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Introduction

Protease inhibitors (PIs) of HIV confer virologi-cal, immunological and clinical, including sur-vival, benefits1,2. A PI in combination with nucleo-

side analogue HIV reverse transcriptase inhibitorsis now standard of care antiretroviral therapy3,4.The potency and sustained effects of combinationPI therapy have led to its widespread usage forpatients at almost every stage of disease, includ-ing primary HIV infection.

Many PI toxicities, including renal calculi andnephropathy with indinavir, nausea, diarrhea andperioral paraesthesiae with ritonavir, and diarrheawith nelfinavir and soft-gel saquinavir, are not usua-

lly serious and resolve rapidly with discontinua-tion. An immune reactivation syndrome can occurin patients with subclinical infections (eg. hepatitisB or C, Mycobacterium avium)5-7. Excessive bleed-

ing in haemophiliacs and portal vein thromboses,although potentially serious, are relatively rare8,9.These adverse effects will not be reviewed here.

Generalised wasting is a common manifesta-tion of advanced HIV infection and is predomi-nantly due to loss of muscle mass10,11. Until re-cently, however, regional fat wasting had not beenreported in patients with HIV infection nor as aconsequence of any drug therapy. We and othersnoted PI recipients developing peripheral wast-ing, central obesity, hyperlipidaemia and diabetesmellitus following the introduction of PI therapy(Fig. 1, Table 1)12-15. Several groups have subse-quently explored the interaction between HIV PIs,

body fat, serum lipids and insulin sensitivity.

AID S Rev 1999 ; 1 : 29-36

HIV Protease Inhibitor-induced

Lipodystrophy Syndrome

Andrew Carr

HIV Medicine Unit, St. Vincents Hospital, Sydney, Australia

Correspondence to:Andrew CarrHIV Medicine Unit

St. Vincents HospitalSydney 2010 Australia

Human immunodeficiency virus (HIV) protease inhibitor (PI) therapy can cause asyndrome of lipodystrophy (peripheral fat wasting and/or central fat accumulation),hyperlipidaemia and insulin resistance. Type 2 diabetes mellitus appears to be arelated, but less common, toxicity. Lipodystrophy occurs with all licensed,

potent PIs after a median of about 10 months PI therapy. Any relationship tonon-PI therapy or HIV disease appears limited. The syndrome may be due tothe inhibition of two lipid regulatory proteins that have substantial homology to thecatalytic site of HIV protease, namely cytoplasmic retinoic acid binding protein type1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). There areno validated, objective diagnostic criteria at present but measurement of body fatmass may be useful. There is no proven therapy for any component of thesyndrome. The full clinical significance of the syndrome is unknown but, inaddition to the cosmetic effect, metabolic disturbances may increase the risk oflongterm cardiovascular disease.

HIV. Lipodystrophy. Protease inhibitors. Insulin resistance. Hyperlipidaemia.Diabetes mellitus.

Abstract

Key words

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Clinical features

In the largest study to date, we cross-sectionallyevaluated 116 HIV-infected, otherwise well, adultsreceiving at least one HIV PI, 32 HIV-infected PI-nave patients and 47 healthy male controls12.Lipodystrophy was defined clinically by patient re-

port of fat wasting in one or more of face, arms orlegs with or without central obesity and confirmedby physical examination. Patients with weightchange but without peripheral fat wasting were notdefined as having lipodystrophy. It should be em-phasised, however, that there is no validated ac-cepted definition of lipodystrophy.

Lipodystrophy was reported by 74 (64%) PI re-cipients after a mean 13.6 months therapy versus1 (3%) PI-nave HIV-infected patient (P=0.0001,Table 2). Wasting occurred with equal frequency inall body regions, including the trunk, except theabdomen where patients reported obesity (Fig. 1).

Lipodystrophy occurred with all potent PIs and themedian time to onset of lipodystrophy was 10months (Fig. 2a). Lipodystrophy did not resolve inany patient but improved in a few who switchedfrom ritonavir-saquinavir to indinavir. Many patientswith lipodystrophy were mistakenly assumed tohave HIV wasting syndrome with its psychological,social and economic consequences.

Dual energy X-ray absorptiometry (DEXA) con-firmed the clinical findings12,16. PI recipients hadcomparable body weight and fat free mass butsignificantly lower fat mass overall and in eachbody region except the central abdomen thanboth PI-nave patients and healthy males. Impor-tantly, PI-nave patients had similar total and cen-

tral fat mass to controls. The estimated loss inbody fat/month during the first year of PI therapywas 0.40 kg/month12.

