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Antiviral Therapy 2012; 17:1385–1388 (doi: 10.3851/IMP2182)
Case report
Severe dyslipidaemia after the addition of raltegravir
to a lopinavir/ritonavir-containing regimen
Emily Huesgen1, Rodrigo Burgos1, Debra A Goldstein2, Blake Max1,3, Olamide D Jarrett4*
Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, IL, USA
Department of Ophthalmology, University of Illinois at Chicago, Chicago, IL, USA
3
CORE Center, John H Stroger, Jr. Hospital of Cook County, Chicago, IL, USA
4
Division of Infectious Diseases, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
1
2
*Corresponding author e-mail: [email protected]
We describe a 55-year-old HIV-1-infected male who
developed severe dyslipidaemia (total cholesterol 600 mg/
dl, triglycerides >5,000 mg/dl, high density lipoprotein
<5 mg/dl) after raltegravir was added to his lopinavir/
ritonavir-containing regimen. To our knowledge, this is the
first reported case of severe dyslipidaemia associated with
the addition of raltegravir to a lopinavir/ritonavir-based
regimen, suggestive of a possible drug interaction. The
lipid profile quickly normalized following discontinuation
of lopinavir/ritonavir and continuation of raltegravir,
suggesting that lopinavir/ritonavir was the primary
driver for the adverse event. With increasing interest
in nucleoside-sparing regimens, knowledge of clinically
significant adverse events such as this is important for
HIV clinicians when selecting regimens for patients with
highly resistant virus or drug tolerability issues.
Introduction
There are currently 24 FDA-approved antiretroviral
medications for the treatment of HIV-1 infection,
resulting in a vast number of potential drug
combinations. More than half of these drugs are
metabolized by hepatic cytochrome P450 enzymes,
of which inhibition or induction can alter drug
pharmacokinetics leading to subtherapeutic or
supratherapeutic plasma concentrations. Although
the pharmaceutical industry has been vigilant in
conducting preclinical drug-interaction and safety
studies, data are limited due to the small size of these
studies and the intra- and inter-patient variability.
Clinicians depend on post-marketing data and case
reports to add to the body of literature regarding
potential drug interactions and adverse events from
antiretroviral medications.
We describe a patient who was diagnosed with
lipaemia retinalis after a routine retinal exam. The acute
onset of severe dyslipidaemia was evident after raltegravir
(RAL) was added to his lopinavir/ritonavir (LPV/RTV)containing regimen, suggesting a possible drug–drug
interaction that led to the significant adverse event. To
our knowledge, this is the first reported case of severe
dyslipidaemia associated with the addition of RAL, an
HIV-1 integrase inhibitor, to an LPV/RTV-based regimen.
©2012 International Medical Press 1359-6535 (print) 2040-2058 (online)
AVT-11-CR-2388_Huesgen.indd 1385
Case report
A 55-year-old asymptomatic African American male
with multidrug resistant HIV-1 infection developed
breakthrough viraemia of 125 and 160 copies/ml on
two consecutive clinic visits, over a 3 month interval,
despite reported 100% adherence to antiretroviral
therapy (ART). He previously had successful viral
suppression for 3 years while receiving a regimen of
LPV/RTV 400/100 mg twice daily, abacavir (ABC) 300
mg twice daily and tenofovir disoproxil fumarate (TDF)
300 mg once daily. Out of concern for evolving ABC
resistance, given known history of multiple thymidine
analogue mutations and the M184V mutation, ABC
was discontinued and RAL was added. Emtricitabine
(FTC) was also added as part of the fixed-dose
combination of FTC/TDF to promote M184V-induced
TDF hypersensitivity. He regained virological control to
<48 copies/ml at the subsequent follow-up visit.
In addition to HIV, the patient’s medical history
included dyslipidaemia, hypertension, benign prostatic
hyperplasia, hypogonadism, cataracts and mild renal
insufficiency (estimated creatinine clearance of 60 ml/
min) and he was taking the following medications
in addition to his ART: atorvastatin 10 mg daily,
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E Huesgen et al.
Figure 1. Fundus photographs of the patient’s retina
A
B
(A) Lipaemia retinalis; creamy appearance of all retinal vessels and salmon-coloured choroidal vasculature and (B) return of normal retinal vasculature colour after
normalization of triglycerides.
