Antiretroviral agents- an approach to adverse effects

Dr Vineeta Shobha MD, DM (Immunology), Associate professor, Department of Medicine, ST John’s Medical College Hospital, Bangalore

Antiretroviral agents

Reverse transcriptase inhibitor Protease inhibitor

Nucleoside RTI Non Nucleoside RTI Nucleotide analogue

Case Scenario-1   30yr, M, newly diagnosed HRV, CD4 counts-112 Prescribed- Duovir N 1 bd  What is wrong with this prescription?

 Returned with maculopapular rash 5 days later   Could it have been prevented?

How to Rx it?

To minimize risk of rash  Lead- in dose of 200mg/day X 14 days, then increase to bd dosage   Prophylactic antihistamine- of limited use Prednisone as prophylactic Rx increases the risk in first 6 weeks

Rx of NVP induced rash    Urticaria Mild to mod rash- pruritus, erythema, diffuse erythematous macular or maculopapular rash- may continue with close monitoring of rash Any progression- to discontinue NVP

Rx of NVP induced rash   Severe rash- extensive erythematous maculopapular rash or moist desquamation,angioedema, serum sickness like reactions, SJS or TEN- immediate & permanent discontinuation of NVP Any rash with constitutional symptoms, LFT abnormality- immediate & permanent discontinuation of NVP

ARV induced rash   NVP induced drug rash – 14%; SJS 0.3%- 1%; more frequent in blacks, females, asians.

Others- EFV-26% (severe-1%), DLV; rarely- APV, ABC, ZDV, ddI, IDV

Efavirenz induced rash    Self limited, resolves spontaneously Rx – antihistaminics, topical/ oral steroids Severe rash- discontinue EFV

Case Scenario-2   30yr, F, HRV, CD4 counts-256 on Triommune 1 bd 5 wks later- flu like symptoms, jaundice, fever; abN AST/ALT  Imp- drug induced hepatotoxicity

Problems…    Is it ART induced hepatotoxicity or something else?

If yes, which ARV drugs is responsible for this?

How to evaluate, manage and prevent further similar problems?

ART induced hepatotoxicity      Implicated drugs- All NNRTIs, All PIs, All NRTIs Onset-wks to months; NRTI- upto years Asymptomatic, anorexia, weight loss Associated skin rash- NVP (50%) Mitochondrial toxicity- micro/ macrovescicular steatosis, lactic acidosis ZDV, ddI, d4T

Risk factors     Hepatitis B or C co infection Alcoholism Concomitant hepatotoxic drugs NVP- CD4 >250/cumm- Females >400 /cumm- Males

Recommended Monitoring   NVP- 2,4 weeks, monthly for 3 months, 3 monthly thereafter Others- every 3-4 months

Management    Rule out other causes of LFT abnormality Asymptomatic pts- discontinue if ALT > 5-10 times; may restart without offending agent Symptomatic pts- Discontinue all ARV, may restart without offending agents

NVP induced hepatotoxicity    Incidence- 3-11%; 11% vs 0.9% in Females with CD4 count > 250 / <250 Males 6.3% vs 2.3% for CD4 count > 400 / <400 More frequent in females, pregnancy, HBV/ HCV coinfection, ALD Rx- discontiuation and not to rechallenge

Is it Lactic acidosis?

   Initially- nonspecific GI symptoms May rapidly progress to tachypnea, tachycardia, jaundice, muscular weakness, altered mentation, resp distress.

May present with- MODS, FHF, acute pancreatitis, encephalopathy and respiratory failure.

How to confirm lactic acidosis?

   Serum lactate >5mmole Increased anion gap acidosis, low bicarbonates, abnormal LFT, PT, low albumin, high lipase, amylase Liver Bx- micro/ macrovesicular steatosis

Risk factors      d4T+ ddI Longer duration of NRTI use Obesity females pregnancy

How to manage Lactic acidosis?

    Discontinue all ARV drugs Symptomatic Rx I/V thiamine, riboflavin, carnitine Methylprednisolone, IVIG, Plasmapheresis

Which alternative ART combination can be used?

