1. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection Adverse Drug Effects

2. March 2008 AETC National Resource Center, www.aidsetc.org About This Presentation These slides were developed using the November 2005 Pediatric Guidelines and the September 2007 DHHS Pediatric Panel Notice on Nelfinavir. The intended audience is clinicians involved in the care of patients with HIV. Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. – AETC NRC http://www.aids-etc.org

3. March 2008 AETC National Resource Center, www.aidsetc.org Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection Developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children François-Xavier Bagnoud Center, UMDNJ; the Health Resources and Services Administration (HRSA); and the National Institutes of Health (NIH )

4. March 2008 AETC National Resource Center, www.aidsetc.org Adverse Drug Effects: General Categories  Mitochondrial dysfunction  Lactic acidosis, hepatic toxicity, pancreatitis, peripheral neuropathy  Metabolic abnormalities  Lipodystrophy, hyperlipidemia, hyperglycemia and insulin resistance, bone disorders  Hematologic complications  Bone marrow suppression  Allergic reactions  Hypersensitivity reactions, skin rashes

5. March 2008 AETC National Resource Center, www.aidsetc.org Adverse Drug Effects  Some drug toxicities may be difficult to distinguish from complications of HIV infection  Individual ARV drugs or classes are associated with specific toxicities  Interactions among ARVs and interactions with other drugs can compound toxicities  Few data on adverse drug events in children; limited experience in managing them

6. March 2008 AETC National Resource Center, www.aidsetc.org Topics  Lactic acidosis  Hepatic toxicity  Fat maldistribution  Hyperlipidemia  Hyperglycemia and insulin resistance  Osteopenia, osteoporosis, osteonecrosis  Hematologic complications  Hypersensitivity reactions and rashes  Teratogenicity

7. March 2008 AETC National Resource Center, www.aidsetc.org Lactic Acidosis  Possibly due to mitochondrial toxicity  Associated with NRTIs  More likely with d4T and/or ddI  Mild, asymptomatic hyperlactatemia is common; symptomatic hyperlactatemia is uncommon  Lactic acidosis is rare but has high mortality rate

8. March 2008 AETC National Resource Center, www.aidsetc.org Lactic Acidosis (2)  Clinical presentation variable and nonspecific (high index of suspicion):  Lactate >2-5 mmol/L plus symptoms  May include fatigue, weakness, myalgias, GI symptoms, respiratory or neurological symptoms  Often associated with hepatic steatosis, pancreatitis  Routine monitoring of serum lactate is not recommended; check only if symptoms present

9. March 2008 AETC National Resource Center, www.aidsetc.org Lactic Acidosis: Diagnosis and Management Diagnostic evaluation:  Serum lactate (confirm with second test)  Serum bicarbonate, anion gap  LFTs  Amylase  Lipase  Arterial blood gas  Imaging studies as indicated (eg, evaluation for hepatic steatosis, pancreatitis)

10. March 2008 AETC National Resource Center, www.aidsetc.org Lactic Acidosis: Diagnosis and Management (2)  Lactate <2 mmol/L and normal bicarbonate  Continue ARV  No lactic acidosis; evaluate for alternative cause of symptoms  Lactate 2.1-5 mmol/L, symptomatic  Can continue ARVs, particularly if bicarbonate is normal, but carefully monitor symptoms, lactate, other laboratory values  Or, temporarily discontinue ARVs while conducting additional diagnostic workup

11. March 2008 AETC National Resource Center, www.aidsetc.org Lactic Acidosis: Diagnosis and Management (3)  Lactate >5 mmol/L and symptomatic, or lactate >10 mmol/L regardless of symptoms  Discontinue all ARVs  Supportive therapy (IV fluids; oxygen, sedation, and respiratory support; as needed)  Unproven supportive therapies:  Bicarbonate infusion  High-dose thiamine (vitamin B1) and riboflavin (vitamin B2)  Oral antioxidants (eg, L-carnitine, coenzyme Q, vitamin C)

12. March 2008 AETC National Resource Center, www.aidsetc.org Lactic Acidosis: Diagnosis and Management (4) After resolution of clinical and lab abnormalities, ARV therapy can be resumed:  NRTI-sparing regimen, or  Revised NRTI-containing regimen (use with caution)  Use NRTI that is less likely to inhibit mitochondria (ABC or TDF; possibly ZDV or 3TC)  Monitor closely (consider monthly lactate measurements for at least 3 months)

