How HIV Medication Effects Nutritional Status

HIV is a worldwide health concern. Since 1981 when the AIDS epidemic was first

recognized in the Untied States, all U.S. states and U.S. dependent areas have conducted AIDS

surveillance by using a standardized reporting system (1). Since 1985 many of the areas have

also implemented HIV case reporting as part of their HIV/AIDS surveillance program (1). The

HIV/AIDS Surveillance Report, for statistical purposes, is based off data from the 37 areas (33

states and 4 US dependent areas) that have had HIV infection reporting since 2001(1). This

ensures enough time for the data to stabilize (1). This data tells us that through 2005 the

prevalence rate of HIV (not AIDS) among adults and adolescents was estimated at 136.5 per

100,000 (1). Also, the CDC estimates that there have been approximately 40,000 new cases of

HIV infection annually since the early 1990s, and currently there are between 850,000 and

950,000 HIV-infected Americans (2).

Currently, there is no cure for HIV infection or AIDS. However, during the last decade

management of HIV infection has dramatically improved thanks to the increasing effectiveness

of antiretrovirals (ARVs) (3). Optimal management of the infection includes at least three ARVs

from at least two different drug classes (3). This is known as HAART: highly active antiretroviral

therapy (3). HAART has proven highly effective in reducing disease-associated mortality and

morbidity in patients infected with HIV (3-6). However, HAART is plagued by a broad range of

side effects (4). Predictably, several of these side effects have a major impact on patient

nutrition, and it is therefore important to understand the relationship between HAART and

nutritional status.

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 There are several ARVs with multiple overlapping side effects. It is useful to know what

the major ARVs are before looking at some of the common nutritional side effects and the

evidence linking certain drugs to these side effects.

HIV is a virus that infects CD4+ T lymphocytes (3). After attaching and binding to the

CD4 receptor and specific chemokine co-receptors, the virus and host cell membranes fuse and

HIV RNA enters the host cell (3). The HIV RNA undergoes reverse transcription from RNA to

DNA and is then transported into the nucleus to integrate with the host DNA (3). Multiple copies

of completed HIV RNA are made and exported from the nucleus (3). Viral proteins are

processed, and together with full-length HIV RNA, are packaged at the cell surface and viral

particles are released (3).

ARVs work to interfere at various points in this cycle. NRTIs (Nucleos(t)ide reverse

transcriptase inhibitors), NNRTIs (Non-nucleoside reverse transcriptase inhibitors), and PIs

(protease inhibitors) are currently the three major prescribed classes of ARVs (3).

In recent years, clinicians have begun to observe elevated cholesterol and often elevated

triglyceride levels in HIV patients on HAART (5). This dyslipidemia (an abnormal concentration

of lipids or lipoproteins in the blood) is often associated with other metabolic abnormalities

including impaired glucose tolerance, insulin resistance and lipodystrophy (a condition

characterized by the accumulation of visceral fat, an enlarged dorsocervical fat pad, and atrophy

of subcutaneous fat in the face, buttocks, and extremities) (3,5,7). This broad array of metabolic

disorders is often referred to as lipodystrophy syndrome in HIV-infected patients, LDHIV, and is

currently considered the most potentially serious side effect of HIV medication (5,7).

LDHIV is recognized primarily by the loss of subcutaneous adipose tissue from the facial

and peripheral regions (7). Some patients also experience deposition of excess adipose tissue

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around the neck (double chin), over the dorsocervial spine (buffalo hump), upper torso, and

intraabdominal region (7). Peripheral fat loss is often considered the primary abnormality, and

excess fat deposition in other regions is often considered as secondary or compensatory (7).

Breast enlargement has been observed in both women and men, and women may develop

menstrual irregularities (7).

Currently, LDHIV does not present in patients naïve to all ARVs and PIs appear to be the

strongest link. (7). LDHIV was not reported before the introduction of PIs in 1993 when only

NRTIs were available, but since then LDHIV has been associated with all PIs and with longer

duration of PI therapy (7). The average rate of LDHIV is 42% in patients treated with PI-

containing HAART, and a generally higher prevalence is reported in patients after long-term

therapy (7).

Estimates vary, but up to 50% of patients with HIV develop one or more features of

LDHIV (5). As previously stated, patients with LDHIV often have an array of symptoms

including dyslipidemia, impaired glucose tolerance, and insulin resistance, and it is therefore

important to understand and look for these conditions individually as well as in association with

each other.

In a study by Johnson et al. fat redistribution (lipodystophy), with a lower percentage leg

fat and a higher percentage of trunk fat, was observed in those subjects taking PIs compared with

those subjects not taking PIs (8). Additionally, each 6 months of treatment with HAART is

associated with a 45% increased risk of fat redistribution (7).

