ABNORMALITIES OF LIPIDS METABOLISM AND BODY FAT DISTRIBUTION - PowerPoint PPT Presentation

15 TH KAP Annual Scientific Conference, 23 rd – 26 th March 2011 KISUMU ABNORMALITIES OF LIPIDS METABOLISM AND BODY FAT DISTRIBUTION Presenter: Dr. Gordon Peter Yossa GSN ‐ Chairman Coast Division Work Places • Aga Khan Hospital ‐ GMC • Bomu Medical Clinic • Pandya Memorial Hospital – Skin Centre/ OPD

PHARMA ACCESS Metabolic Complication Lipodystrophy and Lipoatrophy • Loss of subcutaneous adipose tissue from extremities, gluteal region and face • Excess fat deposition in the neck (causing a buffalo hump) and trunk • Both protease inhibitors and reverse transcriptase inhibitors (d4t/dd1>dd1>d4t>ZDV>ABC and TDF) may cause lipodystrophy and atrophy • P1s are also associated with hyperglycemia, hypertriglyceridemia, and • hypercholesterolemia T o date, there are no treatments for HIV lipodystrophy and lipoatrophy with proven benefit

Possible favourable switches • P1 TO NNRTI and • d4T to ABC or TDF or • If these ARVs are not available, switch to ZDV

AIDS CARE – BRIAN GAZZARD Abnormalities of Lipid metabolism and body fat distribution • The advent of potent antiretroviral therapy has led to marked improvements in morbidity and morality in HIV ‐ infected patients but has been associated with the development of significant metabolic abnormalities. These abnormalities involve major perturbations of lipid, glucose and carbohydrate metabolism and in the long term, may result in increased cardiovascular disease. •

• The prevalence of lipodystrophy varies, but approximately 35% of patients on HAART have increased central adiposity or lipoatrophy and 50% have dyslipidaemia. Of the dyslipidaemias, 11% have Fredrickson’s type Iia hyperlipidaemia (isolated ypercholesterolaemia), 32% type Iib (hypercholesterolaemia and hypertriglyceridaemia) and 53% type IV or V (isolated hypertriglyceridaemia). The long term consequences of these abnormalities i.e. include an increased risk of cardivascular disease and pancreatitis. In addition, the morphological changes have marked phychological effects on the patient. Specifically, lowered self ‐ esteem, stigmatisation and depression have been associated with decreased adherence to HAART and quality of life.

A number of hypotheses have been postulated to explain these changes and these include: • NRTI – induced mitochondrial toxicity; • Impaired adipocyte differentiation and maturation (inhibition of sterol ‐ regulatory ‐ element binding protein ‐ 1 or SREBP ‐ 1 due to Pls; • Reduced entrapment of dietary lipid caused by the liver by Pls and NRTIs; • Inhibition of lipoptotein formation and release by the liver by Pls; • PI –induced increased insulin resistance and impaired glucosetransporter (Glut4) receptor ‐ mediated glucose uptake; and or • HAART ‐ induced immune activation/ cytokine dysregulation.

CASE PRESENTATION  AGE 41years  Sex – Female  Wt – 86kgs  BMI –  Gyne history – LMP 1/12/2010, no hormonal contraception  Obstetric history – Para 3, youngest 11yrs  Past medical history – Skin sepsis, ADR: Nevirapine, stocrin (Rashes), High BP 2005 with pill – pregnancy  Family history – SHPT +, DM – Nil  Social history – Married with children, alcohol/smoking – nil, exercise ‐ nil

Background  HAARTS – Highly Active Antiretroviral Therapy has led to marked improvement in morbidity and mortality in HIV/AIDS disease.  Associated with this is the development of significant abnormalities of lipid glucose and carbohydrate metabolism. End result is increased cardiovascular disease  Despite the impact of lipodystrophy on HIV/AIDS management, little is known about pathogenesis, prevention, diagnosis management and cardiovascular risk (George Behra etc HIV 2010: Hoftman Rockstron)  A case is presented highlighting cardiovascular risk. This is discussed in the light of current literatute on lypodystrophy syndrome at large.

Discussion Body Fat Abnormalities NEJM: 2005:352 – Steven Etali  Prevalence reported up to 40-50% of ambulatory HIV/Aids patient.  Cross sectional studies – (11-83)%  Lipodystrophy may be higher depending on cohort characteristics sex, age, race type/duration ART, criterion for diagnosis.  Intiation of HAARTS- Increase in limb fat in the first few months, then progressive decline in 3years – 14% per year in caucasians [zerit/AZT+3TC+PI/NNRT]  Truncal fat – initially increases and then stabilises in 2-3years  Limb/central fat masses clinically evident in 20-35% of patients in 12-24 months on combination ART.  Peripheral lipoatrophy clinically evident with loss of already 30 %. Lipoatrophy- no validated technique.

