The metabolic puzzle during the evolution of HIV infection

Clinical Nutrition (2001) 20(5): 379–391 & 2001 Harcourt Publishers Ltd doi:10.1054/clnu.2001.0429, available online at http://www.idealibrary.com on

REVIEW

The metabolic puzzle during the evolution of HIV infection J. SALAS-SALVADOŁ,*,{ P. GARCIŁ A-LORDA* *Human Nutrition Unit, Facultat de Medicina i Cie'ncies de la Salut de Reus, Universitat Rovira i V|rgili, {Nutrition Unit, Hospital Universitari Sant Joan de Reus. Spain (Correspondence to: JS-S, Unitat de Nutricio¤ Humana, Facultat de Medicina i Cie'ncies de la Salut de Reus, Universitat Rovira i V|rgili, C/Sant Llorenc°, 21, 43201Reus, Spain)

AbstractöAbnormalities in energy, protein, lipid and glucose metabolism have been described in HIV patients since the beginning of the epidemic.With the new antiretroviral agents, nutritional status and survival have improved dramatically. However, since these therapies were introduced, there have been more descriptions of metabolic abnormalities, some of which were similar to and others of which were in con£ict with those reported in previous years. This paper reviews the complexity of the metabolic abnormalities in HIV infections before and after the introduction of highly active antiretroviral therapy, and discusses such etiopathogenic mechanisms as secondary infections, antiretroviral drugs and persistent immune activation, which may be involved in these derangements. & 2001Harcourt Publishers Ltd.

suppress the replication of the virus in the peripheral blood in a considerable percentage of HIV-infected patients over a selected period of time. Consequently, the clinical profile of the complications of infection with the virus is changing once again. In addition, the incidence of AIDS and the death rate from AIDS in Europe have fallen and, apparently, are still falling (18). The incidence of AIDS has been decreasing since 1996 in all European Union countries except Portugal and, in 1998, ranged from 3.1 cases per million in Finland to almost 90 per million in Spain and Portugal (18). The incidence of weight loss has also decreased substantially, as have the incidence rates for Pneumocystis carinii pneumonia, citomegalovirus infections, criptosporidiosis and other complications of the infection (19). Such infections may also spontaneously resolve in patients started on HAART (20, 21), which indicates that effective viral suppression is associated with substantial immune reconstitution. It could be said that, since highly active antiretroviral therapy was introduced, HIV-infection has become a chronic infection. In contrast to this promising news about the use of the HAART therapy, other problems have been identified. Firstly, these noteworthy advances are limited only to those patients who are given these therapies, so much of the developing world is excluded. Moreover, in developed countries, the benefits are limited to patients who receive regular medical care. Secondly, some patients, in whom antiretroviral therapy results in an undetectable viral load, have relapses because resistance develops or because they are unable to comply with a complicated medical regimen (22). For example, in clinical trials, between 80% and 90% of patients receiving HAART maintain undetectable viral loads, whereas in clinical practice probably less than 50% of patients achieve this

Key words: antiretroviral therapy; AIDS; HIV-infection; energy metabolism; insulin resistance; lipid metabolism; opportunistic infections; cytokines; inflammation.

Nutrition and HIV infection: a new scenario The topic of nutrition and HIV infection has received substantial attention over the past few years. Protein energy malnutrition was a very common complication in the past (1–3) and patients routinely succumbed to complications from opportunistic infections in the cachectic state. Wasting, as defined by the Centers of Disease Control and Prevention, was used as a criterion to establish the diagnosis of AIDS in the absence of concomitant opportunistic infections or other identifiable causes of weight loss (4). Irrespective of the multiple causes of wasting (5, 6), AIDS patients who experienced weight loss beyond a certain percentage of their ideal body weight were at a greater risk of death. Thus, a relationship was established between survival and the extent of body cell mass depletion (1). Several authors found a significant relationship between body weight loss and survival (7, 8). In a large cohort longitudinal study, Wheeler et al. recently observed that patients who have lost 5% of their usual body weight are at the greatest risk of death (9). Therefore, we thought that life expectancy and quality of life should improve if the wasting process could be reversed. However, this has proven to be difficult, and increases in body weight by therapeutic strategies have mainly been in the form of fat and water rather than lean-body mass (10–17). We have now entered the era of highly active antiretroviral therapy (HAART), which can maximally 379

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goal. The main reason for this apparent difference in drug efficacy could be patients’ non-adherence to medication (23) due to adverse effects such as gastrointestinal intolerance or severe lipodistrophy. Finally, HAART therapy has been linked with weight gain and redistribution of fat in a dorsocervical pattern and a truncal pattern, with no change in lean-body-mass (24). This syndrome, increasingly referred to as lipodystrophy syndrome, includes a panoply of metabolic complications that have changed the panorama of HIV-infection (24, 25). This review will focus on the metabolic abnormalities associated with HIV infection from the start of the epidemic to the present day. Therefore, evidence from both before and after the introduction of HAART will be discussed. However, the aim of this study is not to discuss alterations in body composition that affect total body fat and fat-free mass (wasting syndrome) or tissue redistribution (lipodystrophy). Comprehensive revision of both topics, wasting syndrome (5, 6, 26, 27) and fat redistribution (24, 28–30), have been published elsewhere.

