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

15TH KAP Annual Scientific Conference, 23rd – 26th 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]

• thers 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

• f newer DRUG ELUTING STENTS-

[NEJM – Intensive care of Patients with HIV Infection – Lawrence Huang etal] 13th 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,

• verweight

 ?? 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

TABLE 2. SECONDARY DYSLIPIDAEMIA

• Diet rich in saturated fats
• Chronic renal failure
• Nephrotic syndrome
• Hypothyroidism
• Type 2 diabetes
• Chronic liver disease
• Alcohol excess
• Cushing’s disease
• Obesity
• Pregnancy
• Drugs

Thiazides B‐blockers Thyroid hormones Cortocosteroids Oestrogens Progestogens Anabolic steroids

TABLE 3. TREATMENT OPTIONS

• Treat secondary causes
• Lifestyle interventions

Diet/weight loss Exercise Cease smoking

• Antiretroviral therapy regimen changes
• Lipid‐lowering drugs
• Insulin‐sensitising agents
• Plasma apheresis

Specific therapeutic interventions

Diet and lifestyle modifications

• Reduce total fat especially saturated fat
• Increase proportion of complex carbohydrate
• Increase fruit and vegetables; aim for five portions/day
• Eat fish regularly, particularly only fish (three portions/week; and
• Keep alcohol intake <21 units/week (men) or <14 units/week (women).

In addition, 30 minutes of exercise (brisk walking) five times a week will be beneficial. Omega‐3 fatty acids at a dose of 3g daily can reduce plasma triglyceride concentrations by 30%.

Drug Therapy MANAGEMENT OF LIPIDS Symptom

Total cholestrol > 6.5 mmol/l with HDL:LDL ratio >4.1

Intervention

Dietary advice Lifestyle modification Switch PI to PI‐sparing regimen Target Total cholesterol <5.5 mmol/I HDL:LDL ratio >4.1 As above HDL:LDL ratio >3.1 Fasted triglycerides >8 mmol/l Dietary advice Lifestyle modification Switch PI to PI‐sparing regimen Fibrate Fasted triglycerides <4 mmol/l Unfasted triglycerides >10 mmol/l As above Unfasted triglycerides >10 mmol/l

• HDL. high‐density lipoprotein; LDL, low‐density lipoprotein; PI, protease inhibitor

Lipodystrophy

EVALUATION (Lancet 2000;356: 1412; Lancet 2001 ;357:592; AIDS 1999; 13:2493

• Patient perception
• Physical examination, serial photography
• Waist‐hip ratio (>0.85 for women, >0.95 for men)
• Dual energy x‐ray absorptiometry (DEXA)
• Ultrasound
• Computed tomography
• MRI

TREATMENT

• Low fat diet and aerobic exercise can be partly effective in

treating fa accumulation (AIDS 1999;13:231), although they may exacerbate lipoatrophy.

• Testosterone replacement therapy (in hypogonadal men)
• r anabolic steroids (eugonadal men). Lost fat will not be

restored, however.

• Growth hormone (6 mg/kg/day) may reduce fat

accumulation, but the benefits disappear after treatment is

• stopped. Disadvantages include high price and side effects,

including hyperglycemia, further loss of subcutaneous fat, and the need for maintenance treatment.

• Metformin (500mg bid) impoves insulin sensitivity and results

in weight loss and decreased intra‐abdominal fat in patients with fat accumulation and insulin resistance (JAMA 2000;284:472). It also improves some markers of cardiovascular risk.

• Restorative surgery, for fat accumulation, includes removal of

lipomas, breast/fat tissue or dorso‐cervical fat pad by their surgery or liposuction. A number of implants and injections are being investigated for facial fat atrophy. Injections of fat or collagen are associated with rapid resorption, and the changes are short‐lived.

Permanent implants, such as silicone and “semi‐permanent” polylactic acid injections, which are biodegradable but leave a more durable change in the underlying tissue, are undergoing FDA “device” approval. All implants run the risk of skin granuloma formation and scarring, require multiple treatments, and should only be considered by an expert, certified dermatologist or surgeon using pure compound.

