Stéatose et VIH A propos d’un cas clinique Dr Slama Laurence, Dr Maud Lemoine Service des maladies infectieuses, Hôpital Tenon Service d’Hépatologie, Hôpital Jean-Verdier SFLS Bordeaux 10 décembre 2007

Mr COU, 43 ans Pas d’antécédents personnels ou familiaux VIH+ connu depuis Juin 1990 Pas de coinfection VHB, VHC CD4 à 263/mm³ (13%) Traité depuis 1993 par : - AZT pdt 18 mois - AZT+ ddC pdt 1 an: CD4 à 299/mm³ (17%) CV à 124 000 copies/ml en 02/96 - d4T + 3TC (10/96) - d4T+ 3TC+ Saquinavir (97) : CD4 421/mm³ (20%) et CV à 900 copies/ml Ostéonécrose aiguë de tête la fémorale en juin 97

Mr COU , 43 ans Switch pour D4T+ 3TC+ indinavir en 10/97 CD4 à 389/mm³(18%) et CV à 40 000 copies/ml (05/98) Poids 76 kg pour 1m82 (BMI = 23 kg/m2) Apparition progressive d’une lipodystrophie mixte TA 130/80 mmHg Glycémie à jeun 6,1 mmol/l ASAT, ALAT : 2N (arrêt alcool en 1995) TG à 5 mmol/l puis 26 mmol/l puis 13 mmol/l : maxepa + dietéticienne Changement de traitement pour d4T+ddI+EFV Deuxième poussée d’ONA : PTH en juin 1999

Mr COU, 43 ans Normalisation des triglycérides en 2000 Lipodystrophie stable Modification du traitement ARV en 2000 pour du Trizivir Persistance des Transaminases à 1,5-2N Avril 2001 : CD4 464/mm³ et CV< 50 copies/ml 2002 : échappement virologique à 30 000 copies/ml Puis aggravation progressive du bilan hépatique

Mr COU, 43 ans Mars 1999 Mars 2000 Mars 2001 Mars 2002 Dec 2002 ASAT (UI/l) 38 53 68 75 155 ALAT (UI/l) 57 67 52 151 336 PAL (UI/L) 70 29 GGT (UI/l) 40 46 42 123

Quelles sont les causes d’élévation isolée des transaminases chez le patient VIH ? Aiguë Hépatites virales aiguës HBV, HCV Réactivation virale B Séroconversion HBe, HBS Surinfection Delta Hépatite A et hépatite E CMV, EBV, HSV, parvovirus B19 Migration lithiasique Hépatite alcoolique Hépatite médicamenteuse Hépatite auto-immune en poussée Chronique Hépatites virales chroniques HBV (+/-Delta), HCV Hépatite médicamenteuse Hépatite auto-immune

Résultats… VHC- Ac anti HbS + isolés EBV: -, CMV -, HSV- Arrêt de l’alcool depuis 1995 Ac antiTissus négatifs Pas d’introduction de traitements hépatotoxiques Echographie hépatique: Foie hyperéchogène sans lésion focale Voies biliaires fines Pas d’épanchement péritonéale

Quelles hypothèses diagnostiques ?

Hypothèses diagostiques Toxicité mitochondriale « retardée »? Stéatose hépatique non alcoolique associée à la lipodystrophie ?

Rappel AZT+ddC 09/1995 d4T+3TC 10/1996 d4T+3TC+ saquinavir 05/1997 d4T+ 3TC + indinavir 10/1997 d4T+ ddI+ EFV 09/1998 ddI+ AZT+3TC+ABC 10/2000

Résultats Acide lactique normal Pas d’introduction d’autres traitements, pas de signes cutanés Hypothèse retenue Stéatose hépatique non alcoolique

Pourquoi évoquer une stéatose hépatique non alcoolique? Aspect hyperéchogène à l’échographie Toutes les autres causes d’élévation chronique des transaminases ont été éliminées Lipodystrophie très souvent associée à une insulino-résistance Et l’insulino-résistance joue un rôle central dans le développement des lésions de stéatose et de stéatohépatite

Stéatose hépatique non alcoolique Nonalcoholic Fatty Liver Disease (NAFLD) Accumulation intrahépatocytaire de TG Hépatopathie fréquente 1ère cause: obésité et syndrome métabolique Expression hépatique du syndrome métabolique Marchesini et al, Hepatology 2003