Energy and protein metabolism before and after the HAART era From a thermodynamic point of view, weight loss must be viewed as the result of an imbalance between energy input and energy output, so hypermetabolism was soon considered to be a precipitating factor in the aetiology of wasting associated to HIV infection. Several studies evaluated the resting energy expenditure (REE) or basal metabolic rate in HIV-infected patients before HAART was introduced (Table 1). Many of these reported an increase in REE, which supports the notion of HIV infection as a hypermetabolic disease (31–33). However, studies vary considerably and when differences in body composition are taken into account, the resting component of energy expenditure has been found to be increased (34–40), normal (41), or even decreased (42, 43). Although hypermetabolism has already been described in the early asymptomatic phases of the infection (35, 38, 44), the severity of this resting hypermetabolic response seems to increase in all the stages of the disease, and particularly in the presence of secondary infections (44–46). Heterogeneity in energy expenditure parameters, therefore, reflects the clinical heterogeneity of HIV-infected patients, which may explain the apparently divergent results of various studies. However, the hypermetabolic response between studies and between individuals varies considerably, even in the presence of secondary infections. This is exemplified by the energy expenditure measurements performed by our group in a cohort of HIV patients and control subjects (Fig. 1). Here, we can see that while the variability of REE adjusted by fat-free mass is very low in the control group, it increases in

HIV-infected patients and reaches a maximum in the group of patients with opportunistic infections secondary to AIDS. While some patients, in this last group are hypermetabolic, others are frankly hypometabolic. This supports the idea that hypermetabolism is not a constant phenomenon in the course of HIV infection, even in the presence of secondary infections (46). This variability is consistent with the observations of other studies (36, 47, 48). Several factors can modulate the resting metabolic response and contribute to this heterogeneity. Our Nutrition Department evaluated 3 groups of HIV-infected patients and compared them to controls (41). After xylose absorption and triolein breath tests were performed, 54% of patients were determined to have sugar malabsorption, while 42% had fat malabsorption. The prevalence of malabsorption increased from 53% in asymptomatic HIV-infected patients to 82% in AIDS patients with associated infections. Moreover, when comparing patients with or without malabsorption, REE was significantly lower in malabsorptive patients than in controls. After adjustment by fat-free mass, REE remained lower in malabsorptive patients but slightly higher than in controls, although the differences were not statistically significant. Our results suggest that malabsorption is a frequent feature in HIV infection and that in the presence of malabsorption, patients show an appropriate metabolic response via a compensatory decrease in REE. Consequently, the presence of malabsorption, the high prevalence of which has been described even in the HAART era (49), can be an important confounding factor in the determination of energy expenditure.

Determinants of hypermetabolism in HIV-infected patients However, the origin of hypermetabolism remains unclear. Studies conducted in infectious, inflammatory or neoplastic conditions support the widely accepted concept that inflammation causes hypermetabolism (50, 51). Inflammation associated either to infection by HIV or to other secondary infections or malignancies may play a major role in the aetiology of this hypermetabolism via metabolic alterations. In fact, as in other inflammatory states, whole body protein turnover measured by stable isotopes has been shown to increase in AIDS patients even in the absence of secondary infection, and this itself may be energy costly (52). Once more, there are considerable discrepancies between studies and protein turnover has been reported to increase (31, 53, 54), decrease (55), or remain unchanged (52, 56) in patients with HIV infection and to vary with the patient’s physiologic condition. Furthermore, as described by Hellerstein et al., de novo hepatic lipogenesis is markedly increased both in the fasting and postprandial state from initial phases of the infection

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Table 1 Studies on resting energy expenditure in HIV infection Author (references) Hommes 1990 (34)

Control (n ¼ 11)

Kotler 1990 (42)

Control (n ¼ 5)

Hommes 1991 (35)

Control (n ¼ 11)

Melchior 1991 (36)

Control (n ¼ 14)

Grunfeld 1992 (44)

Control (n ¼ 15)

Su¨ttmann 1993 (47)

—

Melchior 1993 (45)

Study groups

REE vs controls (%)

Evaluated variable

Comments

AIDS and ARC (n ¼ 18) AIDS (n ¼ 5)

+ 9%

REEFFM (BIA)

722%

REE:FFM (TBK)

No opportunistic infections Patients with malabsorption; some of them with OI. No OI or diarrhoea

HIV and asympto+8% matic AIDS (n ¼ 11) AIDS or ARC (n ¼ 50) +12%

REEFFM (BIA) REE:FFM (anthropometry)

HIV asymptomatic (n ¼ 14) AIDS (n ¼ 16) AIDS-OI (n ¼ 9) HIV (n ¼ 60)

+11% +25% +29%

REE: Body weight

+7%

REE vs Predicted REE (H-B)

Control (n ¼ 31)

