The use of effective antiretroviral therapy (ART) has resulted in tremendous improvements in morbidity and mortality in HIV-infected individuals. However, the widespread use of effective ART regimens has coincided with increasing reports of metabolic abnormalities such as impaired glucose metabolism and insulin resistance, lactic acidosis, osteopenia, and dyslipidemia. Distressing morphologic changes in body habitus associated with these metabolic abnormalities are characterized by accumulation of fat in the abdomen (visceral fat compartment) and in the dorsocervical area of the neck, as well as by the depletion of fat in the face, buttocks, and extremities. As the metabolic alterations coinciding with the availability of effective ART are similar to the features seen in the metabolic syndrome ("syndrome X"), one of the major concerns has been the potential for increased cardiovascular morbidity and mortality in this cohort.

The causes of the metabolic disturbances and morphologic changes related to ART are incompletely understood. The etiology is likely to involve the effect of HIV specifically as well as the direct and indirect effects of ART superimposed on individual characteristics such as genetic predisposition, gender, and age. There are likely to be both drug class-specific as well as drug-specific differences in the tendency of antiretroviral medications to cause these effects. Furthermore, although some of the metabolic disturbances may be linked to one another, the interconnections between these metabolic abnormalities have yet to be elucidated.

The prevalence of metabolic complications in HIV-infected individuals is high. Estimates vary widely, possibly because of variations in study methodology, defining criteria, treatment regimens, and patient populations. Estimates of abnormalities in fat distribution have ranged from as low as 2% to as high as 84%.(1) Estimates of overt diabetes mellitus have ranged from 1% to as high as 7%; impaired glucose tolerance rates as high as 46% and pathologic insulin sensitivity rates of 61% have been reported in protease inhibitor (PI) recipients.(2) Between 15% and 30% of HIV-infected patients have dyslipidemia, with estimates approaching 60% in patients taking a PI.(1,3) Although lactic acidosis syndrome is an extremely rare event, the prevalence of hyperlactatemia has ranged from 8% to 21%.(4-6) High rates of osteopenia (28-50%) have been reported with rates of osteoporosis from 9% to 21% in patients taking mainly PIs.(7,8,9) The high prevalence rates emphasize the need to assess risk factors proactively and to provide appropriate treatment of these metabolic disorders in HIV-infected patients, as well as the need to integrate metabolic analyses in clinical trials of newer antiretroviral medications.

Background and Definition

Body fat abnormalities are common in patients receiving potent ART, occurring in 30-50% or more of individuals in several large, prospective studies.(9-14) These abnormalities include, singularly or in combination, central fat accumulation, evidenced by increased abdominal girth (due to increase in visceral fat), development of a dorsocervical fat pad ("buffalo hump"), and breast enlargement, as well as loss of peripheral subcutaneous fat (lipoatrophy). The latter designation includes subcutaneous fat loss of the extremities, buttocks, and face. The combination of these morphologic changes and antiretroviral-associated metabolic derangements has been referred to as the lipodystrophy syndrome. Lipodystrophy syndrome is distressing to HIV-infected individuals on ART and has been linked with both short-term and long-term failure to comply with antiretroviral regimens.(15,16) In addition, both the fat accumulation component and the fat depletion component of the syndrome are associated with substantial metabolic dysregulation that may have an impact on long-term cardiovascular morbidity and mortality in HIV-infected patients.

It is important to keep in mind that age is associated with a progressive trend towards increasing central body fat deposition and wasting of fat in the extremities.(17) Among participants in the Multicenter AIDS Cohort Study, many of whom have reached their late 40s, the prevalence of increased abdominal fat was quite high even among HIV-negative men (26%).(18) However, peripheral fat wasting was rare in HIV-negative participants. The prevalence of peripheral fat wasting was 20% among HIV-infected men receiving combination ART for at least 2 years versus 1-2% among HIV-negative men.

Mechanism(s) of Disease

The lipodystrophy syndrome was first described in 1998, shortly after the introduction of PIs.(19) Thus, early studies focused on the role of PIs in the development of lipodystrophy. It is now clear that HIV lipodystrophy can develop in individuals who have never been treated with PIs.(20,21) The use of nucleoside reverse transcriptase inhibitors (NRTIs), and, in particular, stavudine, has been linked specifically to the development of the lipoatrophic component of lipodystrophy.(10,22,21) In the Western Australian Cohort Study, the median time from initiation of a PI-containing ART regimen to clinically apparent fat wasting was 18.5 months for patients receiving stavudine-containing regimens compared to 26 months for patients receiving zidovudine-containing regimens.(22) However, combined PI and dual NRTI therapy leads to dramatically faster fat loss than is seen with dual NRTI therapy alone as shown in. The risk of lipodystrophy increases with both duration of NRTI therapy(22) and duration of PI therapy.(11,23) ART with PIs alone, however, appears rarely to cause lipodystrophy.(24) Lipodystrophy has not been reported in association with nonnucleoside reverse transcriptase inhibitor (NNRTI) use.

