HTB

Lipodystrophy: the current state of play

17 October 2000. Related: Conference reports, Side effects, Lipodystrophy and metabolic complications, .

Dr Graeme Moyle for HIV i-Base

The aetiology of peripheral lipoatrophy and other clinical and metabolic consequences of antiretroviral therapy remain enigmatic. Only through understanding the aetiology can optimal management of these problems be established. Evidence from cross sectional surveys have pointed to an interaction between disease and/or immune recovery and drugs.

Both PI and nucleoside analogues have been associated with the changes and theories published hypothesising how they may play a role. However, patients with the syndrome who have never received PIs or have never received nucleoside analogues have been reported suggesting that while it is possible that these drug classes or specific members of these classes may accelerate the onset of clinical manifestations they are not sufficient alone to cause the problems.

Suggested contributory factors are listed below.

PI factors:

  • interaction with retinoids, LRP, P450 [Lancet 1998;351:1881-1883]
  • interaction with insulin dependent Glut4 receptor (IDV, RTV, APV) [Journal of Biological Chemistry 2000;275:20251-20254]
  • blocking of proteosomes and adipocyte differentiation [J Endochrinol 2000;164:7R-10R.]
  • enhanced retinoid signaling (IDV) [Retrovirus 1999; abs 665]
  • increased hepatic VLDL production [AIDS 2000;14:51-57]
  • drug-hormone interactions: DHEA:Cortisol [AIDS 1999;13:2251-2260]
  • drug-hormone interactions: sex hormones, GH/IGF [Xenobiotica 1999 May;29(5):437-51]

Nucleoside analogue factors:

  • Mitochondrial toxicity. Differences in visceral and peripheral fat mitochondrial reserve. Mitochondria carry key apoptosis factors [AIDS 1999;13:2311-2312] [Lancet 1999;354:1112-1115]
  • Nucleotide integration in to nuclear DNA or Genotoxicity. [AIDS. 1999;13:919 – 925] [Drug Safety 2000; December]
  • Shortening of telomeres and diminished cell cycling [Mol Cell Biol 1996;16:53-65]

HIV factors:

  • Altered cortisol response. [J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:228]
  • Increased adipocyte sensitivity to glucocorticoids [J Clin Endocrinol Metab. 1999;84:1925 – 1931]
  • Vpr activates glucocorticoid receptors [J Exp Med. 1999;189:51 – 62]
  • Tumor necrosis factor alpha [J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20:228]
  • Potent inducer of adipocyte apoptosis [Diabetes. 1997;46:1939 – 1944]
  • Regulates bound leptin [AIDS 1998;12:2233-2235]

Impact of HAART/immune restoration:

  • Cytokine factors such as IFN-alpha, TNF-alpha, IFN-gamma, IL-1, 6 and 12 are involved in both Immune reconstitution and lipid handling [JAIDS 1999;20:228]
  • Dysregulation of TNFa [Blood 2000;95:3191-3195]
  • Increased Serum corticotrophin, increased urinary 17-hydroxycorticosteroid, decreased free cortisol (J [Clin Endochrinol Metab 1999;13:2251-2260]
  • Drugs and response to treatment interactions: multi-factorial syndrome(s)

Consequences of no fat

Several of the plenary presentations at the 2nd Lipodystrophy Workshop were from experts in fat and glucose metabolism from outside the HIV arena.

Dr Mark Reitman [1] discussed the physiology of lipoatrophy, much of the data in this arena being derived from genetically modified mice. Adipose tissue plays a number of roles in mammals including insulation, thermogenesis, and fat storage but also paracrine functions such as producing leptin, TNFalpha, free fatty acids (FFA) and other hormones. Fatless mice have raised FFA, triglycerides and type 2 diabetes mellitus with raised insulin. It is thought that insulin resistance in hyperlipidaemic states relates to free fatty acid blocking GLUT4 mediated transport of glucose into muscle and adipocytes. Fat free mice have low leptin levels and the animals have poor tolerance of fasting due to low energy stores. The circulating triglycerides, with no adipose tissue to be stored in, lodge in and around visceral organs in particular the liver where they cause hepatic steatosis.