• Regimen changes from Pls to an NNRTL or ABC are from d4T

to ABC or AZT or from d4T or AZT to ABC

INSULIN RESISTANCE SCREENING

Random blood glucose, fasting blood glucose, and HgA1c measurements are insensitive methods to measure insulin resistance, due to compensatory increases insulin. Pl treated patients with normal fasting blood glucose levels may have severe insulin resistance demonstrated by glucose clamp techniques (AIDS 2000;25:312) No standardized methods for evaluating insulin resistance. Fasting glucose levels at baseline and at 3 to 6 month intervals in Pl‐treated patients. More measurements based on initial results and diabetes risk. More aggressive testing may include fasting insulin levels, c‐peptide, and, oral glucose tolerance testing for those with borderline fasting glucose levels (110‐126 mg/dL)

RISK The practical application of insulin resistance is its role as a risk for atherosclerosis. Risk assessment should include risk factors for diabetes and atherosclerosis, including family history, smoking hypertension, obesity, and dyslipidemis. TREATMENT: Diet and exercise. 50% to 60% carbohydrates, 10% to 20% protein, and <30% fat, with <100mg cholesterol per day and <10% of total calories from saturated fat. Two major classes of agents are insulin secretagogues (sulfonylumreas) and insulin‐sensitizing agents (metformin and thiazolidinediones). Theoretical risk of lactic acidosis change the HAART regimen to a non‐Pl‐based regimen successful about 50% of the time.

CHD Risks, LDL, Goals, and Treatment Indications From the NCEP Risk LDL Goal Drug Therapy Coronary artery diseases or other form of atherosclerosis, diabetes, or multiple risk factors <100 mg/dL 10 yr risk >20% LDL >130 100‐130: Optional Multiple risks with >2 of the following smoking, HBP, HDL <40, hereditary factors <130 mg/dL 10 yr risk 10% to 20%* >130 10yr risk 10%* >160 Risk factor 0‐1 <160 >190 160‐190:

• ptional

*Risk determined by multiple factors including age, cholesterol,

HDL, and systolic BP Major interventions: Therapeutic life style changes: diet, exercise, and weight reduction. Diet : Reduced saturated fat (<7% calories), reduced cholesterol (<200 mg/d), increased fiber (20‐30 g/day), LDL lowering plant stanols/sterols (2g/day), protein 15% calories, carbohydrates 50%to 60% total calories – predominantly complex carbohydrates. Drugs

Clinical Presentati

• n

Implicate d Drug Class or Drug(s) Onset; Clinical Signs & Symptom s (S&S) Estimated Frequency Risk Factors Preventio n/Monito ring Clinical Managem ent

ADVERSE EFFECTS WITH LONG‐TERM COMPLICATIONS (in alphabetical order): at least, in part, due to HIV replication Atherosclerot ic Mls & CVAs JAIDS 50:54, 2009;AIDS Reader 18(S5), 2008 Data not definitive. Traditional risk factors including uncontrolled HIV most important. Among drugs, perhaps modest risk with abacavir & maybe didanosine & Pls Onset: Months to years S&S: Premature or accelerated atherosclerot ic vascular disease (e.g. Ml, stroke) Relative risk

• f Ml while
• n ABC (1.9‐

fold) or ddl (1.5‐fold). Ln 371:1417, 2008. Tobacco use, age, hyperlipidem ia (see below) Hypertension , diabetes,

• besity, HIV

infection are risk factors (CROL, Abst 146,2009) Address risk factors; suppress HIV viremia Manage risk factors; control HIV viremia.

Hyperlipi demia

Ref.LnlD 7:787,2007;CI D 37:613,2003; JAIDS 50:54,2009

All protease inhibitors (Pls) except atazanavir (Reyataz); stavudine (Zerit); efavirenz (Sustiva)

Modest increases. Onset: weeks to months Lab: LDL &total cholesterol &triglycerid es; HDL d4T: increase i triglycerides n Efavirenz: added to NRTIs increased all serum lipids 1.7 – 2.3 fold increase with Pis

• ther than

atazanavir PIs: ritonavir boosted lopinavir NNRTI: Efavirenz NRTI: Stavudine ART causes modest increase in serum lipids; manage with statins. Darunavir + RTV pravastatin levels; all

• ther Pis

pravastatin

• levels. Pis

levels of simvastatin/ lovastatin— so AVOID. Insulin resistance/d iabetes mellitus.

• Ref. JAC 61

:238, 2008

Protease inhibitors (PIs); atazanavir has minimal effect. Insulin levels with combination

• f d4T & ddl.