Although lipodystrophy almost never occurs in the absence of ART, nondrug factors are also important. Older age has consistently been shown to be associated with increased lipodystrophy risk.(9-11,13,14) Race may be important, with higher rates of lipodystrophy seen in whites.(11,14) Males appear more likely to develop peripheral lipoatrophy, whereas females have greater fat accumulation centrally. CD4 count, viral load, prior AIDS diagnosis, immune reconstitution, and baseline body mass index have been cited as important in some studies, but have not been consistently linked to lipodystrophy risk.(11,13,28)

It has been proposed that mitochondrial toxicity induced by NRTI-mediated inhibition of DNA polymerase gamma may play a role in the development of lipodystrophy. This theory was suggested by the phenotypic similarity in fat maldistribution and metabolic abnormalities to what is seen in some patients with inherited mitochondrial enzyme deficiencies. NRTIs are known to have an inhibitory effect on mitochondrial DNA polymerase gamma, the principal enzyme responsible for mitochondrial DNA (mtDNA) replication. Because mtDNA encodes many of the oxidative phosphorylation chain proteins, a decrease in mtDNA content could theoretically hinder aerobic respiration and other mitochondrial functions.(29) Although this theory is supported by the presence of mitochondrial structural abnormalities and reduced mtDNA in subcutaneous fat biopsies taken from patients with lipodystrophy, a definitive casual relationship has been difficult to establish.(30,31) The ability to reverse peripheral fat loss to some extent following discontinuation of the implicated NRTI (32,33), and the fact that such improvement is associated with decreased adipose cell apoptosis (34), may support the role of NRTI-induced mitochondrial toxicity in this process. PIs may compound the problem by inhibiting adipocyte differentiation and maturation.(35-37) The full molecular basis of this inhibition remains to be determined, but may involve inhibition of specific cellular proteases involved in maturation of nuclear lamin proteins and adipogenic factor sterol regulatory element binding protein-1 (SREBP-1).(38)

It is currently unclear whether central fat accumulation and peripheral fat depletion are part of the same mechanistic syndrome linked by a "maldistribution of fat" or are in fact different syndromes with separate etiologies. Cross-sectional studies using computed tomography (CT) or magnetic resonance imaging (MRI) in HIV-infected subjects with increased abdominal girth have demonstrated that the fat accumulation occurs in the visceral adipose tissue (VAT) (intra-abdominal fat). This observation is of particular concern as studies in HIV-seronegative populations have demonstrated that excess VAT, as part of the metabolic syndrome, is associated with increased risk of coronary artery disease, type II diabetes mellitus, cerebrovascular disease, gallstones, and, in women, breast cancer. Although the cause and effect relationship is unclear, visceral adiposity is also associated--in both the HIV-infected and the general population--with other abnormalities of metabolic regulation, including dyslipidemia, insulin resistance, and hypertension.

In the general population, enlargement of the dorsocervical fat tissue (buffalo hump) occurs in association with a state of glucocorticoid excess (Cushing syndrome). However, hypercortisolism has been excluded as a cause of buffalo hump in HIV-associated lipodystrophy, and the factors associated with its development remain unclear.(39)

Diagnosis

Diagnosis of lipodystrophy is typically made on clinical grounds, based on patient and physician assessment of body composition changes. Although case definitions for use as a research tool have been suggested, consensus is lacking and the applicability to clinical practice is unclear.(22,40) Diagnosis is hampered by several factors. Fat depletion in the periphery may be associated with the AIDS wasting syndrome, which is typically characterized by loss of both lean and fat tissue. Visceral fat accumulation may be associated with general weight gain that may occur shortly after initiating effective ART. In individuals with stable weight, assessment of lipodystrophy relies on demonstration of maldistribution of fat following use of ART and therefore, by necessity, requires knowledge of premorbid fat content and distribution.

Several measures may aid this assessment but are currently appropriate primarily as research tools. Abdominal MRI or CT are probably the most sensitive and specific measures, particularly for the assessment of visceral fat, but they are costly.(41) CT scanning also entails substantial radiation exposure. Single-slice CT measurements of the abdomen at the level of L4-L5 correlate strongly with whole-body measurements for both subcutaneous adipose tissue and VAT.(42-44) Dual-energy x-ray absorptiometry (DEXA) adequately measures subcutaneous limb fat and may be utilized for studies of peripheral fat loss. However, DEXA is not appropriate for assessment of central adiposity as it cannot distinguish between abdominal subcutaneous and visceral fat (41). All anthropometric measurements suffer from wide inter- and intraperson variability and require considerable training for the results to be reproducible.(41) Finally, bioelectrical impedance analysis (BIA) typically estimates whole-body composition. Although attempts have been made to assess regional body composition using BIA, the methods remain unvalidated and cannot be recommended at the present time.(45)

Although the recent IAS-USA Panel did not feel that any technique had sufficient sensitivity, specificity, or predictive value to be recommended for routine clinical use, it may be reasonable to document fat distribution prior to the initiation of ART by photographs and/or simple anthropometric means (weight, height, and circumferences of the arms, thighs, waist, hips, and perhaps the neck).(9)

Therapy

Treatment of lipodystrophy is evolving, with no clear standard of care. The goals of therapy may target the metabolic derangements associated with lipodystrophy or may be purely cosmetic. In addition, fat accumulation and fat depletion may call for different therapeutic interventions.

PI withdrawal or substitution with an NNRTI has not consistently been helpful in correcting lipodystrophy, although dyslipidemia appears to improve following these types of switches.(46-49) Care must be exercised to avoid virologic failure with such substitutions. Substitution of stavudine or zidovudine with alternative NRTIs such as abacavir has led to some improvement, specifically in peripheral lipoatrophy.(32,50) Particularly in individuals on stavudine-containing regimens, change to a more "mitochondria-friendly" NRTI such as abacavir or tenofovir, or a change to an NRTI-sparing regimen might be considered, although studies to date suggest that the improvement in body composition is modest at best.

