INTRODUCTION
Morphological changes attributed to HIV therapies challenge the optimal management of HIV infection. Disfiguring loss or accumulation of regional fat can be distressing to patients-threatening commitment to HIV therapy and jeopardizing the confidentiality of HIV status.1,2 Furthermore, the fear of body shape changes may contribute to patient reluctance to initiate HIV therapy when such treatment is clinically indicated. Last, morphological changes often occur within the context of other potentially related metabolic disturbances, including dyslipidemia and disorders of glucose homeostasis, that increase the risk of cardiovascular disease.3
The major morphological changes observed among patients receiving combination antiretroviral therapy (ART) can be grouped into 2 major categories: lipoatrophy (selective fat loss of the subcutaneous adipose tissue of the limbs, face, and/or abdomen) and lipohypertrophy (accumulation of visceral abdominal, dorsocervical, and/or breast adipose tissue). Significant loss and accumulation of fat were once thought to be closely linked as a syndrome of fat redistribution, but observational and clinical trial data indicate that they generally occur independently4-6; both have been observed to develop during combination ART. However, there are important differences in the associations between each type of change and specific medications, which will be described later in detail. In addition to these pathological body shape changes, generalized obesity is also prevalent among HIV-infected persons in the United States.7 Being overweight or obese in many cases is a result of high caloric intake relative to energy expenditure-an imbalance that can be facilitated by improvements in appetite and sense of well-being after initiation of HIV therapy. Although not a focus of this review, obesity in the HIV infected, as in the general population, raises a number of important health concerns.
Central to the development of interventions to reverse undesirable changes in body shape during HIV therapy is an understanding of their causes. We will review the proposed etiologies of these changes and evidence-based approaches to their management. Given that data suggest that lipoatrophy and lipohypertrophy have different etiologies and require distinct therapies, these disparate changes in fat distribution are discussed individually.
LIPOATROPHY
Etiology
The association between specific antiretroviral exposure and morphological change is strongest for lipoatrophy. Although several patient-level characteristics including advanced immunodeficiency, higher HIV viral load, older age, white race, low body mass index, and longer duration of HIV therapy have been associated with greater risk of lipoatrophy,8 a leading role of the nucleoside reverse transcriptase inhibitors (NRTIs), particularly stavudine, in this morphological change has been clearly confirmed during prospective observational and comparative clinical studies.8-11 More recently, it has been demonstrated that lipoatrophy also occurs during treatment with zidovudine, another thymidine analog. In the GS934 trial, a comparison of zidovudine/lamivudine versus tenofovir/emtricitabine coadministered with efavirenz in treatment-naive patients, reductions in limb fat during study weeks 48-96 were observed in those receiving zidovudine, whereas increases in limb fat were noted in those receiving tenofovir,12 suggesting that the zidovudine-sparing combination may be less associated with the development of lipoatrophy. Limb fat losses appear to be relatively less common and less severe during exposure to zidovudine compared with stavudine. In the AIDS Clinical Trials Group (ACTG) Study A5142, treatment-naive participants were randomized to 1 of 3 study arms: 2 nucleoside analogs plus efavirenz and lamivudine, 2 nucleoside analogs plus lopinavir/ritonavir and lamivudine, or a regimen of only efavirenz plus lopinavir/ritonavir. The nucleoside/tide analogs permitted in the 2 arms containing this class of ART were stavudine, zidovudine, and tenofovir. Clinically significant limb fat loss (defined a priori as a 20% change from baseline to 96 weeks) was more common among patients taking stavudine versus zidovudine (odds ratio 1.9, P = 0.029) regardless of whether the regimen included efavirenz or lopinavir/ritonavir (Fig. 1). Tenofovir produced the lowest rate of significant limb lipoatrophy.13
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FIGURE 1: Change in median percentage of extremity fat from baseline to 96 weeks in patients treated with efavirenz, lopinavir/ritonavir, or a combination of both in the A5142 study. Adapted from Haubrich et al.
