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Highly Active Antiretroviral Therapy Associated Adverse Events

Highly Active Antiretroviral Therapy Associated Adverse Events . Jacqueline Gabbay, B.S., Pharm.D . Bellevue Hospital Center . Overview . Differentiating between common and severe adverse drug events Exploring the fine line between HIV disease and drug toxicities

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Highly Active Antiretroviral Therapy Associated Adverse Events

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  1. Highly Active Antiretroviral Therapy Associated Adverse Events Jacqueline Gabbay, B.S., Pharm.D. Bellevue Hospital Center

  2. Overview • Differentiating between common and severe adverse drug events • Exploring the fine line between HIV disease and drug toxicities • Monitoring for the presence of ADE’s • Management of HAART related ADE’s • Long term effects of HAART as a result of increased survival

  3. Antiretroviral Agents • NRTI • Abacavir (Ziagen) • Didanosine (Videx) • Emtricitabine(Emtriva) • Lamivudine (Epivir) • Stavudine (Zerit) • Tenofovir (Viread) • Zidovudine (Retrovir) • NNRTI • Delaviridine(Rescriptor) • Efavirenz(Sustiva) • Nevirapine (Viramune) • Etravirine (Intelence) • PI • Amprenavir (Agenerase) or fosamprenavir(Lexiva) • Atazanavir (Reyataz) • Darunavir(Prezista) • Indinavir (Crixivan) • Lopinavir(+ ritonavir = Kaletra) • Nelfinavir(Viracept) • Ritonavir (Norvir) • Saquinavir(Invirase) • Tiprinavir(Aptivus) • Entry inhibitor: Enfuviritide(Fuzeon) • Integrase inhibitor: Raltegravir • CCR5-r inhibitor: Maraviroc

  4. HAART Associated Events

  5. Hypersensitivity Reactions • Incidence with all major classes of antiretroviral agents • Most common during induction phase with non-nucleoside reverse-transcriptase analogs • Spectrum of reactions • Mild self limiting maculopapular rash • Severe life threatening reactions

  6. Hypersensitivity Reactions: Viramune® (nevirapine) • Skin reactions- [US Boxed Warning]: Severe life-threatening skin reactions • Stevens-Johnson syndrome • Toxic epidermal necrolysis • Hypersensitivity reactions with rash and organ dysfunction • Incidence • Grade 1 & 2: 13% • Grade 3 & 4: 2%

  7. Hypersensitivity Reactions: Viramune® (nevirapine) • Greatest risk of reactions is within the initial 6 weeks of treatment • Intensive monitoring during initial 18 weeks • Baseline liver function test • Periodic serum transaminases • Management: permanently discontinue therapy

  8. Hypersensitivity Reactions: Viramune® (nevirapine) • Fourteen day lead-in period • 200 mg once daily x 14 days  200 mg BID • Do not increase dose until rash resolves • Not to exceed 28 days • If therapy interrupted > 7 days restart at daily dosing • Avoid in high risk patients • Males CD4 > 400 cells/mm3 • Females CD4 > 250 cells/mm3 • Moderate to severe hepatic impairment

  9. Hypersensitivity Reactions: NNRTI’s • Rescriptor® (delaviridine) • Incidence 16 – 32% • Lasts < 2 weeks • May rechallenge • Intelence® (etravirine) • Incidence 10% • May rechallenge • Sustiva® (efavirenz) • Grade 1 & 2 rash: 5 – 26% • Grade 3 & 4 rash: < 1% (46% in children) • Prophylactic antihistamines • Discontinue if severe

  10. Hypersensitivity Reactions: Ziagen® (abacavir) • [U.S. Boxed Warning]: serious and fatal hypersensitivity reactions • Incidence 5% • Screening for HLA-B 5701 • Reaction worsens with each subsequent dose • Symptoms with two or more of the following warrant discontinuation: • Fever, skin rash, constitutional symptoms, respiratory symptoms, GI symptoms

