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Managing Acute Antiretroviral Complications
Constance A. Benson, MD
CA Benson, MD.Presented at IASUSA/RWCA Clinical
Conference, August 2004.
The International AIDS SocietyUSA
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Systemic Hypersensitivity Reactions

• The most common antiretroviral drugs associated
  with systemic hypersensitivity/skin rash
  reactions are
• NNRTIs
• NVP 15-17
• DLV 18
• EFV 10
• PI
• Amprenavir 15-20
• NRTIs
• Abacavir 3-5

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Abacavir Hypersensitivity

• Incidence 3-5
• Symptoms
• Onset 4-6 wks after initiation of abacavir
  therapy
• Fever, skin rash, fatigue, GI symptoms (nausea,
  vomiting, diarrhea, abdominal pain), and
  respiratory tract symptoms (pharyngitis, dyspnea,
  or cough)
• Management
• Discontinue abacavir
• Do not re-start abacavir severe symptoms will
  recur within hours, including life-threatening
  hypotension and death

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Abacavir Hypersensitivity

• Association with HLA-B5701, HLA-DR7, and HLA-DQ3
  (Mallal S, et al., Lancet 2002)
• HLA-B5701 - 78 of patients with abacavir
  hypersensitivity vs. 2 of abacavir tolerant pts
  (OR 117 95 CI 29-481 plt0.0001)
• Combination of HLA-DR7 and HLA-DQ3 72 of
  hypersensitive patients vs. 3 of abacavir
  tolerant pts (OR 73 20-268 plt0.0001)
• Combination of HLA-B5701, HLA-DR7 and HLA-DQ3
  72 of hypersensitive pts vs. none without (OR
  822 43-15,675 plt0.0001)
• Positive predictive value 100 negative
  predictive value 97

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Abacavir Hypersensitivity

• Association with HLA type (Hetherington S, et
  al., Lancet 2002)
• HLA White Black
• Pts Controls Pts Controls
• B-57 55 3 22 6
• B5701 55 1 0 0
• B5701/DR7 33 1 N/A N/A

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Acute Hepatotoxicity

• Nearly all currently available ARV drugs have
  been associated with hepatotoxic reactions
• NRTIs ? non-alcoholic fatty liver disease (NAFLD)
  and hepatic steatosis longer term exposure (gt 6
  months)
• NNRTIs ? first 3-12 weeks after starting therapy
  often associated with other systemic symptoms of
  hypersensitivity
• PIs ? first 3-12 weeks after starting therapy,
  mild to moderate in severity increased risk in
  those with underlying HBV, HCV
• Unconjugated hyperbilirubinemia with indinavir,
  atazanavir not a toxic reaction

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Antiretroviral Therapy and Hepatotoxicity

• Liver enzyme elevations are common in patients
  initiating ART
• Any elevation 30-50
• Severe elevations 10-15
• Some ARVs may predispose to liver enzyme
  elevations
• Ritonavir, Nevirapine
• Chronic viral hepatitis increases the risk of
  liver enzyme elevations (range 2.5-8 fold)
• Reports of rapid HCV disease progression or acute
  flares of chronic hepatitis B or C after
  initiation of ART

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Hepatic Steatosis

• Mild to moderate liver enlargement due to fat
  accumulation
• Diagnosed by U/S, CT, or MRI
• Multifactorial
• Macrovesicular alcohol, diabetes, obesity,
  protein-calorie malnutrition, total parenteral
  nutrition
• Drugs Vitamin A, steroids, synthetic estrogens
  or androgenic steroids
• Microvesicular Reyes syndrome, acute fatty
  liver of pregnancy, drugs
• Treatment Remove cause, avoid alcohol

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Stavudine and Didanosine During Pregnancy

• Dear Health Care Provider letter (1/5/01)
• 3 deaths in pregnant women receiving d4T and ddI
  each received both drugs throughout pregnancy
  (other drugs were atazanavir, nelfinavir, and
  nevirapine in one each)
• 2 infant deaths one in utero, and the second
  after emergency C-section
• Boxed warning
• The combination of ddI and d4T should be used
  with caution during pregnancy and is recommended
  only in the potential benefit outweighs potential
  risk.

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Acute Nevirapine Hepatotoxicity

• Nevirapine hepatotoxicity
• Incidence 8-18 in clinical trials 2.5-11
  symptomatic hepatitis generally occurs in first
  4-18 weeks of treatment
• Fulminant hepatic failure lt 1
• Reported in HIV-seronegative HCWs receiving NVP
  for post-exposure prophylaxis and pregnant women
  receiving ddI, d4T (MMWR 2001)
• Factors associated with increased risk
• Chronic hepatitis due to HBV, HCV
• Women with CD4 T cell counts gt 250 cells/?L
  (11.9 vs 0.9)

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Acute Hepatotoxicity Management

