Antivirals and Antiretrovirals Flashcards
Antivirals for treating HSV 1 and 2 and Varicella Zoster Virus
Systemic • Acyclovir - comes topically • Valacyclovir • Famciclovir Topical • Penciclovir; Docosanol • Trifluridine
Antivirals for treating CMV in immunosuppressant or transplant patients
Ganciclovir Valganciclovir Foscarnet Cidofovir Letermovir
Acyclovir
Oral, IV, topical - low bioavailability with wide distribution
If therapy is initiated during prodromal phase then healing time may be shortened
Causes inhitibition of Viral Thymidine Kinase - eventual stopping of viral DNA synthesis and chain termination
For Rx Hsv1/2, VZV requires higher dose because acyclovir is less potent against Vericella
What are the resistance mechanisms drugs have against antivirals for HSV and VZV?
mutations in viral thymidine kinase or viral DNA polymerase, absent or def. viral thymidine kinase or altered substrate specificty
There is low degree of resistance to Acyclovir / Valcyclovir; but resistant virus are cross-resistant to penciclovir
Valacyclovir
Oral prodrug - hydrolysis to acyiclivr bioavil 55% with wide distribution
therapy can shorten healing time of HSV or VZV infections
Inhibits Viral thymidine kinase -> inhibition of viral synthesis and chain termination
HSV-1, HSV-2, VZV - provides higher systemic levels of drug than acyclovir
Famciclovir
Oral prodrug or Penciclovir bioavailability ~75%
Initiate during prodromal stage ⇒ may shorten healing time, duration of pain, and period of viral shedding
Inhibits viral thymidine kinase - inhibits viral DNA synthesis and inserts self into DNA causing chain termination
RX – HSV-1, HSV-2, VZV, EBV, HBV
Acyclovir, Valacyclovir, Famciclovir Adverse Effects
In the Rx of HSV, VZV, CMV the drugs can cause adverse effect with high IV or oral doses — normally safe and well tolerated
cystalline nephropathy
CNS - delirium, seizures, tremors, EPS, myoclonus
thrombocytopenia
Topical Rx for HSV infection
frequent application
Acyclovir, penciclovir and docossanol all come in topical cream version
Trifluidine is for ophthalmic solutions in Rx of Primary keratoconjunctivitis and Recurrent epithelial keratitis
Ganciclovir
Valganciclovir is prodrug
deoxy-guanosine analog
Active against all herpes viruses but especially effective against CMV
preferrentially inhibits viral dna polymerases
uses - CMV retinitis, acute herpetic keritiits
valgan - oral for CMV retinitis and propholaxis of CMV infection
Ganciclovir / Valganciclovir - Toxicities and Contraindications
Toxicities include myelosuppression, (dose-limiting: Neutropenia, thrombocytopenia), Gi effects and CNS effects
Contraindication - teratogenic, embryotoxic, inhibits spermatogensis
Blocks renal tubular secretion
Foscarnet
pyrophosphate analog
given IV, treatment of CMV retinitis
Reversible noncompetitive block of pyrophosphate binding site of viral polymerase
AEs – nephrotoxicity is the major dose-limiting effect, hypocalcemia
mutatgenic so caution with pregnancy
Cidofovir
Cytidine Analog -
- Inhibits viral DNA synthesis,
- Incorporation into DNA causes chain termination
cross-resistance with ganciclovir
THERAPEUTIC USE – IV, Treatment of CMV retinitis
Cautions - can cause proximal tubule injury leading to metabolic acidosis – administer with probenecid and saline
probenecid inhibits OAT which slows the tubular secretion of the drug
embryotoxic, mutagenic, gonadotoxic
Letermovir
CMV DNA terminase complex
Given oral and IV, low bioavialbiltiy but greatly increases w/ cyclosporine
high plasma protein binding, Substrate of P-glycoprotein, OATP1B1/1B3, glucuronidation with fecal excretion
Letermovir blocks the pUL56 in CMV DNA terminase complex»_space;> eventual alteration in genome length
used for the prophylaxis of CMV infection and disease, given to adult seropositive recipents of allogeneic bone marrow transplant
Letermovir - Drug Interactions and Adverse Effects
CYP3A4, P-gp, OATP inhibitor
CYP2C9, 2C19 inducer
CONTRAINDICATED drug combinations • pimozide • ergot alkaloids • simvastatin • pitavistatin
Nausea, vomiting, diarrhea, abdominal pain, headache, fatigue, peripheral edema, tachycardia, decrease platelet count and hemoglogin
Standard of care for HIV infection
2 NRTIs + an INSTI, or an NNRTI, or a boosted PI
Outcome of initial therapy - undetectable viral load and a CD4 count increase of 50-150 cells in he first year
Name some general adverse effects on antiretroviral therapy?
