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Complications of Antiretroviral Therapy

Complications of Antiretroviral Therapy. Paul E. Sax, MD Associate Professor of Medicine, Harvard Medical School Clinical Director, Division of Infectious Diseases and HIV Program Brigham and Women’s Hospital Boston, MA Brian A. Boyle, MD, JD

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Complications of Antiretroviral Therapy

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  1. Complications of Antiretroviral Therapy Paul E. Sax, MD Associate Professor of Medicine, Harvard Medical School Clinical Director, Division of Infectious Diseases and HIV Program Brigham and Women’s Hospital Boston, MA Brian A. Boyle, MD, JD Associate Professor of Medicine, Weill Medical College of Cornell University (courtesy) New York, NY Associate Director, ViralED, LLC Medical Editor, HIVandHepatitis.com Calvin J. Cohen, MD Clinical Instructor, Harvard Medical School Research Director, Harvard Vanguard Medical Associates and Community Research Initiative of New England Boston, MA

  2. ART Toxicity: Management Principles • Mild adverse effects • Continue therapy • Patient education, reassurance • Severe or intolerable adverse effects • Single drug substitution, same class • Simultaneous discontinuation of all drugs • Staggered discontinuation • First NNRTIs • NRTIs 5‒7 days later

  3. Potential Toxicities of NRTIs • Common • Lipoatrophy (especially stavudine and zidovudine) • Peripheral neuropathy (didanosine and stavudine) • Bone marrow suppression (zidovudine) • Hypersensitivity reaction (abacavir) • Uncommon/Rare • Mitochondrial toxicity (especially stavudine) • Hepatic steatosis, lactic acidosis (especially stavudine) • Myopathy, myositis (zidovudine) • Pancreatitis (didanosine) • Renal impairment (tenofovir)

  4. Potential Toxicities of PIs • Common • Fat accumulation • Dyslipidemia • Hyperbilirubinemia (atazanavir, indinavir) • Nephrolithiasis/urolithiasis (indinavir) • Skin changes (indinavir) • Uncommon/Rare • Hepatotoxicity • Hyperglycemia • Increased bleeding in hemophilia • Nephrolithiasis/urolithiasis (atazanavir) • ECG changes (atazanavir)

  5. Potential Toxicities of NNRTIs • Hepatotoxicity (especially nevirapine) • Use nevirapine cautiously (CD4 counts <250 cells/mm3 in women or <400 cells/mm3 in men; regular liver function monitoring) • Rash (especially nevirapine) • May induce severe morbidity and mortality • CNS effects (efavirenz) • Usually resolve within 4 weeks of starting therapy • Teratogenicity (efavirenz) • Pregnancy category D (neural tube defects)

  6. Potential Toxicities of Enfuvirtide (Fusion Inhibitor) • Enfuvirtide is the only approved agent in this class • No known systemic toxicity • Injection site reactions in nearly 100% • Redness • Itching • Swelling • Pain • Hard skin or lumps

  7. Long-term Complications of ART:Body Fat Alterations • Lipoatrophy • Most common morphologic abnormality • Likely due to mitochondrial toxicity of NRTIs • Less likely with non-thymidine containing regimens • Fat accumulation • Less common than lipoatrophy • Thought to be due to PI therapy

  8. Changes in Body Fat Indices with ART Change from baseline,% n Adapted with permission from Dubé MP, et al. J Acquir Immune Defic Syndr 2007;45:508-14.

  9. Lipoatrophy by ART Regimen:Changes at 144 Weeks Change in limb fat, % Change in trunk fat, % Dubé MP, et al. J Acquir Immune Defic Syndr 2007;45:508-14.

  10. Lipoatrophy by Regimen:NRTIs vs NRTI-Sparing Regimen P values at week 96 LPV/EFV vs LPV: 0.023 LPV/EFV vs EFV: <0.001 LPV vs EFV: 0.003 Haubrich RH, et al. 14th Conference on Retroviruses and Opportunistic Infections, 2007.

  11. ACTG 5142 Lipoatrophy by NRTI Patients with lipoatrophy, % P values at week 96 ZDV vs TDF: <0.001 d4T vs TDF: <0.001 d4T vs ZDV: 0.038 Haubrich RH, et al. 14th Conference on Retroviruses and Opportunistic Infections, 2007.

  12. Lipoatrophy by Regimen:Effect of Switching Stavudine Moyle et al Martin et al Moyle GJ, et al. AIDS 2006;20:2043-50. Martin A, et al. AIDS 2004;18:1029-36.

  13. Mitochondrial Toxicity by Regimen:Effect of Switching Stavudine mtDNA copies per cell type Apoptosis score Muscle Fat PBMC HIV‒ HIV‒ HIV‒ HIV‒ Wk 0 Wk 48 Wk 0 Wk 48 Wk 0 Wk 48 Adapted with permission from McComsey GA, et al. AIDS 2005;19:15-23.

