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Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy

Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy
Literature review current through: Jan 2024.
This topic last updated: May 24, 2022.

INTRODUCTION — Prior to the availability of effective antiretroviral therapy (ART), severe wasting and decreased levels of cholesterol were common metabolic abnormalities described in advanced acquired immunodeficiency syndrome (AIDS) [1]. With the introduction of effective ART, descriptions of patients with body shape abnormalities such as central fat accumulation and peripheral fat loss emerged [2,3]. The term "human immunodeficiency virus (HIV)-associated lipodystrophy syndrome" was coined, but it soon became clear that there was not a single syndrome but rather the co-occurrence of phenotypes that varies from person to person. It may be that some individuals will present with pure lipoatrophy, others have fat accumulation which may present in a variety of ways, and a subset of patients have a mixed picture of both morphologic features [4-8]. Thus, it is more valid to consider the individual components separately. These morphologic abnormalities can also be associated with disorders in glucose and lipid metabolism [9-11].

Risk factors, clinical manifestations, and diagnosis of HIV-associated lipodystrophy will be discussed here. The management and treatment of these patients is discussed elsewhere. (See "Treatment of HIV-associated lipodystrophy".)

The association between lipodystrophy and metabolic abnormalities is also discussed briefly in this topic. Additional detail on the epidemiology and management of dyslipidemia and disordered glucose metabolism in patients with HIV is found elsewhere. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV" and "Management of cardiovascular risk (including dyslipidemia) in patients with HIV".)

PREVALENCE — Controversy exists about how frequently the lipodystrophy syndrome occurs, with estimates ranging from 10 percent to more than 80 percent [12-15]. The wide variation in prevalence may be partly related to differences in definitions or methodology (eg, patient report versus objective measurements) as well as differences in host factors, including geography, age, genetics, lifestyle factors, and specific antiretroviral use and duration of treatment [16-18]. The presumption is that the prevalence will be lower with the increased use of newer antiretroviral drugs, which are much less prone to contribute to this disorder, but there are few studies looking at the contemporary prevalence of the syndrome [19].

Moreover, lipoatrophy and fat accumulation appear to be different syndromes with different risk factors and differing prevalences. This point was well illustrated in one study of 452 patients with HIV who were followed over one year to assess risk factors for progression of morphologic abnormalities [16]. Lipoatrophy was defined as a triceps skin-fold measurement less than the 10th percentile in the National Health and Nutrition Examination Survey for sex and age. Fat accumulation was defined as a waist-to-hip ratio of >0.95 for men and of >0.85 for women as a surrogate for intra-abdominal fat. The study demonstrated the following:

The baseline prevalence for lipoatrophy, fat deposition, and a mixed picture was 35, 44, and 14 percent, respectively.

The risk of developing new lipoatrophy was increased in patients with low baseline triceps skin-fold values and smaller hips; higher HIV ribonucleic acid (RNA) levels and use of abacavir or stavudine were also predictors of risk. Abacavir is not generally thought to induce lipoatrophy, so this apparent association may represent attempts by clinicians to change antiretroviral therapy to agents thought less likely to contribute to lipoatrophy. (See 'Risk factors' below.)

By contrast, the risk of fat deposition was greater in women and occurred more frequently among those study participants who had higher levels of body fat or higher triglyceride levels at baseline. (See 'Risk factors' below.)

The discussion below will address both lipoatrophy and fat accumulation as two separate and distinct entities.

LIPOATROPHY

Risk factors — While fat atrophy is difficult to quantify, it is quite easily recognized. The main risk factor for lipoatrophy is exposure to thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs), predominantly stavudine, but also zidovudine. The risk with other agents or classes of antiretroviral therapy (ART), such as protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs), is less evident in the absence of concurrent thymidine analogue use. HIV disease severity (such as baseline CD4 cell count and viral load) and certain host factors (age, baseline body type) may also influence the risk of lipoatrophy.