Pharmacologic interventions have yielded mixed results. Decreased testosterone levels are seen in HIV-infected men and are associated with visceral obesity in the general population.(51) Although testosterone replacement has been associated with decreases in visceral fat and improvements in insulin sensitivity, efficacy or safety of this approach in HIV-1-infected individuals with visceral adiposity is currently unknown.(52) Thus, testosterone at physiologic doses may be helpful in treating visceral adiposity in HIV-infected men with lipodystrophy who are also hypogonadal, but cannot be recommended outside this subpopulation. A placebo-controlled trial (A5079) evaluating the role of testosterone in this setting is ongoing within the Adult AIDS Clinical Trials Group (AACTG).

In a prospective, open-label trial of 30 American patients, supraphysiologic doses of recombinant human growth hormone (6 mg/day) administered over 24 weeks led to a significant decrease in VAT. Unfortunately, adverse effects including hyperglycemia, arthralgias, and fluid retention were common, and body composition changes reverted to pretreatment status after therapy was stopped.(53) Lower pharmacologic doses of growth hormone have demonstrated consistent declines in VAT, but alterations in glucose homeostasis continued to occur.(53,54)

Metformin was evaluated at a dose of 500 mg twice a day in a randomized, controlled trial of 26 HIV-infected subjects.(55) A trend toward a decrease in VAT (as measured by CT) was seen but was not statistically significant. This decrease in VAT was associated with general weight loss and proportional reduction in subcutaneous adipose tissue. Diastolic blood pressure and insulin resistance were also noted to improve significantly in the treatment arm. No increase in lactate or liver transaminase levels was observed, and mild diarrhea was the most common adverse effect of metformin noted.

Another class of insulin-sensitizing agents, the thiazolidinediones, can increase adipogenesis in vitro, suggesting that these agents may be able to reverse subcutaneous fat loss. Troglitazone increased subcutaneous fat and reduced visceral fat in patients with type 2 diabetes mellitus and in those with various syndromes of genetic and acquired lipodystrophy.(56-58) The limited number of studies available to date in the HIV-infected population, however, have not shown consistent improvements in visceral adiposity nor in subcutaneous lipoatrophy with thiazolidinedione treatment.(59-61)

Nonpharmacologic modalities may offer some benefit, but large-scale trials are lacking. Currently there are no data to support a role for specialized dietary supplements in HIV-infected patients with lipodystrophy in the absence of other metabolic abnormalities or a general indication for weight reduction. Hypocaloric diets are recommended for overweight individuals with body mass index >27, kg/m², although rapid weight loss should be avoided. Exercise, both aerobic and resistance training, can be pursued at a moderate intensity without adverse effect on HIV control. Both of these measures can reduce central adiposity while improving glycemic control and lipid profiles, but may also lead to loss of peripheral subcutaneous fat.(62)

Facial lipoatrophy is a particularly distressing aspect of lipodystrophy. Plastic surgery has gained increasing attention in the HIV-infected community due to the limited efficacy of other therapeutic options. Web sites, such as that sponsored by the Program for Wellness Restoration (PoWeR) at http://www.facialwasting.org/, have been developed to disseminate information not usually available in the medical literature. Because transplantation of the patient's own fat tends to result in absorption and disappearance of fat cells in a matter of weeks, much interest has focused on synthetic, nonbiodegradable implants. However, long-term safety and efficacy data are lacking. The disfigurement resulting from facial lipoatrophy and the potential for extreme psychological distress, create an urgent need for research into modalities of palliative therapy.

Definition and Background

Insulin resistance and glucose intolerance were uncommon in HIV-1 infected patients prior to the use of potent ART regimens. Since the introduction of effective ART, 40% of patients initiated on a PI-containing regimen have developed impaired glucose tolerance.(63) An observational study found elevated fasting glucose above 120 mg/dL in 14% of patients tested.(63) Although the proportion of HIV-infected individuals who develop overt diabetes mellitus while taking PIs is small (1-6%), the long-term consequences of insulin resistance and its role in cardiovascular disease are unknown.(2,64).

Mechanism(s) of Disease

Impairment of glucose metabolism is thought to result from tissue insensitivity to the effect of insulin (insulin resistance). A compensatory increase in insulin secretion is needed to inhibit hepatic gluconeogenesis and to increase muscle uptake of glucose. An observational study of insulin sensitivity comparing HIV-seronegative controls, HIV-positive individuals receiving ART containing a PI, and HIV-positive individuals receiving ART not including a PI found that insulin sensitivity was 55% lower in HIV-positive individuals receiving a PI than in controls.(64) Insulin sensitivity was also 10% lower in HIV-positive individuals receiving ART without a PI compared to controls, suggesting that other factors besides PIs were involved in impairment of glucose metabolism.

Multiple mechanisms are likely to contribute to insulin resistance in the HIV-infected individual taking ART. These mechanisms are likely to involve both the direct effects of antiretroviral medications and the indirect consequences of fat redistribution. The PI indinavir directly induces the development of insulin resistance when given as a short course or as a single dose in HIV-seronegative individuals.(65,66) This direct response is likely mediated by impaired cellular glucose uptake due to inhibition of both the Glut4 glucose transporter and glucose phosphorylation.(67,68) Reduced insulin sensitivity may also be a result of lipodystrophy mediated by the elevated blood levels of free fatty acids (FFAs) induced by fat redistribution. Elevation of FFAs may interfere with cellular glucose transport through a reduction in the phosphorylation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI 3-kinase), resulting in impaired intracellular signaling and insulin resistance.(69) Interestingly, increases in lipolysis and elevated blood levels of FFAs have been found to be independently associated with both accumulation of VAT (a more metabolically active form of fat) and depletion of peripheral subcutaneous fat.(63,70) Finally, it is now recognized that a variety of proteins derived from adipocytes and adipose stromal cells act both locally and distally to regulate fat-cell differentiation and to sense and adjust systemic energy balance. Antiretroviral-mediated disturbances in the quantity and distribution of fat may disrupt the normal cytokine regulation of glucose homeostasis. Of particular interest is a recently described adipokine named adiponectin (ACRP-30, AdipoQ) that may have insulin-sensitizing properties. A correlation between low adiponectin levels and decreased peripheral subcutaneous fat has been reported, and a possible relationship between low adiponectin levels and increased visceral fat is being studied.(71)

