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Metabolic Complications of HIV Therapy
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Introduction
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HIV-Associated Lipodystrophy
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transparent imageBackground and Definition
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transparent imageMechanism(s) of Disease
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transparent imageAntiretroviral Therapy
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transparent imageHost Factors
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transparent imageMitochondrial Toxicity
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transparent imageDiagnosis
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transparent imageTherapy
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transparent imageAntiretroviral Strategies
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transparent imageDrugs
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transparent imageDietary and Nonpharmacologic Measures
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Insulin Resistance
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transparent imageBackground and Definition
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transparent imageMechanism(s) of Disease
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transparent imageDiagnosis
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transparent imageTherapy
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Dyslipidemia
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transparent imageBackground and Definition
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transparent imageMechanism(s) of Disease
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transparent imageDiagnosis
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transparent imageTherapy
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Hyperlactatemia and Lactic Acidosis
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transparent imageBackground and Definition
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transparent imageMechanism(s) of Disease
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transparent imageDiagnosis
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transparent imageTherapy
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transparent imageLactic Acidosis
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transparent imageSymptomatic Hyperlactatemia
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transparent imageAsymptomatic Hyperlactatemia
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Bone Disease
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transparent imageOsteonecrosis
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transparent imageBackground and Definition
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transparent imageMechanism(s) of Disease
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transparent imageDiagnosis and Therapy
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transparent imageOsteopenia and Osteoporosis
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transparent imageBackground and Definition
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transparent imageMechanism(s) of Disease
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transparent imageDiagnosis
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transparent imageTherapy
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References
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Tables
Table 1.Metabolic and Morphologic Complications Associated with HIV Infection and ART
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Table 2.Disorders of Glycemic Homeostasis
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Table 3.National Cholesterol Education Program's Adult Treatment Panel III Report on the Clinical Identification of the Metabolic Syndrome
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Table 4.Adult AIDS Clinical Trials Group Guidelines for Venous Lactate Specimen Collection
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Figures
Figure 1.Fat Accumulation: Dorsocervical Fat Pad ("Buffalo Hump")
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Figure 2.Fat Accumulation: Abdominal (Visceral) Obesity
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Figure 3.Lipoatrophy: Facial fat loss with deepening of nasolabial fold
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Figure 4.Lipoatrophy: Fat depletion of leg with prominence of veins and enhanced definition of musculature
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Figure 5.Etiologies for the Development of HIV-1 Related Insulin Resistance
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Figure 6.Increased Lactic Acid Production
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Introduction
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The use of effective antiretroviral therapy (ART) has resulted in tremendous improvements in morbidity and mortality in HIV-infected individuals. However, the widespread use of effective ART regimens has coincided with increasing reports of metabolic abnormalities such as impaired glucose metabolism and insulin resistance, lactic acidosis, osteopenia, and dyslipidemia. Distressing morphologic changes in body habitus associated with these metabolic abnormalities are characterized by accumulation of fat in the abdomen (visceral fat compartment) and in the dorsocervical area of the neck, as well as by the depletion of fat in the face, buttocks, and extremities. As the metabolic alterations coinciding with the availability of effective ART are similar to the features seen in the metabolic syndrome ("syndrome X"), one of the major concerns has been the potential for increased cardiovascular morbidity and mortality in this cohort.

The causes of the metabolic disturbances and morphologic changes related to ART are 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 as well as drug-specific differences in the tendency of antiretroviral medications to cause these effects. Furthermore, although some of the metabolic disturbances may be linked to one another, the interconnections among these metabolic abnormalities have yet to be elucidated. Table 1 summarizes the metabolic and morphologic complications associated with HIV infection and ART.

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HIV-Associated Lipodystrophy
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Background and Definition
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Body fat abnormalities are common in patients receiving potent ART, occurring in 30-50% or more of individuals 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 (Figure 1, Figure 2, Figure 3, Figure 4). The lipodystrophy syndrome is distressing to HIV-infected individuals on ART and has been linked with both short-term and long-term failure to comply with antiretroviral regimens.(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-infected patients.