13Importantly, A5142 also found that peripheral lipoatrophy was more likely during treatment with efavirenz compared with lopinavir/ritonavir. This unexpected finding persisted regardless of concomitant nucleoside/tide and suggests that either the nonnucleoside reverse transcriptase inhibitor (NNRTI) potentiated the fat-wasting effect of the companion nucleoside/tide or that the protease inhibitor was protective against this effect. Interestingly, average limb fat volume was observed to increase during the study in the group receiving efavirenz and lopinavir/ritonavir alone.13 Further evidence of a protective role for ritonavir comes from the results of a clinical trial that compared the protease inhibitor atazanavir with and without pharmacological boosting with ritonavir in ART-naive HIV-infected patients who also received lamivudine and an extended-release formulation of stavudine. Among the 129 patients undergoing body shape evaluations, a net loss of limb fat from baseline was observed at 96 weeks of treatment by dual-energy x-ray absorptiometry (DEXA) scanning in both study groups, but the change was significantly less among those receiving ritonavir.14
These results contrast with epidemiological studies conducted before 2000, which found that the use of protease inhibitors contributes to fat wasting; however, these studies were largely limited to the study of older drugs of this antiretroviral class, including indinavir, saquinavir, and nelfinavir-taken without ritonavir.8,15 This association between older protease inhibitor use and lipoatrophy is mirrored in the findings of a substudy of ACTG Study 384, a randomized clinical trial that showed that nelfinavir was associated with greater fat loss than efavirenz in ART-naive participants who also received 2 NRTIs.16
Although the association between antiretrovirals and lipoatrophy has become clearer, the mechanism(s) by which these drugs exert their effects on fat remains to be fully elucidated. NRTIs have been observed to impair, to varying degrees, the γ-polymerase of mitochondrial DNA (mtDNA), an enzyme integral to cellular replication.17-20 In vitro investigations have demonstrated that depletion of this enzyme has been associated with adipocyte apoptosis; other work has demonstrated ultrastructural changes within the fat cells.21,22 In addition to direct mtDNA toxicity, some NRTIs may have an influence on other factors that can contribute to fat cell wasting including deleterious effects on mitochondrial oxidative phosphorylation and RNA transcription.23 Impairment of adipocyte differentiation has been demonstrated in patients with lipoatrophy and exposure to NRTIs and protease inhibitors.24 Some work suggests that this is a result of a number of factors including ART-induced expression of tumor necrosis factor-α which is known to promote adipocyte apoptosis, expression of other proinflammatory cytokines, and dysregulation of the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c).24,25
There are very limited data regarding the effects of NNRTIs on adipocytes. One study found that efavirenz reduced lipid stores in differentiating and mature adipocytes and, at increasing concentrations, induced a decrease in gene and protein expression of SREBP-1c in the mature adipocytes, thereby reducing stores of cellular lipids. This inhibition of SREBP-1c expression was accompanied by a reduction in the expression of SREBP-1c target genes26 and could, in concert with other changes in adipocyte function, explain the reason for the increased risk of lipoatrophy with efavirenz use.
Interventions
Interventions that have been found to reverse lipoatrophy during HIV therapy are listed in Table 1. The clinical evidence linking stavudine and pathological fat loss, later supported by epidemiological comparative treatment and in vitro studies, has provided an obvious intervention to halt or reverse lipoatrophy-eliminating the stavudine. A series of substitution studies have demonstrated gains in limb fat after the discontinuation of stavudine. Specifically, a 35% gain in limb fat over 2 years was observed after the substitution of stavudine or zidovudine with abacavir (MITOX Study)27 and a 12%-35% increase in limb fat at 48 weeks was produced after switching from stavudine to abacavir (TARHEEL Study).28 Switching from thymidine analogs to tenofovir has been found to be as efficacious as a change to abacavir (RAVE Study).29 In a cohort with a median baseline limb fat mass of 6 kg, exchanging an NRTI-containing ART combination for an NRTI-sparing regimen of lopinavir/ritonavir and efavirenz was found to produce a 562 g increase in appendicular fat over 48 weeks, compared with a 242 g loss among those randomized to efavirenz and dual NRTI therapy (P = 0.086).30 Limited data regarding the switch from zidovudine to alternative agents suggest that such an approach can also lead to reversal of limb fat wasting; this evidence, combined with data demonstrating limb fat loss during initial treatment with zidovudine-containing regimens,29,30 has led some clinicians and patients to avoid use of this thymidine analog when possible.
