11. Anti-viral Therapy Flashcards
Describe the agent which causes influenza A.
What do antigenic shifts and drifts result in?
What 4 drugs can be used to manage flu?
Orthomyxovirus: envelope, surface spikes, haemagglutinin protein (HA) 16 types, neuraminidase protein (NA) 9 types, ss(-) RNA, 8 segmented genes.
Antigenic shifts of HA results in pandemics; drifts of HA and NA result in epidemics
Amantidine: effective against A if given early but rapid resistance. Rimantidine: similar to amantidine but fewer neurological SEs. Both inhibit viral M2 protein to decrease H+ influx, resulting in inhibition of viral uncoating and coating as daughter virion prepares to exit host
Ribavirin: effective against A and B, guanine analogue that acts like nucleoside analogue
Neuraminidase inhibitors: v effective and fewer SE than amantidine.
List some neuraminidase inhibitors.
What are they active against?
What does neuraminidase do?
Zanamavir, oseltamavir (tamiflu).
Influenza A and B, avian influenza.
Surface glycoprotein of influenza A and B, cleaves terminal sialic acid residues from glycoconjugate which: allow virion release from infected cells, prevents virion aggregation, reduces inactivation of virus by respiratory tract mucus.
Describe HIV.
Describe HIV replication and the 4 locations where antiviral therapy acts.
Enveloped RNA-virus, ss + strand, 2 types (HIV 1 and 2) with several subtypes, cross spp transmission. Rerverse transcriptase (RNA -> DNA), integrase (facilitates integration into genome), viral protease (virion mutation).
(Pic) NRTIs (neucleoside reverse transcriptase inhibitors): chain termination, Protease inhibitors e.g. ritonavir block virus maturation (no cleavage of precursor proteins)
What is HAART?
What HIV/AIDS drugs can you give prior to exposure, at point of transmission, and after infection?
What steps can be taken for effective prevention of mother-to-child transmission?
Highly active antiretroviral therapy: Use of multiple antiretroviral drugs that act on different viral targets. It decreases the patient’s total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death.
Prior to exposure: Pre-exposure prophylaxis (PrEP). Transmission: anti-retroviral therapy (mother to child), post-exposure prophylaxis (PEP). After infection: Anti-retroviral therapy
Prevent HIV among parents (testing), avoid unwanted pregnancies among HIV positive women (councelling and support), prevent transmission of HIV from mothers to babies during pregnancy, labour, delivery and breastfeeding, integration of HIV care, treatment and support for HIV positive women and their families.
Describe hepatitis C virus.
Why is hepatitis C disease treated? What is the treatment?
What drugs are used to manage hepatitis C pre-2012?
Enveloped, ss(+) RNA genome, 6 serotypes known encodes for structural proteins and enzymes important for replication. Main source of infection: injecting drug use (60%), sex (15%).
Common, chronic, potentially progressive. Complications more common - liver failure, HCC (hepatocellular carcinoma). Treatment: viral cure, or SVR (sustained viral response), is achievable and associated with histologic improvement and gradual fibrosis regression. SVR reduces risk of liver failure and HCC.
Interferon mono-therapy, interferon/ribavirin combo, peginterferon/ribavirin combo.
What are interferons?
Describe the ‘new wave’ of HCV therapy.
Cytokines with potent broad-spectrum anti-viral activities. Induce synthesis of host proteins that can block viral transcription and translation e.g. interferon inducible kinase phosphorylates eIF-2 which inhibits translation initiation.
Oral cocktails of DAAs (direct acting agents), host cofactor inhibitor, RBV. Substitution of better-tolerated IFNs/second generation PIs, nucs etc. 4-drug regimens for pegIFN/RBV/PI failures
Describe herpesviridae.
What 2 things lead to infection risk in transplant patients?
List some drugs used to prevent herpesvirus disease.
Enveloped DNA virus, dsDNA, linear, encodes 100-200 genes. 3 subfamilies. Regulated gene expression, nuclear replication. Ubiquitous. Establish latency.
Immunosuppressive therapy. Technical complication of transplant proceedure.
Ganciclovir (IV, oral), valganciclovir, foscarnet (IV), cidofovir, acyclovir, CMV
Describe the following drugs used to prevent herpesvirus disease:
a) acyclovir
b) gancyclovir/valgancyclovir
c) cidofovir
d) foscarnet (pyrrophosphate analogue)
a) synthetic purine nucleoside analogue with inhibitory activity against HSV-1 and 2, VZV, EBV and CMV. Highly selective, It interferes with herpes simplex virus DNA polymerase and inhibits viral DNA replication. It’s incorperated into growing chains of DNA by viral DNA pol -> terminates chain. It’s preferentially taken up and converted to active form by HSV-infected cells.
b) treats cytomegalovirus (CMV) infection in those with HIV/AIDS or following organ transplant. Often used long term as it suppresses rather than cures
c) host enzymes metabolise drug to active form. Active against CMV, acyclovir-resistant HSV. Nephrotoxicity.
d) binds viral DNA pol preventing pimer-template extensions. Toxicites. Electrolyte abnormalities. Fever. Decreased creatinine clearance.
What are broad-spectrum antivirals used for?
Give some advantages and disadvantages of broad-spectrum antivirals.
Treat emerging viral diseases lacking specific treatments e.g. ebola, dengue. Use for approved drugs that target host functions required by several viruses e.g. interferons (RNA and DNA viruses)
Advantages: reduced treatment complexity and drug-drug interactions. Effective control of emerging pathogens. Essential when quick diagnosis not available. Effective against multiple viruses. Higher barrier to resistance.
Disadvantages: systemic complementation of blocked target. Poor in-vitro to -in-vivo translation. Risk of immune deregulation. Enhanced cellular toxicities. Reduced target specificity.
How does favipiravir work against ebola, norovirus, influenza?
Binds to viral replicase and enhances error rate during replication -> reduced viral load in patient.
Antivirals do not prevent infection. (Except pre-/post exposure prophylaxis, microbicides…)