HIV (n ¼ 129) AIDS-OI (n ¼ 36)

+11% +34%

REE:FFM (anthropometry)

Slusarczyk 1994 (156)

HIV WR 0 (n ¼ 9)

Control (n ¼ 7)

+11% +13% +11% +11.5% +14%

REE absolute values

Poizot-Martin 1994 (37) Macallan 1995 (68)

WR 1 (n ¼ 13) WR 3/4 (n ¼ 10) WR 5 (n ¼ 10) WR 6 (n ¼ 11) HIV and AIDS (n ¼ 16) HIV (n ¼ 9) AIDS with or without OI (n ¼ 19)

Control (n ¼ 14)

Selberg 1995 (31) Sharpstone 1996 (38)

—

Sharpstone 1996 (43)

Asymptomatic HIV (n ¼ 10)

Heiligenberg 1997 (39) Jime´nez-Expo´sito 1998 (41)

Control (n ¼ 9)

Grinspoon 1998 (33) Johann-Liang 2000 (157) Schindler 2000 (40)

Control (n ¼ 26 women) —

Garcı´a-Lorda 2000 (46)

Control (n ¼ 57)

Control (n ¼ 19)

+10.9% +11%

REE: FFM (anthropometry) REEFFM (anthropometry)

AIDS with complica- +8% tions (n ¼ 6) HIV CDC II-CDC III +6% (n ¼ 104)

REE vs Predicted REE (H-B) REE:FFM (DXA)

Micro or criptosporidiasis (n ¼ 10) Pneumonia P. carinii (n ¼ 10) Enteritis Citomegalovirus (n ¼ 9) Systemic MAI (n ¼ 7) HIV (n ¼ 12)

711% +15% +3% +12%

REE:FFM (DXA)

+10%

REEBODY

HIV asymptomatic (n ¼ 17) AIDS (n ¼ 16) AIDS-OI (n ¼ 17) HIV females (n ¼ 33)

WEIGHT

REEFFM (BIA) No differences +17%

HIV children (n ¼ 33)

No differences

Control (n ¼ 20)

HIV (n ¼ 20) and AIDS (n ¼ 17)

+15%

REE vs Predicted REE (H-B) REE vs Predicted REE REEBODY WEIGHT

Control (n ¼ 19)

AIDS-OI (n ¼ 52)

+11%

REEFFM (BIA)

Malnourished patients, including subjects with Kaposi or malabsorption. No OI. Several OI, including those of gastrointestinal tract Patients in different stages (WR 1-6). No OI or Kaposi Gastrointestinal OI were excluded. Patients with evident weight loss 410% Opportunistic infections not described in patients on stage WR6 Stable patients with a variable weight loss OI poorly described. Includes those affecting gastrointestinal tract Includes Kaposi and OI Asymptomatic patients, weight stable and without diarrhoea Patients studied in their first and single episode of OI

Weight-stable patients. No OI. High prevalence of malabsorption in all groups of patients No OI. 85% of patients with AIDS Includes patients with wasting and OI No OI. No differences between HIV and AIDS patients Malnourished patients. Neoplastic diseases excluded

WR, Walter Reed classification; ARC, AIDS related complex; OI, Opportunistic infections; REE, resting energy expenditure; REEFFM, REE adjusted by fat-free mass; REE:FFM, REE divided by kg of fat-free mass; REEBODY WEIGHT, REE adjusted by body weight; REE: Body weight, REE divided by kg of body weight; H-B, REE predicted from Harris-Benedict equations; BIA, Bioelectrical impedance analysis; TBK, total body potassium; DXA: dual X-ray absorptiometry.

(57, 58). This futile or substrate cycling may be another important determinant of hypermetabolism. The role of inflammatory mediators in hypermetabolism and wasting in AIDS has often been postulated

(59), but their relative contribution is controversial. The role of proinflammatory cytokines such as TNF, IL-1 and IL-6 in the hypermetabolism that accompanies HIV infection has been widely discussed but most studies

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Fig. 1 Resting energy expenditure measurements expressed as a percentage of the predicted values by Harris-Benedict equations (Panel A) or adjusted by fat-free mass (Panel B) in a group of control subjects, HIV-infected patients without complications (HIV+) and AIDS patients with active opportunistic infections (AIDS-OI).

