Antiretroviral Drug Toxicities and Side Effects

1. Antiretroviral Drug Toxicities and Side Effects Originally written by Dr. Mathews, Director Owen Clinic Joe Caperna, M.D. UCSD Owen Clinic Given at Cecelia Makiwane 15 January 2009

2. NRTIs All NRTIs have class-specific risk of mitochondrial toxicity syndromes including symptomatic hyperlactatemia and lactic acidosis Agents vary in their potential to be associated with mitochondrial toxicity syndromes

3. NRTIs: Zidovudine (AZT/ZDV) Most common Nausea 50% Anorexia 20% Vomiting 17% Headache 62% Malaise 53% Pigmentation of nails Insomnia Myalgia Macrocytosis Most significant Anemia Granulocytopenia Symptomatic hyperlactatemia and lactic acidosis

4. NRTIs: Lamivudine (3TC) Remarkably well tolerated, in general Reported side effects Headache 35% Nausea 33% Diarrhea 18% Abdominal pain 9% Insomnia 11% (in combination with AZT) Pancreatitis more common in pediatrics

5. NRTIs: Didanosine (ddI) Most common Diarrhea 28% Nausea 6% Rash 9% Headache 7% Fever 12% Hyperuricemia 2% Most significant Pancreatitis 1-9% Peripheral neuropathy 20% Symptomatic hyperlactatemia and lactic acidosis

6. NRTIs: Stavudine (d4T) Most common Diarrhea Nausea Vomiting Headache Macrocytosis (less than with ZDV) Most significant Peripheral neuropathy 15-20% Pancreatitis 1% Symptomatic hyperlactatemia and lactic acidosis Ascending neuromusclar weakness syndrome

7. NRTIs: Abacavir Most common Headache 16% Nausea/vomiting 16% Diarrhea 12% Loss of appetite 11% Malaise Myalgia Arthralgia Edema Paresthesias Hypersensitivity reaction 5% Symptoms malaise fever GI upset rash lethargy respiratory symptoms Re-challenge contraindicated; may be life threatening

8. NRTIs: Zalcitabine (ddC) Most common Oral ulcers 13% Rash 8% Most signficant Pancreatitis <1% Peripheral neuropathy 22-35% Severe continuous pain Slowly reversible when ddC discontinued ? risk with diabetes mellitus Symptomatic hyperlactatemia and lactic acidosis

9. NRTIs: Emtricitabine (FTC) Hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. Headache,diarrhea, nausea, and rash were seen with similar frequency FTC and control treatment groups Most signficant post treatment exacerbation of Hepatitis B (as with 3TC)

10. NtRTI: Tenofovir (TDF) Most common Nausea 11% Diarrhea 9% Vomiting 5% Flatulence 4% Generally well tolerated Most significant Case reports of Fanconi-like syndrome and acute renal failure Less potential for mitochondrial toxicity than NRTIs Renal dosing guidelines important

11. NNRTIs: Efavirenz (EFZ) Most common CNS side effects (52%) Dizziness Insomnia Somnolence Impaired concentration Abnormal dreams Rash 26% Rarely, if ever, nausea and vomiting. Consider other cause. Most significant Teratogenicity in animals Elevated transaminases Stevens-Johnson Syndrome (rare)

12. NNRTIs: Nevirapine (NVP) Most common Rash 37% Women, hispanic race and sulfa allergy at ? risk1 50% of rashes resolve within 2 wks of stopping drug, 80% by 1 month 6.7% discontinuation rate due to rash Prednisone associated with ? risk in clinical trial Most significant Hepatitis including fulminant hepatic necrosis 2/3 during first 12 weeks Overall risk 1% Risk factors pre-existing liver disease Do NOT re-challenge S-J syndrome, TEN, DRESS

13. NNRTIs: Delavirdine (DLV) Most common Nausea Diarrhea Vomiting Headache Most significant Skin rash 18% can continue or restart drug in most cases Stevens-Johnson syndrome (rarely) Hepatic enzyme elevation <5%

14. Protease Inhibitors As a class, protease inhibitors have been associated with morphologic changes involving adipose tissues insulin resistance and occasionally diabetes mellitus dyslipidemias increased bleeding episodes in hemopilia possibly associated with osteopenia/osteoporosis Agents may vary in their potential to be associated with these abnormalities

15. PIs: Amprenavir (APV) Most common Nausea 43-74% Vomiting 24-34% Diarrhea 39-60% Paresthesias 26-31% Most significant Skin rash 28% Stevens-Johnson syndrome in 1% rash onset 7-73 days, median 11 days

16. PIs: Atazanavir (ATZ) Most common Indirect hyperbilirubinemia 35-47% (total bilirubin > 2.6x ULN) similar to IDV effect Most significant Prolong PR interval � some patients experienced asymptomatic 1st degree AV block Use with caution in patients with underlying conduction defects or on concomitant medications that can cause PR prolongation

17. PIs: Indinavir (IDV) Most common Indirect hyperbilirubinemia 10-15% (>2.5 mg%) Gilbert-like, no clinical significance Severe hepatitis (3 cases) Nausea 12% Vomiting 4% Diarrhea 5% Retinoid-like side effects Paronychia (rare) Most significant Urolithiasis 2-3% on 2.4 gm/day, higher in hot climates (6.9%) Nephropathy with sterile pyuria

18. PIs: Nelfinavir (NFV) Most common Diarrhea 14-52% usually mild to moderate Management may include Oatbran Calcium Oral antidiarrheal agents (loperamide, diphenoxylate/atropine)

19. PIs: Ritonavir (RTV) Most common GI bitter after-taste decreased by taking with chocolate milk, Ensure, or Advera nausea 23% decreased by dose titration vomiting 13% diarrhea 13% circumoral paresthesias 5-6% Most significant hepatitis and hepatic failure greatest potential of PIs for toxicities due to drug interactions from potent inhibition of P450 CYP3A system most associated of PIs with dyslipidemias

20. PIs: Saquinavir (SQVsgc/hgc) Most common diarrhea 16-20% abdominal discomfort 9-13% nausea 11-18% headache 5-9%

21. PIs: Fosamprenavir (fos-APV) Most common diarrhea, nausea & vomiting, headache rash 19% median onset 11 days median duration of 13 days discontinuation <1% Most significant Severe skin reactions <1%

22. PI: Lopinavir/r (Kaletra) Most common Diarrhea 14-24% Nausea 2-16% Lipid abnormalities up to 30% Most Significant Pancreatitis Inflammatory edema of the legs (AIDS 16:673, 2002)

23. Fusion inhibitors: Enfuvirtide (T-20) Most common injection site reactions 98% at least one ISR 3% discontinue because of ISR pain, induration, erythema, nodules, cysts, pruritus, ecchymosis Diarrhea 27% Nausea 20% Fatigue 16% Most significant Increased risk of bacterial pneumonia 4.68 pneumonia events/100 py follow-up Hypersensitivity reactions =1% rash, fever, nausea, vomiting, chills, hypotension, hepatitis