13. March 2008 AETC National Resource Center, www.aidsetc.org Lactic Acidosis: Perinatal ARV Exposure  Conflicting data about whether perinatal ARV exposure may cause mitochondrial dysfunction in HIV-uninfected children  Risk, if any, appears to be very low, and ARV prophylaxis for prevention of perinatal HIV transmission is clearly beneficial  Children with in utero ARV exposure should be monitored for potential mitochondrial toxicity

14. March 2008 AETC National Resource Center, www.aidsetc.org Hepatic Toxicity  Liver function abnormalities common in HIV infection, with many possible causes  In adults, drug-related hepatic toxicity reported with all ARVs  Coexisting conditions may predispose (eg, hepatitis B or C, alcohol use)  Drug-drug interactions (especially with PIs) may increase serum levels of hepatotoxins

15. March 2008 AETC National Resource Center, www.aidsetc.org Hepatic Toxicity (2)  NRTIs: lactic acidosis/hepatic steatosis  PIs: transaminase elevations, hepatitis, hepatic failure, especially with TPV or high-dose RTV  NNRTIs: transaminase elevations, hepatitis, hepatic failure, especially with NVP

16. March 2008 AETC National Resource Center, www.aidsetc.org Hepatic Toxicity (3) NVP:  Increased risk of NVP-associated hepatic toxicity in women, and in patients with higher pre-NVP CD4 count (>250 cells/µL in women, >400 cells/µL in men)  Starting NVP in women with CD4 counts of >250 cells/µL is not recommended unless benefits clearly outweigh risks  Liver transaminases should be monitored closely for the first 18 weeks after initiation of NVP

17. March 2008 AETC National Resource Center, www.aidsetc.org Hepatic Toxicity (4)  Few pediatric studies  ARV-related elevations in transaminases appear to be common  Severe drug-related adverse events uncommon; perhaps less common than in adults, but caution with NVP

18. March 2008 AETC National Resource Center, www.aidsetc.org Hepatic Toxicity: Monitoring  Follow LFTs closely on regular basis after starting new ARV  Monitor closely in children with hepatitis B or C coinfection, in children initiating NVP

19. March 2008 AETC National Resource Center, www.aidsetc.org Hepatic Toxicity: Management  More common in adolescents than in prepubertal children  Associated with PIs (especially IDV)  Symptomatic or transaminases >10x ULN:  Investigate for other causes, consider holding ARV  Stop NVP, if present  If using 3TC for hepatitis B coinfection, continue 3TC to avoid hepatitis flare  Follow closely, acute liver failure may progress rapidly  If NVP or ABC is suspected as cause of liver impairment, do not rechallenge

20. March 2008 AETC National Resource Center, www.aidsetc.org Lipodystrophy Fat maldistribution and body habitus changes  More common in adolescents than in prepubertal children  Usually occurs gradually  Related to ARV use but etiology poorly understood; may be multifactorial  May be accompanied by dyslipidemia, insulin resistance

21. March 2008 AETC National Resource Center, www.aidsetc.org Lipodystrophy (2)  Central fat accumulation (lipohypertrophy)  Associated with PIs (especially IDV)  Peripheral fat wasting (lipoatrophy)  Associated with NRTIs (especially d4T and ddI) and PIs

22. March 2008 AETC National Resource Center, www.aidsetc.org Lipodystrophy: Assessment and Monitoring  No standard methods, no standard diagnostic criteria  Anthropometric measurements, CT, MRI, DEXA

23. March 2008 AETC National Resource Center, www.aidsetc.org Lipodystrophy: Treatment  No proven therapies; few data in children  Lipohypertrophy  May improve with switch from PI to NNRTI  Diet, exercise  Lipoatrophy  Avoid d4T and ddI; switch from these if possible  Investigational:  Metformin, thiazolidinediones  Growth hormone, testosterone  Surgery

24. March 2008 AETC National Resource Center, www.aidsetc.org Hyperlipidemia Common in adults, especially with PIs, few reports on syndrome in children  Some ARVs, especially PIs and d4T, may increase lipids  No studies on cardiovascular risk  No studies on lipid-lowering therapy

25. March 2008 AETC National Resource Center, www.aidsetc.org Hyperlipidemia (2) NCEP classifications for children and adolescents: CategoryTotal CholesterolLDL Cholesterol High Borderline Acceptable >200 mg/dL 170-179 mg/dL <170 mg/dL >130 mg/dL 110-129 mg/dL <110 mg/dL Triglyceride levels <200 mg/dL are considered acceptable.

