2. 2
2
Introductory Case: Tewabech
Tewabech, a 40 year-old woman, presents to the
pharmacy for her 2 week follow-up after starting ART
(efavirenz, lamivudine and zidovudine)
She appears tired and feels fatigue. When you ask
her how she is doing on her medication, she replies
that she does not understand why she is feeling
worse after starting ART. She occasionally feels
nausea. Also, she has trouble falling asleep, and
during the night she is awoken with nightmares
3. 3
3
Introductory Case: Tewabech (cont.)
Which of the following statements are true about Tewabech?
1. The tiredness, fatigue and occasional nausea are caused due to
zidovudine.
2. The CNS side effects described are most likely due to zidovudine and
should go away over time.
3. The CNS side effects are most likely due to efavirenz. Central
nervous system (CNS) side effects are not likely to go away and
patients must get used to less sleep.
4. The CNS side effects are most likely due to efavirenz. Over 50% of
patients who take efavirenz may experience these side effects.
5. Trouble sleeping and nightmares are generally protease inhibitor
related side effects
4. 4
4
Unit Learning Objectives
Identify different classes of antiretroviral drugs
Understand the mechanism of action for different
antiretroviral classes
List the ARV drugs currently available and with future
potential availability in Ethiopia
Understand the ARV doses and reasons for dose
modifications
Identify and manage the common side effects of
ARVs
6. 6
What is HAART (ART)?
HAART = Highly Active Antiretroviral Therapy
HAART and ART acronyms may be used interchangeably
ART includes at least three compatible antiretroviral agents
Treatment with HAART:
Controls HIV replication
Allows the body to rebuild its immune system
Reduces HIV transmission from mother to child during pregnancy, birth
or breastfeeding
If treatment is stopped, the virus will start to replicate again
7. 7
Goals of ART
Clinical goal
Prolong and improve quality of life
Virologic goal
Reduce viral load (HIV RNA to “undetectable” within 4-6
months of ART initiation)
Immunologic goal
Immune reconstitution in both qualitatively and quantitatively
Maintain treatment options
Epidemiologic goal
Reduce HIV transmission
8. 8
How Long Will Treatment
Keep People Alive?
People on ART are still doing well after 20 years
with good adherence to treatment
We are all working together in a great effort to make
the best use of limited resources
Everyone has a part to play
9. 9
Factors to Consider When
Starting Therapy
Latest Ethiopia ART
Guidelines (December
2008)
Potential side effects
Concurrent health
conditions
Including abnormal laboratory
values
Drug interactions
Potential for pregnancy
Prior antiretroviral use
Antiretroviral resistance,
whenever required and
possible
Future treatment options
Conditions for storing
medications
Patient ability to follow-up in
clinic and laboratory
monitoring requirements
10. 10
Factors to Consider When
Starting Therapy (2)
Potential barriers to adherence
Recent HIV diagnosis (limited time to process information)
Patient life-style and preferences
Limited ability to follow-up in clinic
Living far from clinic
Compromised food access
Limited support from family / friends
16. 16
16
Classes of Antiretrovirals
Fusion inhibitors
Prevents fusion of the virus into a CD4 cell by preventing
conformational change needed to allow virus to enter a
CD4 cell
Nucleoside reverse transcriptase inhibitors (NRTIs)
or nukes
Mimic naturally occurring nucleosides
Block viral DNA construction as they deceive reverse
transcriptase
17. 17
17
Classes of Antiretrovirals (2)
Non- nucleoside reverse transcriptase inhibitors
(NNRTIs) or non-nukes (Nevirapine or Efavirenz)
Bind to the reverse transcriptase enzyme
Integrase inhibitors (Raltegravir, Elvitegravir)
Inhibit integration of proviral DNA into the host DNA
Protease inhibitors (PIs) (Lopinavir)
Prevents cleavage of the protease chain
Maturation inhibitors (Bevirimat)
Inhibit maturation of the released viruses from CD4 cells
18. 18
18
Antiretroviral Therapy (ART) or HAART
Combination of at least 3 drugs, usually:
2 NRTIs
and
1 NNRTI or 1-2 PIs
Rarely Triple NRTIs
Therapy with only one or two agents allows HIV to
overcome therapy through resistance mutations
22. 22
22
Zidovudine (AZT or ZDV)
Dosing: 300mg BID
Reduce ZDV dose for patients with renal
compromise and hepatic failure
Food Interactions
None – with or without food is ok
Food decreases ZDV-related nausea
23. 23
23
Zidovudine (2)
Drug interactions
Avoid use with:
• D4T (competitive antagonism)
• Other bone marrow suppressing drugs
• TMP/SMX
• Pyrimethamine
26. 26
26
Lamivudine (3TC)
Dosing: 150mg BID or 300mg QD
Reduce dose with renal compromise
Food Interactions: no food interactions
Toxicity: very rare
Headache
Occasional nausea
Lactic acidosis, fatty liver
27. 27
27
Stavudine (d4T)
Dosing
30 mg BID
Reduce dose in patients with renal compromise
Food Interactions: None
Toxicity
Peripheral Neuropathy (5-15%, pain, tingling, and
numbness in extremities – Stop drug
28. 28
28
Stavudine (2)
Toxicities
Lipoatrophy
Lactic acidosis, fatty liver
Pancreatitis
Hypertriglyceridemia
Drug interactions
Do NOT use with ZDV
(competitive antagonism)
Use with caution: Other ‘D’
drugs, INH, phenytoin,
ethambutol
30. 30
30
Introductory Case: Tewabech (cont.)
