Advertisement
Advertisement

  

Metabolic Complications of HIV Therapy

September 2006


Introduction

Metabolic Complications of HIV Therapy
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.


Table 1. Metabolic and Morphologic Complications Associated With HIV Infection and ART

Advertisement
Table 1. 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.


Figure 1. Fat Accumulation: Dorsocervical Fat Pad ("Buffalo Hump")

Figure 1. Fat Accumulation: Dorsocervical Fat Pad ('Buffalo Hump')


Figure 2. Lipoatrophy: Facial Fat Loss With Deepening of Nasolabial Fold

Figure 2. Fat Accumulation: Abdominal (Visceral) Obesity


Figure 3. Fat Accumulation: Abdominal (Visceral) Obesity

Figure 3. Lipoatrophy: Facial Fat Loss With Deepening of Nasolabial Fold


Figure 4. Lipoatrophy: Fat Depletion of Leg With Prominence of Veins and Enhanced Definition of Musculature

Figure 4. Lipoatrophy: Fat Depletion of Leg With Prominence of Veins and Enhanced Definition of Musculature


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.


Table 2. Disorders of Glycemic Homeostasis

Table 2. Disorders of Glycemic Homeostasis


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


Figure 5. Etiologies for the Development of HIV-1-Related Insulin Resistance

Figure 5. Etiologies for the Development of HIV-1-Related Insulin Resistance

Source: Shikuma CM, Day LJ, Gerschenson M. Insulin resistance in the HIV-infected population: The potential role of mitochondrial dysfunction. Curr Drug Targets Infect Disord. 2005;5(3):255-62. Reproduced with permission.


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


Table 3. National Cholesterol Education Program's Adult Treatment Panel III Report on the Clinical Identification of the Metabolic Syndrome

The metabolic syndrome can be identified as the presence of three or more of these components:

Table 3. National Cholesterol Education Program's Adult Treatment Panel III Report on the Clinical Identification of the Metabolic Syndrome

* Being overweight and obesity are associated with insulin resistance and the metabolic syndrome. However, the presence of abdominal obesity is correlated more highly with the metabolic risk factors than is an elevated body mass index. Therefore, the simple measure of waist circumference is recommended to identify the body weight component of the metabolic syndrome.

Some male patients can develop multiple metabolic risk factors when the waist circumference is increased only marginally, e.g., 94-102 cm (37-39 in). Such patients may have a strong genetic contribution to insulin resistance. They should benefit from changes in lifestyle habits, similar to men with categorical increases in waist circumference.

The American Diabetes Association has established a cutpoint of 100 mg/dL, above which persons have either prediabetes (impaired fasting glucose) or diabetes. This new cutpoint may be used to define an elevated glucose as one criterion for the metabolic syndrome.


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


Figure 6. Increased Lactic Acid Production

Figure 6. Increased Lactic Acid Production

NRTI-mediated mitochondrial dysfunction leads to a decrease in oxidative phosphorylation resulting, among other effects, in increased anaerobic metabolism of glucose, characterized by conversion of pyruvate into lactic acid. (Reproduced with permission.)


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


Table 4. Adult AIDS Clinical Trials Group Guidelines for Venous Lactate Specimen Collection

Table 4. Adult AIDS Clinical Trials Group Guidelines for Venous Lactate Specimen Collection


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.


References

  1. Schambelan M, Benson CA, Carr A, et al. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: Recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr. 2002;31:257-275.

  2. Bernasconi E, Boubaker K, Junghans C, et al. Abnormalities of body fat distribution in HIV-infected persons treated with antiretroviral drugs: The Swiss HIV Cohort Study. J Acquir Immune Defic Syndr. 2002; 31:50-55.

  3. Heath KV, Hogg RS, Chan KJ, et al. Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS. 2001;15: 231-239.

  4. Heath KV, Hogg RS, Singer J, et al. Antiretroviral treatment patterns and incident HIV-associated morphologic and lipid abnormalities in a population-based cohort. J Acquir Immune Defic Syndr. 2002;30:440-447.

  5. Thiebaut R, Daucourt V, Mercie P, et al. Lipodystrophy, metabolic disorders, and human immunodeficiency virus infection: Aquitaine Cohort, France, 1999. Groupe d'Epidemiologie Clinique du Syndrome d'Immunodeficience Acquise en Aquitaine. Clin Infect Dis. 2000;31:1482-1487.

  6. Lichtenstein KA, Ward DJ, Moorman AC, et al. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS. 2001;15:1389-1398.

  7. Duran S, Saves M, Spire B, et al. Failure to maintain long-term adherence to highly active antiretroviral therapy: The role of lipodystrophy. AIDS. 2001;15:2441-2444.