This was an important reminder that hepatic steatosis, associated with lactic acidosis and mitochondrial dysfunction during nucleoside therapy, may be caused through mechanisms other than mitochondriopathy. Hepatic steatosis, the accumulation of triacylglycerol in hepatocytes, is a pattern of liver injury that may be seen in alcoholic or non-alcoholic liver disease.

Risk factors for non-alcoholic steatohepatitis (NASH) include obesity, type II diabetes, hyperlipidemia, total parenteral nutrition, jejuno-ileal bypass surgery, and the use of certain drugs. It may also be observed in disorders of ureagenesis, pregnancy or as part of Reye’s syndrome. Thus, finding hepatic steatosis may reflect metabolic disturbances in persons with HIV infection, not mitochondrial injury by nucleoside analogues.

The PI contribution

Following the published data that PIs inhibit cellular proteosomes and effects adipocyte differentiation, two linked presentations [2], [3] looked at in vitro effects of ritonavir and saquinavir in a HepG2 hepatoma cell line. It appears that RTV and SQV block degradation of ubiquinated ApoB (a precursor of triglyceride) which then accumulated in cells. RTV was the more potent inhibitor. However, after addition of oleic acid (mimicking a fat containing meal) triglyceride secretion occurred.

This suggests that there may be an exaggerated rise in triglycerides in response to feeding in persons on PIs. Additionallly, the acetyl-CoA:cholesterol-O-acyltransferase (ACAT) enzyme was inhibited (IC50 15mM for RTV and 60mM for SQV, possibly supratherapeutic concentrations) leading to decreased synthesis of cholesterol esters and accumulation of (potentially cytotoxic) cholesterol precursors.

These findings help explain the effects on triglycerides seen in healthy volunteers given ritonavir. However, administration of indinavir to healthy volunteers, however, was found to have little effect on circulating lipids or lipoproteins [4]. Insulin resistance occurred, however, potentially due to the established effect of this agent on GLUT4 mediated glucose uptake.

In vitro, indinavir was also found to inhibit adipocyte differentiation [5] meaning that if adipocytes are lost (for whatever reason) PIs may slow or block the replacement process. The mechanism of this relates to alterations in expression of key genes involved in the differentiation process secondary to blockade of processing of sterol regulatory-element binding protein 1 (SREBP-1) into its mature form [6].

Refutation of the mitochondrial hypothesis

There was little evidence to support mitochondrial toxicity as the mechanism of lipoatrophy. Indeed, considerable data accumulated to refute this hypothesis.

Two fat biopsy studies [7], [8] demonstrated only modest reductions (mean 44%) in mitochondrial DNA even in samples from lipoatrophic patients. In inherited mitochondrial DNA disorders, reductions in mtDNA to less than 20% are generally required for disease to occur. Importantly, samples from persons with lipoatrophy in some cases (13% of samples) had normal levels of mtDNA and some control samples (from HIV negative individuals) showed diminished mtDNA, underlining that loss of mtDNA is not characteristic or diagnostic of the lipoatrophy in persons with HIV. Additionally, the mtDNA 8344 Madelung’s mutation was absent in all samples in one of the studies [7].

Two groups [9], [10] demonstrated that fat oxidation, a mitochondrial function, is normal or potentially increased in persons with metabolic disturbances on PI+NRTI based regimens. A study of muscle biopsies pre and post exercise and lactate levels found normal oxidative phosphorylation (a key mitochondrial function) with a similar recovery rate in lactate and pyruvate levels after exercise and no significant abnormalities of muscle mitochondria.

The authors suggested that hyperlactatemia seen in some patients may related to decreased clearance of lactate [11]. Many of the patients studied, all of whom clinically had lipodystrophy, had hypertriglyceridaemia. Thus, one potential explanation for these findings is that hypertriglyceridaemia leads to hepatic steatosis (as in fatless mice) hence diminished hepatic function and reduced clearance of lactate. The association of lipoatrophy and hyperlactataemia observed in one study [12] may be explained by this mechanism and enables understanding of why isolated mild hyperlactataemia may be relatively common yet lactic acidosis remains rare.

Investigators at Bristol-Myers reported results of culturing adipocytes with nucleoside analogues and/or PIs yielding different effects on triglyceride accumulation, lipolysis and ATP levels. Whilst PIs had effects at physiologic concentrations on triglyceride accumulation (e.g. 7mM for nelfinavir) and at higher concentrations on lipolysis and ATP production, effects were not observed below 30mM for NRTIs and IC50s for all effects with d4T and AZT were above 100mM [13]. Thus, NRTIs alone at current doses do not appear to affect adipocyte mitochondrial function.