Exposure to NRTIs — Data suggest that exposure to certain nucleoside reverse transcriptase inhibitors (NRTIs) is the major factor associated with lipoatrophy [5,12,16,20-24]. Trials comparing different antiviral regimens suggest that thymidine analogs (in particular stavudine, but also zidovudine) play an important role in pathogenesis of lipoatrophy [21,22,25-29]:

In an open-label trial in which 237 patients with HIV initiating antiretroviral therapy (ART) were randomly assigned to abacavir or stavudine, each combined with lamivudine and efavirenz, a higher proportion of patients taking stavudine developed clinical signs of lipoatrophy (38 versus 5 percent with abacavir) as assessed by anthropometric measurements at 96 weeks [25].

In a trial comparing stavudine and tenofovir disoproxil fumarate (TDF), each in combination with lamivudine and efavirenz, patients randomly assigned to tenofovir demonstrated normal limb fat at 144 weeks of therapy compared with a significant decline in lower limb fat mass in nearly 50 percent of patients receiving stavudine [22].

In a subset of patients participating in an open-label randomized trial comparing TDF-emtricitabine and zidovudine-lamivudine, each in combination with efavirenz, total limb fat at week 48, as measured by dual energy x-ray absorptiometry (DEXA), was less with zidovudine than tenofovir (mean 6.9 versus 8.0 kg fat) [29].

DEXA scans were also performed every 16 weeks on a subset of 157 antiretroviral-naïve patients who were randomly assigned to nelfinavir, efavirenz, or both, combined with zidovudine and lamivudine or stavudine and didanosine [27]. After week 32, limb fat declined by 2 percent per year in the zidovudine plus lamivudine arm compared with 19 percent per year in the stavudine plus didanosine arm.

Other studies have only noted an association between lipoatrophy and duration of NRTI use [30,31]. The risk of lipoatrophy with thymidine analogue use may be due to NRTI-induced inhibition of mitochondrial deoxyribonucleic acid (DNA) polymerase gamma and mitochondrial toxicity. Surgical biopsy specimens of subcutaneous adipose tissue in patients with lipoatrophy are characterized by mitochondrial DNA depletion, inflammation, and signs of apoptosis [32,33]. Neither stavudine nor zidovudine is recommended for use in patients with HIV. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Other considerations for regimen selection'.)

Exposure to other ART classes — Agents from antiretroviral classes other than the NRTIs have been associated with lipoatrophy in some studies, although mainly because of concurrent use with offending NRTIs. Some studies have suggested that although NRTI use contributes to fat wasting, protease inhibitors may act synergistically with NRTIs [23,24]. However, therapy with protease inhibitors alone does not appear to lead to lipoatrophy [8]. Similarly, in a metabolic substudy of a trial evaluating various ART regimens (ACTG 5142), the incidence of lipoatrophy was higher with efavirenz plus two NRTIs compared with lopinavir plus two NRTIs or efavirenz plus lopinavir, but the association between efavirenz and lipoatrophy was mainly in combination with stavudine or lamivudine, not TDF [34]. Other studies have also suggested that the role of efavirenz in the development of lipoatrophy is minimal and mainly directed by the nucleoside analogs that form the backbone [35]. Other studies suggest that integrase inhibitors do not contribute to lipoatrophy [36,37]. Risk of limb-fat loss with rilpivirine appears similar to that with efavirenz [38].

Host and viral factors — HIV disease severity and certain host factors may interact to result in lipoatrophy. Characteristics that have been associated with lipoatrophy, either self-reported or objectively measured, include increased age, lower fat mass at baseline, higher baseline viral loads, and lower CD4 cell counts at initiation of HIV therapy [16,39,40]. However, not all studies using objective measurements of lipoatrophy have confirmed a link with age or lower CD4 cell counts [41,42].

Although fat atrophy is often associated with weight loss, there is no apparent association with nutrition status.

There has also been an epidemiological association between coinfection with hepatitis C virus (HCV) and the development of lipoatrophy in individuals with HIV [43].

Clinical features — Lipoatrophy involves the loss of subcutaneous fat in the face, arms, legs, abdomen, and/or buttocks [16,17,44]. In contrast to AIDS-associated wasting, lipoatrophy is distinguished by the preferential loss of subcutaneous fat tissue without substantial loss of lean tissue mass in patients who are clinically responding to ART [5,45].