TABLE 1: Interventions for Morphological Changes During HIV Therapy Demonstrated to Be Efficacious
In each of the switch studies, the fat changes, as demonstrated by imaging studies, were modest in extent and subjective evaluation of changes in body shape was less evident. At the least, ART switch strategies appear to halt further worsening of lipoatrophy. The potential benefits of manipulating ART to counter lipoatrophy must be weighed against the potential risks of adverse effects from a new medication and loss of virological control. Any preexisting antiretroviral resistance or comorbid diseases, drug-drug interactions, cost considerations, regimen convenience, or other relevant factors must be considered before modification of ART.
Aside from ART switching, a number of pharmacological interventions for lipoatrophy during HIV treatment have been studied. These have been more likely to reveal which therapies to avoid rather than those to adopt. For example, some studies of testosterone supplementation,46 metformin,35,47,48 and recombinant growth hormone (rGH)49 have found that these agents are of limited value in expanding limb fat and in some cases can reduce subcutaneous fat, potentially worsening lipoatrophy. In contrast, 3 interventions have shown initial promise: pioglitazone, uridine, and pravastatin.
Recognition of the role of the transcription factor peroxisome proliferator-activated receptor-γ in adipocyte differentiation led to investigations of the thiazolidinedione class of peroxisome proliferator-activated receptor-γ activators as a treatment for HIV-associated morphological changes. Studies of rosiglitazone have produced mixed results.48,50-52 The largest clinical trial of this agent demonstrated some increase in limb fat during study treatment, but this was not significantly different from the gains observed with placebo.53 A randomized study of pioglitazone in 130 patients with self-reported and clinician-confirmed lipoatrophy produced more encouraging results, with a 380 g increase in limb fat demonstrated by DEXA scanning at 48 weeks of treatment compared with a negligible 5 g increase in the placebo group (P = 0.051). The results were more impressive among those participants no longer receiving stavudine, where a 450 g increase in appendicular fat was observed. At a dose of 30 mg daily, pioglitazone was reported to be well tolerated.31 Although presented in 2006, these results have yet to be published or reproduced in another clinical trial.
In these relatively small clinical trials among HIV-infected patients, rosiglitazone and pioglitazone have been generally well tolerated. However, in the general population, there are notable adverse effects that should be considered before recommending these medications for HIV-infected patients. Both pioglitazone and rosiglitazone cause fluid retention and are contraindicated in patients with congestive heart failure.54,55 Recent data have shown that these agents have differential effects on cardiovascular risk. Rosiglitazone is associated with a 43% increased risk of myocardial infarction compared with patients randomized to other therapies in a recent meta-analysis,56 whereas another meta-analysis of randomized trials comparing pioglitazone with other diabetic treatments showed an 18% reduced risk of death, myocardial infarction, or stroke in those patients randomized to pioglitazone.57 Some of these differences may be due to differential effects of the 2 agents on lipid metabolism. In addition, both rosiglitazone and pioglitazone may be associated with reductions in bone mineral density and subsequent risk of fractures in some populations.32 The magnitude of this association is currently under intense investigation.
