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Long Term Side Effects of ARVs

Learn about the symptoms, diagnosis, management, risk factors, and treatment options for lipodystrophy, neuropathy, diabetes, dyslipidemia, and other long-term side effects of antiretroviral therapy (ARVs).

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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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