  11. Gastrointestinal Effects • Most common adverse effect associated with ART • Nausea, vomiting, anorexia • Diarrhea • Multiple potential etiologies • Advanced HIV disease • Opportunistic infections • Medication induced • Mostly associated with NRTI’s and PI’s

  12. Metabolic Effects • Mitochondrial dysfunction • Lactic acidosis • Dyslipidemia • Lipodystrophy • Abnormal glucose utilization NRTI’s PI’s

  13. NRTI Induced Mitochondrial Dysfunction • Role of mitochondria • Oxidative phosphorylation • Fatty acids and pyruvate used to produce energy as ATP • Generation of reactive oxygen species

  14. NRTI Induced Mitochondrial Dysfunction • Triphosphorylated intracellularly nucleotides  incorporated into viral DNA via viral reverse transcriptase enzyme • Prevent viral DNA elongation and replication • May function as substrates for other enzymes capable of DNA formation • Human polymerase g

  15. NRTI Induced Mitochondrial Dysfunction

  16. NRTI Induced Mitochondrial Dysfunction • Videx® (didanosine) > Zerit® (stavudine) >= Retrovir® (zidovudine) >>> Viread® (tenofovir) = Emtriva® (emtricitabine) = Ziagen® (abacavir)= Epivir® (lamivudine) • Onset may vary depending on individual’s cell type • Variations in copies and numbers of mtDNA • Organelle dysfunction and impairment of oxidative phosphorylation

  17. Clinical Manifestations of Mitochondrial Toxicity

  18. Mechanism of NRTI Induced Lactic Acidosis

  19. NRTI Lactic Acidosis • Hyperlactitemia (lactate > 5 mEq/L) • Chronic hyperlactitemia vs. severe lactic acidosis • Usually occurs after 6 months of treatment • Symptoms: Nausea, vomiting, abdominal pain, weight loss, severe fatigue, hyperventilation • Risk factors • Obesity • Nutritional depletion of cofactors and vitamins • HIV infection • Most common NRTI’s: Videx® (didanosine) , Viread® (tenofovir), Zerit® (stavudine)

  20. Management of Lactic Acidosis L > 5 mmol/L

  21. Renal Toxicity: Viread® (tenofovir) • Forms of renal toxicity • Renal impairment • Acute renal failure • Fanconi syndrome • Interstitial nephritis • Nephrogenic DI • Case reports of acute tubular necrosis • Manifests after 5 weeks or more of therapy • Resolution of proximal tubular dysfunction within 1 – 10 weeks after discontinuation • Mechanism: accumulation in proximal tubular cells • Impaired tubular reabsorption • Renal tubular acidosis • Defects in vitamin D hydroxylation Dominik et atl., AIDS 2005; 19: 1329 - 40

  22. Renal Toxicity: Viread® (tenofovir) • Risk factors • Age, sex, race • Underlying renal impairment • Concomitant nephrotoxic agents • Coadministration with PI’s: inhibition of Viread® (tenofovir) efflux from tubule cells • Coadministration with Videx® (didanosine) • Dose adjustments: • CrCl> 50 mL/min: 300 mg PO daily • 30 – 49 mL/min: 300 mg Q48H • 10 – 29 mL/min: 300 mg Q72-86H • <10 mL/min: not recommended without HD

  23. Renal Safety of Viread® (tenofovir) in HIV-Infected Patients • Systematic review and meta-analysis • Included 17 studies (9 RCT) • Results • Significantly greater loss of kidney function with the use of Viread® (tenofovir) (CrCl difference of 3.92 mL/min, 95% CI, 2.13 – 5.7 mL/min) • Significantly higher risk of acute renal failure (risk difference 0.7%, 95% CI, 0.2 – 1.2) • No evidence of increased risk of severe proteinuria, hypophosphatemia, or fractures Cooper et al., CID 2010; 51(5), 496 - 505

  24. Nephrolithiasis: Crixivan® (indinavir) • Incidence • Adults: 12% • Pediatrics: 29% • Calculi composed of unmetabolizedCrixivan® (indinavir) • Dose dependent effect • Onset 4 weeks – 6 months • Symptoms: • Acute flank pain/renal colic • Hematuria • Urgency and dysuria • Asymptomatic crystalluria