have failed to find a consistent relationship between circulating cytokine levels and metabolic disturbances such as hypermetabolism (60, 61) or protein turnover (52). Methodological difficulties linked to the short half-life and the preferential autocrine and paracrine action of cytokines may account for this lack of results. In a study we performed on AIDS patients with opportunistic infections (46), REE adjusted by fat-free mass was positively related to acute-phase reactants (C-reactive protein, erythrocite sedimentation rate and ferritin), plasma IL-6, and soluble TNF receptors, but had a negative relationship with the albumin, prealbumin and transferrin plasma levels. Furthermore, C-reactive protein was an independent predictor of REE adjusted by fat-free-mass (46). We can therefore conclude that systemic inflammation may be an important aetiologic factor that contributes to hypermetabolism in AIDS patients, at least in the presence of opportunistic infections. Finally, some authors believe that this hypermetabolism is a direct effect of viral infection. In fact, Mulligan et al. described a weak relationship (r ¼ 0.404; P50.011) between plasma viral load and REE after adjustment for lean body mass in 36 clinically stable HIV-positive men (62). This suggests that energy expenditure increases as a part of the host response. However, subsequent studies in wider samples have not confirmed these results (33, 63). The lack of a significant relationship between REE and progression markers of the infection is, perhaps, not surprising. After all, a considerable number of factors known to be present in HIV patients are able to modulate energy expenditure and plasma viral load is not an exact reflection of viral kinetics (64). In contrast to the overwhelming amount of data on energy metabolism in the pre-HAART era, few studies have addressed this topic now that HAART therapy is extensively used. The effectiveness of the new anti-

retroviral therapies in reducing viral load could shed new light on the theory that viral burden is responsible for hypermetabolism. In a cross-sectional study, Shevitz et al. observed a significant relationship between REE and viral load when adjustment by the use of HAART was taken into account (65). Surprisingly, patients on HAART had a significantly higher REE, irrespective of the viral load level. This suggests that HAART directly increases REE and overcomes the potential suppression of viral load (65). In contrast, a prospective study of 37 patients on HAART showed a significant reduction in REE several weeks after an effective reduction in viral load (66), which suggests that sustained viral suppression could decrease REE. However, this is not conclusive proof of the direct role played by HIV in energy expenditure. In fact, the same authors confirmed that HAART decreased REE in HIV and AIDS patients but changes in REE did not correlate with the suppression of the viral load (40). Further longitudinal studies are necessary to confirm the direct action of these therapies on energy metabolism. Moreover, although there is some in vitro evidence that de novo lipogenesis is increased by HAART (67), no in vivo studies have evaluated the potential effect that these therapies can exert on protein or intermediate metabolism. In turn, alterations in these metabolic pathways may explain this HAART-related hypermetabolism.

Reduced caloric intake versus increased energy expenditure as a determinant of body weight loss in HIV-infection Before we discuss this issue, we must make two observations. Firstly, we need to consider the relationship between REE and weight-loss. Several studies have looked into this relationship. Data from our own measurements, as in other studies, show that there does

CLINICAL NUTRITION

not appear to be a significant relationship between resting hypermetabolism and weight change (41, 44, 68). Secondly, we need to recognise that the ultimate determinant of energy balance is not REE but total energy expenditure (TEE), which also includes components for physical activity and diet-induced thermogenesis. Macallan et al. measured total energy expenditure in 51 patients, and found that TEE did not increase but decreased during periods of weight loss (68). Indeed, as the disease progressed, REE tended to increase slightly, but TEE tended to fall. Contrary to widespread belief, therefore, the sickest patients actually had the lowest total energy requirements. This is because patients’ activity levels tend to decline as they become more and more unwell (68, 69). In contrast, Macallan et al. failed to find any significant relationship between REE and weight change. They did find, however, that energy intake was a determining factor in weight loss (68). These two observations show that weight-loss is not driven by energy expenditure but by a decrease in energy intake. However, the role of resting hypermetabolism in weight-loss cannot be underestimated since in situations which produce a drastic reduction in energy intake, as is the case of opportunistic infections, the compensatory mechanisms (i.e. decreased activity levels) may be insufficient to adequately counterbalance the increased requirements. In a prospective study that discussed several episodes of opportunistic infections, Melchior et al. observed a significant relationship between REE and weight loss (8). Other investigators have observed similar results (45, 47). To our knowledge there are no studies evaluating total energy expenditure nor the effect of hypermetabolism on weight change in patients on HAART.

Lipid metabolism before and after the HAART era Alterations in lipid metabolism are common in HIV infection, and they have been recognised since before the era of antiretroviral therapy combinations (see Table 2). One of the first and best-described abnormalities is an increase in plasma fasting triglyceride concentrations (70). In particular, this increase occurs at the time of transition to AIDS (70) and is associated with: (1) an increase in de novo hepatic lipogenesis despite prior

Table 2 Recognised lipid laboratory features during HIV infection

Triglycerides Free fatty acids Total cholesterol HDL cholesterol LDL cholesterol VLDL cholesterol Small dense LDL N ¼ normal.