  14. Long-term Complications of ART: Lipid Effects Lipid effects include elevated TC, LDL-C, TGs • PIs • Highest risk among antiretroviral classes • Risk is highest with ritonavir (dose-dependent) • NRTIs • Highest risk with stavudine, then zidovudine • NNRTIs • Efavirenz may increase lipids more than nevirapine • Improvement in HDL-C seen with both drugs, especially nevirapine

  15. Dyslipidemia Due to HIV and ART Seroconversion ART begun Riddler SA, et al. JAMA 2003;289:2978-82.

  16. Lipid Effects of PIs Table created by Stefan Mauss, MD (Center for HIV and Hepatogastroenterology, Düsseldorf, Germany), using the author’s best judgment about the relative lipid effects of the agents listed, based on accumulated studies to date. Used with permission of the author.

  17. Management of Dyslipidemia Apply NCEP guidelines Lifestyle + lipid-lowering therapy (statin); Consider fibrates if TGs are main concern Lifestyle changes ART substitution Challenges of lipid-lowering therapy Multiple medications Drug-drug interactions (statins, PIs) Difficulty reaching NCEP goals despite therapy NCEP = National Cholesterol Education Program.

  18. Lipid-Lowering Therapy: Drug-Drug Interactions with ART * In rare cases, can induce insulin resistance.

  19. Long-term Complications of ART: Insulin Resistance and Diabetes • Risk factors • Reduction in insulin sensitivity with PIs • Long-term exposure to NRTIs • HCV coinfection • Traditional risk factors • Management • Fasting glucose level before ART • Routine glucose monitoring, possible 2-hr GTT • IGT or diabetes: consider switch from PIs to NNRTIs

  20. Insulin Resistance by ART Regimen OR = odds ratio; QUICKI = quantitative insulin sensitivity check index. * P < 0.05. Brown TT, et al. AIDS 2005;19:1375-83.

  21. Diabetes by ART Regimen NA = not applicable; RR = rate ratio adjusted for age and body mass index. * Prevalence based on 1278 men; adjusted for age and body mass index. †Incidence per 100 person-years, based on 680 men. Brown TT, et al.Arch Intern Med 2005;165:1179-84.

  22. Long-term Complications of ART: Cardiovascular Risk • Risk factors • Dyslipidemia • Insulin resistance • Body fat changes • Endothelial dysfunction • Smoking • Duration of ART • Possible increased risk with PIs • Management • Continue ART • Treat/manage cardiovascular risk factors

  23. Myocardial Infarction by ART Regimen p-yr = person-years. * Relative rate per year of exposure. Friis-Moller N, et al. N Engl J Med 2007;356:1723-35.

  24. Long-term Complications of ART: Lactic Acidosis • Asymptomatic hyperlactatemia • Mildly elevated blood lactate • Does not predict lactic acidosis • May be due to artifacts of sampling • Symptomatic hyperlactatemia • Nonspecific symptoms: fatigue, anorexia, weight loss • Lactic acidosis syndrome • Severe symptomatic hyperlactatemia • Metabolic acidosis, hepatomegaly, steatosis • Rare but may be fatal • Stop NRTI treatment

  25. Hyperlactatemia Risk Factors ALT = alanine aminotransferase, OR = odds ratio. * Multiple logistic regression analysis. † Unadjusted univariate analysis. Vrouenraets SM, et al.Antivir Ther 2002;7:239-44.

  26. Long-term Complications of ART: Distal Sensory Peripheral Neuropathy • Etiology • HIV itself • Secondary infections (CMV, syphilis) • Nutritional deficiency • Alcohol abuse • NRTIs (especially stavudine + didanosine) • Characteristics • Pain, numbness, loss of sensation • Tends to involve longest nerves first, hence first evident in feet • Management • Discontinue offending NRTIs • Adjunctive treatments for persistent pain

  27. Peripheral Neuropathy by ART Regimen HR = hazard ratio; HU = hydroxyurea. Moore RD, et al. AIDS 2000;14:273-8.

  28. Summary: Potential Adverse Effects NRTIs Lipoatrophy Hepatic steatosis Lactic acidosis Peripheral neuropathy Bone marrow suppression Myopathy Pancreatitis Renal impairment Hypersensitivity PIs Fat accumulation Dyslipidemia Hepatotoxicity Hyperglycemia Hemophilia bleeding ECG changes Hyperbilirubinemia Urologic stones Skin changes NNRTIs Hepatotoxicity Rash CNS effects Teratogenicity Fusion inhibitor (enfuvirtide) Injection site reactions

  29. Summary: Management of Adverse Effects • Adjunctive strategies: • Choose agents carefully • Optimize lifestyle • Pharmacologic strategies: • Mild effects: continue therapy • Moderate effects: single-drug substitution • Severe effects: discontinuation