Cirrhose Stéatose 10-25 % Stéatohépatite (NASH) 15 % 50% fibrose CHC 4%

Syndrome métabolique Associé à une Insulino-résistance DEFINITION Obésité abdominale  94 cm H, 80 cm F et au moins deux critères: TG  1,7 mmol/l HDL < 1 mmol/l H, 1,3 mmol/l F TA  130/85 ou traitement Glycémie à jeun  5,6 mmol/l ou D2T Associé à une Insulino-résistance

Chez le patient VIH Anomalies métaboliques et insulino-résistance fréquentes induites par la HAART Patients à risque de stéatose et de stéatohépatite Série autopsique: 30 % des patients VIH+ Trojan et al Pathologe 1998 50 % des patients VIH +, Lipodystrophiques Sutinen et al AIDS 2002

14,5% 57% 28,5% Lemoine et al AIDS 2006

Quel bilan métabolique doit être réalisé ?

Bilan métabolique BMI: 23 kg/m2 Tour de Taille: 95 cm TA : 130/80 mmHg Glycémie à jeun : 5,2 mmol/l Bilan lipidique à jeun : Cholestérol total et LDL/HDL: normal TG 2,3 mmol/l Insulinémie à jeun : 18 µUI/L HOMA : 4,2

Mesure de l’insulino-résistance Homeostasis Model Assessment of Insulin Resistance HOMA: [Insulinémie (µUI/ml) x Glycémie A Jeun (mmol/l)] / 22.5 Résistance à l’insuline si HOMA > 3 Quantitative Insulin Check Index QUICKI: 1 / (log [Ins (µUI/ml)] + log [Gly (mg/dl)])

Comment confirmer le diagnostic de stéatose hépatique non alcoolique ?

Diagnostic histologique Réalisation d’une PBH (2002) Stéatose macrovésiculaire touchant plus de 60 % des hépatocytes Fibrose portale Définition de la NASH Critères de Brunt 1-Stéatose 2-Nécrose, et Ballonisation des hépatocytes Avec ou Sans Fibrose

Les marqueurs non invasifs Fibroscan, Fibrotest, Steatotest, Nashtest, Apri, Fib4… Non validés Outils diagnostiques

Quelle est la conduite thérapeutique ?

Correction des facteurs de stéatose et d’insulino-résitance Traitement de l’hypertriglycéridémie Traitement de l’insulino-résistance: Conseils diététiques Exercise physique Modification du traitement ARV

Evolution ASAT 216 UI/l, ALAT 393 UI/l,GGT 169 UI/l TG 2 mmol/l Modification du traitement ARV pour FTC+ddI+Atazanavir en 2004 Bilan immuno viro stable avec CV< 50 copies/ml Amélioration du BH : ASAT : 77 UI/l (N<40), ALAT 47 UI/l (N<40 UI/L) PAL: 84 UI/l gGT:65 (N<40) PBH de contrôle

Résultats de la deuxième PBH (2004) Biopsie initiale Nouvelle Biopsie

Cirrhose constituée Quel est le bilan et le suivi ?

Prise en charge de la cirrhose FOGD à la recherche de VO ou de varices gastriques Echographie + doppler hépatique/6mois CHC ? Permméabilité du tronc porte + Dosage d’FP sérique Bilan d’hémostase

Depuis sa deuxième PBH… Introduction d’un traitement par pioglitazone (Actos®) Fibrotest A0/F3 en 2005 Fibrotest A0/F1 en 2006 ASAT : 43 UI/l, ALAT 32 UI/l, PAL 59 UI/l GGT: 75 UI/L Fibroscan (élastométrie) : 6,8 kPa

Comment corriger la stéatose et l’insulino-résistance ? Activité physique, amaigrissement Traitement hépatoprotecteur et anti-oxydant Vitamine E, Acide ursodésoxycholique Traitements insulino-sensibilisants Metformine Thiazolidiones: agonistes de PPAR Pioglitazone (Actos) Rosiglitazone (Avandia) Troglitazone Rimonabant : antagoniste du récepteur endocannabinoïde de type 1

Régime diététique et activité physique Régime hypocalorique Huang MA, Am J Gastroenterol 2005 = 16 patients avec une NASH histologiquement prouvée Régime + PBH à M12. Amélioration de l’IR et des lésions histologiques chez 9/15 patients.

