W8 Antiviral therapy for HIV and HCV Flashcards
Human Immunodeficiency Virus (HIV)
Common characteristics of viruses?
- HIV belongs to the Retroviridae family, viruses that insert their genome into the DNA of a host cell
- HIV is classified into: HIV-1 and HIV-2 types. HIV-1 is more virulent and more infective
- HIV-1 is responsible for 95% of all HIV infections worldwide
- HIV causes Acquired Immunodeficiency Syndrome (AIDS), leading to a progressive failure of the immune system (decreasing CD4+ T cells) allows life-threatening opportunistic infections and cancers to thrive
HIV infection progress:
What are the 3 stages?
- Acute HIV: initial flu-like symptoms
(days to weeks after contracting HIV) - Chronic HIV: latent and asymptomatic
(> years) - AIDS: CD4 cell count falls below 200 cell/mm3- patients are severely immunocompromised- vulnerable to
opportunistic infections
If HIV infection is not treated, the median time from infection to the AIDS development is 8-10 years
Antiviral drug resistance of RNA viruses (HIV & HCV
During genome replication, spontaneous mutations occur
* HIV reverse transcriptase and HCV polymerase (NS5B) result in a high mutation rate and do not have proofreading activity
* Combined with the high replication rate of HIV or HCV (> 1010 new viruses/day) results in large genetic variability
*Most mutations are deleterious for the viral replications, but occasional ones can be tolerated and allow them to escape from drug inhibition
=Onset of antiviral drug resistance
Principle of combination therapy:
Advantages of combination therapy over monotherapy? (HIV and HCV)
Combination therapy principle=Combining different antiviral drugs with distinct mechanisms of action having a proven synergistic activity against HIV and HCV
- Delay or prevent the development of drug resistance
- Strengthen the potency of the antiviral effect (synergistic effect)
- Reduce the dose of single drugs and potential toxicity
- Reduce pill burden (HIV) or shorten the treatment (HCV), improving adherence
- Broaden the spectrum of antiviral coverage (only for HCV, pan-genotypic effect)
HIV Combinational therapy (cART/HAART):
What is used as treatment? (no drug name necessary)
- The highly active antiretroviral therapy (HAART) comprises a combination of two/three antiretroviral drugs with different mechanisms of action=Atripla (introduced in 2006)
- Reduced risk of drug resistance= Multiple mutations are required simultaneously
- Synergism = suppress viral replication more efficiently
The goals of ART/HAART in patients with HIV infections include? (6)
Does HAART cure HIV?
- Reduce plasma viral RNA to an undetectable level
- Improve the immune system functions
- Prevent or reduce drug resistance
- Reduce morbidity and mortality
- Improve life quality
- Prevent HIV transmission
Undetectable= Untransmittable
HAART= Highly active antiretroviral therapy
HAART and the anti-HIV drugs dont cure HIV infection (can’t eradicate/clear the virus from an individual) due to the establishment of long-live HIV reservoirs
HIV Persistence during HAART:
What can it be attributed to?
When HAART is interrupted, the viral
load will go up = viral rebound
* HAART is for life =starting ASAP
* HIV integrates its DNA genome or provirus into the host cell genome.
- HIV persistence during antiretroviral therapy could be attributed to:
- Viral replication in drug-privileged anatomical compartments = HAART sanctuary
- Viral replication of a small pool of long-lived cells carrying silent integrated genomes that can be reactivated and reignite infection
Mechanism of Action of Acyclovir:
- Nucleos(t)ide analogues/NRTI e.g. Acyclovir for HSV
Burden of HCV infection (for info)
- Hepatitis C virus (HCV) is classified into six major genotypes
- Each HCV genotype causes chronic infection in 70-75% of people
- the leading cause of liver cirrhosis and hepatocellular carcinoma
-170 million people have chronic HCV infection
-There is no HCV vaccine
-HCV infection is curable
The success rate of HCV treatment is based on the Cure rate (long-term viral clearance)
What are the Drug Classes of DAA used to treat HCV infections? (for overview info)
ASVIR- Inhibitors of NS5A
PREVIR- Inhibitors of NS3/4A
BUVIR- Inhibitors of NS5B Polymerase
Treatment of HCV:
What are the Goals of DAA’s Combinational therapies?
- Eradicate the virus (cure)
- Prevent the emergence of drug resistance
- Reduce risk of all-cause mortality
- Broaden the spectrum of antiviral coverage
- Shorten the treatment, improving adherence
- Improve life quality
- Prevent HCV transmission
DAA= Direct acting antivirals
Features of Approved DAA Regimens:
- > 95% cure rate
- Once daily regimens
- All-oral interferon-free regimens
- Pan-genotypic activity
- Highly tolerable
- Short therapy duration (8-12 weeks)
Is Hepaptitis C Virus (HCV) infection curable?
Yes, there are many effective therapies that can cure more than 95% of HCV chronic infections