The main risk factor for lipodystrophy (apartfrom PI therapy) was longer duration of PI therapy(Fig. 1). After a mean 22 months follow-up theprevalence of lipodystrophy in our PI cohort hadincreased to 83%; using a patient-rated severityscale (that concurred with DEXA), lipodystrophywas severe overall in only 11%17. Peripherallipodystrophy was observed in 25% of patients re-ceiving indinavir for 1 year12. Another cohort studyfound cumulative rates of 3, 11, 29, 63 and 75%after 6, 12, 18, 24 and 30 months PI therapy, res-pectively18. Lipodystrophy has not been found tobe associated with CD4+ lymphocyte counts, HIVRNA levels or use of other drugs including otherclasses of antiretrovirals.

Miller et al showed that the abdominal disten-sion in patients receiving indinavir was due to accu-mulation of visceral fat, with stable or declininglevels of subcutaneous abdominal fat14. Further,

they found that this accumulation occurred inthose receiving at least 6 months therapy. Hengelreported a group of PI recipients with multiple lipo-mata19; it is possible, of course, that this repre-sents fat wasting surrounding a pre-existing in-visible lipoma.

There are several reports of fatty enlargement ofthe dorso-cervical fat pad (buffalo hump) in HIV-infected patients, although some patients were notreceiving PIs and so the relationship of buffalohump to PI therapy is unclear15,20-22. Buffalo humpappears less common than wasting or abdominalobesity17.

Women and children receiving protease in-hibitors also develop lipodystrophy. An additionalfeature in women is breast hypertrophy23-26.Whether there are other differences in prevalencerates or severity between men and women or be-tween ethnic groups is unknown. Controlled,prospective, longterm prevalence studies have notbeen reported.

There have been small numbers of reports of pa-tients not receiving PIs with physical features oflipodystrophy12,14,25; the aetiology in these patientsis unclear.

Metabolic featuresAdvanced HIV infection is associated with low

serum cholesterol levels and mild hypertriglyceri-daemia10. PI therapy is associated with significantdisturbances in both lipid and glucose metabo-lism12,14,27-40. In turn, patients with lipodystrophyhave more abnormal lipid and glucose metabolismthan those without lipodystrophy, confirming thatthe metabolic and clinical disturbances are twocomponents of the one syndrome12.

Combined hyperlipidaemia was identified in bothphase-1 studies of the protease inhibitor ritonavir1,41.This developed within weeks and persisted for the

duration of therapy. Interestingly, no phase 2 or 3studies of any PI systematically evaluated lipid or glu-

Table 1. Physical and metabolic features of lipodystrophysyndrome.

A. Physical features

One or more of the following (on physical examination or by

patient report) since commencing HIV protease inhibitor

therapy:

1. Fat wasting face

arms

legsbuttocks

2. Fat accumulation abdomen

dorso-cervical spine (buffalo hump)

breasts (women)

3. Possible features ingrown toenails

dry skin and lips

B. Metabolic features

One or more of the following since commencing HIV

protease inhibitor therapy:

1. Hyperlipidaemia fasting cholesterol > 5.5 mmol/L

and/or

fasting triglyceride > 2.0 mmol/L

2. Glucose intolerance fasting glucose > 6.1 mmol/L

2 hour OGTT glucose > 7.8 mmol/L

Changes should not be attributed to therapy if:

1. AIDS-defining event or other severe clinical illness in the

last 3 months.

2. Use of anabolic steroids, glucocorticosteroids, immune

modulators in the last 3 months.

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Fig. 1. Characteristic physical features of the lipodystrophy syndrome in several patients receiving HIV protease inhibitors. There isfat wasting of the face (a) legs (b) and buttocks (c) and fat accumulation in the abdomen (d), breasts (e) and dorso-cervical fatpad (f).

cose metabolism. Numerous studies have now con-firmed that combined hyperlipidaemia is commonwith all potent PIs and persists in those remaining ontherapy17. The effect of PI withdrawal is unknown.

