Metabolic Complications of HIV Therapy

• Introduction
• HIV-Associated Lipodystrophy
• Insulin Resistance
• Dyslipidemia
• Hyperlactatemia and Lactic Acidosis
• Bone Disease
• References

Introduction

The use of effective antiretroviral therapy (ART) has resulted in tremendous improvements in morbidity and mortality in HIV-positive patients. However, the widespread use of effective ART 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 not understood completely. The etiology is likely to involve the effect of HIV per se 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 and 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 among these metabolic abnormalities have yet to be elucidated. Table 1 summarizes the metabolic and morphologic complications associated with HIV infection and ART.

HIV-Associated Lipodystrophy

Background and Definition

Body fat abnormalities are common in patients receiving potent ART, occurring in 30% to 50% or more of participants in several large, prospective studies.^1-6 These abnormalities have been reported to 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 (Figures 1-4). The lipodystrophy syndrome is distressing to HIV-positive patients on ART and has been linked with both short-term and long-term failure to comply with antiretroviral regimens.^7,8 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-positive patients.

It is important to keep in mind that age is associated with a progressive trend toward increasing central body fat deposition and wasting of fat in the extremities.⁹ Among participants in the Multicenter AIDS Cohort Study (MACS) and the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), the prevalence of increased abdominal fat was quite high even among HIV-negative participants.^10,11 However, peripheral fat wasting was rare in HIV-negative participants. The prevalence of peripheral fat wasting was 20% among HIV-positive men receiving combination ART for at least two years versus 1% to 2% among HIV-negative men.

Mechanism(s) of Disease

Considerable controversy exists regarding the pathophysiologic mechanisms underlying the development of HIV-associated lipodystrophy. While the majority of researchers have advocated a view that this syndrome is predominantly a drug-related side effect mediated by contributions from both the nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI) classes of antiretroviral medications, some studies, such as the recent HIV Outpatient Study (HOPS), have demonstrated no evidence of antiretroviral class-specific effects.¹² Other investigators have suggested that HIV-associated lipodystrophy is an immune reconstitution or cytokine-mediated phenomenon.^13,14 Elevated levels of cytokines as well as macrophages capable of producing such cytokines have been reported in subcutaneous adipose tissue from lipoatrophic subjects.¹⁵

HIV-associated lipodystrophy has been viewed as a reciprocal syndrome in which peripheral fat loss is accompanied by central fat gain, including an increase in visceral adipose (intra-abdominal fat) tissue accumulation. However, the paradigm of increased central fat gain recently has been challenged by magnetic resonance imaging (MRI) findings within the FRAM analysis, which found that HIV-positive men who had the clinical syndrome of peripheral lipoatrophy had less adipose tissue in both peripheral and central depots than did HIV-positive men without peripheral lipoatrophy. Furthermore, HIV-positive men with or without the clinical syndrome of peripheral lipoatrophy had less adipose tissue in both peripheral and central depots compared with control subjects.¹¹

Antiretroviral Therapy

The HIV-associated lipodystrophy syndrome was first described in 1998, shortly after the introduction of PIs.¹⁶ Thus, early studies focused on the role of PIs in the development of HIV-associated lipodystrophy, although PIs alone appeared to rarely cause lipodystrophy.¹⁷ It is now clear that HIV lipodystrophy can develop in patients who have never been treated with PIs.^18,19 The use of NRTIs, stavudine (d4T) in particular, has been linked specifically to the development of the lipoatrophic component of HIV-associated lipodystrophy syndrome.^2,19,20

In the Western Australian Cohort Study, the median time from initiation of PI-containing ART to clinically apparent peripheral lipoatrophy was 18.5 months for patients receiving d4T-containing regimens compared with 26 months for patients receiving zidovudine (ZDV)-containing regimens.²⁰ However, combined PI and dual NRTI therapy leads to peripheral lipoatrophy dramatically faster than does dual NRTI therapy alone.²⁰ The risk of lipodystrophy increases with both duration of NRTI therapy and duration of PI therapy.^3,20,21 This finding is further supported by the FRAM analysis, in which the duration of treatment with d4T and the duration of treatment with the PI indinavir (IDV) were each associated with significant decreases in leg subcutaneous adipose tissue (SAT) but not visceral adipose tissue (VAT).¹¹ Nonnucleoside reverse transcriptase inhibitors (NNRTIs) have not been reported to result in lipodystrophic tendencies.²²

Host Factors

Although HIV-associated lipodystrophy is uncommon in the absence of ART, nondrug factors are also important. Older age has consistently been shown to be associated with increased lipodystrophy risk.^1-3,5,6 Race may be important, with higher rates of lipodystrophy seen in Caucasians.^3,6 Males appear more likely to develop peripheral lipoatrophy, whereas females have greater fat accumulation centrally. Viral load, CD4 count, prior AIDS diagnosis, immune reconstitution, and baseline body mass index (BMI) have been cited as important in some studies, but have not been linked consistently to HIV-associated lipodystrophy risk.^3,5,23

