Antivirals and antiretrovirals Flashcards
Oseltamivir, Zanamivir
- Neuraminidase inhibitors - inhibit release of virus
- Effective against BOTH Type A and Type B Influenza
- Administered prior to exposure as prophylaxis
- Administered within 24 - 48h after infection drugs have modest effect on symptoms
PK
• Oseltamivir: orally active prodrug (hydrolyzed in liver)
• Zanamivir: NOT orally active (inhaled, intranasal)
SE
• Oseltamivir: GI discomfort, nausea (alleviated when taken with food)
• Zanamivir: airway irritation (avoid in severe asthma, COPD)
Amantadine, Rimantadine
- Ion channel blockers -> prevent viral uncoating
- EXCLUSIVELY ACTIVE ON INFLUENZA A VIRUS
- Equally effective in prophylaxis and treatment (70-90%)
- Since 2006 not recommended as first-line treatments due to resistance
2012-2013 Influenza Season
• Amantadine & rimantadine are NOT effective for the treatment or prevention of the currently circulating strains of influenza A.
- Block viral membrane protein, M2 (H+ channel)
- Channel is required for fusion of viral with cell membrane to endosome (requirement for viral uncoating)
PK
• Oral
• Amantadine is widely distributed & crosses BBB (Rimantadine is NOT), not extensively metabolized & excreted into urine where it may accumulate
• Rimantadine IS metabolized before elimination in urine
SE
• Amantadine: CNS (~10%) (insomnia, dizziness, ataxia leading to hallucinations, seizures)
• Rimantadine: fewer problems
• Both: GI intolerance
CI
• Amantadine should be monitored in psychiatric patients, cerebral atherosclerosis, renal impairment, epilepsy
• Pregnancy, nursing (FDA Category C)
- Up to 50% individuals are naturally resistant
- Cross-resistance between drugs occurs
Ribavirin
- Synthetic guanosine analog
- Active against broad spectrum of RNA & DNA viruses (eg, RSV, HCV, Lassa fever)
- Commonly used in combination with interferon a for the treatment of HCV
- Converted to ribavirin-triphosphate which inhibits guanosine triphosphate formation and prevents viral mRNA capping.
- Inhibits RNA-dependent RNA polymerase resulting in inhibition of viral protein synthesis
PK
• Oral, IV, & aerosolized
• Distribution significantly prolonged in RBC (16-40 days)
SE
• Dose-dependent transient anemia (can bind to RBC)
• GI (nausea, anorexia)
• CNS (fatigue, headache, insomnia)
CI
• Pregnancy (FDA Category X)
• Negative pregnancy tests required before treatment and monthly during treatment of female patients or female partners of male patients
Interferon a
• a and B produced by many cell types, y by immune cells (T cells)
- Use innate immune response.
- DO NOT target viral gene products directly
- Inhibit RNA & DNA synthesis by activating / inducing protein expression that inhibit virus infection eg, PKR
- Cellular uptake and metabolism by liver & kidney
- Usually pegylated to improve PK profile
SE
• Flu-like (fever, chills, myalgias & GI disturbances)
• Fatigue & mental depression
- Interferes with hepatic drug metabolism. Can cause toxic accumulation of theophylline.
- May potentiate zidovudine induced myelosuppression
Tx
• HCV (in combination with ribavirin)
• HBV, condyloma acuminata, hairy-cell leukemia, Kaposi’s sarcoma
Lamivudine, Entecavir
- Nucleoside/nucleotide analogs. Must be phosphorylated by cellular enzymes to triphosphate (active) form
- Actions are suppressive rather than curative
LAMIVUDINE
• Effective against hepatitis B and HIV
• Triphosphate form inhibits HBV and HIV reverse transcriptase
• Monophosphate form is incorporated into DNA (by HBV polymerase) resulting in chain termination
• Well tolerated (headache, dizziness, GI complaints)
ENTECAVIR
• Effective against lamivudine-resistant strains of HBV & HIV
• Phosphorylated form competes with natural substrates for viral polymerase.