• Mild to moderate (transaminases lt 3-5x ULN)
• May continue therapy, supportive care, close
  observation
• If transaminase levels increase to gt 5x ULN (or gt
  3-5x pre-treatment values) or if other symptoms
  develop or progress, therapy should be held
• Severe (transaminases gt 5x ULN)
• Stop therapy
• Re-challenge
• Depends on the severity of the reaction, presence
  of underlying liver disease or need to use other
  hepatotoxic drugs, and the availability of
  alternative ARV drugs

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Immune Reconstitution Inflammatory Syndrome

• Syndrome characterized by an acute systemic
  inflammatory response following start of potent
  ART
• Signs and symptoms may be clinically
  indistinguishable from underlying OIs
• MAC, TB most common
• Also seen with CMV, chronic HCV or HBV, HSV, VZV
• Occurs 4-16 weeks after initiation of potent ART
• More common in those with baseline CD4 counts lt
  100 cells/µL large ? (gt 100 cells/µL) on potent
  ART

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CNS Side Effects of Efavirenz

• Reported incidence 7 - 25
• Range from dizziness to hallucinations, including
  vivid dreams/nightmares, insomnia, restlessness,
  irritability, disorientation, depression,
  suicidal ideation
• May be more common in those with underlying
  psychiatric disorders or substance use/abuse
• Onset with initial dosing mild to moderate in
  severity, subside over 4-6 weeks with
  continuation of drug
• 4-10 unable to continue on treatment because of
  severity and persistence of symptoms.

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Efavirenz Metabolism Is Reduced in African
Americans ACTG 5095/5097s

• Plasma EFV levels measured from 190 patients
  treated with EFV-based regimens
• 53 white, 32 black, 15 Hispanic
• EFV metabolism was increased by 32 in whites
  compared to the other two groups
• Trend favored increased rates of early EFV
  discontinuation in those with reduced EFV
  metabolism/clearance

Ribaudo H, et al. 11th CROI, 2004
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Efavirenz Metabolism as a Function of CYP2B6
Polymorphisms (ACTG 5128)

• Efavirenz is metabolized by CYP2B6
• CYP2B6 is a mixed function oxidase with several
  SNP-associated functional polymorphisms
• Homozygous G516T mutation (T/T) is associated
  with reduced clearance
• T/T found in 20 of blacks and 3 of whites.
• T/T mutation may partially explain reduced
  clearance and increased CNS side effects among
  blacks

Haas D, et al., 11th CROI, 2004
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CNS Side Effects of Efavirenz

• Management issues
• Avoid simultaneous administration of efavirenz
  (or other NNRTIs) and abacavir if possible
• Difficulty distinguishing abacavir
  hypersensitivity from NNRTI hypersensitivity
• Reduced doses untested but may be the focus of
  TDM evaluation
• Splitting efavirenz doses unsuccessful

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Acute Lactic Acidosis

• Venous lactate level gt 2 mmol/L (18 mg/dL) and
  arterial blood pH lt 7.3
• 1.3 cases/1000 person-yrs exposure to NRTIs
• Onset acute or subacute, usually within 1-4
  months
• d4T gtgt ddI gtgt ZDV gt 3TC, ABC, TDF
• Obesity, female sex
• Symptoms Fatigue, nausea, abdominal pain,
  dyspnea
• Liver enzyme elevations (3-5 x pre-Rx levels)
  hepatic steatosis
• Diagnosis Clinical symptoms venous lactate
  level (proper sampling critical)

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Symptomatic Hyperlactatemia

• Symptoms
• Nausea, vomiting, abdominal pain, distention,
  elevated AST/ALT
• Clinical Course (Lonergan et al., 2001)
• 31/33 pts on d4T-based therapy
• Mean time to normalization of lactate 49 days
• 17 pts re-challenged with NRTIs 16/17
  substituted ZDV or ABC for d4T, 12/12 re-started
  3TC
• No recurrence of increased lactate after 6 months
  of follow-up

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Management of Hyperlactatemia and Lactic Acidosis

• Stop all therapy
• Withhold treatment until lactate level near
  normal
• Re-initiate treatment with agents less likely to
  be associated with mitchondrial toxicity if
  possible
• d4T gt ddI gt ZDV gt 3TC, ABV, TDF
• Possible but untested treatment interventions
• L-acetyl-carnitine
• Ubiquinone (Co-enzyme Q10)
• Vitamin B12 (riboflavin)
• Vitamin B1 (thiamine)
• Antioxidants (Vitamin C, E)

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Other Acute Adverse Effects of Antiretroviral
Drugs

• Zidovudine nausea, headache, anemia,
  neutropenia
• Didanosine nausea, diarrhea, pancreatitis
• Indinavir acute interstitial nephritis,
  nephrolithiasis, retinoid effects (dry skin,
  alopecia, paronychia)
• Ritonavir nausea, vomiting, circumoral
  paresthesia
• PIs (nelfinavir gt ritonavir gt saquinavir gt
  indinavir gt lopinavir/ritonavir) diarrhea,
  gastrointestinal upset
• Adjunct Rx with anti-emetics, anti-diarrheal
  agents
• Drug discontinuation results in rapid reversal
  for most