Antiviral therapy

willis

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 Acyclovir -HSV-1, HSV-2, and VZV.
• Clearance
• Pharmacokinetics - acyclovir – Glomerular filtration
• Absorption – Tubular secretion.
– oral acyclovir ---- 15–20% bioavailability – Readily cleared by hemodialysis but not peritoneal
dialysis
– unaffected by food.
– An intravenous formulation is available.  
• T1/2
– 3 hours--- normal renal function
• Distribution
– 20 hours in patients with anuria
– Topical formulations --- high concentrations in
herpetic lesions
– systemic concentrations are undetectable by this route. • Clinical indications
– diffuses readily into most tissues and body fluids - Herpes genitalis
– Cerebrospinal fluid concentrations are 50% of serum - Herpes labialis
values - Prophylaxis in organ transplantation

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 Antiretroviral agents
• administration of highly active antiretroviral therapy (HAART),
typically comprising a combination of 3–4 antiretroviral agents,
has become the standard of care.

• Such regimens may be composed of

– nucleoside reverse transcriptase inhibitors, NRTIs
– nonnucleoside reverse transcriptase inhibitors, NRTIS
– protease inhibitors
– fusion inhibitors
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 Drug interactions
• rifampin--- potent 3A4 inducer, may
– either decrease efficacy (eg, atazanavir, lopinavir) or increase toxicity
(eg, saquinavir) of concurrent antiretroviral agents,
– when co-administered with ritonavir, may markedly increase toxicity.

• Decreased levels of clarithromycin with efavirenz may reduce

antibacterial efficacy.

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 Nucleoside & Nucleotide Reverse Transcriptase Inhibitors- NRTIs
• competitive inhibition of HIV-1 reverse transcriptase

• incorporated into the growing viral DNA chain to cause termination.

• intracytoplasmic phosphorylation by cellular enzymes to the triphosphate form.

• Most have activity against HIV-2 as well as HIV-1

• mitochondrial toxicity
• risk of lactic acidosis with hepatic steatosis
• disorders of lipid metabolism.
• Stopped  rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of
unknown cause.

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 • metabolism of the NNRTI and PI agents by the
CYP450 enzyme system, primarily the 3A4 isoform.

• Rifampin, potent 3A4 inducers, may either decrease

efficacy (eg, atazanavir, lopinavir) or increase
toxicity (eg, saquinavir) of concurrent antiretroviral
agents, owing to alteration of serum levels

• these types of interactions have been used to

advantage in the form of dual protease inhibitor
regimens (boosted regimens), based on resultant
increased plasma concentrations of the substrate (eg,
lopinavir, saquinavir) when co-administered with an
inducer (most often ritonavir).

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 NRTIS

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 Nucleoside and nucleotide reverse transcriptase inhibitors
• associated with
• competitive inhibition of HIV-1 reverse
– mitochondrial toxicity -- inhibition of
transcriptase mitochondrial DNA polymerase gamma
– risk of lactic acidosis with hepatic steatosis
• incorporated into the growing viral – disorders of lipid metabolism.
DNA chain to cause termination
• NRTI treatment should be suspended in the
setting of
• Each requires intracytoplasmic – rapidly rising aminotransferase levels,
activation via phosphorylation by – progressive hepatomegaly
cellular enzymes to the triphosphate – metabolic acidosis of unknown cause.
form

• activity against HIV-2 and HIV-1.

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 1. abacavir • Symptoms, which generally occur within the
first 6 weeks of therapy, include
• guanosine analog. well absorbed following oral – fever, malaise, nausea, vomiting, diarrhea,
administration (83%). unaffected by food. and anorexia.
– Respiratory symptoms-- dyspnea,
• elimination half-life is 1.5 hours
• intracellular half-life ranges from 12 to 26 hours pharyngitis, cough
• Cerebrospinal fluid levels 1/3 plasma. – skin rash
– Laboratory abnormalities-- mildly elevated
• High-level resistance to abacavir appears to require at least serum aminotransferase or creatine kinase
two or three concomitant mutations (eg, M184V, L74V,
D67N) and thus tends to develop slowly.
levels.
– Although the syndrome tends to resolve
• The K65R mutation is associated with reduced quickly with discontinuation of medication,
susceptibility to lamivudine, abacavir, tenofovir, and rechallenge with abacavir results in return
emtricitabine of symptoms within hours and may be
fatal.
• Hypersensitivity reactions, occasionally fatal, have been
reported in approximately 5% of patients receiving
abacavir.

