Agents against hepatitis viruses (7) Flashcards
Treatment of viral hepatitis HAV
HAV: no specific treatment, vaccination
Treatment of viral hepatitis HBV
HBV infection: nucleoside/nucleotide derivatives or INFα-derivative
- Goals:
- total suppression of virus replication
- normalizing enzyme levels and tissue presentation.
- Total eradication is not yet possible
• vaccination, passive immunization
• starting therapy if
• cirrhosis: a nucleoside analog
• HBeAg+ phase: INF for 1y,
nucleoside for 1y after HBeAg- status: sustained viral response state
• HBeAg- phase: INF for 1y, nucleoside until HBsAg-
• HDV co-infection: INF only
Treatment of viral hepatitis HCV
HCV:
• 6(9+) genotypes, regional differences • Combination therapies
• Aviremia often achieved
which NRTis for HBV and HIV 1 and 2
Lamivudine, emtricitabine and tenofovir:
for HBV as well as HIV 1 and 2
Treatment of viral hepatitis: Nucleoside / nucleotide analogs for HBV
Lamivudine, Emtricitabine
Entecavir
(Telbivudine)
(Adefovir), Tenofovir alafenamide
inhibition of replication: 80-100% immunomodulation: No chance of relapse: high seroconversion (HBs->anti-HBs): 1-8% admin.: P.o. duration of therapy: >2 years resistance: +->+++ applicability in decreased kidney function: lower dose side effects: mild
Entecavir
• Guanosine analog
- Inhibits HBV DNA
polymerase
indication:
- Hepatitis B infection
kinetics:
- Oral
- Renal elimination
• Well-tolerated
• almost no primary resistance
adverse effects:
- Headache, dizziness
- Fatigue
- Nausea
Tenofovir
Tenofovir alafenamide? (Adefovir)
NRTI !!
• AMP analogs
- Nucleotide analogue (requires less phosphorylation steps for activation)
• Can be nephrotoxic
• no cross-resistance
• teno: less primary resistance, higher efficacy
Indication: HIV-1 and HIV-2 infection
for HBV as well
- High genetic barrier: for complete resistance more mutations are needed
- no cross-resistance
oral administration
• side effects: •GI problems (nausea, vomiting, diarrhea), -lactic acidosis, -lipodystrophy, headache, malaise, hepatitis (elevated transaminases)(mitochondrial toxicity) \+nephrotoxicity
Telbivudine
not on the list
- Thymidine analog
* Well tolerated, no cross-resistance with cytidine analogues • fast primary resistance development.
Treatment of viral hepatitis – HBV, HDV
not on the list
Bulevirtide
- synthetic N-acylated pre-S1 lipopeptide
- first in class
- inhibits primary entry mechanisms of HBV and HDV: blocking binding of virus to NTCP, a sodium/bile acid cotransporter
- aim: decreasing HDV viral load in adults
- with tenofovir or other nucleoside analog
- once daily, s.c., for 48 weeks
- side effects: raised levels of bile salts in blood
Treatment of viral hepatitis IV - HBV
previous standard therapy:
Interferon α (INFα2a, INFα2b) – recombinant protein
Ribavirin???
Interferon α (INFα2a, INFα2b) – recombinant protein
• Complex antiviral activity (induces more than 20 antiviral proteins)
- Acts via activation of cytokine receptors, increasing activity of JAK-STAT pathway
- Selective antiviral activity via the activation of host cell defence mechanisms
kinetics:
- Intramuscular/subcutaneous inj.
- Renal elimination via proteolytic hydrolysis
- Administered once daily or 3
times a week
- ‘Pegylated form IFN’
(conjugated to polyethylene glycol) can be administered once weekly
• S.c.; PEGylation: once a week administration possible
• Adverse effects: - Flu-like symptoms (fever, fatigue myalgia etc.) - GI symptoms - Alopecia - Bone marrow suppression - Ototoxicity (reversible) - Thyroid dysfunction - CNS effects (mood disorders, depression)
Indications: - Hepatitis B chronic infection (monotherapy/combination) - Hepatitis C infection (acute and chronic); in combination with ribavirin - Further indications: Kaposi sarcoma (HHV-8) Hairy cell leukemia Malignant melanoma Papillomatosis Renal cell carcinoma Genital warts (HPV)
• HBV: faster and longer effect than nucleoside analogues, but less-tolerated
inhibition of replication: 40-70% immunomodulation: yes chance of relapse: low seroconversion (HBs->anti-HBs): 6-11% admin.: S.c. duration of therapy: 1 year resistance: 0 applicability in decreased kidney function: no side effects: pronounced, many
Ribavirin
• Guanosine analog - Monophosphate form inhibits IMP dehydrogenase (prevent GMP synthesis) - Triphosphate form inhibits viral RNA polymerase and end-capping of viral RNA
Indication:
- Hepatitis C infection (acute and chronic);
in combination with IFN-α
- Respiratory syncytial virus (aerosol preparation)
- Other viral infections:
influenza A and B, paramyxovirus, HIV, parainfluenza virus
- Early IV administration is effective against viral hemorrhagic fever: Dengue-, Yellow-, Lassa- fever, Ebola, Bunya virus
• Broad spectrum – HCV and RSV. (Lassa, Hanta, Krim-Kongo fever)
kinetics:
- P.o.,
- i.v.;
- aerosol for RSV
Renal elimination (dose adjustment in renal dysfunction)
• Adverse effects: • malaise, insomnia, coughing, itching • anemia, bone marrow suppression - Drug-induced hemolytic anemia (IV) - Conjunctival, bronchial irritation (aerosol)
- possibly carcinogenic and teratogenic
- HCV: 12 to 48 week p.o. as adjunct therapy in patients with decompensated cirrhosis and in genotype 4
Treatment of viral hepatitis - HCV
Ribavirin (acute and chronic) in combination with IFNalpha
INFalpha
Direct-acting antivirals (DAA’s)
NS3(/4A) Protease inhibitors: (Simeprevir), (Telaprevir,) 1. Paritaprevir!, (Glecaprevir,) 2. Grazoprevir!
NS5a inhibitors: 3. Elbasvir!, (Daclatasvir,) 4. Velpatasvir!, (Pibrentasvir)
NS5B polymerase inhibitor
5. Sofosbuvir!
Non-nucleoside NS5B polymerase inhibitor
6. Dasabuvir!
most effective treatments of HCV for all genotypes: • sofosbuvir + velpatasvir
• glecaprevir + pibrentasvir
*Safety profiles of all the combination regimens are generally excellent, with adverse events of mild severity and very low rates of discontinuation due to adverse events in clinical trials
Common side effects:
- Fatigue
- GI distress
- Headaches
- Anemia
Paritaprevir
NS3(/4A) Protease inhibitors
- PO, metabolized by CYP3A, 2C8
- Adverse effects:?
- Resistance develops in short time: no monotherapy
Dasabuvir
• used as a part of a combination for Type1 HCV with Paritaprevir (+ ritonavir booster)
Grazoprevir
NS3(/4A) Protease inhibitors
- PO, metabolized by CYP3A, 2C8
- Adverse effects:?
- Resistance develops in short time: no monotherapy