Mitochondrial Toxicity

There is now strong evidence that NRTI-induced mitochondrial toxicity plays a major role in the development of the lipoatrophic component of HIV-associated lipodystrophy syndrome. The NRTIs are known to have an inhibitory effect on mitochondrial DNA (mtDNA) polymerase gamma, the principal enzyme responsible for mtDNA replication. Because mtDNA encodes many of the oxidative-phosphorylation chain proteins, a decrease in mtDNA content theoretically could hinder aerobic respiration and other mitochondrial functions.²⁴ A decrease in mtDNA is indeed found in SAT from subjects with lipoatrophy.^25,26 However, more recent evidence suggests that the mitochondrial toxicity of NRTIs may involve not only the depletion of mtDNA but also negative effects on the proteins and enzymatic activity of the oxidative-phosphorylation system even prior to such depletion. Decreased transcription of mitochondrial RNA without significant depletion of mtDNA is seen by two weeks after initiation of dual-NRTI therapy (ZDV/lamivudine [3TC] or d4T/3TC) in HIV-negative controls, suggesting the NRTIs cause mitochondrial dysfunction by means other than through inhibition of DNA polymerase gamma.²⁷ Improvement in both mtDNA and complex I mitochondrial enzyme activity level as well as in the rate of adipocyte apoptosis have been demonstrated following removal of the offending NRTIs.²⁸ Protease inhibitors may compound the problem by inhibiting adipocyte differentiation and maturation.^29-31 The full molecular basis of this inhibition remains to be determined, but may entail inhibition of specific cellular proteases involved in maturation of nuclear lamin proteins and the adipogenic factor sterol regulatory element binding protein-1 (SREBP-1).³²

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 the development of this form of fat accumulation remain unclear.³³

Diagnosis

Diagnosis of HIV-associated lipodystrophy is typically made on clinical grounds, based on patient and physician assessment of body composition changes. Whereas case definitions for use as a research tool have been suggested, consensus is lacking and the applicability to clinical practice is unclear.^20,34 Diagnosis is hampered by several factors. Fat depletion in the periphery may be associated with the AIDS wasting syndrome, which typically is 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 patients with stable weight, assessment of lipodystrophy relies on demonstration of changes in regional fat content following use of ART, and therefore, by necessity, requires knowledge of premorbid fat content and distribution.

Abdominal MRI and computed tomography (CT) are sensitive and specific measures of visceral fat, but they are costly and likely to remain primarily research tools.³⁵ In addition, CT scanning entails some radiation exposure. Single-slice CT measurements of the abdomen at the level of L4-L5 correlate strongly with whole-body measurements for both SAT and VAT.^36-38 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.³⁵ All anthropometric measurements suffer from wide inter- and intra-person variability among participants interpreting the tests, and require considerable training for the results to be reproducible.³⁵ Finally, bioelectrical impedance analysis (BIA) typically estimates whole-body composition. Whereas attempts have been made to assess regional-body composition using BIA, the methods remain unvalidated, and cannot be recommended at the present time.³⁹

Although none of the above techniques has sufficient sensitivity, specificity, or cost-effectiveness 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, and hips, and perhaps the neck).¹

Therapy

Because their pathogenic mechanisms differ, fat accumulation and fat depletion are expected to require different therapeutic interventions. For peripheral lipoatrophy, switching antiretroviral drugs from NRTIs with high potential for mitochondrial toxicity to more "mitochondrially friendly" regimens has been demonstrated to result in some improvement in SAT. Otherwise, no effective treatment for HIV-associated lipodystrophy has been established. Evidence from the various approaches that have been studied is summarized in this section:

Switch Therapies and NRTI-Sparing Regimens

PI withdrawal or substitution with an NNRTI is not helpful in correcting HIV-associated lipodystrophy, although dyslipidemia improves following these types of switches.^40-43 There is now substantial evidence that switching subjects off NRTIs known to have mitochondrial toxicity, in particular d4T, results in some increase in SAT. This improvement was observed following the substitution of either ZDV or abacavir (ABC) for d4T in the Trial to Assess the Regression of Hyperlactatemia and to Evaluate the Regression of Established Lipodystrophy in HIV-1-Positive Subjects (TARHEEL) study, which demonstrated mean increases by DEXA of 35% in arm fat, 12% in leg fat, and 18% in trunk fat at week 48 compared with baseline levels.²⁸ A switch from ZDV or d4T to ABC was demonstrated in the Mitochondrial Toxicity (MITOX) Extension Study to result in a mean gain in limb fat by DEXA of 1.26 + 2.02 kg compared with 0.49 + 1.38 kg in the ZDV/d4T control arm at week 104.⁴⁴ The time-weighted change for limb fat was significantly different between controls and those who switched antiretroviral agents (0.43 kg; P = 0.008). In other studies, a switch to a completely NRTI-sparing regimen of lopinavir/ritonavir (LPV/r) plus efavirenz (EFV) resulted in a median improvement after 104 weeks of 782 g of appendicular fat compared with a loss of 900 g in a group receiving EFV plus two NRTIs.⁴⁵ Similarly, a switch from a d4T- or ZDV-containing regimen to LPV/r plus nevirapine (NVP) resulted in a 17% median increase in subcutaneous thigh fat after 48 weeks.⁴⁶ Collectively, switching antiretroviral agents has resulted in statistically significant gains in peripheral fat; however, the clinical relevance of these improvements is unclear.

Switching antiretrovirals therefore may result in modest improvements, but care must be exercised to avoid virologic failure with such substitutions. In a randomized, open-label study of 236 patients, a higher rate of treatment discontinuation and a trend toward virologic failure occurred in the NRTI-sparing regimen arm (LPV/r plus EFV) compared with EFV plus two NRTIs.⁴⁷ The return of peripheral fat in all studies, however, has been partial and does not restore the level present before starting ART, leading to concerns that fat loss may be partially irreversible or that a prolonged recovery phase is needed for complete resolution of lipoatrophy.