  8. Duran S, Spire B, Raffi F, et al. Self-reported symptoms after initiation of a protease inhibitor in HIV-infected patients and their impact on adherence to HAART. HIV Clin Trials. 2001;2:38-45.

  9. Shimokata H, Tobin JD, Muller DC, et al. Studies in the distribution of body fat: I. Effects of age, sex, and obesity. J Gerontol. 1989;44:M66-M73.

  10. Kingsley L, Smit E, Riddler S, et al. Prevalence of lipodystrophy and metabolic abnormalities in the Multicenter AIDS Cohort Study. 8th Conference on Retroviruses and Opportunistic Infections. February 4-8, 2001. Chicago. [Abstract 538]

  11. Bacchetti P, Gripshover B, Grunfeld C, et al. Fat distribution in men with HIV infection. J Acquir Immune Defic Syndr. 2005;40:121-131.

  12. Lichtenstein KA, Delaney KM, Armon C, et al. Incidence of and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients. J Acquir Immune Defic Syndr. 2003;32:48-56.

  13. Ledru E, Christeff N, Patey O, et al. Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: Contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome. Blood. 2000; 95:3191-3198.

  14. Kotler DP, Rosenbaum K, Wang J, Pierson RN. Studies of body composition and fat distribution in HIV-infected and control subjects. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:228-237.

  15. Hammond E, Nolan D, McKinnon E, et al. Assessing the contribution of ART, HIV and host factors to adipose tissue changes occurring in HIV-infected individuals: Risk profile for lipoatrophy. 7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. November 13-16, 2005. Dublin. [Abstract 2]

  16. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 1998;12:F51-F58.

  17. van der Valk M, Gisolf EH, Reiss P, et al. Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS. 2001;15:847-855.

  18. Galli M, Ridolfo AL, Adorni F, et al. Body habitus changes and metabolic alterations in protease inhibitor-naive HIV-1-infected patients treated with two nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr. 2002;29:21-31.

  19. Saint-Marc T, Partisani M, Poizot-Martin I, et al. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS. 1999;13:1659-1667.

  20. Mallal SA, John M, Moore CB, James IR, McKinnon EJ. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS. 2000;14:1309-1316.

  21. Carr A. HIV protease inhibitor-related lipodystrophy syndrome. Clin Infect Dis. 2000;30(Suppl 2):S135-S142.

  22. Nolan D. Do non-nucleoside reverse transcriptase inhibitors contribute to lipodystrophy? Drug Saf. 2005;28:1069-1074.

  23. Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in HIV-1-infected patients: Results of a substudy from a comparative trial. AIDS. 2002;16:2447-2454.

  24. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet. 1999;354:1112-1115.

  25. Walker UA, Bickel M, Lutke Volksbeck SI, et al. Evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr. 2002;29: 117-121.

  26. Shikuma CM, Hu N, Milne C, et al. Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy. AIDS. 2001;15:1801-1809.

  27. Mallon PW, Unemori P, Sedwell R, et al. In vivo, nucleoside reverse transcriptase inhibitors alter expression of both mitochondrial and lipid metabolism genes in the absence of depletion of mitochondrial DNA. J Infect Dis. 2005;191:1686-1696.

  28. McComsey GA, Paulsen DM, Lonergan JT, et al. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS. 2005;19: 15-23.

  29. Caron M, Auclair M, Vigouroux C, et al. The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. Diabetes. 2001;50:1378-1388.

  30. Lenhard JM, Furfine ES, Jain RG, et al. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral Res. 2000;47:121-129.

  31. Dowell P, Flexner C, Kwiterovich PO, Lane MD. Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors. J Biol Chem. 2000;275:41325-41332.

  32. Bastard JP, Caron M, Vidal H, et al. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet. 2002;359:1026-1031.

  33. Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M. "Buffalo hump" in men with HIV-1 infection. Lancet. 1998;351:867-870.

  34. Carr A, Puls R, Law M. An objective comparison of physician and patient-related severity of HIV lipodystrophy. 10th Conference on Retroviruses and Opportunistic Infections. February 10-14, 2003. Boston. [Abstract 731]

  35. Schwenk A. Methods of assessing body shape and composition in HIV-associated lipodystrophy. Curr Opin Infect Dis. 2002;15:9-16.

  36. Engelson ES, Kotler DP, Tan Y, et al. Fat distribution in HIV-infected patients reporting truncal enlargement quantified by whole-body magnetic resonance imaging. Am J Clin Nutr. 1999;69:1162-1169.