Prevalence of metabolic complications. John Morlese – Research Registra St Stephens Centre – Chelsea West minister Hospital London – AIDs/CARE – Brian Gazzard Lipodystrophy/Lipoatrophy – 35% [Dexa/CT. (15-83)% - Average 50% at 12-24 months. CTC – Radiation Risk] Dyslipidemia – 50% 11% Fredrichsen Type IIa. (Isolated Hypercholestrolaemia) 32% Type IIb. [cholesterol /Triglycerides) 53% Type IV/V [Isolated Triglycerides] others increase - F.F.A - Decreased HDL Insulin Resistance / Glucose Intolerance (20-50)% Frank Diabetes (1-6)% - De Jesus 2010 Newer/Safer Drugs -Atazanavir (PI) -Maraviroc – (CCR5) – SAAG 2009 -Raltegravir(Integrase Inhibitor)

CARDIOVASCULAR Disease DAD Study 23, 468 126 – MI 29 Fatal (6%) 77 – Ischaema / CVA

DAD 2008: Increased rate of CHD – with ART paticularly Abacavir containing regimen Benefit of viral suppression Improved immune function with reduced morbility/mortality argues in favor of ART according to relevant guidelines – “Viral load RESISTANCE monitoring and pre-existing cardiovascular risk”

PRACTICE POINTS – (HIV: 2010) Therapeutic Options for HIV associated lipodystrophy and related metabolic complication.  Lifestyle – Less saturated fat and cholesterol, increase physical activity, stop smoking.  ART – replace PI, d4T(zerit) or AZT [-ATAZANAVIR – preferred] -TENOROVIR-  Status – Artovastatin, Pravastatin, Fluvastatin’ ?Rosuvastatin  Fibrates – Gemifibrozol, Bezafibrat  Metformin – Glucophage  Thiazolidinediones –Rosiglitazone(Avandia) - Pioglitazone (Actos)  Recombinant Human growth Hormones – Serostin  Surgical Intervention (specialist care)/liposuction Polylactic Acid (New Fill)

CASE PRESENTATION CLINICAL EPIDEMILOGICAL PROBLEM - ACUTE CORONARY SYDROME – STEMI -Multiple cardiovascular Risk factors with HIV/HAARTs -PREMATURE CARDIOVASCULAR EVENT

Management of A.C.S C.A.B.G – Coronary Artery By PASS GRAFTING Cardiac Transplanting in appropriate patients. Percutaneous Coronary Intervention – Increased rate of restenosis ?consideration of newer DRUG ELUTING STENTS- [NEJM – Intensive care of Patients with HIV Infection – Lawrence Huang etal] 13 th July, 2006

 HAARTS – Since initiation  Aluvia II BD,  Combivir – II BD now third year  ?? Monitoring – CD4 decline (Oct 2010)  ?? Dosing – erratic recently from FB centre  Generally ‐ satisfactory health  Hypotensives wef Oct 2010– Aldomet 250mgs, Lasix 40mgs

Complaints  Seen 13/12/2010  Severe chest pain radiating to the left arm  Acute onset  Recently on hypotensive  Treatment for malaria ‐ ?B/S MPS +ve – Artequick 2 OD 2/7 Clinical  Young lady over nourished slightly in pain  BP 180/110 mHg  CVS: Large radial pulse 170/110mHg, taxofandin slight, not in CEP  PIA – epigastric tenderness  RIS – chest clear Impression  Acute coronary syndrome, uncontrolled severe systemic hypertension, overweight  ?? Recent malaria  ?? Immunological failure  ? Adherence (?dosing)

Follow up/progress (Abstract)  DOA – 13/12/2010 DOD – 19/12/2010  Cardiologist consulted  Full work up for ACS – serial  Troponin/cardiac enzymes/ECU, echocardipgraphy/later stus test  Confirmed acute ST elevation MI and standard treatment/stabilization – aspirin/morphin/capote/ metaprol, hydrallazine/rozal/clexane  Cost constraints – stable in general ward and thrombolytic therapy differed

Final diagnoses  Acute STE MI – infero port lateral, EF 38%, IHD/CAD  Systemic arterial hypertension  Recent malaria therapy – (ARCO)  Hyperlipidaemia IIA  R/V illness ‐ ? Adherence, dosage error. (Viral load 40cps/nil plasma)  Others – overweight, urinary tract infection, peptic ulcer disease and anxiety state.

Discharge drugs  Lipitor 80mgs nocte  Variace 5mgs BD  Junior Asa 100mgs OD  Clopidogrel 75mgs OD  Lexotan 1.5mgs BD, 3mgs noctre  Betalac Z OK ½ TB OD  Pantocid 40mgs OD  For OGTT (stress test) (Withhold HAARTS)

MANAGEMENT Principles of management • Characterise the lipid abnormality • Identify reversible/secondary causes of dyslipidaemia • Determine whether there is established caardiavascular disease (secondary prevention) or the patient is at high risk of cardiovascular disease (primary prevention) • Institute therapy

TABLE 1. LIPODYSTOPHY CHARACTERISTICS 1. Biochemical • Insulin resistance • Type 2 diabetes • Hypercholesterolaemia increased total cholesterol (C) Increased LDL ‐ C Decreased HDL ‐ C • Hypertriglyceridaemia 2. Morphological • Lipoatophy Face, limbs and buttocks • Increased dorsocervical fat pads Gynaecomastia • • Increased abnominal girth