HIV and Antiviral Medications: Cause for Lipid Abnormality?

Brittany J. Brockner

FN-655

Fall 2017

The College of Saint Elizabeth

Abstract
Human immunodeficiency virus (HIV) is a chronic infection which is currently being

treated with antiviral therapy (ART). ART are potent medications which treat HIV infected

persons through maintenance of CD4 cells and suppression of HIV RNA replication. These

drugs however, pose unique complications to lipid metabolism. The etiology of these

complications is multifactorial and are related to the virus itself and the use of ART. Evidence

shows HIV itself stimulates changes in the expression of genes involved in lipid metabolism,

and is associated with intracellular cholesterol accumulation. In addition, nucleoside reverse-

transcriptase inhibitors (NRTI’s), a specific class of ART, induce the development of an

atherogenic profile through mitochondrial toxicity. Protease inhibitors (PI’s) also have evidence

for increasing total cholesterol, LDL, VLDL, and triglyceride levels. The combination of HIV and

different classes of ART each pose their own complication on lipid metabolism. This literature

review will focus on the evidence for HIV and ART on alterations in lipid metabolism, with

specific focus on the potential mechanism for these alterations. Potential consequences on

health with respect to cardiovascular risk and insulin resistance will also be discussed.

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Introduction
Human immunodeficiency virus (HIV) is an infection that compromises the immune

system by attacking CD4+T-cells, which are used to help fight off disease and infection. By

replicating and reducing the number of CD4 cells, the HIV infection can advance to become

acquired immune deficiency syndrome (AIDS). The CDC defines AIDS as a CD4 count below

200cells/mm1. Healthy adults have about 500- 1800 CD4 cells/mm. Under the proper treatment,

the HIV viral load can become undetectable as defined by the CDC as less than 40 copies per

milliliter of blood. The lower the viral load the less frequently CD4 cells are attacked, thus

leading to a healthier immune system. From the beginning of the epidemic in the early 1980’s

until 2015, 1,216,917 people were diagnosed with AIDS in the United States2. If untreated, this

infection can lead to death. In 2014,12,332 deaths were reported in people with HIV infection

classified AIDS in the United States.

HIV is a chronic infection that poses unique challenges in metabolism and treatment.

Among the common comorbidities of HIV are hypertension, elevated triglycerides, and low HDL

levels4. Antiviral medications therapy (ART) is a contributing factor to these abnormalities 4,6,7.

Antiviral medication for the treatment of HIV can be classified into the following classes: NRTI

(nucleoside reverse transcriptase inhibitors), NNTRI (nonnucleoside-analog RT inhibitors), PI

(protease inhibitors or maturation inhibitors) ,integrase inhibitors, and entry inhibitors3. Most HIV

treatment drugs use a combination of these drug classes. These drugs are used to suppress

HIV viral replication, thereby repletion of CD4+Tcell counts. The backbone and major constitute

for many ART medications is NRTI’s which inhibit HIV reverse transcriptase by activating

triphosphates through intracellular and intramitochondrial phosphorylation7.

HIV is currently managed through ART medications. PI’s and NRTI’s are specific

classes of ART that have been reported in the guide for HIV/AIDS Clinical Care to be

associated with increased risk for dyslipidemia, and insulin resistance. These medications have

direct effects on hepatic steatosis and fat redistribution. For these reasons, before initiation of

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ART in persons with HIV, assessment and monitoring is recommended in the following: glucose

and lipid abnormalities, body fat distribution, lactic academia, and osteopenia/ osteoporosis5.

Medical providers are also recommended to conduct routine tests of fasting blood glucose

levels with people on ARV. In addition, HbA1C was reported to not be an effective screening

tool for diabetes among HIV infected person5. This is due to the relationship between elevated

state of mean corpuscular volume (MCV) and HbA1C4. Elevated MCV levels can cause HbA1C

values to underestimate glycemic control. Routine monitoring for lipid profile is also supported

by a more recent study conducted at the Burayu Health center, which demonstrated higher

prevalence of dyslipidemia among HIV positive participants treated with ART than those not

treated with ART11.