1. The tiredness, fatigue and occasional nausea
are caused due to zidovudine.
TRUE
The most common side effects of AZT are fatigue,
tiredness due to anemia and nausea.
31. 31
31
Introductory Case: Tewabech (cont.)
2. The CNS side effects described are most likely due
to zidovudine and should go away over time.
FALSE
Zidovudine does not cause the above CNS side effects.
31
32. 32
32
Didanosine (ddI)
Dosing
1 x 400mg enteric coated capsule QD (if <60kg: 250mg
QD)
or
2 x 100mg buffered tab BID or 4 x 100mg QD (if <60kg:
125 mg BID or 250mg QD)
• NOTE: If using buffered tablets, 2 or more tablets must be
used at each dose to provide adequate buffer.
or
250mg reconstituted buffered powder BID (if <60kg:
167mg BID)
33. 33
33
Didanosine (2)
Food Interactions: take on empty stomach
If taken with tenofovir (TDF), can take with or without food
Reduce dose to 250 mg qd with tenofovir
Stop ddI or reduce dose to 250mg QD for patients
that develop peripheral neuropathy
34. 34
34
Didanosine (3)
Drug interactions
Alcohol: risk of pancreatitis
Other ‘D’ drugs: risk of peripheral neuropathy, pancreatitis
Drugs that require gastric acidity for absorption:
ketoconazole
INH: risk of peripheral neuropathy
36. 36
36
Tenofovir Disoproxil Fumarate (TDF)
Actually, a nucleoTIDE
Dosing: 1 x 300mg tablet QD
Reduce dose with renal compromise
Also has activity against Hepatitis B
Dosed 300mg QD
Food Interactions: Can be taken with or without
food
38. 38
38
Abacavir (ABC)
Dosing: 1 x 300mg tablet BID or 600 mg QD
Food Interactions: no food interactions
No dose adjustment for renal failure
Toxicity
Hypersensitivity
• Occurs within first 6 weeks of therapy
GI intolerance
Rash
Flu-like symptoms
39. 39
39
Hypersensitivity to Abacavir (2)
Observed in approximately
5% of all patients receiving
abacavir
Multi-organ system
involvement
NEVER rechallenge—May
be fatal
Most common signs and
symptoms:
Fever (>80%)
Rash (maculopapular or
urticarial) (70%)
Fatigue (>70%)
Flu-like symptoms (50%)
GI (nausea, vomiting,
diarrhea, abdominal pain)
(50%)
40. 40
40
Time to Onset of 636 Cases
0
10
20
30
40
50
60
1 15 29 43 57 71 85 99 113 127 141 155 169
Days
No.
of
Cases
* One additional ABC HSR Reported at
318 days
93% of reported cases
occurred within the first 6
weeks of initiating abacavir
Hetherington S et al. In: Abstracts of the 7th Conference of Retroviruses and Opportunistic
Infections. San Francisco, CA. January 30- February 2, 2000, Poster No. 60.
Median time to onset 11 days
41. 41
41
Emtricitabine (FTC)
Dosing: 1 x 200mg capsule QD
Dose should be reduced for patients with renal
compromise
Food Interactions: no food interactions
Toxicity
Mild abdominal discomfort
Occasional nausea
Lactic acidosis, fatty liver
51. 51
51
Efavirenz (EFV)
Dosing: 600mg tablet QHS
Food Interactions
Take with low-fat meal - High-fat meals increase
absorption 50% increases side effects
Contraindicated in pregnancy
Known to cause birth defects
Drug interactions (induces liver enzymes)
Changing from a EFV to a PI, may need to increase dose
of PI for first two weeks
53. 53
53
Introductory Case: Tewabech (cont.)
3. The CNS side effects are most likely due to
efavirenz. Central nervous system (CNS) side
effects are not likely to go away and patients must
get used to less sleep.
FALSE
The onset of CNS side effects (such as insomnia and
nightmares) is usually at the start of therapy and usually
resolves after 2 to 4 weeks. CNS side effects rarely
continue after the first month of therapy
54. 54
54
Introductory Case: Tewabech (cont.)
