Part B: Module B1

1
Drug Interactions and Adverse Drug Reactions
Side Effects and Toxicities

• Part B Module B1
• Session 4

2
Objectives

• Describe the important drug interactions between
  different ARVs and discuss the significance of
  these interactions
• List the toxicities and common side effects of
  each drug
• Discuss monitoring and management of toxicities
  and side effects
• Describe class adverse drug reactions, including
  class-specific and ARV-specific adverse effects
  of ART

3
Antiretroviral Drug Interactions
4
Introduction

• Phamacokinetic interactions occur when one drug
  alters the serum or tissue concentration of
  another by changing its absorption, distribution,
  metabolism, or elimination
• Such interactions can result in clinically
  significant changes in drug concentration which
  may require the dose of one or more drugs to be
  modified or may necessitate the use of an
  alternative drug or drugs

5
Changes in Drug Absorption

• Alterations of gastric pH
• If a drug changes the gastric pH, it can affect
  the absorption and thus concentration of other
  drugs that have specific pH requirements for
  absorption
• Presence or absence of food
• Food can enhance or decrease the bioavailability
  of a drug--often because of gastric acidity
• Some drugs, such as ddI and IDV, must be
  administered one hour before or two hours after
  eating
• Chelation
• Binding of two drugs/compounds to form insoluble
  complexes that cannot be absorbedthis changes
  absorption of a drug

6
Changes in Drug Distribution

• Protein-binding
• Things that alter the protein-binding of a drug
  affect the amount of free drug that is available
  to produce the necessary therapeutic effect
• Hypoalbuminemia
• Patients with low albumin levels can experience
  an increased therapeutic effect and/or risk for
  toxicity
• This occurs with drugs that are highly
  protein-bound, such as warfarin or phenytoin

7
Changes in Metabolism

• Metabolism in the liver cytochrome P450 system
• The induction or inhibition of various P450
  enzymes by one drug can significantly alter the
  serum concentration of another drug that is
  metabolized by the same P450 enzyme
• PIs and NNRTIs are primarily metabolized by the
  same P450 CYP3A4 isoenzyme and can inhibit or
  induce this isoenzyme. This result in increases
  or decreases in the concentration of
  concomitantly administered drugs
• Other drugs that inhibit or induce this isoenzyme
  can bring about increases and decreases in the
  concentration of concomitantly administered PIs
  and/or NNRTIs

8
Changes in Metabolism, continued

• Each PI and NNRTI has a different drug
  interaction profile, depending primarily on its
  potency as an inducer or inhibitor of CYP3A4
  and/or other P450 enzymes
• Ritonavir is the most potent CYP3A4 inhibitor and
  consequently has the most drug interactions and
  contraindications
• NVP is a CYP3A4 inducer.
• EFZ is both an inducer and inhibitor of CYP3A4
• Rifampicin is a potent inducer of hepatic
  metabolism and significantly decreases the
  concentration of PIs to subtherapeutic levels

9
Changes in Metabolism, continued

• NFV, RTV, and the NNRTIs can significantly
  decrease the estrogen levels in contraceptives.
• Women taking these drugs cannot rely on oral
  contraceptives and should use another or an
  additional method of contraception.
• PIs and EFZ can raise the serum concentration of
  cisapride and non-sedating antihistamines
  (astemizole, terfenadine), which can lead to
  cardiotoxicity. They can also increase the serum
  concentration of benzodiazapines, and this can
  result in prolonged sedation. Therefore, PIs and
  these other drugs should not be administered
  together.

10
Changes in Elimination

• Kidney function
• The inhibition of the tubular secretion of one
  drug by another that is eliminated by the kidney
  can result in changes in drug concentration
• For example, probenecid can increase levels of
  ZDV

11
Summary of ARV Interactions
12
ARV Interactions

• Do not give Indinavir (Crixivan?) and Nelfinavir
  (Viracept?) with
• Rifampicin (Rifadine?)
• Terfenadine (Triludan?)
• Astemizole (Hismanal?)
• Cisapride (Cyprid?, Prepulsid?)

13
Interactions with Ritonavir
14
Protease inhibitors and anti-tuberculous
treatment

• can be given when boosted with ritonavir

15
ARV Dosage Adjustments Due to Drug Interaction

• Adapt ARV dose because of drug interactions

16
Common Side Effects and ToxicitiesHow to Monitor
17
Common Side Effects and ToxicitiesHow to
Monitor, continued
18
Common Side Effects and ToxicitiesHow to
Monitor, continued
19
Common Side Effects and Toxicities --How to
Monitor, continued
20
Common Side Effects and Toxicities --How to
Monitor, continued
21
Class Adverse Drug Reactions (ADRs)
22
HIV-Related Metabolic Complications
Lipid(cholesterol/triglyceride) abnormalities
Abnormal blood sugar (glucose) metabolism
Body fat redistribution

• One syndrome or several ?
• One etiology or multifactorial ?