  25. Nephrolithiasis: Crixivan® (indinavir) • Risk factors: low body weight, low CD4 count, changes in kidney function, liver disease, high urinary pH • Management: • Fluids • Acidification of urine • Pain control – NSAID’s not recommended • Monitoring: renal function and urinalysis • Prevention: 48 oz water daily

  26. Pancreatitis • Implicating agents: • NRTI’s: Videx® (didanosine) , Zerit® (stavudine), and Epivir® (lamivudine) (pediatrics) • PI’s: associated with severe increases in triglycerides • Occurs within 1 – 6 months after induction • Resolves 1 – 3 weeks after discontinuation • Suggested mechanisms: mitochondrial toxicity • Risk factors • Alcohol use, hyperlipidemia, cholelithiasis, h/o pancreatitis, advanced HIV disease, CD4 < 50 cells/mm3 • Clinical manifestations • Abdominal pain, nausea, and vomiting • Elevated triglycerides and glucose prior to onset

  27. Hepatic Steatosis • 1993 – eight cases of severe hepatomegaly with diffuse steatosis were reported in HIV infected patients taking Retrovir® (zidovudine) • NRTI’s: Videx® (didanosine) , Zerit® (stavudine), and Retrovir® (zidovudine) • Mechanism: esterification of TG and decreased egress from the liver  accumulation of small lipid droplets • Management: cessation of offending NRTI and supportive care

  28. Peripheral Neuropathy • Implicating agents: • NRTI’s: Videx® (didanosine), Zerit® (stavudine), Epivir® (lamivudine) (peds) • NNRTI’s: Viramune® (nevirapine) • Appear to be dose related • Incidence is higher than other mitochondrial toxicity related adverse events • Clinical manifestations: Bilateral tingling, burning, or aching sensation in the hands and lower extremities • Risk factors: • Advanced HIV, aging, diabetes, nutritional deficiencies, concomitant isoniazid • Management: discontinue when neuropathic pain is severe due to possible irreversible nerve damage

  29. Myopathy: Retrovir® (zidovudine) • Incidence of 9% • Onset after months of therapy • Clinically resembles idiopathic polymyositis and HIV myopathy • Muscle tenderness • Proximal muscle weakness • Muscle atrophy • Elevations in CK (10x ULN) • Mechanism: affects muscle mitochondrial DNA polymerase g • Treatment • May consider discontinuing Retrovir® (zidovudine) • NSAIDs • Muscle strength usually returns within months of discontinuation

  30. Hematologic toxicity: Retrovir® (zidovudine) • [US Boxed Warning]: associated with hematologic toxicity -granulocytopenia, severe anemia requiring transfusions, and rarely, pancytopenia • Incidence • Granulocytopenia 2 %; onset 6 – 8 weeks • Anemia 1%; onset 2 – 4 weeks • Mechanisms: direct bone marrow toxicity via inhibition of heme/globin synthesis and effect on iron supply • Management: • Dose interruption for significant anemia (HgB< 7.5 mg/dL or > 25% reduction from baseline) until recovery of bone marrow is evident • Epoetin alfa and neupogen

  31. Lipodystrophy • Onset within 2 – 12 months after induction • Implicating agents: • PI • NRTI: Zerit® (stavudine) • Clinical features • Lipoatrophy - peripheral fat loss in the face, limbs, buttocks • Fat accumulation in the abdomen, breasts, and dosocervical spine (“buffalo hump”) • Risk factors: longer duration of treatment, increasing age, advanced HIV disease • Management: protease-sparing regimen, resistance training, aerobic exercise