Anabolic Steroids

Pharmacologic interventions have yielded mixed results. Decreased testosterone levels are seen in HIV-positive men and are associated with visceral obesity in the general population.⁴⁸ Although testosterone replacement has been associated with decreases in VAT and improvements in insulin sensitivity in HIV-negative men, testosterone replacement did not reduce VAT over a 24-week period in HIV-positive patients with mildly to moderately low testosterone levels.^49,50 Testosterone replacement was associated, however, with a net loss of limb SAT and total adipose tissue content. It is not known whether these changes correlate with laboratory assessments of insulin, glucose, or lipid metabolism.

Growth Hormone

In a prospective, open-label trial of 30 HIV-positive patients, supraphysiologic doses of recombinant human growth hormone (6 mg/day) administered over the course of 24 weeks led to a significant decrease in VAT. Unfortunately, side effects including hyperglycemia, arthralgias, and fluid retention were common, and body composition changes reverted to pretreatment status after the therapy was stopped.⁵¹ Lower, pharmacologic doses of growth hormone have demonstrated consistent declines in VAT, but alterations in glucose homeostasis continued to occur.^51,52

Metformin

Metformin was evaluated at a dose of 500 mg twice a day in a randomized controlled trial of 26 HIV-positive subjects.⁵³ 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 SAT. Diastolic blood pressure and insulin resistance were noted to improve significantly in the treatment arm. No increase in lactate or liver transaminase levels was observed, and mild diarrhea was the most commonly noted adverse effect of metformin.

Thiazolidinediones

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. Thiazolidinediones are peroxisome proliferator-activator receptor (PPAR)-gamma agonists. Adipose tissue from HIV-positive patients has reduced expression of SREBP-1c and PPAR-gamma.³² Troglitazone increased SAT and reduced VAT in HIV-negative patients with type 2 diabetes mellitus and in those with various syndromes of genetic and acquired lipodystrophy.^54-56 However, this drug was withdrawn from the market in 2000 because of severe liver toxicity.⁵⁷ The limited number of studies available to date involving HIV-positive patients have not shown consistent improvements in VAT or in subcutaneous lipoatrophy with thiazolidinedione treatment.^58-60 Rosiglitazone at 4 mg twice daily failed to improve subcutaneous limb fat compared with placebo after 48 weeks of treatment in 108 lipoatrophic HIV-positive patients.⁶¹ As a result, the authors state that rosiglitazone cannot be recommended for the treatment of lipoatrophy in HIV-positive adults.

Uridine

Uridine is a pyrimidine nucleoside that has been shown to prevent the adverse effects of zalcitabine (ddC) on mitochondrial function in HepG2 cells with respect to lactate synthesis, hepatocyte proliferation, intracellular lipids, and cyclooxygenase-2 levels.⁶² Similarly, in 3T3-F442A preadipocytes, uridine prevented toxicity-related effects of pyrimidine analogs on adipocytes, including apoptosis, intracellular lipids, mitochondrial mass, membrane potential, and mtDNA depletion.⁶³ Moreover, uridine does not appear to interfere with the efficacy of ART.⁶⁴

In a small pharmacokinetic study, uridine levels increased after supplementation, peaked after 1.3 hours, then returned to baseline after 24 hours.⁶⁵ Adequately powered safety and efficacy studies are needed to determine the clinical effects of uridine in patients with lipoatrophy.

Dietary and Nonpharmacologic Measures

There are limited data to support a role for specialized dietary supplements in HIV-positive patients with lipoatrophy. However, recent data suggest there may be some benefit in treating or preventing NRTI-mediated mitochondrial dysfunction with dietary supplementation.

Exercise

Hypocaloric diets are recommended for overweight patients with BMI >27, although rapid weight loss should be avoided. Exercise, both aerobic and resistance training, can be beneficial for cardiopulmonary fitness and strength without adverse effect on virologic or immunologic control.^66-68 Although both diet and exercise can reduce central adiposity while improving glycemic control and lipid profiles, they also may lead to loss of peripheral subcutaneous fat.⁶⁹

Plastic Surgery

Facial lipoatrophy is a particularly distressing aspect of lipodystrophy. Plastic surgery has gained increasing attention in the HIV-positive community due to the limited efficacy of other therapeutic options. 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, for which long-term safety and efficacy data are lacking. Poly-L-lactic acid, a biodegradable synthetic polymer, is the only product currently approved by the US Food and Drug Administration (FDA) for the treatment of facial lipoatrophy. The disfigurement resulting from facial lipoatrophy and the potential for extreme psychological distress create an urgent need for research into other modalities of palliative therapy.

Insulin Resistance

Background and Definition

Insulin resistance and glucose intolerance were reported to be uncommon in HIV-1 infection prior to the use of potent antiretroviral regimens. The era of combination ART has seen an increase in these abnormalities. Fasting glucose levels from a group of 1,278 men in the MACS cohort showed that 14% of HIV-positive men on ART had diabetes mellitus compared with 5% of HIV-negative men adjusted for age and BMI. Moreover, the incidence of diabetes mellitus over a four-year observation period in HIV-positive men with ART exposure was 4.7 cases per 100 person-years, a level more than four times that of HIV-negative control men.⁷⁰ The well-known long-term cardiovascular consequences of insulin resistance and diabetes have raised concerns regarding such risks in the HIV-positive population currently being treated with ART.^71,72 Disorders of glucose metabolism are defined in Table 2.