23
Lipodystrophy Fat distribution

• Diagnosis
• Fat accumulation abdomen, dorsal neck, (buffalo
  hump), breasts
• Fat atrophy Extremities, buccal fat, buttocks
• Measurement
• Waist-hip ratio gt0.85 (women) or gt0.95 (men)
• Patient perception
• Intervention
• Results with changing therapy, including use of
  different classes, are inconclusive

24
Lipodystrophy
25
Lipodystrophy, continued
26
Incidence of Lipodystrophywith PI-containing
Regimens
Martinez Lancet 2001
27
Hyperlipidemia

• Evaluation
• Baseline for patient at risk for cardiovascular
  disease and prior to ART
• Triglycerides
• Normal levels lt150 mg/dl
• Elevated levels 200-499 mg/dl
• Very high levels requiring immediate intervention
  to prevent pancreatitis and reduce risk of
  cardiovascular disease gt500 mg/dl

28
Hyperlipidemia, continued

• Drug selection
• ACTG expert panel recommendations for statins
  with concurrent PI or NNRTI Atorvastin or
  Pravastatin
• Therapeutic switch
• PIs and possibly NNRTI agents appear to be
  associated with increases in blood lipids,
  including cholesterol, LDL cholesterol and
  triglycerides
• Use of non-PI containing regimens may reverse
  these changes. Changing from PI-based regimens to
  an NRTI/NNRTI regimen may improve lipid profile

29
Diabetes

• Diabetes risk is associated with the use PIs
• Frequency - 3-17 of diabetic patients on PIs
  have a reaction that occurs at median of 60 days
• Cause - peripheral insulin resistance
• Monitoring
• fasting blood glucose at pre-ART baseline
• some recommend fasting blood sugar at 3 to 4
  month intervals for first year of PI therapy
• Treatment
• Insulin sensitizers metformin or glitazones
  preferred over insulin or sulfonylureas based on
  mechanism of diabetes
• most do not recommend ART changes unless there is
  severe diabetes

30
Mitochondrial Toxicity Lactic Acidosis ?
Steatosis

• Rate 1.3 per 1000 patient years
• Risk Prolonged NRTI use, obesity, female sex,
  pregnancy, d4T gt AZT, ddl gt ABC, 3TC
• Symptoms Fatigue, nausea, vomiting, wasting,
  abdominal pain, dyspnea, diarrhea, anorexia,
  weakness, myalgias, paresthesias, hepatomegaly.
• May cause respiratory failure requiring
  ventilator therapy.

31
Hyperlactatemia Clinical Syndromes
symptoms
Lactate mmol/L
2.5 3.0 3.5 4.0 4.5 5.0 5.5

• Compensated
• hyperlactatemia
• chronic
• varies over time
• common
• risk factors ddIgtABC,
• AZTd4T, time on therapy
• raised LFTs and glucose

• Decompensated
• lactic acidosis/hepatic steatosis
• rapidly progressive
• life-threatening
• HCOlt20mmol/L
• risks women, HCV/HBV, infections,
  liver disease

vs.
After John Mallal Current opinion in Infectious
Diseases in press.
32
Mitochondrial Toxicity, continued

• Nucleoside analogues and mitochondrial toxicity

33
Mitochondrial Toxicity, continued

• Lab
• Technique for drawing blood for lactic acid
  levels
• do not use a tourniquet
• do not allow patient to clench the fist
• avoid stasis
• use pre-chilled fluoride-oxalate tubes.
• transport on ice for processing within 4 hours

34
Mitochondrial Toxicity, continued

• Interpretation of lab results
• lt2 mmol/mL normal
• 2-5 mmol/mL d/c NRTI if symptomatic (after
  ruling out other
• cause of symptoms. at this low level may be
  something else)
• gt5 mmol/mL d/c NRTI
• gt10 mmol/mL potentially lethal

35
Mitochondrial Toxicity, continued

• Other lab findings
• variable ? CPK, LDH, lipase, amylase, ALT4 anion
  gap
• ? HCO3
• CT scan or echofatty liver
• liver biopsysteatosis
• Management
• discontinue NRTI or switch to NRTI with reduced
  frequency of lactic acidosis (ABC, AZT,
  tenofovir)
• NRTI-sparing regimens with established efficacy
  LPV/RTV, EFV/IDV ? RTV, SQV/RTV, APV/RTV/EFV
• Recovery Mean time to normal lactic acid levels
  after stopping NRTIs is 50 days