As for impaired glucose tolerance and insulin resistance, “most studies report a

prevalence of hyperglycemia ranging from 0-20% during PI-containing HAART therapy” (7).

Additionally, “impaired glucose tolerance was reported in 62% of patients taking PIs, and a rise

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in fasting blood glucose levels was reported after initiation of PI-based therapy” (7). In

conjunction with the overall syndrome, a study by Vigouroux et al. reported diabetes occurring in

79% of patients with LDHIV compared with 20% of patients taking PI-containing HAART

without LDHIV (7). As for drug differences, reports have shown a higher prevalence of insulin

resistance in patients taking PI-containing HAART compared with those taking NRTIs alone, and

this was more prevalent in those receiving prolonged treatment with PIs (7). Of interest in

regards to the actual body morphology, Mynarcik et al. were able to show that insulin resistance

in patients with LDHIV was related to the loss of limb fat and not the accumulation of truncal fat

(7). It has subsequently been concluded that glucose intolerance, hyperinsulinemia, and insulin

resistance in patients receiving PI-containing HAART therapy may be early manifestations of

LDHIV (7).

Hypertriglyceridemia, hypercholesterolemia, and low HDL levels are some of the

defining characteristics of dyslipidemia in patients with LDHIV (7). But, with or without

LDHIV, anomalies of lipid metabolism have been increasingly recognized in HIV-infected

patients since the introduction of HAART (4). “In patients who receive a PI-containing ARV

regimen, the prevalence of hyperlipidaemia ranges from 28-80%, and it includes

hypertriglyceridaemia in a majority of cases (40-80%), followed by hypercholesterolaemia (10-

50%)” (4). Additionally, “the development of hyperlipidaemia during PI administration appears

to be dose and time related” (4). As seen earlier, this is also true of LDHIV in general.

The important thing to gather from this data is that exposure to PIs is clearly associated

with the entire range of metabolic abnormalities known as LDHIV. Exposure can result in the

syndrome or individual manifestations (5). “PI-naïve patients on NRTIs may develop

lipodystropy, insulin resistance, hypercholesterolemia, and possibly modest elevations in

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triglycerides, but not severe hypertriglyceridaemia, which appears to be linked to PIs alone” (5).

“Fat redistribution and dyslipidemia are correlated in patients on HAART, but PIs, in particular

may also cause hypertriglyceridaemia directly in patients without lipodystrophy” (5).

Taking a look at LDHIV and everything it includes is a good place to begin

understanding the full implications of HIV medication on nutritional status. Knowing the risks of

dyslipidemia, impaired glucose tolerance, and insulin resistance help in understanding a whole

host of other side effects.

For instance, PIs can also increase a patient’s risk of developing osteopenia and

osteoporosis (9). PI related negative side effects such as lipodystrophy and hyperlipidemia are

risk factors for development of weakened bones (9). Also, it is hypothesized that PIs may

contribute to avascular necrosis, a condition in which the thigh bone is no longer connected to

the hip bone (9). The theory is that the elevated blood fats, especially triglycerides, caused by the

drugs may block blood supply to the bones and lead to tissue death (9).

Making the correlation to osteoporosis is one connection; however, given the support

behind HAART causing dyslipidemia, it is important to look at a more broad and life threatening

problem. Prior to research, anecdotal reports suggested “that premature cardiovascular events

(coronary artery disease and myocardial infarction), may be associated with HAART and

abnormal plasma lipid value” (4). For example, many doctors reported serious arterial blockage

and resulting angina (pain around the heart) in patients on HAART, and a significant increase in

the incidence of myocardial infarction was found among HIV-positive subjects after the

introduction of PI-containing HAART (4,10). The thought began to form that since

“hypertriglyceridaemia, elevated total and LDL cholesterol levels, decreased HDL cholesterol

levels, insulin resistance, diabetes mellitus, and truncal adiposity are known to increase CVD risk

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in the general population, they may similarly predispose HIV-infected subject to accelerated

coronary illness” (4).

Interesting research into the specifics of this correlation has begun to show how this

happens. “Given the fat accumulation or fat wasting that occurs in [LDHIV, Addy et al.]

hypothesized that adipocyte function may play a very important role in the development of

associated metabolic abnormalities” (6). Adipocytes are metabolically and hormonally active

cells that secrete proteins. An excess or deficiency of these proteins in conjunction with obesity

or lipoatrophy is thought to play an important role in the development of pathophysiological

processes commonly observed in the metabolic syndrome, which is characterized by

hyperinsulinemia, type 2 diabetes mellitus, hypertension, hyperlipidemia, and coronary heart

disease (6). A new protein, adiponectin, has been inversely correlated with features of the

metabolic syndrome (6). What remained to be seen was whether adiponectin was also associated

with metabolic abnormalities in patients with LDHIV (6).

