Transcript Session 10 - Teaching Slides

Second Line ARV:
Doses & Side Effects
HAIVN
Harvard Medical School AIDS Initiative
in Vietnam
Learning Objectives
At the end of this lecture, each trainee should
know:
• The second-line ARV regimen recommended by
the Vietnam MOH
• The common side effects of second line drugs
• How to manage side effects
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Content
• Second-line ARV regimen
• Second-line ARV drugs
 Formulations
 Dosing
 Common Side effects
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Switching from 1st line to 2nd
line regimens
Failure on 1st regimens
Change to 2nd regimens
AZT or d4T + 3TC + NVP ABC +3TC/ddI + LPV/r
AZT or d4T + 3TC + EFV
AZT or d4T + 3TC + ABC
ddI + EFV + LPV/r
ddI + NVP + LPV/r
ABC + 3TC + NVP or EFV AZT + 3TC/ddI + LPV/r
Second-Line ARV
• NRTIs
 Abacavir (ABC)
 Didanosine (ddI)
• Protease Inhibitors
 Lopinavir / ritonavir (LPV/r)
Didanosine
(ddI; Videx)
• Formulations*:
 Liquid mixed in antacid (usually Maalox)
 Chewable/dispersible tablet (with an
antacid buffer)
 Extended release, enteric coated capsule
(Videx EC)
* Absorption of ddI in the stomach is affected by
acid.
ddI: Dosing
Vietnam MOH HIV/AIDS Treatment Guidelines, 2009.
ddI: Pharmacokinetics
• DDI should be given on an empty stomach (1
hour before or 2 hours after a meal)
• DDI liquid should be stored under refrigerated
conditions
• DDI tablets: minimum dose is two tablets at a
time.
 Tablets contain an antacid and two tablets are
needed to supply enough antacid to provide
adequate buffering.
• EC capsules: enteric coating protects the ddI
during its transport through the stomach
ddI: Side Effects
• Peripheral neuropathy:
 Presents as paresthesias, most often of the feet
 May appear as a gait disturbance in younger
children
• Pancreatitis:
 Presents as abdominal pain, nausea, and vomiting
 Associated with a rise in amylase and lipase levels
• Lipoatrophy:
 d4T+ddI > d4T > ddI
• Lactic acidosis:
 d4T+ddI > d4T > ddI
Abacavir
(ABC; Ziagen)
• Formulations:
 Capsule 300 mg
 Syrup 20 mg/ml
• Administered on an every 12-hour
schedule.
• There is no food effect on absorption.
ABC: Dosing
Vietnam MOH HIV/AIDS Treatment Guidelines, 2009.
Abacavir – Hypersensitivity
• Incidence: 3 - 6%
• Time of presentation:
 median = 11th day
 93% of cases occur in the first 6 weeks
• Clinical symptoms:
 Most common: fever, maculopapule rash, fatigue
 GI Symptoms: nausea, vomiting, diarrhea, abdominal pain
 Respiratory symptoms: cough, shortness of breath
• Contraindications:
 Previous ABC hypersensitivity
• Hypotension or death upon re-challenge!
Patients with hypersensitivity should
never receive ABC again!
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Abacavir Hypersensitivity –
Laboratory Abnormalities
• Common
 Lymphopenia: redistribution effect
 elevated liver enzymes
• Less frequent




elevated creatine phosphokinase: may be pronounced
mild thrombocytopenia: not clinically significant
renal: increased serum creatinine
lungs: chest X-ray may be normal or display diffuse
bilateral or lobar infiltrates
• Laboratory abnormalities resolve a few days after
discontinuing abacavir
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Abacavir Hypersensitivity –
Treatment
• Stop Abacavir immediately if hypersensitivity
is suspected
 Symptoms will usually improve within a few
days
 Never give Abacavir again
 Note Abacavir hypersensitivity in the
patient record
 Notify the patient and caregiver of the
reaction and counsel them not to take
abacavir again
• For severe reactions or hypotension:
 Admit to hospital or ICU
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Lopinavir/ritonavir
(LPV/r; Aluvia)
• Formulations*:
 Syrup ((LPV 80mg / RTV 20 mg) per ml)
 Coated tablet (LPV 100 mg / RTV 25 mg)
 Coated tablet (LPV 200 mg / RTV 50 mg)
* LPV/r should be taken with food, both to
enhance absorption and improve
tolerability
LPV/r: Dosing
Vietnam MOH HIV/AIDS Treatment Guidelines, 2009.
LPV/r: Dosing
LPV/r: Pharmacokinetics
Ritonavir boosting
• Most potent liver enzyme (Cytochrome P 450
3A4) inhibitor available
 inhibits the break down of drugs in the liver,
including other protease inhibitors
• Now used to boost other PIs
“boosted PI”
Increases AUC of the other PI
Can use lower dose of other PI
Increases the Cmin (trough concentration) of other
PI, decreasing the risk for resistance
 Allows once or twice daily dosing of PI




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Ritonavir Boosting
AUC increased:
Saquinavir
20x
Lopinavir
15 – 20 x
Indinavir
2–5x
Nelfinavir
1.5 x
Atazanavir
2.4 x
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LPV/r: Pharmacokinetics
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LPV/r: Drug interactions
• Rifampin:  LPV by 75%
 Generally should avoid combination
 If necessary can give additional ritonavir to “super”
boost the LPV (consult with expert)
• Clarithromycin levels 
 Adjust clarithromycin dose only in renal failure
• Itraconazole levels 
 Use with caution at itraconazole doses > 200
mg/day
LPV/r: Side Effects
• GI intolerance (nausea, vomiting)
• Diarrhea
• Long-term side effects:
 Fat accumulation (lipodystrophy)
 Lipids: increased cholesterol, triglycerides
 Insulin resistance, increased glucose
LPV/r Side Effects:
Lidodystrophy
• Changes in body fat distribution
(lipodystrophy) have been reported to occur
in 1%–33% of children with HIV infection.
• Lipohypertrophy or central fat accumulation is
most often associated with protease inhibitor
therapy.
• In children, physical examination showa
increased abdominal girth, dorso-cervical fat
accumulation, and/or breast enlargement.
LPV/r Side Effects:
Lidodystrophy
• Development of lipohypertrophy is probably related
to:
 Genetic and developmental characteristics
 Lifestyle factors (diet and exercise/activity)
 ARV exposure and duration
• Treatment:
 Low-fat diet
 Exercise
 Switch PI to NNRTI (if not resistant to NNRTI already)
• Support of the patient and family is an important
aspect of care.
PI: Metabolic Effects
• Elevated Cholesterol
 Check lipids yearly (Cholesterol, LDL,
HDL, Triglycerides)
 Treatment:
•
•
•
•
Dietary changes
Exercise
Lipid lowering drugs
Change in ARV regimen if possible
Lipid-Lowering Medications in
Pediatric Patients with HIV
DHHS Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection, Feb 2008
PI: Metabolic Effects
• Insulin resistance, hyperglycemia
 When starting PIs, caregivers and patients
should be educated about the signs and
symptoms of diabetes mellitus
 Check glucose every 6-12 months
 Lifestyle modification if impaired glucose
tolerance
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Key Points
• The MOH second-line ARV regimens for children is
ABC-DDI-LPV/r
• Patients with abacavir hypersensitivity should never take
abacavir again due to the risk of recurrent reaction and
death.
• Be aware of potential drug interactions with patients on
LPV/r.
• Patients on LPV/r should have glucose and lipid tests
done at least once a year to screen for metabolic side
effects.
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Thank you!
Questions?