Diagnosis

The IAS-USA's recommendations on the management of metabolic complications advise that fasting glucose should be assessed before and during treatment (prior to starting ART, 3-6 months after starting, and annually thereafter) with a regimen containing one or more PIs.(9) It may be appropriate to extend this recommendation to all subjects initiating antiretroviral regimens, given that insulin resistance may also be seen with regimens that do not include a PI, particularly in association with the development of lipodystrophy. Serial fasting plasma glucose assessments and/or oral glucose tolerance testing may help to identify individuals with impaired glucose tolerance, and may be especially helpful in those at risk for type 2 diabetes mellitus.

Therapy

In antiretroviral-naive individuals with preexisting impaired glucose tolerance, consideration should be given to avoiding the use of PIs in initial therapy. In those individuals already taking PIs who develop diabetes, switching antiretroviral regimens to improve insulin sensitivity may be considered with attention to possible adverse effects of the new regimen and risk of viral recurrence. Short-term improvement in insulin resistance has been demonstrated with the substitution of an NNRTI or abacavir for the PI component of an antiretroviral regimen.(48,72,73)

The treatment of HIV-associated impaired glucose metabolism is based on studies in the diabetes literature. Lifestyle modification promoting healthy diet and exercise is important. The Diabetic Primary Prevention Trial found that weight loss, healthy diet, and exercise delayed the onset of diabetes in individuals with impaired glucose tolerance.(74) For patients with persistent fasting hyperglycemia requiring drug therapy, insulin-sensitizing agents (such as metformin) and thiazolidinediones (such as rosiglitazone and pioglitazone) have been shown to be safe and effective in reducing insulin resistance in the general population, and may be used as first-line agents despite limited information about safety and efficacy in the HIV-infected population. A study of metformin in a small number of HIV-infected subjects suggested that metformin use may reduce insulin resistance and improve other cardiovascular risk factors.(55,75) Close monitoring for excessive weight loss and development of lactic acidemia is warranted. Rosiglitazone therapy in 8 HIV-infected subjects was associated with improvement in insulin sensitivity as well as improvements in fat redistribution.(61) Because of the known association of the thiazolidinediones with liver dysfunction, serial monitoring of liver enzymes is warranted. Oral sulfonylureas, meglitinides, and insulin should be reserved for severe cases of diabetes in which insulin-sensitizing agents are ineffective or contraindicated. Testosterone therapy has been found to improve insulin sensitivity in hypogonadal men and may be used in this specific subgroup of HIV-infected men.(51)

Background

Abnormalities of lipid metabolism are common complications of HIV disease and HIV therapy. Similar to the link suggested between atherosclerosis and chronic infections such as Chlamydia pneumoniae, the inflammatory response to chronic HIV infection, which is probably mediated by cytokines, may in itself be proatherogenic.(76) Prior to the availability of effective ART, proatherogenic lipid profiles characterized by reduced levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, but with appearance of small dense LDL (subclass pattern B), and increased triglyceride levels were reported.(77,78) Small dense LDL is believed to be proatherogenic because it is particularly susceptible to oxidation and can penetrate the endothelium and bind to intimal proteoglycans more effectively than large buoyant LDL, resulting in retention in the arterial wall. Since the advent of potent ART, particularly with the use of PIs, elevations in triglycerides, LDL, and total cholesterol are commonly seen in practice. In a prospective study of 221 HIV-infected individuals followed for a median of 5 years, the incidence of new-onset hypercholesterolemia and hypertriglyceridemia was 24% and 19%, respectively.(79)

These proatherogenic lipid profiles have raised concerns about increased cardiovascular disease risk in the HIV-infected population. Although this issue remains controversial, results from prospective studies have begun to demonstrate the validity of such concerns. The HOPS study, a prospective observational cohort study, reported an increased incidence of myocardial infarction and angina in HIV-infected individuals taking PIs compared to those not taking PIs. This increased risk remained evident even after adjustment for other risk factors, including smoking, gender, age, diabetes, hyperlipidemia, and hypertension.(80) However, the investigators noted that most of the patients who had a myocardial infarction or an anginal episode also had traditional risk factors for cardiovascular disease aside from hyperlipidemia, such as smoking, hypertension, and insulin resistance. A prospective assessment of 23,490 patients from 11 cohorts on three continents (D:A:D Study) found that combination ART was associated with a 27% relative increase in the rate of myocardial infarction per year of exposure over the first 7 years of treatment.(81)

Mechanism(s) of Disease

PIs have been implicated as a major cause of the lipid abnormalities seen with ART. PI use is associated with the development of dyslipidemia independent of treatment with other drugs, viral load, or body weight changes. Different PIs have differing effects on lipid metabolism. Ritonavir has the greatest effect on levels of triglyceride, LDL, and cholesterol, whereas indinavir has minimal effect.(66,82) Interestingly, atazanavir may have a beneficial effect on serum triglycerides, LDL, HDL, and total cholesterol levels.(83) PIs are thought to inhibit the degradation of apolipoprotein B, which in turns results in lipid elevations.(84) Genetic susceptibility has been found to play an important role in lipid metabolism in individuals receiving PIs. Patients who are heterozygous or homozygous for the apolipoprotein E-2 genotype have been found to have higher serum triglyceride and cholesterol levels when receiving PIs.(85,86)