AZT

Onset: Insidious S&S: Polydipsia, polyuria, polyphagia Diabetes in 2‐7%. Impaired glucose tolerance in 35% (ArIM 165: 179,2005) Obesity, genetics, dyslipidemia ,lipoatrophy, Pis, thymidine, NRTIs. Non‐PI regimen. Ideally, monitor fasting blood glucose levels. Diet & exercise, metformin, “glitazones,” sulfonylurea s, insulin

• steonecrosis All protease

inhibitors (Pis); caused by ART or HIV? Onset: Insidious S&S: Periarticular

• pain. 85%

involve one

• r both

femoral heads Symptomatic 0.08‐1.3% Asymptomati c by MRI 4% Diabetes; prior steroid use; alcohol use; hyperlipidem ia No steroids, periodic MRIs to assess diseases progression. Remove risk factors; less weight‐ bearing; some require total joint arthroplasty ADVERSE EFFECTS THAT INFLUENCE QUALITY OF LIFE Fat maldistribution (AIDS reader 18 (Supp):S11,2008) Lipoatrophy NRTIs, especially Stavudine > zidovudine. >TDF,ABC,3T C,FTC, esp. When combined with EFV Loss of subcuteneou s fat on face, buttocks &extremities Precise frequency unknown Low nadir CD4 count,

• lder age.

Low baseline body mass index (BMI). If possible avoid stavudine and zidovidine What makes it worse? Exercise, testosterone, metformin, recombinant human growth hormone. What helps? Pravastatin, drug switch. Dermal fillers limited helps.

Fat Accumulatio n: Lipodistrop hy PI or NNRTI combined with d4T or ZDV Excess adipose tissue in abdominal viscera, breast size, dorsocervica l fat pad Precise frequency unknown Obesity prior to HIV infection; low CD4 count prior to therapy;

• lder age;

low baseline BMI. Avoid combination

• f PI or

NNRTI with d4T or AZT What helps? Growth hormone releasing factor (tesamorelin ) (NEJM 357:2359, 2007)

Mitochondrial toxicity

Mitochondrial toxicity is

mostly caused by:

Stavudine - d4T

Zidovudine - AZT/ZDV Didanosine - ddI Zalcitabine - ddC

Nucleoside action in mitochondria

Polymerase -Gamma mtDNA mtDNA mtDNA nDNA N O R M A L N R T I s mtDNA mtDNA Proteins encoded by nDNA

Brinkman K et al. Lancet 1999; 354: 1112-1115

Metabolic changes associated with HAART Long term side effects

Hyperlipidaemias

hypercholesterolaemia (HDL + LDL) Hypertriglyceridaemia

Insulin resistance Diabetes mellitus (rarely) Osteoporosis

Pseudovenomegaly because of loss of subcutaneous fat

*Risk determined by multiple factors including age, cholesterol,

HDL, and systolic BP Major interventions: Therapeutic life style changes: diet, exercise, and weight reduction. Diet : Reduced saturated fat (<7% calories), reduced cholesterol (<200 mg/d), increased fiber (20‐30 g/day), LDL lowering plant stanols/sterols (2g/day), protein 15% calories, carbohydrates 50%to 60% total calories – predominantly complex carbohydrates. Drugs

Management of hyperlipidaemia

Risk factor reduction Dietary modification Switch HAART? Lipid lowering agents

 Fibrates

ACKNOWLEDGEMENT – GSN‐Technical Committee – Aphia II COAST ‐ MSD ‐S.S.A. II ‐Pharma Access KMA/HIV Committee/KAP

References: SANFORD Guide to HIV/AIDs Therapy 2010 (18th Edition) ‐Bartlet –Medical Management of HIV (2009) –ADR ‐AIDS Care‐ Brian Gazzard. (BHIVA Guidelines) ‐ PHARMA ACCESS – Clinical Mamual – ARP (DDHS Guidelines) HIV 2010 : Hoftman / Rockslsh NEJM – Intensive Care of Patients with HIV Infection Lawrence Huang etal July 13 2006. NEJM- Cardiovascular Risk and Body-Fat Abnormalities in HIV-Infected Adults Steven Grinspoon, M.D., and Andrew carr, M.D. October 20, 2005

END ASANTE SANA