Nausea Most common side effect for AZT Eating prior to dose helps reduce nausea Macrocytosis is common and not associated with anemia, see increase in MCV of 25-40 units after 6-24 weeks, serves as crude indicator of adherence.
Minimal Side Effects: Best tolerated of all antiretrovirals. Resistance Low barrier to resistance: a single point mutation (M184V) is sufficient for loss of effectiveness Advantages of the M184V mutation include: Improves the susceptibility of certain ZDV-resistant viruses in some patients Impairs viral fitness Keeping 3TC as part of a combination despite proven resistance is therefore sensible because this drug will continue reduce the replicative capacity of HIV
Nucleoside Analog: Cytosine analogue Mechanism of Action: It is phosphorylated 3 times by thymidine kinase to the active metabolite, 3TC-triphosphate Bioavailability (F): 86% CSF Levels: 13% of serum levels (these levels have been shown to clear HIV RNA from CSF) T1/2: 3-6 hours Intracellular T1/2: 12 hours
The flourinated version was designed to reduce toxicity and prolong drug half-life, but clinically there does not appear to be any difference between the 2 drugs. FTC has demonstrated activity against Hepatitis B, but it is not FDA approved for this indication.
Nucleoside Analog: Cytosine analogue Mechanism of Action: It is phosphorylated 3 times to the active metabolite, emtricitabine 5’-triphosphate Bioavailability (F): Good oral bioavailability. CSF Levels: Estimated to be low (in monkeys, CSF level was 4% of serum levels) T1/2: 8-9 hours Intracellular T1/2: > 20 hours
Patients should be counseled about abacavir hypersensitivity reaction (see next slides).
Reference Notes Nucleoside Analog: Guanine analogue Mechanism of Action: It is phosphorylated 3 times to the active metabolite. Bioavailability (F): 83% CSF Levels: 27%-33% of serum levels T1/2: 1.5 hours Intracellular T1/2: > 12 hours Elimination: 81% metabolized by alcohol dehydrogenase and glucouronyl transferase with renal excretion of metabolites; 16% recovered in stool, and 1% unchanged in urine. Dose does not need to be adjusted for compromised renal function. No data on hepatic failure, use usual dose. Pediatric Dose: 8mg/kg BID Pregnancy: (Category C) Crosses placenta. Drug Interaction: Alcohol increases ABC levels by 41%. Abacavir does not impact alcohol levels. Clinically, moderate alcohol use appears to be fine, do not need to adjust dose. Resistance: ABC selects for the following mutations: 65, 74, 115, and 184. The 184 mutation leads to complete cross-resistance with 3TC, but by itself does not significantly decrease ABC susceptibility. Mutations at codons 65 and 74 lead to cross-resistance to ddI and ddC. Significant resistance requires multiple mutations, usually in addition to the 184 mutation. If have M184V + at least 3 NAMS, expect ABC failure.
Monitor for renal impairment monthly: decreasing CrCl; glucose, phosphate, or protein in urine, low serum phosphate or potassium. Renal compromise is rare, but TDF should be stopped if patient develops renal compromise
Nucleotide Analog: TDF is different from nucleosides in that it has already been phosphorilated once. Mechanism of Action: Tenofovir disoproxil fumarate is a pro-drug of tenofovir. After oral administration, TDF is rapidly cleaved by nonspecific extracellular carboxyesterases into tenofovir. Once inside cells tenofovir is metabolized by adenylate cyclase and nucleoside diphosphate kinase to the active moiety, tenofovir diphosphate (PMPApp). Bioavailability (F): 25% (fasting) to 40% (with food). Bioavailability improves with food, especially high-fat meals. CSF Levels: unknown % of serum levels T1/2: 12 to 18hours Intracellular T1/2: 10 to 50 hours
ddI is a “D” drug Use lower dose to reduce risk of S/E development for patients < 60kg. Dose-related side effects Peripheral Neuropathy: Frequency: 5%-12%. Onset usually after 2-6 months of therapy. If patient develops peripheral neuropathy discontinue ddI at onset (or reduce dose to 250mg QD). Symptoms will dissipate slowly after stopping ddI or reducing dose. Following improvement in peripheral neuropathy, can re-introduce agent at reduced dose if needed. If provider does not discontinue therapy (or reduce dose) at onset, peripheral neuropathy will become permanent and increasingly painful and debilitating. Pancreatitis: Reported in 1%-9%, fatal in 6%. Risk factors include: renal failure, alcohol abuse, morbid obesity, history of pancreatitis, increased triglycerides, gall stones, and concurrent use of d4T, hydroxyurea, allopurinol, or pentamidine. If develops, discontinue therapy. When symptoms resolve, do not re-challenge with didanosine.
This drug is used only at a dose that alone has virtually no antiretroviral effect (that is why boosted protease combination – e.g. LPV/r - is considered “one” of the three drugs in a PI-based regimen). However, combined with other PI’s, it has a powerful effect on the other PI’s metabolism – boosting the other PI’s effect.