The nucleoside uridine has been found to attenuate mitochondrial toxicity in adipocytes and hepatocytes exposed in vitro to stavudine and zalcitabine.33,34 Clinical study of dietary supplementation with uridine has been limited to 2 pilot studies, including a small placebo-controlled randomized trial of 20 patients with lipoatrophy receiving thymidine analogs. This study found that 36 g of the supplement 3 times a day for 10 consecutive days each month for 3 months produced significant gains in DEXA-determined limb fat compared with placebo (880 vs 230 g, P < 0.05). Intra-abdominal fat, but not liver fat, also increased.58 A single-arm study among patients receiving stavudine found that uridine, administered as 36 g every other day for 16 weeks, improved subjective appreciation of lipoatrophy (objective evaluation of regional fat was not performed) but did not alter fat or peripheral blood and mononuclear cell mtDNA content. The lack of an effect of uridine on adipocyte mtDNA in this study is unexplained and illustrates the currently incomplete understanding of how this agent acts. It has been proposed that, as a pyrimidine, uridine or its metabolites simply compete with antiretroviral pyrimidine analogs at the mitochondrial polymerase-γ or other critical steps of mtDNA replication.59 Supplementation of uridine may also reverse NRTI-induced intracellular depletion of endogenous pyrimidines, which in and of itself promotes preferential NRTI uptake by cellular enzymes and has been found to be associated with cell cycle arrest and apoptosis.59 This latter effect provides an explanation for evidence from clinical studies showing an absence of an impact on fat mtDNA content, yet improvement in overall fat content. A larger clinical trial of uridine for the treatment of lipoatrophy is currently being performed by the US ACTG.60 Uridine is currently available as a dietary supplement, marketed under the name NucleomaxX®.61
Last, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin (40 mg per day) was found to significantly increase limb fat over 12 weeks in men with elevated total cholesterol, although on a protease inhibitor-based regimen in a small (n = 33) randomized placebo-controlled trial. Dual-energy x-ray absorptiometry-assessed limb fat increased 720 g with pravastatin compared with 190 g with placebo (P < 0.04); subcutaneous, but not intra-abdominal, abdominal fat also significantly increased with the study drug compared with placebo.62 The mechanism by which this statin increased subcutaneous fat is not known, and these findings have yet to be replicated.
The absence of a therapeutic intervention to reverse lipoatrophy has led to reliance on reconstructive procedures, particularly those that fill the areas of facial fat tissue loss.63 Polylactic acid has been reported to produce lasting changes in dermal thickness of the cheeks with minimal adverse effects and has become a popular option.41 There are fewer data regarding the safety and efficacy of other fillers.
LIPOHYPERTROPHY
Etiology
Although lipohypertrophy was the first morphological change ascribed to combination HIV therapy, compared with lipoatrophy, considerably less is understood regarding the etiology of regional lipohypertrophy in ART-receiving patients. In contrast to the strong associations between individual ART agents and fat wasting, intra-abdominal lipohypertrophy has been observed with disparate HIV regimens, including those containing protease inhibitors and NNRTIs, with and without NRTIs (Fig. 2). For example, in ACTG Study A5142, significant gains in trunk fat were observed in each of the 3 treatment arms (protease inhibitor-based, NNRTI-based, and NRTI-sparing) and were similar in magnitude.13 Likewise, a study comparing efavirenz and non-ritonavir-boosted protease inhibitor atazanavir, when coadministered with zidovudine and lamivudine, found nearly identical changes in regional fat, including trunk fat.64 A near-universal increase in abdominal fat after initiation of potent HIV therapy is also supported by the findings of an ACTG 384 Trial substudy, where overall median trunk fat increased by 1.1 kg over 144 weeks with gains seen across study groups, including those with nelfinavir and/or efavirenz in addition to 2 NRTIs.16
FIGURE 2: Change in percentage of trunk fat from baseline to end point reported in clinical trials of initial treatment regimens for patients in the A5142 study. Adapted from Haubrich et al.
13Further evidence of a generalized effect of ART on abdominal fat is provided by the Multicenter AIDS Cohort Study, where increases in abdominal girth among HIV-infected and -uninfected men were observed over time but the rate of increase was greater among the infected men, who had smaller body circumferences at baseline.65 These results suggest that HIV therapies may improve health and return abdominal fat relatively rapidly to premorbid levels.