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

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Mechanism(s) of Disease
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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 predominantly is 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 increase in visceral adipose (intraabdominal 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-infected men who had the clinical syndrome of peripheral lipoatrophy had less adipose tissue in both peripheral and central depots than did HIV-infected men without peripheral lipoatrophy. Furthermore, HIV-infected 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)

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Antiretroviral Therapy
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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 individuals who never have been treated with PIs.(18,19) The use of NRTIs, stavudine 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 a PI-containing ART regimen to clinically apparent peripheral lipoatrophy was 18.5 months for patients receiving stavudine-containing regimens compared with 26 months for patients receiving zidovudine-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 stavudine and the duration of treatment with the PI indinavir each were associated with significant decreases in leg subcutaneous adipose tissue (SAT) but not visceral adipose tissue (VAT).(11) Nonnucleoside reverse transcriptase inhibitor (NNRTI) medications have not been reported to result in lipodystrophic tendencies.(22)

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Host Factors
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Although HIV-associated lipodystrophy is uncommon in the absence of ART, nondrug factors also are important. Older age consistently has 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. CD4 count, viral load, 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)

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Mitochondrial Toxicity
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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. 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 indeed is 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 2 weeks after initiation of dual-NRTI therapy (zidovudine/lamivudine or stavudine/lamivudine) 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) PIs 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)

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Diagnosis
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Diagnosis of HIV-associated lipodystrophy typically is 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 individuals with stable weight, assessment of lipodystrophy relies on demonstration of changes in regional fat content following use of antiretroviral therapy 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 as research tools.(35) CT scanning also 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 individuals 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)

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Therapy
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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 below.

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Antiretroviral Strategies
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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 stavudine, results in some increase in SAT. This improvement was observed following the substitution of either zidovudine or abacavir for stavudine 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 zidovudine or stavudine to abacavir 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 zidovudine/stavudine 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 = .008). In other studies, a switch to a completely NRTI-sparing regimen of lopinavir/ritonavir (Kaletra) plus efavirenz 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 efavirenz plus 2 NRTIs.(45) Similarly, a switch from a stavudine- or zidovudine-containing regimens to lopinavir/ritonavir plus nevirapine 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 (lopinavir/ritonavir plus efavirenz) compared with efavirenz plus 2 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 the lipoatrophy.

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Drugs
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Anabolic Steroids

Pharmacologic interventions have yielded mixed results. Decreased testosterone levels are seen in HIV-infected men and are associated with visceral obesity in the general population.(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-infected patients with mild 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.

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Growth Hormone

In a prospective, open-label trial of 30 HIV-infected 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)

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Metformin

Metformin was evaluated at a dose of 500 mg twice a day in a randomized controlled trial of 26 HIV-infected 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.

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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-infected 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-infected 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-infected patients.(61) As a result, the authors state that rosiglitazone cannot be recommended for the treatment of lipoatrophy in HIV-infected adults.

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Uridine

Uridine is a pyrimidine nucleoside that has been shown to prevent the adverse effects of zalcitabine 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.

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

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Exercise

Hypocaloric diets are recommended for overweight individuals 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)

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Plastic Surgery

Facial lipoatrophy is a particularly distressing aspect of lipodystrophy. Plastic surgery has gained increasing attention in the HIV-infected community due to the limited efficacy of other therapeutic options. 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 approved currently by the U.S. 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.

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Insulin Resistance
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Background and Definition
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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-infected men on ART had diabetes mellitus compared with 5% in HIV-negative men adjusted for age and BMI. Moreover, the incidence of diabetes mellitus over a 4-year observation period in HIV-infected men with ART exposure was 4.7 cases per 100 person-years, a level more than 4 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-infected population currently being treated with ART.(71,72) Disorders of glucose metabolism are defined in Table 2.