Effet de la Rosiglitazone sur le stéatose 47 % (15/32) 16 % (5/31) ROSIGLITAZONE PLACEBO P<0.015 % pts HISTOLOGICAL RESPONSE (>30% reduction in steatosis) Ratziu et al, AASLD 2006

Effet de la Rosiglitazone sur L’IR Placebo (N=31) Serum glucose (mmol/l) Insulin*, (median mUI/l) HOMA* -0.93 0.55 -5.5 2.5 -1.4 0.59 <0.001 0.001 P D EOT - Baseline HbA1c*, (%) -1.15 0.26 <0.02 Ratziu et al, AASLD 2006 * In non-diabetics

A Placebo-Controlled Trial of Pioglitazone in Subjects with Nonalcoholic Steatohepatitis Dec 2006 Belfort et al Amélioration de l’Insulinosensibilité hépatique

Belfort et al NEJM Dec 2006 Effet anti-stéatosique

Belfort et al NEJM Dec 2006 Effet anti-fibrosant ?

Effet de la Rosiglitazone chez le patient VIH Effet insulino-sensibilisant Correction de la lipoatrophie selon les études MAIS Augmentation du cholestérol sérique Sutinen Antiv Ther Juin 2003, Hadigan et al 2004, Car et al Lancet 2004, Van Mijk et al Ann Intern Med 2005 Calvanti JID 2007 Infection 2006 Pas d’évaluation histologique

En soumission à l’ANRS ETUDE CONTROLEE RANDOMISEE COMPARANT L’EFFET DE LA PIOGLITAZONE VERSUS PLACEBO DANS LA STEATOHEPATITE NON ALCOOLIQUE CHEZ LES PATIENTS VIH SOUS HAART

antagoniste des récepteurs endocannabinoïdes de type 1: CB1 Rimonabant: antagoniste des récepteurs endocannabinoïdes de type 1: CB1 Van Gaal et al Lancet 2005

Rimonabant: antagoniste des récepteurs endocannabinoïdes de type 1: CB1 Van Gaal et al , Lancet 2005

Rimonabant: antagoniste des récepteurs endocannabinoïdes de type 1: CB1 Van Gaal et al Lancet 2005

Rimonabant: antagoniste des récepteurs endocannabinoïdes de type 1: CB1 Effet anti-fibrosant Aire de fibrose Souris traitées par un antagoniste CB1 Teixeira-Clerc et al Nat Med 2006

Conclusions: Stéatose et stéatohépatite: fréquentes chez le patient VIH lipodystrophique Y penser ! Potentiellement grave: cirrhose et CHC Diagnostic histologique Marqueurs non invasifs non validés Traitements en cours d’évaluation

Rosiglitazone in the treatment of HAART-associated lipodystrophy— a randomized double-blind placebo-controlled study. Sutinen Antiv Ther Juin 2003 Highly active antiretroviral therapy (HAART) is associated with metabolic adverse events such as insulin resistance and lipodystrophy, that is, atrophy of subcutaneous fat and accumulation of intra-abdominal fat. Currently, there is no pharmacological treatment for lipoatrophy. Glitazones, a novel class of insulin-sensitizing anti-diabetic agents, increase subcutaneous fat in patients with type 2 diabetes. There are no controlled studies of glitazones in patients with HAART-associated lipodystrophy (HAL). In this randomized, double-blind, placebo-controlled study, 30 patients with HAL received either rosiglitazone (8 mg daily) or placebo for 24 weeks. Baseline characteristics were compared to a group of 30 age-, sex- and weight-matched HIV-negative controls. At baseline, patients with HAL had 1.8-fold (P<0.001) more intra-abdominal and 2.4-fold (P<0.05) more liver fat than HIV-negative controls, who had 1.8-fold (P<0.001) more subcutaneous fat than the patients. After 24 weeks of treatment, rosiglitazone had no effect on body weight, subcutaneous or intra-abdominal fat (magnetic resonance imaging), total body fat (bioimpedance analysis), anthropometric measurements or serum leptin concentrations (a circulating marker of adipose tissue mass). However, rosiglitazone decreased % liver fat (spectroscopy) and serum insulin concentrations, and normalized liver function tests. During the first 12 weeks of rosiglitazone treatment, serum triglycerides increased from 3.5 +/- 0.5 to 6.5 +/- 2.0 mmol/l (from 310 +/- 44 to 575 +/- 177 mg/dl) (P<0.05) and serum cholesterol from 6.0 +/- 0.4 to 7.8 +/- 0.7 mmol/l (from 232 +/- 15 to 301 +/- 27 mg/dl) (P<0.01). Contrary to data in other patient groups, rosiglitazone did not increase subcutaneous fat in patients with HAL after 24 weeks of treatment. Rosiglitazone seemed to ameliorate insulin resistance judged by the decreased serum insulin concentrations and % liver fat. Rosiglitazone unexpectedly caused significant increases in serum triglyceride and cholesterol concentrations, which must be carefully monitored if glitazones are used in these patients.

