Download Use of HMG-CoA Reductase Inhibitors in the HIV Population

C O M M E N TA R Y
Use of HMG-CoA Reductase Inhibitors in the HIV Population:
Implications for Individualized Treatment Selection
Ashish Advani, PharmD; Manish Patel, PharmD, BCPS;
Roberto V. Pichardo, PharmD; Yolanda Whitty, PharmD; and Shreena Advani, PharmD
T
he World Health Organization reports that 34 million
people are living with human immunodeficiency virus
(HIV) worldwide.1 Several global organizations are
making concerted efforts to treat and prevent HIV, centered
around providing antiretroviral therapy (ART) to those who
are infected and those at risk for infection. The first antiretroviral (ARV), zidovudine, was approved in 1987. Zidovudine
belongs to the subclass known as nucleoside reverse transcriptase inhibitors (NRTIs). Since the advent of zidovudine, additional NRTIs and numerous other classes of ARVs have been
introduced to the market, including nonnucleoside reverse
transcriptase inhibitors (NNRTIs), protease inhibitors (PIs),
integrase inhibitors, fusion inhibitors, and coreceptor inhibitors. The use of these various classes in combination, known
as highly active ART (HAART), provided yet another breakthrough in HIV treatment. In 2008, the Antiretroviral Therapy
Cohort Collaboration collected data from several developed
countries that showed increased life expectancy for those who
began HAART at a CD4+ cell count > 200 per microliter of
blood.2
Although HAART benefits people living with HIV, ARVs are
not without significant risks. For instance, PIs, a key component of HAART, are associated with insulin resistance, lipodystrophy, dyslipidemia, and hepatoxicity. Notably, it has been
estimated that the prevalence of hyperlipidemia in patients
receiving PI-based ART may be close to 80%. The Department
of Health and Human Services (DHHS) guidelines recommend
the use of at least 3 ARVs in combination; of the 4 preferred
regimens for nonpregnant, treatment-naïve HIV patients,
2 contain PIs.3 Increased use of PIs and other ARVs, along
with an increase in life expectancy, are suggested factors that
explain a trend of increased hyperlipidemia diagnoses seen in
the HIV-infected population.
Statins are a class of medications used to block cholesterol
production in the liver. While statins are generally deemed
well tolerated, serious side effects such as lethal rhabdomyolysis can occur when concentrations are increased. Recently, a
review of drug-drug interactions between statins and PIs, with
an emphasis on metabolic pathways, was published. Of the
7 statins currently available (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin),
3 (atorvastatin, lovastatin, and simvastatin) are metabolized
through cytochrome P450 (CYP) 3A. All PIs except nelfinavir
are coadministered with ritonavir, which is considered a potent
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March 2014
3A inhibitor. Therefore, concurrent use of PIs and statins can
lead to decreased hepatic metabolism of statins and resultant
increased serum statin concentration. Further, cobicistat, a
new agent to be used in combination with various ARVs, is
considered another potent CYP3A inhibitor.4
Drug interactions between statins and ARTs are not limited
to PIs. Agents within the NNRTI class are also known to interact. In particular, efavirenz and etravirine have been noted to
alter levels of certain statins. These agents are known inducers of CYP3A enzymes, so they have the capacity to increase
metabolism of statins reliant on CYP3A4 for breakdown. The
DHHS guidelines report a 68% decrease in simvastatin levels,
up to a 43% decrease in atorvastatin levels, and a 44% decrease
in pravastatin levels when administered with efarvirenz. The
potential implication of this interaction is significant, since
efavirenz is a component of a preferred ARV regimen for nonpregnant, treatment-naïve HIV patients. Additionally, efavirenz
use has been associated with dyslipidemia. Other NNRTIs that
are noted to have the potential for an interaction with statins
include rilpivirine and nevirapine.3
This commentary offers a comprehensive collection of relevant clinical literature as well as analysis and discussion of
the potential interaction between statins and treatments for
HIV. After an overview of the HIV population and treatment,
observational data regarding statin use are examined. Finally,
implications are discussed in the context of personalized medication selection based on HIV population considerations.
■■  Overview of HIV Population and
Use of Concomitant Medications
HIV Comorbities
HIV infection is associated with several chronic conditions,
including cardiovascular disease (CVD), diabetes, renal disease, and bone disease. Deaths attributed to these non-AIDS
(acquired immune deficiency syndrome)-related comorbidities
in HIV-infected patients has increased over the past 15 years,
and an increasing number of guidelines are recommending
evaluation of risks for these conditions.5
The relative risk of developing CVD in HIV patients has
been estimated to be 61% higher than in non-HIV patients.6
The manifestation of coronary atherosclerosis in HIV patients
is hypothesized to be due to a higher prevalence of conventional risk factors (smoking, dyslipidemia, hypertension,
and insulin abnormalities); emerging risk factors (chronic
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Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection
inflammation, immune activation, and HIV-related senescence);
and the role of ART. These factors are suggested to play a crucial
role in the increased risk of CVD in the HIV population.7
The effects of HIV infection and ART on surrogate markers
of atherosclerosis and lipoprotein metabolism were evaluated
in HIV-positive treated and nontreated male patients (N = 46).
Participants were assigned to 1 of 3 study groups: treatmentnaïve (n = 19), treatment with an NNRTI-containing regimen
(n = 18), or treatment with a PI-containing regimen (n = 9).