The study by Addy et al. involved 112 subjects and concluded that adiponectin levels

were significantly lower in a sample of HIV infected subjects with fat redistribution caused by

HAART compared with those subjects without fat redistribution (6). The results further

demonstrated that adiponectin is significantly inversely correlated with insulin resistance and

triglycerides, while there is a strong direct correlation of adiponectin with HDL in HIV infected

patients treated with HAART (6). In addition, adiponectin was found to be “inversely associated

with abdominal visceral fat and positively associated with subcutaneous fat; [findings which are]

consistent with the role of visceral adiposity in the development of insulin resistance and lipid

abnormalities associated with the metabolic syndrome” (6). In regards to specific ARVs,

adiponectin was found to be inversely related with cumulative months of NRTI use, but not in

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the other ARV classes including PIs (6). This is somewhat contrary to what would be expected

and the lack of association is potentially a type two error (the accidental labeling of a truth as

false) (6).

Understanding the meaning of this research is important. Low adiponectin can be a result

of fat redistribution caused by HAART. The decreased adiponectin levels are correlated with

several factors that accompany the fat redistribution in LDHIV, such as dyslipidemia, insulin

resistance, and impaired glucose intolerance, in such a way as to parallel metabolic syndrome in

non-HIV positive patients and thus strongly support a hypothesis of increased development of

coronary heart disease in HIV positive patients on HAART with LDHIV.

Further research has been done by Johnson et al. Through their work they have been able

to show that HIV-infected subjects with fat redistribution have increased adipose tissue secretion

and circulating levels of proinflammatory markers, and that these increases were more

pronounced in patients undergoing HAART (8). Their conclusion was that “increased adipose

tissue production and serum levels of proinflammatory cytokines may play a significant role in

the occurrence of the fat redistribution/metabolic syndrome in the HIV-infected patients

undergoing HAART” (8). As previously stated, an excess or deficiency of certain

adipocytokines can lead to the symptoms of metabolic syndrome, one being coronary heart

disease. We have seen how HAART causes a deficiency in adiponectin resulting in symptoms,

and here we see a correlation with HAART influencing excess production. These, and further

studies, are what have allowed scientists officially to acknowledge the increased risk for

cardiovascular disease while on HAART, and as of the most recent literature, the conclusion is

that the “association between PI exposure and the risk for increased cardiovascular events is well

established [and, although weaker,] has also been demonstrated with NRTIs and NNRTIs” (3).

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Recent switch studies looking into the effects of altering the medication used have shown that

blood fats that were elevated during PI therapy fell after people switched to other medications

(10).

Of further concern among those with dyslipidemia is the substantiated fact that prolonged

hypertriglyceridaemia is associated with the occurrence of acute pancreatitis (4,5). Pancreatitis

is the inflammation of the pancreas, an important organ that secretes enzymes, to aid in

digestion, and insulin, to aid in glucose utilization (10). It can also cause symptoms such as

vomiting and nausea which further increases health concerns (10). “High triglyceride levels are

usually associated with fasting chylomicronemia and can cause the ‘chylomicronemia

syndrome,’ which includes acute pancreatitis, abdominal pain with normal pancreatic enzymes,

dyspnea, memory loss, lipemia retinalis, and eruptive xanthomata” (5). “In addition, non-

alcoholic steatohepatitis is associated with hypertriglyceridaemia but can also be seen in patients

with normal lipids” (5). With specific regards to HAART, “in HIV patients on PIs with extremely

high triglycerides clinicians reported cases of pancreatitis and lipemia retinalis, both of which

resolved with discontinuing the PI and initiating lipid lowering therapy” (5).

Another thing to look at is mitochondrial toxicity. “Mitochondrial toxicity is damage to

the mitochondria that can cause problems in the heart, nerves, muscles, pancreas, kidneys, and

liver” (9). “It can also cause changes in the blood such as thrombocytopenia, anemia, and

neutropenia” and can manifest as hyperlactataemia, myopathy, peripheral neuropathy, hepatic

steatosis and lipodystrophy (3,9). “Its pathogenesis in an HIV-infected individual is commonly

attributed to inhibition of mitochondrial DNA polymerase by NRTIs” (3).

