Metabolic Syndromes Associated With HIV
Mitigating the Side Effects of Drug Therapy
William W. Stringer, MD; Fred R. Sattler, MD
THE PHYSICIAN AND SPORTSMEDICINE - VOL 29 - NO.12 - DECEMBER 2021
In Brief: HIV infection and highly active antiretroviral therapy (HAART) are associated with a variety of metabolic disorders such as AIDS wasting syndrome, cachexia, sarcopenia, metabolic dysregulation, lipodystrophy, abnormalities of serum lipids, and lactic acidosis. Adjunctive therapies (eg, diet, antilipid therapy), risk-factor modification (eg, smoking cessation, blood pressure control), aerobic exercise, and anabolic treatments can be used to mitigate the effects of HIV infection and the adverse effects of HAART, thereby improving long-term health in individuals infected with HIV.
In the past, a positive blood test for human immunodeficiency virus (HIV) meant certain death within a short period. Recent medical discoveries and continuing research have led to treatments that allow many patients to survive longer and feel well enough to continue normal activities for a greater length of time. HIV infection is increasingly becoming a more chronic disease that may eventually result in a near-normal life span.
Current Medical Therapy for HIV
Before 1996, essentially the only medicines available to treat HIV infection were zidovudine (AZT), didanosine, and zalcitabine, and life expectancy was short. However, in recent years several new classes and types of HIV medications have been combined to form the basis for highly active antiretroviral therapy (HAART) (1-3). This has resulted in dramatic decreases in the mortality and morbidity from HIV in the United States and Western Europe (4); therefore, increasing consideration must be given to the long-term health of individuals infected with HIV, especially because HIV infection and treatment may increase the risk of other common diseases such as heart disease, diabetes, or hypercholesterolemia.
The major classes of HIV medications used today are nucleoside analog reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (table 1) (5,6). As new classes and medications become available, it is important to consult sources that are routinely updated and accurate. The US Department of Health and Human Services/Henry J. Kaiser Family Foundation document (1) is an excellent source for information, as are the Internet resources at the Medscape Web site and the Journal of the American Medical Association HIV/AIDS information center Web site (table 2).
TABLE 2. Web Sites Offering Regular Updates on HIV Treatment
JAMA HIV/AIDS information: https://www.ama-assn.org/special/hiv/
HIV/AIDS Treatment Information Service: https://www.hivatis.org
Adult AIDS Clinical Trials Group: https://aactg.s-3.com
American Diabetes Association (ADA): https://www.diabetes.org
National Cholesterol Education Program (NCEP): https://www.nhlbi.nih.gov/chd
In addition to the metabolic syndromes associated with HIV, common side effects and complications of the medications include nausea, abdominal pain, diarrhea, fatigue, headache, myopathy, peripheral neuropathy, rash, and hypersensitivity reactions. Changes in blood tests observed with these medications may include liver abnormalities, anemia, hyperamylasemia, and neutropenia. Because the side effects and the drug interactions are myriad, patients require close monitoring for detection of adverse drug events. In addition, HIV medications are known to affect the absorption, metabolism, and excretion of other HIV drugs and common tuberculosis drugs. Such intricacies make HIV therapy quite complex, and treatment is usually best performed by a specialist in HIV therapy. The cost of drug therapy can be up to $2,000 per month, and the routine laboratory monitoring for complications imposes an additional expense. Finally, resistance can develop to all HIV medications, due to virion mutations caused primarily by subtherapeutic drug levels and lack of adherence.
Metabolic Syndromes Associated With HIV
Several distinct syndromes are observed with HIV infection (7) and HAART.
AIDS wasting syndrome (AWS), the loss of body mass from decreased calorie intake, reduced appetite, and starvation, is case defining for AIDS in up to 18% of subjects who test positive for HIV (HIV+). AWS is diagnosed when there is an involuntary loss of greater than 10% of body weight (8). Loss of weight from inadequate calorie intake usually occurs during serious secondary infections when appetite is impaired (9). Diarrhea and malabsorption are additional contributing factors common to AWS. The effect of weight on survival is very important, because patients who have lost more than 10% of their preinfection body weight have a median survival of only 48 days, compared with 520 days for patients with less significant weight losses (10).