The following sections discuss the evidence for the metabolic complications of HIV and

its medications, specifically in respect to lipid metabolism. The purpose of this article is to review

the research about the effects of HIV and ART medications on lipid metabolism, with special

attention given to potential mechanisms by which these alterations of metabolism occur.

Considerations for the consequent effect on health will also be discussed.

Potential mechanisms

Altered expression of lipid metabolism genes

The human immunodeficiency virus (HIV) has been shown to increase risk for

cardiovascular disease and dyslipidemia4,5,6. HIV has also been shown to adversely affect lipid

metabolism on the cellular level through altered expression of lipid metabolism genes, and

mitochondrial dysfunction 6,12. Higher replication of HIV RNA has been associated with

dyslipidemia by decreased HDL levels, this association suggests the HIV virus itself has an

effect on HDL metabolism. Intracellular cholesterol accumulation is found in the formation of

atherosclerotic plaque. For example, Feeny et al. compared gene expression associated with

cellular cholesterol uptake, metabolism, and efflux among HIV positive participants on ART,

untreated HIV positive participants, and HIV negative participants. Results of the study found
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HIV positive participants, both treated and untreated, had lower gene expression of cholesterol

uptake (LDLR, CD36), regulation (SREBP2, LXRA), and synthesis (HMGCR)6. HDL levels were

found to be lowest in HIV untreated participants due to HIV impairment of monocyte cholesterol

movement by upregulation of ABCA1 mRNA. Because both treated and untreated HIV positive

participants experienced decreased expression in genes associated with cholesterol

metabolism, HIV and ART are suggested to affect monocyte cholesterol metabolism. This effect

is associated with the accumulation of intracellular cholesterol accumulation6. Moreover, Riddle

et al. demonstrated increased cholesterol levels due to increased cholesterol biosynthesis in

both adipose and liver tissues after initiation of ART with protease inhibitors13. As found in the

study by Feeny et al, Riddle et al, reported an accumulation of activated sterol regulatory

binding protein (SREBP-2). The increase of activated SREBP-2 in the nucleus, causes an

increase in lipid biosynthesis.

Mitochondrial Dysfunction

Another mechanism by which HIV and ART can adversely affect lipid metabolism is

through mitochondrial dysfunction. A randomized control trial by Mallon et al. examined the

effects of nucleoside reverse-transcriptase inhibitors (NRTI’s) ,a specific type of ART, on the

expression of mitochondrial and lipid metabolism genes in persons without HIV7. NTRI’s are

thought to be associated with lipodystrophy by affecting mitochondrial function. Results found

adipose tissue expression of mtRNA’s were significantly decreased without a decrease in

mtDNA. In addition, a nuclear response of decrease expression of PPARG, which aids in the

regulation of lipid metabolism genes, was observed7. The expression of the gene for leptin

(LEP) was significantly increased along with the expression of the gene for lipoprotein lipase

(LPL)7. These findings suggest that NRTI’s itself also increase body fat.

In contrast, a newer study by Sievers et al. reported NTRI’s contribute to lipodystrophy

by decrease in mtDNA among participants with HIV8. The study compared mtDNA and gene

expression among persons with HIV treated with antiviral therapy either with or without ART

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induced lipodystrophy. Results found a significant decrease in mtDNA in the lipoatrophy group

as well as a decrease in gene expression of SREBP1c and CEBPB which is involved in

adipogenesis8. The lipodystrophy group also had a decrease in gene expression for fatty acid

synthase and glucose metabolism through decreased GLUT 4 expression when compared to

the group without lipodystrophy. Both studies indicate that NTRI induced mitochondrial toxicity

which affects gene expression associated with impaired adipocyte differentiation(PPARG),

increased oxidative stress, and activation of apoptosis.7,8 A 25-year review study also supports

that NTRI may lead to lipodystrophy through adipocyte apoptosis through the mitochondrial

pathway21. In addition to HIV, its accompanying antiviral therapy (ART) contributes to altered

expression of lipid metabolism genes. These alterations are potential mechanisms by which HIV

and ART contribute to lipodystrophy and hyperlipidemia.