Patients underwent assessment of surrogate markers of atherosclerosis and variables of lipoprotein metabolism at baseline
and at 12 months.8
In the PI treatment group, total cholesterol (TC) rose from
4.4 ± 0.9 to 6.1 ± 1.6 millimole per liter (mmol/L; P < 0.05 vs.
baseline) and triglycerides rose from 1.7 ± 1.0 to 2.5 ± 0.5
mmol/L (P < 0.05 vs. baseline), but no significant changes
were seen in other study groups. Carotid intima thickness,
low-density lipoprotein cholesterol (LDL-C), and high-density
lipoprotein cholesterol (HDL-C) did not significantly change
from baseline in any study groups.8
A cross-sectional study evaluated the effects of HIV infection
and ART on lipoprotein metabolism in HIV-positive treated
and nontreated and HIV-negative Caucasian male patients
(N = 86). Participants were assigned to 1 of 4 study groups:
HIV-negative (n = 33), HIV-infected treatment naïve (n = 11),
HIV-infected currently untreated (n = 14), or HIV-infected with
PI treatment (n = 28).9
TC and LDL-C were significantly lower in the HIV-infected
treatment-naïve group compared with each of the other 3 study
groups. Triglycerides were significantly lower, and HDL-C was
significantly higher in the HIV-negative group compared with
each of the other 3 study groups.9
A retrospective cohort analysis compared the mean age at
diagnosis, incidence rates (IR), and adjusted incidence rates
(aIR) by HIV status for myocardial infarction (MI), end-stage
renal disease (ESRD), and non-AIDS-defining cancer. The
study population included patients from the Veterans Aging
Cohort Study who were matched 1 HIV-positive to 2 HIVnegative by age, race, and clinical site from October 2003 to
September 2008. Outcomes were measured by incident occurrences of MI, ESRD, and non-AIDS-defining cancer.10
The number of MI, IR, and aIR was 286 versus 231, 1.31
(95% confidence interval [CI] = 1.17-1.47) versus 2.18 (95%
CI = 1.92-2.48), and 1.00 versus 1.81 (95% CI = 1.49-2.20) for
the HIV-negative (n = 56,456) and HIV-positive (n = 27,988)
groups, respectively.10
A Cox proportional hazards analysis was conducted to
examine the association of cumulative exposure to any statin
drug and mortality or onset of non-AIDS complications (CVD,
malignancies, and fragility fractures) in patients infected with
HIV on HAART. The study assessed 25,884 patients with HIV
with HAART exposure of greater than 14 days with a median
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follow-up time of 6.62 years. The association of cumulative
exposure to any statin and occurrences of death, CVD, malignancies, and fragility fractures was assessed.11
Of the patients evaluated, 9,082 (35%) were prescribed
statins. The total statin exposure was 26,487 patient years. The
hazard ratios per year of statin exposure of death, CVD, malignancies, and fragility fractures were 0.96 (95% CI = 0.90-1.02),
1.02 (95% CI = 0.98-1.06), 0.96 (95% CI = 0.92-1.00), and 0.90
(95% CI = 0.81-1.01), respectively.11
In summary, CVD disease is a significant comorbidity factor in the HIV population. Increased triglycerides have been
reported in HIV patients, especially those on protease inhibitors. HIV patients are also at increased risk for MI.
Concomitant Medication Needs
A cross-sectional analysis was conducted among patients
within the HIV Outpatient Study (HOPS) cohort who were
prescribed ARV therapy to characterize the extent of polypharmacy and its consequences in HIV-infected patients. The
HOPS is an ongoing prospective observational cohort study of
HIV-infected adults that has been collecting data since 1993.
Patients selected for this analysis (N = 3,810) had to have a
CD4 + T-lymphocyte count and HIV RNA viral load (VL)
recorded within 6 months before or during the 5-year study
period and had to have taken ARV therapy for > 2 weeks during the study period. The percentage of patients who were
prescribed ≥ 1 ARV/non-ARV combination that was contraindicated or had moderate to high evidence of interaction was
assessed within the 5-year study period.12
Lipid-lowering medications were used concomitantly within
the study’s 5-year observation period in 10% of the population
under 50 years of age (n = 2,498) and 22% of the population
aged 50 years or greater (n = 1,312). Among the patients analyzed, 267 (7%) were prescribed at least 1 contraindicated
ARV/non-ARV combination. The contraindicated combination
of ARV and statin therapy (lovastatin or simvastatin) was seen
in 50 out of 267 (19%) of these patients.12
A retrospective cohort study was performed to examine
drug trends associated with the concomitant use of statins
and PIs before new National Cholesterol Education Program
(NCEP) II guidelines (January 1, 1996, through December 31,
2000) were published, and after the guidelines were published
(January 1, 2001, through June 20, 2002). Adult patients who
had at least 2 prescriptions filled for ARV therapy (N = 4,505)
were categorized into 3 groups according to PI in combination
with pravastatin or atorvastatin (recommended), fluvastatin or
cerivastatin (alternative), and simvastatin or lovastatin (contraindicated). The incidence of PI use, overall combination PI and
statin use, and contraindicated PI-statin use combination in
the pre- and postguideline publication periods were recorded.13
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Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection
TABLE 1
TABLE 2
Prevalence of PI and Combined
PI-Statin Use Before and After
NCEP II Guidelines13
Preguidelines
Postguidelines
4,505
4,196
2,893(64.2) 2,122(50.6)
100(3.5) 168(7.9)
P Value
Included in cohort, N
Any PI use, n (%)
< 0.001
Combined PI-statin
< 0.001
use, n (%)
42(42.0) 35(20.8)
< 0.001
Contraindicated
combinations,a n (%)
aContraindicated combinations=PI+simvastatin or lovastatin.
NCEP = National Cholesterol Education Program; PI = protease inhibitor.
A total of 5,392 people received prescriptions for ARV drugs
during the study period. PI use decreased from 64.2% during
the preguideline period to 50.6% during the postguideline
period (P < 0.001).13 The results are summarized in Table 1.
These 2 studies show that lipid-lowering agents are often
prescribed in HIV patients, especially those over the age of 50.
Consequently, national cholesterol guidelines are important to
guide clinicians to prevent unintentional prescribing of contraindicated statins in patients receiving PI therapy.