Cachexia, the loss of lean body mass despite adequate or even increased intake of calories, is likely associated with hypermetabolism and may be associated with inflammation caused by increased levels of cytokines, interleukins, and interferons (11-13). This type of loss of lean body mass, especially muscle, is associated with active retroviral replication and opportunistic infections and should therefore be treated with appropriate antiretroviral therapy.
Sarcopenia, also called muscle wasting, can be seen with AWS and cachexia and results in decreased lean body mass. It can also result from muscle myopathy caused by the effect of NRTIs, especially AZT (14), on mitochondrial function, or from myositis (an immunodysregulatory effect associated with muscle pain, tenderness, sarcopenia, and elevated muscle enzymes); or it may be related to an HIV-induced myopathy. These may occur with well-controlled HIV infection [high CD4 lymphocyte counts and low HIV polymerase chain reaction (PCR) titers]. These two laboratory markers are used to evaluate the effects of HAART. Specifically, high CD4 counts and low viral titers imply successful HAART; low CD4 counts and high viral titers suggest the opposite.
Metabolic dysregulation, such as lipodystrophy (LD) (lipohypertrophy or lipoatrophy), glucose intolerance, frank diabetes mellitus, and hyperlipidemia are more common in patients who are on HAART. The changes in fat storage, fat distribution, and lipid metabolism are likely related to changes in adipose cell function. LD has a prevalence of 2% to 84% in patients treated with HAART (15), although some patients who were not previously exposed to protease inhibitors (PI-naïve patients) have had similar changes. There is no current gold standard for the diagnosis of LD.
Lipohypertrophy is the deposition of fat that may be observed in 1% to 56% of patients infected with HIV (15). The initial reports of this syndrome in several men involved adipose tissue just behind the neck ("buffalo hump") or visceral abdominal fat ("crix belly" or "protease paunch") that formed without evidence of adrenal cortical overactivity (16). However, deposition of adipose tissue in the breasts, upper torso, or neck is observed in both men and women. Lipohypertrophy with central obesity may be an acceleration of the normal aging process in men that usually results in increased waist-to-hip ratio; however, these changes have been observed in young patients and some infants receiving HAART.
Conversely, lipoatrophy may occur with loss of adipose tissue in the face, arms, or legs. Prevalence is estimated at 1% to 24% (15). Moreover, lipohypertrophy and lipoatrophy may occur in the same patient, and that raises the question of whether we are observing one, or more than one, syndrome (17).
Although changes in fat deposition are troublesome and usually progressive, the most important changes may be at the biochemical level. Carr et al (18) studied 113 HIV+ patients receiving PI therapy. In addition to the morphologic changes described above, biochemical changes in lipid, glucose, uric acid, and insulin levels were observed. Increases were common in serum lipids, total cholesterol, low-density lipoprotein cholesterol (LDL), and triglycerides; reductions in high-density lipoprotein cholesterol (HDL) were also common.
The elevation in blood sugar observed with PI therapy was similar to the changes observed in patients who had type 2 diabetes mellitus (high blood sugars, high insulin levels, and insulin receptor resistance). Associated risk factors frequently seen in type 2 diabetes, including hypertension and hyperuricemia, may also be observed in individuals who have HIV. HIV control was excellent in this study (18), as evidenced by increases in CD4 lymphocyte counts and undetectable levels of HIV RNA with PCR amplification, suggesting that the changes in lipids were not related to poor control of HIV.
HIV infection and PI treatment are associated with elevations in triglycerides and cholesterol, similar to the changes observed with type 2 diabetes in individuals who are not HIV infected (19). Using the 192021 American Diabetes Association (ADA) guidelines, the same study by Carr et al (18) found overt diabetes mellitus in 7% of the PI-treated subjects and impaired glucose tolerance in an additional 16%. Subjects not treated with PIs did not have overt diabetes or glucose intolerance. Most subjects with HAART-induced diabetes were asymptomatic and required an oral glucose tolerance test for diagnosis. Also, the degree of insulin resistance was significantly associated with the degree of lipodystrophy (none, mild, moderate, or severe lipodistrophy was associated with increasing insulin resistance levels of 1.73, 2.25, 2.60, or 3.86 mIU, respectively). Carr et al (18) proposed the HIV case definition for PI-related lipid changes (table 3).