  37. Seidell JC, Bakker CJ, van der Kooy K. Imaging techniques for measuring adipose-tissue distribution -- a comparison between computed tomography and 1.5-T magnetic resonance. Am J Clin Nutr. 1990;51:953-957.

  38. Schoen RE, Thaete FL, Sankey SS, Weissfeld JL, Kuller LH. Sagittal diameter in comparison with single slice CT as a predictor of total visceral adipose tissue volume. Int J Obes Relat Metab Disord. 1998;22:338-342.

  39. Schwenk A, Breuer P, Kremer G, Ward L. Clinical assessment of HIV-associated lipodystrophy syndrome: Bioelectrical impedance analysis, anthropometry and clinical scores. Clin Nutr. 2001;20:243-249.

  40. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: A randomized trial. JAMA. 2002;288:207-215.

  41. Ruiz L, Negredo E, Domingo P, et al. Antiretroviral treatment simplification with nevirapine in protease inhibitor-experienced patients with HIV-associated lipodystrophy: 1-year prospective follow-up of a multicenter, randomized, controlled study. J Acquir Immune Defic Syndr. 2001;27:229-236.

  42. Martinez E, Garcia-Viejo MA, Blanco JL, et al. Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy. Clin Infect Dis. 2000;31:1266-1273.

  43. Smith DE, Carr A, Law M, et al. Thymidine analogue withdrawal for lipoatrophic patients on protease-sparing therapy improves lipoatrophy but compromises antiviral control: The PIILR extension study. AIDS. 2002;16:2489-2491.

  44. Martin A, Smith DE, Carr A, et al. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: The MITOX Extension Study. AIDS. 2004;18:1029-1036.

  45. Tebas P, Zhang J, Yarasheski K, et al. Switch to a protease inhibitor-containing/nucleoside reverse transcriptase inhibitor-sparing regimen increases appendicular fat and serum lipid levels without affecting glucose metabolism or bone mineral density. The results of a prospective randomized trial, ACTG 5125s. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. [Abstract 40]

  46. Murphy R, Zhang J, Hafner R, et al. Peripheral and visceral fat changes following a treatment switch to a nonthymidine analog or nucleoside-sparing regimen in patients with peripheral lipoatrophy: 48 week final results of ACTG A5110, a prospective, randomized, multicenter clinical trial. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. [Abstract 755]

  47. Fischl M, Bassett R, Collier A, et al. Randomized, controlled trial of lopinavir/ritonavir + efavirenz vs efavirenz + 2 nucleoside reverse transcriptase inhibitors following a first suppressive 3- or 4-drug regimen in advanced HIV disease. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. [Abstract 162]

  48. Hadigan C, Corcoran C, Stanley T, et al. Fasting hyperinsulinemia in human immunodeficiency virus-infected men: Relationship to body composition, gonadal function, and protease inhibitor use. J Clin Endocrinol Metab. 2000;85:35-41.

  49. Rebuffe-Scrive M, Marin P, Bjorntorp P. Effect of testosterone on abdominal adipose tissue in men. Int J Obes. 1991;15:791-795.

  50. Shikuma C, Parker R, Sattler F, et al. Effects of physiologic testosterone supplementation on fat mass and distribution in HIV-infected men with abdominal obesity: ACTG 5079. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver. [Abstract 149]

  51. Engelson ES, Glesby MJ, Mendez D, et al. Effect of recombinant human growth hormone in the treatment of visceral fat accumulation in HIV infection. J Acquir Immune Defic Syndr. 2002;30:379-391.

  52. Schwarz JM, Mulligan K, Lee J, et al. Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab. 2002;87:942.

  53. Hadigan C, Corcoran C, Basgoz N, et al. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA. 2000;284:472-477.

  54. Mori Y, Murakawa Y, Okada K, et al. Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care. 1999;22: 908-912.

  55. Kelly IE, Han TS, Walsh K, Lean ME. Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care. 1999;22:288-293.

  56. Arioglu E, Duncan-Morin J, Sebring N, et al. Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes. Ann Intern Med. 2000;133:263-274.

  57. US Food and Drug Administration. Rezulin To Be Withdrawn from the Market. Rockville, MD: US Food and Drug Administration. March 21, 2000. Available at: www.fda.gov/bbs/topics/NEWS/NEW00721.html (Accessed May 11, 2006).

  58. Calmy A HB, Karsegaard L, et al. A pilot study for the use of pioglitazone in the treatment of highly active antiretroviral therapy lipodystrophy syndromes. Antivir Ther. 2001;6 (Suppl 4):32.