HIV and Cholesterol
Treatment with PIs has been associated with hypercholesterolemia and hypertriglyceridemia in clinical trials.14 Ritonavir,
a PI used to boost drug concentrations of other PIs, increased
LDL-C by 16% and triglycerides by 26% after 2 weeks of
therapy at a boosting dose of 100 milligrams (mg) twice daily
in a study of healthy volunteers.15 Dyslipidemia has been
demonstrated with other PIs, including newer agents such as
tipranavir; however, dyslipidemia is not prominent with all
PIs.14 Atazanavir and darunavir, when boosted with ritonavir,
have demonstrated less dyslipidemia than the PI lopinavir at 48
weeks in clinical trials.16,17
When compared with PIs, NNRTIs have been associated
with less dyslipidemia in clinical studies.15 However, a trial
comparing use of the NNRTI efavirenz to atazanavir, a PI,
reported significantly increased dyslipidemia with efavirenz.18
In a multicenter, randomized trial comparing efavirenz to the
NNRTI nevirapine, efavirenz was shown to cause a 31.1%
increase in TC and a 49% increase in triglycerides compared
with a 26.9% and 20% increase for nevirapine, respectively.19
In general, NRTIs cause less dyslipidemia than both PIs and
NNRTIs.14 However, in clinical trials, treatment with NRTI
stavudine has been associated with larger increases in TC,
LDL-C, and triglyercides than with tenofovir, an NNRTI.20,21
Newer agents that are not classified as PIs, NNRTIs, or NRTIs,
such as raltegravir and maraviroc, are reported in clinical studies as being options that avoid dyslipidemia.14
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Overall Effects of Main ARV Drugs on
Lipid Profiles in HIV-Infected Patients14
Total
Antiretroviral
Cholesterol
PIs (boosted)
Lopinavir
hh
Atazanavir
h
Fosamprenavir
h
Saquinavir
hh
Darunavir
h
Tipranavir
hh
NNRTIs
Efavirenz
h
Nevirapine
h
NRTIs
Tenofovir
n/h
Abacavir
n/h
Lamivudine
n
Zidovudine
h
Stavudine
hh
CCR5 inhibitors
Maraviroc
n
Integrase inhibitors
Raltegravir
n/h
LDL-C
HDL-C
TGs
hh
n/h
h
hh
h
hh
n/i
n/i
n/i
n/i
n/i
n/i
hhh
n
hh
h
h
hhh
h
h
h
hh
h
n/h
n/h
h
n
h
hh
n/h
h
n
h
h
n/h
h
n
hh
hh
n
n/h
n
n/h
n/h
n
Note: hhh = very large increase; hh = moderate increase; h = small increase; n = no
change; n/h = no change or small increase; n/i = no change or small decrease.
ARV = antiretroviral; CCR5 inhibitors = CC chemokine receptor 5 entry inhibitors;
HDL-C = high-density lipoprotein cholesterol; HIV = human immunodeficiency
virus; LDL-C = low-density lipoprotein; NNRTIs = nonnucleoside reverse transcriptase inhibitors; NRTIs = nucleoside analog reverse transcriptase inhibitors;
PIs = protease inhibitors; TGs = triglycerides.
Finally, the effects on lipids attributed to enfuvirtide and
the newer antiretrovirals—rilpivirine, etravirine, elvitegravir/cobicistat and dolutegravir—have also been evaluated.
Compared with efavirenz, rilpivirine led to minimal changes
in LDL-C, HDL-C, TC, and triglycerides in 2 recently reported
trials.22,23 Similar observations were reported when etravirine
was compared with efavirenz in the Study of Etravirine
Neuropsychiatric Symptoms Versus Efavirenz Trial.24 In the
etravirine group, TC, HDL-C, and LDL-C increased by 0.40
mmol/L, 0.10 mmol/L, and 0.20 mmol/L, respectively. In the
efavirenz group, TC, HDL-C, and LDL-C increased by 1.0
mmol/L, 0.30 mmol/L, and 0.60 mmol/L, respectively. In univariate analyses, increases in TC, HDL-C, and LDL-C were all
significantly greater in the efavirenz group as compared with
the etravirine group.25 In another study, elvitegravir/cobicistat
(EVG/COBI) was compared with efavirenz. In the EVG/COBI
group, TC, HDL-C, and LDL-C increased by 0.25 mmol/L,
0.13 mmol/L, and 0.26 mmol/L, respectively. In the efavirenz
group, TC, HDL-C, and LDL-C increased by 0.49 mmol/L,
0.20 mmol/L, and 0.44 mmol/L, respectively.26 Similar to
elvitegravir, dolutegravir has minimal effects on lipids. In the
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Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection
TABLE 3
Statin Pharmacokinetics
Lovastatin57
CYP3A4
Simvastatin58 Pravastatin59
Fluvastatin60
a
CYP3A4
No CYP
CYP2C9 (75%), CYP2C8
(~5%), CYP3A4 (~20%);
saturable first-pass
metabolism
Rosuvastatin62
Pitavastatin63
Metabolism
CYP2C9 and
Primary: Hepatic
CYP2C19
glucuronidation (UGT1A3
and UGT2B7); minimal
CYP2C9 and, to a lesser
extent, CYP2C8
Bioavailability
< 5%
< 5%
17%
24%
Parent drug: 14% 20%; higher
51%; Cmax and AUC
lower in blacks
systemic active;
in Asians
than whites
metabolite: 30%
Lipophilic
Yes
Yes
No
Yes
Yes
No
Yes
Protein binding
> 95%
95-98%
~50%
98%
96%
88%
99%
Active metabolites
Yes
Yes
No
No
Yes
Yes
No
Elimination
3 hours
2 hours
1.8 hours
1.2 hours
7 to 14 hours;
19 hours
12 hours
half-life
metabolites: 20
to 30 hours
Onset of action
3 days
> 3 days
Several days
4 weeks
3 to 5 days;
1 week;
NA
max: 2 weeks
max: 4 weeks
Time to peak
2 to 4 hours 1.3 to 2.4 hours 1 to 1.5 hours
1 hour
1 to 2 hours
3 to 5 hours
1 hour
Excretion
Feces (~83%); Feces (60%);
Feces (70%);
Feces (90%);
NA
Feces (90%)
Feces (79%);
urine (10%)
urine (13%)
urine (20%)
urine (5%)
urine (15%)
a Pravastatin is not a CYP enzyme substrate, is in active drug form, and has no active metabolites formed via pharmacokinetic processes.30
AUC = area under the curve; Cmax = maximal concentration; CYP = cytochrome family of enzymes; NA = information not available.
