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Long Term Side Effects of ARVs

Long Term Side Effects of ARVs. HAIVN Harvard Medical School AIDS Initiative in Vietnam. Learning Objectives. By the end of this session, participants should be able to: Describe the symptoms and explain how to diagnose and manage the following side effects: Lipodystrophy syndrome

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Long Term Side Effects of ARVs

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  1. Long Term Side Effects of ARVs HAIVN Harvard Medical School AIDS Initiative in Vietnam

  2. Learning Objectives By the end of this session, participants should be able to: • Describe the symptoms and explain how to diagnose and manage the following side effects: • Lipodystrophy syndrome • Peripheral neuropathy • Diabetes • Dyslipidemia • Gynecomastia • Bone disorders

  3. Lipodystrophy

  4. Overview of Lipodystrophy (1) • Lipodystrophy is a syndrome of body shape abnormalities characterized by: • central fat accumulation • peripheral fat loss • Some patients have only fat loss, others have fat gain, and others have a mixed picture of both • There can also be associated disorders in glucose and lipid metabolism

  5. Overview of Lipodystrophy (2) Lipoatrophy: • Loss of subcutaneous body fat: • Extremities • Face • Buttocks Lipohypertrophy: • Increased fat accumulation in the center of the body: • Abdomen • Breasts • Dorso-cervix

  6. Prevalence of Lipodystrophy

  7. Lipodystrophy: Prevalence in Asian Cohorts • Cambodian cohort: • D4T-associated lipodystrophy in 20% of patients after 24 months of follow-up • Singapore cohort: • Lipoatrophy 46% • Fat accumulation 32% • Mixed 8% Sources: Ferradini AIDS 2007; Nicholas CID 2002

  8. Lipoatrophy: Risk Factors Risk factors for lipoatrophy include: NRTIs • D4T is strongest risk factor • AZT to a lesser extent • 3TC, TDF, ABC much less common Other non-drug factors • Older age • Lower body weight • AIDS diagnosis • Lower pretreatment CD4 cell count

  9. Lipohypertrophy: Risk Factors Risk factors for lipohypertrophy include: • Older age • Female sex • Amount of body fat • Longer duration of ART • Exposure to protease inhibitors

  10. Manifestations of Lipoatrophy • Face • Extremities: • Prominent vein • Buttocks

  11. Manifestations of Lipohypertrophy • Dorsocervical • Area • Breasts • Abdomen

  12. Treatment of Lipodystrophy Lipoatrophy: • Change d4T to AZT, ABC or TDF • Cosmetic surgery or injections Lipohypertrophy: • Change PI’s to NNRTI • Exercise • Liposuction

  13. Metabolic Disorders • Insulin resistance and diabetes • Dyslipidemia • Lactic acidosis/hyperlactatemia • Cardiovascular risk

  14. Insulin Resistance and Diabetes (1) • Incidence of 3-5 % among ARV patients • After months or years • Risk factors • Use of PI-containing ARV regimen • Previous hyperglycemia • Family history of diabetes • Laboratory diagnosis: the same as for non-HIV patients

  15. Insulin Resistance and Diabetes (2) • Screening: • Fasting glucose before starting ARV, then every 6-12 months • Treatment: • Treat diabetes as in non-HIV patients • Consider switch PI to another PI (such as ATV if available) or NNRTI (if not already resistant to 1st line ARV)

  16. Dyslipidemia

  17. Dyslipidemia – Terms

  18. ART – Induced Lipid Abnormalities

  19. Dyslipidemia - ARV Specific Effects

  20. PI – Induced Lipid Effects

  21. Dyslipidemia: Screening • Dyslipidemia occurs is up to 75% of patients on PIs • Screening should be performed for all patients on ART and especially for those on PIs: • Baseline fasting lipid level • Yearly lipid screening

  22. Management of Dyslipidemia • Screen for other cardiovascular risk factors to assess likelihood of future cardiovascular events • Encourage positive behavior change • Consider lipid lowering drugs • Consider changing PI to another agent that does not cause lipid elevations (NNRTI or ATV)

  23. Drug Management of Dyslipidemia (1) HMG-coAreductase inhibitors “Statins” • Start for elevated TC and/or LDL • Very effective at  LDL ( 20-60%) • Beware of drug interactions • Atorvastatin & Pravastatin: safe to use with PI • Lovastatin & Simvastatin:  levels when used with PI  Do Not Use

  24. Drug Management of Dyslipidemia (2) Fibrates (Fenofibrate, Gemfibrozil ) • Indication usually if TG > 500 mg/dL • Best for isolated  TG: •  TG 30-50% •  LDL 10-20%;  HDL 5-15 % • No significant drug interactions with ARV • Less expensive than statins