  32. Lipidystrophy

  33. Dyslipidemia • Features of dyslipidemia • Elevated triglycerides ( > 150 mg/dL) • Elevated LDL (> 130 mg/dL) • Low levels of HDL (< 40 mg/dL) • Obtain baseline lipid panel • Incidence highest with PI’s • Highest with lopinavir/ritonavor combination • Lowest with Reyataz® (atazanavir) • PI sparing regimens containing Zerit® (stavudine), Retrovir® (zidovudine), or efavirenz • Viramune® (nevirapine) may have beneficial effect • Pathogenesis unclear • Disruption of lipid metabolism

  34. SQV/RTV atorvastatin 347% AUC simvastatin 3059% AUC pravastatin 50% AUC NFV atorvastatin 74% AUC simvastatin 505% AUC LPV/r atorvastatin 588% AUC pravastatin 30% AUC fibrates fluvastatin pravastatin rosuvastatin statin-fibrates atorvastatin lovastatin simvastatin Lipid Lowering Agents and Protease Inhibitors Low interaction potential Use cautiously Contraindicated • Antimicrob Agents Chemother 2001; 45: 3445-3450. AIDS 2002; 16: 569-577 40th ICAAC 2000; abstract 1644

  35. Altered Glucose Metabolism • 1997 – FDA issued a public health advisory concerning reports of hyperglycemia and new-onset diabetes mellitus related to PI’s • Incidence with PI’s is 1 – 6% • Mechanism of insulin resistance unknown • Increased concentration of insulin, C- peptide, proinsulin, and glucagon • Peripheral insulin resistance • Elevated endogenous glucocorticoid levels • Obtain baseline and follow-up blood glucose concentration • Increased doses of antidiabetic agents may be indicated

  36. Hepatotxicity • Transaminitis and hepatotoxicity associated with most antiretroviral agents • PI’s: Norvir® (ritonavir) (full dose – < 2 %) • NRTI’s: Videx® (didanosine) and Zerit® (stavudine) • NNRTI’s: Viramune® (nevirapine) • Risk factors: coinfection with viral hepatitis, other hepatotoxic agents, and baseline abnormalities of aninotransferases

  37. Hyperbilirubinemia: Reyataz® (atazanavir) • Most common side effect of atazanavir • Usually asymptomatic elevations • Incidence of increase > 2.6x ULN is 35 – 49% • Mechanism • Inhibition of enzyme that conjugates bilirubin • Correlates with serum concentrations • Management: • Discontinue if bilirubin is 5x ULN • Evaluate alternative etiology if transaminases concomitantly elevated

  38. Central Nervous System Effects: Sustiva® (efavirenz) • Manifestations • CNS depression – impaired concentration (8%), dizziness (28%), drowsiness (7%), insomnia (16%) • Psychiatric – severe depression (1 – 2%), suicide, paranoia, mania, vivid dreams (6%) • Overall incidence as high as 50% with 3% severe enough to cause discontinuation • Associated with higher serum concentrations • Onset within a few days to weeks of initiation • Resolution within a four weeks of therapy

  39. QT Prolongation: Invirase® (saquinavir) • Recent labeling updates 2010: potential for prolonged QT or PR intervals when saquinavir is administered with Norvir® (ritonavir) • Dose dependent effect • Contraindications: patients with congenital or acquired QT prolongation, refractory hypokalemia, concomitant use of medication that increase saquinavir concentrations or prolong QT interval, or AV block • Obtain baseline ECG • Management: if QT prolongation exceeds pretreatment value by 20 msec discontinue

  40. Overall Cardiovascular Risk • Significantly higher rates of CHD and MI when compared to the general population • HOPS – HIV Outpatient Study • Nine year follow-up study including 5500 patients with HIV • Increased frequency of MI after initiation of PI’s • Controlled for hypertension, smoking, diabetes, age, sex, and dyslipidemia • Risks • Hyperlipidemia • Altered glucose metabolism • Direct cytotoxic effects on myocardium Schiller D. Am j Health SystPharm 2004; 61 (23)

  41. Clinical Relevance of HAART ADE’s • Decreased mortality with the use of HAART • Increased risk for long term effects • Important to monitor and identify common vs. severe adverse drug events • Management of HAART related adverse events

  42. Questions

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