Mechanism(s) of Disease

Impairment of glucose metabolism is thought to result predominantly 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.

Multiple mechanisms are likely to contribute to insulin resistance in the HIV-positive patient taking ART. These mechanisms are likely to involve the direct effects of antiretroviral medications, the indirect consequences of fat redistribution, chronic inflammatory changes induced by HIV, and hepatic steatosis, as summarized in Figure 5.⁷³ The PI IDV directly induces the development of insulin resistance when given as a short course or as a single dose in HIV-negative patients.^74,75 This direct response is likely mediated by impaired cellular glucose uptake due to inhibition of both the Glut4 glucose transporter and glucose phosphorylation.^76,77 Reduced insulin sensitivity may also be a result of lipodystrophy mediated by the elevated blood levels of free fatty acids (FFA) induced by both the fat accumulation and depletion components of lipodystrophy. Elevation of FFA may interfere with cellular glucose transport through a reduction in the phosphorylation of insulin receptor substrate-1-associated phosphatidylinositol 3-kinase, which results in impaired intra-cellular signaling and insulin resistance, especially in muscle and hepatic tissue.^78-80 Interestingly, increases in lipolysis and elevated blood levels of FFA have been found to be independently associated with both accumulation of VAT (a more metabolically active form of fat) and depletion of peripheral SAT.^81,82 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. HIV infection and antiretroviral-mediated disturbances in the quantity and distribution of fat may disrupt the normal cytokine regulation of glucose homeostasis. Of particular interest is an adipokine called adiponectin (ACRP-30, adipoQ) that may have insulin-sensitizing properties. A correlation between low adiponectin levels and decreased peripheral subcutaneous fat has been reported.⁸³

The effect on insulin resistance of initial exposure to ART by quantitative insulin-sensitivity check index (QUICKI) was assessed within the MACS cohort.⁸⁴ Comparing HIV-negative men with HIV-positive men stratified by therapy status for the preceding six months (no ART, mono or dual NRTI, ART including a PI, or ART without a PI), insulin resistance was higher in all HIV-positive subjects compared with HIV-negative controls, suggesting a potential role for HIV per se as well as for antiretroviral medications.⁸⁵ After adjusting for age, BMI, ethnicity, nadir CD4 count, hepatitis C (HCV) serostatus, and family history of diabetes mellitus, subjects treated with ART including a PI had the highest insulin resistance compared with the other groups. Total cumulative exposure (years of use for each therapy class) to NRTIs, but not to PIs or NNRTIs, was associated with the development of insulin resistance, suggesting an indirect lipoatrophic effect of NRTIs on insulin resistance rather than a direct effect.⁸⁵ Of individual medications examined, d4T was associated with the highest risk of hyperinsulinemia.

Diagnosis

The International AIDS Society-USA Panel recommendations on the management of metabolic complications advise that fasting glucose should be assessed before and during treatment (prior to starting ART, three to six months after starting, and annually thereafter) with a regimen containing one or more PI.¹ 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 patients with impaired glucose tolerance, and may be especially helpful in those at risk for type 2 diabetes mellitus.

Therapy

In ART-naive patients with preexisting impaired glucose tolerance, consideration should be given to avoiding the use of older-generation PIs, such as IDV, in initial therapy. Among PIs, atazanavir (ATV) and amprenavir/fosamprenavir (APV/FPV) may be less likely to cause impaired glucose tolerance.^86,87 In those patients already taking older PIs who develop diabetes, switching antiretroviral regimens to improve insulin sensitivity may be considered with attention to possible side effects of the new regimen and risk of virologic failure. Short-term improvement in insulin resistance has been demonstrated with the substitution of an NNRTI or ABC for the PI component of an antiretroviral regimen.^42,88,89 The choice of the NRTI backbone is also important in glucose homeostasis, as d4T use is associated with the highest risk of hyperinsulinemia. The initial use of ABC or tenofovir (TDF) may reduce overall insulin resistance.

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 patients with impaired glucose tolerance.⁹⁰ 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 HIV-positive population. Metformin has been shown to improve visceral fat accumulation, fasting lipid profile, and endothelial function.⁹¹ The combination of exercise training with metformin significantly improves cardiovascular and biochemical parameters more than metformin alone in HIV-positive patients with fat redistribution and hyperinsulinemia.⁹² Close monitoring for the development of lactic acidemia is warranted with metformin use. Rosiglitazone therapy is associated with improvement in insulin sensitivity.^60,91 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, but should be considered only in this specific subgroup of HIV-positive men because of the potential adverse effects of excess testosterone.⁴⁸

Dyslipidemia

Background and Definition

Abnormalities of lipid metabolism are common complications of HIV disease and ART. 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.⁹³ 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.^94,95 Small dense LDL is believed to be proatherogenic because it is particularly susceptible to oxidation and can penetrate the endothelium and bind to intima proteoglycans more effectively than large buoyant LDL, resulting in retention in the arterial wall. Since the initiation of potent ART, particularly with the use of PIs, elevations in triglycerides and LDL and total cholesterol are commonly seen in practice. In a prospective study of 221 HIV-positive patients followed for a median of five years, the incidence of new-onset hypercholesterolemia and hypertriglyceridemia was 24% and 19%, respectively.⁹⁶

These proatherogenic lipid profiles have raised concerns about increased cardiovascular disease risk in the HIV-positive population. Metabolic syndrome is common among HIV-positive men, with a prevalence of 13% to 23%.⁹⁷ Lower CD4 counts, tobacco use, advancing age, and combination ART use were associated with greater risk for metabolic syndrome within the Strategies for Management of Anti-Retroviral Therapy (SMART) trial.⁹⁸ This trial compared episodic use of ART based on CD4 count against continuous therapy, and was stopped early after an excess of AIDS-defining events as well as an increase in major complications including cardiovascular events in the group receiving episodic ART. These findings suggest a combined effect of HIV infection and ART on overall cardiovascular disease risk.