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 didanosine
• Dosage reduction is therefore required for low
• synthetic analog of deoxyadenosine
creatinine clearance and for low body weight

• Oral bioavailability -- 30–40% • Resistance to didanosine is typically associated with

the L74V mutation
• empty stomach is required
• major clinical toxicity --- dose-dependent
• CSF concentrations --- 20% of serum concentrations pancreatitis

• elimination half-life is 1.5 hours • Other risk factors for pancreatitis

– alcoholism, hypertriglyceridemia -- relative
• intracellular half-life of the activated compound is contraindications to didanosine therapy
20–24 hours
– drugs with the potential to cause pancreatitis ---
• eliminated by glomerular filtration and tubular secretion
zalcitabine and stavudine, should be avoided

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 emricitabine
• fluorinated analog of lamivudine • Also, because of its in vitro activity against HBV, patients
• long intracellular half-life (> 39 hours), allowing for once- co-infected with HIV and HBV should be closely
daily dosing. monitored if treatment with emtricitabine is interrupted or
discontinued, owing to the likelihood of hepatitis flares.
• Oral bioavailability of the capsules is 93% and is
unaffected by food, but penetration into the cerebrospinal • cross-resistance to lamivudine but not to other NRTI
fluid is low. agents.
• Elimination is by both glomerular filtration and active • Because of their similar mechanisms of action and
tubular secretion. resistance profiles, the combination of lamivudine and
emtricitabine is not recommended.
• The mean plasma elimination half-life is 8–9 hours.
• most common adverse effects --- headache, diarrhea,
nausea, and asthenia.
• The oral solution, which contains propylene glycol, is
contraindicated in
• hyperpigmentation of the palms and/or soles may be
– young children, observed
– pregnant women,
• No drug-drug interactions
– patients with renal or hepatic failure,
– using metronidazole or disulfiram.
•  
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 lamivudine
• cytosine analog
• in vitro activity against HIV-1 that is synergistic with a • Potential adverse effects are headache, insomnia, fatigue,
variety of antiretroviral nucleoside analogs—including and gastrointestinal discomfort, although these are typically
zidovudine and stavudine—against both zidovudine- mild.
sensitive and zidovudine-resistant HIV-1 strains.
• Lamivudine's bioavailability increases when it is co-
• Oral bioavailability exceeds 80% and is not food- administered with trimethoprim-sulfamethoxazole.
dependent.
• cerebrospinal fluid:plasma ratio --- 0.2. • Lamivudine and zalcitabine may inhibit the intracellular
phosphorylation of one another in vitro, thus decreasing
• intracellular half-life of the active 5'-triphosphate potency; therefore, their concurrent use should be avoided
metabolite in HIV-1-infected cell lines is 10.5–15.5 hours. if possible.

• The majority of lamivudine is eliminated unchanged in the

urine, and the dose should be reduced in patients with renal
insufficiency or low body weight

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 stavudine
• major dose-limiting toxicity
• thymidine analog – dose-related peripheral sensory neuropathy

• oral bioavailability (86%) that is not food-dependent

– Increased when stavudine is administered with other
• plasma half-life is 1.2 hours neuropathy-inducing drugs such as didanosine and
zalcitabine
• intracellular half-life is 3.5 hours
– resolve completely upon discontinuation of stavudine
• mean CSF concentrations are 55% of those of plasma.
• co-administration of stavudine and didanosine may
• Excretion is by active tubular secretion and glomerular increase the incidence of lactic acidosis and pancreatitis,
filtration concurrent use should be avoided

• dosage reduced in patients with renal insufficiency and low • zidovudine may reduce the phosphorylation of stavudine,
body weight these two drugs should generally not be used together.