36
Hepatoxicity

• Definition ALT or AST elevation to 3-4 x the
  upper limits of normal that is not otherwise
  explained
• Frequency with ART 2 to 18
• Mechanism NRTImitochondrial toxicity PI and
  NRTI unclear liver biopsy usually not helpful
• Agents All retroviral agents, especially RTV and
  NVP.
• Risk Chronic hepatitis (HCV, HBV), d4T use,
  alcoholism, and increased baseline transaminase
  levels.
• Decrease dose of the following drugs in presence
  of hepatic failure due to any cause
• AZT, all PIs, all NRTIs

37
Osteoporosis

• Risk Osteopenia in 25-50 of ART recipients
  osteoporosis in 5-10
• Routine screening Not indicated
• Treatment Increase intake of calcium and vitamin
  D plus weight bearing exercises

38
Avascular Necrosis

• Rate 0.3 to 1.3
• Risks ETOH abuse, hyperlipidemia, steroid use,
  hypercoagulability, hemoglobinopathy,
  relationship with ART is unclear
• Diagnosis MRI or CT scan
• Most frequent sites femoral head, shoulder

39
Rash

• Most common with NNRTIs NVP, DLV, EFV
• Frequency10 to 20
• Most are cutaneous and can be treated with
  antihistamines
• Severe or life threatening reactions include
  Stevens-Johnson syndrome and DRESS (drug rash,
  eosinophilia and systemic symptoms) with fever,
  and multiple organ involvement
• Indications to D/C NNRTI Symptoms of DRESS or
  rash with fever, desquamation, mucous membrane
  involvement, blistering or arthritis (1 to 2 )

40
Rash, continued

• Safety of alternative NNRTIs unknown
• Chemical structure of NNRTIs are very different
  and limited experience shows that a switch from
  NVP to EFV for rash is safe
• PI most likely to cause rash APV22
  (sulfonamide)
• NRTI most likely to cause rash ABC

41
Summary
42
Antiretrovirals

• Potential Problems in Tropical Countries
• AZT (Retrovir?) watch for anemia, e.g., caused
  by HIV, malaria, ankylostomiasis, malnutrition,
  cotrimoxazole, hydroxyurea
• ddI (Videx?) d4T (Zerit?) watch for
  polyneuritis caused by HIV, isoniazid, dapsone,
  vitamin deficiency, ethylism, diabetes 

43
NRTIs Adverse Effects
44
NNRTI's Adverse Effects
45
Protease inhibitors Adverse Effects
46
Long-term Adverse Effects of PIs

• Hepatitis
• ? cholesterol
• ? triglycerides
• Diabetes
• Other
• Lipodystrophy (60-65 of patients)
• Sexual dysfunction?
• Atherosclerosis ? Coronary insufficiency ?

47
Summary Overview of ART Adverse Effects
48

• Management of
• Side Effects

49
ZDV-associated Anemia
Hb lt 8 g/dl at the
start of the ART?
and OI excluded
No
Hb drops by 25
or more from
stop AZT and
Yes
baseline
switch to ddI or d4T
and OI excluded
No
Treat OI
Give folic acid
Continue all ART
50
Didanosine-associated Pancreatitis
High baseline amylase
Avoid ddI if possible
combination
YES
or
history of pancreatitis?
Avoid ddI d4T
Monitor carefully and
Yes
Patient develops
measure serum amylase
abdominal pain
Stop all ART
while taking ddI?
treat as acute
pancreatitis
Amylase gt 800 IU/L
when better, switch to a
Yes
or severe abdominal pain
regimen that does not
contain ddI
No
Repeat amylase every 2
weeks until symptoms
resolve or amylase lt 400
IU/L
No
No
Symptoms improve
or amylase
decreasing
Yes
Continue treatment
no need for routine check of
amylase, unless patient
develops abdominal pain
51