  59. Sutinen J, Hakkinen AM, Westerbacka J, et al. Rosiglitazone in the treatment of HAART associated lipodystrophy (HAL): A randomised, double-blind, placebo-controlled study. 9th Conference on Retroviruses and Opportunistic Infections. February 24-28, 2002. Seattle. [Abstract LB13]

  60. Gelato MC, Mynarcik DC, Quick JL, et al. Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: A pilot study. J Acquir Immune Defic Syndr. 2002;31:163-170.

  61. Carr A, Workman C, Carey D, et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: Randomised, double-blind, placebo-controlled trial. Lancet. 2004;363:429-438.

  62. Walker UA, Venhoff N, Koch EC, et al. Uridine abrogates mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors in HepG2 cells. Antivir Ther. 2003;8:463-470.

  63. Walker UA, Auclair M, Lebrecht D, et al. Uridine abrogates the adverse effects of antiretroviral pyrimidine analogues on adipose cell functions. Antivir Ther. 2006;11:25-34.

  64. Koch EC, Schneider J, Weis R, Penning B, Walker UA. Uridine excess does not interfere with the antiretroviral efficacy of nucleoside analogue reverse transcriptase inhibitors. Antivir Ther. 2003;8:485-487.

  65. Venhoff N, Zilly M, Lebrecht D, et al. Uridine pharmacokinetics of mitocnol, a sugar cane extract. AIDS. 2005;19:739-740.

  66. O'Brien K, Nixon S, Tynan AM, Glazier RH. Effectiveness of aerobic exercise in adults living with HIV/AIDS: Systematic review. Med Sci Sports Exerc. 2004;36:1659-1666.

  67. Bopp CM, Phillips KD, Fulk LJ, et al. Physical activity and immunity in HIV-infected individuals. AIDS Care. 2004;16:387-393.

  68. Rigsby LW, Dishman RK, Jackson AW, Maclean GS, Raven PB. Effects of exercise training on men seropositive for the human immunodeficiency virus-1. Med Sci Sports Exerc. 1992;24:6-12.

  69. Jones SP, Doran DA, Leatt PB, Maher B, Pirmohamed M. Short-term exercise training improves body composition and hyperlipidaemia in HIV-positive individuals with lipodystrophy. AIDS. 2001;15:2049-2051.

  70. McComsey GA, Ward DJ, Hessenthaler SM, et al. Improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: The results of the TARHEEL study. Clin Infect Dis. 2004;38:263-270.

  71. Dube MP, Johnson DL, Currier JS, Leedom JM. Protease inhibitor-associated hyperglycaemia. Lancet. 1997;350:713-714.

  72. Mulligan K, Grunfeld C, Tai VW, et al. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr. 2000;23:35-43.

  73. Shikuma CM, Day LJ, Gerschenson M. Insulin resistance in the HIV-infected population: The potential role of mitochondrial dysfunction. Curr Drug Targets Infect Disord. 2005;5:255-262.

  74. Noor MA, Seneviratne T, Aweeka FT, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: A randomized, placebo-controlled study. AIDS. 2002;16:F1-F8.

  75. Noor MA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS. 2001;15:F11-F18.

  76. Behrens GM, Boerner AR, Weber K, et al. Impaired glucose phosphorylation and transport in skeletal muscle cause insulin resistance in HIV-1-infected patients with lipodystrophy. J Clin Invest. 2002;110:1319-1327.

  77. Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS. 2002;16:859-863.

  78. Dresner A, Laurent D, Marcucci M, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999;103:253-259.

  79. Anai M, Funaki M, Ogihara T, et al. Enhanced insulin-stimulated activation of phosphatidylinositol 3-kinase in the liver of high-fat-fed rats. Diabetes. 1999;48:158-169.

  80. Shao J, Yamashita H, Qiao L, Draznin B, Friedman JE. Phosphatidylinositol 3-kinase redistribution is associated with skeletal muscle insulin resistance in gestational diabetes mellitus. Diabetes. 2002;51:19-29.

  81. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis. 2001;32:130-139.

  82. Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC. Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr. 2000;25:312-321.

  83. Mynarcik DC, Combs T, McNurlan MA, et al. Adiponectin and leptin levels in HIV-infected subjects with insulin resistance and body fat redistribution. J Acquir Immune Defic Syndr. 2002;31:514-520.

  84. Brown TT, Cole SR, Li X, et al. Incidence of pre-diabetes and diabetes in the Multicenter AIDS Cohort Study. 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. July 8-11, 2003. Paris. [Abstract 8:L33]

  85. Brown TT, Li X, Cole SR, et al. Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS. 2005;19:1375-1383.

  86. Noor MA, Parker RA, O'Mara E, et al. The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS. 2004;18:2137-2144.

  87. Dube MP, Qian D, Edmondson-Melancon H, et al. Prospective, intensive study of metabolic changes associated with 48 weeks of amprenavir-based antiretroviral therapy. Clin Infect Dis. 2002;35:475-481.

