Antivirals Flashcards
Cidofovir
CYTOSINE ANALOGUE
MOA: Cidofovir is converted to cidofovir triphosphate (the active intracellular metabolite); cidofovir diphosphate suppresses CMV replication by selective inhibition of viral DNA synthesis. Incorporation of cidofovir diphosphate into growing viral DNA chain results in viral DNA synthesis rate reduction
Doses:
CMV: 5 mg/kg/dose once weekly for 2 consecutive weeks, with concomitant probenecid (Ref).
Maintenance: 5 mg/kg/dose once every 2 weeks with concomitant probenecid
Adeno: IV: 5 mg/kg/dose once weekly
Resistant HSV: Mucosal infections: 5 mg/kg/dose once weekly for 3 weeks (Ref), then 5 mg/kg/dose once every 2 weeks for 3 doses (Ref); with concomitant probenecid
Orthopox: Use in combination with tecovirimat; only use as monotherapy in patients who have a contraindication to tecovirimat use (Ref).
IV: Limited data available: 5 mg/kg once weekly for 2 doses, with concomitant probenecid
Ribavirin
PURINE ANALOGUE
3 mechanisms: SEE IMAGE
- RBV monophosphate - INPDH inhibition and GTP depletion
- Triphosphate - chain termination
- Immune modulation and synergy with IF alpha
Ribavirin specifically binds to the substrate-binding site (inhibits) of the IMPDH enzyme leading to the decreased synthesis and lower levels of GTP
Moderately Synergistic with Alpha Interferon.
- RSV
- Paraflu
- Hanta
- Nipah
- HEPE
- HBV + HCV
- Lassa
Side effect: Haemolytic anaemia & teratogenesis. Contraception for 4 months in women & 7 months in men. Routine pregnancy testing monthly.
Aciclovir & Valaciclovir
Converted by viral thymidine kinase to aciclovir monophosphate which is then converted by host cells kinase to aciclovir triphosphate.
aciclovir triphosphate competitively inhibits the DNA polymerase.
Aciclovir monophosphate also incorporated into viral DNA and causes chain termination.
Poor bioavailability: 15 to 30%
Valaciclovir is an esterified aciclovir with better bioavailability- 55%. Converted by esterases to aciclovir and valine in hepatic first pass metabolism.
ADRs: Nephrotoxicity - crystal precipitation, encephalopathy
Dosing:
HSV encephalitis: 10mg/kg TDS 14-21 days
VZV PEP - 800mg 4 times a day x 7 days
Zoster - 800mg 5 times x 7 days
aciclovir & CMMG levels
patients with renal failure and/or on ECMO, in cases of suspected neurotoxicity, or suspected poor absorption and in some patients receiving valaciclovir.
For aciclovir monitoring, we recommend a pre dose sample and a post dose sample, taken either 1 hour after the end of iv administration or 2 hours after oral administration.
For CMMG monitoring, we require a pre dose sample only.
Ref: CMMG pre-dose <2.6mg/L
Acivlovir: Based on dosing regimen
Tecovirimat
Tecovirimat - inhibits viral envelope protein p37 highly conserved in all orthopox viruses. Prevents formation and egress of virions.
No published trial data - given authorisation under ‘exceptional circumstances’
Ongoing RCT - PLATINUM. Various observational trials show benefit.
Eligibility:
Confirmed Mpox &
Symptomatic &
Meeting criteria for severe disease - ocular, pain, critical illness, >100 lesions, CNS disease etc
Dosing:
600mg BD for 2 weeks
Resistance: F13 protein mutations - T289A mutation resulted in 8 fold increase in 50% effective concentration.
Foscarnet
Foscarnet blocks the pyrophosphate binding site, preventing cleavage of pyrophosphate from dNTPs. Viral DNA polymerase is inhibited at foscarnet concentrations 100-fold lower than those required to inhibit cellular DNA polymerase.
UL54 Polymers gene
CMV: Initially 60 mg/kg every 8 hours for 2–3 weeks, alternatively initially 90 mg/kg every 12 hours for 2–3 weeks, then maintenance 60 mg/kg daily, then increased if tolerated to 90–120 mg/kg daily, if disease progresses on maintenance dose, repeat induction regimen.
HSV: 40 mg/kg every 8 hours for 2–3 weeks or until lesions heal.