HIV+

AIDS

Lipodystrophy syndrome

: N N ; N; N N

:: : ; ; ; :: :

::: :: :: N; :: :: :

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weight loss (57, 58); (2) increased lipolysis and lipid disposal despite this hypertriglyceridemia (70), and (3) a decreased tryglyceride clearance associated to a decrease in the lipoprotein lipase activity (71). This hypertriglyceridemia was not usually associated with wasting (72), but it was significantly associated with serum concentrations of alpha-interferon (73–75). There is an even stronger correlation between levels of interferon alpha and both the decrease in triglyceride clearance (71) and the increase in hepatic synthesis of fatty acids while fasting (57, 58). Despite the increased levels of other cytokines described in HIV-infected patients, plasma lipid abnormalities were not consistently linked with these cytokines. For example, it was first suggested that TNFa was an etiologic factor that determines lipid abnormalities, but several authors observed no significant relationship between plasma triglycerides and the levels of TNF or their soluble receptors (46, 61, 73). In contrast, Zangerleet al., described a significant relationship between plasma lipid levels and soluble TNF receptors (76). Other features described in the pre-HAART era included: (1) Increased concentrations of free fatty acids (71); (2) a decrease in high density lipoprotein cholesterol (73), which occurs early in HIV infection (71), followed by a decrease in low density lipoprotein cholesterol (71); (3) a decrease in serum concentrations of total cholesterol (71,74); and (4) the appearance of small dense LDL proatherogenic particles that are easily oxidised (77). In the lipodystrophy syndrome associated with HAART therapy, however, studies have shown a rise rather than a fall in serum triglycerides once antiretroviral therapy has begun (78). Patients with normal levels before therapy may develop hypertriglyceridemia, and patients with high pre-treatment levels undergo further rises. Moreover, unlike previously studied patients, protease inhibitor therapy is associated with higher total serum cholesterol (79, 80), which includes increases in both cholesterol fractions, LDL and VLDL (78, 81, 82), but not in HDL cholesterol (78, 79). Hypertrygliceridemia and hypercholesterolemia have been observed especially in patients who take protease inhibitors (PIs) irrespective of the marketed drug (81, 83). Nevertheless, several studies specifically suggest that ritonavir, nelfinavir and the combination of ritonavir and saquinavir therapy have the greatest effects on lipid metabolism (24, 67, 79, 84). The different effects of PIs on lipid abnormalities may be due to drug–drug interactions or by the affectation of multiple metabolic pathways. In a recent study on a large cohort of patients, there were no lipid elevations in patients on non-nucleoside reverse transcriptase inhibitors (NNRTIs) but PIs showed the strongest association with elevated triglycerides after HIV treatment had been begun. It should be pointed out, however, that other factors, such as the AIDS stage, also played a role (85).

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Glucose metabolism before and after the HAART era Abnormalities in glucose metabolism have also been documented in HIV patients (Table 3). In the pre-PIs era, subjects with HIV infection generally had normal or lower than normal levels of glucose without insulin resistance (55, 86). Furthermore, Hommes et al. observed that advanced HIV patients have a significant increase in insulin clearance and sensitivity, which indicates that this infection by itself does not contribute to insulin resistance (87). In contrast, the introduction of HAART led to the description of several abnormalities in glucose metabolism. Hyperglycemia and hyperinsulinemia, if not universal, have been reported in several studies performed in the post-PI era (82, 88, 89). Another feature that has been described is insulin resistance, which has been documented by high fasting insulin-to-glucose ratios and consistently reported in association with PI use (79, 84, 90). On the other hand, in three studies oral glucose tolerance testing showed impaired glucose tolerance that was accompanied by higher levels of insulin and C-Peptide after glucose stimulation (78, 82, 91). Glucose intolerance was found in 62% of patients receiving protease inhibitor therapy (82)—the highest prevalence reported to date. Several authors consider, from patient metabolic charts, that the prevalence of hyperglycemia is between 5% and 15%, although the real prevalence of diabetes seems to be lower than 6% (88, 92). However, we believe that the prevalence and severity of these conditions require further evaluation. In a cross-sectional controlled study of HIV-infected patients, the sensitivity to insulin of patients treated with PIs decreased in relation to patients who had never been treated with PIs and to controls. This suggests that there is a relationship between insulin sensitivity and these antiretroviral agents (84). In fact, the observation that hyperglycemia resolves spontaneously several weeks after the PI therapy is stopped argues strongly against a mechanism that irreversibly damages pancreatic islet cells (88, 93). In addition, the therapeutic response of these patients to sulfinylureas supports the theory that the pathogenesis of this hyperglycemia is similar to that of type II diabetes, which is also characterised by peripheral insulin resistance (94). On the other hand, the fact that alterations in the proinsulin/insulin ratio have been described in subjects with PI-associated diabetes Table 3 Abnormalities in glucose metabolism during HIV infection HIV infection Glucose levels Insulin levels Insulin:Glucose ratio C-Peptide levels Insulin sensitivity OGTT N ¼ normal.