TABLE 3. Indicators for Lipid Changes Related to Protease Inhibitor Therapy
*The development of one or more of these features since the start of protease inhibitor therapy indicates a lipid change.
Lactic acidosis with hepatic steatosis is a metabolic syndrome associated with HIV infection and HAART. Although fatal cases with markedly elevated lactic acidosis levels and fulminant hepatic steatosis are rare, more modest elevations of lactic acid are not uncommon in patients treated with HAART. It appears that certain HIV medications, especially NRTIs, can affect the ability of the muscle and liver cells to generate adenosine triphosphate (ATP). HIV medications appear to affect the ability of the cytosolic processes (eg, glucose metabolism, tricarboxylic acid cycle) or mitochondria (oxidative phosphorylation) to produce energy, resulting in lactic acidosis. This is not associated with a lack of oxygen but appears to be a disturbance in the metabolic machinery.
Mitochondrial myopathy has been described with long-term zidovudine therapy (20-23); however, other newer NRTI medications, including didanosine, stavudine, and zalcitabine, have also been associated with this syndrome (24-26). Some evidence suggests that the mitochondrial DNA polymerase-gamma function is impaired, resulting in altered mitochondrial DNA and protein synthesis (27).
Recognition of the clinical syndrome of lactic acidosis and hepatic steatosis is difficult because the symptoms (eg, nausea, vomiting, fatigue, muscle or abdominal pain), are usually mild and nonspecific and have a subacute presentation lasting weeks to months. The elevations of hepatic enzymes (eg, aspartate transaminase, alanine transaminase) are not uniformly present. Indeed, even muscle markers of inflammation or dysfunction (eg, creatine kinase or aldolase) may not be seen with myopathy. The electrolytes or arterial blood gases may indicate severe metabolic acidosis or lactic acidosis; a serum lactate level can be obtained to document the diagnosis. Liver biopsy or computed tomography images should document hepatic fat deposition. Withdrawal of all medications with cautious reinstitution of HIV medications (avoiding the suspected NRTI) when the metabolic abnormalities have resolved is usually effective.
Adjuvant Therapies for Metabolic Syndromes
Newer drug therapy has improved life expectancy in individuals infected with HIV to a point where consideration should be given to preventing and mitigating of common metabolic diseases such as coronary artery disease, diabetes, and hypercholesterolemia. Optimal patient management, therefore, may involve a combination of diet therapy, aerobic exercise, antilipid medication, risk-factor modification (eg, smoking cessation, hypertension therapy), and anabolic therapy similar to the long-term health recommendations in people who are not infected with HIV. Some possible therapies related to metabolic syndromes are detailed in table 4 (28-32).
Diet. The long-term diet in individuals infected with HIV who have normal body weight and do not have severe weight loss or protein-calorie malnutrition should conform to recommendations from the ADA (33) and National Cholesterol Education Program (NCEP III) (34). These include reducing the lipid content to 30% of total calories with saturated fat less than 10%, 10% to 20% of calories as protein, and the remainder as carbohydrate (34). These dietary recommendations are especially important in patients treated with PIs who develop metabolic dysregulation. A substantial portion of patients with HIV who are receiving HAART therapy have cholesterol or triglyceride levels that exceed the current NCEP guidelines (table 5) (34,35).
TABLE 5. National Cholesterol Education Program Guidelines for CAD Risk Factors (34,35)
Total cholesterol > 200 mg/dL
Triglyceride level > 200 mg/dL
2 or more risk factors for CAD including:
*If CAD is already present, the LDL recommendation should decrease to ¾ 100 mg/dL.