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Mechanism(s) of Disease
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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-infected individual 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 indinavir directly induces the development of insulin resistance when given as a short course or as a single dose in HIV-negative individuals.(74,75) This direct response likely is mediated by impaired cellular glucose uptake due to inhibition of both the Glut4 glucose transporter and glucose phosphorylation.(76,77) Reduced insulin sensitivity also may 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 intracellular 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 named adiponectin (ACRP-30, adipoQ) that may have insulin-sensitizing properties. A correlation between low adiponectin levels and decreased peripheral subcutaneous fat has been reported.(83)

The effect of initial exposure to ART on insulin resistance by quantitative insulin-sensitivity check index (QUICKI) was assessed within the MACS cohort.(84) Comparing HIV-negative men with HIV-infected men stratified by therapy status for the preceding 6 months (no ART, mono or dual NRTI, ART including a PI, or ART without a PI), insulin resistance was higher in all HIV-infected 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 cell count, hepatitis C 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, stavudine was associated with the highest risk of hyperinsulinemia.

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Diagnosis
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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, 3-6 months after starting, and annually thereafter) with a regimen containing 1 or more PI.(1) It may be appropriate to extend this recommendation to all subjects initiating antiretroviral regimens, given that insulin resistance also may be seen with regimens that do not include a PI, particularly in association with the development of lipodystrophy. Serial fasting plasma glucose assessments and/or oral glucose tolerance testing may help to identify individuals with impaired glucose tolerance, and may be especially helpful in those at risk for type 2 diabetes mellitus.

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Therapy
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In antiretroviral-naive individuals with preexisting impaired glucose tolerance, consideration should be given to avoiding the use of older-generation PIs, such as indinavir, in initial therapy. Among PIs, atazanavir and amprenavir/fosamprenavir may be less likely to cause impaired glucose tolerance.(86,87) In those individuals 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 abacavir for the PI component of an antiretroviral regimen.(42,88,89) The choice of the NRTI backbone also is important in glucose homeostasis, as stavudine use is associated with the highest risk of hyperinsulinemia. The initial use of abacavir or tenofovir 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 individuals 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-infected 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-infected 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-infected men because of the potential adverse effects of excess testosterone.(48)

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Dyslipidemia
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Background and Definition
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Abnormalities of lipid metabolism are common complications of HIV disease and HIV therapy. Similar to the link suggested between atherosclerosis and chronic infections such as Chlamydia pneumoniae, the inflammatory response to chronic HIV infection, which is probably mediated by cytokines, may in itself be proatherogenic.(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 susceptible to oxidation particularly 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, LDL, and total cholesterol are seen commonly in practice. In a prospective study of 221 HIV-infected individuals followed for a median of 5 years, the incidence of new-onset hypercholesterolemia and hypertriglyceridemia was 24 percent, and 19 percent, respectively.(96)

These proatherogenic lipid profiles have raised concerns about increased cardiovascular disease risk in the HIV-infected population. Metabolic syndrome is common among HIV-infected men, with a prevalence of 13-23%.(97) Lower CD4 cell 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 trial.(98) This trial compared episodic use of ART based on CD4 cell 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-infected individuals 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-infected individuals 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. A prospective assessment of 23,490 patients from 11 cohorts on 3 continents (D:A:D Study) found that combination ART was associated with a 27% relative increase in the rate of myocardial infarction per year of exposure during the first 7 years of treatment.(100)