4. The CNS side effects described are most likely due
to EFV. Over 50% of patients who take EFV may
experience CNS side effects
TRUE
CNS changes are very common (noted in 52% of
patients), but require discontinuation in a much smaller
percentage (2%-5%). Patients must be counseled
appropriately to prepare them for possible CNS side
effects from EFV
54
55. 55
55
NNRTI Class Effects
Side effects
Rash
• EFV > DLV > NVP
Hepatotoxicity manifested by elevated transaminase
Cross resistance across entire class
Essentially a one chance class of drugs
55
58. 58
58
Lopinavir/ritonavir (LPV/r)
Dosing: 250mg tabs and BID 500mg BID
Each tablet contains LPV 200 mg/RTV 50 mg
Food Interactions:
The tablet can be taken without food
Toxicity
Nausea, diarrhea
Lipid abnormalities
Hyperglycemia
Tablets can be stored at room temperature
59. 59
59
Lopinavir/ritonavir (2)
Interactions with other ARVs
EFV and NVP decrease LPV/r levels
• Increase LPV/r to 4 caps bid or 3 tablets bid
LPV/r decreases fosamprenavir levels
• This combination is not recommended
60. 60
60
Atazanavir/ritonavir (ATZ/r)
Dosing: 2 x 200mg capsules QD
Dosed with ritonavir 100mg QD, ATZ dose = 2 x 150mg
QD (for PI experienced patients)
Food Interactions: Take with food
Toxicity:
Nausea
Diarrhea
Elevated bilirubin
61. 61
61
Atazanavir/r (2)
Pregnancy
Potential for ATZ to cause hyperbilirubinemia in neonates
Drug interactions
Inhibits liver enzymes
If used with RTV, decrease dose to 300 mg qd + RTV 100
mg qd
TDF decreases ATZ levels
• Use boosted ATZ with TDF
Use boosted ATZ with any NNRTI
62. 62
62
Introductory Case: Tewabech (cont.)
5. Trouble sleeping and nightmares are generally
protease inhibitor related side effects
FALSE
In general, protease inhibitors are not known to cause
CNS side effects
It is rather efavirenz which can cause drowsiness or
insomnia, abnormal dreams, confusion, abnormal
thinking, impaired concentration, and dizziness
63. 63
63
PI Class Side Effects
Metabolic Disorders
Hepatotoxicities
Hyperglycemia, insulin
resistance
Lipid abnormalities
Fat redistribution
Bone Disorders
Avascular necrosis
Osteoporosis and
Osteopenia
GI intolerance
Drug interactions
Due to CYP450 3A4
Inhibition
63
64. 64
64
PIs induced Hepatotoxicity
RTV use linked to increased risk of severe
hepatotoxicity
Increased LFT’s observed with all PI’s
More common in patients with chronic viral hepatitis (HBV,
HCV)
Data do not, however, support withholding PI’s from
patients co-infected with HBV or HCV
66. 66
66
HAART and the Heart
Some HIV drugs, especially PIs, can increase fats
and sugar levels, increasing heart disease risk
Studies suggest that the longer patients are on
HAART, the higher the risk of heart disease
Smoking, pre-existing heart disease and diabetes
and age are risk factors.
67. 67
67
HAART and Lipodystrophy
After 3-4 years of combination therapy 30-40% of
people will develop body fat changes
Body fat changes may have a serious effect on a
patient’s quality of life
People who are overweight more likely to have
increase in central fat
Lipodystrophy most likely occurs when:
• Taking nukes and PIs together
68. 68
68
What Causes Lipodystrophy?