Several reports have identified diabetes with PI

therapy

12,28-30

. In previously non-diabetic patients, theclinical presentation was usually asymptomatic and

non-ketotic (i.e. type-2 diabetes) and in long stand-ing, type-1 diabetics, daily insulin requirements in-creased within weeks of commencing therapy. Seruminsulin, C-peptide, insulin secretion and insulin resis-tance all increase12,30, and proportionally to lipodys-

trophy severity

17

. Type-2 diabetes was thought to beuncommon (0.1 to 1%), but systematic studies using

a

b

f

e

d

c

d

c

b

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oral glucose tolerance testing found a prevalence of6 to 9% with a further 16% of patients in one studyhaving impaired glucose tolerance17,30. Type-2 dia-

betes in the general population usually results fromboth insulin resistance and impaired insulin secretion.This may explain why lipodystrophy is more commonwith PI therapy than hyperglycaemia.

It should be noted that neither PI use nor pres-ence of lipodystrophy has been associated withsignificant differences in liver function, or in plasmaleptin, testosterone, sex hormone binding globulin,prolactin, cortisol, C3 or tumour necrosis factor-alpha levels12,15. Additionally, dexamethasone sup-pression tests are normal15.

Comparison of indinavir, ritonavir-saquinavir and nelfinavir

Both the clinical and metabolic features of thesyndrome are more abnormal in patients receivingritonavir-saquinavir when compared to those re-ceiving indinavir, at least early in therapy (Table 2;Fig. 2b)12,25,31. Several studies have reported thatnelfinavir has similar effects to indinavir early intherapy17,25. However, with prolonged therapy (amean 22 months), all features of the syndrome (ex-cept for hypertriglyceridaemia) became similar re-gardless of PI type, suggesting that fat changeshave finite limits that are merely reached earlier withritonavir-saquinavir17. One early report suggestedthat diabetes associated with indinavir may improvein some patients who switch to nelfinavir37.

The early differential effect of ritonavir-saquinavirversus indinavir or nelfinavir might arise becausePIs have differential capacities to cause this syn-

drome or may merely represent the use of morethan one PI. The relative contributions of ritonavirand saquinavir has not been assessed, althoughthe syndrome was not reported when hard-gelsaquinavir was the only widely available PI.Whether soft-gel saquinavir, amprenavir, or non-peptidomimetic protease inhibitors such astipranivir cause lipodystrophy is not known.

Cardiovascular disease and proteaseinhibitors

There have been two reports of patients receiv-ing PIs developing ischaemic heart disease42,43.

However, a causal link has not been demonstratedand there are no data estimating prevalence or riskfactors of cardiovascular disease in patients receiv-ing PIs or non-PI therapy. Some cases have oc-curred in patients with other risk factors, and others inthose who had received PI therapy for a very shortperiod and therefore are more likely to represent aprothrombotic effect of PI therapy rather than an ath-erosclerotic effect.

Patients with diabetes mellitus or impaired glu-cose tolerance are at increased risk for microvas-cular diabetic disease such as retinopathy, neu-ropathy and nephropathy over a 5-year period44.Patients on longterm stable PI therapy should prob-ably be monitored for these conditions.

Table 2. Possible therapeutic strategies.

Problem Possible therapy (example) Comments

Fat wasting anabolic steroids testosterone anabolic for muscle not fat

growth hormone increases insulin resistance

anabolic for muscle not fat

glitazones troglitazone PPAR-! agonist (? anabolic for fat)

potential P450 interaction (? increased risk of troglitazone-induced

hepatitis)

rexinoid cis-9-RA RXR agonist (? anabolic for fat)

Fat accumulation growth hormone ? intralesional for buffalo hump

low fat diet could exacerbate peripheral fat wasting

increased exercise could exacerbate peripheral fat wasting

Hyperlipidaemia statins atorvastatin potential P450 interaction (? increased risk for statin-induced myositis)

fibrates clofibrate -

Insul in resistance diet

exercise

Diabetes mellitus diet treat as for type 2 diabetes mellitus in general population

exercise

oral hypoglycaemics sulphonylureas

insulin

For all manifestations, unproven options include: switching from ritonavir-saquinavir to indinavir or nelfinavircessation of all protease inhibitors

Patients should be monitored for cardiovascular symptoms and signs

Potential cardiovascular risk factors should be addressed: hypertension, smoking, physical inactivity

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Diagnosis

Patient report appeared useful for diagnosis oflipodystrophy as self-reported presence or ab-sence of fat wasting related to body fat mass using

DEXA12. Nevertheless, given the large variability inbody fat in the general and HIV-infected popula-tions, mean body fat appeared insufficient for diag-nosis of all cases. Metabolic abnormalities may alsobe useful diagnostically17. Changes in body fat andmetabolic parameters following commencement ofPI therapy may well improve diagnosis, but this hasnot been demonstrated. As there is no gold diag-nostic standard for diagnosing lipodystrophy, diag-nostic criteria may eventually resemble those fordiseases such as rheumatoid arthritis and systemiclupus erythematosis, where presence of a minimumnumber of clinical and laboratory abnormalities will

confirm the diagnosis. Consensus guidelines areclearly needed.