A study of d4T in mice, feeding substantially supratherapeutic doses of 100 or 500mg/kg/day of drug (human dose ~1.0mg/kg/day although mice metabolise d4T more rapidly than humans) over 6 weeks found 40-60% depletion in mtDNA in liver and skeletal but not brain and cardiac muscle tissue at the 500mg/kg/day dose. This magnitude of depletion is probably insufficient to cause mitochondrial disease. At 100mg/kg/day effects on skeletal muscle or adipose tissue mtDNA were not seen and changes in liver mtDNA were observed only in week 1 samples but not at week 6 suggesting a compensatory recovery in mtDNA [14].

The findings of these studies are perhaps not surprising for the thymidine analogues ZDV and d4T as adipocytes, and other resting cells, are unlikely to express thymidine kinase type 1 (TK1), the enzyme involved in the first step of activation of these drugs, and these drugs are poor substrates for the mitochondrially located TK2. Thus, adipocytes are unlikely to have active concentrations of phosphorylated thymidine analogues [15]. Interestingly, a marked synergy between PI and NRTI was observed on a range of adipocyte functions in vitro [13] in line with clinical observations.

The end of the era of blaming PI exclusively for lipodystrophy came with the recognition that lipoatrophy and metabolic disturbances could occur in PI naive individuals. However, NRTI-naive but ART treated individuals are relatively rare making evaluation of NRTI-sparing more difficult.

A first survey from the DMP-006 study [16] indicated that patients in the EFV-IDV arm had been diagnosed with lipodystrophy. Two reports at this meeting, evaluating patients on dual PI regimens (both RTV-SQV) observed lipodystrophy in NRTI spared individuals but higher rates when NRTIs were added to the regimen. In the Prometheus study, after 96 weeks follow-up, 22/88 (25%) of d4T/RTV/SQV patients but also 7/87 (8%) RTV/SQV alone treated patients were diagnosed with lipodystrophy, including 5/44 (11%) RTV/SQV treated patients who had never received NRTIs [17].

A second study with 144 weeks of follow-up, mostly in persons who discontinued prior NRTI therapy and then received RTV/SQV found 6% of NRTI spared individuals had both buttock and facial wasting with 9% having increase in waist size. Patients who added NRTIs during the study were more likely to have lipoatrophy [18].

These studies provide several important observations. Most importantly that lipodystrophy/lipoatrophy can occur in the absence of NRTIs. Previous studies have suggested that use of PIs can accelerate the onset of or increase the incidence of lipoatrophy in NRTI treated individuals [19]. These data suggest this interaction works both ways, that NRTIs also accelerate the onset or increase the incidence of lipoatrophy in PI treated individuals.

Other NRTI effects

Recent data have indicated that dysregulation of TNF alpha production [20] may occur in persons on HAART with some cells continuing to produce high levels of TNFalpha. TNFalpha is a known inducer of apoptosis in adipocytes and may be produced by adipocytes or by pericapillary T cells located in adipose tissue. In a study evaluating oxidative stress gene expression in liver cell of mice differential effects were observed between ZDV and d4T. The mice were given 5mg/kg/day of each drug; of note the human dose of d4T is 1mg/kg/day and of ZDV 8mg/kg/day however mice metabolism of these agents is more rapid than humans so the d4T exposure in this study may equate to high therapeutic exposure but the ZDV exposure is likely to low or sub-therapeutic. The reasons for choice of these doses was not explained by the investigators at Glaxo-Wellcome. However, the findings were interesting, particularly given the current interest in the potential role of cytokines in lipodystrophy.

The use of d4T resulted in increased expression in a number of genes including TNF alpha and down regulation of PPAR-gamma whereas ZDV resulted in increased expression of PPAR-gamma. Clearly these studies need to be repeated at exposures in mice which equate to therapeutic exposures as, for example, low exposures of one drug may lead to one set of effects, higher exposures a different set of effects.

The use of d4T resulted in increased expression in a number of genes including TNF alpha and down regulation of PPAR-gamma whereas ZDV resulted in increased expression of PPAR-gamma. Clearly these studies need to be repeated at exposures in mice which equate to therapeutic exposures as, for example, low exposures of one drug may lead to one set of effects, higher exposures a different set of effects.