Immune reconstitution inflammatory syndrome
lipodystrophy syndrome
drug interaction - with inhibitors or inducers of metabolic enzymes
What are the NRTI’s - Nucleoside/tide Reverse Transcriptase Inhibitors
activity against HIV-1 and HIV-2, some have activity against HBV
zidovudine (ZDV)* stavudine (d4T) zalcitabine (ddC) lamivudine (3TC)* emtricitabine (FTC)* abacavir (ABC)* didanosine (ddi) tenofovir (TFV)*
Viral Resistance to NRTIs - single amino acid substitution: M184V/I
lamivudine and emtricitabine
Mitochondrial Toxicity - antivirals
NRTIs - Zalcitabine, didanosine, stavudine, zidovudine
associated with DNA polymerase-γ inhibition
common effects - myopathy, lipoatrophy, hepatic steatosis and lactic acidosis
antiviral therapy should be discontinued when which mitochondrial toxic effects occur?
(NRTIs)
inc ALT/AST, progressive hepatomegaly, metabolic acidosis with unknown origin, peripheral neuropathy or pancreatitis
NRTI Drug Interactions
Renal OAT inhibition - causes decreased renal clearance of one or both drugs
-effects probenecid, acyclovor, other anti-herpes drugs, and anti-HBV drugs
mechanisms of DI’s through competition at active site and additive toxicities
why is zidovudine + stavudine a bad combination for antiviral drugs
they are both thymidine analogs which have antagonistic effects
why are the antiviral drugs Didanosine + Stavudine a bad combination?
fatal lactic acidosis
Didanosine + Zalcitabine = bad effects, why?
Additive peripheral neuropathy
Didanosine + Tenofovir — why are these drugs contraindicated?
They are both adenosine analogs that compete at the site of function and lead to virologic failure
Lamivudine + Zalcitadine = bad effects, why?
They are both cytidine analogs and are antagonist to each others efficacy - inhibit the intracellular phosphrylation of one another
Lamivudine + Emtricitabine —- contraindicated together for what reason?
they are analogs leading to enhanced toxicity
Zidovudine
NRTIs - Alternative agent for antiretroviral therapy - thymidine analog
HIV-1, HIV-2, and human T-cell lymphotrophic viruses (HTLV) I and II
Used IV for prevention of mother-to-child HIV transmission
exhibits mitochondrial toxicity
Lamivudine
NRTI - cytidine analog in antiretroviral: at a higher dose once daily dosing and lower doses twice daily dosing.