Whilst many side effects develop in the first few weeks on new medication, some do not emerge until the medication has been used over the longer term. As more information becomes available about the mechanisms that cause long-term side effects, it will be more possible to develop effective interventions to prevent and treat these side effects. Metabolism A general term for the breakdown of food and production of energy within the body. Sugar and fat are sources of energy. Abnormalities in sugar and fat levels or abnormalities in the processing of fats and sugars may indicate metabolic disorders and cause physical symptoms. Metabolic disorders Have caused the greatest concern in developed countries. A number of metabolic disorders have been reported among people taking anti-HIV therapy. These include hyperlipidemia (high levels of fat in the blood); diabetes, high blood sugar (hyperglycemia), and insulin resistance; and high levels of lactate (a by-product of sugar metabolism in the body); elevated ALT (a liver enzyme); and lipodystrophy (fat redistribution). Drug interactions: In addition, PIs are known to interact with multiple other medications. The role of the pharmacist is critical for recognizing and identifying and preventing potential drug interactions through dosage adjustment or preventing co-administration of contraindicated medications.
Pharmacists play a critical role in detecting drug interactions, before they happen. Pharmacists need to ask patients what other medications they are currently taking whenever dispensing a new medication to avoid potential interactions. Be aware that changing or discontinuing medications may result in altered drug levels and potential adverse outcomes.
Class antiretroviral drugs
Viruses have no cell wall and made up of nucleic acid
Viruses contain envelope – antigenic in nature
Viruses are obligate intracellular parasite
They do not have a metabolic machinery of their
own – uses host enzymes
Able to enter the cells infected with virus
Interfere with viral nucleic acid synthesis and/or regulation
Some drugs interfere with ability of virus to bind to cells
Some drugs stimulate the body’s immune system
Best responses to antiviral drugs are in patients with
competent immune systems
A healthy immune system works synergistically with the drug
to eliminate or suppress viral activity
When HIV infects a cell, reverse transcriptase copies
the viral single stranded RNA genome into a double-
stranded viral DNA.
The viral DNA is then integrated into the host
chromosomal DNA, which then allows host cellular
processes, such as transcription and translation to
reproduce the virus.
RTIs block reverse transcriptase's enzymatic
function and prevent completion of synthesis of the
double-stranded viral DNA, thus preventing HIV
Pigmentation of nail
Lactic acidosis, fatty
Dosing: 150mg BID or 300mg QD
Food Interactions: none
Toxicity: very rare
Component of all first-line regimens
Also active against Hepatitis B
Main disadvantage: rapid development of resistance
Dosing: 1 x 200mg capsule QD
Food Interactions: no food interactions
Mild abdominal discomfort
Emtricitabine is the fluorinated version of
Dosing: 1 x 300mg tablet BID
Food Interactions: no food interactions
Generally well tolerated
Occurs within first 6 weeks of therapy
Dosing: 1 x 300mg tablet QD
Food Interactions: None
Very well tolerated, side effects are minimal
Toxicity Renal insufficiency (rare)
Must dose adjust with renal failure
Also has activity against Hepatitis B
Dosed 300mg QD
Active against Lamivudine resistant HBV strains
HBV resistance 1% at 1 year
If TDF is stopped, may have HBV hepatitis flare
If taken withTDF must reduce ddI dose:
> 60 kg < 60 kg
250 mg/d 200 mg/d
Without dose adjustment – bluntedCD4
Lactic acidosis, fatty liver
PIs prevent viral replication by inhibiting the
activity of proteases
Protease inhibitors were the second class of
antiretro viral drugs developed.
Substantial GI intolerance prevents use at
full, original dose
Now used to boost other PIs
Doses < 400 mg/day – no anti-HIV activity
Nomenclature: /r (LPV/r, SQV/r)
Hard to make
Saquinavir was the first protease inhibitor
HIV protease is vital for both viral replication within
the cell and release of mature viral particles from an
infected cell. Saquinavir inhibits both HIV-1 and HIV-
Integrase inhibitors are a class of antiretoviral
designed to block the action of integraace, a
viral enzyme that inserts the viral genome
into the DNA of the host cell.
Raltegravir targets integrase, an HIV enzyme
that integrates the viral genetic material into
human chromosomes, a critical step in the
pathogenesis of HIV. The drug is metabolized
away via glucuronidation
Entry inhibitors, also known as fusion inhibitors
This class of drugs interferes with the binding, fusion
and entry of an HIV virion to a human cell. By
blocking this step in HIV’s replication cycle, such
agents slow the progression from HIV infection to
Maraviroc is an entry inhibitor. Specifically,
maraviroc is a CCR5 receptor antagonist, and binds
to the chemokine receptor CCR5 and blocks the HIV
gp120 (V3 loop) from associating with the receptor.
HIV is then unable to bind and enter human
Statins (simvistatin &
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