  88. Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS. 1999;13:805-810.

  89. Walli RK, Michl GM, Bogner JR, Goebel FD. Improvement of HAART-associated insulin resistance and dyslipidemia after replacement of protease inhibitors with abacavir. Eur J Med Res. 2001;6:413-421.

  90. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

  91. van Wijk JP, de Koning EJ, Cabezas MC, et al. Comparison of rosiglitazone and metformin for treating HIV lipodystrophy: A randomized trial. Ann Intern Med. 2005;143:337-346.

  92. Driscoll SD, Meininger GE, Lareau MT, et al. Effects of exercise training and metformin on body composition and cardiovascular indices in HIV-infected patients. AIDS. 2004;18:465-473.

  93. Khovidhunkit W, Memon RA, Feingold KR, Grunfeld C. Infection and inflammation-induced proatherogenic changes of lipoproteins. J Infect Dis. 2000;181(Suppl 3):S462-S472.

  94. Grunfeld C, Pang M, Doerrler W, et al. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992;74:1045-1052.

  95. Constans J, Pellegrin JL, Peuchant E, et al. Plasma lipids in HIV-infected patients: A prospective study in 95 patients. Eur J Clin Invest. 1994;24:416-420.

  96. Tsiodras S, Mantzoros C, Hammer S, Samore M. Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: A 5-year cohort study. Arch Intern Med. 2000;160:2050-2056.

  97. Palella F, Wang Z, Chu H, et al. Correlates and prevalence of the metabolic syndrome over time in the Multicenter AIDS Cohort Study (MACS). 3rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro. [Abstract TuPe2.2B18]

  98. US National Institute of Allergy and Infectious Diseases. International HIV/AIDS Trial Finds Continuous Antiretroviral Therapy Superior to Episodic Therapy. Bethesda, MD: National Institutes of Health; January 18, 2006. Available at: www3.niaid.nih.gov/news/newsreleases/2006/smart06.htm (Accessed May 11, 2006).

  99. Holmberg SD, Moorman AC, Williamson JM, et al. Protease inhibitors and cardiovascular outcomes in patients with HIV-1. Lancet. 2002;360:1747-1748.

  100. Friis-Moller N, Weber R, Reiss P, et al. Cardiovascular disease risk factors in HIV patients -- Association with antiretroviral therapy. Results from the DAD study. AIDS. 2003;17:1179-1193.

  101. Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. The Advanced HIV Disease Ritonavir Study Group. Lancet. 1998; 351:543-549.

  102. Murphy R, Mancini M. Twelve weeks of atazanavir treatment reverses nelfinavir-associated hyperlipidemia: Results from BMS AI0424-044. Antivir Ther. 2002:L10.

  103. Mobius U, Lubach-Ruitman M, Castro-Frenzel B, et al. Switching to atazanavir improves metabolic disorders in antiretroviral-experienced patients with severe hyperlipidemia. J Acquir Immune Defic Syndr. 2005;39:174-180.

  104. Liang JS, Distler O, Cooper DA, et al. HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: A potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med. 2001;7:1327-1331.

  105. Grunfeld C, Doerrler W, Pang M, et al. Abnormalities of apolipoprotein E in the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1997;82:3734-3740.

  106. Behrens G, Schmidt HH, Stoll M, Schmidt RE. ApoE genotype and protease-inhibitor-associated hyperlipidaemia. Lancet. 1999;354:76.

  107. Shikuma C, Yang Y, Meyer W, et al. Metabolic analyses within A5095: Effect of efavirenz against an all-nucleoside/nucleotide background. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver. [Abstract 746]

  108. Domingo P, Labarga P, Palacios R, et al. Improvement of dyslipidemia in patients switching from stavudine to tenofovir: Preliminary results. AIDS. 2004;18:1475-1478.

  109. van der Valk M, Kastelein JJ, Murphy RL, et al. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an antiatherogenic lipid profile. AIDS. 2001;15:2407-2414.

  110. Knechten H, Sterner KH, Hohn C, et al. 24-week follow-up of patients switching from a protease inhibitor (PI) containing regimen with lamivudine (3TC) and stavudine (d4T) or zidovudine (AZT) to an efavirenz (EFV) based therapy. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 2000. Toronto. [Abstract 1532]

  111. Calza L, Manfredi R, Colangeli V, et al. Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia. AIDS. 2005;19:1051-1058.

  112. Dube MP, Sprecher D, Henry WK, et al. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clin Infect Dis. 2000;31: 1216-1224.