CAD = coronary artery disease; HDL = high-density lipoprotein;
LDL = low-density lipoprotein
Aerobic exercise. Used as an adjuvant therapy to improve functional status and stimulate the immune system in both uninfected (36) and HIV-infected individuals (37-44), aerobic exercise training may have a positive effect. In individuals with HIV, bicycle or treadmill exercise done in 1-hour sessions, three times per week, for 6 to 12 weeks at a moderate rate (below the lactic acidosis threshold [LAT]), or heavy rate (above the LAT), has been shown to improve aerobic capacity (LAT and maximal oxygen uptake), functional status, lean body mass, weight, mood (reduced depressive symptoms), and quality of life.
Aerobic exercise training does not appear to have harmful effects on the immune system of an individual with HIV. No increase in opportunistic infection, decrease in CD4 count, or increase in HIV PCR titers was noted in the above studies. Immune indices (increased candida skin test reactivity and small increases in CD4 counts) may improve (45). The changes observed in immune function with exercise training are quite small and probably not clinically significant; however, the lack of a detrimental effect is clearly important. Therefore, regular aerobic exercise can be recommended with confidence as an important adjunctive therapy.
Aerobic exercise may also have a role in mitigating metabolic dysregulation associated with HIV and HIV therapy, although future research will be required to resolve this issue. Specifically, the adverse changes in glucose, insulin levels, insulin resistance, lipids, weight, and waist-to-hip ratio may be improved in both uninfected (19,41,46,47) and HIV-infected individuals (44,45) who perform aerobic exercise; however, regional changes in adipose tissue may not be ameliorated. Studies are currently underway to confirm the role of aerobic exercise training on metabolic syndromes in individuals with HIV, both in those receiving HAART, and in those about to start.
Lipid-lowering medication. Initial attempts to achieve lipid goals should include a low-fat, low-cholesterol diet combined with aerobic exercise. However, if these attempts fail to achieve the expected result within 6 months, medications to reduce lipids (cholesterol and/or triglycerides) should be considered, especially if other risk factors for coronary artery disease are present.
To reduce cholesterol in individuals who are HIV+, the Adult AIDS Clinical Trials Group (see table 2) recommends statins as excellent first-line agents for lowering cholesterol. PIs may increase serum statin drug levels (eg, simvistatin: 31-fold increase, atorvastatin calcium: 4.5-fold increase) or decrease them (pravastatin sodium: 0.5-fold decrease); therefore, initial dosage and monitoring of lipid-lowering effects are important. In addition, the statins might also lower PI drug levels since all of these are metabolized by CYP3A4, the same cytochrome P-450 enzymes that are induced by all of the statins except pravastatin. Until more data are available on the interactions of these classes of drugs, statin therapy should be instituted only after aggressive attempts have been made to lower levels of LDL cholesterol by other means, such as diet and exercise.
The preferred approach for lipid-lowering therapy is to begin with 20 mg of pravastatin or 10 mg of atorvastatin calcium given each evening at bedtime. If triglycerides are also elevated, fibrates such as gemfibrozil (600 mg twice a day) or micronized fenofibrate (200 mg once a day) are effective and have minimal risk for adverse effects. Of course, concern exists that the concomitant use of statins and fibrates may increase the risk for rhabdomyolysis. Niacin should be avoided because its use has frequent side effects and may increase insulin resistance, and bile sequestering resins may affect gastrointestinal absorption of other HIV drugs.
Risk-factor modification. Long-term smoking cessation and control of hypertension (defined as >140 mm Hg systolic and > 90 mm Hg diastolic) should also be a part of adjuvant therapy for HIV+ individuals. Efforts to achieve and sustain these goals are very important to modify long-term CAD risk.
Anabolic therapies. Additional adjunctive therapies, used specifically to improve lean body mass and weight while decreasing fat mass, have focused primarily on the syndrome of HIV-associated wasting (defined as more than 10% loss in body weight). These interventions are primarily anabolic agents such as recombinant human growth hormone, testosterone, anabolic steroids such as oxandrolone (28), or possibly insulin-like growth factor-1 (29-32). Testosterone replacement therapy appears especially promising in patients with low serum testosterone levels and weight loss, although it may not have an additive effect beyond resistance exercise training alone (48). In studies using anabolic androgens, however, the effects of the androgen and progressive resistance training were additive in augmenting lean body tissue and strength (28,49).
