Transcript Antiretroviral agents- an approach to adverse effects

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
Nucleoside
RTI
Non
Nucleoside
RTI
Nucleotide
analogue
Protease
inhibitor
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 Rxincreases 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 sicknesslike 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%; SJS0.3%- 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 acidosisZDV, 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
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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 suppressantscotrimoxazole, 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 RxDuovir 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 ifpast 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 monthsddI 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 ifPre 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, depressionnight 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
Lamivudine
Stavudine
Didanosine
300mg bd
150mg bd
30,40 mg bd
200mg bd
GI intolerance
Safe drug
peripheral
neuropathy
peripheral
neuropathy
pancreatitis
pancreatitis
Lipodystrophy,
Dyslipidemia
Nausea, diarrhea
Headache, malaise,
anorexia
Bone marrow
suppression
Lactic acidosis with
hepatic steatosis
Proximal Myopathy
Lactic acidosis Lactic acidosis
with hepatic
with hepatic
steatosis
steatosis
Lactic acidosis
with hepatic
steatosis
Adverse effects of NNRTIs
Nevirapine
Efevirenz
200mg OD-- BD
600mg HS
Rash, SJS, TEN
Rash
Hepatitis, fatal
hepatic necrosis
CNS symptoms
High transaminases
Teratogenecity
Adverse effects of PIs
Indinavir
Nelfinavir
800mg tid
1.5 gm bd
Lopinavir/
ritonavir
400+100mg bd
nephrolithiasis
Diarrhea
Diarrhea
GI intolerance
Dyslipidemia,
hyperglycemia
GI intolerance
Dyslipidemia,
hyperglycemia
Dyslipidemia,
hyperglycemia
Fat maldistribution Fat maldistribution
Fat maldistribution
Increased bleeding
Increased bleeding
Indirect
hyperbilirubinemia
Asthenia
Overlapping toxicities
Bone marrow
suppression
Peripheral
neuropathy
Rash
ddI
Pancreatiti Hepato
s
toxicity
STV
NVP
ZDV
Co
trimoxazole
Ampho
STV
ddI
EFV
EFV
Linezolid
Co trimox
NRTIs
Cotrimox
Linezolid
INH
ritonavir
INH, Rif
sulpha
HU/RBV
fluconazole ABC
pyrimethamine Zalcitabine
NVP
Thank you