N; N:: N; N :: Normal

Lipodystrophy syndrome N:: :: :: : ;; Altered

and in PI-treated subjects suggests that PI therapies may be related to defects in pancreatic B-cell function (82, 95). Although a randomized comparison with non-protease therapy has not been performed, the prevalence of insulin resistance was clearly lower in those receiving nucleoside analogue therapy alone (96). Adverse consequences of metabolic alterations Finally, glucose and lipid alterations are often (although not necessarily) closely related to lipodystrophy and especially to the accumulation of perivisceral fat. Miller et al., demonstrated that indinavir users have a higher visceral-to-total fat ratio than patients without PI, and that this parameter is correlated with serum triglyceride values (81). Other authors have reported an association between hyperinsulinemia and the higher waist-to-hip ratio of HIV-infected patients (93). These changes are not different from those observed in Raven syndrome, which suggests an increased coronary risk in these patients. In fact, several case reports of death by myocardial infarction in young people receiving combined therapy have already been described in the literature (83, 98, 99). Several studies have evaluated the prevalence of ischemic heart disease both before and after the protease inhibitor era. In a retrospective analysis of a cohort of 4,993 HIV infected patients treated in a hospital, age and previous HAART therapy were still significantly associated with myocardial infarction in a multiple regression model (100). In a cross-sectional study, HIV patients who were either PInaı¨ ve or PI-experienced, showed an increased frequency of atherosclerotic carotid lesions but the use of PI exerted the greatest influence on the risk of lesions (101). These data suggest that HIV infection confers a higher risk of endothelial damage and that this risk increases in the case of PI use (101). The fact that coronary artery disease was reported in patients with HIV infection prior to the HAART era, and that no other studies have clearly demonstrated an increase in cardiovascular deaths in these patients since the introduction of HAART fuel the controversy surrounding this topic (102). Longer epidemiological studies and wider samples are required if the risk of long-term cardiac heart disease is to be confirmed.

Bone metabolism before and after the HAART era Data on bone metabolism in HIV infection are still scarce, but the reports of bone disorders such as avascular necrosis and hip fractures in patients receiving HAART have increasingly focused attention on this topic. Before HAART was used, bone mineral metabolism was described as normal (103) or minimally affected

CLINICAL NUTRITION

(104) in HIV-infected patients. For example, Paton et al. observed a marginally lower bone mineral density (BMD) in the lumbar spine of HIV patients compared to controls, but no differences in total or hip BMD (104). Other authors have reported a decrease in bone formation and turnover and an increase in bone resorption markers in advanced HIV disease (103, 105, 106). Recently, however, increased bone mineral loss has been described in patients receiving HAART therapy (107). Indeed, Tebas et al. described a higher incidence of osteopenia and osteoporosis in patients receiving PIs, whereas HIV patients on non-PI containing regimens showed no differences with controls. Moreover, these bone complications appear to be independent of adipose tissue maldistribution (107). Preliminary data show that, in contrast to previous findings, patients on HAART present an increase in bone turnover markers (108) and it has been suggested that osteopenia may be linked to lactic acidemia (109). Further studies are required to determine whether this effect is directly produced by PIs or whether it is the consequence of immune reconstitution in the context of effective antiretroviral therapy. Finally, although there are anecdotal reports of pathologic fractures in HIV patients, the precise relevance of this osteopenia remains to be elucidated. Furthermore, descriptions of osteonecrosis and avascular necrosis were only sporadic prior to the HAART era, but they have increased in recent years. This has led to speculation that there may be a link with PI use. However, no association was established between antiretroviral treatments and necrosis in a recent casecontrol study (110), although there did seem to be an association between treatment with corticosteroids and necrosis. However, as hyperlipidemia has been associated to aseptic necrosis in HIV-negative patients, lipid alterations could be the connection between PI-containing regimens and osteonecrosis.

Potential pathogenic mechanisms underlying metabolic alterations in lipodystrophy syndrome Several theories have been put forward to explain these metabolic alterations. However, to date none have been fully confirmed and many points still need to be clarified. Theories involving PIs Since the first descriptions of lipodystrophy appeared to be temporally related to the introduction of regimens containing protease inhibitors, the first hypotheses regarding pathogenesis focused on the direct effect of these drugs. Because PIs have a high affinity for binding to the catalytic site of the HIV-1 protease, Carr et al. suggested that they might also bind to human proteins involved in lipid metabolism (91). They uncovered significant homologies of about 60%, between the