NRTIs have not been demonstrated to cause dyslipidemia directly. However lipoatrophy epidemiologically linked to the use of NRTIs has been associated with increases in FFA production and triglyceride levels.(21) Medications within the NNRTI class may have differing effects on lipid levels. However, favorable decreases in levels of cholesterol, triglycerides, or both have generally been demonstrated following a switch from PIs to nevirapine or efavirenz.(47,48,72) In addition, some studies have found an association between nevirapine or efavirenz use and favorable increases in HDL cholesterol.(87,88)

Diagnosis

Prospective serial evaluation for dyslipidemia in HIV disease appears warranted considering the high likelihood of its association with increased cardiovascular risk. In addition, triglyceride levels >1,000 mg/dL (11.3 mmol/L) are associated with an increased risk of pancreatitis. As suggested in preliminary guidelines by the AACTG Cardiovascular Disease Focus Group, it is reasonable to obtain a fasting lipid profile at baseline and approximately 3 months after starting a new ART regimen.(89) If the lipid profile is normal, annual repeats are currently recommended.

Because appropriate management of dyslipidemia in HIV-infected subjects is incompletely known, it appears reasonable to follow the general guidelines of the National Cholesterol Education Program (NCEP) III as a reference and framework for identifying patients who require lipid-lowering interventions.(90) Information on NCEP III can be obtained at http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm. A risk assessment tool for determining the 10-year cardiovascular disease risk of an individual is available within that Web site: (http://hin.nhlbi.nih.gov/atpiii/calculator.asp). A 10-year cardiovascular disease risk >10% indicates a need for intervention.

Lipid panels should be performed in a fasting state (no food or drink except water for >=12 hours) and should include triglyceride, HDL, LDL, and total cholesterol levels. LDL cholesterol (in mg/dL) can be calculated using the Friedewald equation: calculated LDL cholesterol = total cholesterol - HDL cholesterol - triglycerides/5.(91) The Friedewald equation is not accurate for triglyceride levels above 400 mg/dL, and a direct LDL cholesterol measurement should be obtained. If direct LDL cholesterol measurement is not possible, non-HDL cholesterol levels (total cholesterol minus HDL cholesterol) at least 30 mg/dL greater than the established upper limit of LDL cholesterol indicate that intervention is appropriate.(9)

Detection of comorbidities such as hypogonadism, thyroid disease, liver disease, and alcoholism are also important initial steps in the evaluation of dyslipidemia in HIV-infected individuals.

Therapy

Randomized clinical trials to establish optimal treatment of ART-associated hyperlipidemia have not been completed. According to general NCEP III guidelines, lifestyle modification is essential; smoking cessation, dietary modification (American Heart Association step 1 and 2 diets), and regular exercise should be promoted. Only after lifestyle modification has failed or when lipid levels are severely elevated are lipid-lowering agents necessary. For elevated LDL cholesterol, HMG-CoA reductase inhibitors (statins) have produced favorable responses.(92) These drugs must be used with caution, as elevated levels of statins resulting from the inhibitory effect of PIs on cytochrome P450 3A4 may result in myositis and rhabdomyolysis. The preferred statins are pravastatin or atorvastatin, because these agents have relatively modest pharmacokinetic interactions with antiretrovirals.(93,94) A lower initial starting dose of atorvastatin (10 mg daily) is recommended. Results from the AACTG study A5087 found monotherapy with either pravastatin or fenofibrate for HIV-related dylipidemia was safe but unlikely to achieve the NCEP goal. Pravastatin appears to be most effective in lowering LDL, although subjects who received fenofibrate had larger increases in HDL and decreases in triglycerides. Dual therapy appeared safe although the relative risk of rhabdomyolysis may be increased with combination therapy. Manufacturers do not currently recommend routine creatine kinase (CK) surveillance when statins are used in the general population. The utility of such surveillance in the HIV-infected population is unclear, as isolated elevations of CK of uncertain clinical significance are seen occasionally in HIV-positive individuals. It seems prudent, however, to inform the patient of this potential adverse effect and to maintain a high index of suspicion for myalgias and other signs and symptoms of myositis and rhabdomyolysis. It may be best to avoid bile acid sequestrants, as these may interfere with absorption of antiretrovirals.

For hypertriglyceridemia (serum triglyceride levels >500 mg/dL), fibric acid analogues such as gemfibrozil and fenofibrate have been used. The magnitude of reduction of LDL, total cholesterol, and triglycerides through the use of statin, fenofibrate, or the combination of the two, has been less than robust in patients taking PIs.(95-97) The IAS-USA Panel recommends that when combination therapy with a fibric acid derivative and a statin is anticipated--in the setting of hypertriglyceridemia accompanied by LDL cholesterol elevation--therapy should begin with a statin, followed by the addition of the fibric acid derivative after month 4 if the response is suboptimal. Although niacin may worsen insulin resistance, the use of niacin may be safe for the treatment of hypertriglyceridemia in individuals at low risk for glucose intolerance, and the safety and efficacy of niacin in combination with ART is being investigated in a number of pilot studies.(98-100)

Background and Definitions

Lactic acidemia has been associated with NRTI use since the early 1990s when it was first described as a complication of didanosine therapy.(101) Lactic acidemia refers to increased plasma lactate (hyperlactatemia) with a normal blood pH, whereas lactic acidosis consists of a high lactate level accompanied with metabolic acidosis. The spectrum of disease within this syndrome ranges from fulminant multiorgan dysfunction characterized by severe acidosis and hemodynamic instability, to less severe symptomatic hyperlactatemia with hepatic steatosis (fatty liver), to intermittent or chronic low-grade hyperlactatemia without acidosis, steatosis, or symptoms.

