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Leon Levin ARV Toxicity ANTIRETROVIRAL THERAPY IN CHILDREN anaemia

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Leon Levin ARV Toxicity ANTIRETROVIRAL THERAPY IN CHILDREN anaemia Powered By Docstoc
					Paediatric Antiretroviral Toxicity
         Dr Leon J. Levin
         Head - Paediatric HIV Programmes
         Right to Care
  Side Effects


Adverse Effects
Side Effects
Perspective
       Perspective




Every drug has side effects
         Perspective
Dont read Package inserts!
              Perspective

Serious Side effects to ARVs occur in less than
7% of cases
              Perspective

Some ARVs have worse side effects than others
             The Baddies
• Stavudine
• Nevirapine
• Zidovudine (Short Term)
*
                 Side Effects
    • The same side effects seen in adults occur
      in children.
      – Generally side effects are less common in
        children
      – Some are rare in children, e.g., Stavudine
        related peripheral neuropathy
      – Some are less common in children eg EFV
        CNS effects 14% vs > 50%
      – Some are more common, e.g. EFV-related rash
      – Some occur only in children, e.g. Tenofovir-
        related osteopaenia
             Adverse Drug Effects:
              General Categories
• Mitochondrial dysfunction
   – Lactic acidosis, hepatic toxicity, pancreatitis, peripheral
     neuropathy
• Metabolic abnormalities
   – Lipodystrophy, hyperlipidemia, hyperglycemia and
     insulin resistance, bone disorders
• Haematologic complications
   – Bone marrow suppression
• Allergic reactions
   – Hypersensitivity reactions, skin rashes
            Mitochondria
• Factories of the body.
• Convert glucose to Energy (ATP)
• Have own DNA
          Lactic Acidosis
• Due to mitochondrial toxicity
• Associated with NRTIs
  – More likely with d4T and/or ddI
  – Least likely 3TC, ABC, TDF
• Mild, asymptomatic hyperlactataemia is
  common; symptomatic hyperlactataemia is
  uncommon
• Lactic acidosis is rare but has high mortality
  rate
                  Lactic Acidosis
• Clinical presentation variable and nonspecific
  (high index of suspicion):
   – Lactate >2-5 mmol/L plus symptoms
   – May include fatigue, weakness, myalgias, GI symptoms
     especially vomiting , abd pain, 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: Diagnosis and
            Management
Diagnostic evaluation:
• Serum lactate (confirm with second test) (uncuffed)
• Serum bicarbonate, anion gap
• Liver function tests
• Amylase
• Lipase
• Arterial blood gas
• Imaging studies as indicated (eg, evaluation for
   hepatic steatosis, pancreatitis)
     Lactic Acidosis: Diagnosis and
             Management
• Lactate <2 mmol/L and normal bicarbonate
  – Continue ARV
  – No lactic acidosis; evaluate for alternative cause of
    symptoms

• Lactate 2.1-5 mmol/L, asymptomatic
  – Can continue ARVs, if bicarbonate is normal, but
    carefully monitor symptoms, lactate, other laboratory
    values
     Lactic Acidosis: Diagnosis and
             Management
• 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)
       Lactic Acidosis: Diagnosis and
               Management
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 affect mitochondria (ABC
     or TDF or 3TC)
   – Monitor closely (consider monthly lactate measurements
     for at least 3 months)
             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
• Additive effect with other Hepatotoxic drugs
   e.g. TB drugs
                   Hepatic Toxicity

• NRTIs – lactic acidosis/hepatic steatosis
• PIs – transaminase elevations, hepatitis, hepatic
  failure, especially with high-dose RTV
• NNRTIs – transaminase elevations, hepatitis,
  hepatic failure, especially with nevirapine
                 Hepatic Toxicity
Nevirapine (NVP):
– Increased risk of NVP-associated hepatic toxicity in
  women, and in patients with higher pre-NVP CD4
  count (>250 cells/mm3 in women, >400 cells/mm3
  in men)
– Starting NVP in women with CD4 counts >250
  cells/mm3 is not recommended unless benefits
  clearly outweigh risks
– Liver transaminases should be monitored closely for
  the first 18 weeks after initiation of NVP
             Hepatic Toxicity
• 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: Monitoring
– Follow liver function tests closely on regular basis
  after starting new ARV
– Monitor closely in children with hepatitis B or C
  coinfection, in children initiating NVP
   Hepatic Toxicity: Management
– Asymptomatic, mild to moderate transaminase elevation:
   • Observe; usually can continue ARV
– 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
Metabolic abnormalities
               Lipodystrophy
• Visceral Fat accumulation
  (lipohypertrophy)
  – Associated with Pis
• Peripheral fat wasting (lipoatrophy)
  – Associated with NRTIs (especially d4T and
    AZT)
• Isolated Lipomastia (Fat deposited in the
  Breasts)
  – Associated with Efavirenz
             Lipodystrophy:
        Assessment and Monitoring

• No standard methods, no standard diagnostic
  criteria
  – Anthropometric measurements, CT, MRI, DEXA
         Lipodystrophy: Treatment
• No proven therapies; few data in children
   – Lipohypertrophy
      • Generally will not improve with switch from PI to NNRTI
      • Diet, exercise
   – Lipoatrophy
      • Avoid d4T and AZT; switch from these at slightest sign of
        lipoatrophy
   – Lipomastia
      • Resolves spontaneously without switching. May consider
        switching from Efavirenz in severe cases
• Investigational:
   – Growth hormone, testosterone
   – Surgery
*
              Lipodystrophy

THEREFORE SWITCH
 FROM d4T to ABACAVIR
 AT THE SLIGHTEST SIGN
 OF LIPOATROPHY

    Also for lactic acidosis, peripheral neuropathy
            Hyperlipidemia

Common in adults, especially with PIs,
 few reports on syndrome in children
• Some ARVs, especially PIs, d4T and EFV,
   may increase lipids
• No studies on cardiovascular risk
• No studies on lipid-lowering therapy
Haematologic complications
Haematologic complications
Allergic reactions
                                 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, DRV (sulfonamides)
              Rash: Management

Severe: permanently discontinue suspected agent
Mild to moderate: may resolve, but monitor
  closely
        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
• Usually in first 6 weeks of treatment
• Hypersensitivity linked to HLA B*5701
• HLA B*5701 rare in Black population
• HSR 5% in whites, 0.2% in Blacks

NVP: fever, myalgia, arthralgia, hepatitis,
 eosinophilia
        Hypersensitivity Reaction
Management
• If hypersensitivity reaction is suspected,
  offending drug must be discontinued
  permanently
• ABC: rechallange may be fatal
• NVP: avoid other NNRTIs
             Conclusion
• Adverse reactions generally uncommon
  especially in children
• Adherence may be affected
• Choose regimens wisely (avoid d4T,NVP)
• Monitor for adverse reactions
• Switch from d4T at first signs of
  lipoatrophy
          Acknowledgement
• AIDS Education and Training Centers
  National Resource Center
  – http://www.aids-etc.org

				
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