A 65-year-old man comes to the office after his wife insisted he get a checkup. The patient feels well and has no chronic medical conditions but has not seen a physician in many years. He received blood transfusions after a motor vehicle trauma in his 20s. The patient does not use tobacco or illicit drugs but drinks 2 or 3 alcoholic beverages daily. Physical examination reveals no hepatomegaly, ascites, or dilation of the superficial abdominal veins. The remainder of the examination shows no abnormalities. Serology is positive for hepatitis C antibodies. Chronic hepatitis C infection is confirmed with positive HCV RNA testing. After appropriate counseling is provided, combination therapy with sofosbuvir and ledipasvir is planned. This treatment is most likely to help clear the infection through which of the following mechanisms?

Question

A 65-year-old man comes to the office after his wife insisted he get a checkup.  The patient feels well and has no chronic medical conditions but has not seen a physician in many years.  He received blood transfusions after a motor vehicle trauma in his 20s.  The patient does not use tobacco or illicit drugs but drinks 2 or 3 alcoholic beverages daily.  Physical examination reveals no hepatomegaly, ascites, or dilation of the superficial abdominal veins.  The remainder of the examination shows no abnormalities.  Serology is positive for hepatitis C antibodies.  Chronic hepatitis C infection is confirmed with positive HCV RNA testing.  After appropriate counseling is provided, combination therapy with sofosbuvir and ledipasvir is planned.  This treatment is most likely to help clear the infection through which of the following mechanisms?

Quizplus · Accepted Answer

Hepatitis C virus (HCV) is a blood-borne pathogen that is primarily transmitted via injection drug use or transfusion of blood products (prior to widespread screening in 1992). Chronic infection develops in most individuals and increases the risk for cirrhosis and hepatocellular carcinoma. Because chronic HCV infection is often asymptomatic for decades, patients are often unaware that they have contracted the virus until they receive HCV screening. Treatment of chronic HCV infection is with direct-acting antiviral (DAA) agents, which target specific enzymes in the HCV life cycle to inhibit viral replication and assembly, as follows: RNA-dependent RNA polymerase inhibitors - HCV binds to and enters host cells, uncoats, and subsequently replicates its genome using HCV-encoded RNA-dependent RNA polymerase. Nucleotide/non-nucleoside RNA polymerase inhibitors such as sofosbuvir target this step. Protease inhibitors - HCV mRNA is translated by host ribosomes into a polyprotein, which is cleaved by HCV protease into the individual proteins that compose the virus. HCV protease inhibitors such as simeprevir target this step. NS5A inhibitors - The HCV protein NS5A is crucial for viral replication and assembly (through unclear mechanisms) and is targeted by HCV medications such as ledipasvir. DAA treatment results in a sustained virologic response (complete elimination of virus) in >97% of treated individuals. (Choice A) HCV does not contain a reverse transcriptase enzyme so it does not integrate its genome into the host cell. Therefore, there are no reverse transcriptase inhibitors for HCV. Reverse transcriptase inhibitors are a mainstay of therapy for HIV. (Choice B) Interferon-alpha was previously used in the treatment of chronic HCV (in combination with ribavirin) to trigger a broad antiviral immune response. However, interferon therapy has a lower cure rate (50%-80%) and a much higher incidence of side effects (eg, flu-like symptoms). Therefore, DAAs are now used preferentially. (Choice C) HIV fusion inhibitors (eg, enfuvirtide) and CCR5 inhibitors (eg, maraviroc) inhibit the ability of HIV to enter cells. DAAs do not target viral entry. (Choice E) Although HCV virion release could be a target for DAAs, there are currently no approved medications that target this step. Virion release (budding) is targeted by neuraminidase inhibitors in the treatment of influenza. Educational objective: Chronic hepatitis C virus infection is treated with direct-acting antiviral (DAAs) medications such as ledipasvir and sofosbuvir. These medications target specific HCV enzymes (eg, protease, NS5A, RNA polymerase), which inhibits viral replication and assembly. Treatment with DAAs results in cure in >97% of patients. __________ References: HCV NS5A replication complex inhibitors. (http://www.ncbi.nlm.nih.gov/pubmed/27643675) Virology and cell biology of the hepatitis C virus life cycle: an update. (http://www.ncbi.nlm.nih.gov/pubmed/25443344)

A 65-Year-Old Man Comes to the Office After His Wife