Although the exact incidence of cardiovascular disease among HIV-positive patients treated with ART is a matter of debate, results from prospective studies suggest increased risk. The HOPS, a prospective observational cohort study, reported an increased incidence of myocardial infarction and angina in HIV-positive patients taking PIs compared with those not taking PIs. This increased risk remained evident even after adjustment for other risk factors, including smoking, gender, age, diabetes, hyperlipidemia, and hypertension.⁹⁹ 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 besides hyperlipidemia, such as smoking, hypertension, and insulin resistance. The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D Study), a prospective assessment of 23,490 patients from 11 cohorts on three continents, found that combination ART was associated with a 27% relative increase in the rate of myocardial infarction per year of exposure during the first seven years of treatment.¹⁰⁰

Mechanism(s) of Disease

Protease inhibitors have been implicated as a major cause of the lipid abnormalities seen with ART. Use of PIs is associated with the development of dyslipidemia independent of treatment with other drugs, viral load, or body weight changes. Different PIs have various effects on lipid metabolism. Ritonavir (RTV) has the greatest effect on levels of triglycerides, LDL, and cholesterol, whereas IDV has minimal effect.^75,101 Interestingly, ATV has been shown to have a beneficial effect on serum triglycerides, LDL, HDL, and total cholesterol levels.^102,103 Protease inhibitors are thought to inhibit the degradation of apolipoprotein B, which in turn results in lipid elevations.¹⁰⁴ Genetic susceptibility has been found to play an important role in lipid metabolism in patients 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.^105,106

The effect of NRTIs on dyslipidemia is difficult to assess due to the usual coadministration with NNRTIs or PIs. However, as a class, NRTIs appear to have less of a tendency than PIs to cause dyslipidemia, particularly on a short-term basis. The combination of ZDV/3TC/ABC given as a first-time antiretroviral regimen to antiretroviral-naive subjects caused little to no changes in triglyceride and cholesterol levels over the first 24-week period of administration.¹⁰⁷ However, d4T has been demonstrated to cause dyslipidemia. A prospective, multicenter study by the RECOVER Study Group found that HIV-positive patients who replaced d4T with TDF had significant decreases in triglyceride and cholesterol levels. This suggests, at least partly, a d4T-associated dyslipidemia.¹⁰⁸ Additionally, lipoatrophy epidemiologically linked to the use of NRTIs has been associated with increases in free fatty acid production and triglyceride levels.¹⁹ Medications within the NNRTI class also have effects on lipid levels, although not to the same degree as PIs. The use of EFV in addition to an NRTI backbone of ZDV/3TC with or without ABC has been demonstrated to result in increased total cholesterol and directly measured LDL as well as HDL cholesterol levels.¹⁰⁷ Compared with PIs, use of NNRTIs has been noted to result in generally higher HDL cholesterol levels.^109,110 Favorable decreases in levels of cholesterol, triglycerides, or both generally have been demonstrated following a switch from PIs to NVP or EFV.^41,42,88,111

Diagnosis

Prospective serial evaluation for dyslipidemia in patients with HIV appears warranted considering the association between dyslipidemia and 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 Adult AIDS Clinical Trials Group (ACTG) Cardiovascular Disease Focus Group, it is reasonable to obtain a fasting lipid profile at baseline and approximately three months after starting a new ART regimen.¹¹² If the lipid profile is normal, annual repeats are recommended.

Because optimal management of dyslipidemia in HIV-positive subjects is not established fully, it appears reasonable to follow the general guidelines of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III) as a reference and framework for identifying patients who require lipid-lowering interventions.¹¹³ The NCEP has a risk assessment tool for estimating the 10-year cardiovascular disease risk of an individual. 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 at least 12 hours) and should include triglyceride, HDL, LDL, and total cholesterol levels. The Friedewald equation can be used to calculate LDL cholesterol (in mg/dL): calculated LDL cholesterol = total cholesterol - HDL cholesterol - triglycerides/5.¹¹⁴ The Friedewald equation is not accurate for triglyceride levels >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.¹

In addition to lipid levels, evaluations for comorbidities such as hypogonadism, thyroid disease, liver disease, and alcoholism are important initial steps in the evaluation of dyslipidemia in HIV-positive patients. Recognition of the metabolic syndrome is also an important step in cardiovascular risk stratification. Identification of the metabolic syndrome, as defined by the NCEP ATP III, is shown in Table 3.¹¹³