Pretelivir
Pretelivir - Pritelivir targets the helicase primase complex, which is a novel and unique target. It needs no activation by TK and thus is active against TK-resistant strains, but resistance can be selected for in culture and maps to single mutations in UL5 helicase or UL52 primase.
Used in HSV
Amenamavir
Helicase primase inhibitor
Same as pretelivir
Used in HSV & VZV
Baloxavir
Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease; it blocks influenza proliferation by inhibiting the initiation of mRNA synthesis [78]. Baloxavir has activity against influenza A viruses, including H7N9 and H5N1 viruses, and influenza B viruses [78]. It has activity against influenza viruses that are resistant to oseltamivir and it appears to have synergistic activity with neuraminidase inhibitors.
PA138T - Resistance mutation
Ganciclovir & valganciclovir
Ganciclovir is an acyclic analog of the nucleoside guanosine. The drug is converted intracellularly to ganciclovir 5’-monophosphate by a viral kinase, which is encoded by the CMV gene UL97 during infection.
Subsequently, cellular kinases catalyze the formation of ganciclovir diphosphate and ganciclovir triphosphate, which is present in 10-fold greater concentrations in CMV or HSV-infected cells than uninfected cells.
Ganciclovir triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases.
In addition, ganciclovir triphosphate serves as a poor substrate for chain elongation, thereby disrupting viral DNA synthesis by a second route
Mutations in the UL97-encoded CMV phosphotransferase have been associated with resistance [9], as have alterations in UL54-encoded viral DNA polymerase
Valganciclovir, an L-valyl ester of ganciclovir, is well absorbed after oral administration and rapidly hydrolyzed to ganciclovir in the intestinal wall and liver.
60% bioavailability.
DOSING:
induction therapy: 5 mg/kg every 12 hours, followed by 5 mg/kg as a single daily infusion for maintenance therapy for 14 to 21 days.
Valgan: 900 mg BD during induction therapy followed by 900 mg OD during maintenance therapy
Molnupiravir
Molnupiravir promotes mutagenesis by incorporating the prodrug NHC into virus RNA via the viral RNA-dependent RNA polymerase (RdRp).5 When the RdRp uses the NHC-modified RNA as a template it promotes a so-called error catastrophe5 that inhibits the replication of SARS-CoV-2. Molnupiravir behaves like cytosine (C) during RNA synthesis by pairing with guanine (G), but once incorporated, it shifts into a tautomeric form analogous to uracil (U). This leads to G-to-A mutations in the subsequent replication round of the SARS-CoV-2 genome
Favipiravir
2 mechanisms
- FTP forms intracellularly, acts as a nucleoside analog to simulate GTP/ATP, and subsequently incorporates itself into the RNA of nascent viruses, resulting in the termination of RNA synthesis;
- FTP incorporation into viral RNA induces high rates of genome mutation that leads to the loss of infectivity or the production of nonviable virions, further inhibiting viral replication and reproduction
Remdesivir
Remdesivir is administered as 200 mg IV on day 1, followed by 100 mg IV daily on days 2 and 3. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp).
Mutations masterchart
- HIV - Stanford Database
A. TAMs - M41L & D67N (AZT)
B. Non-TAMs - M184VI (3TC & FTC but BOOSTS TFV) & K65R (TFV & ABV)
C. MDR - Q151M (Pan NRTI) & T69 deletions
C. NNRTI - L100I & K101P (All except DOR)
D. INSTI - G118R
E. PI - V32I
- HBV - M204V/I (nucleosides)
L180M + M204 V/I + T184G + S202I (ETV)
G145R - vaccine escape - CMV - UL97 (GCV/MBV), UL54 (GCV/FOS/CDV), UL56 & UL 89 (LET) targets
Letermovir resistance : UL56 C325W
Canonical mutations: The canonical UL97 mutations confer 5- to 10-fold GCV EC50 increases, except 3-fold for C592G
M460V/I
H520Q
C592G
A594V
L595S
C603W
- HEV - G1634R (Ribavirin failure)
- Mpox - F13 mutations, eg- T289A
- Influenza - H275Y - ONLY oseltamavir resistance.
R292K - both Oseltamavir & Zanamavir resistance - HSV - TK - UL23 & UL30.
- HCV:
NS5As:
L31MV - 1a & 1b
Y93HN - 1a, 1b, 3a
Q30R - 1a
