KITSO AIDS Training Program Lecture 6: ARV Drug Side Effects and Toxicities delivered by Dr. J.H. Mukendi Kazadi, BHP ARV Drug Toxicity

Adverse Effects of Antiretroviral Drugs KITSO AIDS Training Program 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! ARV Drug Toxicity 3

KITSO AIDS Training Program 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. ARV Drug Toxicity

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.

Recommended Drug Regimens KITSO AIDS Training Program Recommended Drug Regimens NRTIs NNRTIs PIs 1st Line AZT+3TC NVP* or EFV** 2nd Line ddI + d4T NFV or LPV/r The second line regimens are the same as for adults. DDI/d4T and the protease-inhibitor NFV. The Third line regimen is still being evaluated but one may be able to recycle 2 of the NRTI’s previously used to make up a complete regimen with other PI’s. *Age < 3 years or woman with reproductive potential **Age > 3 years or women with no reproductive potential ARV Drug Toxicity

Potential Toxicities of NRTIs KITSO AIDS Training Program Potential Toxicities of NRTIs AZT Zidovudine Retrovir™ 3TC Lamuvidine Epivir™ ddI Didanosine Videx™ d4T Stavudine Zerit™ ARV Drug Toxicity

KITSO AIDS Training Program 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 ARV Drug Toxicity

AZT Pigmentation (nail beds)

AZT Pigmentation of the Mucosa

AZT Pigmentation (hard and soft palate)

KITSO AIDS Training Program 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. ARV Drug Toxicity

KITSO AIDS Training Program 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. ARV Drug Toxicity

KITSO AIDS Training Program 3TC (Lamivudine) Common: -- None (well-tolerated) Less common: -- Occasional nausea, headaches, vomiting, and diarrhea Serious: -- Pancreatitis (very rare) ARV Drug Toxicity

KITSO AIDS Training Program 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) ARV Drug Toxicity

KITSO AIDS Training Program ddI (Didanosine) Common: Nausea Bloating Diarrhoea Peripheral neuropathy (up to 20%) Serious: Pancreatitis, optic neuritis ARV Drug Toxicity

Recognition of ARV Drug-induced Peripheral Neuropathy KITSO AIDS Training Program Recognition of ARV Drug-induced Peripheral 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.) ARV Drug Toxicity

KITSO AIDS Training Program Management of ARV Drug-induced Peripheral 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. ARV Drug Toxicity

Recognition of ARV Drug-induced Pancreatitis KITSO AIDS Training Program 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). ARV Drug Toxicity

Management of ARV Drug-induced Pancreatitis KITSO AIDS Training Program 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. ARV Drug Toxicity

Lactic Acidosis Syndrome KITSO AIDS Training Program 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). ARV Drug Toxicity

Recognition of Lactic Acidosis Syndrome KITSO AIDS Training Program 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) ARV Drug Toxicity

Management of Lactic Acidosis Syndrome KITSO AIDS Training Program 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. ARV Drug Toxicity

KITSO AIDS Training Program Potential Toxicities of NNRTI Class KITSO AIDS Training Program EFV (Efavirenz) NVP (Nevirapine) ARV Drug Toxicity

KITSO AIDS Training Program 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. ARV Drug Toxicity 81

KITSO AIDS Training Program 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. ARV Drug Toxicity

KITSO AIDS Training Program 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. ARV Drug Toxicity

KITSO AIDS Training Program EFV (Efavirenz) Other possible side effects: Lipodystrophy (body habitus changes) -- Elevated triglycerides/cholesterol -- Breast enlargement ARV Drug Toxicity

KITSO AIDS Training Program 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) ARV Drug Toxicity

KITSO AIDS Training Program 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. ARV Drug Toxicity

KITSO AIDS Training Program 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. ARV Drug Toxicity

KITSO AIDS Training Program 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 ARV Drug Toxicity

KITSO AIDS Training Program NVP-Related SJS ARV Drug Toxicity

KITSO AIDS Training Program ARV Drug Toxicity

Stevens-Johnson Syndrome

Management of NVP-induced Severe Skin Reaction KITSO AIDS Training Program 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. ARV Drug Toxicity

KITSO AIDS Training Program 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). ARV Drug Toxicity

Practical Considerations with NVP Treatment KITSO AIDS Training Program 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. ARV Drug Toxicity

Toxicities of Protease Inhibitors KITSO AIDS Training Program 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 Ritonavir RTV Saquinavir SQV ARV Drug Toxicity

KITSO AIDS Training Program 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 ARV Drug Toxicity

KITSO AIDS Training Program LPV/r (Kaletra) Common side effects: Diarrhea, nausea, vomitting, increased lipids Less common side effects: hepatitis, pancreatitis ARV Drug Toxicity

KITSO AIDS Training Program 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) ARV Drug Toxicity

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

Lipodystrophy 1

Lipodystrophy 2

KITSO AIDS Training Program 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. ARV Drug Toxicity

Food Requirements of ARV Meds KITSO AIDS Training Program 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. ARV Drug Toxicity

KITSO AIDS Training Program Summary / Conclusions KITSO AIDS Training Program 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. ARV Drug Toxicity 87

Summary / Conclusions (2) KITSO AIDS Training Program 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. ARV Drug Toxicity 88