Although most cases of lactic acidemia are asymptomatic, a variety of nonspecific presenting complaints have been described. The most common symptoms include nausea, vomiting, and diffuse abdominal pain; fatigue, weakness, weight loss, tachypnea or dyspnea on exertion, arrhythmias, and neurologic findings have also been reported in the absence of gastrointestinal complaints.(9,102) Liver abnormalities, including hepatomegaly, hepatic steatosis, and elevated serum transaminases are common in symptomatic hyperlactatemia and almost ubiquitous in NRTI-induced lactic acidosis.(5,9,102-106) The onset of symptoms is usually subacute, occurring over weeks to months, although acute fulminant cases associated with multiorgan (especially liver) dysfunction occur rarely.(102)

Several large observational studies have been performed to determine the prevalence of and risk factors for lactic acidemia.(4-6) Although published estimates of the prevalence of lactic acidemia range from 8% to as high as 21% of patients receiving at least one NRTI (9), failure to follow stringent guidelines for lactate collection may have lead to overestimation in earlier studies.(107) Mild asymptomatic acidemia does not appear to predict progression to more severe acidemia or symptomatic disease (symptomatic acidemia or lactic acidosis syndrome); chronic mild asymptomatic hyperlactatemia with stable lactate concentrations of 1.5-3.5 mmol/L was the most common pattern of hyperlactatemia observed among 349 participants in the Western Australian Cohort Study.(103) The Swiss Cohort Study of 880 patients on ART receiving treatment in one of seven centers in Switzerland found increased risk of lactic acidemia with stavudine use compared with zidovudine-containing regimens, with an incidence of 11% vs. 4.2%, respectively.(5) Didanosine also conferred increased risk, whereas zidovudine and lamivudine were associated with comparatively lower risk of lactic acidemia. There was no effect of age, gender, HIV stage, or other demographic factors. Patients with lactic acidemia tended to have concomitant lipid abnormalities, hyperglycemia, and lipoatrophy. However, chronic hyperlactatemia on routine testing at 1- to 3-month intervals in asymptomatic patients showed poor sensitivity in predicting the development of severe lactic acidosis or hepatic steatosis.(103) So far, studies have not demonstrated any association between NNRTI or PI therapy and lactic acidemia.

It has been estimated that symptomatic hyperlactatemia occurs at a rate of 13.6-14.5 events per 1,000 patient-years, and that lactic acidosis occurs less frequently at a rate of 1.2-3.9 events per 1,000 patient-years.(108) The high mortality (33-57%) of NRTI-associated lactic acidosis has prompted the investigation of specific predictors of acidosis. The largest case series of 12 Spanish patients with literature review of 60 additional cases of ART-associated lactic acidosis found presenting complaints mirroring those of less severe acidemia. CD4 count, viral load, specific NRTI use, and age were not predictive of increased disease severity. Stavudine was the thymidine analogue used in 48%, whereas zidovudine was used in 45% of cases, with a median 9 months of therapy prior to presentation. Women were overrepresented, accounting for 43% of severe acidosis cases, although they account for only approximately 20% of HIV-infected individuals in the developed world. On multivariate analysis, only lactate level >10 mmol/L was associated with increased mortality (odds ratio [OR] 13.23).(102) Pregnancy may also be a risk factor for more severe disease, and cases of acidosis with maternal and fetal deaths have been reported.(109,110) Patients with preexisting liver disease and hepatitis B and C coinfection are overrepresented in both lactic acidemia and lactic acidosis.(111) Concomitant use of didanosine and ribavirin in HIV/hepatitis C-coinfected individuals may represent a risk factor for lactic acidosis as well as for other syndromes attributed to NRTI-mediated mitochondrial toxicity.(112)

Mechanism(s) of Disease

At a cellular level, lactate is the metabolic product of glycolysis favored under anaerobic conditions or when mitochondrial oxidative function is impaired. Lactic acidosis is believed to result from the overproduction of lactate as a consequence of NRTI-induced mitochondrial toxicity. The proposed mechanism of this drug toxicity is the inhibition of mtDNA polymerase gamma, the enzyme responsible for replication of mtDNA. Diminished polymerase activity decreases the amount of mtDNA and its gene products, which include proteins involved in oxidative phosphorylation, resulting in impaired aerobic metabolism and hyperlactatemia.(9,102) Didanosine and stavudine show relatively high inhibition of DNA polymerase gamma in vitro, consistent with the finding of increased risk of lactic acidemia with these NRTIs.(102)

Venous or arterial lactate reflects the net balance between lactate production and release from metabolically active tissues and lactate uptake by tissues (predominantly liver and kidney) with the capacity to oxidize lactate or use it as a substrate for gluconeogenesis. Homeostatic regulation is highly efficient, with conditions of lactate excess normally leading to augmentation of lactate clearance by the liver, kidneys and lungs. Sustained elevations in blood lactate levels therefore indicate a significant loss of homeostasis.(103,113) Possible explanations for the lactic acidosis/acidemia syndrome include massive overproduction of lactate, marked decrease in the ability to oxidize lactate, or, most likely, a combination of both. The almost uniform involvement of liver pathology in severe cases of lactic acidosis and acidemia suggests that hepatic dysfunction with respect to lactate metabolism may be an important component of this syndrome.