SPRING-2 trial, dolutegravir raised TC, HDL-C, LDL-C, and
TG by 0.17 mmol/L, 0.07 mmol/L, 0.07 mmol/L, and 0.09
mmol/L, respectively.27 Finally, a substudy that prospectively
pooled data from the T-20 Versus Optimized Background
Regimen Only trials for 48 weeks evaluated the metabolic
effects of enfuvirtide. Optimized background (OB) was defined as
3 to 5 ARVs prescribed based on treatment history and genotypic and phenotypic resistance data. In the enfuvirtide + OB
group, TC, HDL-C, LDL-C, and triglycerides increased by
0.6 (95% CI = 0.37-0.78) mmol/L, 0.11 (95% CI = 0.08-0.13)
mmol/L, 0.28 (95% CI = 0.15-0.40) mmol/L, and 0.48 (95%
CI = -0.16-1.11) mmol/L, respectively. In the OB only group,
TC, HDL-C, LDL-C, and triglycerides increased by 0.9 (95%
CI = 0.53-1.34) mmol/L, 0.15 (95% CI = 0.08-0.21) mmol/L,
0.31 (95% CI = -0.02-0.64) mmol/L, and 0.78 (95% CI = 0.01.56) mmol/L, respectively. The authors concluded that the
addition of enfuvirtide to an OB regimen did not appear to
have unfavorable effects on metabolic parameters.28 A summary of the effects of HIV medications on cholesterol and
triglycerides is presented in Table 2.
■■  Statin Use in the HIV Population
Metabolism of Statins
Most of the statins undergo significant metabolism via 1 or
more of the CYP450 enzymes located in the gastrointestinal
tract and liver, but some have minor or no metabolism via the
CYP450 system. The pharmacokinetic parameters of statins
available in the United States are summarized in Table 3.
Lovastatin, simvastatin, and, to a lesser extent, atorvastatin undergo significant metabolism via CYP3A4 isozymes.
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Atorvastatin61
CYP3A4
Pravastatin depends on glucuronidation for metabolism, has
minimal interaction with the CYP450 system, and is excreted
in an unchanged form. Fluvastatin is metabolized predominantly by CYP2C9 isozymes. Rosuvastatin undergoes minimal
metabolism via CYP450 (CYP2C9 and CYP219) and is primarily excreted in a nonmetabolized form in the feces. Pitavastatin
undergoes metabolism predominantly through glucuronidation (UGT1A3 and UGT2B7), with some minor metabolism
via CYP2C9 and CYP2C8. An understanding of the metabolic
pathways of statins may help predict potential drug-drug
interactions between statins and drugs that inhibit or induce
CYP450 enzymes, including ARVs.
Potential Drug Interactions with ART
The PIs, the NNRTI delavirdine, and cobicistat inhibit the
CYP3A4 enzymes and thus have the potential to significantly
increase statin levels. No significant interactions occur between
statin drugs and nucleoside (or nucleotide) reverse transcriptase inhibitors raltegravir, enfuvirtide, or maraviroc.
Nevirapine and efavirenz have the potential to induce
CYP3A4 and thus reduce the level of statin drugs that are
metabolized via CYP3A4. Although efavirenz is a mixed inhibitor and inducer of CYP3A4, it primarily induces metabolism of
CYP3A4 substrates. Co-administration of efavirenz (600 mg)
with either simvastatin (40 mg once daily), atorvastatin (10
mg once daily), or pravastatin (40 mg once daily) resulted in
significant reductions in the area under the curve (AUC) at 0 to
24 hours for all 3 statins: 58% reduction for simvastatin, 43%
for atorvastatin, and 40% for pravastatin.29 A separate study
found that patients on an efavirenz-based ARV regimen who
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Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection
TABLE 4
Statin
Crestor
(rosuvastatin)
Severity of Clinically Significant Drug Interactions Between Statins and PIs Reported64
PI
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir/ritonavir
Nelfinavir
Saquinavir
Tipranavir
Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir/ritonavir
Nelfinavir
Saquinavir
Tipranavir
All PIs
Risk Categorya
D
D
D
D
D
D
D
D
D
D
D
D
D
D
D
X
NA
Level of
Documentation
Good
Fair
Fair
Fair
Excellent
Fair
Fair
Fair
Fair
Excellent
Excellent
Fair
Excellent
Fair
Good
Excellent
NA
Recommendation/Clinical Management
• Initiate lowest possible rosuvastatin dose of 5 mg/day not to exceed
10 mg/day when combined with atazanavir or lopinavir/ritonavir.
• Monitor for statin toxicity.
• Evaluate benefit/risk ratio.
• Titrate atorvastatin dose and use lowest clinically effective dose, not
to exceed 20 mg daily.
• Monitor for RhM, during initial months of therapy and titrations
upward of the statin or PI.
Lipitor
• Consider periodic creatine phosphokinase level monitoring.
(atorvastatin)
• If RhM is diagnosed or suspected, temporarily withhold or discontinue atorvastatin.