385

catalytic region of HIV-1 protease and two important proteins: the low-density-lipoprotein-receptor-related protein (LPR), which is necessary for removing chylomicron remnants in the liver and clearing tryglicerydes in the capillary endothelium, and the cytoplasmatic retinoic-acid-binding-protein type 1 (CRABP-1), which transports the retinoic acid in the adipocyte (91). The authors speculate that HIV-1 protease inhibitors bind to the CRABP-1 and thus inhibit the binding of retinoic acid and the production of cis-9RA, and that they can also block the P450 cytochrome. This leads to a reduced differentiation and increased apoptosis in peripheral adipocytes, which in turn contributes to hypertryglyceridemia via reduced tryglyceride storage and release into the circulation and, therefore contributes to insulin resistance. Carr’s hypothesis is supported by some indirect evidence. Firstly, metabolic alterations appear after PI therapy has begun and precede any changes in fat distribution (25, 79–81, 111). Secondly, subcutaneous adipocyte apoptosis has been shown to occur in lipoatrophic areas of patients with protease-inhibitorassociated lypodystrophy (112). Moreover, ritonavir, the most potent cytochrome P450 3A-inhibitor of the protease inhibitors appears to be the PI that is most strongly associated with lipid abnormalities and lipodistrophy (91, 113). In vitro, PIs have been shown to inhibit adipocyte growth or promote adipocyte lysis, and also to interfere with retinoid signalling within adipocytes (114). Finally, protease inhibitors are able to inhibit adipocyte differentiation in vitro conditions (115). However, the Australian group’s hypothesis needs to be proven because some experimental data do not support it. Firstly, the key role of cytochrome P450 A3 in adipocytes has not been confirmed and no evidence of significant interaction between CRABP-1 and PIs has been found (116). Secondly, unlike the study by Zhang et al., HIV-1 protease inhibitors have been shown to induce adipocyte differentiation in vitro (117, 118). Thirdly, other substances, such as leptin or TNF, have been suggested as candidates for lipid changes and apoptosis in vitro and in vivo (119). Finally, experimental studies in liver cells performed by Lenhard et al. suggest that PIs induce an increase in triglyceride synthesis affecting molecular pathways other than retinoid signalling (67). These authors suggest that the variability of lipid changes associated to PIs may depend on different factors such as the type of PI used, which could condition the metabolic pathway affected. A group of investigators from Missouri recently suggested that HIV protease inhibitors reduce insulin sensitivity via the glucose transporter Glut4 (120). They observed a significant dose-dependent decrease in insulin-stimulated glucose uptake in 3T3-L1 adipocytes treated with indinavir. Moreover, after indinavir was removed, the normal insulin response to glucose was rapidly restored. The effect of other protease inhibitors was similar, which suggests that the inhibition of glucose uptake is a general property of these drugs. To

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determine whether protease inhibitors directly affect the intrinsic transport activity of glucose transporters, Glut1 and Glut4 isoforms were expressed and analysed in Xenopus laevis oocytes. Indinavir had no effect on Glut1 transport activity, whereas Glut4 activity was significantly inhibited. The same authors reproduced the effect on glucose transport with other protease inhibitors. Interestingly, the knockout mice for Glut4 are almost devoid of fat tissue, their cells respond poorly to insulin and they are prone to developing a type-II diabetes (121). If peripheral adipocytes preferentially synthesize lipid de novo from blood glucose, while abdominal adipocytes obtain their lipid primarily from circulating tryglicerides, the protease inhibitors may account for the clinically observed lipodistrophy as well as for the resistance to insulin. The physiological in vivo relevance of this mechanism needs to be studied further. Another hypothesis regarding the ability of PIs to inhibit human enzymes involved in insulin degradation has been suggested (89), but there are no data to confirm it. Whatever the mechanism, a variety of evidence supports the involvement of PIs in metabolic derangements: (1) The initiation of PI has been linked to an increase in glucose, insulin, triglycerides, and total and LDL cholesterol (78, 93, 122); (2) The prevalence of the lipodystrophy syndrome is greater in cohorts that take PIs than those on PI-sparing regimens (82, 84); (3) The duration of PI use is a contributing factor in the appearance of the syndrome (79, 123); (4) Metabolic abnormalities associated with potent antiretroviral regimens including PIs may revert, at least partially, after the PIs are replaced by nevirapine (124); (5) Administrating ritonavir for 14 days increases triglycerides, Lp(a) and apoprotein B in HIV-seronegative subjects (125); and (6) Normal subjects without HIV infection develop insulin resistance when given indinavir monotherapy for 4 weeks (126). However, the PI theories cannot overcome the fact that some of these metabolic alterations, particularly those concerning lipid metabolism, existed prior to the era of protease inhibitors. Moreover, the main criticism of the etiologic hypotheses involving PI therapies is the growing evidence documenting metabolic abnormalities in PI-naive patients (111, 127–131).

Theories involving NRTIs Therefore, another recently suggested mechanism involves the potential relationship between lipodystrophy and mitochondrial toxicity that is the result of nucleoside reverse transcriptase inhibitors (NRTIs) inhibiting DNA polymerase gamma, which is used in mitochondrial DNA replication (132). Although serious toxicity related to mitochondrial dysfunction has been recognised for these drugs (lactic acidosis [123], myopathy, polyneuropathy, cardiopathy), the link between these

alterations and lipodystrophy is less clear. In fact, this link is indirectly based on a resemblance to a congenital lipodystrophy syndrome (Madelung’s syndrome) that includes the accumulation of fat in the neck, shoulders and mediastinum and the loss of fat in the extremities, hypertriglyceridemia and insulin resistance, and which may involve similar mitochondrial alteration (133). However, there are a number of physical differences between both syndromes, particularly in relation to the accumulation of truncal fat, which is not a feature of Madelung’s syndrome. Also, although the mitochondrial DNA concentration has decreased in cultured cells exposed to NRTIs (134) and in the muscle of patients with zidovudine-induced myopathy (135), this hypothesis has not yet been proven.