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Mechanism(s) of Disease
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PIs have been implicated as a major cause of the lipid abnormalities seen with ART. PI use is associated with the development of dyslipidemia independent of treatment with other drugs, viral load, or body weight changes. Different PIs have various effects on lipid metabolism. Ritonavir has the greatest effect on levels of triglyceride, LDL, and cholesterol, whereas indinavir has minimal effect.(75,101) Interestingly, atazanavir has been shown to have a beneficial effect on serum triglycerides, LDL, HDL, and total cholesterol levels.(102,103) PIs 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 individuals receiving PIs. Patients who are heterozygous or homozygous for the apolipoprotein E-2 genotype have been found to have higher serum triglyceride and cholesterol levels when receiving PIs.(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 zidovudine/lamivudine/abacavir 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, stavudine has been demonstrated to cause dyslipidemia. A prospective, multicenter study by the RECOVER Study Group found that HIV-infected patients who replaced stavudine with tenofovir had significant decreases in triglyceride and cholesterol levels. This suggests, at least partly, a stavudine-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 efavirenz in addition to an NRTI backbone of zidovudine/lamivudine with or without abacavir 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 nevirapine or efavirenz.(41,42,88,111)

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Diagnosis
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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 Trial Group Cardiovascular Disease Focus Group, it is reasonable to obtain a fasting lipid profile at baseline and approximately 3 months after starting a new ART regimen.(112) If the lipid profile is normal, annual repeats are recommended.

Because optimal management of dyslipidemia in HIV-infected 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. LDL cholesterol (in mg/dL) can be calculated using Friedewald's equation: calculated LDL cholesterol = total cholesterol - HDL cholesterol - triglycerides/5.(114) Friedewald's 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-infected individuals. Recognition of the metabolic syndrome also is 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)

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Therapy
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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 efavirenz. Results from the AIDS Clinical Trials Group 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-infected population is unclear as isolated elevations of CK of uncertain clinical significance are seen frequently in HIV-positive individuals. 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 antiretrovirals. The use of ezetimibe in combination with statin therapy is being studied.(119,120)

For hypertriglyceridemia (serum triglyceride levels >500), fibric acid analogues such as gemfibrozil and fenofibrate have been used. The magnitude of reduction of LDL, total cholesterol, and triglycerides through the use of statin, fenofibrate, or the combination of the two has been less than robust in patients taking PIs.(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 4 if the response is suboptimal. Although niacin may worsen insulin resistance, the use of niacin may be safe for the treatment of hypertriglyceridemia in individuals at low risk for glucose intolerance. 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)

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Hyperlactatemia and Lactic Acidosis
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Background and Definition
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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 also have 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 usually is 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 1 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 1 of 7 centers in Switzerland found increased risk of lactic acidemia with stavudine use compared with zidovudine-containing regimens, with an incidence of 11% vs 4.2%, respectively.(134) Didanosine also conferred increased risk, whereas zidovudine and lamivudine 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 1-3 monthly 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-infected 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 analogues also appear to be at risk for hyperlactatemia. In one study, nearly half of 127 infants with NRTI exposure had at least 1 elevated lactate measurement over the course of 1 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 13.6-14.5 per 1,000 patient-years and that lactic acidosis occurs less frequently, at a rate of 1.2-3.9 events per 1,000 patient-years in HIV-infected individuals receiving NRTIs.(141) The high mortality (33-57%) 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. CD4 count, viral load, use of specific NRTIs, and age were not predictive of increased disease severity. Stavudine was the thymidine analogue used in 48% of cases, whereas zidovudine was used in 45%, with a median 9 months of therapy prior to presentation. Women were overrepresented, accounting for 43% of severe acidosis cases, though women account for approximately 20% of HIV-infected individuals in the developed world. On multivariate analysis, only lactate level >10 was associated with increased mortality (odds ratio: 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 and C coinfection are overrepresented in both lactic acidemia and lactic acidosis.(144) Concomitant use of didanosine and ribavirin in HIV/hepatitis C-coinfected individuals may represent a risk factor for lactic acidosis as well as for other syndromes attributed to NRTI-mediated mitochondrial toxicity.(145) A case of lactic acidosis in association with coadministration of tenofovir and didanosine also has been reported, possibly related to augmented didanosine levels with this antiviral combination.(146) Finally, a case-control study involving 9 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)