• Consider using other statins such as pravastatin or fluvastatin.
• Avoid this combination.
Lescol (fluvastatin)
• No interactions of risk category A or greater identified.
• Monitor clinical response to pitavastatin closely, including lipid
Atazanavir
C
Fair
Livalo
response and signs and symptoms of muscle and liver toxicity.
(pitavastatin)
Lopinavir/ritonavir
B
Fair
• No action needed.
Mevacor (lovastatin) All PIs
X
Fair
• Avoid this combination.
Darunavir
C
Fair
• Monitor for signs and symptoms of pravastatin toxicity.
• Monitor for increased effects of Pgp substrates such as pravastatin
Lopinavir/ritonavir
C
Fair
since lopinavir/ritonavir is a Pgp inhibitor.
Pravachol
Nelfinavir
C
Good
•
Monitor for reduced pravastatin pharmacological effects/increased
(pravastatin)
dose requirements.
Saquinavir
C
Good
• Monitor for increased effects of Pgp substrates such as pravastatin,
Tipranavir
C
Fair
since tipranavir is a Pgp inhibitor.
Zocor (simvastatin) All PIs
X
Fair-Good
• Avoid this combination.
a Risk categories: X = avoid combination; D = consider therapy modification; C = monitor therapy; B = no action needed.
mg/day = milligrams per day; NA = not applicable; Pgp = P-glycoprotein; PI = protease inhibitor; RhM = rhabdomyolysis.
received simvastatin (20 mg once daily) had good but not optimal decreases in LDL-C levels and no major adverse effects.30
Etravirine is an inducer of CYP3A, but an inhibitor of CYP2C9,
CYP2C19, and P-glycoprotein. Efavirenz, nevirapine, and etravirine have the potential to decrease plasma concentrations
of statins and thus lead to a reduced lipid-lowering response.
Rilpivirine is not likely to cause significant alterations in the
levels of statins. Delavirdine inhibits CYP3A4, but this ARV
medication is rarely used.31
All PIs are metabolized by the enzyme CYP3A4, and all inhibit
CYP3A4 to some degree. Accordingly, all PIs can increase the
plasma concentration of the statin drugs that also undergo metabolism via CYP3A4. The degree of PI inhibition of CYP3A4 varies,
with the greatest effect caused by ritonavir-boosted PI combinations.31 Simvastatin and lovastatin are contraindicated with all PIs
and elvitegravir/cobicistat because of the potential for significant
elevations in statin drug concentration and risk of toxicity.3 Both
lopinavir/ritonavir and atazanavir/ritonavir may significantly
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increase plasma concentrations of rosuvastatin. Because of this,
the U.S. Food and Drug Administration (FDA) recommends not
exceeding rosuvastatin doses greater than 10 mg once daily when
used in conjunction with either lopinavir/ritonavir or atazanvir/ritonavir. Similarly, atorvastatin plasma concentration may
increase when given with PIs. The FDA recommends not exceeding an atorvastatin dose of 20 mg daily when prescribed with
darunavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, or fosamprenavir alone. Atorvastatin doses should not exceed
40 mg daily when given with nelfinavir and should be avoided
altogether when given with tipranavir/ritonavir. For patients on
lopinavir/ritonavir, atorvastatin should be cautiously used at
the lowest atorvastatin dose necessary. Neither pravastatin nor
pitavastatin are expected to be affected significantly by PIs. No
dose limitations are recommended with either of these medications when prescribed with lopinavir/ritonavir or darunavir/
ritonavir. Also, no dose limitation is recommended when
pitavastatin is given with atazanavir/ritonavir.32 Limited
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Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection
interaction data is available for fluvastatin; however, given its
inferior anticholesterol activity, this particular statin is infrequently used in the clinical setting. The major reported drug
interactions between statins and PIs are summarized in Table 4.
Efficacy Studies of Statins in HIV Patient Population
A pharmacokinetic/pharmacodynamic study based in the
Netherlands evaluated the effects of concomitant use of
rosuvastatin and lopinavir/ritonavir in HIV-infected patients
(N = 22). Patients aged a mean of 48 years and taking lopinavir/
ritonavir with a TC > 239 milligrams per deciliter (mg/dL) were
treated with rosuvastatin 10-40 mg for 12 weeks. The primary
outcome was a mean percentage decrease in TC and LDL-C at
weeks 4, 8, and 12.33
At baseline, week 4, week 8, and week 12, TC was 7.1 ± 0.95,
5.2 ± 0.81, 4.9 ± 1.20, and 4.7 ± 0.79, respectively; LDL-C was
4.2 ± 0.99, 2.8 ± 0.61, 2.7 ± 0.77, and 2.5 ± 0.61, respectively (in
mmol/L). Reported adverse events included diarrhea (n = 2),
headache (n = 2), and an upper respiratory tract infection
(n = 2). Three patients experienced transient muscle pain/
cramps, and 3 patients had clinically asymptomatic creatine
kinase increases greater than 250 units per liter (U/L), ranging
from 363 to 676 U/L. Lopinavir and ritonavir concentrations
were not significantly altered.33
A retrospective cohort study was conducted to compare
the effectiveness and toxicity of statins among HIV-infected
patients who started a statin between January 1, 2000, and
March 1, 2008 (N = 700). The 3 most common statins prescribed were atorvastatin, mean dose 20 mg daily (n = 303);
pravastatin, mean dose 40 mg daily (n = 280); and rosuvastatin,
mean dose 10 mg daily (n = 95). Other statins were prescribed
for 22 patients, but results were not included in the analysis.