Effects on Lipid Profile

Prevalence

HIV lipoproteins have been reported to be proatherogenic as a result of increased

platelet activating factor acetyl hydrolase5. In addition, the use of antiviral medications with

protease inhibitors is associated with increased LDL cholesterol and triglyceride levels. For

example, an observational study at the Gandhi Memorial and Associated Hospital found the

prevalence of low HDL levels among HIV positive patients to be 69.41%. In addition, the

prevalence of elevated LDL levels was 10.58% and hypertriglyceridemia was found in 29.41%

of patients9. Interestingly, Muhammad et al found higher prevalence of low HDL levels among

HIV positive participants not treated with ART than those treated with ART10. Abebe et al also

found higher prevalence of low HDL levels among participants not treated with ART11. These

findings suggest HIV itself contributes to low HDL levels. Furthermore, Muhammad et al

demonstrated higher total cholesterol levels among HIV positive subjects on ART than those

without ART10. The atherogenic lipid profile reported secondary to ART treatment in addition to

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the proathergenic change in HIV infected lipoprotein provides further evidence for lipid

abnormalities among HIV infected persons.

Protease Inhibitors

Protease inhibitors come in various forms and each has a different effect on the lipid

profile. The common generic names for protease inhibitor ART medications are: ritonavir,

atazanavir, darunavir, and lopinavir. A 96- week randomized clinical trial was conducted to

examine the differences in cholesterol levels between participants taking atazanavir/ ritonavir

and darunavir/ritonavir14. Total cholesterol at week 24 was increased more by the

darunavir/ritonavir group than the atazanavir/ ritonavir group with an average cholesterol

increase of 11.47mg/dL and 7.26mg/dL, respectively14. A randomized exploratory study also

found darunavir/ritonavir increased total cholesterol more than atazanavir/ ritonavir15. After 12

weeks of initiation on the medication, the darunavir/ritonavir group had an increase in average

total cholesterol by 20.3mg/dl. Whereas the atazanavir/ ritonavir had an increase by

4.6mg/dl15.Both of these studies examined the same drug with different outcomes, however,

both reported a higher increase in average total cholesterol in the darunavir/ritonavir group.

These studies show the varied effects of different protease inhibitor ART medications on the

lipid profile. However, both studies demonstrated an increase in total cholesterol levels after

initiation of each PI medication. The drug induced increase in total cholesterol levels,

contributes to the development of an atherogenic lipid profile.

Protease Inhibitors vs Other ART therapy classes

As reported by numerous studies, ART drugs containing PI’s contribute to an

atherogenic profile through increased total cholesterol and LDL levels14,15. How do other classes

of ART therapy affect lipid profiles? A retrospective cohort study aimed to examine the

difference between PI medications and non- nucleotide reverse transcriptase inhibitors (NNRTI)

on lipid profile concentrations. After 3 years, the study reported PI medications resulted in

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higher atherogenic profile than the NNRTI medications, with comparable effects on HIV viral

suppression16. PI medication was reported to have a statistically significant increase in total

cholesterol, LDL, and triglyceride levels. Whereas NNRTI did not have such statistical significant

changes. NNRTI did however significantly increase HDL levels with an average increase of

11.6mg/dL/year16!

NNRTI and PI medications where also evaluated with respect to lipodystrophy and lipid

profile levels17. In the study, women switched from either a PI or NNRTI medication to

raltegravir, an integrase inhibitor. A decrease in visceral adipose tissue was observed in the

Raktegravir group by 3.6% compared to the control group which continued PI or NNRTI

medication. The control group had the opposite effect on visceral adipose tissue with an

increase of 1.9%. A significant reduction in triglycerides was observed in the raltegravir group

with an average reduction of 16.0mg/dL after 24 weeks. The raltegravir group also experienced

a reduction in total cholesterol and LDL levels by 17.0mg/dL and 12.0mg/dL, respectively.

Although not statistically significant, the raltegravir group reduced HDL levels whereas the PI

and NNRTI group increased HDL cholesterol levels. Recent research demonstrates lower HDL
6,
cholesterol levels in HIV positive untreated individuals when compared to treated individuals

. The specific type of ART therapy has an impact on the lipid profile changes. PI’s have
10,11

shown to have the most significant adverse effects on lipid profile with respect to LDL,

triglycerides, and total cholesterol levels15. Integrase inhibitors (raltegravir) have shown less

atherogenic effects on the lipid profile when compared to PI’s and NNRTI’s17. However,

NNRTI’s have been reported to increase HDL cholesterol levels with statistically insignificant

changes in LDL, triglyceride, and total cholesterol levels16.