As for an explanation and specific example, when the mitochondria do not work properly

excess lactate is produced and severe hyperlactatemia leads to lactic acidosis, a somewhat rare,

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but very serious side effect that can harm the body’s cells (9). NRTIs can also cause the liver to

become fatty which is known as hepatic steatosis, and a fatty liver cannot break down the lactate

efficiently (9). Some side effects of lactic acidosis are persistent nausea, vomiting, and weight

loss among other things (9). These are obviously of concern from a nutritional standpoint and

would need to be addressed if present.

To further discuss HAARTs effects on the liver, hepatoxicity, or liver damage, has

developed in HIV patients taking all three of the main types of HIV medication: PIs, NRTIs, and

NNRTIs (9). Hepatoxicity can present itself as hepatitis, hepatic necrosis, or hepatic steatosis

which, as previously discussed, can lead to lactic acidosis (9). The symptoms of hepatoxicity are,

unsurprisingly, similar to those for lactic acidosis and thus of obvious concern from a nutritional

standpoint: nausea, vomiting, loss of appetite, and diarrhea (9). Elevated bilirubin levels are also

an indicator of liver damage and can result in jaundice (10).

Common side effects such as nausea and diarrhea, which are seen with serious

complications like hepatoxicity, can also be primary symptoms of ARVs. Nausea is very

common, especially in the first few weeks of starting HAART (10). Nausea is caused by a wide

array of drugs and almost always disappears with the discontinuation of the drug (10).

Unfortunately, nausea will persist if there has been liver damage (10). Diarrhea is caused by

many ARVs and it is very important to monitor (10). Besides the common solutions and

precautions, increasing fiber intake and drinking water to prevent dehydration, other nutritional

methods are being developed to deal with the diarrhea on certain drugs. Another excretory

problem is kidney stones which have been found to have a direct link to PI use (10).

From this brief overview, it is obvious that living with HIV/AIDS is taxing in many

ways. The medications that have evolved in recent years have increased the life expectancy of

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patients diagnosed with HIV infection, but they come with a high cost. May patients cannot

tolerate the side effects. The physical and psychological toll they take can be devastating.

Unfortunately, once a patient has started HAART therapy, it is highly unadvisable to quit as the

first regimen has the best chance for long-term success (9). It is up to current doctors and health

care providers to make sure patients are aware of the side effects and risks and are

psychologically prepared before starting treatment, and it is up to the rest of the world to keep

funding research for better medications and, hopefully, a cure.

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 References
1. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report. 2005;17:5-9.
Available at: http://www.cdc.gov/hiv/topics/surveillance/resources/
reports/2005report/pdf/2005SurveillanceReport.pdf. Accessed April 6, 2007.
2. Position of the american dietetic association and dietitians of canada: nutrition
intervention in the care of persons with human immunodeficiency virus infection. J Am
Diet Assoc. 2004;104(9):1425-1441.
3. Chen LF, Hoy J, Lewin SR. Ten years of highly active antiretroviral therapy for HIV
infection. MJA. 2007;186 (3):146-151.
4. Calza L, Manfredi R, Chiodo F. Dyslipidaemia associated with antiretroviral therapy in
HIV-infected patients. JAC. 2003;53(1):10-14.
5. Green ML. Evaluation and management of dyslipidemia in patients with HIV infection. J
Gen Intern Med. 2002;17:797-810.
6. Addy CL, Gavrila A, Tsiodras S, Brodovicz K, Karchmer AW, Mantzoros CS.
Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat
redistribution in human immunodeficiency virus-infected patients treated with highly
active antiretroviral therapy. J Clin Endocrinol Metab. 2003;88(2):627-636.
7. Chen D, Misra A, Garg A. Lipodystrophy in human immunodeficiency virus-infected
patients. J Clin Endocrinol Metab. 2002;87(11):4845-4856.
8. Johnson JA, Albu JB, Engelson ES, Fried SK, Inada Y, Ionescu G, Kotler DP. Increased
systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy. Am
J Physiol Endocrinol Metab. 2004;286:261-271.
9. A Service of the U.S. Department of Health and Human Sciences. Health topics.
Available at: http://www.aidsinfo.nih.gov/HealthTopics/HealthTopicDetails
.aspx?MenuItem=HealthTopics&Search=Off&HealthTopicID=67&ClassID=51.
Accessed April 6, 2007.
10. Canadian AIDS Treatment Information Exchange. Living with HIV. Available at:
http://www.catie.ca/sideeffects_e.nsf/TOC/CE2E82 F5B07F397E85256C7
0006367AD?OpenDocument. Accessed April 7, 2007.

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