Toxicity was based on laboratory abnormalities and symptomatic complaints such as myalgias, gastrointestintal symptoms,
and fatigue. The primary outcome measured was the change in
lipid levels during statin therapy after 12 months.34
The median follow-up time was 19 months. TC was lowered
by 39 (95% CI = 31-48) mg/dL in the atorvastatin group, 25
(95% CI = 16-34) mg/dL in the pravastatin group, and 43 (95%
CI = 31-55) mg/dL in the rosuvastatin group. LDL-C was lowered by 26 (95% CI = 20-32) mg/dL in the atorvastatin group,
12 (95% CI = 5-19) mg/dL in the pravastatin group, and 23
(95% CI = 14-32) mg/dL in the rosuvastatin group. Statin toxicity was reported in 7.3% of patients on atorvastatin, 6.1% of
patients on pravastatin, and 5.3% of patients on rosuvastatin.
An elevation in creatine phosphokinase was the most common potentially serious toxicity followed by elevation in liver
enzymes. Symptomatic adverse events were experienced by 29
patients, including myalgias/arthralgias (62%), gastrointestinal
symptoms (21%), and fatigue (7%).34
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A phase 4, multicenter, 12-week, randomized, double-blind,
double-dummy study evaluated the use of pitavastatin 4 mg
and pravastatin 40 mg on LDL-C reduction after 12 weeks of
therapy in HIV-infected adults on stable ART (N = 252) with
dyslipidemia. The primary outcome measure was the percent
change in fasting serum LDL-C from baseline to week 12.35
TC was lowered by 20.4% in the pitavastatin group, compared with 13.8% in the pravastatin group (P < 0.001). LDL-C
was lowered by 35.1% in the pitavastatin group, compared with
20.9% in the pravastatin group (P < 0.001). Treatment-emergent
adverse events caused 6 patients in the pitavastatin group and
5 patients in the pravastatin group to discontinue treatment.
Reported adverse events in the pitavastatin arm included
arthralgia (n = 3), myalgia (n = 1), back pain (n = 1), and pain
in an extremity (n = 2). Adverse events in the pravastatin arm
included arthralgia (n = 4), myalgia (n = 3), back pain (n = 2),
and pain in an extremity (n = 3).35
A randomized, multicenter, open-label trial was conducted
to compare the efficacy of rosuvastatin 10 mg and pravastatin
40 mg, after 45 days treatment, on plasma lipid levels in 88
HIV-1-infected patients taking a combined ART regimen containing at least 1 PI boosted with ritonavir. The primary outcome measure was the change in LDL-C.36
Median change in TC was -14% in the pravastatin group
compared with -28% in the rosuvastatin group (P < 0.001).
Median change in LDL-C was -19% in the pravastatin group
compared with -37% in the rosuvastatin group (P < 0.001).36
An open-label, randomized, prospective, monocentric study
assessed the safety and efficacy of rosuvastatin, pravastatin,
and atorvastatin in the management of PI-associated hypercholesterolemia. Ninety-four patients with hypercholesterolemia on a stable PI regimen were assigned rosuvastatin 10 mg
daily, pravastatin 20 mg daily, or atorvastatin 10 mg daily for
12 months. The primary endpoint was the decrease in TC and
LDL-C levels relative to baseline.37
The overall decrease in TC was 25.2% in the rosuvastatin
group, 17.6% in the pravastatin group (P = 0.01), and 19.8% in
the atorvastatin group (P = 0.03). The reduction in LDL-C level
was 26.3% in the rosuvastatin group, 18.1% in the pravastatin
group (P = 0.04), and 20.3% in the atorvastatin group (P = 0.02).
The most common adverse event seen was persistent gastrointestinal symptoms: 2 patients in the rosuvastatin group, 1
in the pravastatin group, and 2 in the atorvastatin group. No
serious adverse events were reported.37
In summary, pravastatin, rosuvastatin, and atovorvastatin
are commonly prescribed to manage hyperlipidemia in HIV
patients. Among these 3 agents, rosuvastatin has the greatest
cholesterol-lowering activity in this population.
■■  Personalized Medication Selection
Based on HIV Population Considerations
According to the Guidelines for the Evaluation and Management
of Dyslipidemia in HIV-Infected Adults Receiving Antiretroviral
March 2014
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Journal of Managed Care & Specialty Pharmacy 267
Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection
Therapy, drug intervention for elevated lipids in HIV patients
is recommended if lifestyle and diet changes have not shown to
be effective. The guidelines recommend patients be evaluated
in accordance with NCEP Adult Treatment Panel (NCEP-ATP)
III guidelines for dyslipidemia (however, NCEP-ATP III guidelines do not specifically address HIV-infected patients). For
HIV patients with elevated LDL-C (or elevated non-HDL-C if
triglycerides are between 200-500 mg/dL), pravastatin or atorvastatin therapy is recommended, with fluvastatin considered
a safe alternative. If triglyceride levels are elevated above 500
mg/dL, then fibrate therapy with gemfibrozil or fenofibrate is
recommended.38 However, in December 2011, the FDA issued
a statement that the concomitant use of gemfibrozil and simvastin is contraindicated.39
When determining whether pharmacological therapy is
appropriate, a cardiovascular risk assessment of the patient is
advised per NCEP-ATP III guidelines using the following steps:40
1.Identify clinical atherosclerotic disease: (a) coronary heart
disease (CHD), (b) MI, (c) unstable angina, (d) coronary
angioplasty, or (e) stent.
2. Identify CHD risk equivalents:
• Peripheral artery disease
• Abdominal aortic aneurysm
• Symptomatic carotid artery disease
• Carotid stenosis > 50%
• Stroke or transient ischemic attack
• Diabetes
3. Count the number of risk factors summarized in Table 5 (in
patients without clinical CHD or equivalents).
4. If there are ≥ 2 risk factors, determine the 10-year risk with
Framingham scoring, using:
• Age
• TC
• HDL-C
• Blood pressure
• Cigarette smoking status
Considering the findings gathered from the risk assessment, recommendation for pharmacological therapy initiation
is summarized in Table 6.
