What is the mechanism of resistance to Ribavirin?
Content Reviewers:Yifan Xiao, MD
Now, viral hepatitis can be acute or chronic.
Acute hepatitis lasts for six months or less, and usually resolves on its own without any antiviral treatment.
Chronic hepatitis lasts for more than six months, sometimes even for decades.
Alright, so, HCV is a single stranded RNA virus.
What this means is that HCV inject its RNA into the host’s cell and it can immediately use its host’s ribosomes and translate the proteins needed to make more viruses, like capsomere proteins and enzymes like RNA-dependent RNA polymerase.
This RNA-dependent RNA polymerase uses the viral RNA as a template, and uses the hepatocyte’s nucleotides to transcribe a complementary strand of RNA, which is then used to form new baby viruses!
HBV on the other hand is a double stranded DNA virus.
Once the DNA gets injected into a new cell, it enters the cell’s nucleus and is replicated by the host cell’s machinery.
It’s also transcribed into several messenger RNAs and a pregenomic RNA, and then the messenger RNAs are used to make capsomere proteins and enzymes like DNA polymerase.
DNA polymerase uses the pregenomic RNA to synthesize new copies of the viral DNA, which is combined with the capsomere proteins to assemble new viruses.
With each type of virus, whether it’s RNA or DNA, it’s turning your own cells into virus making factories and pumping out new viruses.
This process strains, damages and potentially kills the infected hepatocytes.
When these liver cells die, the liver gets inflamed and that’s called hepatitis.
Let’s start with the nucleoside and nucleotide analogues. This group includes nucleoside analogues like ribavirin, entecavir and lamivudine; nucleotide analogues like adefovir, tenofovir, and sofosbuvir.
In both types of infected cells, the analogues are first phosphorylated by cellular enzymes into either a diphosphate, or triphosphate form.
Viral enzymes will try to use these fake nucleotide molecules when trying to synthesize new nucleic acid.
In the HBV infected cell, this enzyme is HBV DNA polymerase, while in the HCV infected cell, the target enzyme is RNA-dependent RNA polymerase.
In addition to this, ribavirin also has another mechanism.
Ribavirin is initially phosphorylated to a monophosphate form, which inhibits the enzyme inosine-5′-phosphate dehydrogenase.
Inosine-5′-phosphate dehydrogenase is an enzyme in the host cell, which converts inosine monophosphate into xanthosine monophosphate, which then goes on to make guanine nucleotides.
Ribavirin monophosphate resembles inosine monophosphate, and binds to its site on the enzyme.
This inhibits the inosine-5′-phosphate dehydrogenase, reducing the synthesis of guanine nucleotides, which in turn reduces the synthesis of viral mRNA.
These nucleoside and nucleotide analogues are given per oral.
These prodrugs are rapidly absorbed and converted into adefovir and tenofovir, respectively, in the intestinal cells by an esterase enzyme.
Eventually nucleotide and nucleoside analogues are transported out into the blood, and carried to the kidneys, where they are excreted via urine.
Ribavirin undergoes another extra step where it is first dephosphorylated by a phosphatase present in the host cell’s nucleus.
This causes ribavirin to start accumulating within cells which lack a nucleus like the red blood cells.
Now, nucleoside and nucleotide analogues commonly cause side effects like headache, nausea, fatigue, and abdominal pain.
In addition, ribavirin can cause hemolytic anemia and hyperuricemia, or increase in uric acid levels due to its accumulation within the red blood cells.
Ribavirin increases the efficacy of interferons when used together.
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