Lecture 6: ARV Drug Side Effects and Toxicities delivered by Dr. J.H. Mukendi Kazadi, BHP

1. KITSO AIDS Training Program Lecture 6:ARV Drug Side Effects and Toxicitiesdelivered byDr. J.H. Mukendi Kazadi, BHP

2. Adverse Effects of Antiretroviral Drugs • Do occur commonly. • Can be a potential barrier to successful therapy. • May lead to a reduction in the quality of life. • May be an important cause of non-adherence to therapy. REMEMBER: Overall experience in Botswana has shown that ARV medications are very well tolerated by the vast majority of patients!

3. Outline • Common side effect profiles of each ARV drug (grouped by class). • Serious and rare toxicities of each ARV drug. • Recognition & management strategies. • Brief review of long-term complications of PIs. • Food requirements of ARV drugs. • Summary / Conclusions.

4. Side Effects and Toxicities • Side effects are usually self-limited and not life-threatening, and usually resolve over a short period of time and with symptomatic support. Side effects usually occur early after ARV initiation. • Toxicities are more severe, potentially life-threatening effects of ARVs and can occur at anytime.

5. Recommended Drug Regimens *Age < 3 years or woman with reproductive potential **Age > 3 years or women with no reproductive potential

6. Potential Toxicities of NRTIs AZTZidovudine Retrovir™ 3TC Lamuvidine Epivir™ ddIDidanosine Videx™ d4T Stavudine Zerit™

7. AZT(Zidovudine) • Most common: -- Nausea, vomiting, headaches, fatigue, myalgias • Common: -- Macrocytosis -- not significant, but a marker for adherence • Serious: -- Anemia and neutropenia -- Myositis (elevated CPK) and myopathy -- Lactic Acidosis • Other: -- Darkening of skin, mucous membranes, nails

8. AZT Pigmentation (nail beds)

9. AZT Pigmentation of the Mucosa

10. AZT Pigmentation (hard and soft palate)

11. AZT Anemia • Modification of AZT therapy must be considered when patients have substantial drop in HB (< 7.0 gm/dL) or more than 25% decrease from their baseline. • AZT-induced anemia can occur as early as 2-4 weeks following initiation, but typically occurs after 4-12 weeks, sometimes later.

12. Severe AZT Anemia If significant drop in HB from baseline: STOP AZT  Substitute d4T for AZT Transfuse if HB < 5.5 gm/dL Do not treat with AZT again, unless absolutely necessary and hemoglobin has substantially improved.

13. 3TC(Lamivudine) • Common: -- None (well-tolerated) • Less common: -- Occasional nausea, headaches, vomiting, and diarrhea • Serious: -- Pancreatitis (very rare)

14. D4T(Stavudine) • Common side effects: - Peripheral neuropathy (up to 20%) - Lipid elevations - Lipoatrophy • Uncommon: - Lethargy, myalgia, headache • Serious: -Liver toxicity, pancreatitis (rare) - Lactic acidosis (rare)

15. ddI(Didanosine) • Common: Nausea Bloating Diarrhoea Peripheral neuropathy (up to 20%) • Serious: Pancreatitis, optic neuritis

16. Recognition of ARV Drug-inducedPeripheral Neuropathy • ARV drugs implicated: d4T > ddI > > AZT • Document presence of PN at baseline visit since HIV alone can cause significant PN, which often improves with ARV therapy. • Typical symptoms (parasthesia, numbness) -- Usually in hands / feet (“stocking-glove distribution”) -- As progresses, can cause loss of reflexes and vibratory sense -- Important to assess how PN affects activities of daily living (walking, sleeping, working, etc.)

17. Management of ARV Drug-inducedPeripheral Neuropathy • Mild/Moderate PN -- Treat side effects and continue same regimen. -- Treat with amitriptyline (begin at 25 mgs), carbamazepine, phenytin, or gabapentin. NOTE: [Need to document presence of PN at baseline visit since HIV alone can cause significant PN]. • Severe PN -- Discontinue causative ARV drugs (d4T and/or ddI) -- May take weeks-months for symptoms to resolve even after discontinuing causative ARV drugs.

