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Constance A. Benson, MD

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

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Constance A. Benson, MD

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  1. Managing Acute Antiretroviral Complications Constance A. Benson, MD CA Benson, MD.Presented at IAS–USA/RWCA Clinical Conference, August 2004. The International AIDS Society–USA

  2. 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%

  3. 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

  4. Abacavir Hypersensitivity • Association with HLA-B*5701, HLA-DR7, and HLA-DQ3 (Mallal S, et al., Lancet 2002) • HLA-B*5701 - 78% of patients with abacavir hypersensitivity vs. 2% of abacavir tolerant pts (OR 117; 95% CI 29-481; p<0.0001) • Combination of HLA-DR7 and HLA-DQ3: 72% of hypersensitive patients vs. 3% of abacavir tolerant pts (OR 73 [20-268]; p<0.0001) • Combination of HLA-B*5701, HLA-DR7 and HLA-DQ3: 72% of hypersensitive pts vs. none without (OR 822 [43-15,675]; p<0.0001) • Positive predictive value 100%; negative predictive value 97%

  5. 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% B*5701 55% 1% 0 0 B*5701/DR7 33% 1% N/A N/A

  6. 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 (> 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

  7. 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

  8. 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: Reye’s syndrome, acute fatty liver of pregnancy, drugs • Treatment: Remove cause, avoid alcohol

  9. 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.”

  10. 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 < 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 > 250 cells/L (11.9% vs 0.9%)

  11. Acute Hepatotoxicity: Management • Mild to moderate (transaminases < 3-5x ULN): • May continue therapy, supportive care, close observation • If transaminase levels increase to > 5x ULN (or > 3-5x pre-treatment values) or if other symptoms develop or progress, therapy should be held • Severe (transaminases > 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

  12. 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 < 100 cells/µL; large  (> 100 cells/µL) on potent ART

  13. 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.

  14. 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

  15. 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

  16. 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

  17. Acute Lactic Acidosis • Venous lactate level > 2 mmol/L (18 mg/dL) and arterial blood pH < 7.3 • 1.3 cases/1000 person-yrs exposure to NRTIs • Onset acute or subacute, usually within 1-4 months • d4T >> ddI >> ZDV > 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)

  18. 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

  19. 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 > ddI > ZDV > 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)

  20. 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 > ritonavir > saquinavir > indinavir > lopinavir/ritonavir) – diarrhea, gastrointestinal upset • Adjunct Rx with anti-emetics, anti-diarrheal agents • Drug discontinuation results in rapid reversal for most

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