The FDA has provided safety warnings regarding interactions between certain PIs and statin drugs that can increase the
risk of muscle injury and has subsequently required the labels
of both the PIs and affected statins (lovastatin, rosuvastatin,
simvastatin, and atorvastatin) to be updated.32
Cost-Effectiveness Considerations
The determinants of statin cost-effectiveness are based on the
relationship between effectiveness and total cost of care among
statins. A small cost-effectiveness ratio can be achieved by
decreasing cost or increasing effectiveness of the statin. Statin
effectiveness increases with increased dosage or by using the
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JMCP
March 2014
TABLE 5
NCEP-ATP III LDL-C Goal Modifying
Risk Factors (Exclusive of LDL-C)40
Positive Risk Factors
Cigarette smoking
Hypertension
HDL-C < 40 (mg/dL)
Family history of premature CHD
(male < 55; female < 45)
Age (men ≥ 45; women ≥ 55)
Negative Risk Factors (Subtract 1 Positive Risk Factor)
HDL-C > 60 (mg/dL)
CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol;
LDL-C = low-density lipoprotein cholesterol; mg/dL = milligrams per deciliter;
NCEP-ATP = National Cholesterol Education Program Adult Treatment Panel.
same dose of another statin with greater efficacy. The primary
measure of statin effectiveness is survival, which can be measured as the number of life-years saved. Costs include drug
costs, dose titration (including the cost of the office visit and
laboratory tests), medical treatment for CHD, and all other
long-term medical costs. The incremental cost-effectiveness
ratio of a statin is lower in a high-risk population because the
number of coronary events avoided is greater. Therefore, the
recommendation is to use statins with the greatest effectiveness
in high-risk patients and a less expensive statin in low-risk
patients who require less LDL-C lowering.41
■■  Discussion
HIV Treatment Implications
CVD is the leading cause of death for people living in the
United States.42 In the era of HAART, CVDs are among the
most important non-AIDS-related causes of morbidity and
mortality in infected patients. The prevalence of CVD is
expected to increase as HIV-infected patients live longer as a
result of HAART. Recent projections estimate that by 2015,
more than half of the HIV-positive population in the United
States will be aged 50 years and older.43
HIV-associated dyslipidemia represents a clinically significant risk factor for cardiovascular disease. The most
pronounced effect on triglyceride levels occurs with fulldose ritonavir; somewhat reduced effects are associated with
ritonavir-boosted PIs; and a neutral effect is noted with
unboosted atazanavir.44 Among “older” PIs, statistically significant elevations of triglyceride levels are observed with ritonavir and lopinavir/ritonavir.16,38,45 Compared with lopinavir/
ritonavir, boosted darunavir has been shown to induce less
dyslipidemia.46 Among NNRTIs, efavirenz has been associated with dyslipidemia.18,19 It is important for clinicians to
recognize the differing extent of cholesterol abnormalities
observed among individual PIs and NNRTIs. These differences
become important when selecting specific ARV regimens for
individual patients, especially those with risk factors for CHD.
Until recently, lopinavir/ritonavir-based HAART therapy was
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Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection
TABLE 6
NCEP-ATP III LDL-C Goal Modifying Risk Categories40
Risk Category
Category Level
LDL-C Goal (mg/dL)
LDL-C Level to Initiate Drug Therapy
≥ 190, optional 160 to 189
0 to 1 risk factor
Low to moderate
< 160a
≥ 160
≥ 2 risk factors + risk score < 10%
Moderate
< 130a
≥ 130
≥ 2 risk factors + risk score 10-20%
Next highest
< 130a
≥ 130, optional 100 to 129
CHD or risk equivalents or risk score > 20%
High or very high
< 100a or < 70
a Initiate lifestyle changes when LDL-C is greater than LDL-C goal.
CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol; mg/dL = milligrams per deciliter; NCEP-ATP = National Cholesterol Education Program Adult
Treatment Panel.
recognized as first-line treatment for nonpregnant HIV-infected
ARV-naïve patients. Efavirenz-based HAART therapy continues to be considered first line since 1998.3,47 Consequently,
many HIV-infected individuals have been initiated on these
specific therapies. Because of the high percentage of virologic
and immunologic success, patients and clinicians are often
reluctant to switch to alternate lipid neutral ARV regimens.
Because of this, treating dyslipidemia to reduce CHD is common in the HIV population, especially as infected individuals
grow older. Dyslipidemia in the HIV population is managed in
accordance with the same guidelines established for the general
population, namely the NCEP ATP III guidelines.38
Given the prevalence of lipid abnormalities among HIVinfected patients, statins have become one of the most prescribed drug classes in HIV care. Statin therapy is very effective in lowering LDL-C and non-HDL-C levels. Depending on
the agent, they also moderately reduce triglyceride levels.48,49
Among HIV-infected patients, atorvastatin and rosuvastatin are
associated with statistically significantly greater decreases in
TC, LDL-C and non-HDL-C than pravastatin. The likelihood
of reaching NCEP goals for LDL-C levels is higher with the use
of rosuvastatin (odds ratio [OR], 2.1; P = 0.03) and atorvastatin
(OR, 2.1; P = 0.001) compared with pravastatin.34 In another
trial, patients taking atorvastatin or rosuvastatin had a greater
reduction in triglycerides (26.8% and 26.1%, respectively) than
those taking simvastatin or pravastatin (14.8% and 13.2%,
respectively) for the 40 mg dose of each drug.49 A recent study
reports superior reduction in LDL-C with pitavastatin 4 mg
daily compared with pravastatin 40 mg daily (31.1% vs. 20.9%,
respectively, P < 0.001) in HIV-infected adults. The investigators noted pitavastatin was associated with significantly greater
reductions in Apolipoprotein B and TC compared with pravastatin 40 mg, but changes in triglycerides and HDL-C were
not significantly different between treatments. There were no
significant differences between pitavastatin 4 mg and pravastatin 40 mg in HIV-1 RNA VL or CD4+ cell counts. The overall
adverse event profiles of pitavastatin 4 mg and pravastatin 40
mg appeared similar.35
PIs, NNRTIs (except rilpivirine), and cobicistat are known
to inhibit and/or induce CYP450 iso-enzymes.3,50-52 Depending
on the specific combination of statin drug and antiretroviral, a
harmful drug-drug interaction may occur. Out of this concern,
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Vol. 20, No. 3
clinicians must be attentive to the specific statin drug recommended when treating dyslipidemia in the HIV population.