PIs and a number of other
factors
Treatment with PIs and
NRTIs together
Fat accumulation and fat
loss may have separate
causes
D4T
Type and duration of anti-
HIV therapy
Duration of HIV infection or
low CD4 count
Gender, age and race
Higher body mass and fat
prior to treatment
69. 69
69
Dorsocervical Fat Pad
Source: Dominic C. Chow, MD, University of Hawaii; Larry J. Day, MD,
University of Michigan; Cecilia M. Shikuma, MD, University of Hawaii
72. 72
72
HAART and Bone Disorders
Osteopenia, osteoporosis, and avascular necrosis
are being reported in patients with HIV infection
Associated with PI-containing HAART regimens
74. 74
Regimen Drugs Monitoring Tests Frequency
First-line Regimens TDF/FTC/EFV CD4 Baseline and every 6 months
Pregnancy test Baseline and as indicated
ALT Symptom-directed
Creatinine symptom-directed
D4T/3TC/NVP CD4 count At baseline and 6 monthly (if available)
ALT Symptom-directed
ZDV/3TC/NVP Haemoglobin At baseline, 4th, 8th, and 12th weeks. thereafter symptom-directed
ALT Symptom-directed
CD4 Count Baseline and 6 monthly (if available)
d4T/3TC/EFV Pregnancy Test Baseline, thereafter as indicated
ALT Symptom-directed
CD4 Count At baseline and 6 monthly
ZDV/3TC/EFV Haemoglobin, At baseline, 4th, 8th, and 12th weeks; thereafter symptom-directed
Pregnancy test At baseline, thereafter as indicated
ALT Symptom-directed
CD4 count At baseline and 6 monthly
74
75. 75
75
HAART: Baseline Labs at
First Appointment
HIV antibody test
Full blood count and
differential
AST or ALT
Serum creatinine or blood
urea nitrogen
Serum glucose
Pregnancy tests for women
Urine dipstick
Hep B surface antigen
Serum RPR
Serum amylase (for patients
on d4T or ddI)
Serum lipids (for patients
with other cardiac risk
factors or to receive PIs or
EFV)
CD4 lymphocyte count
75
77. 77
77
ART Dosing Adjustments for
Renal Compromise
Med Normal Dose CrCl 10-50mL/min CrCl <10mL/min
ddI 200mg tabs bid
400mg qd (EC)
200mg qd
125-200mg qd
100mg q24-48h
125mg qd
3TC 150mg bid 100-150mg qd 50mg qd
d4T 30-40mg bid 50% q12-24h > 60kg: 20mg qd
< 60kg: 15mg qd
TDF 300mg* qd CrCl=30-50, * q 2 days
Cr Cl=10-29, * q 3-4 days
300mg q 7 days
ZDV 300mg bid 300mg bid 300mg qd
FTC 200mg# qd CrCl=30-49, # q 2 days
CrCl=15-29, # q 3 days
CrCl<15= #q 4 days
Source: Madison Clinic HIV treatment Guidelines, Harborview Medical Center, Univ. of Wash., Seattle, WA. www.madisonclinic.org
and Johns Hopkins AIDS Service - Medical Management of HIV Infection. www.hopkins-aids.edu 77
78. 78
78
ART Dosing Adjustments for Hepatic Failure
Medication Dose for hepatic failure
3TC, d4T, ABC No data, usual dose
TDF Avoid
ZDV 200mg BID
LPV/r, NFV, RTV, TPV No dose change, use with caution
ddI, NVP, EFV Consider empiric dose reduction
Source: Madison Clinic HIV treatment Guidelines, Harborview Medical Center, Univ. of Wash., Seattle, WA. www.madisonclinic.org
and Johns Hopkins AIDS Service - Medical Management of HIV Infection. www.hopkins-aids.edu
78
80. General Information
Patients on HAART commonly suffer from side effects.
Patients should be counseled about potential side effects of
ARV drugs and their management:
Pharmacological
Non-pharmacological
Side effect
Any unintended effect of drugs occurring at doses normally
used in man and is related to the pharmacological properties of
the drug.
Adverse reaction
A noxious and unintended effect which occurs in doses
normally used in man and may not be related to its
pharmacological properties. 80
81. GI – related side effects: Overview
Gastrointestinal problems are the most common side
effects of almost all antiretroviral drugs.
Some NRTIs and most PIs induce GI associated side
effects especially during initiation of ART.
Typical GI signs and symptoms include:
abdominal discomfort, loss of appetite, diarrhea, nausea
and vomiting.
81
82. Nausea and Vomiting (1)
Which ARV Drug Causes it?
AZT and ddI - containing regimens.
Non-pharmacologic management
If administration on an empty stomach leads to nausea
and vomiting:
• most drugs can also be taken together with meals.
When a drug (e.g. didanosine) has to be administered on
an empty stomach:
• small quantities of low-fat meal may lessen the nausea.
82
83. Pharmacologic management
For symptomatic treatment, metoclopramide is useful.
Dimenhydrinate or ondansetron can also be used.
If nausea persists for more than two months, a
change of treatment should be considered.
Nausea and Vomiting (2)
83
84. Diarrhea
Which ARV drugs cause diarrhea?
zidovudine, didanosine and all PIs, particularly with
lopinavir and nelfinavir
Non-pharmacologic management
In patients with massive diarrhea, the priority is to treat
dehydration and loss of electrolytes.
Food stuffs: potato, rice, etc
Pharmacologic management
PI-associated diarrhea can also be managed by calcium,
taken as calcium carbonate, at a dosage of 500 mg bid.
Symptomatic treatment consists of loperamide (initially 2 -
4 mg, followed by 2 mg, up to a maximum of 16 mg daily).
84
85. Hepatotoxicity (1)
Elevated liver function tests are common with ART
Which ARV Drugs Cause Hepatotoxicity?
Among the PIs: toxic hepatitis is seen most frequently in
patients on boosted atazanavir, indinavir and tipranavir.