Facial lipoatrophy is characterized by loss of the buccal and/or temporal fat pads, leading to facial skeletonization with concave cheeks, prominent nasolabial folds, periorbital hollowing, and visible facial musculature (picture 1) [46]. Atrophy of the buccal fat pads is of particular concern to patients since it gives the appearance of facial wasting and can have an impact on self-esteem; lipoatrophy may also contribute to stigma as it is recognized to be associated with HIV infection [47].

Lipoatrophy is also readily apparent in the extremities, as veins and musculature become more prominent with the loss of supporting subcutaneous fat. Truncal fat atrophy may be detectable by a minimal amount of subcutaneous "pinchable" fat in the abdomen, but it is often less obvious than lipoatrophy elsewhere, especially if there is fat deposition within the abdominal cavity. In this situation, waist circumference may not change, as the intraabdominal volume may be increasing at the same time as the subcutaneous fat is decreasing (figure 1). This may only be determined by computed tomography (CT) (image 1) or magnetic resonance imaging (MRI) scans, which can distinguish intraabdominal and subcutaneous fat; however, these scans are rarely performed for this purpose as a part of clinical care.

Studies evaluating body composition following initiation of ART have suggested that limb fat increases during the first few months of treatment and then progressively decreases over the subsequent few years [12,48]. A substantial amount of fat may need to be lost before lipoatrophy is clinically apparent, as this depends on the amount of fat that was present at baseline. In one study of patients with HIV who underwent DEXA to quantify fat loss, a limb fat loss of 30 percent was needed for it to be visually evident [49].

Fat accumulation coexists with lipoatrophy in a number of patients. In a classic case of fat atrophy and fat accumulation, the abdominal wall of such an individual would have scant pinchable fat but would have a high waist circumference with increased intraabdominal fat [5,50]. Dyslipidemia and disordered glucose metabolism are also often seen in patients with HIV-associated lipoatrophy. (See 'Metabolic abnormalities' below and "Epidemiology of cardiovascular disease and risk factors in patients with HIV".)

Diagnosis and evaluation — We routinely evaluate patients with HIV on ART for the development of lipoatrophy. The diagnosis of HIV-associated lipoatrophy is made by detection of characteristic findings on visual inspection and physical exam (see 'Clinical features' above). Patient self-report may be an early and the best indicator of body shape changes. Additionally, it may be possible to diagnose truncal fat atrophy by a minimal amount of pinchable (subcutaneous) fat on the abdomen.

Anthropometric evaluations of limb circumferences and skin folds provide data regarding body shape but can vary depending on the evaluator. Objective quantification of fat can be obtained by CT, MRI, and DEXA scanning, but these are usually limited to research venues and offer no additional benefit to patient self-report and physical examination [8], as they are difficult to interpret and norms are not available.

Various staging scales have been suggested to characterize the severity of facial atrophy, but many of these are subjective [51-53]. Intraobserver variability was satisfactory with one scale that incorporated objective anatomic findings (eg, malar depression, buccal extension, nasolabial ridge) [54]. Nevertheless, there are no widely accepted objective techniques for assessing malar atrophy.

Although patients with HIV should be routinely assessed for abnormalities in lipid and glucose metabolism regardless of lipodystrophy, the presence of lipoatrophy should prompt such evaluation if not already performed. (See 'Metabolic abnormalities' below and "Management of cardiovascular risk (including dyslipidemia) in patients with HIV", section on 'Assessing cardiovascular risk'.)

The main differential diagnosis of HIV-associated lipoatrophy is severe wasting, in which there is loss of both subcutaneous fat and lean tissue, and can be difficult to distinguish from fat atrophy in a thin individual. However, severe wasting is rarely seen in the setting of effective ART.

FAT ACCUMULATION

Risk factors — Although fat accumulation is mainly described in patients with HIV on antiretroviral therapy (ART), the use of specific antiretroviral agents has not been clearly implicated, and fat accumulation can occur to some degree with any regimen. Other risk factors associated with the development of fat accumulation/deposition in treated patients with HIV include mainly host instead of viral factors.