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 tenofovir
• acyclic nucleotide analog of adenosine • Gastrointestinal complaints (eg, nausea, diarrhea,
• competitively inhibits HIV reverse transcriptase and causes vomiting, flatulence) are the most common side
chain termination after incorporation into DNA. effects
 
• Tenofovir disopoxilfumarate is a water-soluble prodrug of • Other adverse effects -- headache and asthenia
active tenofovir
• oral bioavailability in fasted patients is approximately 25%
and increases to 39% after a high-fat meal • acute renal failure and Fanconi's syndrome,
tenofovir.
• Serum half-life is 17 hours
• intracellular half-life is prolonged at more than 60 hours. • Tenofovir may compete with other drugs that are
  actively secreted by the kidneys, such as cidofovir,
• Elimination by glomerular filtration and active tubular acyclovir, and ganciclovir.
secretion
• dosage must be adjusted in patients with renal
insufficiency.
• The combination of tenofovir with didanosine is
associated with both decreased virologic efficacy
and increased toxicity (due to increased didanosine
levels) and therefore should be avoided.
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 zalcitabine
• oral and esophageal ulcerations.
• cytosine analog
• high oral bioavailability (> 80%)
• Pancreatitis occurs less frequently than with didanosine
• long intracellular half-life (10 hours) despite its elimination half- administration, but co-administration of other drugs that
life of 1–2 hours cause pancreatitis may increase the frequency of this
• plasma levels decrease by 25–39% when the drug is administered adverse effect.
with food or antacids
• Headache, nausea, rash, and arthralgias may occur but tend
• Cerebrospinal fluid concentrations are approximately 20% of those to be mild or resolve during therapy.
in the plasma
 
• dose-dependent peripheral neuropathy ---reversible if treatment is
stopped promptly. • The AUC of zalcitabine increases when co-administered
with probenecid or cimetidine, and bioavailability
• potential for causing peripheral neuropathy constitutes a relative decreases with concurrent antacids or metoclopramide.
contraindication to use with other drugs that may cause this
toxicity, including stavudine, didanosine, and isoniazid. • Lamivudine inhibits the phosphorylation of zalcitabine in
• Decreased renal clearance caused by amphotericin B, foscarnet, vitro, potentially interfering with its efficacy.
and aminoglycosides may increase the risk of zalcitabine
neuropathy.  

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 zidovudine
• Deoxythymidine analog • In pregnancy, a regimen of oral zidovudine beginning between 14
• well absorbed from the gut and distributed to most body tissues and and 34 weeks of gestation (100 mg five times a day), intravenous
fluids, including the cerebrospinal fluid, where drug levels are 60– zidovudine during labor (2 mg/kg over 1 hour, then 1 mg/kg/h by
65% of those in serum. continuous infusion), and zidovudine syrup to the neonate from
•   birth through 6 weeks of age (2 mg/kg every 6 hours) has been
shown to reduce the rate of vertical (mother-to-newborn)
• serum half-life averages 1 hour
transmission of HIV by up to 23%.
• intracellular half-life of the phosphorylated compound is 3–7 hours • most common adverse effect of zidovudine is myelosuppression,
•   resulting in macrocytic anemia (1–4%) or neutropenia (2–8%).
• Zidovudine is eliminated primarily by renal excretion following • Gastrointestinal intolerance, headaches, and insomnia may
glucuronidation in the liver. occur but tend to resolve during therapy.
• Clearance of zidovudine is reduced by approximately 50% in • Less frequent toxicities include thrombocytopenia,
uremic patients, and toxicity may increase in patients with hyperpigmentation of the nails, and myopathy.
advanced hepatic insufficiency.
•  
• decrease the rate of clinical disease progression and prolong
survival in HIV-infected individuals.
• treatment of HIV-associated dementia and thrombocytopenia
•  

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 zidovudine
• Very high doses can cause anxiety, confusion, and tremulousness.
 
• Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin, methadone, fluconazole, atovaquone,
valproic acid, and lamivudine, either through inhibition of first-pass metabolism or through decreased clearance.

• Zidovudine may decrease phenytoin levels, and this warrants monitoring of serum phenytoin levels in epileptic patients taking both agents.

• Hematologic toxicity may be increased during co-administration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic
agents.

• Combination regimens containing zidovudine and stavudine should be avoided; antagonism has been demonstrated in vitro.

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