  30. CRIXIVAN® (indinavir sulfate) • Indication • CRIXIVAN in combination with other antiretroviral agents is indicated for the treatment of HIV infection. This indication is based on 2 clinical trials of approximately 1 year’s duration that demonstrated • a reduction in the risk of AIDS-defining illnesses or death • a prolonged suppression of HIV RNA • Contraindication • CRIXIVAN is contraindicated in patients with clinically significant hypersensitivity to any of its components. • Inhibition of CYP3A4 by CRIXIVAN can result in elevated plasma concentrations of the following drugs, potentially causing serious or life-threatening reactions: Drug Interactions With CRIXIVAN: Contraindicated Drugs

  31. CRIXIVAN® (indinavir sulfate) Selected Warnings • ALERT: Find out about medicines that should NOT be taken with CRIXIVAN. • Nephrolithiasis/urolithiasis has occurred with CRIXIVAN therapy. The cumulative frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range across individual trials: 4.7% to 34.4%). The cumulative frequency of nephrolithiasis events increases with increasing exposure to CRIXIVAN; however, the risk over time remains relatively constant. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure, pyelonephritis with or without bacteremia. If signs or symptoms of nephrolithiasis/urolithiasis occur, (including flank pain, with or without hematuria or microscopic hematuria), temporary interruption (e.g., 1-3 days) or discontinuation of therapy may be considered. Adequate hydration is recommended in all patients treated with CRIXIVAN. • Acute hemolytic anemia, including cases resulting in death, has been reported in patients treated with CRIXIVAN. Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted, including discontinuation of CRIXIVAN.

  32. CRIXIVAN® (indinavir sulfate) Selected Warnings (cont) • New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. • Concomitant use of CRIXIVAN with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including CRIXIVAN, are used concurrently with other HMG-CoA reductase inhibitors metabolized by the CYP3A4 pathway (eg, atorvastatin or rosuvastatin). The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including CRIXIVAN, are used in combination with these drugs • Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving indinavir. Coadministration of CRIXIVAN with these medications is expected to substantially increase plasma concentrations of sildenafil, tadalafil, and vardenafil and may result in an increase in adverse reactions, including hypotension, visual changes, and priapism, which have been associated with sildenafil, tadalafil, and vardenafil.

  33. CRIXIVAN® (indinavir sulfate) Selected Drug Interactions Drugs That Should Not Be Coadministered with CRIXIVAN

  34. CRIXIVAN® (indinavir sulfate) Selected Precautions • Indirect hyperbilirubinemia has occurred frequently during treatment with CRIXIVAN and has infrequently been associated with increases in serum transaminases. It is not known whether CRIXIVAN will exacerbate the physiologic hyperbilirubinemia seen in neonates. • Reports of tubulointerstitial nephritis with medullary calcification and cortical atrophy have been observed in patients with asymptomatic severe leukocyturia (>100 cells/high-power field). • There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. • In patients with hepatic insufficiency due to cirrhosis, the dosage of CRIXIVAN should be lowered because of decreased metabolism of CRIXIVAN. Patients with renal insufficiency have not been studied. • Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance, has been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

  35. CRIXIVAN® (indinavir sulfate) Selected Precautions (cont) • Indinavir is an inhibitor of the cytochrome P-450 isoform CYP3A4. Coadministration of CRIXIVAN and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects. • Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of CRIXIVAN and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir. • There are no adequate and well-controlled studies in pregnant patients. CRIXIVAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

  36. CRIXIVAN® (indinavir sulfate) Established and Other Potentially Significant Drug Interactions Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction HIV Antiviral Agents Note: ↑ = increase;↓ = decrease

  37. CRIXIVAN® (indinavir sulfate) Established and Other Potentially Significant Drug Interactions (cont) Note: ↑ = increase;↓ = decrease

  38. CRIXIVAN® (indinavir sulfate) Established and Other Potentially Significant Drug Interactions (cont) Note: ↑ = increase;↓ = decrease

  39. CRIXIVAN® (indinavir sulfate) Selected Adverse Reactions • Clinical adverse experiences reported in ≥2% of patients in study ACTG 320 of unknown drug relationship and of severe or life-threatening intensity for CRIXIVAN plus zidovudine plus lamivudine (n=571) • Abdominal pain, 1.9%; asthenia/fatigue, 2.4%; fever, 3.8%; nausea, 2.8%; diarrhea, 0.9%; vomiting, 1.4%; acid regurgitation, 0.4%; anorexia, 0.5%; anemia, 2.4%; back pain, 0.9%; headache, 2.4%; dizziness, 0.5%; pruritus, 0.5%; rash, 1.1%; cough, 1.6%; difficulty breathing/dyspnea/shortness of breath, 1.8%; nephrolithiasis/urolithiasis (including renal colic, and flank pain with and without hematuria), 2.6%; dysuria, 0.4%; taste perversion, 0.2%.

  40. Before prescribing CRIXIVAN (indinavir sulfate), please read the accompanying Prescribing Information.CRIXIVAN is a registered trademark of Merck & Co., Inc. 20707440(2)-CRX

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