Hadigan et al 2004Metabolic effects of rosiglitazone in HIV lipodystrophy: a randomized, controlled trial. BACKGROUND: Patients with HIV infection who are treated with antiretroviral agents often lose subcutaneous fat and have metabolic abnormalities, including insulin resistance and reduced adiponectin levels, which may be related to disrupted subcutaneous adipogenesis and altered peroxisome proliferator-activated receptor-gamma signaling. OBJECTIVE: To investigate the effects of rosiglitazone (4 mg/d), a peroxisome proliferator-activated receptor-gamma agonist, in HIV-infected men and women with hyperinsulinemia and lipoatrophy. DESIGN: A randomized, double-blind, placebo-controlled, 3-month study. SETTING: University hospital. PATIENTS: 28 HIV-infected men and women with hyperinsulinemia and lipoatrophy. MEASUREMENTS: Insulin sensitivity measured by euglycemic hyperinsulinemic clamp testing; subcutaneous leg fat area measured by computed tomography; adiponectin, free fatty acid, and lipid levels; and safety variables. RESULTS: Rosiglitazone, when compared with placebo, improved insulin sensitivity (mean [+/-SD] change, 1.5 +/- 2.1 mg of glucose/kg of lean body mass per minute vs. -0.4 +/- 1.6 mg/kg per minute; P = 0.02), increased adiponectin levels (mean [+/-SD], 2.2 +/- 2.2 micro g/mL vs. 0.1 +/- 1.1 microg/mL; P = 0.006), and reduced free fatty acid levels (mean [+/-SD], -0.09 +/- 0.1 mmol/L vs. 0.01 +/- 0.1 mmol/L; P = 0.02). Mean percentage (+/-SD) of body fat (1.38% +/- 3.03% vs. -0.83% +/- 2.76%; P = 0.03) and subcutaneous leg fat area (2.3 +/- 8.4 cm2 vs. -0.9 +/- 1.9 cm2; P = 0.02) increased significantly with rosiglitazone compared with placebo. Mean total cholesterol levels (+/-SD) also increased with rosiglitazone compared with placebo (0.6 +/- 1.0 mmol/L [25 +/- 37 mg/dL] vs. -0.4 +/- 0.6 mmol/L [-15 +/- 25 mg/dL]; P = 0.007). LIMITATIONS: The study was relatively small and of short duration. CONCLUSIONS: The authors demonstrated positive effects of rosiglitazone on lipoatrophy; insulin sensitivity; and metabolic indices, including adiponectin levels, in HIV-infected patients with lipoatrophy and insulin resistance. Peroxisome proliferator-activated receptor-gamma agonists may correct the metabolic abnormalities associated with disrupted adipogenesis in this population. Further studies must determine the clinical utility of such agents in HIV-infected patients.

Hadigan AIDS 2007 Rosiglitazone increases small dense low-density lipoprotein concentration and decreases high-density lipoprotein particle size in HIV-infected patients. After 12 weeks of rosiglitazone treatment, significant increases in total and small dense low-density lipoprotein, and the total: high-density lipoprotein (HDL)-cholesterol ratio were found. The large HDL concentration and HDL particle size decreased significantly with rosiglitazone compared with placebo. These data indicate the production of a more atherogenic lipid profile with rosiglitazone, a consideration when selecting treatment for the growing population of HIV-infected patients with type 2 diabetes and dyslipidemia.

Calvanti: J Infect Disease 2007 A randomized, placebo-controlled trial of rosiglitazone for HIV-related lipoatrophy. BACKGROUND: Thiazolidinediones such as rosiglitazone may have benefit in ameliorating human immunodeficiency virus (HIV) lipoatrophy. METHODS: HIV-positive patients receiving stable, protease inhibitor-containing highly active antiretroviral therapy with HIV lipodystrophy were prospectively randomized to rosiglitazone (4 mg/day) or placebo. The primary end point was the 24-week percentage change in arm fat by dual-energy x-ray absorptiometry (DEXA). Clinical and anthropometric evaluations, fasting lipid parameters, oral glucose tolerance testing, CD36 expression, quality of life measures, and DEXA scanning were performed at baseline and week 24. RESULTS: Seventy-eight of the 96 enrolled patients were evaluated. Median age was 46.8 years, 97.4% were male, and 54% were treated with thymidine analogues. Median baseline limb fat was 3.76 and 2.99 kg in the rosiglitazone and control groups, respectively. Median changes in arm, leg, trunk, and total body fat at 24 weeks were not significantly different between groups (7.1% vs. 5.0% [P=.94]; 0.1% vs. -2.4% [P=.90]; 1.2% vs. -1.4% [P=.81]; and 1.7% vs. 0.4% [P=.76]). There were no significant changes in secondary end points. There was no correlation between changes in body fat or treatment-arm and CD36 expression. CONCLUSIONS: This randomized, placebo-controlled trial did not show benefit of 4 mg/day of rosiglitazone on lipoatrophy or metabolic parameters in patients with HIV lipodystrophy.

