Antivirals Flashcards
Goals of ART?
reduce HIv infection-related morbidity and prolong duration and quality of survival
resotre and preserve immunologic function
maximally and durably suppress viral load
prevent vertical HIV transmission
Key - achieve and maintain durable viral suppression
HAART
highly active antiretroviral therapy
increase survivability
how would you determine which drugs to choose?
-Pre ART - determine CD4 count, measure HIV RNA and perform resistance testing
-determine viral tropism - prior to initiation of CCr5 antagonist
HLAB*5701 testing - prior to initiation of abacavir (ABC) due to risk of hypersensitivity reaction
What shows success of ART treatment?
high potency of ARV regimen
excellent adherence to treatment regimen
low baseline viremia
higher baseline CD4 count - >200 cells/mm3
rapid reduction of viremia in response to treatment
Classes of Antiretrovirals
Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease Inhibitors
Integrase inhibitor
Fusion inhibitors
Chemokine receptor antagonists - CCR5 antagonists
What can Antiretrovirals NOT do?
do not cure HIV infection or AIDS
do not eliminate risk of passing HIV to other
HIV medicines must be taken in combination with other HIV medicines
not all medicines are right for all ppl and treatments may be different for each person
Mechanism of Nucleoside reverse transcriptase inhibitors
- competitively inhibit RT effectively blocking ability of virus to make a provirus copy
- the NRTIs gets added to the growing proviral chain by RT leading to chain termination
- bind at the RT active site
Zidovudine
ZDV (was AZT)
Thymidine analogue
When ZDV was used as monotherapy
HIV quickly became resistant
so currently used in combination drug regimens
Side effects of ZDV
anemia and granulocytopenia
avoid using with other myelosuppressive drugs
Examples of Nucleoside reverse transcriptase inhibitors
Zidovudine - AZT,ZDV Lamivudine Abacavir (this is the one associated with hypersens. reaction) Didanosine Emtricitabine Stavudine Tenofovir
Non nucleoside Reverse transcriptase inhibitors mechanism?
bind to and alter reverse transcriptase
bind directly to RT
can be used synergistically with NRTIs due to differences in binding location
what is a concern with NNRTI?
whether the virus will be susceptible or resistant
Examples of NNRTIs
Efavirenz* Delavirdine Nevirapine Rilpivirine Etravirine - has anti HIV-2 activity as well
Mechanism of Protease Inhibitors
binds to HIV protease (which essential for proteolytic processing of nascentt polypeptides into individual proteins during maturation)
Activity of PIs
against HIV-1 and HIV-2
Mechanism of resistance to PIs
due to mutations inside and outside the active protease domain
Examples of Protease Inhibitors
Ritonavir* Darunavir Atazanavir Fosamprenavir Indinavir Nelfinavir Saquinavir Tipranavir
Potency of NRTI
less potent than NNRTIs and PIs
Mechanism of ZDV/AZT resistance?
mutations remove ZDV from DNA chain
a conformational change allowed Thymine to continue to bind but disabled
ZDVs ability to bind RT
also able to remove ZDV from the proviral DNA
NRTI is active against?
HIV-1 and HIV-2
Efavirenz
preferred drug for combination therapy in treatment naive individuals
Etravirine
has anti-HIV-2 activity as well
Ritonavir side effects?
inhibits host protein cytochrome P450 3A4 which results in failure to metabolize other drugs, including other PIs, this leads to higher serum levels and sometime an increase in toxicity
Lipodystrophy
Fat wasting - fat is lost from arms, legs, face and buttocks
fat redistribution due to PIs (&NNRTIs)
disturbs the way the body produces, uses, and stores fat
Hyperadiposity
fat accumulation
fat builds up in belly, breasts and back of the neck
Clinical signs of Lipodystrophy
back of neck and upper shoulders - buffalo hump
abdomen - protease paunch or crixivan potbelly
breasts - both men and women
Lipomas - fatty growths in different parts of the body
Proviral integration
Proviral integration is 2 step process
- 3’-processing in host cell cytoplasm to prepare proviral strands for attachment
- strand transfer where proviral DNA is covalently linked to cellular DNA
Mechanism of Integrase Inhibitors (INSTI)
competitively inhibits Mg+2 or Mn+2 both essential cofactors for integrase binding to proviral DNA
Examples of INSTIs
Raltegravir
Elvitegravir
Dolutegravir
INSTI resistance
mutations in integrase gene associated with resistance to raltegravir and elvitegravir
which step of proviral integration do INSTIs block?