Fat accumulation has been described since the introduction of combination ART [9,16,44,55-57], but not all studies have found a clear association between ART and increasing body mass index (BMI) or waist and hip circumferences [31,58]. Furthermore, no particular antiretroviral agent or class has been specifically implicated in the development of fat accumulation. The use of protease inhibitor therapy, specifically, was initially thought to lead to the development of fat accumulation [44,55,59]. However, in studies that have replaced protease inhibitor agents with alternative ART (eg, non-nucleoside reverse transcriptase inhibitors [NNRTIs] or integrase inhibitors), there has been no observed decrease in visceral fat [60-62]. In randomized controlled trials comparing boosted protease inhibitors with other agents as initial therapy for treatment-naïve patients (atazanavir versus efavirenz and atazanavir or darunavir versus raltegravir), gains in abdominal and limb fat over time with protease inhibitors and the comparators were similar [36,63]. In addition, fat accumulation has also been described in patients on ART who had never been exposed to a protease inhibitor [45,57]. As an example, in a randomized study of 422 antiretroviral-naïve patients initiating ART, there was no difference in the development of regional fat between any of the three treatment arms, which were a protease inhibitor with nucleoside reverse transcriptase inhibitor (NRTI) backbone, a NNRTI with NRTI backbone, or a protease inhibitor plus a NNRTI [64]. (See "Treatment of HIV-associated lipodystrophy", section on 'Prevention'.)

With increased use of integrase inhibitors, an association between weight gain and dolutegravir or bictegravir use has been identified, although it is unknown whether this weight gain is related to fat accumulation [65]. Similarly, use of the tenofovir alafenamide formulation of tenofovir has been associated with weight gain relative to the tenofovir disoproxil fumarate formulation [66,67]. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach", section on 'Commonly used agents'.)

A higher risk of developing fat deposition has also been described with increasing age, female sex, elevated baseline triglycerides, and higher body fat percentage [16]. Some evidence has suggested that fat deposition in patients with HIV may reflect the epidemic of obesity occurring in the general population, rather than an effect of HIV infection or ART. As such, the appearance of lipodystrophy may be obesity with concurrent fat atrophy. One study that compared patients with HIV with controls without HIV (Fat Redistribution and Metabolic Abnormalities in HIV or FRAM study) suggested that overall fat deposition was no more common in individuals with HIV [5,50]. It also showed that the prevalence of cervical dorsal fat pad (buffalo hump) was similar in controls with and without HIV; however, the size of the buffalo hump may be significantly greater in individuals with HIV. Another study demonstrated that BMI, as well as waist and hip circumference, increased over five years among 266 women without HIV but remained stable in 942 women with HIV [58]. By contrast, in the Multicenter AIDS Cohort Study, men with HIV had more rapid increases in waist circumference over five years than men without HIV [31]. It should be noted that neither BMI or waist or hip measurements are specific for visceral (intraabdominal) fat.

There does seem to be an association between fat accumulation and nutrition status. Studies that have examined the diet of individuals with HIV, with and without visceral adiposity, have suggested that poorer quality of diet, as measured by amount of fiber, are associated with the occurrence of fat deposition [68,69]. The increasing frequency of obesity in the population with HIV may obscure the ability to detect fat accumulation.

Clinical features — Abdominal fat accumulation is an excess of visceral adipose tissue (VAT) that results in an increase in abdominal girth. "Buffalo hump" results from an accumulation of fat in the dorsocervical area. Fat accumulation can also occur in the trunk and upper chest. Both males and females may develop deposition of extra breast fat or symmetrical deposits of subcutaneous fat nodules on their trunk and extremities (eg, lipomas).

In many cases, it may be difficult to distinguish this syndrome from simple obesity, in which visceral fat is also accompanied by increased amounts of subcutaneous fat in the abdominal wall (figure 1). HIV-associated fat accumulation is primarily visceral fat deposition with normal or decreased (but not increased) amounts of subcutaneous fat [5,50]. Visceral or intraabdominal fat is not palpable externally; thus, pinchable fat at the waistline is a helpful clinical distinguishing feature of subcutaneous fat. A patient with HIV and both lipoatrophy and fat deposition would have minimal pinchable fat at the waistline despite a possibly increased waist circumference. Computed tomography (CT) or magnetic resonance imaging (MRI) can distinguish between visceral and subcutaneous fat but are rarely performed for this purpose (image 1).