Therapy

Randomized clinical trials to establish optimal treatment of ART-associated hyperlipidemia have not been completed. According to general NCEP ATP 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 proved ineffective or when lipid levels are elevated severely are lipid-lowering agents necessary. For elevated LDL cholesterol, HMG-CoA reductase inhibitors (statins) have produced favorable responses.¹¹⁵ Use of these drugs must be undertaken with caution, as elevated levels of statins resulting from the inhibitory effect of PIs on cytochrome P450 may result in myositis and rhabdomyolysis. The preferred statins are pravastatin or atorvastatin, as these agents have relatively modest pharmacokinetic interactions with antiretrovirals.^116,117 A lower initial starting dosage of atorvastatin (10 mg daily) is recommended. Efavirenz has been shown to reduce the inhibition of HMG-CoA reductase activity and therefore may result in diminished antilipid efficacy of statins.¹¹⁸ Higher doses of statins to control dyslipidemia may be necessary when coadministered with EFV. Results from ACTG study A5087 found monotherapy with either pravastatin or fenofibrate for HIV-related dyslipidemia safe but unlikely to achieve the composite NCEP goal. Pravastatin appears to be effective primarily in lowering LDL, while 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 currently do not recommend routine creatine kinase (CK) surveillance to detect myositis when statins are used in the general population. The utility of such surveillance in the HIV-positive population is unclear as isolated elevations of CK of uncertain clinical significance are seen frequently in HIV-positive patients. It seems prudent, however, to inform the patient of this potential side 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 antiretroviral drugs. The use of ezetimibe in combination with statin therapy is being studied.^119,120

For hypertriglyceridemia (serum triglyceride levels >500 mg/dL), fibric acid analogs such as gemfibrozil and fenofibrate have been used. The magnitude of reduction of LDL, total cholesterol, and triglycerides through the use of statins, fenofibrate, or the combination of the two has been less than robust in patients taking PIs.^121-123 The International AIDS Society-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 addition of the fibric acid derivative after month four if the response is suboptimal. Although niacin may worsen insulin resistance, the use of niacin may be safe for the treatment of hypertriglyceridemia in patients at low risk for glucose intolerance. The safety and efficacy of niacin in combination with ART has been investigated in a small number of studies.^124-126 Fish oil has been shown in a randomized study to reduce triglyceride levels by 26% compared with placebo.¹²⁷ When fish oil was combined with fenofibrate, further triglyceride lowering was observed.¹²⁸

Hyperlactatemia and Lactic Acidosis

Background and Definition

Lactic acidemia has been associated with NRTI use since the early 1990s. Lactic acidemia refers to increased plasma lactate (hyperlactatemia) that does not cause an abnormal blood pH, whereas lactic acidosis consists of a high lactate level accompanied by metabolic acidosis and decreased blood pH. The spectrum of disease within this syndrome ranges from fulminant decompensated 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.^1,129 Liver abnormalities, including hepatomegaly, hepatic steatosis, and elevated serum transaminases are common in symptomatic hyperlactatemia and almost ubiquitous in NRTI-induced lactic acidosis.^1,129-134 Onset of symptoms is usually subacute, occurring over weeks to months, although acute fulminant cases associated with multiorgan (especially liver) dysfunction occur rarely.¹²⁹

Several large observational studies have been performed to determine the prevalence of and risk factors for lactic acidemia.^134-137 Published estimates of the prevalence of lactic acidemia range from 8% to as high as 29% of patients receiving at least one NRTI,^1,137 though failure to follow stringent guidelines for lactate collection may have led to overestimation in earlier studies.¹³⁸ 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 mmol/L to 3.5 mmol/L was the most common pattern of hyperlactatemia observed among 349 participants in the Western Australian Cohort Study.¹³⁰ 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 d4T use compared with ZDV-containing regimens, with an incidence of 11% versus 4.2%, respectively.¹³⁴ Didanosine (ddI) also conferred increased risk, whereas ZDV and 3TC were associated with comparatively lower risk of lactic acidemia. Patients with lactic acidemia tended to have concomitant lipid abnormalities, hyperglycemia, and lipoatrophy. However, chronic hyperlactatemia on routine testing at one- to three-month intervals in asymptomatic patients showed poor sensitivity in predicting the development of severe lactic acidosis or hepatic steatosis.¹³⁰ Many of these findings were demonstrated in the Aquitaine Cohort of 768 HIV-positive participants; increasing age and CD4 count <500 cells/µL also were associated with the development of lactate elevations in this group.¹³⁷ Children with in utero or postnatal exposure to nucleoside analogs also appear to be at risk for hyperlactatemia. In one study, nearly half of 127 infants with NRTI exposure had at least one elevated lactate measurement over the course of one year. Fortunately, most of these elevations were asymptomatic and self-limited; this finding has been confirmed in other series.^139,140 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 to 14.5 per 1,000 patient-years, and that lactic acidosis occurs less frequently, at a rate of 1.2 to 3.9 events per 1,000 patient-years in HIV-positive patients receiving NRTIs.¹⁴¹ The high mortality (33% to 57%) of NRTI-associated lactic acidosis has prompted 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. Viral load, CD4 count, use of specific NRTIs, and age were not predictive of increased disease severity. Stavudine was the thymidine analog used in 48% of cases, whereas ZDV was used in 45%, with a median nine months of therapy prior to presentation. Women were over-represented, accounting for 43% of severe acidosis cases, though women account for approximately 20% of HIV-positive patients in the developed world. On multivariate analysis, only lactate level >10 mg/dL was associated with increased mortality (odds ratio [OR]: 13.23).¹²⁹ Pregnancy also may be a risk factor for more severe disease, and cases of acidosis with maternal and fetal deaths have been reported.^142,143 Patients with preexisting liver disease and hepatitis B virus (HBV) and HCV coinfection are over-represented in both lactic acidemia and lactic acidosis.¹⁴⁴ Concomitant use of ddI and ribavirin in HIV/HCV-coinfected patients may represent a risk factor for lactic acidosis as well as for other syndromes attributed to NRTI-mediated mitochondrial toxicity.¹⁴⁵ A case of lactic acidosis in association with coadministration of TDF and ddI has also been reported, possibly related to augmented ddI levels with this antiviral combination.¹⁴⁶ Finally, a casecontrol study involving nine patients with lactic acidosis found creatinine clearance <70 mL/min and low nadir CD4 count to be most strongly associated with lactic acidosis risk.¹⁴⁷