Almost all large comparative ART clinical trials have used whole-body DEXA scanning to evaluate regional fat. However, DEXA does not distinguish between subcutaneous and visceral adipose tissue, so it has been unclear whether increases in abdominal girth are a consequence of accumulation of visceral fat, subcutaneous fat, or both. Given case reports of massive visceral lipohypertrophy during HIV therapy, expansion of this compartment was assumed to be responsible for gains in waist circumference. Two of the previously described trials that examined the drug atazanavir (atazanavir vs efavirenz and atazanavir vs atazanavir/ritonavir) included DEXA and abdominal computed axial tomography (CT) scanning.14,64 In both studies, the 2 imaging techniques were concordant, registering increases in both visceral adipose tissue and general trunk fat. However, a recently presented trial comparing the ritonavir-boosted protease inhibitors tipranavir and lopinavir, in which both DEXA and CT scans were also performed, found that subcutaneous and not visceral fat increased during the first year of HIV treatment; this effect highlights a need to apply caution when assuming that gains in trunk fat during HIV therapy are due to visceral adipose hypertrophy.66
A number of risk factors for lipohypertrophy have been identified, which are similar to those reported to be associated with lipoatrophy.8 Derived from epidemiological studies, these risk factors should be interpreted with caution given the design limitations inherent in such studies (ie, retrospective, nonrandomized, select cohorts). The early attention paid to the protease inhibitors and their effects on adipocytes are being reexamined in light of more recent data implicating protease inhibitor-sparing regimens in abdominal fat increases.4,13 Several theories regarding the pathogenesis underlying regional fat accumulation have been proposed, but no unifying mechanism has been accepted, and many investigators have finally concluded that the etiology of this complication is multifactorial. Abnormalities in levels of adiponectin, growth hormone, and proinflammatory cytokines36 have been associated with lipohypertrophy in patients with HIV infection, but whether they are a cause or consequence of fat accumulation remains unclear.8,25,37,38 The same holds true for 11-β-hydroxysteroid dehydrogenase type-1, an enzyme that catalyzes cortisone to active cortisol, which in turn promotes adipocyte differentiation.8
Interventions
Substitution of ART has been found to have had limited impact on lipohypertrophy-an unsurprising result given that this morphological change has been observed during treatment with a variety of antiretroviral regimens. As such, substitution of HIV medications to reduce regional fat accumulation cannot be advocated.39
A number of clinical trials of potential therapeutic interventions have been conducted, but none have provided robust support for any particular agent (Table 1). Metformin can reduce weight and central obesity in individuals who are not HIV infected but has been inconsistently demonstrated to reduce visceral fat in HIV-infected patients. In 2 small studies of patients with moderate-to-severe insulin resistance and abdominal fat accumulation, metformin was found to reduce visceral fat by a median of 6%-37% and to improve insulin sensitivity.40,47 Similarly, visceral fat decreased by a median of 13% in a study of 18 patients with abdominal lipohypertrophy who were not required to have insulin resistance.67 However, in a randomized placebo-controlled trial of 48 patients with increased abdominal girth on HIV therapy who received 1500 mg of metformin daily over 24 weeks, the 10% decline in visceral abdominal adipose volume was almost identical to that observed in the placebo group after controlling for age, height, baseline visceral adipose tissue, and insulin resistance.35 Another trial found that aerobic and resistance exercises in conjunction with metformin reduced waist-to-hip ratio significantly more than metformin alone. Yet there was no significant difference between study arms in the change in visceral fat volume, and the median change in central fat actually increased slightly in the metformin-alone arm. Of note, subcutaneous abdominal fat dropped significantly in the combination exercise-metformin group,42 and loss of subcutaneous fat, including limb fat, has been seen with metformin.35,67 Collectively, these limited studies suggest that metformin probably has a modest effect on visceral fat and that those patients with glucose intolerance, insulin resistance, or diabetes mellitus may obtain the greatest benefit from this medication. However, metformin should be used with caution, if at all, in those patients with concomitant lipoatrophy.39
From an efficacy standpoint, no pharmacological intervention has a greater impact on visceral and dorsocervical fat volume than rGH. Several small studies using various (generally high) doses of rGH have demonstrated reductions in visceral and dorsocervical fat in HIV-infected patients.43 The most recent and largest trial examined an induction and then maintenance strategy of 4 mg/day of rGH for 12 weeks followed by 2 mg/every other day for an additional 24 weeks. ART-receiving patients (n = 326) with high waist-to-hip ratios were enrolled in this placebo-controlled randomized trial during which CT and DEXA scanning were performed. At the end of the induction period, visceral fat volume fell 20% in those receiving rGH; however, 40% of those who lost visceral fat after induction regained at least 50% of this loss during the lower dose maintenance phase. Overall, at the end of 36 weeks of treatment, the change in visceral fat between subjects continuously receiving rGH and those assigned to continuous placebo was not significantly different. Subcutaneous abdominal and limb fat also fell significantly during rGH induction, but by week 36, the difference from baseline diminished and was not statistically different from placebo.49 At the relatively high doses of rGH studied, the drug can be difficult to tolerate due to arthralgias, peripheral edema, and carpal tunnel syndrome, leading to treatment discontinuation rates of 15%-17% during the trials.43,49 The expense and lack of an approved indication for the treatment of HIV-associated lipohypertrophy have severely limited access to the drug.