Table 1. Lipid panel timeline in relation to changes in antiretroviral therapy
Date
28/12/06
28/9/09
11/11/09
1/6/10
3/6/10
24/6/10
4/5/11
ART regimen
ABC, TDF, –
–
TDF, FTC, –
TDF, FTC, ETR, –
LPV/RTV
LPV/RTV, RAL
RAL
ART change–
–
ABC stopped; –
LPV/RTV stopped; ––
FTC, RAL added
ETR added
Cholesterol, mg/dl
225
143–600a
515
307
195
Triglycerides, mg/dl
449
193–5,364
5,168
90
198
HDL, mg/dl
43
36–
<5
<5
67
43
LDL, mg/dl
NA
68–NA
NA
222
112
Random lipid profile. All other lipid profiles listed are fasting. ABC, abacavir; ART, antiretroviral therapy; ETR, etravirine; FTC, emtricitabine; HDL, high-density
lipoprotein; LDL, low-density lipoprotein; LPV/RTV, lopinavir/ritonavir; NA, not able to calculate; RAL, raltegravir; TDF, tenofovir disoproxil fumarate.
a
ezetimibe 10 mg daily, fenofibrate 48 mg daily,
hydrochlorothiazide (HCTZ)/triamterene 25/37.5 mg
daily, feldopine ER 5 mg daily, tamsulosin 0.4 mg
daily and testosterone patch 5 mg/24 h daily. Of note,
no changes were made to these medications when his
ART was changed.
Seven months after starting his new ART regimen,
the patient presented to an ophthalmology clinic for a
routine follow-up visit to assess his cataracts. Dilated
fundoscopic exam revealed bilateral creamy arterioles
(Figure 1A), consistent with a diagnosis of lipaemia
retinalis due to severe hypertriglyceridaemia. During
physical examination the patient denied chest pain,
abdominal pain, dyspnea, nausea/vomiting or headache.
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A stat lipid profile was obtained and the results
confirmed the diagnosis of severe dyslipidaemia with
total cholesterol 600 mg/dl, triglycerides 5,364 mg/dl
and high-density lipoprotein (HDL) less than 5 mg/dl. A
fasting lipid panel 48 h later confirmed the results with
total cholesterol 515 mg/dl, triglycerides 5,168 mg/dl
and HDL <5 mg/dl (Table 1). Of note, six weeks prior
to the ART change, the patient’s total cholesterol was
143 mg/dl, triglycerides 193 mg/dl, HDL 36 mg/dl, and
low-density lipoprotein (LDL) 68 mg/dl. Medication
non-adherence and new alcoholism were ruled out as
potential causes of the acute worsening of dyslipidaemia.
Follow-up laboratory testing also ruled out new onset
diabetes mellitus, hypothyroidism, pancreatitis and
©2012 International Medical Press
26/10/2012 14:34:48
Raltegravir and lopinavir/ritonavir-associated dyslipidaemia
nephrotic syndrome as potential causes, with fasting
glucose, haemoglobin A1C, thyroid stimulating hormone,
lipase and random urine protein all within normal limits.
Thus, the patient’s severe dyslipidaemia was believed to
be due to the recent changes in his antiretroviral therapy.
LPV/RTV was subsequently discontinued because it was
felt to be the main driver of his lipid abnormalities and
etravirine 200 mg twice daily was initiated. In addition,
his fenofibrate was increased to 160 mg daily and he
was started on omega-3 fatty acids 2 gm twice daily.
The atorvastatin was held temporarily out of concern
for increased risk of rhabdomyolysis when combined
with high-dose fenofibrate. A repeat fasting lipid panel
was performed two weeks later and his triglycerides
had decreased to 90 mg/dl. His prior lipid-lowering
regimen was resumed. The patient followed up with
ophthalmology 4 months later and on exam the previous
retinal findings had completely resolved (Figure 1B).
Triglycerides, LDL-cholesterol and total cholesterol
have remained well controlled since that time.
Discussion
Dyslipidaemia is a known side effect of RTV-boosted
protease inhibitors (PI). The mechanism of action
for PI-induced dyslipidaemia is not well understood.
Genetics, prior use of PIs and boosting with RTV
are thought to contribute to dyslipidaemia [1–3].
Some studies have shown a correlation between LPV
concentrations and lipid abnormalities [4,5], however,
a recent study did not find this association [6]. The
onset of dyslipidaemia following initiation of LPV/
RTV typically occurs during the first 2–3 months of
therapy and stabilizes thereafter [7–9]. Our patient had
significant dyslipidaemia during LPV/RTV initiation,
which required three-drug therapy for management;
however, this had been controlled with antilipidaemic
medications for almost 3 years prior to the addition of
RAL (Table 1).