  113. US National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary of the third report. JAMA. 2001;285:2486-2497.

  114. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502.

  115. Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of HMG-CoA reductase inhibitors for treatment of hyperlipidemia in patients with HIV infection. Pharmacotherapy. 2000;20:1066-1071.

  116. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet. 2002;41: 1195-1211.

  117. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS. 2002;16:569-577.

  118. Gerber JG, Rosenkranz SL, Fichtenbaum CJ, et al. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: Results of AIDS Clinical Trials Group 5108 Study. J Acquir Immune Defic Syndr. 2005;39:307-312.

  119. von Lintig FC, Lee D, Patel P, et al. Effectiveness of ezetimibe on hyperlipidemia in HIV-1-infected patients. 6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. October 25-28, 2004. Washington. [Abstract 83]

  120. Negredo E, Rey-Joly C, Puig J, et al. Ezetimibe, a selective inhibitor of cholesterol absorption, as a new strategy for treatment of hypercholesterolemia secondary to antiretroviral therapy. 45th Annual International Conference on Antimicrobial Agents and Chemotherapy. December 16-19, 2005. San Francisco. [Abstract H-336]

  121. Hewitt RG, Shelton MJ, Esch LD. Gemfibrozil effectively lowers protease inhibitor-associated hypertriglyceridemia in HIV-1-positive patients. AIDS. 1999;13:868-869.

  122. Thomas JC, Lopes-Virella MF, Del Bene VE, et al. Use of fenofibrate in the management of protease inhibitor-associated lipid abnormalities. Pharmacotherapy. 2000;20:727-734.

  123. de Luis DA, Aller R, Rachiller P, Ignacio Tortosa J. Reversibility of severe hyperlipemia secondary to indinavir with micronized phenofibrate. Med Clin (Barc). 1999;113:716-717.

  124. Fessel WJ, Luu TT, Anderson B, Young TP, Rego J. Fat expansions in patients on HAART with fat redistribution syndrome shrink after niacin-induced increase in plasma HDL. Antivir Ther. 2000;5 (Suppl 5):L80.

  125. Souza S CD, Walsh E, et al. A 36-week safety and tolerability study of extended-release niacin for the treatment of hypertriglyceridemia in subjects with HIV. Antivir Ther. 2002;7:L33.

  126. Gerber M, Yarasheski K, Dreschsler H, et al. Niacin in HIV-infected individuals with hyperlipidemia receiving potent antiretroviral therapy. 10th Conference on Retroviruses and Opportunistic Infections. February 10-14, 2003. Boston. [Abstract 726]

  127. Wohl DA, Tien HC, Busby M, et al. Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clin Infect Dis. 2005;41: 1498-1504.

  128. Gerber J, Kitch D, Aberg J, et al. The safety and efficacy of fish oil in combination with fenofibrate in subjects on ART with hypertriglyceridemia who had an incomplete response to either agent alone: Results of ACTG A5186. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006. Denver. [Abstract 146]

  129. Falco V, Rodriguez D, Ribera E, et al. Severe nucleoside-associated lactic acidosis in human immunodeficiency virus-infected patients: Report of 12 cases and review of the literature. Clin Infect Dis. 2002;34:838-846.

  130. John M, Moore CB, James IR, et al. Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy. AIDS. 2001;15:717-723.

  131. Lonergan JT, Behling C, Pfander H, Hassanein TI, Mathews WC. Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens. Clin Infect Dis. 2000;31:162-166.

  132. Coghlan ME, Sommadossi JP, Jhala NC, et al. Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: A report of 12 cases. Clin Infect Dis. 2001;33:1914-1921.

  133. Moyle G. Mitochondrial toxicity hypothesis for lipoatrophy: A refutation. AIDS. 2001;15:413-415.

  134. Boubaker K, Flepp M, Sudre P, et al. Hyperlactatemia and antiretroviral therapy: The Swiss HIV Cohort Study. Clin Infect Dis. 2001;33: 1931-1937.

  135. Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: Contribution to protease inhibitor-related lipodystrophy syndrome. AIDS. 2000;14:F25-F32.

  136. Gerard Y, Maulin L, Yazdanpanah Y, et al. Symptomatic hyperlactataemia: An emerging complication of antiretroviral therapy. AIDS. 2000;14:2723-2730.

  137. Bonnet F, Balestre E, Bernardin E, et al. Risk factors for hyperlactataemia in HIV-infected patients, Aquitaine Cohort, 1999-2003. Antivir Chem Chemother. 2005;16:63-67.

  138. Wohl DA, Pilcher CD, Evans S, et al. Absence of sustained hyperlactatemia in HIV-infected patients with risk factors for mitochondrial toxicity. J Acquir Immune Defic Syndr. 2004;35:274-278.