step 1 - 3’ processing in host-cell cytoplasm
1 pill with 4 drugs
Raltegravir
Elvitegravir
both have same mechanism - blocks Mg binding
(only told two of them)
Mechanism of Fusion Inhibitors
prevent HIV from entering
binds gp41 and prevents fusion to host cell and viral entry
ONLY for HIV-1
used in combo with other ART drugs
Enfuvirtide (T-20)
36 AA peptide derived from EC domain of gp41 of HIV-1 envelop
given when other drugs have failed
Mechanism of chemokine receptor antagonists
blocks binding of virus to target cell
directly competes with gp120 for site
Maraviroc
its a CRA
blocks gp120 from binding CCR5
only works for CCR5 tropic viruses
What viruses are there antivirals available for?
Influenza viruses Herpes viruses - HSV-1, and 2 VZV, CMV Respiratory syncytial virus (RSV) Hep B virus Hep C virus Papillomaviruses HIV
Inhibiting Antiviral drugs can target
attachment/adsorption
penetration/entry
nucleic acid synthesis
release
A drug that affects viral inhibition of cellular processes could do so by
prevent viral inhibition by interferon production
How could anti virals support the immune system to combat viral infections?
by affecting antibodies and immune modulators
- polyclonal antisera
- monoclonal antibodies
- Imiquimod
Anti-Influenza drugs
Permavir
Oseltamivir (Tamiflu)
Zanamivir (Relenza)
-these inhibit cleavage of HA-SA bonds by NA - thus no viral release
Amantadine
Rimantadine
-these block M2 ion channel - no viral coating
Neuraminidase inhibitors for Inf A and B
inhibits viral release and virion clumping promoted
must be started
reduces severity and shortens duration of symptoms
- Peramivir - IV adults only
- Oseltamivir
- Zanamivir
H+ ion channel (M2) inhibitors for Influenza A
not currently rec. due to high levels of resistance to circulating strains of Influenza A
interfers with H+ transport, necessary component for uncoating to occur thus RNA transcription cannot happen
- Adamantes
- Rimantadine
M2
required by Influenza to uncoat and release its genome
Activation of Nucleoside Analogues for HSV,VZV
converted to active drug by 3 phosphorylation steps in viral-infected cells
1-first phosphorylation step by viral thymidine kinase
2-Next 2 phosphorylation steps by host cell enzymes
3-Acyclovir tri phosphate added to growing chain of herpes virus DNA - results in chain termination
Mechanism of Nucleoside Analogues for HSV
Acyclovir - prodrug
Added to growing chain of virus DNA
Acyclovir related compounds
Valacyclovir - better bioavaible than oral acyclovir
Famciclovir - higher intracellular levels
Penciclovir - higher intracellular levels
CMV is opportunisitc in IC pts, clinical manifestations of infection
AIDS pts tend to be infected, pts may be on myelosuppressive (AZT) or nephrotoxic drugs Retinitis Esophagitis Coliis Encephalitis Pneumonia
HIV+ patients are resistance to
Acyclovir
CMV doesnt encode
Thymidine Kinase
Nucleoside Analogues for CMV
Acyclovir and related not active because uses different enzymes to initiate phosphorylation
Ganciclovir - bone marrow toxicity - leads to neutropenia, CMV retinitis
Valganciclovir
Cidofovir - cytosine analog
Foscarnet
…
Fomivirsen
…
Palivizumab
monoclonal antibody to RSV F protein
Ribavirin mechanism
Broad spectrum antiviral
synthetic nucleoside analog - GTP analog
interferes with viral RNA-dep RNA polymerase (RdRP)
Side effects of Ribavirin
dose dep hemolytic anemia
dry cough, dyspnea
Teratogenic
Indications for Ribavirin
RSV - hospitalized infants
Hep C
Vaccinia, Monkeypox
Nucleoside analogues for HBV -RT inhibitor
Lamivudine, telbivudine
blocks HBV DNA synthesis by incorporating into the growing DNA chain, causing premature chain termination
NA -RT AND DNA poly inhibitor - HBV
Adefovir - rare cases Renal toxic
Tenofovir - rare cases Hepatotoxic
Entecavir
what does cellular release of Type 1 IFN
induces antiviral state in uninfected cells - induces enzymes that block viral replication
Increases expression of MHC I on infected cells to accelerate killing by CTLs
Type 1 IFN for HCV
IFN given to up general cellular responses to viral infection
Immunomodulatory - increases MHC I expression on infected cells to enhance killing
Hep C antivirals Protease Inhibitors
Boceprevir
Telaprevir
block production of structural proteins