Treatment

There is no proven therapy for any component ofthe syndrome. Options worthy of investigation aresummarised in Table 2, based on anecdotal andcase reports. Some options have theoretical hand-icaps which may prevent their routine use. Also, itis not known whether hyperlipidaemia or insulin re-sistance in the absence of glucose intoleranceshould be treated, nor at what level. Treatment oflipids alone may not affect cardiovascular risk if in-sulin resistance is not also addressed (and viceversa). Factors that would affect a decision to treat

would include the patient status, the likelihood thatPI therapy would be ongoing, the severity of anyfeature, and the presence of other cardiovascularrisk factors (Table 3).

The role of diet and exercise have not been eva-luated. Although increased exercise or a very res-trictive diet might theoretically reduce central fataccumulation, lipids and insulin resistance, thismight be at the expense of increased peripheral fatwasting. Certainly, no diet should interfere with PIdrug absorption or overall patient wellbeing.

Some agents may be problematic. Anabolicsteroids are anabolic for muscle not fat, although in-creased muscle mass may partially disguise fatloss. Intralesional growth hormone appeared to re-duce the size of buffalo humps in 2 patients45, butcan exacerbate insulin resistance if given parenter-ally and so precipitate diabetes. The statins (lipidlowering agents) and glitazones (insulin sensitisersand possible peripheral adipocyte growth factors -see below) are metabolised by cytochrome P4503A (which is inhibited by PIs) and so their use with

PIs could increased the risks for myositis and he-patitis, respectively. Brief reports suggest that gem-fibrozil and atorvastatin may be safe and havesome efficacy in lowering lipids32,46.

Surgery (excision or liposuction) has been per-formed on some patients with severe fat accumula-tion, although fat may reaccumulate within a matterof months. There is no report of surgery for fat wast-ing, an approach used for some forms of congen-tial lipodystrophy.

One theoretical treatment option is PI withdrawalor substitution. It should be emphasised, however,that it is not known whether lipodystrophy is re-versible if PI therapy is withdrawn. Several studiesare currently evaluating this strategy, using newernucleoside analogues and non-nucleoside agents.Non-PI strategies may well fail in future for otherreasons, however. Therefore, even if non-PI strate-gies are successful, it is essential that therapiesthat prevent the syndrome in those commencingPIs be developed. Cessation of PIs should be con-sidered for patients who have failed therapy if thereis evidence of lipodystrophy or insulin resistance.The data mentioned above suggests that substitu-tion with another PI is not likely to be effective for alarge proportion of patients.

Pathogenesis

All HIV PIs have high affinity for the catalytic siteof HIV protease and so might induce this syndromeby binding and inhibiting an homologous humanprotein(s) involved in lipid metabolism47. A 12amino acid sequence (aa 19 to 30) spanning thecatalytic region of HIV protease has homologies atthe protein level of 63 percent with a region incor-porating a lipid binding domain in the low densitylipoprotein-receptor-related protein (LRP) and of58 percent with a C-terminal region of the cyto-plasmic retinoic acid binding protein type 1(CRABP-1).

CRABP-1 binds all intracellular RA and presents

Fig. 2. Times to development of lipodystrophy for all patientsreceiving protease inhibitors (a) and those receivingindinavir or ritonavir-saquinavir (b). Lipodystrophy developedsignificantly earlier in those receiving ritonavir-saquinavir(P=0.013).(Reprinted from ref.12 with permission).