  139. Noguera A, Fortuny C, Munoz-Almagro C, et al. Hyperlactatemia in human immunodeficiency virus-uninfected infants who are exposed to antiretrovirals. Pediatrics. 2004;114:e598-e603.

  140. Alimenti A, Burdge DR, Ogilvie GS, Money DM, Forbes JC. Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy. Pediatr Infect Dis J. 2003;22:782-789.

  141. Brinkman K. Management of hyperlactatemia: No need for routine lactate measurements. AIDS. 2001;15:795-797.

  142. Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Sex Transm Infect. 2002;78:58-59.

  143. US Food and Drug Administration. FDA/Bristol Myers Squibb issues caution for HIV combination therapy with Zerit and Videx in pregnant women [FDA Talk Paper]. January 5, 2001. Available at: www.fda.gov/bbs/topics/ANSWERS/ANS01063.html (Accessed May 9, 2006).

  144. John M, Mallal S. Hyperlactatemia syndromes in people with HIV infection. Curr Opin Infect Dis. 2002;15:23-29.

  145. Fleischer R, Boxwell D, Sherman KE. Evidence suggesting mitochondrial toxicity in HIV/HCV co-infected patients receiving ribavirin and didanosine. 10th Conference on Retroviruses and Opportunistic Infections. February 10 -14, 2003. Boston. [Abstract 763]

  146. Guo Y, Fung HB. Fatal lactic acidosis associated with coadministration of didanosine and tenofovir disoproxil fumarate. Pharmacotherapy. 2004. 24:1089-1094.

  147. Bonnet F, Bonarek M, Morlat P, et al. Risk factors for lactic acidosis in HIV-infected patients treated with nucleoside reverse-transcriptase inhibitors: A case-control study. Clin Infect Dis. 2003;36:1324-1328.

  148. Madias NE. Lactic acidosis. Kidney Int. 1986;29:752-774.

  149. Bartley PB, Westacott L, Boots RJ, et al. Large hepatic mitochondrial DNA deletions associated with L-lactic acidosis and highly active antiretroviral therapy. AIDS. 2001;15:419-420.

  150. Gallagher EJ, Rodriguez K, Touger M. Agreement between peripheral venous and arterial lactate levels. Ann Emerg Med. 1997; 29:479-483.

  151. Astles R, Williams CP, Sedor F. Stability of plasma lactate in vitro in the presence of antiglycolytic agents. Clin Chem. 1994;40:1327-1330.

  152. Dube MP, Kitch DW, Parker RA, Alston-Smith BL, Mulligan K. The effect of long-term storage on measured plasma lactate concentrations and prospective lactate results from a multicenter trial of antiretroviral therapy. Clin Chem Lab Med. 2005;43:947-952.

  153. Schramm C, Wanitschke R, Galle PR. Thiamine for the treatment of nucleoside analogue-induced severe lactic acidosis. Eur J Anaesthesiol. 1999;16:733-735.

  154. Arici C, Tebaldi A, Quinzan GP, et al. Severe lactic acidosis and thiamine administration in an HIV-infected patient on HAART. Int J STD AIDS. 2001;12:407-409.

  155. Johri S, Alkhuja S, Siviglia G, Soni A. Steatosis-lactic acidosis syndrome associated with stavudine and lamivudine therapy. AIDS. 2000;14:1286-1287.

  156. Claessens YE, Cariou A, Chiche JD, Dauriat G, Dhainaut JF. L-carnitine as a treatment of life-threatening lactic acidosis induced by nucleoside analogues. AIDS. 2000;14:472-473.

  157. Lenzo NP, Garas BA, French MA. Hepatic steatosis and lactic acidosis associated with stavudine treatment in an HIV patient: A case report. AIDS. 1997;11:1294-1296.

  158. Lonergan JT, Barber RE, Mathews WC. Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis. AIDS. 2003;17:2495-2499.

  159. Lonergan JT, McComsey GA, Fisher RL, et al. Lack of recurrence of hyperlactatemia in HIV-infected patients switched from stavudine to abacavir or zidovudine. J Acquir Immune Defic Syndr. 2004;36: 935-942.

  160. McComsey GA, Yau L. Asymptomatic hyperlactataemia: Predictive value, natural history and correlates. Antivir Ther. 2004;9:205-212.

  161. Moyle GJ, Datta D, Mandalia S, et al. Hyperlactataemia and lactic acidosis during antiretroviral therapy: Relevance, reproducibility and possible risk factors. AIDS. 2002;16:1341-1349.