Used for HIV-1, HIV-2, HBV
Rebound HBV infection can happen in patients if lamivudine is d/c and replaced with a drug not also effective against HBV
Emtricitabine
NRTI - cytidine analog. Fluorinated version of lamivudine. Antiretroviral Rx
daily dose
used for HIV1, HIV2, HBV- supresses not approved for treatment of HBV
-rebound HBV infection when d/c
hyperpigmentation of palms or soles
Abacavir
antiretroviral treatment, NRTI- guanosine analog, used for both HIV-1 and HIV-2
Associated with a gene - HLA-B 5701 that causes hypersensitivity syndrome
metabolized by alcohol dehydrogenase - alcohol increases abacavir levels
Tenofovir
antiretroviral - NRTI, adenosine analog
used for HIV1 and HIV2, HBV
rebound HBV
fanconi syndrome and decreased bone marrow density
NNRTI’s - Non-nucleoside Reverse Transcriptase Inhibitors
highly effective HIV infection when used with 2 NRTIs
They bind to allosteric site on reverse transcriptase
Efavirenz* Nevirapine* Etraverine* Rilpivirine* Delavirdine
Viral Resistance to NNRTIs
Efavirenz, nevirapine, delavirdine, and rilpivirine
Resistance is seen to these drugs with a single point mutation in the HIV virus
Nervirapine can induce resistance with just a single dose
cross-resistance is seen K103N and Y181C
Etravirine - 2 mutation, cross resistance with rilpivirine
NNRTI Class Toxicities
antiretroviral drugs NNRTI toxicities are
rashes - usually in the first 4 weeks of treatment, usually mild and self-limited with rare SJS/TEN
long term use causes fat redistribution
Nevirapine - fatal hepatitis
NNRTI’s have high potential for drug interactions
Efavirenz
Antiretroviral, alternate with 2 NRTIs
tolerable and potent
displays CNS symptoms - impaired concentration, dysphoria, vivid or disturbing dreams, insomnia and psychosis
1teratogenic - causes neural tube and CNS defects
Efravirenz is a inducer of CYP2B6 and CYP3A4 and inhbitor of CYP2C9/19
Nevirapine
NNRTI, antiretroviral, used for initial therapy in HIV, salvage therapy and in neonates
adverse effect is hepatitis, considered safe during pregnancy
-risk factor is pregnant women with CD4 counts greater than 250 cells
Nevirapine is autometabolic inducer at CYP3A4, also induces CYP2B6
Rilpivirine
NNRTI, antiretroviral
HIV treatment in naive adults (ones who have not been treated yet)
virologic failure is common in patients with a high baseline plasma viral load
adverse effects - CNS effects, QT interval prolongation
no evidence of fetal harm in animal studies
substrate of CYP3A4
Etravirine
NNRTI, antiretroviral
Treatment in experienced HIV infected adults only
no evidence of harm during pregnancy
can be used in pediatric patients
Etravirine - inducer of CYP3A4 and UGTs (maraviroc dose should be doubled in concurrent therapy) and inhibitors of CYP2C9/19
NNRTI Drug Interactions
Efavirens/Nevirapine cannot be used with Tenofovir and Didanosine
Efravirenz is a inducer of CYP2B6 and CYP3A4 and inhbitor of CYP2C9/19
Nevirapine is autometabolic inducer at CYP3A4, also induces CYP2B6
Etravirine - inducer of CYP3A4 and UGTs (maraviroc dose should be doubled in concurrent therapy) and inhibitors of CYP2C9/19
Rilpivirine is a substrate of CYP3A4
HIV Protease Inhibitors
Activity against HIV-1 and HIV-2
subtrates of P-glycoprotein, cleared by CYP3A4
Fosamprenavir
Lopinavir-Ritonavir
Atazanavir
Darunavir
Prevent proteolytic cleavage of HIV gag and pol proteins
what is the purpose of ritonavir and cobicistat with protease inhibitors?
potent CYP3A4 / P-glycoprotein inhibitors
↑concentrations, ↑duration of action and improve virologic activity of the protease inhibitor
all PI’s are given with these except Nelfinavir
What are the mechanisms of resistance against PI’s?
