Title: Part B: Module B1
1Drug Interactions and Adverse Drug Reactions
Side Effects and Toxicities
- Part B Module B1
- Session 4
2Objectives
- 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
3Antiretroviral Drug Interactions
4Introduction
- 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
5Changes 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
6Changes 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
9Changes 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.
10Changes 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
11Summary of ARV Interactions
12ARV Interactions
- Do not give Indinavir (Crixivan?) and Nelfinavir
(Viracept?) with - Rifampicin (Rifadine?)
- Terfenadine (Triludan?)
- Astemizole (Hismanal?)
- Cisapride (Cyprid?, Prepulsid?)
13Interactions with Ritonavir
14Protease inhibitors and anti-tuberculous
treatment
-
-
- can be given when boosted with ritonavir
15ARV Dosage Adjustments Due to Drug Interaction
- Adapt ARV dose because of drug interactions
16Common Side Effects and ToxicitiesHow to Monitor
17Common Side Effects and ToxicitiesHow to
Monitor, continued
18Common Side Effects and ToxicitiesHow to
Monitor, continued
19Common Side Effects and Toxicities --How to
Monitor, continued
20Common Side Effects and Toxicities --How to
Monitor, continued
21Class Adverse Drug Reactions (ADRs)
22HIV-Related Metabolic Complications
Lipid(cholesterol/triglyceride) abnormalities
Abnormal blood sugar (glucose) metabolism
Body fat redistribution
- One syndrome or several ?
- One etiology or multifactorial ?
23Lipodystrophy 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
24Lipodystrophy
25Lipodystrophy, continued
26Incidence of Lipodystrophywith PI-containing
Regimens
Martinez Lancet 2001
27Hyperlipidemia
- 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
28Hyperlipidemia, 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
29Diabetes
- 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
30Mitochondrial 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.
31Hyperlactatemia 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.
32Mitochondrial Toxicity, continued
- Nucleoside analogues and mitochondrial toxicity
33Mitochondrial 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
34Mitochondrial 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
35Mitochondrial 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
36Hepatoxicity
- 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
37Osteoporosis
- 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
38Avascular 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
39Rash
- 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 )
40Rash, 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
41Summary
42Antiretrovirals
- 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
43NRTIs Adverse Effects
44NNRTI's Adverse Effects
45Protease inhibitors Adverse Effects
46Long-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
49ZDV-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
50Didanosine-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
52Stavudine-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
53Efavirenz 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
55Efavirenz-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
56Managing 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
57NFV/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
58ARV 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
59Drug Information
- Type of drugs
- Dose
- Frequency of administration
- Dosing in relation to
- meal times
- fluid intake
- timing with other drugs
- Drug timetable
- Drug interactions
60Drug 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)
61Importance 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.
62Case Studies