26. March 2008 AETC National Resource Center, www.aidsetc.org Hyperlipidemia (3) Check fasting lipid profile before ART initiation and every 3-6 months thereafter Management:  Diet and exercise, trial 6-12 months  If TG >500 mg/dL, immediate treatment indicated  Goal: LDL <130 mg/dL, TG <150 mg/dL  If inadequate response, initiate drug therapy  Consider changing ARVs to avoid PIs or other suspect ARVs

27. March 2008 AETC National Resource Center, www.aidsetc.org Hyperlipidemia: Drug Therapy Statins (HMG-CoA reductase inhibitors)  For treatment of elevated cholesterol and (to lesser degree) triglycerides  Hepatic metabolism (many drug-drug interactions)  PIs inhibit and NNRTIs induce hepatic metabolism  Pravastatin preferred, atorvastatin (low dose, used with caution) is alternative  Simvastatin and lovastatin contraindicated in patients receiving PIs

28. March 2008 AETC National Resource Center, www.aidsetc.org Hyperlipidemia: Drug Therapy (2) Statins  Start at low dose, titrate slowly  Adverse effects: liver and muscle toxicity  Monitor LFT and creatine kinase  Teratogenic; avoid in patients who may become pregnant

29. March 2008 AETC National Resource Center, www.aidsetc.org Hyperlipidemia: Drug Therapy (3) Fibrates  For treatment of elevated triglycerides  Adverse effects: myositis, bone marrow suppression  Increased risk of muscle toxicity if combined with statins

30. March 2008 AETC National Resource Center, www.aidsetc.org Hyperlipidemia: Drug Therapy (4) Ezetimibe (Zetia)  Inhibits intestinal absorption of cholesterol  Limited pediatric information; appears to be safe and effective in HIV-uninfected children >10 years of age Bile acid sequestrants  Avoid – may interfere with absorption of ARVs Niacin  Many side effects (flushing, hepatic toxicity, insulin resistance)

31. March 2008 AETC National Resource Center, www.aidsetc.org Hyperglycemia and Insulin Resistance  ARVs, especially PIs, associated with insulin resistance +/- hyperglycemia and DM  New-onset DM appears to be rare  Unclear whether insulin resistance is associated with growth delay in HIV infection  Unclear whether associated with atherosclerosis  May be associated with lipodystrophy

32. March 2008 AETC National Resource Center, www.aidsetc.org Hyperglycemia and Insulin Resistance: Monitoring  Educate patients and caretakers about symptoms of DM  For asymptomatic patients with no risk factors for DM, routine testing is not indicated  For patients with lipodystrophy or risk factors for DM, check fasting glucose or do oral glucose tolerance test  If random glucose is >140 mg/dL, check fasting glucose

33. March 2008 AETC National Resource Center, www.aidsetc.org Hyperglycemia and Insulin Resistance: Treatment  Consider switching from PI (unproven)  Diet and exercise, if lipodystrophy present  Oral medications or insulin, as required

34. March 2008 AETC National Resource Center, www.aidsetc.org Osteopenia, Osteoporosis  Abnormal bone formation and resorption may have critical effects on growing children  Mechanism unclear, likely multifactorial  Possible relationship with HIV infection  Possible relationship with ARVs (PIs and NRTIs), lactic acidosis, and lipodystrophy  TDF: decreased bone mineral density in animal studies; unclear whether this effect occurs in children

35. March 2008 AETC National Resource Center, www.aidsetc.org Osteopenia, Osteoporosis (2)  Diagnosis  Reduced BMD (by DEXA) in symptomatic patients  No recommendation for screening asymptomatic patients  Management  Prophylaxis: no data; consider calcium/vitamin D, weight-bearing exercise, avoidance of alcohol and smoking  Treatment: consider bisphosphonates (no studies in HIV-infected children)

36. March 2008 AETC National Resource Center, www.aidsetc.org Osteonecrosis Osteonecrosis (avascular necrosis [AVN])  Mechanism unknown  Unclear whether associated with ARVs  In adults, associated corticosteroid treatment, alcohol abuse, hemoglobinopathies, hyperlipidemia, hypercoagulable states  AVN of the hip (Legg-Calve-Perthes disease) and shoulder reported in HIV-infected children