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Consequent health effects

Impact of lipodystrophy on Insulin resistance

Medical providers can benefit from increased understanding on the effects HIV and its

accompanying medications has on the patient’s overall health. It is documented that HIV can

increase risk for insulin resistance, hyperglycemia, lipodystrophy, and diabetes4,5. The guide for

HIV/AIDS Clinical Care states that protease inhibitors (PI’s) and nucleoside reverse

transcriptase inhibitors (NRTI’s) are two specific antiviral drugs that are associated with drug

induced insulin resistance among persons with HIV4. This relationship has also been found in

the journal of acquired immune deficiency syndrome.

However, how does drug induced lipodystrophy contribute to the adverse effects of ART

therapy? Lipodystrophy as defined as increased visceral fat has been reported to be common

among women and those with increased triglyceride levels, although men also experience

lipodystrophy after initiation of ART medication18. ART medication is reported to impair glucose

tolerance by way of insulin resistance5. This drug induced insulin resistance appears to be

secondary to the inhibition of glucose transporter GLUT4. Another potential mechanism includes

the ART’s negative effects on cellular glucose uptake. In addition, abnormal fat distribution

caused by ART can also contribution to insulin resistance. Specifically, the redistribution of fat to

increased visceral and decreased extremity fat as observed in the study conducted by Lake et

al17.

Impact on cardiovascular risk

In addition to HIV itself, each class of its accompanying ART medication has its own

impact on the lipid profile, specifically protease inhibitors (PI’s), nucleoside reverse-transcriptase

inhibitors (NRTI’s), and integrase inhibitors have been shown to contribute to the development

of an atherogenic lipid profile. In a multicenter AIDS cohort study, HIV positive men on ART

were associated with an atherogenic lipid profile when compared to HIV negative men19. Among
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the Art treated participants, 48% were on a PI regimen, 44% were on NNRTI, and 8% were on

NRTI medication. Those on PI and NRTI had significantly higher small particle LDL and total

VLDL with lower large particle LDL and total HDL19. As large particle LDL size is associated with

cardiovascular risk, PI and NRTI contribute to the atherogenic profile not only by serum levels of

LDL, but also by particle size.

On the contrary, NNRTI medications had no significant effects on total LDL and VLDL

levels. These findings are consistent with more recent research on NNRTI medication on lipid

profile16. Another cohort study examined cardiovascular risk among HIV positive, ART treated

participants in Brazil, with respect to HIV viral load and CD4 count20. Results of the study found

that high viral load (detectable), and CD4 count ≤ 50cell/mm3 was significantly associated with

increased CVD risk (p<.05). The results of this study bring to attention the unique risk factors

that HIV infection has on CVD risk in addition to traditional risk factors such as an atherogenic

lipid profile.

Conclusion

HIV and its accompanying ART therapy has adverse effects on lipid metabolism which

contribute to the development of an atherogenic lipid profile. The potential mechanisms by

which these alterations of lipid metabolism occur begins at the cellular level though altered

expression of lipid metabolism genes and mitochondrial dysfunction, which contribute to

increase cholesterol biosynthesis and cellular accumulation of cholesterol. In addition, to HIV

itself, the various classes of ART therapy also contribute to changes in lipid metabolism. The

most documented class of ART are PI’s, which have consistency shown to increased total

cholesterol, triglyceride, and LDL levels in literature. NRTI’s and integrase inhibitors have also

been shown to increase total cholesterol, triglyceride and LDL levels, however the literature

reports variations on their effects. NNRTI’s have shown some different effects on lipid

metabolism than the other ART drug classes by causing an increase in HDL levels. Overall the

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literature consistency shows HIV and ART contribute to the development of an atherogenic lipid

profile by increased total cholesterol, LDL, VLDL, and triglyceride levels. These changes in lipid

profile may have other health implications such as drug induced insulin resistance and

increased cardiovascular risk. Further research is needed to establish which classes of ART

medication are the most effective in suppressing the replication of HIV and the safest in

preventing the development of an atherogenic lipid profile.

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