• Subsequent inhibition of polymerase blocks reverse transcriptase activity
• Renal function must be assessed and drugs with renal toxicity avoided
• Monitor after discontinuation in case of exacerbation of severe hepatitis
Boceprevir, Telaprevir
- Used in the treatment of HCV in adult patients who have been previously untreated or failed treatment with interferon a and ribavirin
- Administered in combination with interferon a and ribavirin
• Bind reversibly to nonstructural protein 3 (NS3) serine protease and inhibit replication of HCV
SE • fatigue • anemia • nausea • headache • dysgeusia
Acyclovir
- Prototypic antiherpetic therapeutic agent
- Activity against: herpes simplex virus (HSV) Types 1 and 2, varicella-zoster virus (VZV) & some Epstein- Barr (HSV4) infections
- TREATMENT OF CHOICE IN HSV ENCEPHALITIS
- Commonly used for genital herpes infections & prophylactically in immunocompromised and transplant patients
- CMV is resistant at clinically achievable levels (does not encode thymidine kinase)
- Valacyclovir = prodrug of acyclovir
- Requires 3 phosphorylation steps for activation
- Monophosphorylated by herpes virus-encoded enzyme (thymidine kinase)
- Host cell enzymes complete phosphorylation to di- and triphosphate forms
- Competes with dGTP; once incorporated into DNA causes chain termination & inhibition of viral DNA polymerase
Acyclovir resistance, PK
• Resistance is rare in immunocompetent host
• Cross resistance to other ‘cyclovirs’ does occur
Occurs by:
• Altered or deficient thymidine kinases
• Altered viral DNA polymerase with decreased affinity for acyclovir
PK
• IV, oral or topical
• Valacyclovir has greater oral bioavailability than acyclovir
• Partially metabolized thus can accumulate with renal failure
SE
Depends on route of admin. eg,
• topical = local irritation
• oral = headache, diarrhea, nausea & vomiting
• IV = acute renal failure. Risk can be minimized by slow infusion and prior hydration of patient
Ganciclovir
- Valganciclovir = pro-drug with greater oral bioavailability
- Analog of acyclovir (8-20 x activity against CMV)
- Drug of choice for CMV retinitis & CMV prophylaxis in immunocompromised
- Phosphorylated by viral (UL97) and cell kinases
- DNA chain terminator & DNA polymerase inhibitor
RESISTANCE
• Reduced intracellular phosphorylation
• Mutations in phosphotranferase (UL97), or viral DNA polymerase
PK
• Ganciclovir (IV)
• Valganciclovir (oral) undergoes rapid hydrolysis in intestine & liver to ganciclovir
• Excretion via urine
SE
• Myelosuppression
• Severe dose-dependent neutropenia
CI
• Pregnancy (FDA Category C)
Cidofovir
- Major use is treatment of CMV-induced retinitis in HIV/AIDS
- Not phosphorylated by viral kinases
- Requires activation by host cell kinases
- Effective against HSV & ganciclovir resistant HSV
• DNA chain terminator & DNA polymerase inhibitor
RESISTANCE
• Mutations in viral DNA polymerase
PK
• IV, intravitreal & topical
• Must be co-administered with probenecid (blocks renal tubular secretion)
SE
• Nephrotoxicity
Penciclovir
- Active against HSV-1, 2 and VZV
- Used for the topical treatment of HSV (cold sores)
- Monophosphorylated by viral thymidine kinase
- Further phosphorylation occurs to give active triphosphate form
- Inhibit HSV DNA polymerase / chain terminator
RESISTANCE
• Low occurrence clinically
PK
• Topical only
SE
• Dermatologic: mild erythema
Trifluridine
• Effective against HSV-1, 2, and vaccina virus
• Drug of choice for HSV keratoconjunctivitis and
recurrent epithelial keratitis
• Triphosphate form incorporated into viral DNA causing fragmentation
PK
• Ophthalmic ointment (too toxic for systemic)
• t1/2 = ~12 min (apply frequently)
SE
• Transient irritation of eye & palpebral (eyelid) edema
Foscarnet
- Organic analog of inorganic pyrophosphate
- DOES NOT require phosphorylation!!