acculmulation of at least 4 or 5 codon substitutions
primary mutations in enzymatic active site causes a 3 to 5x decreased sensitivity
Cross-resistance to other PIs due to 2° mutations
Effects Protease Inhibitors on HIV
Favorable long-term suppression of viremia
↑ CD4 lymphocyte counts
Reduce disease progression
Improve long-term survival
must be balanced against short- and long-term toxicities, including the risk of insulin resistance and lipodystrophy
HIV PIs Class Toxicities
Nausea, vomiting, diarrhea
Cushingoid appearance, e.g. central obesity, buffalo hump, Triglyceride and LDL increased levels, and hyperglycemia
skin rashes, SJS, TEN
Peripheral neuropathy, myalgia
Cardiac conduction abnormalities
Protease Inhibitor Drug Interactions
CYP3A4 inhibition → drugs with narrow TI, increase statin levels and muscle toxicity, increase digitoxin, decreased oral contraceptive efficacy and decreases methadone levels
Ritonavir
Pharmacokinetic enhancer (low doses) (antiretroviral effects at higher doses) • dose-dependent GI toxicities • Paresthesias, metabolic toxicities
adverse effects - paresthesia, asthenia, hepatitis, PR interval prolongation
Fosamprenavir
Prodrug, protease inhibitor
dephosphorylated to amprenavir in the intestinal mucosa, better tolerated than amprenavir
GI effects common
fatigue, depression, rash
Lopinavir/r
protease inhibitor
adverse effects - GI and metabolic effects are common, cardiotoxicity, lactic acidosis, CNS depression, respiratory complications, acute renal failure and death
toxic to neonates
Atazanavir
protease inhibitor, formulated with cobicstat
Lowest pill burden of PIs (once daily)
Can cause unconjugated bilirubinemia through UGT inhibition
Also causes pancreatitis, asthenia, increase in transaminases, PR or QT prolongation
interacts with tenofovir increases the levels, and PPIs and H2 inhibitors
Darunavir
protease inhibitor, formulated with cobicstat
Use: Treatment-naïve and treatment-experienced patients
has sulfonamide moiety - rash in up to 10% of patients
Causes hepatitis and elevations in serum transaminases
HIV Integrase Strand Transfer Inhibitors
Raltegravir
Elvitegravir / cobicistat
Dolutegravir
Bictegravir
Activity against HIV-1 and HIV-2
block HIV-encoded integrase prevents integration of virus DNA into the host chromosome
Raltegravir
used in treatment-naive and experienced patients, safe in children
Metabolized UGT1A1 and excreted in the feces and urine, taken orally
Resistance is through integrase gene mutations
well tolerated but adverse effects possible are myopathy and hypersensitivity reactions
Entry Inhibitors
Enfuvirtide
Maraviroc
Ibalizumab-uiyk
Enfuvirtide - MOA and Uses
Entry Inhibitors - Synthetic peptide, binds to a hydrophobic groove of the gp41 subunit
SubQ; Metabolized by proteolytic hydrolysis
Treatment-experienced: Adults and children ≥ 6 years old, not effective as monotherapy - needs to be given with 2 other antiretroviral drugs
Enfuvirtide - Adverse Effects and Resistance
Injection site reactions; Hypersensitivity reactions, and Pneumonia
resistance - mutations in the codon which binds domain gp41, increased with more changes
Maraviroc
HIV Entry Inhibitor
oral, variable bioavailability, CYP3A4, fecal and urine excretion
Mechanism: Maraviroc blocks gp120 to CCR5 receptor
resistance through changing tropism to CXCR4
Used for CCR5 HIV virus infected patients older than 16, in combination with other agents
Prior to therapy, tropism testing should be performed
Maraviroc Cautions
Adverse effects: • Dizziness; depression; paresthesias • Hepatotoxicity with allergic features • Hypersensitivity reaction • Orthostatic hypotension • Bacterial respiratory infection / Herpes
Drug interactions:
• Strong CYP3A4 inducers and inhibitors
Ibalizumab-uiyk
HIV Entry Inhibitor
IV every 14 days, blocks CD4 2nd extracellular domain away from MHC2
prevents HIV attachment and entrance
preserves normal immune function
Used for therapeutic experienced patients