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Mechanism(s) of Disease
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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 stavudine show relatively high inhibition of DNA polymerase gamma in vitro, consistent with the finding of increased risk of lactic acidemia with these NRTIs (see Figure 6).(129)

Venous or arterial lactate reflects the net balance between lactate production and release from metabolically active tissues and lactate uptake by tissues (predominantly liver and kidney) with the capacity to oxidize lactate or use it as a substrate for gluconeogenesis. Homeostatic regulation is highly efficient, with conditions of lactate excess normally leading to augmentation of lactate clearance by the liver, kidneys, lungs, and muscle. Sustained elevations in blood lactate levels therefore indicate a significant loss of homeostasis.(130,148) Possible explanations for the lactic acidosis/acidemia syndrome include massive overproduction of lactate, marked decrease in the ability to oxidize lactate, or, most likely, a combination of both. The almost-uniform involvement of liver pathology in severe cases of lactic acidosis and acidemia suggests that hepatic dysfunction with respect to lactate metabolism may be an important component of this syndrome.

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Diagnosis
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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 AIDS Clinical Trials Group may be helpful in this regard (see 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-infected subjects was associated with only small increases (0.4-0.6 mmol/L) in lactate measurements at 64 weeks compared with baseline values.(152)

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

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

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Lactic Acidosis
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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 individuals. Other antivirals also should 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)

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Symptomatic Hyperlactatemia
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Management depends on the severity of symptoms and the judgment of the physician regarding the clinical significance of the lactate elevation. There are no randomized, controlled clinical trials in HIV-infected patients to evaluate how and when withdrawal of antiretrovirals should be considered in those individuals with hyperlactatemia without acidosis. However, the 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 abacavir and tenofovir, 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)

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Asymptomatic Hyperlactatemia
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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)

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Bone Disease
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Osteonecrosis
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Background and Definition
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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-infected 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 individuals having at least 1 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)

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Mechanism(s) of Disease
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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 50-86% of the HIV-infected 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-infected 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, also have 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)

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Diagnosis and Therapy
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The International AIDS Society-USA Panel does not recommend routine screening of HIV-infected patients for the presence of osteonecrosis. A high index of suspicion is warranted, however, in individuals who present with pain over the joints or bone. MRI is the most sensitive and specific imaging technique for early detection of osteonecrosis and is indicated if plain films are normal and symptoms of osteonecrosis persist.(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 antiinflammatory 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.

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Osteopenia and Osteoporosis
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Background and Definition
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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 4 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. 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 (25-30 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 individuals. Osteopenia is defined as a T-score between 1 and 2.5 standard deviations below the average found in young people. Osteoporosis is a T-score >2.5 standard deviations below the average found in young people. Established osteoporosis is a T-score >2.5 standard deviations below the mean in the presence of fragility fractures.

Osteopenia and osteoporosis occur at high frequency in the HIV-infected population on ART compared with age-matched, HIV-negative controls. Observational studies have reported higher rates of osteopenia in individuals having a CD4 count <=100 cells/µL,(45%) individuals 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)

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Mechanism(s) of Disease
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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) PI 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 a NNRTI-based one does not result in improvements in bone mineral density.(179) Gilead Study 903 found tenofovir to have the greatest bone-demineralizing effect among antiretroviral agents.(183)

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Diagnosis
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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 U.S. Preventive Task Force in all women above age 65 and selected women in the 60-65 age range because of the increased prevalence of osteopenia and osteoporosis in these groups.(174,184) In the HIV-infected 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)

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Therapy
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Osteopenia usually is asymptomatic. Individuals suffering from severe osteoporosis may present with pain over the joints or bones as a result of 1 or more fractures. Current therapies used to treat bone demineralization have not been studied completely in the HIV-infected 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 immediate period 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. Individuals diagnosed with osteopenia or osteoporosis should consume 1,500 mg of calcium and 400-1,000 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-infected 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 AIDS Clinical Trials Group 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.

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