- Used for CMV retinitis in immunocompromised patients, acyclovir-resistant HSV & CMV retinitis & ganciclovir-resistant CMV & VZV
• Structural analog of the anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases
RESISTANCE
• Point mutations in polymerase
PK
• IV only
SE
• Nephrotoxicity
• Electrolyte disturbances (Ca2+, Mg2+, K+, PO43-)
• Anemia,
• Genital ulceration (mainly men)
• CNS: hallucinations, seizures, headache (25%)
NRTIs
• Analogs of native ribosides (lack 3’OH)
• Phosphorylated by cellular enzymes and incorporated into viral DNA by reverse transcriptase
• Lack of 3’OH terminates DNA elongation
ie. they are competitive inhibitors of reverse transcriptase
• Most have activity against HIV-2 as well as HIV-1
RESISTANCE
• Emerges rapidly if used alone
• Most common mutation at viral codon 184: lamivudine (restores sensitivity to zidovudine & tenofovir)
• Cross-resistance between agents of same analog class can occur
PK
• Dosage adjustments required with renal insufficiency
SE
• If more than one NRTI given toxicities may overlap
• AE mainly due to inhibition of mitochondrial DNA polymerase: peripheral neuropathy, myopathy, lipoatrophy & lactic acidosis
• Pancreatitis, myelosuppression & cardiomyopathy can also occur
• Liver toxicity is rare but fatal (lactic acidosis, hepatomegaly with steatosis).
• Zidovudine & stavudine may be particularly associated with dyslipidemia & insulin resistance
DRUG INTERACTIONS
Didanosine & tenofovir
• Tenofovir increases plasma didanosine levels ~60%.
• Doses of didanosine have to be reduced.
• NRTIs are not generally metabolized by cytochrome enzymes
Zidovudine (ZDV, AZT)
- Thymidine analog. Oral
- Penetrates well across BBB
- Dosage adjustments required in patients with cirrhosis
SE
• Bone marrow suppression (neutropenia, anemia)
• GI intolerance, headaches, insomnia
CI
• Toxicity potentiated by coadmin. of probenecid, acetaminophen, lorazepam, indomethacin & cimetidine.
• Stavudine & ribavirin activated by same pathways (might reduce active levels of zidovudine)
Stavudine (d4T)
• Thymidine analog. Strong inhibitor of B and y DNA polymerases (high affinity for mitochondrial DNA polymerase, which can lead to toxicity)
PK
• Oral
• Dosage adjustment required in renal insufficiency
SE
• Peripheral neuropathy, lactic acidosis
• Hyperlipidemia, neuromuscular weakness
Didanosine (DDL)
• Adenosine analog
PK
• Absorption best if taken in fasting state (acid labile) or combined with antacid
• Penetrates into CSF
• Dosage adjustment required in renal insufficiency
SE
• High affinity for mitochondrial DNA polymerase
• Pancreatitis (esp. alcoholics and patients with hypertriglyceridemia)
• Peripheral neuropathy, diarrhea, hepatic dysfunction
• CNS effects
Tenofovir (TDF)
• Adenosine analog. One of preferred NRTIs in currently recommended regimens
Fixed-Dose Combinations Available
• Tenofovir + emtricitabine
• Tenofovir + emtricitabine + efavirenz
PK
• Should be taken with food to increase bioavailability
• Long t1/2 (can dose once daily)
SE
• GI (nausea, diarrhea, vomiting, flatulence)
CI
• Serum creatinine monitored with renal insufficiency
• Only NRTI with sig. drug interactions (increases didanosine concentrations and dosage reductions are usually required)
• Decreases concentrations of atazanavir. Atazanavir can be ‘boosted’ with ritonavir
Lamivudine (3TC)
- Cytosine analog. DOES NOT affect mitochondrial DNA synthesis or bone marrow precursor cells
- High level resistance occurs with single amino acid substitutions
PK
• Dosage adjustment required with renal insufficiency
SE
• Few significant (headache, dry mouth)
Emtricitabine (FTC)
- Cytosine analog. Structural relative of lamivudine
- One of preferred NRTIs in currently recommended regimens
PK
• Once-a-day administration
SE
• Hyperpigmentation of palms and soles (occurs most frequently in dark-skinned people)
Abacavir (ABC)
• Guanosine analog. HIV resistance requires several mutations and tends to develop slowly.