Drug and disease associations

After these two meetings we have now seen the limits of cross-sectional studies to address syndrome, drug and disease associations reached. Several cross-sectional studies indicated that lipodystrophy, not surprisingly, is seen in HIV+ treated populations in Singapore (mostly Chinese) [22], Japan (mostly Japanese) [23] and Nigeria (all Nigerians) [24]. Prevalence rates appeared similar to other surveys in US, Australia and Europe.

Other cross-sectional surveys looked at closed cohorts, for example all patients starting therapy in 1996 or consecutive patients at a single clinic. As with previous cross-sectional studies, risk factors include host factors (age >40, gender), treatment factors (duration of therapy, duration of nucleoside analogues, duration of PI therapy, specific agents such as d4T, 3TC, IDV in some but not other studies), and disease factors such as CD4 nadir, complete viral suppression [25 – 37].

Surveys of patients from randomised studies, attempting to assess differences in drugs, mostly suffered from differences in baseline characteristics [38], lack of baseline measures of fat distribution (all), high rates of lost to follow-up creating selection biases in those surveyed [38], absence of information on those who changed therapy [38], [28] and, at worst, conclusions which did not match the data [38].

When associations with specific drugs were rigorously examined such as in the CDC’s HOPS study, it was observed that drugs alone were not sufficient to have association with lipoatrophy but that the prevalence of lipoatrophy increased with additional host and disease factors including age over 40, caucasian race, CD4 nadir and complete viral suppression. In a sub-cohort of this study surveyed on two occasions lipoatrophy, by physician assessment was observed to have progressed in some individuals but regressed in others [26], [39].

Bone mineral density

Whether HAART also leads to loss of bone mineral density remains unclear. Several possible mechanisms were discussed for bone loss.

An in vitro study found that inhibition of conversion of 25(OH)-vitamin D to the bioactive 1, 25(OH)-vitamin occurred with ‘high-therapeutic’ exposures of ritonavir, indinavir and nelfinavir. The most potent effects were observed with ritonavir [40]. However, the studies were performed in only 1% bovine albumin, hence correction for protein binding is likely to have been insufficient and free drug concentrations are likely to have been supratherapeutic.

An association with gain of bone mineral density (BMD) with loss of subcutaneous fat was observed in patients on indinavir but not nelfinavir in one study [41]. However, in a second survey patients commencing therapy had lower BMD than patients on therapy. Indeed, time on HAART appeared protective against loss of BMD [42] and BMD did not worsen over 48 weeks of PI based therapy or improve after switch of PI [43]. Whereas duration of HIV infection appeared a risk factor for low BMD in two studies [42], [44]. However, it is established that raised LDL and lipoprotein-A inhibit differentiation of preosteoblasts and encourage differentiation into adipocytes [45]. Therefore, raised LDL in persons with metabolic disturbances of HAART, most well documented with PI therapy, may subsequently contribute to loss of BMD.

This leads to the possibility that BMD is lost secondary to chronic infection prior to therapy and then begins to recover with therapy (at least with certain regimens) until the effects of raised LDL come into play and bone forming osteoblasts are replaced in bone with adipocytes leading to recurrence or worsening of BMD. Certainly, markers of bone turnover appear raised in a substantial proportion of PI treated patients [46]. Low body mass index is also associated with low BMD and thus is likely to fall with both AIDS-wasting and weight loss with lipoatrophy. An association with low pre-therapy weight was reported in on study [47].

Management of Lipodystrophy

Few abstracts at these meetings dealt with management approaches beyond switching therapy. Broadly management depends on the current assumption of ætiology.

  • Assume PI ætiology: switch to NNRTI/Triple NA regimen
  • Assume thymidine analogue ætiolog; switch to ddI, ABC based regimen
  • Assume NA ætiology: switch to PI + NNRTI regimen
  • Assume cytokine ætiology: use SIT/pulse therapy, use loose viral control
  • Assume multifactorial: treat individual manifestations
  • Assume adipocyte apoptosis: use rosiglitazone.

The majority of switch studies maturing now are focused on switching away from PIs.

Details of comparative switch studies are available in The AIDS Reader 10(8):479-485, 2000 and in the ICAAC meeting reports.