Nevirapine-associated Rash
NVP lead-in dose
d4T/3Tc/NVP in the morning
first two weeks
d4T/3TC in the evening
Stop all ARV
Vesicles, moist
Wait until rash gone
desquamation,
severe wet
Yes
rash
switch to
AZT/3TC/EFV
mucous membrane
involvement?
if Hb gt 8 g/dl
No
Dry rash?
Systemic signs?
Maculopapular rash,
Yes
Yes
fever?
dry desquamation?
No
Non-severe rash
Observe
Ÿ
Ÿ
Ÿ
Chlorpheniramine 4mg HS
Ÿ
No
Continue NVP lead-in dose
Switch to 3TC/
Rash still
present
AZT/efavirenz
Yes
after 1 month?
if Hb gt 8 g/dl
Yes
No
If not, replace AZT
Switch to full dose
with d4T
Switch to full dose
nevirapine after 2 weeks
nevirapine after 1 month
Wet rash or dry rash
systemic signs?
No
Continue full dose
in case of mild rashes
give chlorpheniramine if
necessary
52
Stavudine-associated Polyneuropathy
Only numbness or paresthesias of
Yes
No
fingers and toes
Continue d4T
Numbness or paresthesias
Give vi tB complex
higher than toes and fingers
amytriptiline
Any weakness of hands and
feet, unable to walk on heels
or toes
The efficacy of
amytriptiline for this
indication is not proven
in randomized controlled
trials. Only give it if
Better or the
symptoms cause sleep
same but can
disturbance.
be tolerated by
the patient
Stop d4T and switch
Yes
No
to AZT
Continue
treatment
53
Efavirenz associated rash
Vesicles, moist
desquamation,
Severe wet
Stop all ARVs
YES
rash
mucous membrane
Wait until rash
resolves
involvement?
AZT/3TC/IDV/RTV
Switch to
No
Dry rash?
Systemic signs?
Yes
Maculopapular rash,
Yes
fever?
Dry desquamation?
No
Non-severe rash
Observe
Chlorpheniramine 4mg HS
Continue ARV
No
Switch to 3TC/AZT/
IDV/RTV
Rash still
Yes
present after 1
Continue ARV
No
month?
54
Indinavir-associated
Nephrotoxicity
Check creatinine
before start of IDV regimen
Start IDV-containing regimen
Educate your
patient before
the use of IDV !!!
RTV 100/IDV 400 BID
if IDV boosted with RTV
2 NRTI
Adults should drink more than 2
litres a day in a hot climate!
Drugs have to be taken with food,
Check ultrasound of
Colicky flank pain
the kidneys, urine
irradiating to the
Yes
microscopy and serum
groin?
creatinine
Nephrolithiasis
No
?
No
Check creatinine every month
for the first 3 months and then
Worsening or new
Yes
Yes
once every 3
months
onset renal failure?
Is the patient
drinking enough?
Is IDV/RTV taken
No
No
with food?
Continue the same
give advice on food and fluid intake
treatment
Yes
Stop all ARVs and seek
advice
Continuous renal
colic ?
Yes
Will most likely have to
switch to another regimen
Worsening renal
failure
55
Efavirenz-associated CNS Effects
Before starting EFV give clear
explanation to the patient
Give efavirenz at bedtime
Nightmares, dizziness,
insomnia, anxiety,
personality change
Patient and his/her
Continue all ART, symptoms will
environment can
usually improve after 1 month
Yes
tolerate it?
Amitryptiline at bedtime
No
Stop EFV
switch to IDV/RTV
56
Managing CNS Side Effects of Efavirenz

• CNS side effects are often mild and transitory,
  resolving within 2 - 4 weeks of therapy
  initiation
• Advise patients to

• start on a weekend
• take EFZ in the evening
• alter behaviors according to side effects
  Example do not drive if feeling dizzy
• avoid alcohol and other recreational drugs
  when starting therapy

57
NFV/RTV-associated Diarrhea

• Prescribe loperamide, calcium carbonate
• (500mg bid), and/or psilium
• Give dietary advice
• Maintain good fluid intake
• Avoid foods that worsen diarrhea
• Use BRAT diet (bananas, rice, applesauce, tea)
• Take into account patients experience

58
ARV Treatment Counseling Prior to Treatment
Initiation

• A patient should understand
• The goals of therapy
• ARVs are not a cure
• During ARV the virus can still be transmitted ?
  the
• need for save sex practices
• ARV is a Iife-long treatment
• The cost and consequences for family budget
• The importance of optimal adherence
• Disclosure issues of ARV-use to family members
• The possibilities for psychosocial support
• Drug information to include

59
Drug Information

• Type of drugs
• Dose
• Frequency of administration
• Dosing in relation to
• meal times
• fluid intake
• timing with other drugs
• Drug timetable
• Drug interactions

60
Drug Information

• Storage
• Clinical and laboratory monitoring
• Side effects - management
• Possibility of treatment failure
• Criteria for cessation or changing therapy
• Life style considerations (poor nutrition,
• alcoholism)

61
Importance of Adequate Hydration

• Adequate hydration is essential to healthy body
  function.
• Patients taking CRIXIVAN should drink at least
  1.5 L (approximately 48 oz) of water or other
  liquids every day.

62
Case Studies