir slows the clearance of saquinavir (Invirase), resulting
in elevated levels of saquinavir.4 A double-boosted protease
inhibitor regimen of atazanavir, saquinavir and ritonavir results in
elevated levels of saquinavir and ritonavir and may be useful in
salvage therapy.5 6 7
Atazanavir should not be taken with indinavir, since both drugs
can cause elevated bilirubin levels. Although it has not been
tested in human trials, taking both drugs together is expected to
increase drug levels and the risk of this side-effect occurring.
Nevirapine use is also not recommended with atazanavir.
When atazanavir is dosed with efavirenz (Sustiva), atazanavir
levels are reduced by around 70%. Adding low-dose ritonavir
counteracts this effect in HIV-negative volunteers, but a small
study has found that this may not be the case in people with
HIV.8 9 10 A similar effect of nevirapine has also been seen in a
small study. Both drugs are CYP3A4 inducers, which means that
they speed up metabolism of other drugs metabolised by the
same route.10
Combining atazanavir with tenofovir (Viread) may put a patient at
risk of treatment failure, since tenofovir can reduce atazanavir
levels by up to 40%.11 12 Atazanavir can also increase the
likelihood of tenofovir-associated adverse events, including kidney
disorders. Doctors should consider boosting atazanavir levels with
ritonavir, if atazanavir and tenofovir must be used together,
although studies have shown that this is not always successful in
restoring atazanavir levels.13 10
Given the poor results of the ACTG 5175 study arm looking
at atazanavir with enteric-coated didanosine and emtricitabine, an
alternative regimen is recommended.14 If this is the only treatment
option, patients are advised to take the ec-ddI/FTC on an empty
stomach and at least two hours before or after taking atazanavir
with food.
Sildenafil is contraindicated when used for treatment of pulmonary
arterial hypertension.
 Some drugs require dose adjustments when taken with
atazanavir. The following drugs need to be taken at lower doses:
Clarithromycin (Klaricid / Klaricid EC): the dose should be
halved.
Diltiazem (Tildiem / Angiozem / Optil): the dose should be
halved.
Rifabutin (Mycobutin): the dose should be reduced by up to
75% (150mg every day or three times a week) when atazanavir
is dosed at 400mg once daily.15
Atazanavir has been observed to increase levels of the hormonal
contraceptives ethinylestradiol and norethindrone. No guidance is
available at present on appropriate dose reductions or
interactions with other contraceptives. There have also been at
least three case reports of elevated levels of buprenorphine,
which is used to treat opiate addiction, in patients taking
atazanavir.16 A dose reduction may be necessary. In contrast, no
dose adjustment of methadone (Methadose) is needed.17
References
1. Guiard-Schmid JB et al. Proton pump inhibitors do not reduce
atazanavir concentrations in HIV-infected patients treated with
ritonavir-boosted atazanavir. AIDS 19: 1937-1938, 2005
2. Furtek KJ et al. Proton pump inhibitor therapy in atazanavir-treated
patients: contraindicated? J Acquir Immune Defic Syndr 41: 394-395,
2006
3. Guiard-Schmid JB et al. Lack of interaction between atazanavir and
proton pump inhibitors in HIV-infected patients treated with ritonavir-
boosted atazanavir. J Acquir Immune Defic Syndr 41: 393-394, 2006
4. Haas DW et al. Therapy with atazanavir plus saquinavir in patients
failing highly active antiretroviral therapy: a randomized comparative
pilot trial. AIDS 17: 1339-1349, 2003
5. von Hentig NH et al. The ATSAQ-1 cohort study: pharmacokinetic
interactions of atazanavir (AZV) and saquinavir (SQV) in a ritonavir
(RTV) boosted protease inhibitor therapy regimen. 15th International
AIDS Conference, Bangkok, abstract WeOrB1235, 2004
6. Boffito M et al. Atazanavir but not ritonavir impacts the elimination half-
life of saquinavir hard gel in HIV+ subjects. 44th Interscience
Conference on Antimicrobial Agents and Chemotherapy, Washington,
abstract A-452, 2004
7. Boffito M et al. Pharmacokinetics of saquinavir hard-gel / ritonavir and
atazanavir when combined once daily in HIV type 1-infected
individuals administered different atazanavir doses. AIDS Res Hum
Retroviruses 22: 749-756, 2006
8. Tackett D et al. Atazanavir: a summary of two pharmacokinetic drug
interaction studies in healthy subjects. Tenth Conference on
Retroviruses and Opportunistic Infections, Boston, abstract 543, 2003
9. Poirier JM et al. Critical drug interaction between ritonavir-boosted
atazanavir regimen and non-nucleoside reverse transcriptase
inhibitors. AIDS 20: 1087-1089, 2006
10. Dailly E et al. Influence of tenofovir, nevirapine and efavirenz on
ritonavir-boosted atazanavir pharmacokinetics in HIV-infected
patients. Eur J Clin Pharmacol 62: 523-526, 2006
11. Kaul S et al. Pharmacokentic evaluation of the combination of
atazanavir (ATV), enteric coated didanosine (ddI-EC), and tenofovir