Pravastatin, low-dose atorvastatin, and low-dose rosuvastatin
are commonly prescribed in HIV patients concurrently on a
PI-containing regimen. In healthy volunteers, administration
of pitavastatin 4 mg daily in the presence of steady state lopinavir/ritonavir 400/100 mg twice daily or darunavir/ritonavir
800/100 mg once daily did not result in clinically significant
changes in pharmacokinetic exposures of either drug.53,54 In
contrast, simvastatin and lovastatin are contraindicated for
individuals on HIV PIs or cobicistat because of the potential
for significant elevation in statin blood concentrations and
increased risk for toxicity.35,49 Co-administration of the NNRTI
efavirenz with simvastatin, atorvastatin, or pravastatin can
result in significant induction of statin metabolism.55 The
reduced inhibition of HMG-CoA reductase activity during
co-administration of efavirenz may result in diminished antilipid efficacy at usual doses, and statin dosages may need to
be cautiously increased. Unlike PIs, NNRTIs, and cobicistat,
raltegravir has no inhibitory or inductive potential in vitro.56
Thus, clinically relevant drug interactions between raltegravir
and statins are unexpected.
Management of dyslipidemia to reduce CHD risk in HIVinfected patients is important. After lifestyle interventions,
drug therapy with statins may be required. Clinicians should
consider potency, toxicity, and potential for drug-drug interactions when choosing a statin drug for patients on ART.
Managed Care Implications
With the continual growth of managed care in the United
States, financial and quality goals must be considered and
equally balanced when selecting statin therapy. Many quality measures focus on numerical goals as defined by the
Healthcare Effectiveness Data and Informational Set (HEDIS)
and the Physician Quality Reporting System. Because Medicare
5-Star Quality Ratings are composed of HEDIS measures,
Medicare Advantage health plans increasingly need to improve
quality metrics. In many cases, appropriate medication use
is the quickest and easiest method to attain quality goals.
HEDIS cholesterol targets are met when LDL-C < 100 mg/dL is
achieved in patients with coronary artery disease or diabetes
and are best achieved by the use of statins.
March 2014
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Journal of Managed Care & Specialty Pharmacy 269
Use of HMG-CoA Reductase Inhibitors in the HIV Population: Implications for Individualized Treatment Selection
Dyslipidemia is highly prevalent in patients with chronic
HIV infection, subsequently increasing the risk of coronary
artery disease in this patient population. ARV therapies consist
of numerous agents with varying effects on lipids. In addition,
drug interactions between statins and ARV therapies may lead
to decreased efficacy or potential for increased toxicity. Many
of the PIs used by HIV patients inhibit CYP3A4, raising the
concentration of many of the commonly used statins. As a
result, the choice of statin therapy should be carefully evaluated for HIV-positive patients with dyslipidemia.
Optimal dyslipidemia therapy in this patient subgroup
should begin with a statin that does not primarily depend
on CYP3A4 for its metabolism. In the managed care sector,
generic pravastatin would be a reasonable choice with the
lower potential for CYP mediated drug-drug interactions. In
addition, because of recent data in the HIV population and its
largely non-CYP3A4-based metabolism, pitavastatin could also
serve as a suitable alternative in the HIV positive subgroup of
patients.
The risk and benefit of statin therapy should be considered
on an individualized patient basis. Subsequently, each managed care plan needs to evaluate statin therapy and access of
specific statins for HIV-positive patients based on their specific
membership make-up.
Authors
ASHISH ADVANI, PharmD, is Clinical Assistant Professor, Mercer
University College of Pharmacy, Atlanta, Georgia. MANISH PATEL,
PharmD, BCPS, is Clinical Pharmacist Specialist, and SHREENA
ADVANI, PharmD, is Pharmacy Resident, Grady Health Systems,
Atlanta, Georgia. ROBERTO V. PICHARDO, PharmD, is Pharmacy
Director, Coventry Healthcare, Sunrise, Florida, and YOLANDA
WHITTY, PharmD, is Pharmacy Resident, Atlanta Medical Center,
Atlanta, Georgia.
AUTHOR CORRESPONDENCE: Ashish Advani, PharmD,
Clinical Assistant Professor, Mercer University College of
Pharmacy and Health Sciences, 3001 Mercer University Dr.,
Atlanta, GA 30341. Tel.: 678.547.6223; Fax: 678.547.6384;
E-mail: [email protected].
DISCLOSURES
Funding was provided by Kowa Pharmaceuticals America, Inc., to support
travel for a poster presentation at a national meeting. Authors attest to full
access to all data and accountability for study findings and reporting. There
has been no outside influence upon study design, data acquisition, interpretation of data, writing and revising the manuscript, and the decision to approve
the final manuscript for publication.
Concept and design were primarily contributed by A. Advani, with assistance from Patel. Data collection was primarily performed by Whitty, with
assistance from Patel, and data interpretation was done by Patel and Pichardo.
The manuscript was jointly written by Patel, Pichardo, Whitty, and S. Advani,
with revision by A. Advani.
270 Journal of Managed Care & Specialty Pharmacy
JMCP
March 2014
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