Effects of metformin and rosiglitazone in HIV-infected patients with hyperinsulinemia and elevated waist/hip ratio AIDS 2007 Mulligan et al San Fran OBJECTIVE: To evaluate the effects of metformin and rosiglitazone, alone or in combination, on fat distribution, insulin sensitivity, and lipids in HIV-infected patients with insulin resistance and changes in fat distribution. METHODS: A total of 105 subjects were randomly assigned to receive metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks) with rosiglitazone placebo (Met/P, N = 26); rosiglitazone (4 mg/day) with metformin placebo (Rosi/P, N = 27); rosiglitazone (4 mg/day) plus metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks; Met/Rosi, N = 25); or dual placebo (P/P, N = 27) for 16 weeks. Efficacy assessments included oral glucose tolerance testing, abdominal computed tomography, whole-body dual-energy X-ray absorptiometry, and the measurement of fasting lipids and other biochemical indices. Safety was monitored throughout. Intent-to-treat analyses were performed using non-parametric methods. RESULTS: The median insulin area under the curve (AUC) decreased significantly compared with baseline in both groups randomly assigned to rosiglitazone (Rosi/P -25.7 microIU/ml, P = 0.012; Met/Rosi -17.7 microIU/ml, P = 0.002); and tended to decrease in the Met/P group (-11.1 microIU/ml, P = 0.058). The change in AUC with combination therapy was significant compared with placebo (P = 0.032). No treatment was associated with significant changes in visceral or subcutaneous abdominal fat. Leg fat increased in subjects on Rosi/P compared with placebo (+4.8 versus -8.3%, P = 0.034). Rosiglitazone, but not metformin, increased adiponectin but also increased LDL-cholesterol and decreased HDL-cholesterol. Gastrointestinal effects occurred frequently in subjects on metformin. CONCLUSION: Both treatments improved insulin sensitivity, but neither reduced visceral fat. Rosiglitazone may increase subcutaneous fat in some individuals.

Evaluation of Safety and Efficacy of Rosiglitazone in the Treatment of HIV-Associated Lipodystrophy Syndrome. Infection. 2006 Apr;34(2):55-61. BACKGROUND: HIV-associated lipodystrophy syndrome (LDS) as a long-term side effect of HAART is becoming increasingly important and negatively affects adherence to medication. Currently, an effective therapy is not available. There is some evidence that the drug class of thiazolidindiones might be effective in the treatment of LDS. PATIENTS AND METHODS: Prospective open-label study with 20 HIV-infected patients suffering from severe LDS. Patients received 4 mg rosiglitazone once daily for a 24-week study period. Efficacy was assessed by measurement of metabolic and anthropometric parameters, total body DXA scan, CT scan of the abdomen, photo documentation and self-assessment. RESULTS: Rosiglitazone treatment was well tolerated. DXA scans demonstrated a highly significant increase in adipose tissue of the limbs (2644 +/- 1334 g vs 3380 +/- 1614 g, p </= 0.001) without any change in total fat mass. Abdominal CT-scans revealed a significant increase in subcutaneous adipose tissue (113.7 +/- 82.4cm(2) vs 125.3 +/- 83.7 cm(2), p = 0.04). Abdominal circumference decreased significantly (94.7 +/- 8.7 cm vs 92.2 +/- 8.45 cm, p = 0.03) without any relevant change of body weight or BMI. We observed an increase in serum cholesterol (248 vs 281 mg/dl, p = 0.006) and serum triglycerides (301 vs 351 mg/dl, p = 0.1). Furthermore, no side effects of clinical relevance were observed. The insulin sensitivity index improved without reaching statistical significance. Thirteen patients (65%) reported general improvement of LDS symptoms. Evaluation of photo documentation by five HIV-experts revealed poor concordance and no relevant change of LDS. CONCLUSIONS: The results of this study suggest that rosiglitazone is safe in the treatment of HAART-associated lipodystrophy and has moderate clinical efficacy. We found a trend towards improved insulin sensitivity and as a possible limiting factor an unfavorable increase in serum cholesterol and triglycerides.