  25. Cardiovascular Risk

  26. What are the Traditional Cardiac Risk Factors? • Male gender • Older age • Hypertension • Diabetes mellitus • Tobacco use • Hyperlipidemia • Family history of premature coronary artery disease (CAD) • Personal history of CAD

  27. HIV and ARVs As Risk Factors for Cardiovascular Disease • Use of ART has been associated with an increased risk of cardiovascular events: • May be seen from a few months to years after the start of ARV • Can occur in patients without any other cardiac risk factor • PIs have highest risk • Presence of the lipodystrophy syndrome has been shown to add further risk of cardiovascular events in some studies

  28. Management of Cardiovascular Complications of ARV • Early diagnosis and treatment of traditional cardiac risk factors • Behavioral changes • Diet • Regular physical exercise • Smoking cessation • Diminish further risks from ARV by: • Use NNRTI instead of PI • Use NRTIs, but avoid d4T

  29. Peripheral Neuropathy

  30. Peripheral Neuropathy • NRTIs and other drugs may cause peripheral neuropathy: • D4T and DDI have the highest risk • Increased risk when D4T combined with DDI or Ribavirin

  31. Risk Factors • The risk of NRTI-induced neuropathy is higher in the following circumstances: • Preexisting neuropathy • Concurrent diabetes • Lower pretreatment CD4+ cell count • Higher viral load • Alcoholism • Poor nutrition • Older age

  32. Symptoms • Onset after many weeks or months • “Stocking and glove” distribution: starts at fingertips/toes and spreads inward • Symptoms: numbness, tingling, pain • Progressive and irreversible if left untreated

  33. Treatment • Eliminate other causes or contributing factors: • Stop alcohol use • Screen for and treat other diseases: diabetes, thyroid dysfunction, syphilis • Stop use of other neurotoxic agents (INH) • Switch from D4T to AZT, ABC or TDF • Neuropathic pain can be treated with Amitriptyline

  34. Lactic Acidosis

  35. Lactic Acidosis • Incidence 0.5% - 1.5% per year • Risk of lactic acidosis: • D4T+DDI > D4T > DDI > AZT • Very Low risk: 3TC, TDF, ABC • Symptoms: can develop slowly • Mild: fatigue, body aches, nausea, vomiting, diarrhea, weight loss • Severe: wasting, dyspnea, abdominal pain, coma

  36. Lactic Acidosis: Diagnosis • Elevated lactic acid levels • If lactic acid testing is not available: • Increased anion gap [Na-(Cl+HCO3)] > 16 • LFT, CPK, LDH, pH, HCO3

  37. Lactic Acidosis: Treatment No or mild symptoms Lactic acid level ≤10 Severe symptoms Lactic acid level >10 Change NRTI: d4T AZT ABC or ddI TDF • Hospitalize • Provide supportive care • Stop all ARVs • When stable, restart ARV: • use ABC or TDF plus 3TC • or use NRTI-sparing regimens

  38. Bone Disorders

  39. Osteonecrosis (1) • Ischemic death of the cellular components of the bone, normally at the epiphyseal or subarticular regions • 85% of cases are at one or both femoral heads but, may affect any bone

  40. Symptoms and Diagnosis • Presentation often insidious onset with subtle symptoms • The most common presenting symptom is pain • Groin pain is most common location • Pain on movement or weight bearing  • Diagnosis is made clinically in a symptomatic patient with typically radiologic findings

  41. Risk Factors • Diabetes • Prior history of prolonged steroid use • Older age • Excessive use of alcohol • Hyperlipidemia • HIV infection • Use of protease inhibitors Glesby M, Clin Inf Dis.2003;37:S91-S95

  42. Treatment • Eliminate contributing factors: alcohol, steroids • Treat the pain with NSAIDS and/or opiate drugs • Severe pain in the hip may be an indication for hip replacement surgery

  43. Gynecomastia

  44. Gynecomastia (1) • Enlargement of one or both breasts as a result of increased glandular tissue • Most common with EFV, D4T is less common

  45. Gynecomastia (2) • Symptoms: may be painful • Differential diagnosis • Other medications (INH, ketoconazole, cimetidine, metronidazole) • Pseudo-gynecomastia (fatty deposit such as in lipodystrophy) • Hypogonadism (testicular tumors) • Breast cancer

  46. Treatment of EFV-Induced Gynecomastia • NSAIDS for pain • Treatment options: • Continue EFV: • Complete regression after 2 months when no change in treatment was done • (One author noted) • Stop EFV: • Complete regression seen after 5 months when EFV changed to NVP • (in a cohort of patients in Haiti)

  47. Key Points • Patients on ARVs may develop one or more long term side effects • Screening and early recognition of these potential side effects is important • Cardiovascular disease is an increasingly recognized complication of long-term HIV infection and ARV use

  48. Thank you Questions?

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