disoproxil fumarate (TDF) for a once-daily antiretroviral regimen. 43rd
Interscience Conference on Antimicrobial Agents and Chemotherapy,
abstract A-1616, 2003
12. Agarwala S et al. Pharmacokinetic interaction between tenofovir
and atazanavir in healthy subjects. Third International AIDS Society
Conference on HIV Pathogenesis and Treatment, Rio de Janeiro,
abstract WePe3.3C07, 2005
13. Taburet AM et al. Interactions between atazanavir-ritonavir and
tenofovir in heavily pretreated human immunodeficiency virus-infected
patients. Antimicrob Agents Chemother 48: 2091-2096, 2004
14. National Institute of Allergy and Infectious Disease Monitoring
Board recommends stopping experimental treatment regimen in
international study of patients new to HIV treatment. NIAID Bulletin,
available online at
www3.niaid.nih.gov/news/newsreleases/2008/ACTG_5175 [accessed
28 October 2008], 2008
15. Agarwala S et al. Pharmacokinetic (PK) effect of rifabutin (RIF) on
atazanavir (ATV) with and without ritonavir (RTV) in healthy
 subjects. Ninth Conference on Retroviruses and Opportunistic
Infections, Seattle, abstract 445, 2002
16. Bruce RD et al. Three case reports of a clinical pharmacokinetic
interaction with buprenorphine and atazanavir plus ritonavir. AIDS 20:
783-784, 2006
17. Friedland G et al. Lack of an effect of atazanavir on steady-state
pharmacokinetics of methadone in patients chronically treated for
opiate addiction. AIDS 19: 1635-1641, 2005
PreviousNext

Children
In 2008, the US Food and Drug Administration (FDA) issued
revised dosing recommendations for the use of the atazanavir
(Reyataz) in children, to allow its use in children six years of age
and older.
Atazanavir dosing in children up to age 18 is based upon body
weight, but should never exceed the adult
recommended dose. Atazanavir with ritonavir-boosting can be
used in all children 6 to 18 years, regardless of ARV experience.
Atazanavir should always be taken with food. Weight-based
dosing can be found at the Bristol-Myers Squibb website online
at http://packageinserts.bms.com/pi/pi_reyataz.pdf or at the
website of the National Institutes of Health
(NIH), http://aidsinfo.nih.gov.
In the US, if a treatment-naive patient aged 13 years and older
and weighing at least 39 kilos cannot tolerate ritonavir, the
recommended dose is atazanavir 400mg once daily with food.
The use of atazanavir is not recommended in children younger
than 6 years; without ritonavir in children from 6 to 12 years, or for
any child whose weight is less than 25 kilos.
Additionally, based on results from the ACTG 5175, unboosted
atazanavir should not be used in a regimen for treatment-naive
patients with enteric-coated didanosine (ddI) and emtricitabine
(FTC).1
In clinical trial P1020A it was discovered that to achieve
pharmacokinetic targets in children between the ages of 6 and 13
years when using unboosted atazanavir required dosing
at 520mg/per metre2 of body surface, never to exceed 400mg.2
Atazanavir cannot be used in infants because of the risk of
kernicterus, a type of brain damage caused by excess levels of
bilirubin.
The safety profile of atazanavir in children is similar to adults. The
most commonly observed moderate to severe side-effects are
cough (21%), fever (19%), jaundice (13%), diarrhoea (8%),
vomiting (8%), headache (7%), and runny nose (6%). Increased
levels of bilirubin were found in the blood of 49% of patients. In
the P1020A study, 8.5% of patients had a bilirubin level more than
5 times the upper limit of normal.3
References
1. National Institute of Allergy and Infectious Disease Monitoring Board
recommends stopping experimental treatment regimen in international
study of patients new to HIV treatment. NIAID Bulletin, available online
at www3.niaid.nih.gov/news/newsreleases/2008/ACTG_5175
[accessed 28 October 2008], 2008
2. Panel on antiretroviral therapy and medical management of HIV-
infected children Guidelines for the use of antiretroviral agents in
pediatric HIV infection. August 16, 2010; pp1-219. Available at
 http://aidsinfo.nih.gov/ContentFiles/PediatricGuidelines.pdf (accessed
November 13, 2010)., 2010
3. Rutstein R et al. Effect of atazanavir on serum cholesterol and
triglyceride levels in HIV-infected infants, children and adolescents:
PACTG 1020A. Twelfth Conference on Retroviruses and Opportunistic
Infections, Boston, abstract 774, 2005
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Pregnancy
Atazanavir is only recommended in pregnancy if potential benefits
outweigh the risks. There is little known about the drug's use in
pregnancy. In a small observational study involving nine pregnant
women, the drug was well tolerated. Six of the women used
ritonavir-boosted atazanavir.1
References
1. Morris A et al. Atazanavir use in pregnancy. Third International AIDS
Society Conference on HIV Pathogenesis and Treatment, Rio de
Janeiro, abstract TuPe5.2P01, 2005
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