Sofosbuvir for the Treatment of Chronic Hepatitis C Infection

Hepatitis C is a viral infection of the liver that may lead to cirrhosis (scarring of the liver), cancer, liver transplantation and death.[1] Limited-duration oral drug regimens can cure hepatitis C in more than 90% of cases.[2] Among the newer treatment regimens that the Food and Drug Administration (FDA) has approved for chronic hepatitis C are sofosbuvir, alone (SOVALDI) or in combination with other antivirals (EPCLUSA, HARVONI, VOSEVI).

Background on hepatitis C

Hepatitis (inflammation of the liver) can damage that organ’s function.[3],[4] Heavy alcohol use and exposure to other toxins (for example, the dry-cleaning solvent carbon tetrachloride),[5] including some medications (for example, acetaminophen [TYLENOL] or antibiotics), can cause hepatitis. The most common of the viruses that cause such liver illness are hepatitis A, hepatitis B and hepatitis C.

Hepatitis C disease can be mild to severe; it may last a few weeks to many years. According to a 2016 estimate, 2.7 million to 3.9 million people in the United States have chronic hepatitis C, and many are unaware that they are infected. Hepatitis C is the most common reason for liver transplantation in the United States, and in 2018 the Centers for Disease Control and Prevention estimated that it was related to nearly 16,000 deaths. Globally, only 20% of chronic hepatitis cases are diagnosed, and only 7% initiate treatment.[6]

Hepatitis C is usually spread when someone comes into contact with an infected person’s blood.[7] Health workers, people who had blood transfusions before screening of donor blood for hepatitis C was routine, and injection-drug users who share needles are at elevated risk. Although sexual contact and sharing personal hygiene items such as toothbrushes and razors also increase the risk of transmission, the risk of monogamous sexual transmission is low. Hepatitis C is not spread by sharing food, kissing or sneezing.[8]

Early diagnosis and treatment of hepatitis C can prevent liver damage. Although there are no preventive vaccines, there are effective oral medications that typically require eight to 24 weeks of treatment. Direct-acting antivirals, first approved by the FDA in 2013, inhibit the ability of hepatitis C to control the gene-expressing machinery of a person’s cells, thereby blocking the virus from reproducing and invading more cells.[9]

Many of the drug regimens for hepatitis C include sofosbuvir. Collectively, regimens that include sofosbuvir can treat all six major genetic variants of the hepatitis C virus.[10] For example, the combination antiviral sofosbuvir and ledipasvir (Harvoni) specifically targets two of the six hepatitis C variants using an eight- to 12-week daily regimen for patients without cirrhosis and a 12-week regimen for those with compensated cirrhosis (cirrhosis that has not led to extensive liver dysfunction).[11]

Sofosbuvir effectiveness and safety

Chronic hepatitis C infection can be effectively managed with antiviral therapy. According to an authoritative (UpToDate) overview, “antiviral therapy is the cornerstone of treatment….with current antiviral therapies, [hepatitis C virus] is relatively easily treated and can be eliminated in all patients.”[12] Similarly, a recent review article about managing cirrhosis and its complications stated that “hepatitis C is now curable with direct-acting antivirals.”[13]

A 2019 systematic review that supported the effectiveness of sofosbuvir also noted that available clinical trials were generally of “low quality.”[14] Still, across subsets of data from 28 randomized trials involving more than 7,000 hepatitis C patients, the researchers calculated that for every 1,000 patients treated, clearance of the virus was achieved approximately 240 more times with a 12-to-24-week course of direct-acting antivirals (including sofosbuvir) as compared with placebo. Calculated another way, viral clearance was found to be approximately 45% more likely with the use of direct-acting antivirals than with placebo.

When sofosbuvir is used without other medications, the prescribing information refers to seven clinical trials that evaluated the drug’s safety and effectiveness as a treatment for hepatitis C infection.[15] All seven trials combined sofosbuvir with other drugs; three trials involved non-sofosbuvir comparators. One of the two such trials where the prescribing information included the outcomes was a randomized, open-label (unblinded) comparison of 12 weeks of sofosbuvir and ribavirin with 24 weeks of peginterferon alpha and ribavirin. Viral elimination rates at the end of each treatment period were 95% and 78%, respectively. The rates were only reported for one of the two genetic hepatitis C variants (genotype 2) tested because the results for the other were “suboptimal.” The second trial was a randomized, doubled-blinded trial that compared sofosbuvir and ribavirin with placebo; the viral elimination rates were 93% and 0%, respectively, but results again were limited to hepatitis C genotype 2.