Case reports also exist due to Indinavir, Atazanavir,
Efavirenz, Nelfinavir and different nucleoside analogs.
Patients with pre-existing liver disease should receive the
above mentioned drugs only under strict monitoring.
85
86. When is it expected?
NNRTIs specially Nevirapine often cause hypersensitivity
reaction within the first 12 weeks.
NRTIs lead to hepatic steatosis; which occurs after more
than 6 months on treatment.
PIs cause hepatotoxicity at any stage of treatment: patients
with chronic viral hepatitis are particularly at risk.
Hepatotoxicity (2)
86
87. Nevirapine – induced Hepatotoxicity (1)
Liver toxicity occurs more commonly on nevirapine
than on other antiretroviral drugs.
One risk factor was hepatitis C co-infection, if
possible nevirapine should be avoided
Liver toxicity occurs usually early during therapy.
87
88. 88
88
Symptoms are observed in 4.0%
About half of these cases were associated with rash
Women more likely than men to experience symptomatic
hepatic events during the first 6 weeks of therapy
Women are at greater risk when CD4+ cell counts >250
cells/mm3 (11% vs. 0.9%)
Men are at greater risk when CD4+ cell counts >400
cells/mm3 (6.4% vs 2.3%)
Source: Boehringer Ingelheim Pharmaceuticals, Inc., www. Viramune.com
Nevirapine – induced Hepatotoxicity (2)
88
89. 89
89
Risk factors for symptomatic hepatic events:
Elevated pre-treatment ALT or AST
HBV and/or HCV co-infection
Higher CD4+ cell count at initiation of Nevirapine therapy
Female gender (especially women with CD4+ cell counts
>250 cells/mm3)
History of alcohol abuse
Nevirapine – induced Hepatotoxicity (3)
89
90. 90
90
Assess Rash and Evaluate ALT/AST
Mild or moderate rash with no
constitutional symptoms
Rash and no increase in ALT or AST
Severe rash or
Rash + constitutional
symptom ± organ
dysfunction or
Rash + Incr ALT/ AST
Can continue
Permanently discontinue
Source: Boehringer Ingelheim Pharmaceuticals, Inc., www. Boehringer-ingelheim.com
Nevirapine – induced Hepatotoxicity (4)
90
91. Renal problems: Tenofovir (1)
Severe renal toxicity occurs rarely
Risk factors include:
a relatively high tenofovir exposure,
pre-existing renal impairment,
low body weight,
increased age,
co-administration of nephrotoxic drugs such as didanosine.
94
92. In case of renal dysfunction, especially in patients
with low body weight,
If possible, avoid tenofovir or adjust dosing interval.
Renal function tests including:
creatinine, urea, creatinine clearance, proteinuria,
glycosuria, blood and urine phosphate.
Administer tenofovir:
every 48 hours in patients with a creatinine clearance
between 30 and 49 ml/min
twice a week between 10 and 29 ml/min.
Renal problems: Tenofovir (2)
95
93. Neurological side effects:
Peripheral neuropathy (1)
Which ARV Drugs cause Peripheral Neuropathy?
NRTIs mainly: didanosine and stavudine.
Patients complain of paresthesia and pain in their hands
and feet.
Risk factors for polyneuropathy:
vitamin B12 deficiency,
alcohol abuse,
diabetes mellitus,
malnutrition,
treatment with other neurotoxic drugs, e.g. INH,
96
94. Neurological side effects:
Peripheral neuropathy (2)
Pharmacologic (Symptomatic) treatment includes:
Acetaminophen (paracetamol), Carbamazepine,
Amitriptyline, Gabapentine and Opioids
Vitamin B supplementation can help to improve peripheral
neuropathy faster.
Non-Pharmacologic management:
Tight shoes or long periods of standing or walking should
be avoided; cold showers may relieve pain before going to
bed.
97
95. Neurological side effects: CNS
toxicities (1)
Treatment with efavirenz leads to CNS side effects
such as:
dizziness, insomnia, nightmares, mood fluctuations,
depression, depersonalization, paranoid delusions,
confusion and suicidal ideation
These side effects are observed mainly during the
first days and weeks of treatment.
98
96. Neurological side effects: CNS
toxicities (2)
If the CNS side effects persist for more than two to
four weeks,
the dose can be divided into a 400 mg night dose and a
200 mg morning dose.
Lorazepam can diminish the CNS side effects, and
haloperidol can be given for panic attacks and nightmares.
99
97. AZT – induced Haematological
toxicities (1)
Zidovudine is myelosuppressive, especially with
respect to the red cells, and therefore leads to
anemia.
Most commonly affected are patients with:
advanced HIV infection, pre-existing myelosuppression,
chemotherapy or co-medication with other myelotoxic
drugs such as cotrimoxazole, pyrimethamine, amphotericin
B, ribavirin, and interferon.