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RA to cytochrome P450 3A isoforms that catalyseRA conversion to cis-9-RA (Fig. 3). Cis-9-RA is thesole ligand of the retinoid X receptor (RXR) which inadipocyte nuclei functions as a heterodimer with

peroxisome proliferator activated receptor typegamma (PPAR-!). Ligand binding to RXR or PPAR-!inhibits adipocyte apoptosis and upregulatesadipocyte differentiation and proliferation andPPAR-! is preferentially expressed in peripheral ver-suscentral fat. Of note, RXR or PPAR-! agonists im-prove abnormal insulin sensitivity and hyperlipi-daemia, and result in peripheral fat accumulation.

CRABP-1 has multiple RA binding residues. HIVPIs may, therefore, bind this homologous regionwithin CRABP-1 and so inhibit the binding of RA toits binding pocket. Reduced cis-9-RA productionwould lead to reduced RXR activity and hence toreduced differentiation and increased apoptosis of

peripheral adipocytes. Both circumstances lead tohyperlipidaemia via reduced triglyceride storageand lipid release into the circulation. Necrosisseems less likely than apoptosis as the condition ispainless12-15.

Cytochrome P450 3A is the sole enzyme thatconverts RA to cis-9-RA. HIV PIs are potent in-hibitors of cytochrome P450 3A. Indeed, lipodystro-phy was worst in those receiving ritonavir12, themost potent cytochrome P450 3A inhibitor of the PIs.

LRP is an hepatic receptor important for post-prandial chylomicron clearance. LRP is complexedon capillary endothelium with lipoprotein lipase

(LPL), which cleaves fatty acids from circulatingtriglycerides, permitting free fatty acid entry intoadipocytes for storage as fat. The homologous re-gion in LRP contains a probable lipid binding do-main. PI binding of LRP could, therefore, exacer-bate hyperlipidaemia.

Central adipocytes (including perhaps those ofthe breast and dorso-cervical fat pad) are moremetabolically active than peripheral adipocytes. Inthe presence of impaired peripheral fat storage andhyperlipidaemia, central fat accumulation may oc-cur by default. In the presence of oestrogen, lipidwould also be sequestered in the breasts. Hyper-

lipidaemia also causes insulin resistance, by inter-ference with post-receptor insulin signalling, com-petition between glucose and lipid oxidation path-ways in skeletal muscle or inhibition of glycogensynthase.

CRABP-2 has 97 percent homology with CRABP-1 and is predominantly expressed in epidermis.Other adverse events of PI therapy, such as der-matitis, dry lips and nail dystrophy may, therefore,be a consequence of inhibited RA metabolism inthe integument. LRP is also the primary clearancereceptor for endogenous proteases including tissueplasminogen activator, a natural anti-coagulant. In-creased bleeding in hemophiliacs receiving PIssuggests that PIs do inhibit LRP function, in thiscase its uptake of tissue plasminogen activator.

Future research

Prospective studies are in progress to furtherassess the syndromes incidence and severity, andto determine if any clinical or biochemical parame-ter predicts the syndrome. Studies of lipodystrophyin women and children receiving PIs and its re-versibility upon ceasing or switching antiretroviralregimens are required. In vitroand in vivostudiesare required to explore the above hypothesis. A rel-evant animal model would be welcome.

Longer term follow-up is required to assesswhether vascular complications of insulin resis-tance and hyperlipidaemia will develop and if thereis any significant morbidity associated with longterm, severe fat depletion.

Newer HIV PIs that do not cause lipodystrophy,hyperlipidaemia and insulin resistance are re-

quired. Candidates include PIs that bind neitherCRABP-1 nor LRP, particularly the non-peptidic PIs.

Summary

The lipodystrophy syndrome is common with pro-longed PI therapy. Hyperlipidaemia and impairedglucose tolerance may lead to longterm micro andmacrovascular disease. Nevertheless, patients withadvanced HIV disease clearly benefit from PIs interms of disease progression, survival2 and reversalof some opportunistic infections48. Any survival ad-vantage in early HIV disease is unproven, however,

although biologically plausible and widely advo-cated 3,4. Non-PI therapy may be as potent as PIcombination therapy49 and needs to be explored asa therapeutic option for HIV infection, particularlyearly disease.

The manner in which this syndrome has beenidentified highlights the need for more thorough in-terpretation of pre-licensing data and for morethorough post marketing surveillance of agents ap-proved under accelerated licensing processes. Un-derstanding the underlying mechanisms shouldlead to treatment strategies and to the design ofnew PIs that do not cause this syndrome

Table 3. Factors that might influence treatment of metabolicabnormalities.