Mechanism(s) of Disease

At a cellular level, lactate is the metabolic product of glycolysis 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.^1,129 Didanosine and d4T show relatively high inhibition of DNA polymerase gamma in vitro, consistent with the finding of increased risk of lactic acidemia with these NRTIs (see Figure 6).¹²⁹

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, lungs, and muscle. Sustained elevations in blood lactate levels therefore indicate a significant loss of homeostasis.^130,148 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.^130,149

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 Adult ACTG may be helpful in this regard (Table 4). If carefully collected, venous lactate is equivalent to the arterial level in most clinical situations.¹⁵⁰ It is particularly important to arrest continued anaerobic metabolism by blood cellular components following a blood draw by the use of sodium fluoride/potassium oxalate tubes.¹⁵¹ However, these guidelines are based on scant data, and the exact importance of hydration, avoiding prior exercise, the need to collect blood without fist clenching or tourniquet application, and the need for ice or refrigeration is unknown. In one multicenter study, frozen storage of lactate specimens from HIV-positive subjects was associated with only small increases (0.4 to 0.6 mmol/L) in lactate measurements at 64 weeks compared with baseline values.¹⁵²

The significance of a single lactate value is difficult to interpret, and values over time show wide variations in a single patient. It is important, therefore, 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 >90 mg/dL (10 mmol/L), but no patient with lactate levels <90 mg/dL died.¹ Over time, characteristic features that may assist in identification of subjects with NRTI-induced lactic acidosis have emerged: patients almost always have hepatic steatosis and are symptomatic with nausea, vomiting, anorexia, abdominal pain or distension, tender hepatomegaly, fatigue, malaise, and prostration.¹⁴⁴

Withdrawal of the inciting NRTI drug forms the cornerstone of therapy for this group of participants. Other antivirals should also be held in the acute setting to limit the development of viral resistance until appropriate ART can be reinstituted safely. In addition, therapy directed at the correction of acidosis is indicated and may include hemodynamic or respiratory support in an intensive care unit as well as the use of hemodialysis in severe cases.¹⁴⁴ Additional therapies without proven efficacy that have been used empirically in subjects acutely ill with this syndrome include intravenous thiamine,^153,154 riboflavin,¹⁴⁹ L-carnitine,^155,156 coenzyme Q,^155,157 and vitamin C.¹⁵⁵

Symptomatic 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-positive patients to evaluate how and when withdrawal of antiretrovirals should be considered in those patients with hyperlactatemia without acidosis. However, the International AIDS Society-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).¹ 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, as with lactic acidosis, there are case reports of cofactor administration using thiamine, riboflavin, L-carnitine, coenzyme Q, and antioxidants. These agents may be beneficial, although randomized trials of their efficacy are lacking. Reinstitution of ART with alternative "mitochondrial-friendly" NRTIs such as ABC and TDF, NRTI-sparing regimens based on PI/NNRTI combinations, or reinstitution of the offending NRTI at lower dosages have been successful in some patients.^158,159

Asymptomatic Hyperlactatemia

Asymptomatic, low-level increases in lactate are believed to not require intervention, as there is no conclusive evidence that asymptomatic lactate elevations are dangerous in the short term or predictive of more severe lactic academia.¹⁶⁰ 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 of the need to seek medical care promptly should these occur. A high index of suspicion is warranted specifically during episodes of infection, as antecedent minor, mainly respiratory, infections have been noted to precede cases of symptomatic lactic acidemia.¹⁶¹

Bone Disease

Osteonecrosis

Background and Definition

Osteonecrosis or avascular necrosis is defined as bone tissue death as a result of compromised blood flow to bone. Osteonecrosis had been reported in the setting of HIV infection even prior to the availability of potent ART.^162-164 Affected bones included 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-positive outpatients in San Francisco, MRI detected evidence of osteonecrosis in 4.4% of 339 asymptomatic patients surveyed, compared with 0.02% to 0.14% in the general population.¹⁶⁵ 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 patients having at least one risk factor previously associated with osteonecrosis in the HIV-uninfected population.^166-168 Common risk factors in the general population include use of systemic corticosteroids, ethanol abuse, hyperlipidemia (particularly hypertriglyceridemia), hypercoagulable states, hemoglobinopathies, autoimmune disorders, pancreatitis, pregnancy, heavy weight bearing, trauma, and osteomyelitis.¹⁶⁹

Mechanism(s) of Disease

Osteonecrosis involves the death of bone tissue through vascular compromise. The exact mechanism of this vascular occlusion is not known.¹⁷⁰ A possible mechanism of osteonecrosis is the development of vasculitis and thrombosis resulting in disruption of the vascular endothelium and luminal occlusion.¹⁶⁹ HIV infection has been associated with the development of anticardiolipin antibodies, which have been reported to occur in 50% to 86% of the HIV-positive population in a cross-sectional study.¹⁷¹ Deficiency of the antithrombotic factor protein S has been associated with HIV infection and may result in thrombotic events.¹⁷¹ Several case-control studies in HIV-positive subjects have associated corticosteroid use with osteonecrosis.^165,167,172 Patients with osteonecrosis also tend to have histories of more severe immunosuppression and a higher BMI compared with controls.¹⁷³ Hyperlipidemia and alcohol use, rather than any specific antiretroviral agent, have also been associated with osteonecrosis.¹⁶⁷ Based on available studies, there is little evidence to suggest that ART is directly involved with the development of osteonecrosis.¹⁷³