Zidovudine should be discontinued in severe cases
and a blood transfusion may be necessary.
100
98. In patients with advanced HIV infection and multiple
viral resistance and therefore no options to change
to less myelotoxic drugs,
erythropoietin is an option, but should be avoided as a
long-term option if possible, due to the associated high
costs.
AZT – induced Haematological
toxicities (2)
101
99. Due to drug-induced neutropenia, despite viral
suppression, the CD4+ T-cell count may remain low
after an initial rise.
Change the treatment to less myelotoxic ARVs such as
stavudine, lamivudine, most of the PI and all NNRTIs.
Zidovudine should be avoided.
Leukopenia may also occur with abacavir or tenofovir.
AZT – induced Haematological
toxicities (3)
102
100. NNRTI-induced allergy is a reversible, systemic
reaction and typically presents as:
Erythematous, maculopapular, pruritic and confluent rash, distributed
mainly over the trunk and arms.
Fever may precede the rash.
Other symptoms include myalgia, fatigue and mucosal ulceration.
The allergy usually begins in the second or third week of
treatment.
Women are more often and more severely affected.
If symptoms occur later than 8 weeks after initiation of
therapy, other drugs should be suspected.
NNRTIs – induced allergic reactions (1)
103
101. Treatment should be discontinued immediately in
cases with:
mucous membrane involvement, blisters and exfoliation
hepatic dysfunction (transaminases > 5 times the upper
limit of normal)
or fever > 39°C.
If patients present with a suspected nevirapine -
associated rash,
hepatotoxicity should be looked for in addition and liver
function tests should be performed.
Patients with rash-associated AST or ALT elevations
should be permanently discontinued from nevirapine.
NNRTIs – induced allergic reactions (2)
104
102. Antihistamines may be helpful.
Following a severe allergic reaction, the drug
responsible for the reaction should never be given
again.
NNRTIs – induced allergic reactions (3)
105
103. Abacavir - induced allergic reactions (1)
Abacavir causes a hypersensitivity reaction (HSR),
which may be life threatening if not recognized in
time.
Rash associated with abacavir is often discrete.
30% may not have rash at all
80% of patients have fever.
general malaise (which gets worse from day to day),
other frequent symptoms include GI side effects such as
nausea, vomiting, diarrhea and abdominal pain
106
104. Never attempt to start HAART with Abacavir and
NNRTIs together.
If abacavir is part of the initial therapy and flu-like
symptoms occur,
it is difficult to distinguish between immune reconstitution
inflammatory syndrome (IRIS) and HSR.
Criteria in favor of HSR due to abacavir include:
development of symptoms within the first six weeks of
treatment,
deterioration with each dose taken and
the presence of gastrointestinal side effects.
Abacavir - induced allergic reactions (2)
107
105. If abacavir is discontinued in time,
the HSR is completely reversible within a few days.
Following discontinuation of abacavir, further
supportive treatment includes,
intravenous hydration and possibly steroids.
Abacavir - induced allergic reactions (3)
108
106. NRTI – induced lactic acidosis (1)
Rare but potentially fatal and linked to
prolonged use of NRTIs
Lactic acidosis occurs:
most frequently on treatment with stavudine and didanosine
less often in patients on zidovudine, abacavir and
lamivudine
Risk factors are:
obesity, female sex, pregnancy, therapy with ribavirin or
hydroxyurea, a diminished creatinine clearance and low
CD4 cell count.
109
107. 110
110
Common symptoms include:
Lethargy, fatigue
Weight loss
Nausea, abdominal pain
Dyspnea
Cardiac arrhythmias
Concomitant hepatotoxicity with hepatomegaly,
hepatic steatosis and even ascites and
encephalopathy may be seen
NRTI – induced lactic acidosis (2)
110
108. 111
111
Lactate levels between 3 and 5 mmol/l, "watchful waiting" with
regular monitoring is recommended.
If the resistance profile allows, NRTI treatment may be
modified, e.g. switch from stavudine/didanosine to abacavir,
zidovudine or tenofovir.
At levels above 5 mmol/l,
NRTI treatment should be stopped immediately and supportive
treatment initiated; such as correction of the acidosis.
Mortality of patients with lactate levels above 10 mmol/l is
approximately 80%.