1. Patient status CD4 count "

HIV RNA #

prior AIDS

2. Likelihood that PI therapy would be ongoing (non-PI therapy

possible but switching not proven to be effective in

suppressing viral load nor in reversing metabolic

disturbances)3. Presence of both hyperlipidaemia and impaired glucose

tolerance

4. Diabetic symptoms

5. Pancreatitis related to hyperlipidaemia

6. Presence of known cardiovascular risk factors smoking

hypertension

family history

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References

1. Danner S, Carr A, Leonard J, et al. Safety, pharmacokinetics

and preliminary efficacy of ritonavir, an inhibitor of HIV-1 pro-

tease. N Engl J Med 1995; 333: 1528-33.

2. Hammer S, Squires K, Hughes M, et al. A controlled trial of two

nucleoside analogues plus indinavir in persons with human im-

munodeficiency virus infection and CD4 cell counts of 200 per cu-

bic millimeter or less. N Engl J Med 1997; 337: 725-33.

3. Carpenter C, Fischl M, Hammer S, et al. Antiretroviral therapy for

HIV infection in 1997: updated recommendations of the Interna-

tional AIDS Society - USA panel. JAMA 1998; 280: 78-86.

4. Gazzard B, Moyle G, on behalf of the BHIVA Guidelines Writing

Committee. 1998 revision to the British HIV Association Guide-

lines for Antiretroviral Treatment of HIV Seropositive Individuals.

Lancet 1998; 352: 314-6.

5. Carr A, Cooper D. Restoration of immunity to chronic hepatitis B

infection in HIV-infected patient on protease inhibitor (letter).

Lancet 1997; 349: 995-6.

6. Race E, Adelson-Mitty J, Kriegel G, et al. Focal mycobacterial

lymphadenitis following initiation of protease-inhibitor therapy in

patients with advanced HIV-1 disease.Lancet 1998; 351: 252-5.

7. French M, Lenzo N, John M, et al. Immune restoration disease

after treatment of immunodeficient HIV-infected patients with

potent anti-retroviral therapy. In: Abstracts of the 12th World

AIDS Conference, Geneva, June, 1998 (abstract 22323).

8. Deeks S, Smith M, Holodny M, et al. HIV-1 Protease inhibitors:

a review for clinicians. JAMA 1997; 277: 145-53.

9. Carr A, Brown D, Cooper D. Portal vein thrombosis in patients

receiving indinavir (letter). AIDS 1997; 11: 1657-8.10. Grunfeld C, Feingold K. Metabolic disturbances and wasting in

the acquired immunodeficiency syndrome. N Engl J Med 1992;

327: 329-37.

11. Paton N, Macallan D, Jebb S, et al. Longtitudinal changes in

body composition measured with a variety of methods in pa-

tients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol

1997; 14: 119-27.

12. Carr A, Samaras K, Burton S, et al. A Syndrome of peripheral

lipodystrophy, hyperlipidaemia and insulin resistance in patients

receiving HIV protease inhibitors. AIDS 1998; 12: F51-8.

13. Viraben R, Aquilina C. Indinavir-associated Lipodystrophy. AIDS

1998; 12: F37-9.

14. Miller K, Jones E, Yanovski J, et al.Visceral abdominal-fat accumu-

lation associated with use of indinavir. Lancet 1998; 351: 871-5.

15. Lo J, Mulligan K, Tai V,et al

. Buffalo hump in men with HIV-1infection. Lancet 1998; 351: 867-70.

16. Bonjoch A, Veny A, Johnston S, et al. Body composition mea-

surements by anthropometry and bioelectrical impedance to

evaluate redistribution of body fat in HIV-positive patients on an-

tiretroviral treatment. In: Abstracts of the 37th ICAAC, San

Diego, September, 1998 (abstract 1-94).

17. Carr A, Samaras K, Thorisdottir A, et al. Prevalence and sever-

ity of protease inhibitor-induced lipodystrophy and insulin resis-

tance. In: Abstracts of the 12th World AIDS Conference, Gene-

va, June, 1998 (abstract 22323).

18. Veny A, Bonjoch A, Romeu J, et al. Cumulative risk for develop-

ing protease inhibitor-associated lipodystrophy in HIV-infected

patients. In: Abstracts of the 37th ICAAC, San Diego, Septem-

ber, 1998 (abstract 1-92).