18. Recognition of ARV Drug-induced Pancreatitis • Symptoms of pancreatitis typically during first 1-6 months • Begins with abdominal pain, nausea and vomiting • More common with ddI, but also reported with d4T, rarely with 3TC. • Elevated amylase/lipase (asymptomatic hyperamylasemia may be due to parotid/salivary gland source).

19. Management of ARV Drug-induced Pancreatitis • Treat abdominal pain, nausea, vomiting. • Bowel rest with IVF’s (stop all ARVs, until pancreatitis resolves); consider imaging with abdominal ultrasound / CT scan. • Do not re-challenge with offending ARV(s) if pancreatitis is confirmed.

20. Lactic Acidosis Syndrome • Entire NRTI class implicated: -- Recently described / reported -- Probably due to mitochondrial toxicity -- Very rare. -- Presentation is very vague (fatigue, nausea, vomiting, abdominal pain, weight loss, malaise, dyspnea, and motor weakness).

21. Recognition of Lactic Acidosis Syndrome • Laboratory Clues: -- Increased anion gap: Na – [Cl + CO2] -- Increased lactic acid (check with a grey-top tube on ice), modest elevation in SGOT/SGPT, and low HCO3 NOTE: If lab is not able to perform HCO3 on U/E, can run heparinised blood specimen on blood gas analyzer. • Diagnosis: -- Above symptoms with elevated lactate level (> 5.0 mmol/L in adults)

22. Management of Lactic Acidosis Syndrome • High mortality rate (60%) • Consider administering bicarbonate and vitamin supplements (riboflavin). • Discontinue all ART; administer NRTI-sparing HAART after patient recovers and lactate levels return to normal. Consult HIV specialist. • Recovery from elevated lactic acid levels may be prolonged.

23. Potential Toxicities of NNRTI Class • EFV (Efavirenz) • NVP (Nevirapine)

24. EFV (Efavirenz) • Common (not class-related): Central nervous system side effects Headaches Light-headedness Confusion Sleep disturbances (abnormally vivid dreams) These side effects typically resolve within the first 14-21 days of treatment and are lessened by taking EFV at bedtime.

25. EFV(Efavirenz) • Serious (class-related): -- Skin rash; progressing to Steven’s Johnson Syndrome -- Hepatotoxicity • The above toxicities are less common with EFV than with NVP.

26. EFV(Efavirenz) • EFV is the only ARV absolutely contra-indicated in pregnancy (not recommended for use in women with child-bearing potential). • Contraindicated in children under 3 years. • Safe to administer with ATT medications.

27. EFV(Efavirenz) • Other possible side effects: Lipodystrophy(body habitus changes) -- Elevated triglycerides/cholesterol -- Breast enlargement

28. NVP(Nevirapine) • Common: -- Cutaneous -- Skin rash, reported up to 20%, usually appears in the first few weeks to months of therapy. -- Progresses to Stevens-Johnson Syndrome (SJS) in < 1.0%. • Less Common: -- Liver toxicity (more common than with EFV)

29. Mild NVP Rash Moderate maculopapular rash, typically on face, trunk, and/or extremities, with or without pruritus. • Usually appears within the first few weeks to months of therapy. • Treat with antihistamines, topical skin creams, do not use systemic steroids. • Usually resolves within a few weeks. • Safe to continue NVP, but if patient is still on OD dose, do not dose escalate until rash resolves. • Advise patient to return if rash worsens or mucous membrane involvement appears.

30. Severe NVP Rash (1) Severe Hypersensitivity Reaction SJS is quite rare, occurs within the first 6-8 weeks of ARV therapy, and can be fatal. Treat with steroids and stop ALL ARV drugs until patient recovers, and do not re-challenge with NVP.