37. March 2008 AETC National Resource Center, www.aidsetc.org Osteonecrosis (2)  Diagnosis  Physical examination, X ray, MRI  Treatment  Early: symptomatic, decreased weight bearing  Advanced: surgical treatment

38. March 2008 AETC National Resource Center, www.aidsetc.org Hematologic Complications  Common in HIV-infected children  Many possible causes  Bone marrow suppression, autoimmune effects  AIDS-related conditions (eg, MAC, CMV, lymphoma)  Adverse drug effects (ARVs and non-ARVs)  Identification of cause may be difficult

39. March 2008 AETC National Resource Center, www.aidsetc.org Hematologic Complications: Adverse Drug Effects Anemia  Seen most frequently with ZDV Neutropenia  Usually no complications unless absolute PMN <250 cells/µL  Seen most frequently with ZDV  Non-ARV drugs: TMP-SMX, ganciclovir, rifabutin, hydroxyurea Thrombocytopenia  Usually associated with untreated HIV, not with ARVs

40. March 2008 AETC National Resource Center, www.aidsetc.org Hematologic Complications: Monitoring  Routine monitoring of CBC, differential, platelets  Consider increased frequency in children on ZDV  Evaluate for possible causes: OI, malignancy, nutritional deficiency, drug effect, etc

41. March 2008 AETC National Resource Center, www.aidsetc.org Hematologic Complications: Management If due to drug toxicity, change medications if possible Anemia (pronounced; ie, Hgb <7-8 g/dL)  Consider erythropoietin or transfusions  Nutrition, iron supplementation as indicated Neutropenia  Mild to moderate (PMN > 250 cells/µL), without concerning ssx: monitor  Severe (PMN < 250 cells/µL): consider changing medications; G-CSF

42. March 2008 AETC National Resource Center, www.aidsetc.org Hematologic Complications: Management (2) Thrombocytopenia  Severe (platelets <20,000 cells/µL or significant bleeding): Consider IVIG or anti-D antibody (WinRho), corticosteroids, splenectomy (if medical treatment fails)

43. March 2008 AETC National Resource Center, www.aidsetc.org Rash Most cases mild to moderate, occur in first 1-6 weeks of therapy; occasionally serious (eg, Stevens-Johnson syndrome, DRESS) May accompany hypersensitivity reaction  Most common with NNRTIs, especially NVP  No benefit of prophylactic steroids  NRTIs: especially ABC (evaluate for hypersensitivity syndrome)  PIs: especially APV, FPV (sulfonamides)  ENF: injection-site reactions

44. March 2008 AETC National Resource Center, www.aidsetc.org Rash: Management  Severe: permanently discontinue suspected agent  Mild to moderate: may resolve, but monitor closely

45. March 2008 AETC National Resource Center, www.aidsetc.org Hypersensitivity Reaction May or may not be accompanied by rash Systemic symptoms, may be severe ABC: fever, nausea, vomiting, diarrhea, fatigue, myalgia, arthralgia, other symptoms  Occurs in approx 4% of patients, usually in first 6 weeks of treatment NVP: fever, myalgia, arthralgia, hepatitis, eosinophilia ENF: fever, shortness of breath

46. March 2008 AETC National Resource Center, www.aidsetc.org Hypersensitivity Reaction: Management  If hypersensitivity reaction is suspected, offending drug must be discontinued permanently  ABC: rechallenge may be fatal  NVP: avoid other NNRTIs

47. March 2008 AETC National Resource Center, www.aidsetc.org Teratogenicity EFV is potentially teratogenic (FDA pregnancy category D)  It should be avoided during pregnancy, especially in the first trimester, and when there is the potential of pregnancy  Effective contraception should be used by women taking EFV

48. March 2008 AETC National Resource Center, www.aidsetc.org Potential Teratogenicity: Nelfinavir and Ethyl Methane Sulfate  NFV manufactured in Europe was recalled in July 2007 because of high levels of EMS, a byproduct of the manufacturing process  EMS has been teratogenic, mutagenic, and carcinogenic in animal studies; in humans, there is no evidence of birth defects or increased cancer risk associated with NFV  NFV manufactured in the United States has lower levels of EMS  U.S. DHHS recommends: do not start NFV in children; children who are already taking nelfinavir may continue NFV (anticipated benefits outweigh risks)