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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Adverse Drug Effects

March 2008 AETC National Resource Center, www.aidsetc.org

About This PresentationAbout 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Users are cautioned that, because of the rapidly changing field of HIV care, this information could become out of date quickly.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


Guidelines for the Use of Antiretroviral Guidelines for the Use of Antiretroviral Agents in Pediatric HIV InfectionAgents 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)


Adverse Drug Effects: General CategoriesAdverse 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


Adverse Drug EffectsAdverse 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


TopicsTopics

Lactic acidosis Hepatic toxicity Fat maldistribution Hyperlipidemia Hyperglycemia and insulin resistance Osteopenia, osteoporosis, osteonecrosis Hematologic complications Hypersensitivity reactions and rashes Teratogenicity


Lactic Acidosis 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


Lactic Acidosis Lactic Acidosis (2)(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


Lactic Acidosis: Lactic Acidosis: Diagnosis and ManagementDiagnosis 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)


Lactic Acidosis: Lactic Acidosis: Diagnosis and Management Diagnosis and Management (2)(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



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)



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)


Lactic Acidosis: Lactic Acidosis: Perinatal ARV ExposurePerinatal 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


Hepatic ToxicityHepatic 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


Hepatic Toxicity Hepatic Toxicity (2)(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



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 initiationof NVP



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


Hepatic Toxicity: Hepatic Toxicity: MonitoringMonitoring

Follow LFTs closely on regular basis after starting new ARV

Monitor closely in children with hepatitis B or C coinfection, in children initiating NVP


Hepatic Toxicity: Hepatic Toxicity: ManagementManagement

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


LipodystrophyLipodystrophy

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


Lipodystrophy Lipodystrophy (2)(2)

Central fat accumulation (lipohypertrophy) Associated with PIs (especially IDV)

Peripheral fat wasting (lipoatrophy) Associated with NRTIs (especially d4T and

ddI) and PIs


Lipodystrophy: Lipodystrophy: Assessment and MonitoringAssessment and Monitoring

No standard methods, no standard diagnostic criteria Anthropometric measurements, CT, MRI,

DEXA


Lipodystrophy: Lipodystrophy: TreatmentTreatment

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


HyperlipidemiaHyperlipidemia

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


Hyperlipidemia Hyperlipidemia (2)(2)

NCEP classifications for children and adolescents:

Category Total Cholesterol LDL 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.


Hyperlipidemia Hyperlipidemia (3)(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


Hyperlipidemia: Hyperlipidemia: Drug TherapyDrug 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


Hyperlipidemia: Hyperlipidemia: Drug Therapy Drug Therapy (2)(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



Fibrates For treatment of elevated triglycerides Adverse effects: myositis, bone marrow

suppression Increased risk of muscle toxicity if combined

with statins



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)


Hyperglycemia and Insulin ResistanceHyperglycemia 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


Hyperglycemia and Insulin Resistance:Hyperglycemia and Insulin Resistance:MonitoringMonitoring

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


Hyperglycemia and Insulin Resistance:Hyperglycemia and Insulin Resistance:TreatmentTreatment

Consider switching from PI (unproven) Diet and exercise, if lipodystrophy

present Oral medications or insulin, as

required


Osteopenia, OsteoporosisOsteopenia, 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


Osteopenia, Osteoporosis Osteopenia, Osteoporosis (2)(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)


OsteonecrosisOsteonecrosis

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


Osteonecrosis Osteonecrosis (2)(2)

Diagnosis Physical examination, X ray, MRI

Treatment Early: symptomatic, decreased weight

bearing Advanced: surgical treatment


Hematologic ComplicationsHematologic 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


Hematologic Complications:Hematologic Complications:Adverse Drug EffectsAdverse Drug Effects

Anemia Seen most frequently with ZDVNeutropenia Usually no complications unless

absolute PMN <250 cells/µL Seen most frequently with ZDV Non-ARV drugs: TMP-SMX, ganciclovir,

rifabutin, hydroxyureaThrombocytopenia Usually associated with untreated HIV,

not with ARVs


Hematologic Complications: Hematologic Complications: MonitoringMonitoring

Routine monitoring of CBC, differential, platelets Consider increased frequency in children

on ZDV Evaluate for possible causes: OI,

malignancy, nutritional deficiency, drug effect, etc


Hematologic Complications: Hematologic Complications: ManagementManagement

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 indicatedNeutropenia Mild to moderate (PMN >250 cells/µL), without

concerning ssx: monitor Severe (PMN <250 cells/µL): consider changing

medications; G-CSF


Hematologic Complications: Hematologic Complications: Management Management (2)(2)

Thrombocytopenia Severe (platelets <20,000 cells/µL or significant

bleeding): Consider IVIG or anti-D antibody (WinRho), corticosteroids, splenectomy(if medical treatment fails)


RashRash

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


Rash: Rash: ManagementManagement

Severe: permanently discontinue suspected agent

Mild to moderate: may resolve, but monitor closely


Hypersensitivity ReactionHypersensitivity 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


Hypersensitivity Reaction: Hypersensitivity Reaction: ManagementManagement

If hypersensitivity reaction is suspected, offending drug must be discontinued permanently

ABC: rechallenge may be fatal NVP: avoid other NNRTIs


TeratogenicityTeratogenicity

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


Potential Teratogenicity: Nelfinavir and Potential Teratogenicity: Nelfinavir and Ethyl Methane SulfateEthyl Methane SulfateNFV 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)

Documents

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