19. Hengel R, Watts N, Lennox J. Multiple symmetrical lipomatosis

associated with protease inhibitors. Lancet 1997; 350: 1596.20. Roth V, Kravcik S, Angel J. Development of cervical fat pads

Fig. 3. Proposed mechanism of HIV protease inhibitor (PI)-induced peripheral lipodystrophy, hyperlipidaemia, central obesity,breast hypertrophy and insulin resistance.Sites of protease inhibitor action are represented by solid bars, dashed arrows and encircled numerals.The primary event isimpaired generation of cis-9-retinoic acid (cis-9-RA) from retinoic acid (RA), either by direct binding to cytoplasmic retinoic acidbinding protein type 1 (CRABP-1)1 or by inhibition of cytochrome P450 3A isoforms that metabolise RA to cis-9-RA2. This leads toreduced retinoid X receptor (RXR) stimulation and so to apoptosis and impaired differentiation of peripheral adipocytes, with lipidrelease and/or reduced lipid storage. Inhibition of low density lipoprotein receptor-related protein (LRP) would lead to reducedcleavage of fatty acids from circulating triglycerides by the LRP-lipoprotein lipase (LPL) complex on vascular endothelium3andreduced hepatic uptake of chylomicrons4. The resulting hyperlipidaemia would lead to some fat redistribution to the abdomen (andin the breasts under the influence of oestrogen) and to insulin resistance, with secondary type 2 diabetes mellitus in susceptibleindividuals. Inhibition of CRABP-2 would result in ectodermal dysplasia (ingrown toenails, dry lips and skin)5. Inhibition of LRPwould also block uptake of tissue plasminogen activator (tPA) and so lead to increased bleeding in haemophiliacs6.(Modified from ref. 38 with permission).

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8/8

36

A

I

D

S

R

EV

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W

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AIDS Rev 1999 ; 1

following therapy with human immunodeficiency virus type 1

protease inhibitors. Clin Infect Dis 1998; 27: 65-7.

21. Miller K, Daly P, Sentochnik D, et al. Pseudo-cushings syn-

drome in human immunodeficiency virus-infected patients. Clin

Infect Dis 1998; 27: 68-72.

22. Striker R. Localized adipose tissue hypertrophy in patients re-

ceiving human immunodeficiency virus protease inhibitors. Clin

Infect Dis 1998; 27: 218-9.

23. Herry I, Bernard L, de Truchis P, Perronne C. Hypertrophy of the

breasts in a patient treated with indinavir (letter). Clin Infect Dis

1997; 25: 937-8.24. Dong K, Flynn M, Dickinson B, et al. Changes in body habitus in

HIV+ women after initiation of protease inhibitor therapy. In: Ab-

stract of the 12th World AIDS Conference, Geneva, June, 1998

(abstract 12373).

25. Gervasoni C, Ridolfo AL, Trifiro G, et al. Redistribution of body fat

in HIV-infected women undergoing combined antiretroviral thera-

py:Clinical immunological, and Metabolic Analyses. In: Abstracts

of the 37th ICAAC, San Diego, September, 1998 (abstract 1-93).

26. Regan AM, Babl FE. Abnormal body fat accumulations in HIV-

infected children on antiretroviral therapy. In: Abstract of the 37th

ICAAC, San Diego, September, 1998 (abstract 1-86).

27. Mulligan K, Tai VW, Algren H, et al. Evidence of unique meta-

bolic effects of protease inhibitors. In: Abstract of the 5th Con-

ference on Retroviruses and Opportunistic Infections, Chicago,

February, 1998, (abstract 414).

28. Lumpkin M. Reports of diabetes and hyperglycaemia in patients re-

ceiving protease inhibitors for the treatment of human immunodefi-

ciency virus infection.FDA Public Health Advisory, June 11, 1997.

29. Dube M, Johnson D, Currier J, et al. Protease inhibitor-associ-

ated hyperglycaemia (letter). Lancet 1997; 350: 713-4.

30. Walli R, Herfort O, Michl G, et al. Treatment with protease in-

hibitors associated with peripheral insulin resistance and im-

paired glucose tolerance in HIV-1-infected patients.AIDS 1998;

12: F167-74.

31. Nelson M, Moyle G, Newell A, et al. The incidence of hyperlipi-

daemia with protease inhibitors. In: Abstracts of the 37th ICAAC,

San Diego, September, 1998 (abstract 1-87).