Studies evaluating body composition following initiation of ART have suggested that central fat increases soon after initiation of ART, within the first several months, but may subsequently level off [12,48].

In addition to fat accumulation in pre-existing fatty tissue, fat deposition can also occur in the muscles and liver.

Lipoatrophy coexists with fat accumulation in a number of patients. Dyslipidemia and disordered glucose metabolism are also often seen in patients with HIV-associated fat accumulation. (See 'Metabolic abnormalities' below and "Epidemiology of cardiovascular disease and risk factors in patients with HIV".)

Diagnosis and evaluation — We routinely evaluate patients with HIV on ART for the development of fat accumulation. The diagnosis of HIV-associated fat accumulation is made by detection of characteristic findings on visual inspection and physical examination (see 'Clinical features' above). Abdominal obesity can be detected and quantified by simple measures, including measurement of the waist circumference. An abdominal circumference >102 cm for men and >88 cm for women is considered abnormal and considered more accurate than a waist/hip circumference ratio [70]. If the ratio of waist/hip measure increased because of decrease in hip circumference, it may be mistakenly interpreted as increasing abdominal girth.

HIV-associated abdominal fat accumulation is predominantly visceral but appears similar to simple obesity, in which visceral fat is also accompanied by increased amounts of subcutaneous fat in the abdominal wall (figure 1). An inability to pinch the fat in the setting of abdominal obesity is suggestive of visceral fat accumulation, which cannot be palpated externally. Quantitative measurements of visceral adipose tissue can be assessed by CT or MRI, but these are usually done in research trials only. Dual x-ray absorptiometry (DEXA) measures trunk fat but cannot distinguish between visceral and subcutaneous adipose tissue and is not recommended.

Keeping a log of weight, BMI, and measures of waist, hip, and mid-upper-arm circumferences can be useful. Measuring height and weight to calculate the BMI, which can be followed over time, may also be useful to detect progressive changes, although patients with fat redistribution can have increased visceral fat but a normal or only modestly elevated BMI. If the BMI is stable and the waist circumference is increasing, this strongly suggests that lipoatrophy is also occurring. It may also be useful to follow the evolution of body shape changes or places where the body shape is disproportionate.

Although patients with HIV should be routinely assessed for abnormalities in lipid and glucose metabolism regardless of lipodystrophy, the presence of fat accumulation should prompt such evaluation if not already performed. (See 'Metabolic abnormalities' below and "Management of cardiovascular risk (including dyslipidemia) in patients with HIV", section on 'Assessing cardiovascular risk'.)

Simple obesity as opposed to HIV-associated fat accumulation is suggested by the presence of high BMI with large abdominal girth and pinchable trunk fat. In patients with HIV and fat accumulation in the dorsocervical region (buffalo hump), an alternative possible cause is Cushing’s syndrome, which can be distinguished by the presence of hypercortisolism. (See "Establishing the diagnosis of Cushing syndrome".)

METABOLIC ABNORMALITIES — Both lipoatrophy and fat accumulation have been associated with abnormalities in glucose and lipid metabolism, even in the absence of frank obesity.

The development of visceral obesity, insulin resistance, and atherogenic lipid profiles raises concern regarding a potential increased risk of cardiovascular disease in individuals with HIV, since these are all well-established risk factors [70,71]. Visceral adiposity itself has also been independently associated with subclinical atherosclerosis in males and females with HIV [72,73]. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV".)

Pathogenesis — The association between lipodystrophy and metabolic abnormalities may be related to adipokines. Adipocytes secrete hormones, such as adiponectin, leptin, and resistin, which are involved in metabolic pathways.

In humans, decreased adiponectin levels are associated with insulin resistance and type 2 diabetes mellitus [74]. In patients with HIV, adiponectin levels are decreased in patients with peripheral lipoatrophy and central lipohypertrophy [75]. It has been postulated that decreased adipocyte differentiation may lead to decreased adiponectin levels and insulin resistance in patients with HIV [76].