Statins with dietary advice appear useful for managing hypercholesterolaemia with a fall in LDL of 20% (compared with 6% with advice alone) being reported with pravastatin 40mg od. Whilst no adverse events or loss of virological control occurred in this study only 25% of treated patients established a total cholesterol below recommended intervention levels [48]. Most likely secondary to a significant drug interaction with PIs, a patient treated with simvastatin was reported to develop rhabdomyolysis [49] underlining the importance of statin choice.

References:

  1. Reitman M et al. The physiology of lipoatrophy. Abstract O1. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  2. Ginsberg H et al. HIV protease inhibitors increase secretion of apolipoprotein B-lipoproteins from hpatoma cells by preventing proteasomal degradation. Abstract O18. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  3. Distler O et al. Direct effects of protease inhibitors on lipid metabolism in cultured mammalian cells. Abstract O19. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  4. Noor M et al. Metabolic effects of indinavir in healthy HIV-seronegative subjects. Abstract O10. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  5. Capeau J et al. The HIV-protease inhibitor indinavir impairs adipocyte differentiation and induces insulin resistance by probably altering ADD1/SREBP-1 maturation. Abstract O3. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  6. Stevens GJ et al. Inhibition of adipocyte differentiation by HIV-1 protease inhibitors: potential mechanisms based on changes in gene expression. Abstract P3. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  7. Walker U et al. Decrease of mitochondrial DNA content in adipose tissue of HIV-1 infected patients treated with NRTI’s. Abstract O6. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  8. Shikuma C et al. Subcutaneous adipose tissue mitochondrial DNA analysis from individuals with HAART associated lipodystrophy. Abstract O7. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  9. Ware L et al. Differences in postprandial lipid metabolism in patients with PI-associated and NRTI-associated lipodystrophy. Abstract O20. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  10. 10. Balaubramanyam A et al. Dysregulation of lipid turnover is a key defect in the lipodystrophy syndrome. Abstract P24. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  11. St John J et al. Multiple mtDNA deletions in human spermatozoa from long term HAART. Abstract P23. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  12. White AJ et al. Raised lactate levels are common and may be predictive of subcutaneous fat wasting. Abstract P82. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  13. Parker R et al. Effects of nucleoside reverse transcriptase inhibitors and HIV protease inhibitors on adipogenesis and adipocyte metabolism. Abstract O4. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  14. Gaou I et al. Effects of stavudine (d4T) on mitochondrial DNA in mice. Abstract I-1628. 40th ICAAC, Toronto, Canada, Sep 2000.
  15. Moyle GJ et al. Hypothesis: is long-term nucleoside analogue toxicity related to nuclear DNA integration? Abstract P21. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  16. Tashima K et al. A Phase III, Multicenter, Randomized, Open-Label Study to Compare the Antiretroviral Activity and Tolerability of Efavirenz (EFV) + Indinavir (IDV), versus EFV + Zidovudine (ZDV) + Lamivudine (3TC), versus IDV + ZDV + 3TC at 48 Weeks (Study DMP 266-006). 6th CROI. Chicago, IL. January 31-February 4, 1999.
  17. van der Valk M et al. Increased risk of lipodystrophy when including NRTIs in the treatment of HIV-1 infection with Pis: Results from a randomised controlled trial. Abstract 78. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  18. Ryan J. Effects of NRTI intensification on prevalence of body composition abnormalities at week 144 of ritonavir plus saquinavir therapy in an HIV-infected cohort. Abstract P56. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  19. Mallal SA et al. Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS. 2000 Jul 7;14(10):1309-16.
  20. Ledru et al. Alteration of tumor necrosis factor-alpha T-cell homeostasis following potent antiretroviral therapy: contribution to the development of human immunodeficiency virus-associated lipodystrophy syndrome. Blood. 2000 May 15;95(10):3191-8.