High levels of immunoglobulin with specificity to the antivasoactive intestinal peptide/NTM region of the HIV GP120 protein (50,51) may improve long-term survival (52). High levels can be achieved either through passive infusion (53,54) or possibly as a result of exercise training—a potent inducer of this immunoglobulin (55,56).
Vaccine. A final adjunctive therapy that may hold promise is a vaccine to prevent HIV infection or stimulate immune function if HIV infection exists (57). Unfortunately, it is not immediately forthcoming (58).
Evaluating the Effects of Therapy
Several specialized tests are available for clinical and research use to determine the current metabolic status and assess the benefits of HAART, nutritional and medical therapies, aerobic exercise training, and other adjuvant therapies. The tests supplement the history and physical exam (questions and exam focused on weight loss or gain, changes in body habitus and image, dietary habits, drug regimen and schedule, functional capacity, regular exercise activity, etc), and laboratory evaluation of metabolism (fasting insulin, fasting lipid panel, lactic acid level, and, in cases of wasting, total testosterone level). Documentation and quantification of the current physiologic, anatomic, and nutritional status can be used singularly or in combination to assess the current status of the patient with HIV and to evaluate the response to medical and adjuvant therapies.
Cardiopulmonary exercise testing (CPXT) is an integrative physiologic test that continuously measures oxygen uptake, lactic acidosis threshold, ventilation, heart rate, 12-lead electrocardiogram, and oxygen saturation during exercise. CPXT can be used to evaluate exercise limitation in patients with HIV (59,60) and document the effects of aerobic exercise, medical intervention, or other adjunctive therapy, from the level of the respiratory system to the muscle mitochondria.
Strength testing evaluation (48) can be effort-dependent (maximal voluntary muscle strength) or effort-independent (amount of electromyogram signal at a specific work intensity). It objectively evaluates the effects of a strength training program.
Bioelectrical impedance (BIA) (61) is used to assess body composition by determining fat-free mass (FFM) and fat mass. The test measures electrical conductivity through ionically charged liquid media. When validated against established measures of body composition, differential equations can be generated to estimate body cell mass or FFM, which are indirect measures of muscle and other components of lean tissue. Fat is derived by subtracting FFM from total weight. BIA may not be optimal to assess changes in body fat in HIV+ patients because the test is insensitive to regional changes in body composition.
Dual-energy x-ray absorptiometry (DEXA) is used to evaluate the changes in body composition of muscle, fat, and bone using the differential absorption of two different electron energy sources by tissues of different density (18,62).
Computerized axial tomography and magnetic resonance imaging are perhaps the most anatomically precise clinical methods to determine body composition, allowing quantification of fat, muscle, bone, and visceral and regional fat accumulation or loss (63). Although expensive, the tests are readily available.
HIV infection and HAART can result in various metabolic syndromes. These can range from weight loss with AWS and sarcopenia, to redistribution of body fat, metabolic dysregulation, or drug-induced lactic acidosis. Recognition of these individual syndromes is important for optimal and timely treatment with applicable drug and nondrug therapies. Finally, HIV infection should now be considered a chronic disease, and both drug and nondrug therapy should be offered to mitigate the long-term risk of the metabolic complications of HIV and HAART.
The authors wish to acknowledge the National Institutes of Health for its support of Dr Sattler's work (DK-49308 and NCRR GCRC MOI RR-43).
Dr Stringer is the acting chair of the Department of Medicine and chief of General Internal Medicine at Harbor-UCLA Medical Center in Torrance, California. Dr Sattler is a professor of medicine in the Division of Infectious Diseases at Keck School of Medicine at the University of Southern California in Los Angeles. Address correspondence to William W. Stringer MD, Dept of Medicine, Harbor-UCLA Medical Center, 1000 W Carson St, Box 459, Torrance, CA 90509; e-mail to [email protected].