Antiretroviral agents- an approach to adverse effects

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Antiretroviral agents- an approach to adverse
effects

• Dr Vineeta Shobha
• MD, DM (Immunology),
• Associate professor, Department of Medicine,
• ST Johns Medical College Hospital, Bangalore

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Antiretroviral agents
Reverse transcriptase inhibitor
Protease inhibitor
Nucleotide analogue
Nucleoside RTI
Non Nucleoside RTI
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Case Scenario-1

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

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• Returned with maculopapular rash 5 days later
• Could it have been prevented?
• How to Rx it?

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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

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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

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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

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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

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Efavirenz induced rash

• Self limited, resolves spontaneously
• Rx antihistaminics, topical/ oral steroids
• Severe rash- discontinue EFV

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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

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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?

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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

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Risk factors

• Hepatitis B or C co infection
• Alcoholism
• Concomitant hepatotoxic drugs
• NVP- CD4 gt250/cumm- Females
• gt400 /cumm- Males

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Recommended Monitoring

• NVP- 2,4 weeks, monthly for
• 3 months, 3 monthly thereafter
• Others- every 3-4 months

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Management

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

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NVP induced hepatotoxicity

• Incidence- 3-11 11 vs 0.9 in Females with CD4
  count gt 250 / lt250
• Males 6.3 vs 2.3 for CD4 count gt 400 / lt400
• More frequent in females, pregnancy, HBV/ HCV
  coinfection, ALD
• Rx- discontiuation and not to rechallenge

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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.

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How to confirm lactic acidosis?

• Serum lactate gt5mmole
• Increased anion gap acidosis, low bicarbonates,
  abnormal LFT, PT, low albumin, high lipase,
  amylase
• Liver Bx- micro/ macrovesicular steatosis

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Risk factors

• d4T ddI
• Longer duration of NRTI use
• Obesity
• females
• pregnancy

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How to manage Lactic acidosis?

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

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Which alternative ART combination can be used?
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HUMAN IMMUNODEFECIENCY VIRUS
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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

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• Why he developed hematologic abnormalties?
• How to investigate and manage him?

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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

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Risk factors

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

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Management

• Replace ZDV with another NRTI if gt 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

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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

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• What is your diagnosis?
• Could this have been prevented?
• How to manage current problem?

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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

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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

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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

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• What is your diagnosis?
• Could this have been prevented?
• How to manage current problem?

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ARV induced pancreatitis

• Onset- Weeks- months
• Incidence- ddI alone- 1.7
• ddI STV
• ddI HU/ RBV
• Higher risk- alcoholism
• Past pancreatitis
• Hypertriglyceridemia
• Combination drugs

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Prevention Treatment

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

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HUMAN IMMUNODEFECIENCY VIRUS
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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

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• Is ART responsible for this event?
• What preventive and therapeutic measures can be
  taken?

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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

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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 gtNFV APV gtIDV SQV gt ATV
• Monitor lipids 3-6 monthly
• ACTG recommendations for Rx

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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

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• Why does she have these symptoms?
• What is the appropriate Rx for these?

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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

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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

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HUMAN IMMUNODEFECIENCY VIRUS
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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

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• Is it related to her drugs or something else?
• Could this have been prevented?
• How to manage current problem?

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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

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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

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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

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To recapitulate.
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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

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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

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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

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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

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How to Rx side effects?

• SJS/ TEN
• NVPgtgt EFV, ABC, ZDV, ddI
• days to weeks, discontinue ART, aggressive
  symptomatic Rx, not to rechallenge

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To summarize.
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Adverse effects of NRTIs
Zidovudine Lamivudine Stavudine Didanosine
300mg bd 150mg bd 30,40 mg bd 200mg bd
GI intolerance Safe drug peripheral neuropathy peripheral neuropathy
Headache, malaise, anorexia pancreatitis pancreatitis
Bone marrow suppression Lipodystrophy, Dyslipidemia Nausea, diarrhea
Lactic acidosis with hepatic steatosis Lactic acidosis with hepatic steatosis Lactic acidosis with hepatic steatosis Lactic acidosis with hepatic steatosis
Proximal Myopathy
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Adverse effects of NNRTIs
Nevirapine Efevirenz
200mg OD-- BD 600mg HS
Rash, SJS, TEN Rash
Hepatitis, fatal hepatic necrosis CNS symptoms
High transaminases
Teratogenecity
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Adverse effects of PIs
Indinavir Nelfinavir Lopinavir/ ritonavir
800mg tid 1.5 gm bd 400100mg bd
nephrolithiasis Diarrhea Diarrhea
GI intolerance GI intolerance
Dyslipidemia, hyperglycemia Dyslipidemia, hyperglycemia Dyslipidemia, hyperglycemia
Fat maldistribution Fat maldistribution Fat maldistribution
Increased bleeding Increased bleeding
Indirect hyperbilirubinemia Asthenia
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Overlapping toxicities
Bone marrow suppression Peripheral neuropathy Pancreatitis Hepato toxicity Rash
ZDV ddI STV NVP NVP
Co trimoxazole STV ddI EFV EFV
Ampho Linezolid Co trimox NRTIs Cotrimox
Linezolid INH ritonavir INH, Rif sulpha
pyrimethamine Zalcitabine HU/RBV fluconazole ABC
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Thank you