Agents used for treatment of congenital mitochondrial
disorders may hasten recovery (thiamine, riboflavin,
coenzyme Q, L-carnitine)
NRTI – induced lactic acidosis (3)
111
109. 112
112
PIs induced Insulin Resistance
Progression to frank diabetes mellitus possible
Monitor with fasting glucose values
Switching from PI-based regimens often allows
improvement
Some success with metformin
Caution - metformin also causes lactic acidosis
112
110. 113
113
PIs induced Lipid Abnormalities
Hypertriglyceridemia; risk of pancreatitis
Low HDL, high LDL
Increased deaths from coronary artery disease
Generally treated with fibrates and/or statins
Beware of drug interactions between ART, statins,
and fibrates risk of myositis
113
111. 114
114
Lipoatrophy – induced by d4T and
Lipodystrophy - induced PIs
For lipoatrophy on d4T, changing to either ABC or
TDF may prevent progression
Weight-bearing exercise to maintain muscle mass
and diet can be beneficial to prevent and treat
lipodystrophy
114
112. Bone disorder: Avascular necrosis (1)
Risk factors for avascular necrosis are:
alcohol abuse,
hyperlipidemia,
steroid treatment,
hypercoagulability, hemoglobinopathy,
trauma,
nicotine abuse and
chronic pancreatitis.
The most common site of necrosis are:
The femoral head and less frequently the head of the
humerus.
115
113. Once the diagnosis is confirmed, refer patients to an
orthopedic surgeon .
Identify risk factors and take measure to eliminate.
Physiotherapy, rest and sometimes surgery are
recommended.
Bisphosphonate medications, such as alendronate.
Nonsteroidal anti-inflammatory drugs (e.g. ibuprofen)
are the treatment of choice for analgesia.
Bone disorder: Avascular necrosis (2)
116
114. Bone disorder: Osteopenia /
Osteoporosis (1)
Treatment with PIs and NRTIs may cause bone
disorders such as Osteopenia / osteoporosis.
Osteopenia should be treated with vitamin D daily
and a calcium-rich diet or calcium tablets with a dose
of 1200 mg/day.
Patients should be advised to exercise and stop
alcohol and nicotine.
117
115. In cases with osteoporosis,
Bisphosphonates should be added. Tablets should be
taken on an empty stomach 30 min before breakfast, and
an upright position should be maintained for at least 30
min.
No calcium should be taken on this day.
Since testosterone suppresses osteoclasts,
hypogonadism should be treated.
Alcohol and smoking should be avoided; regular
exercise is an essential part of the therapy.
Bone disorder: Osteopenia /
Osteoporosis (2)
118
116. Spontaneous ADR reporting
The basis for pharmacovigilance in most countries
Allows for the collection and systematic analysis of adverse
drug reaction reports
Advantages
large population
all medicines, all reactions
hospital and out-patient care
continuous - long perspective
potentially quick
possible in settings with limited structure
inexpensive
patient analyses possible
119
118. 121
121
Group Exercise: Side Effects
1. List the main side effects of ARVs used
2. Divide side effects into two groups
a. Serious and life threatening
b. Treatable
3. Brain storm local remedies that might relieve less
serious side effects
4. Feed back to the main group
121. 124
124
Case Study: Abebe
Abebe, a 25 year-old man, was tested for HIV
because his wife tested positive in a prenatal clinic
He has seborrheic dermatitis and enlarged bilateral
posterior cervical lymph nodes. He weighs 72 kg.
He has felt well, and his physical exam is otherwise
normal.
His HIV antibody test was positive, and his CD4+
lymphocyte count was 140 cells/mm3. His other
baseline laboratory tests were normal, and he
fulfilled the CD4 criteria to start antiretroviral therapy.
122. 125
125
Case Study: Abebe (2)
He started cotrimoxazole prophylaxis six weeks ago
He began treatment with d4T, 3TC and NVP two
weeks ago
At his first follow-up visit he reported perfect
adherence and some itching of his skin.
On his exam, he had mild diffuse erythematous
macules on his torso, arms and legs.
123. 126
126
Case Study: Abebe (3)
1. What other information do you need to know to
confirm your diagnosis?
2. What is your diagnosis?
3. How do you treat him?
124. 127
127
Case Study: Abebe Follow-up (4)
He returns one week later. The rash has spread
onto his palms and soles. He now has fever,
conjunctivitis, and oral ulcers
The ALT is normal
125. 128
128
Case Study: Abebe (5)
Now he has Stevens-Johnson syndrome (SJS), or
severe erythema multiforme
What is your diagnosis?
How do you alter his current therapy?
126. 129
129
Case Study: Abebe (6)
Three weeks later the fever, rash and mucous
membrane disease have healed
How do you treat him now?
128. 131
131
Case Study: Mulnesh
Six months ago, Mulnesh was started on HAART for
the first time because her T-cells had dropped from 400
to 160cells/ml. Today she comes to the pharmacy to
refill only her TMP/SMX.
When you ask her if she needs to pick up her
antiretrovirals, she replies, “No, I’m going to stop taking
those when I run out because I’m having so many side
effects. I can’t feel my feet mostly in the morning”.