31. Severe NVP Rash (2) Any of the following signs/symptoms suggest impending SJS: - Fever - Conjunctivitis - Extensive, moist, peeling rash - Mucous membrane involvement (lip sores/ulcers/swelling, new vaginal lesions) - Patient appears unwell

32. NVP-Related SJS

34. Stevens-Johnson Syndrome

35. Management of NVP-induced Severe Skin Reaction Discontinue ARVs and all other medications Treatment: -- Prednisone (40-60 mgs, taper) -- Chlorpheniramine -- Brufen -- Paracetamol -- Close observation, realizing that patient may deteriorate over next 72-96 hours. After recovers, new ARV regimen may substitute EFV or a PI for NVP. Do not re-challenge with NVP.

36. NNRTI Liver Toxicity If LFT’s up to 2x upper limit of normal values, monitor closely. If LFT’s ≥ 5x upper limit of normal values: • Stop all medications, including ARVs, and monitor LFTs. • When LFTs have normalized, restart HAART but without NVP. • If previously on NVP, substitute EFV or a PI for NVP. • If previously on EFV, substitute a PI for EFV (do not use NVP).

37. Practical Considerations with NVP Treatment • LFTs should be drawn at 2 week follow-up visit after initiation of NVP. • NVP: Need to monitor patients closely during first 6-8 weeks on ART. • If possible, try to avoid simultaneous initiation of NVP with other drugs having potential hepatotoxicity, eg., ATT, IPT, cotrimoxazole. • However, INH and cotrimoxazole may safely be used with NVP.

38. Toxicities of Protease Inhibitors To be used for first/second treatment failures (cost, pill burden, interactions with TB meds, and side effects). Nelfinavir NFV Kaletra LPV/r RitonavirRTV Saquinavir SQV

39. NFV(Nelfinavir) • Common side effects: Diarrhea - Up to 20%, usually mild - Treat with loperamide, change dosing schedule; may need to take with porridge or calcium carbonate. • Less common side effects: Nausea / vomiting / abdominal bloating

40. LPV/r(Kaletra) • Common side effects: Diarrhea, nausea, vomitting, increased lipids • Less common side effects: hepatitis, pancreatitis

41. Long-Term Metabolic Complications of PIs Insulin Resistance /Diabetes Mellitus (elevated blood glucose) Lipodystrophy Syndrome (body habitus changes) Lipid Abnormalities (increased cholesterol/triglyceride levels) Osteoporosis / Avascular Necrosis (rare)

42. Lipodystrophy: Body Habitus Changes Fat loss(lipoatrophy*): Facial fat loss Subcutaneous fat loss in the extremities Fat loss in buttocks *NRTIs, especially D4T Fat accumulation: (lipodystrophy*) Neck fat pad Breast enlargement (gynecomastia in men) Visceral / central obesity Lipomas *EFV and PIs

43. Lipodystrophy 1

44. Lipodystrophy 2

45. Lipid Monitoring of Patients on HAART • Patients should have baseline and then 6-monthly lipid assessments if on PI-containing or EFV-containing HAART, or if on d4T. • Check fasting glucose if diabetes is suspected.

46. Food Requirements of ARV Meds • Most ARV drugs may be taken with or without food. • However, side effects may be less if taken with some food (AZT-induced nausea). • ddI must be taken on empty stomach (otherwise poorly absorbed), 1 hour before or 2 hours after meals. • NFV and SQV (PIs) should be taken with food.

47. Summary / Conclusions • Adverse effects of antiretroviral agents are common and may be a cause of therapy change, non-adherence, and treatment failure. • Mild to moderate side effects, and those that resolved with time, may be managed with symptomatic therapy. • Serious or disabling side effects or toxicities may necessitate discontinuation of the offending drug.

48. Summary / Conclusions (2) • It is important to EDUCATE patients about the potential adverse effects of these medications. • It is important to be vigilant to these adverse effects when initiating therapy and also during follow-up. • It is important to perform careful, comprehensive evaluations at baseline to see what side effects are pre-existing.