SE
• GI, headache, dizziness
• 5% - ‘hypersensitivity’ reaction (one or more of rash, GI, malaise, respiratory distress).
• Sensitized individuals should NEVER be rechallenged (can be genetically screened)
NNRTIs
- Highly selective, noncompetitive inhibitors of HIV-1 RT
- Bind at a distinct site away from active site (NNRTI pocket)
- All NNRTI’s bind within the same pocket
- All result in inhibition of RNA- and DNA-dependent DNA polymerase
- DO NOT REQUIRE PHOSPHORYLATION BY CELLULAR ENZYMES
- Lack in vitro activity against HIV-2
ADVANTAGES
• Lack of effect on host blood-forming elements
• Lack of cross resistance with NRTIs (binding sites are distinct)
DISADVANTAGES
• Cross-resistance with NNRTIs
• Drug Interactions
• High incidence of hypersensitivity reactions (eg, rash)
SEs
• Skin rash (including Stevens-Johnson syndrome)
• GI intolerance
• All are CYP3A4 substrates and can act as inducers, inhibitors or both of CYPs
Nevirapine (NVP)
PK
• Excreted mainly in urine as metabolites (CYP 3A4 & CYP 2B6)
SE
• Potential severe hepatotoxicity (don’t use in women with CD4+ counts >250 cells/mm3 & men >400 cells/mm3)
• Rash (16%), dermatologic effects (Stevens-Johnson syndrome & toxic epidermal necrolysis)
• 14 day titration period at 1⁄2 dose is mandatory to reduce risk of serious epidermal reactions
CI
• Inducer of CYP 3A4
• Increases metabolism of PI’s (no dosage adjustment necessary), oral contraceptives, ketoconazole, methadone, metronidazole, quinidine, theophylline & warfarin
RESISTANCE
• Target site of nevirapine is HIV-1 specific & not essential to enzyme (reverse transcriptase), thus mutations and resistance can develop rapidly
Delavirdine (DLV)
• Not as widely used as other NNRTIs due to short t1/2
PK
• Well absorbed orally (especially at pH <2; antacids, H2 blockers etc may decrease absorption)
• Excreted mainly in urine as metabolites (CYP 3A4 & 2D6)
• Non-linear PK (t1/2 increases with increasing doses)
SE
• Rash (18-36%), Stevens-Johnson syndrome & toxic epidermal necrolysis
• Fever, headache & depression also common • Teratogenic
CI
• Inhibitor of and substrate of CYP3A4
• CYP 3A4 inducers (eg, rifampin, phenytoin) may decrease delavirdine concentrations
• Pregnancy (Cat C)
RESISTANCE
• Target site of delavirdine is HIV-1 specific & not essential to enzyme (reverse transcriptase) therefore resistance develops rapidly
Etravirine (ETV)
- Approved for use in treatment-experienced patients
- May be effective against HIV strains resistant to first-generation NNRTIs
PK
• Metabolized by CYP 3A4, 2C9 and 2C19
• Metabolites have ~10% HIV activity of parent compound
SE
• Rash (normally resolves within 1-2 weeks), nausea, diarrhea
• Transaminase elevations (esp. in patients co-infected with hepatitis)
CI
• CYP 3A4 inducer
• CYP 2C9 and 2C19 inhibitor
• Some interactions are difficult to predict
Efavirenz (EFV)
- Preferred NNRTI on DHHS guidelines
- Results in increased CD4+ counts & decreased viral load
PK
• Oral
• t1/2 >40h (once-a-day dosing)
• Extensively metabolized to inactive products
SE
• Mostly CNS (50%) (dizziness, headache, vivid dreams, loss of concentration) – resolve after few weeks.