Diagnosis

Measurement of blood lactate is indicated in patients on NRTI therapy who present with the signs and symptoms described above, and in those with low bicarbonate, chloride, or albumin levels, elevated anion gap, unexpected increases in liver enzymes, or new onset of clinical liver failure. Anion gap has not been found to correlate reliably with lactic acid level, and a normal anion gap cannot be used to exclude the diagnosis of hyperlactatemia or acidosis. Routine measurements of venous lactate are not indicated in asymptomatic patients because of the poor positive predictive value for future symptomatic lactic acidosis or hepatic steatosis.(103,114)

Care must be taken to ensure proper collection of lactate samples, as failure to do so may lead to falsely elevated lactate levels. Guidelines such as those developed by the AACTG may be helpful in this regard. If carefully collected, venous lactate is equivalent to the arterial level in most clinical situations.(115) It is particularly important to arrest continued anaerobic metabolism of blood cellular components following a blood draw by the use of NaF/KOx tubes.(116) However, these guidelines are based on scant data, and the exact importance of lack of prior exercise, hydration, the need to collect blood without fist clenching or tourniquet application or on the need for ice or refrigeration is unknown. A recent study suggested that, for research purposes, 3 months of storage of NaF/KOx plasma had no significant effect on lactate measurements.(117)

The significance of a single lactate value is difficult to interpret, and values over time show wide variations in a single patient. It is therefore important that any elevated value be confirmed with repeat testing with careful attention to specimen collection guidelines.

Therapy

The management of hyperlactatemia depends on the degree of elevation and the severity of symptoms.

Lactic Acidosis

Considering the high morbidity and mortality of lactic acidosis and the potential for acute presentation, a high index of suspicion is essential for the successful management of this syndrome. In published reports of HIV-related lactic acidemia, overall mortality was 80% in patients with lactate levels above 90 mg/dL (10 mmol/L), but no patients with lactate levels below 90 mg/dL died.(9) Over time, characteristic features have emerged that may assist in identification of subjects with NRTI-induced lactic acidosis: patients almost always have hepatic steatosis and are highly symptomatic with nausea, vomiting, anorexia, abdominal pain or distension, tender hepatomegaly, fatigue, malaise, and prostration.(111)

Withdrawal of the inciting NRTI drug forms the cornerstone of therapy for this group of individuals. Other antivirals should also be held in the acute setting to limit the development of viral resistance until appropriate ART can be safely reinstituted. In addition, therapy directed at the correction of acidosis is indicated and may include hemodynamic or respiratory support in an ICU setting as well as the use of hemodialysis in severe cases.(111) Additional therapies without proven efficacy that have been used empirically in subjects acutely ill with this syndrome include intravenous thiamine(118,119), riboflavin(114), L-carnitine(120,121), coenzyme Q(120,122), and vitamin C.(120)

ymptomatic Hyperlactatemia

Management depends on the severity of symptoms and the judgment of the physician regarding the clinical significance of the lactate elevation. There are no randomized, controlled clinical trials in HIV-infected patients to evaluate how and when withdrawal of antiretrovirals should be considered in those individuals with hyperlactatemia without acidosis. However, the IAS-USA Panel recommends withdrawal of antiretrovirals in all patients with lactate levels >90 mg/dL (10 mmol/L) and in all symptomatic subjects with lactate levels >45 mg/dL (5 mmol/L).(9) It may be reasonable to consider NRTI withdrawal in symptomatic subjects with any degree of lactate elevation if no other reasons for symptoms are identified.

Aside from discontinuation of ART, the treatment of severe hyperlactatemia is supportive. In addition, there are case reports of cofactor administration using thiamine, riboflavin, coenzyme Q, L-carnitine, and antioxidants, similar to the treatment of lactic acidosis. These agents may be beneficial, although randomized trials of their efficacy are lacking. Reinstitution of ART with alternative mitochondria-friendly NRTIs such as abacavir or tenofovir, NRTI-sparing regimens based on PI/NNRTI combinations, or reinstitution of the offending NRTI at lower doses have been successful in some patients.(123)

Asymptomatic Hyperlactatemia

Asymptomatic, low-level increases in lactate are currently not thought to require intervention, as there is no conclusive evidence that asymptomatic lactate elevations are dangerous in the short term or predictive of more severe lactic acidemia. The long-term consequences of low-level lactate elevation merit further investigation.

Because there is no way to predict who will develop lactic acidemia, patients on NRTI therapy should be made aware of the signs and symptoms of this syndrome and the need to seek medical care promptly should they occur. A high index of suspicion is specifically warranted during episodes of infection, as antecedent minor--mainly respiratory--infections have been noted to precede cases of symptomatic lactic acidemia.(124)

Osteonecrosis

Background and Definition

Osteonecrosis, or avascular necrosis--defined as the death of bone tissue resulting from compromised blood flow to that tissue--has been reported in the setting of HIV infection even prior to the availability of potent ART.(125-127) Affected bones include the femoral head and condyle, humeral head, proximal tibia, and bones of the hand and wrist. Interruption of the vascular supply to bone results in a stepwise progression through ischemia, hyperemia, an increase in intraosseous pressure, and eventually death of osteocytes. Osteonecrosis usually affects bone closest to the joint space. Imaging studies reveal subchondral lucency followed by the collapse of bone and narrowing of the joint space. In a cross-sectional study of HIV-infected outpatients in San Francisco, MRI detected evidence of osteonecrosis in 4.4% of 339 asymptomatic patients surveyed, compared with 0.02-0.14% in the general population.(128) Osteonecrosis has been seen predominantly in patients with advanced HIV disease and in males between the ages of 20 and 50 years, with the majority of affected individuals having at least one risk factor previously associated with osteonecrosis in the HIV-uninfected population.(129-131) Common risk factors in the general population include use of systemic corticosteroids, alcohol abuse, hyperlipidemia (particularly hypertriglyceridemia), hypercoagulable states, hemoglobinopathies, autoimmune disorders, pancreatitis, pregnancy, bearing heavy weight, trauma, and osteomyelitis.(132)