129. 132
132
Case Study: Mulnesh (2)
Current medications include:
Trimethoprim/sulfamethoxazole DS QD
Efavirenz 600mg OD
Lamivudine 150mg BID
Stavudine 30mg BID
What is the likely culprit for the numbness Mulnesh is
experiencing in her feet and what can be done to
alleviate the neuropathy?
131. 134
134
Case Study: Yimam
Yimam is a 38 year-old male who has been on NVP
and a ZDV + 3TC combination tablet for 5 months
He reports that he has become very tired in the last
two weeks. In fact, he has missed 4 days of work in
the past 2 weeks because he just couldn’t get out of
bed. He also has felt nauseated on and off ever
since he started the medications
He believes these changes are a result of his
antiretroviral medications, therefore he has begun
missing doses
132. 135
135
Case Study: Yimam (2)
What do you think is going on with Yimam? Do you
need any additional information to diagnose the
cause of the problem(s)?
What drug(s) might be responsible for his fatigue?
133. 136
136
Case Study: Yiman Follow-up (3)
His Hgb = 7.2 and his Hct = 20%
He says that he eats food before some of his doses,
but not all of the time. Usually he takes the dose
with a piece of injera. He hasn’t tried anything else
to control the nausea.
What management strategy would you suggest?
How would you counsel the patient?
135. 138
138
Case Study: Samson
Samson is a 32 year-old male who has been on nelfinavir and
a ZDV + 3TC combination tablet since 2001, through the
black market.
Six months ago, he began noticing body shape changes that
he believes are a result of his ARVs.
Consequently, he started missing doses frequently. Two
months ago his CD4 count began dropping and his VL went
from undetectable to 45,000. He stopped taking all HAART
Two weeks ago, he and his provider decided to restart
antiretroviral therapy.
136. 139
139
Case Study: Samson (2)
Samson began the following medications:
Lopinavir/ritonavir Two tablets (200/50 per tablet) BID
Efavirenz 600mg OD
Abacavir 300mg BID
Didanosine 400 mg qd
SMX/TMP QD
Today he comes to the pharmacy with a rash on his
extremities, back and trunk that started 3 days ago
137. 140
140
Case Study: Samson Follow-up (3)
Which drug(s) would most likely cause lipodystrophy?
Which drug(s) might be responsible for the rash?
What management strategy would you suggest for the
rash?
138. 141
141
Case Study: Samson (4)
When you ask Samson what type of body changes
he is having
His belly has gotten bigger, arms and legs are skinnier and
this area on his upper back is starting to poke up
Lipodystrophy could be caused by any of his ARVs.
The greatest contribution is likely from his PIs,
nelfinavir (he’s been on through black market) and
then his NRTIs.
140. 143
143
Case Study: Samson (6)
Three possible causes of
rash:
Efavirenz
Abacavir
SMX/TMP
Management strategies you
could suggest:
Ask if he has ever had
SMX/TMP before? Did it ever
give him a rash? He could
have had a rash to SMX/TMP
previously that was
overlooked.
• He has had SMX/TMP
before for a urinary tract
infection without problem.
Determine the rash severity –
mild or severe
141. 144
144
Case Study: Samson (7)
1. Is he presenting with any other hypersensitivity
symptoms? Does he have any blistering or mucous
membrane involvement? Why is this important?
2. Have his symptoms worsened with each dose?
Does he have any relief between doses?
3. What do his answers lead you to believe is the
culprit?
4. How can it be treated?
142. 145
145
Case Study: Samson (8)
It’s difficult to determine his exact resistance profile, but he
has not had an NNRTI in the past so we would expect him to
have good response to it alone with 2 NRTIs
We could stop the lopinavir/ritonavir to give the patient a PI
sparing regimen. Patients have reported improvements with
these measures
He is likely to have resistance to ZDV and 3TC, so switching
to ddI + ABC gives the patient a new 3-drug regimen
Make sure that he is >60 kg for appropriate dosing of ddI. We
would like to avoid using d4T as this has been implicated in
the development of lipodystrophy
143. 146
146
Key Points
Antiretrovirals cannot kill the existing virus; they can
only prevent the production of new virus
The classes of antiretrovirals are:
(1) nucleoside reverse transcriptase inhibitors (NRTI),
(2) non-nucleoside reverse transcriptase inhibitors (NNRTI),
(3) protease inhibitors (PI), and
(4) fusion inhibitors (FI)
(5) integrase inhibitors (IIs)
(6) maturation inhibitors (MIs)
144. 147
147
Key Points (2)
A combination of at least three drugs is necessary in
order to overcome resistance and manage HIV
Some side effects can have psychosocial as well as
physical implications
The side effects of some antiretrovirals can be
managed, while others may require a dose
modification or a change in the antiretroviral regimen
REMEMBER to counsel patients about the benefits
of these medications as well as the side effects