• Rash (25%)
CI
• Potent inducer of CYP P450 enzymes.
• Pregnancy (D) (can be used after 1st trimester if considered best choice)
Protease inhibitors (PIs)
- Reversible inhibitors of HIV aspartyl protease (enzyme responsible for cleavage of viral polyprotein into RT, protease & integrase)
- Protease inhibition prevents virus maturation & results in production of non-infectious virions
- DO NOT REQUIRE INTRACELLULAR ACTIVATION • Active against both HIV-1 and HIV-2
PK
• Poor oral bioavailability
• High-fat meals can increase (nelfinavir) or decrease (indinavir) bioavailability
• Substrates for CYP 3A4
• Substrates for P-glycoprotein pump
• Bound to plasma proteins (a1-acid glycoprotein which can increase in response to trauma & surgery)
SE
• Parathesias, nausea, vomiting, diarrhea
• Disturbances in lipid metabolism (diabetes,
hypertriglyceridemia, hypercholesterolemia)
• Chronic admin
Enfuvirtide (T-20)
• First approved drug that inhibits viral fusion
• Approved for use in treatment-experienced adults
with evidence of HIV replication
• No activity against HIV-2
- Structurally similar to gp41 (HIV protein mediates membrane fusion)
- Binds to gp41 subunit of the viral envelope glycoprotein, preventing ability of virion to fuse cell membrane
PK
• Parenteral admin. only
SE
• Injection-related (3% discontinue)
• Hypersensitivity reactions & eosinophilia rarely
• No drug interactions with other antiretrovirals have been noted
Maraviroc
- Binds specifically and selectively to CCR5 (one of two coreceptors necessary for entrance of HIV into CD4+ cells)
- Result in blocking HIV entry (only CCR5-tropic virus can be treated with maraviroc)
PK
• Metabolized by CYP 3A4 (reduce dose when given with PIs)
SE
• Well tolerated, risk of hepatotoxicity
INSTI - Raltegravir (RAL)
• In combination with other antiretrovirals, raltegravir is approved for treatment-experienced and treatment- naive patients with evidence of viral replication
- Binds integrase (enzyme essential to the replication of both HIV-1 and HIV-2)
- Leads to specific inhibition of the final step in integration of viral DNA into host cell DNA
PK
• Metabolism via UGT1A1-mediated glucuronidation
SE
• Well tolerated (nausea, headache, diarrhea)
• Can cause increases in creatine phosphokinase
DRUG INTERACTIONS
• Rifampin, tipranavir & efavirenz may decrease [raltegravir]
• PPI’s may increase [raltegraivr]
Recommendations for treatment-naive pts
NNRTI-based regimen
Efavirenz + tenofovir + emtricitabine
PI-based regimen
(1) Ritonavir-boosted atazanavir + tenofovir + emtricitabine
(2) Ritonavir-boosted darunavir + tenofovir + emtricitabine
INSTI-based regimen
Raltegravir + tenofovir + emtricitabine
Recommendations for pregnant pts
Ritonavir-boosted lopinavir (twice daily) + zidovudine/lamivudine
Recommendations for infant born to HIV+ mother
Zidovudine (start immediately after birth and administer for 6 weeks)
HIV prophylaxis following needle stick
Treat for 1 month after injury (best treated within 1-2 h of injury)
Less severe (solid needle and superficial injury_
• HIV positive: 2 NRTIs (eg, AZT + Lamivudine)
• HIV status unknown: Generally nothing – consider 2 drug treatment
More severe (large-bore hollow needle, deep puncture)
• HIV positive: 3-drugs (eg, 2 NRTIs + PI or NNRTI)
• HIV status unknown: Generally nothing – consider 2 drug treatment
HIV prophylactic vaccines
- Streptococcus pneumoniae
- Hepatitis A
- Hepatitis B and
- Influenza
Vaccines contraindicated in HIV+ pts w/CD4 count <200 cells
Live vaccines eg,
• MMR
• Varicella and
• Zoster
Other vaccines may be administered without regard to the patient’s CD4+