Leptin levels are lower in the subgroup of patients with significant lipoatrophy compared with patients with HIV and without lipoatrophy [77]. In mice, leptin deficiency is associated with insulin resistance. However, the absolute threshold of leptin deficiency that is associated with metabolic abnormalities is unclear.

Treatment-naïve patients who developed significant body composition and metabolic changes on antiretroviral therapy were found to have a single nucleotide polymorphism in the resistin gene, which has been linked to diabetes mellitus in patients who are obese [78,79].

Whether metabolic abnormalities are due to reduced adipose tissue mass or a change in hormone expression in adipose tissue is unknown [76]. One study has also suggested that genetic polymorphisms involved in apoptosis and adipocyte metabolism may influence the emergence of lipoatrophy versus fat accumulation [80]. Another study examining the effect of mitochondrial haplogroups did not find any association with any specific changes in anthropomorphic measures [81]. Emerging data suggest that dysregulated microRNAs may play a role in adipose dysfunction and metabolic abnormalities in people with HIV [82].

Abnormal glucose metabolism — Fat redistribution may contribute to insulin resistance in individuals with HIV [83,84]. In a study of 41 men with HIV (21 with lipodystrophy and 20 without) and 20 controls without HIV, waist to hip measurement ratio was superior to other body-composition measures in predicting fasting hyperinsulinemia [83]. Another study suggested that the severity of lipoatrophy among patients taking either stavudine or zidovudine was associated with an increased risk of insulin resistance [33].

Dyslipidemia — Atherogenic lipid profiles are also associated with body fat changes in individuals with HIV [48]. The relation between regional body fat measurements and lipid levels was examined in the Fat Redistribution and Metabolic Changes in HIV Infection study [85,86]. Proatherogenic lipid profiles were more common in patients with HIV compared to controls without HIV, particularly in association with certain fat redistribution patterns. Both increased visceral fat and decreased subcutaneous leg fat were associated with elevated triglycerides and decreased high-density lipoprotein cholesterol.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary care of adults with HIV".)

SUMMARY AND RECOMMENDATIONS

Definitions − Despite the commonly used term "HIV-associated lipodystrophy syndrome," it does not describe a single syndrome. Some patients have pure lipoatrophy (fat atrophy), others have fat accumulation which may present in a variety of ways, and still others have a mixed picture of both morphologic features.

Prevalence − The exact prevalence of lipoatrophy and fat accumulation is uncertain, with reports ranging from 10 to 80 percent. (See 'Introduction' above and 'Prevalence' above.)

Lipoatrophy − The main risk factor for lipoatrophy is exposure to thymidine analogue nucleoside reverse transcriptase inhibitors, predominantly stavudine but also zidovudine. Lipoatrophy involves the loss of subcutaneous fat in the face, arms, legs, abdomen, and/or buttocks (picture 1). (See 'Lipoatrophy' above.)

Fat accumulation − Although fat accumulation is mainly described in patients with HIV on antiretroviral therapy, the use of specific drugs or drug classes has not been clearly implicated, and fat accumulation can occur to some degree with any regimen. Other risk factors include increasing age and female sex. Fat accumulation occurs in the trunk, abdomen, cervical-dorsal area ("buffalo hump"), breasts, and/or upper chest. (See 'Fat accumulation' above.)

Diagnosis and evaluation − The diagnoses of HIV-associated lipoatrophy and fat accumulation are made by the detection of characteristic findings on physical examination. Sequential measures of waist, hip, and mid arm or mid-thigh circumference may be helpful in interpreting changes in body shape or body mass index. (See 'Diagnosis and evaluation' above and 'Diagnosis and evaluation' above.)

Metabolic complications − Both lipoatrophy and fat accumulation have been associated with abnormalities in glucose and lipid metabolism, even in the absence of frank obesity. (See 'Metabolic abnormalities' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Christine Wanke, MD, who contributed to an earlier version of this topic review.

UpToDate also gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

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Topic 3733 Version 42.0

References

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