Recently, tesamorelin, an analog of growth hormone-releasing factor that increases the pituitary secretion of growth hormone, has been studied in a trial of 412 HIV-infected patients with a waist circumference of at least 95 cm and waist-to-hip ratio of at least 0.94 for men and a waist circumference of at least 94 cm and waist-to-hip ratio of at least 0.88 for women. Visceral adipose tissue, as assessed by CT scanning, declined by 15% over 26 weeks in the treatment group compared with a 5% increase in the placebo-assigned arm (P < 0.001). Subcutaneous and limb fat increased in both study groups but tended to be greater in the placebo-assigned group. Triglyceride levels were observed to decline and high-density lipoprotein cholesterol increase with growth hormone-releasing factor. Although arthralgias, peripheral edema, and injection site reactions were not significantly more common among those on active drug compared with placebo, a greater proportion of subjects receiving growth hormone-releasing factor experienced an adverse event leading to treatment discontinuation (12.1% vs 2.9%, P = 0.002).37 Further studies of this drug are ongoing.
Reconstructive surgical procedures to correct physical abnormalities associated with lipohypertrophy, including liposuction of regional fat accumulation, have been attempted in HIV-infected individuals. Most reports describe initial improvements in appearance, especially of dorsocervical fat pad enlargement, but subsequent reaccumulation of fat is not uncommon.44 Longer lasting reductions in visceral and subcutaneous abdominal fat have been accomplished with exercise and diet interventions. Small studies suggest that diets low in saturated fats and high in fiber, when combined with regular rigorous aerobic and weight training exercises, can reduce and even prevent abdominal fat accumulation during HIV therapy. An additional benefit of dietary and exercise interventions is reduction of both visceral and subcutaneous abdominal fat accumulation,45,68-70 both of which are causes of increased abdominal girth that are difficult to distinguish clinically.
SUMMARY
The association between alterations in regional fat and other serious metabolic disorders serves to warn HIV-infected individuals and their clinicians that the consequences of morphological changes during HIV infection extend beyond cosmetic concerns. Strategies to prevent and treat these changes hinge on an understanding of the etiologies of changes in regional fat during the treatment of HIV; however, for both lipoatrophy and lipohypertrophy, the clinical and laboratory data indicate that unifying mechanisms underlying these changes in fat depots are unlikely to be found. Rather, these complications appear to be a consequence of complex and multifaceted pathological processes influenced by host-, disease-, and treatment-level factors. It is also increasingly evident that fat accumulation and wasting have different etiologies and treatment approaches and should be considered separately.
A variety of interventions to reverse morphological changes have been studied-many based on putative etiological mechanisms-but most have proved ineffective. Those interventions that have produced positive results require additional careful study using appropriate outcome measures. Finally, as new drugs to treat HIV infection are developed and adopted, early attention to their effects on morphology are essential to the informed use of these agents.
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