  21. Paulik M et al. Anti-oxidants rescue NRTI-induced metabolic changes in AKR/J mice. Abstract O8. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  22. Paton N et al. Prevalence of lipodystrophy in a cohort of Asian HIV patients. Abstract O15. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  23. Fraser H et al. Prevalence survey of lipodystrophy in HIV-positive patients in Japan. Abstract O17. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  24. Ekong E et al. Prevalence of lipodystrophy syndrome in a cohort of patients exposed to antiretroviral drug therapy. Abstract O16. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  25. Lichtenstein K et al. Changes in HIV-associated fat maldistribution over time. Abstract O13. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  26. Martinez E et al. A prospective cohort study on the risk for lipodystrophy in HIV-1 infected patients treated with protease inhibitor containing regimens. Abstract O14. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  27. Lopes J et al. Interactions among sex, HIV infection and fat redistribution. Abstract P29. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  28. Bogner JR et al. No difference in lipodystrophy incidence in stavudine versus zidovudine nucleoside backbone: blinded evaluation in a cohort on first line HAART. Abstract P54. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  29. Galli M et al. Risk of developing metabolic and morphologic alterations under antiretroviral therapy according to the drug combinations. Abstract P59. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  30. Galli M et al. Risk of developing adipose tissue alterations after starting antiretroviral therapy in na•ve patients. Abstract P60. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  31. Mauss S et al. Risk factors for the HIV-associated lipodystrophy syndrome in patients with uniform duration of antiretroviral therapy (LipART). Abstract P68. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  32. Miller JE et al. The Australian lipodystrophy prevalence survey. Abstract P70. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  33. Muurahainen N et al. Different factors are associated with abnormal fat accumulation and fat depletion in men and women with HIV. Abstract P71. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  34. Polo R et al. Prevalence of lipodystrophy (lipoatrophy, hypertrophy and mixed syndrome) and metabolic complications in HIV-infected patients: a cross sectional survey. Abstract P72. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  35. Rickerts V et al. Incidence and factors associated with body shape changes in HIV-infected patients. Abstract P74. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  36. Polo S et al. Prevalence of lipodystrophy and metabolic complications in HIV-infected patients: a cross-sectional study. Abstract I-1281. 40th ICAAC, Toronto, Canada, Sep 2000.
  37. Ward DJ et al. Lipid elevation in a survey of lipodystrophy in HIV-infected ambulatory patients. Abstract I-1294. 40th ICAAC, Toronto, Canada, Sep 2000.
  38. Law M et al. Lipodystrophy and metabolic abnormalities in a cross-sectional study of participants in randomised controlled studies of combination antiretroviral therapy (ARV). Abstract O28. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  39. Lichtenstein KA et al. Clinical factors associated with incidence and prevalence of fat atrophy and accumulation. Abstract P64. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  40. Tebas P et al. Protease inhibitors inhibit in vitro conversion of 25(OH)-vitamin D to 1,25(OH)2-vitamin D. Abstract O30. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  41. Nolan D et al. Longitudinal analysis of bone mineral density (BMD) in HIV-infected patients treated with HAART: changes in BMD correlate with change in subcutaneous fat; with an additional independent effect of indinavir therapy to increase BMD. Abstract O31. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  42. Moyle GJ et al. Osteopenia: a consequence of HIV not HAART? Abstract P33. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  43. Hoy J et al. Osteopenia in a randomised, multicentre study of protease inhibitor substitution in patients with the lipodystrophy syndrome – extended follow up to 48 weeks. Abstract 32. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  44. Billaud E et al. Osteopenia and osteoporosis in HIV infected patients: Role of antiretroviral therapy (ART)? Abstract I-1304. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  45. Morlese J et al. HAART-associated osteopenia is caused by oxidised lipoproteins: a hypothesis. Abstract P40. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  46. Tebas P et al. Serum and urine markers of bone mineral metabolism in HIV-infected patients taking protease inhibitor containing potent antiretroviral therapy. Abstract O29. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  47. Carr A et al. Osteopenia in HIV-infected men: association with lactic academia and lower weight pre-antiretroviral therapy. Abstract O32. 2nd Intl Workshop on Adverse Drug Interactions and Lipodystrophy, Toronto, Sep 2000.
  48. Moyle GJ et al. A randomised open label trial of dietary advice with or without pravastatin for the management of protease inhibitor (PI)-associated hypercholesetrolemia. Abstract I-1296. 40th ICAAC, Toronto, Canada, Sep 2000.
  49. Martin CM et al. Rhabdomyolysis in a patient receiving simvastatin concurrently with highly active antiretroviral therapy. Abstract I-1297. 40th ICAAC, Toronto, Canada, Sep 2000.

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