Mechanism(s) of Disease

Osteonecrosis involves the death of bone tissue through vascular compromise. The exact mechanism of this vascular occlusion is not known. A possible mechanism of osteonecrosis is the development of vasculitis and thrombosis resulting in disruption of the vascular endothelium and luminal occlusion.(132) HIV infection has been associated with the development of anticardiolipin antibodies, which have been reported to occur in 50-86% of the HIV-infected population in a cross-sectional study.(133) Antithrombotic factor S deficiency has been associated with HIV infection and may result in thrombotic events.(133) Several case-controlled studies in HIV-infected subjects have associated corticosteroid use with osteonecrosis.(128,130,134) Hyperlipidemia and alcohol use, rather than any specific antiretroviral agent, have also been associated with osteonecrosis.(130) Based on available studies, there is little evidence to suggest that ART is directly involved with the development of osteonecrosis.

Diagnosis and Therapy

The IAS-USA Panel does not recommend routine screening of HIV-infected patients for the presence of osteonecrosis. However, a high index of suspicion is warranted in individuals who present with pain over the joints or bone. MRI is the most sensitive and specific imaging technique for early detection of osteonecrosis and is indicated if plain films are normal and symptoms of osteonecrosis persist.(134) Early detection of this disease can help reduce its extent and morbidity. The same principles of management for osteonecrosis should be followed as in HIV-uninfected patients.(134) Bone pain can be treated with nonsteroidal anti-inflammatory drugs. Surgical resection with joint replacement is the only effective therapy for the treatment of symptomatic osteonecrosis. Physical therapy can help retain functionality. Discontinuation of all corticosteroids and abstinence from alcohol may be indicated.

Glucocorticoids are prescribed for various conditions associated with HIV. Because there are studies suggesting that even the short-term use of glucocorticoids may predispose patients to osteonecrosis, these agents should be used judiciously, in the lowest effective dosages, and for the shortest possible length of time.(132)

Osteopenia and Osteoporosis

Background and Definitions

Osteopenia refers to bone demineralization, and osteoporosis to bone demineralization of sufficient significance that it is likely to lead to or be associated with fractures after minimal trauma. A more specific classification has been devised that uses four diagnostic categories related to bone mineralization: normal, osteopenia, osteoporosis, and established osteoporosis with fragility fractures.(135,136) The classification relies on the use of DEXA scanning, typically of the hip and spine, to determine bone density. DEXA results are reported in absolute terms (g/m²) and relative terms: t score and z score. The t score is the number of standard deviations between the obtained result and the value expected in a young individual (25-30 years old). The z score represents the number of standard deviations between the obtained result and an age-matched average value from healthy individuals. Osteopenia is defined as a t score between 1 and 2.5 standard deviations below the average found in young people. Osteoporosis is a t score >2.5 standard deviations below the average found in young people. Established osteoporosis is a t score >2.5 standard deviations below the mean in the presence of fragility fractures.

Osteopenia and osteoporosis occur at high frequency in the HIV-infected population on ART compared to age-matched, HIV-negative controls. Furthermore, observational studies have reported higher rates of osteopenia in individuals having a CD4 cell count at or below 100 cells/mm³ (45%), individuals taking PIs (50%), and those with evidence of lipodystrophy (28%).(7,8) These same studies found osteoporosis to occur in 40% of those with a CD4 cell count at or below 100 cells/mm³, 21% of those taking PIs, and 9% of those with lipodystrophy. Preliminary investigations have also suggested that osteopenia may be linked to lactic acidemia.(137)

Mechanism(s) of Disease

Subjects receiving potent ART have increased bone alkaline phosphate and osteocalcin, which are markers of bone turnover.(138) PI use has been associated with increased osteocalcin, suggesting a possible mechanism for bone demineralization.(138) Some PIs may block the differentiation of osteoblasts, thereby reducing the rate of new bone formation.(139) However, the specific contributions of antiretroviral agents and HIV infection to osteopenia and osteoporosis are not well defined.

Diagnosis

Similar to the recommendations on osteonecrosis, the IAS-USA Panel does not recommend routine screening for the presence of osteopenia or osteoporosis.(9) However, recommendations may change as the prevalence of osteoporosis in this population, its association with fracture risk, and safety and efficacy of various modalities for therapy become clearer. In the general population, routine DEXA scans are now recommended by the U.S. Preventative Task Force in all women above age 65 and selected women in the 60- to 65-year-old age group because of the increased prevalence of osteopenia and osteoporosis in these groups.(135,140)

Therapy

Osteopenia is usually asymptomatic. Individuals suffering from severe osteoporosis may present with pain over the joints or bones as a result of one or more fractures. Current therapies used to treat bone demineralization have not been completely studied in the HIV-infected population and are extrapolated from recommendations in the general population. The goal of therapy--as in the elderly population--is to reduce fractures and maintain function. Lifestyle modifications generally accepted as part of the overall treatment of bone demineralization include increased physical activity, weight loss, and smoking cessation. Individuals diagnosed with osteopenia or osteoporosis should consume 1,500 mg of calcium and 400-1,000 IU of vitamin D daily. Bisphosphonates, such as alendronate, which function by retarding bone resorption, have been effective in treating osteoporosis in the general population and are the only treatment approved by the U.S. Food and Drug Administration for osteoporosis in men. The use of bisphosponates in the HIV-infected population is currently under evaluation.