Important risks of sofosbuvir include reactivation of hepatitis B infection (a black-box warning for this risk is included on the drug label), bradycardia (slow heart rate) with concomitant use of the abnormal heart rhythm drug amiodarone (PACERONE), fatigue and headaches.[16] As sofosbuvir is often prescribed with other antiviral medications, the risks of those drugs also should be considered.[17] Accordingly, for example, nausea, insomnia (with ribavirin), anemia (less common) and severe flu-like symptoms may be experienced when sofosbuvir is combined with ribavirin or interferon.

What You Can Do

Laboratory screening for hepatitis C may require two tests — one to identify past exposure and a second to determine whether that infection is active.[18] As of 2020, the U.S. Preventive Services Task Force recommends screening for hepatitis C virus infection in adults aged 18 to 79.[19] The recommendation applies to adults without symptoms (including pregnant persons) and without known liver disease. For most people, one-time screening is sufficient. The exception is persons at continued risk of hepatitis C virus infection, such as those with past or current injectiondrug use. If you are between ages 18 and 79 and have not been screened, you should discuss screening with your clinician. Because directly acting antivirals can cure hepatitis C in more than 95% of people infected and because early infection can be readily detected with blood screening, the Biden administration (backed by some of the nation’s leading scientists) has proposed a five-year national hepatitis C elimination program.[20]
 

References

[1] National Institute of Diabetes and Digestive and Kidney Diseases. Hepatitis C. Last reviewed March 2020. https://www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis/hepatitis-c. Accessed July 13, 2023.

[2] Alshuwaykh O, Kwo PY. Current and future strategies for the treatment of chronic hepatitis C. Clin Mol Hepatol. 2021;27(2):246-256.

[3] Centers for Disease Control and Prevention. Viral Hepatitis: Hepatitis C questions and answers for the public. Last reviewed July 28, 2020. https://www.cdc.gov/hepatitis/hcv/cfaq.htm. Accessed July 13, 2023.

[4] National Institute of Diabetes and Digestive and Kidney Diseases. Hepatitis C. Last reviewed March 2020. https://www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis/hepatitis-c. Accessed July 13, 2023.

[5] Mayo Clinic. Toxic Hepatitis. https://www.mayoclinic.org/diseases-conditions/toxic-hepatitis/symptoms-causes/syc-20352202. Accessed July 19, 2023.

[6] Alshuwaykh O, Kwo PY. Current and future strategies for the treatment of chronic hepatitis C. Clin Mol Hepatol. 2021;27(2):246-256.

[7] National Institute of Diabetes and Digestive and Kidney Diseases. Hepatitis C. Last reviewed March 2020. https://www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis/hepatitis-c. Accessed July 13, 2023.

[8] Centers for Disease Control and Prevention. Viral Hepatitis: Hepatitis C questions and answers for the public. Last reviewed July 28, 2020. https://www.cdc.gov/hepatitis/hcv/cfaq.htm. Accessed July 13, 2023.

[9] Chopra S, Pockross PJ. Overview of management of chronic hepatitis C virus infection. UpToDate. April 29, 2022.

[10] Alshuwaykh O, Kwo PY. Current and future strategies for the treatment of chronic hepatitis C. Clin Mol Hepatol. 2021;27(2):246-256.

[11] Gilead Sciences. Label: ledipasvir and sofosbuvir (HARVONI). March 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205834s032,212477s003lbl.pdf. Accessed July 13, 2023.

[12] Chopra S, Pockross PJ. Overview of management of chronic hepatitis C virus infection. UpToDate. April 29, 2022.

[13] Tapper EB, Parikh ND. Diagnosis and management of cirrhosis and its complications: a review. JAMA. 2023;329(18):1589-1602.

[14] Pecoraro V, Banzi R, Cariani E, et al. New direct-acting antivirals for the treatment of patients with hepatitis C virus infection: a systematic review of randomized controlled trials. J Clin Exp Hepatol. 2019;9(4):522-538.

[15] Gilead Sciences. Label: sofosbuvir (SOLVADI). March 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204671s017,212480s002lbl.pdf. Accessed July 13, 2023.

[16] Ibid.

[17] Chopra S, Pockross PJ. Overview of management of chronic hepatitis C virus infection. UpToDate. April 29, 2022.

[18] Fleurence RL, Collins FS. A National Hepatitis C Elimination Program in the United States: A Historic Opportunity. JAMA. 2023;329(15):1251-1252.

[19] US Preventive Services Task Force; Owens DK, Davidson KW, et al. Screening for Hepatitis C Virus Infection in Adolescents and Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2020;323(10):970-975.

[20] Fleurence RL, Collins FS. A National Hepatitis C Elimination Program in the United States: A Historic Opportunity. JAMA. 2023;329(15):1251-1252.