Other potential mechanisms Finally, it can be hypothesised that the human immunodeficiency virus itself is the direct cause of the metabolic alterations, which are expressed more strongly as a result of improved nutritional and clinical status and longer survival. This hypothesis cannot be excluded, since glucose and lipid metabolism were not systematically studied in the pre-HAART era. Moreover, it appears that lipodystrophy syndrome occurs more frequently in patients with an optimal response to antiretroviral therapy (129, 131). In this context, we can hypothesise that some immunological changes or perhaps changes in the anabolic signals secondary to a positive energy balance may be needed to reproduce these metabolic alterations. A provocative possibility is that the changes are the result of the activation of inflammatory cytokine production during effective antirretroviral therapy. Prior to the HAART era a number of studies reported increased levels of proinflammatory cytokines such as TNFa or its soluble receptors, particularly in the advanced stages of the disease (46, 61, 136–140). These increases were not supported in other studies however (52, 60), and production was even reported to decrease (141). It must be remembered that tumor necrosis factor can reduce lipoprotein lipase activity (142), and adipocyte glucose uptake via Glut4 (143), and modify the hormone-sensitive lipase activity (144). The increased production of TNF and other pro-inflammatory cytokines may therefore explain the lipid abnormalities and insulin resistance of these patients, especially those who achieve a positive energy balance. Theoretically, TNF may also contribute to fat wasting by triggering the production of leptin (145), inhibiting adypocite differentiation (146) and inducing apoptosis (147), and to bone alterations by stimulating osteoclast activity and inhibiting osteoblast function (148). Supporting this theory, Ledru et al. have reported that HAART is associated with a progressive accumulation of T-cells that produces TNFa secondary to the immune

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restoration achieved with the treatment (149). Also, this accumulation of proinflammatory cells has been proven to be linked to the plasma lipid parameters usually altered in the lipodystrophy syndrome (149). Similarly, after an initial reduction, TNFa concentrations seemed to increase several months after therapy with zidovudine was begun (150). Supporting this theory, elevated serum levels of the soluble TNF receptor type 2 have been reported to be strongly associated with diminished insulin sensitivity in lipodystrophic patients (151). In addition, bone metabolism alterations have been shown to be positively associated to the TNF system activity (105). Recently, it has been shown that a polymorphism at the 7308 position of the TNFa gene is more frequent in lipodystrophy patients than in non-lipodystrophy patients (152), which suggests that there may be a genetic component to the development of lipodystrophy. However, the frequency of the mutant allele seems too low to be the only explanation for these abnormalities. The theory that chronic inflammatory response is a contributing factor in metabolic alterations has been suggested in obesity, where a certain degree of hypercor-

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tisolism has been described (153). The urinary excretion of free-cortisol (79) and the serum levels of this hormone (154, 155) have been found to increase in AIDS patients either before or after the HAART era. Moreover, several authors have reported a decrease in DHEA levels in AIDS patients with (155) and without (154) lypodistrophy. Both factors can increase lipoprotein lipase activity, and so favour lipolisis and insulin resistance.

Conclusions HIV infection is a complex and progressive disease in which several factors (HIV itself, opportunistic infections, the host’s immune response, and antiretroviral therapies) are able to mediate metabolic changes either directly or indirectly. The multiple interactions between these factors (Fig. 2), combined with the predisposition of the individual, may partly explain the differences in metabolic abnormalities (e.g. the heterogeneous expression of the lipodystrophy syndrome) that have been reported since the disease began. As the metabolic

Fig. 2 Etiologic factors behind the metabolic alterations associated to the AIDS lipodystrophy syndrome. Cytokines produced in response to HIV infection during the immunologic restoration secondary to antiretroviral drugs may determine the development of metabolic alterations associated to the lipodystrophy syndrome. Protease inhibitors and nucleoside-analogs may contribute to these lipid and glucose metabolic abnormalities either indirectly, through the immunologic improvement secondary to an effective antiretroviral therapy or directly by affecting cell differentiation, lipid and glucose metabolism in adipose or muscle cells, or by inducing mithocondrial damage. Some patients probably have a special genetic predisposition to developing these metabolic alterations associated to the lipodystrophy syndrome. In fact, HIV-infected patients who present a mutation in the beta-3-adrenergic receptor gene are at a greater risk of developing the syndrome (158) and it has been suggested that ApoE polymorphism affects PI-associated lipid abnormalities in HIV patients (159). Moreover, race and gender act as predisposing factors behind these metabolic abnormalities. The multiple interactions between all the factors represented in this figure may explain the heterogeneity of the metabolic and morphologic expression of the lipodystrophy syndrome.

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puzzle of HIV-infection is still incomplete, we must stress the importance of determining the causes and consequences of the metabolic alterations associated to HIV infection. Only by knowing the physiopathology of these alterations we will be able to propose effective therapies, and so reduce the risk associated with them, lower the rate of mortality and improve the quality of life of HIV-infected patients.

Acknowledgements This work has been supported in part by a grant from the Fondo de Investigaciones Sanitarias de la Seguridad Social (FISS no. 96/0040/ 41/42).

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Submission date: 21 November 2000 Accepted: 8 March 2001 Published online: 5 July 2001