HUMAN IMMUNODEFECIENCY VIRUS

Case Scenario-3    30yr, M, HRV, CD4 counts-62 on Duovir N 1 bd & Bactrim prophylaxis Presented with tiredness and one episode of syncope Ix- Hb 5.6gm%, TC 2300/cumm, PC 1.4l

 Why he developed hematologic abnormalties?

 How to investigate and manage him?

ZDV induced bone marrow suppression •      Onset- Weeks to months Macrocytic anemia- Late ds (7%), early ds (1%) Granulocytopenia (1.8- 8%) Folate, vit B12 levels N; decreased reticulocyte count Bone marrow- absence of RBC precursors Due to competitive inhibition of cellular thymidylate kinase

Risk factors    Advanced HIV Pre- existing anemia or neutropenia Concomitant use of other bone marrow suppressants cotrimoxazole, ribavirin, ganciclovir etc

Management      Replace ZDV with another NRTI if > 25% fall in Hb or severe neutropenia Recovery in 7-14 days Erythropoeitin Folinic acid, B12- of no benefit GM- CSF for life threatening neutropenia

Case Scenario-4    25 yr,M, CD4- 106 on following Rx Duovir 1 bd Indivan 400 2tid bactrim 1od Rt flank pain, hematuria & urgency Ix- creat 2.3mg/dl, urine- pyuria, hematuria

 What is your diagnosis?

 Could this have been prevented?

 How to manage current problem?

Indinavir induced nephrolithiasis    Onset- any time after Rx Incidence- 12.4% Higher risk if past H/O nephrolithiasis inadequate fluid intake long duration of Rx

Prevention & Treatment     Drink 1.5- 2 litres of water To increase fluid intake if notices darkening of urine Urinalysis and creat every 3-6 months Rx- Pain control Alternative ARV drug

Case Scenario-5    25 yr,M, CD4- 106 on following Rx for past 1.5 months ddI 200mg bd STV 40mg bd NVP 200mg bd, Bactrim OD C/O post prandial abdominal pain, nausea and vomitting Ix- AbN Amylase & lipase

 What is your diagnosis?

 Could this have been prevented?

 How to manage current problem?

ARV induced pancreatitis    Onset- Weeks- months Incidence- ddI alone- 1.7% ddI+ STV ddI + HU/ RBV Higher risk- alcoholism Past pancreatitis Hypertriglyceridemia Combination drugs

Prevention & Treatment    Avoid ddI in patients with past H/O pancreatitis Discontinue offending drug Rx pancreatitis as indicated depending on its severity

HUMAN IMMUNODEFECIENCY VIRUS

Case Scenario-6   45yr,M, Chronic smoker, Diabetic and hypertensive, CD4 count (current)-266 Virocomb 1bd Lopinavir+ ritonavir 3bd for 2yrs C/O exertional angina- 1month EKG, TMT

 Is ART responsible for this event?

 What preventive and therapeutic measures can be taken?

Cardiotoxicity and PIs      Incidence- 3-6/1000 pt years Risk factors- Age, sex, smoking, DM, HTN, dyslipidemia, past/ family H/O CAD Early diagnosis and medical/ interventional management as indicated Life style modification Switch to cardiac safe drugs- Atazanavir, NNRTI, NRTI except STV

Hyperlipidemia & ARV        All PIs except ATV, STV, EFV Onset- weeks to months High LDL, TG, TC, Low HDL Incidence- 45-75% Risk- LPV/r& RTV >NFV& APV >IDV& SQV > ATV Monitor lipids 3-6 monthly ACTG recommendations for Rx

Case Scenario-7     33yr, F, teacher, pulmonary TB on INH + Rif, Bactrim CD4 –76, started one week back on Virolis 30 1bd Efferven 600mg HS C/O Feeling out of sorts, bad dreams, dizziness, inability to concentrate O/E NAD

 Why does she have these symptoms?

 What is the appropriate Rx for these?

Effavirenz induced CNS toxicity    Begins in first few days, occur in 50% Subside or diminish by 2-4 weeks Drowsiness, somnolence, insomnia,abnormal dreams, dizziness, impaired concentration and attention span,depression, hallucinations, exacerbation of psychiatric disorders, psychosis, suicidal ideation

EFV induced CNS toxicity     Risk factors- Pre-existing or unstable psy illness - Concomitant use of drugs with CNS side effects Prevention- night time dosing warn patient Symptomatic Rx, subside by 2-4 weeks Discontinue if severe symptoms persist

HUMAN IMMUNODEFECIENCY VIRUS

Case Scenario-8   Same pt returned 2months later with pain in calf region, numbness and paresthesias of toes and feet O/E severe hyperesthesia, diminished ankle jerks

 Is it related to her drugs or something else?