Diagnosis and Therapy

The International AIDS Society-USA Panel does not recommend routine screening of HIV-positive patients for the presence of osteonecrosis. A high index of suspicion is warranted, however, in patients who present with pain over the joints or bone. Magnetic resonance imaging 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.¹⁷² Early detection of this disease can help reduce its extent and morbidity. The same principles for management of osteonecrosis as those for treating HIV-negative patients should be followed.¹⁷² 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.¹⁷⁰ Physical therapy can help retain functionality. Discontinuation of all corticosteroids and abstinence from alcohol and smoking 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.

Osteopenia and Osteoporosis

Background and Definition

Osteopenia refers to bone demineralization, and osteoporosis refers 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,^174,175 using four diagnostic categories related to bone mineralization: Normal, Osteopenia, Osteoporosis, and Established Osteoporosis with Fragility Fractures. The classification relies on the use of DEXA scanning, typically of the hip and spine, to determine bone density. The DEXA results are reported in absolute terms (g/m²) and in 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 at peak bone density (25 to 30 years old). The Z-score represents the number of standard deviations between the obtained result and an age, ethnicity, and gender-matched average value from healthy patients. Osteopenia is defined as a T-score between one 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-positive population on ART compared with age-matched, HIV-negative controls. Observational studies have reported higher rates of osteopenia in patients having CD4 counts <100 cells/µL (45%), patients taking PIs (50%), and those with evidence of lipodystrophy (28%).^176,177 These same studies found osteoporosis to occur in 40% of those with a CD4 count <100 cells/µL, 21% in those taking PIs, and 9% of those with lipodystrophy. An association of osteopenia with lactic acidemia also has been found.¹⁷⁸ However, despite the high prevalence of bone demineralization, a greater-than-expected occurrence of fragility fractures has not been documented. The accelerated bone loss observed during ART does not appear to be progressive beyond the period immediately after ART initiation.¹⁷⁹

Mechanism(s) of Disease

In ART-naive patients, there is a significant increase in bone resorption and a decrease in bone formation compared with seronegative controls.¹⁸⁰ Although a role for cytokine-mediated bone resorption has been demonstrated, the initiation of ART appears to be the greatest contributor to bone demineralization.¹⁸¹ Patients receiving potent ART have increased bone alkaline phosphatase and osteocalcin, which are markers of bone turnover.¹⁸¹ Protease inhibitor use has been associated with increased osteocalcin, suggesting a possible mechanism for bone demineralization.¹⁸¹ Although some PIs may block the differentiation of osteoblasts, thereby reducing the rate of new bone formation, recent longitudinal studies have shown a smaller contribution of PIs to osteopenia and osteoporosis.¹⁸² Switching from a PI-based regimen to an NNRTI-based one does not result in improvements in bone mineral density.¹⁷⁹ Gilead Study 903 found TDF to have the greatest bone-demineralizing effect among antiretroviral agents.¹⁸³

Diagnosis

As with its approach to osteonecrosis, the International AIDS Society-USA Panel does not recommend routine screening for the presence of osteopenia or osteoporosis.¹ However, recommendations may change as more information becomes available regarding the prevalence of osteoporosis in this population, its association with fracture risk, and safety and efficacy of various modalities for therapy. In the general population, routine DEXA scans are now recommended by the US Preventive Task Force in all women above age 65 and selected women in the 60 to 65 age range, because of the increased prevalence of osteopenia and osteoporosis in these groups.^174,184 In the HIV-positive population, until more information is available, it may be reasonable to conduct screening DEXA scans for those at high risk for fragility fractures. Risk factors for fragility fractures include duration of HIV infection, low BMI, history of weight loss, previous use of corticosteroids, smoking, excessive alcohol intake, inactivity, and history of inadequate calcium intake.^179,185

Therapy

Osteopenia is usually asymptomatic. Patients 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 studied completely in the HIV-positive population and are extrapolated from recommendations in the general population. Complicating the decision to initiate therapy for osteoporosis is the finding that the observed bone demineralization does not appear to be rapidly progressive beyond the period immediately after ART initiation.¹⁷⁹ The goal of therapy, as in the elderly population, is to reduce fractures and maintain function. Accordingly, initiation of therapy for osteopenia and osteoporosis should be tailored to individual risk for future fragility fractures. Lifestyle modifications generally accepted as part of the overall reduction of bone demineralization include increased physical activity, weight loss, and smoking cessation. Patients diagnosed with osteopenia or osteoporosis should consume 1,500 mg of calcium and 400 to 1,000 international units 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 FDA-approved treatment of osteoporosis in men. The safety and efficacy of bisphosphonates in the treatment of osteopenia and osteoporosis in HIV-positive patients has been demonstrated in a small number of prospective studies.^186,187 A larger randomized multicenter trial examining the use of alendronate is under evaluation (Adult ACTG A5163). The use of raloxifene, a selective estrogen receptor modulator, may be contraindicated because of its inhibition of cytochrome P450 and potential drug interactions with ART.

Dominic C. Chow, Scott A. Souza and Cecilia M. Shikuma are with the University of Hawaii; Larry J. Day is with the University of Michigan.

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