Emtricitabine is not known to cause dyslipidaemia,
but was added at the same time as RAL, so it cannot be
excluded. However, it is an unlikely contributor, as his
lipid profile remained within normal limits while on this
medication, following the discontinuation of LPV/RTV.
In reviewing his non-HIV medications, HCTZ has been
reported to cause lipid increases, but elevations typically
occur within the first two weeks of initiation [10]. Our
patient had been taking HCTZ for several years without
any side effects and thus it is unlikely that HCTZ was
associated with the acute lipid changes.
The patient was never re-challenged with the
LPV/RTV–RAL combination. However, the onset
of dyslipidaemia after RAL initiation and rapid
resolution following LPV/RTV cessation is suggestive
of a combined effect of LPV/RTV and RAL on lipids.
Antiviral Therapy 17.7
AVT-11-CR-2388_Huesgen.indd 1387
We believe that LPV/RTV was the main driver of our
patient’s dyslipidaemia because his lipid profile rapidly
normalized following discontinuation of LPV/RTV
and continuation of RAL. Using the Naranjo Adverse
Drug Reaction Probability Scale, a well-validated
method for establishing causality of an adverse
drug-related event, the calculated Naranjo score is
8, indicating a probable adverse drug event (definite
adverse drug-related event defined as a score ≥9) [11].
The elevations in total cholesterol and triglycerides
observed in our patient coincide with preliminary
data from the PROGRESS Study, a safety and efficacy
study comparing RAL plus LPV/RTV to LPV/RTV
plus FTC/TDF in treatment-naive patients. Data at
48-weeks suggest that LPV/RTV in combination with
RAL was associated with significant mean increases
in triglycerides (99 versus 59 mg/dl; P=0.044),
total cholesterol (46 versus 29 mg/dl; P=0.008) and
HDL-cholesterol (12 versus 8 mg/dl; P=0.015) from
baseline in comparison to LPV/RTV plus FTC/TDF,
an unexpected finding [12]. Our patient, however,
experienced a significant decrease in HDL-cholesterol
in contrast to the HDL increases reported in the
PROGRESS study.
RAL has not been associated with hyperlipidaemia
in large randomized clinical trials [13]. In the
SWITCHMRK trials, patients who were switched
from LPV/RTV to RAL had greater reductions in total
cholesterol (-12.6% versus 1%), non-HDL cholesterol
(-15% versus 2.6%) and triglycerides (-42.2% versus
6.2%) compared to patients that remained on regimens
containing LPV/RTV (P<0.0001) [14]. Lipid data from
two other nucleoside-sparing studies comparing RAL
plus a PI (either unboosted atazanavir or boosted
darunavir) to RAL plus FTC/TDF were similar between
study arms, suggesting that lipid elevations observed
in the PROGRESS study are unique to LPV/RTV plus
RAL [15,16].
The mechanism for the lipid elevations observed in
our patient and in the PROGRESS study is unknown.
LPV is a known substrate of CYP3A4 and RTV
is a potent inhibitor of multiple cytochrome P450
enzymes [17]. However, RAL has not been shown to
be an inhibitor of CYP3A4 or P-glycoprotein mediated
transport, so it is unlikely that RAL-induced increases
in plasma LPV/RTV concentrations would explain
the effect seen [13]. It is plausible that RAL and LPV/
RTV share an unknown efflux or uptake transport
protein, which have been associated with unexpected
interactions with other antiretrovirals [18,19]. If
that is the case, then RAL could increase LPV/RTV
levels through alternate pathways leading to the
dyslipidaemia seen in our patient.
Of particular concern is that our patient was
asymptomatic when diagnosed with lipaemia retinalis
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E Huesgen et al.
so it is unknown how quickly our patient’s lipids
reached such dangerously elevated levels in relation to
his regimen change. HIV infection and dyslipidaemia
are both known risk factors for cardiovascular disease,
which can lead to life-threatening acute coronary
syndromes [20].
Conclusion
This is the first reported case of a possible drug
interaction between RAL and LPV/RTV leading to
severe dyslipidaemia. Clinicians should be alerted to the
possibility that regimens containing this combination
may greatly alter lipid profiles, even in patients that
have tolerated LPV/RTV in the past. We recommend
careful monitoring of fasting lipid profiles for patients
on this antiretroviral combination. Further prospective
safety studies with this antiretroviral combination are
warranted.
Disclosure statement
The authors declare no competing interests.
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Accepted 13 February 2012; published online 22 June 2012
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