 Could this have been prevented?

 How to manage current problem?

Peripheral Neuropathy   Offending drugs- ddI- 12-34% - stavudine- 52% - Zalcitabine- 22-35% Higher risk if Pre existing peripheral neuropathy, Advanced HRV Concomitant use of other neurotoxic drugs Prolonged exposure

Prevention & Treatment      Avoid in high risk patients Avoid combination with other neurotoxic drugs Discontinue at first sign of peripheral neuropathy as it may be irreversible Tricyclic antidepressants, gabapentin Local capsaicin cream

Gastrointestinal Intolerance    All PIs, ZDV, ddI Begins with first few doses Nausea, vomitting, abdominal pain  Diarrhea- NFV, LPV/r, ddI   Rx- Take with food ( not ddI, IDV) Symptomatic Rx- antiemetics, antimotility agents,pancreatic enzymes, bulk forming agents

To recapitulate….

How to Rx side effects?

    Nausea- Take with food, symptomatic Rx, self limiting Headache- ZDV, EFV; self limiting, symptomatic Rx, rule out meningitis Anxiety, nightmares, depression night dosing, reassure, self limiting, amitryptiline Discoloured nails- Reassurance

How to Rx side effects?

  Acute hepatitis- NVP, EFV, ZDV,ddI, STV Monitor LFT, stop ART, supportive mgt, discontinue NVP permanently Acute pancreatitis- ddI, STV Stop ART, supportive Rx, change to ZDV/ ABC

How to Rx side effects?

  Peripheral neuropathy- ddI, STV stop and switch to non neurotoxic NRTI- ZDV/ ABC symptoms resolve in 2-3 weeks may be irreversible Bone marrow suppression- ZDV, switch to another NRTI, discontinue other marrow suppressants

How to Rx side effects?

 Lactic acidosis- all NRTIs – STV, ddI Wks-months; discontinue drug, supportive Rx, plasmapheresis, high dose steroids, IVIG, carnitine Recovery over few months Not to rechallenge with same drug

How to Rx side effects?

 SJS/ TEN NVP>> EFV, ABC, ZDV, ddI days to weeks, discontinue ART+, aggressive symptomatic Rx, not to rechallenge

To summarize….

Adverse effects of NRTIs Zidovudine 300mg bd GI intolerance Lamivudine Stavudine 150mg bd 30,40 mg bd Safe drug peripheral neuropathy Headache, malaise, anorexia Bone marrow suppression pancreatitis Lipodystrophy, Dyslipidemia Lactic acidosis with hepatic steatosis Lactic acidosis with hepatic steatosis Lactic acidosis with hepatic steatosis Proximal Myopathy Didanosine 200mg bd peripheral neuropathy pancreatitis Nausea, diarrhea Lactic acidosis with hepatic steatosis

Adverse effects of NNRTIs Nevirapine 200mg OD-- BD Rash, SJS, TEN Hepatitis, fatal hepatic necrosis Efevirenz 600mg HS Rash CNS symptoms High transaminases Teratogenecity

Adverse effects of PIs Indinavir 800mg tid nephrolithiasis GI intolerance Dyslipidemia, hyperglycemia Nelfinavir 1.5 gm bd Diarrhea Dyslipidemia, hyperglycemia Lopinavir/ ritonavir 400+100mg bd Diarrhea GI intolerance Dyslipidemia, hyperglycemia Fat maldistribution Fat maldistribution Fat maldistribution Increased bleeding Increased bleeding Indirect hyperbilirubinemia Asthenia

Overlapping toxicities Bone marrow suppression ZDV Co trimoxazole Ampho Peripheral neuropathy ddI STV Linezolid Pancreatiti s STV Hepato toxicity NVP ddI Co trimox EFV NRTIs Linezolid INH ritonavir pyrimethamine Zalcitabine HU/RBV Rash NVP EFV Cotrimox INH, Rif sulpha fluconazole ABC

Thank you