  162. Blacksin MF, Kloser PC, Simon J. Avascular necrosis of bone in human immunodeficiency virus infected patients. Clin Imaging. 1999;23:314-318.

  163. Goorney BP, Lacey H, Thurairajasingam S, Brown JD. Avascular necrosis of the hip in a man with HIV infection. Genitourin Med. 1990;66:451-452.

  164. Gerster JC, Camus JP, Chave JP, Koeger AC, Rappoport G. Multiple site avascular necrosis in HIV infected patients. J Rheumatol. 1991;18:300-302.

  165. Miller KD, Masur H, Jones EC, et al. High prevalence of osteonecrosis of the femoral head in HIV-infected adults. Ann Intern Med. 2002;137:17-25.

  166. Gutierrez F, Padilla S, Ortega E, et al. Avascular necrosis of the bone in HIV-infected patients: Incidence and associated factors. AIDS. 2002;16:481-483.

  167. Glesby MJ, Hoover DR, Vaamonde CM. Osteonecrosis in patients infected with human immunodeficiency virus: A case-control study. J Infect Dis. 2001;184:519-523.

  168. Plate AM, Boyle BA. Review of avascular necrosis and HIV. AIDS Read. 2000;10:570-573.

  169. Allison GT, Bostrom MP, Glesby MJ. Osteonecrosis in HIV disease: Epidemiology, etiologies, and clinical management. AIDS. 2003;17:1-9.

  170. Qaqish RB, Sims KA. Bone disorders associated with the human immunodeficiency virus: Pathogenesis and management. Pharmacotherapy. 2004;24:1331-1346.

  171. Hassell KL, Kressin DC, Neumann A, Ellison R, Marlar RA. Correlation of antiphospholipid antibodies and protein S deficiency with thrombosis in HIV-infected men. Blood Coagul Fibrinolysis. 1994;5:455-462.

  172. Scribner AN, Troia-Cancio PV, Cox BA, et al. Osteonecrosis in HIV: A case-control study. J Acquir Immune Defic Syndr. 2000;25:19-25.

  173. Hasse B, Ledergerber B, Egger M, et al. Antiretroviral treatment and osteonecrosis in patients of the Swiss HIV Cohort Study: A nested case-control study. AIDS Res Hum Retroviruses. 2004;20:909-915.

  174. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: Scientific review. JAMA. 2002;288:1889-1897.

  175. Kanis JA. Assessment of fracture risk and its application to screening for post-menopausal osteoporosis: Synopsis of a WHO report. WHO Study Group. Osteoporos Int. 1994;4:368-381.

  176. Hoy J, Hudson J, Law M, et al. Osteopenia in a randomized, multicenter study of protease inhibitor (PI) substitution in patients with the lipodystrophy syndrome and well-controlled HIV viremia. 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000. San Francisco. [Abstract 208]

  177. Tebas P. Fat redistribution and bone abnormalities in HIV-infected patients. J Int Assoc Physicians AIDS Care. 2003;2:59-65.

  178. Carr A, Miller J, Eisman JA, Cooper DA. Osteopenia in HIV-infected men: Association with asymptomatic lactic acidemia and lower weight pre-antiretroviral therapy. AIDS. 2001;15:703-709.

  179. Amorosa V, Tebas P. Bone disease and HIV infection. Clin Infect Dis. 2006;42:108-114.

  180. Teichmann J, Stephan E, Lange U, et al. Osteopenia in HIV-infected women prior to highly active antiretroviral therapy. J Infect. 2003;46:221-227.

  181. Aukrust P, Haug CJ, Ueland T, et al. Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: Indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab. 1999;84:145-150.

  182. Teitelbaum S. Effects of protease inhibitors on osteoblast and osteoclast formation and function. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. September 22-25, 2002. San Diego.

  183. Jacobson D, Huang J, Shevitz A, et al. Duration of ART and change in bone mineral density over time. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. [Abstract 825]

  184. US Preventive Services Task Force. Screening for osteoporosis in post-menopausal women: Recommendations and rationale. Ann Intern Med. 2002;137:526-528.

  185. Nelson HD, Helfand M, Woolf SH, Allan JD. Screening for post-menopausal osteoporosis: A review of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2002;137:529-541.

  186. Mondy K, Powderly WG, Claxton SA, et al. Alendronate, vitamin D, and calcium for the treatment of osteopenia/osteoporosis associated with HIV infection. J Acquir Immune Defic Syndr. 2005;38:426-431.

  187. Negredo E, Martinez-Lopez E, Paredes R, et al. Reversal of HIV-1-associated osteoporosis with once-weekly alendronate. AIDS. 2005;19:343-345.



This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication IAPAC Monthly.
 

Advertisement