32. Hewitt R, Shelton L. Gemifibrozil effectivity lowers protease in-

hibitor-associated hypertriglyceridemia in HIV-1+ patients. In:

Abstracts of the 37th ICAAC, San Diego, September, 1998 (ab-

stract 1-88).33. Yarasheski KE, Tebas P, Sigmund CM, et al. Insulin resistance

in HIV-protease inhibitor-associated diabetes. In: Abstracts of

the 37th ICAAC, San Diego, September, 1998 (abstract 1-90).

34. Rothstein A, Caldwell R, Allmon C, et al. Investigation of pro-

tease Inhibitor-associated hypercholesterolemia in a university-

based HIV Clinic. In: Abstracts of the 37th ICAAC, San Diego,

September, 1998 (abstract 1-91).

35. Green R, Raghavan S, Levin K, et al. Change in weight, body

composition, and serum lipids prior to and after initiation of pro-

tease inhibitors. In: Abstracts of the 37th ICAAC, San Diego,

September, 1998 (abstract 1-94).

36. Keruly J, Mehta S, Chaisson R, et al. Incidence of and factors

associated with the development of hypercholesterolemia and

hyperglycemia in HIV-infected patients using a protease In-

hibitor. In: Abstracts of the 37th ICAAC, San Diego, September,

1998 (abstract 1-95).

37. Dube M, Johnson D, Currier J, et al. Protease inhibitor-associ-

ated hyperglycaemia: results of switching from indinavir to nelfi-

navir. In: Abstract of the 12th World AIDS Conference, Geneva,

June, 1998 (abstract 32172).

38. Papadopoulos A, Evangelopoulou E, Nicolaidi N, et al. Serum

lipid changes in HIV-infected patients under combination thera-

py containing a protease inhibitor.In: Abstract of the 12th World

AIDS Conference, Geneva, June, 1998 (abstract 60018).39. Vancouwenberghe C, King JH, Gordon J, et al. Clinical investi-

gation of the incidence and severity of elevated cholesterol and

triglycerides in AIDS patients receiving protease inhibitor thera-

py. In: Abstracts of the 37th ICAAC, San Diego, September,

1998 (abstract 1-69).

40. Bernasconi E, Carota A, Megenta L, et al. Metabolic changes in

HIV-infected patients treated with protease inhibito therapy. In:

Abstract of the 12th World AIDS Conference, Geneva, June,

1998 (abstract 12375).

41. Markowitz M, Saag M, Powderly W, et al. A preliminary study of

ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection.

N Engl J Med 1995; 333: 1534-8.

42. Henry K, Melroe H, Huebsch J, et al. Severe premature coro-

nary artery disease with protease inhibitors. Lancet 1998; 351:

1328.

43. Behrens G, Schimdt H, Meyer D, et al. Vascular complications

associated with HIV protease inhibitors. Lancet 1998; 351: 1958.

44. Expert Committee on the Diagnosis and Classification of Dia-

betes Mellitus. Report of the Expert Committee on the Diagno-

sis and Classification of Diabetes Mellitus.Diabetes Care 1998;

21: S5-19.

45. Torres R.Treatment of dorsocervial fat pads and truncal adipos-

ity with recombinant growth hormone in patients with AIDS

maintained on HAART. In: Abstract of the 12th World AIDS Con-

ference, Geneva, June, 1998 (abstract 32164).

46. Henry K, Melroe H, Huebesch J, et al. Atorvastatin and gemfi-

brozil for protease inhibitor-related lipid abnormalities. Lancet

1998; 352: 1031.

47. Carr A, Samaras K, Chisholm D, et al. Pathogenesis of HIV Pro-

tease inhibitor-associated syndrome of peripheral lipodystrophy,

hyperlipidaemia and insulin resistance.Lancet 1998;351: 1881-3.48. Carr A, Marriott D, Field A, et al. Combination antiretroviral ther-

apy of HIV-associated microsporidiosis and cryptosporidiosis.

Lancet 1998; 351: 256-61.

49. Staszewski S, Morales-Ramirez J, Flanigan T, et al. A Phase

II, multicenter, randomized, open-label study to compare the

antiretroviral activity and tolerability of efavirenz + indinavir,

versus efavirenz + zidovudine + lamivudine, versus indinavir

+ zidovudine + lamivudine at 24 weeks. In: Abstracts of the

12th World AIDS Conference, Geneva, June, 1998 (abstract

22336).