Direct-acting antivirals

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The term Direct-acting antivirals (DAA) has long been associated with the combination of antiviral drugs used to treat hepatitis C infections. These are the more effective than older treatments such as ribavirin (partially indirectly acting) and interferon (indirect acting). The DAA drugs against hepatitis C are taken orally, as tablets, for 8 to 12 weeks. [1] The treatment depends on the type or types (genotypes) of hepatitis C virus that are causing the infection. [2] Both during and at the end of treatment, blood tests are used to monitor the effectiveness of the treatment and subsequent cure. [1]

The DAA combination drugs used include: [3]

The United States Food and Drug Administration approved DAAs on the basis of a surrogate endpoint called sustained virological response (SVR). [4] SVR is achieved in a patient when hepatitis C virus RNA remains undetectable 12–24 weeks after treatment ends. [5] [6] Whether through DAAs or older interferon-based regimens, SVR is associated with improved health outcomes and significantly decreased mortality. [7] [8] [9] For those who already have advanced liver disease (including hepatocellular carcinoma), however, the benefits of achieving SVR may be less pronounced, though still substantial. [9]

Despite its historical roots in hepatitis C research, the term "direct-acting antivirals" is becoming more broadly used to also include other anti-viral drugs with a direct viral target such as aciclovir (against herpes simplex virus), letermovir (against cytomegalovirus), or AZT (against human immunodeficiency virus). In this context it serves to distinguish these drugs from those with an indirect mechanism of action such as immune modulators like interferon alfa. This difference is of particular relevance for potential drug resistance mutation development. [10]

Related Research Articles

<span class="mw-page-title-main">Hepatitis</span> Inflammation of the liver

Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), poor appetite, vomiting, tiredness, abdominal pain, and diarrhea. Hepatitis is acute if it resolves within six months, and chronic if it lasts longer than six months. Acute hepatitis can resolve on its own, progress to chronic hepatitis, or (rarely) result in acute liver failure. Chronic hepatitis may progress to scarring of the liver (cirrhosis), liver failure, and liver cancer.

<span class="mw-page-title-main">Hepatitis C</span> Human viral infection

Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include fever, dark urine, abdominal pain, and yellow tinged skin. The virus persists in the liver, becoming chronic, in about 70% of those initially infected. Early on, chronic infection typically has no symptoms. Over many years however, it often leads to liver disease and occasionally cirrhosis. In some cases, those with cirrhosis will develop serious complications such as liver failure, liver cancer, or dilated blood vessels in the esophagus and stomach.

<span class="mw-page-title-main">Ribavirin</span> Antiviral medication

Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, peginterferon alfa-2b or peginterferon alfa-2a. Among the viral hemorrhagic fevers it is used for Lassa fever, Crimean–Congo hemorrhagic fever, and Hantavirus infection but should not be used for Ebola or Marburg infections. Ribavirin is taken by mouth or inhaled.

<span class="mw-page-title-main">Viral hepatitis</span> Liver inflammation from a viral infection

Viral hepatitis is liver inflammation due to a viral infection. It may present in acute form as a recent infection with relatively rapid onset, or in chronic form, typically progressing from a long-lasting asymptomatic condition up to a decompensated hepatic disease and hepatocellular carcinoma (HCC).

Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) co-infection is a multi-faceted, chronic condition that significantly impacts public health. According to the World Health Organization (WHO), 2 to 15% of those infected with HIV are also affected by HCV, increasing their risk of morbidity and mortality due to accelerated liver disease. The burden of co-infection is especially high in certain high-risk groups, such as intravenous drug users and men who have sex with men. These individuals who are HIV-positive are commonly co-infected with HCV due to shared routes of transmission including, but not limited to, exposure to HIV-positive blood, sexual intercourse, and passage of the Hepatitis C virus from mother to infant during childbirth.

Pegylated interferon alfa-2b is a drug used to treat melanoma, as an adjuvant therapy to surgery. Also used to treat hepatitis C, it is no longer recommended due to poor efficacy and adverse side-effects. Subcutaneous injection is the preferred delivery method.

<span class="mw-page-title-main">Boceprevir</span> Chemical compound

Boceprevir is a protease inhibitor used to treat hepatitis caused by hepatitis C virus (HCV) genotype 1. It binds to the HCV nonstructural protein 3 active site.

<span class="mw-page-title-main">Telaprevir</span> Chemical compound

Telaprevir (VX-950), marketed under the brand names Incivek and Incivo, is a pharmaceutical drug for the treatment of hepatitis C co-developed by Vertex Pharmaceuticals and Johnson & Johnson. It is a member of a class of antiviral drugs known as protease inhibitors. Specifically, telaprevir inhibits the hepatitis C viral enzyme NS3/4A serine protease. Telaprevir is only indicated for use against hepatitis C genotype 1 viral infections and has not been proven to be safe or effective when used for other genotypes of the virus. The standard therapy of pegylated interferon and ribavirin is less effective than telaprevir in those with genotype 1.

<span class="mw-page-title-main">Hepatitis C virus nonstructural protein 5A</span>

Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without trans-membrane helices.

<span class="mw-page-title-main">Sofosbuvir</span> Chemical compound

Sofosbuvir, sold under the brand name Sovaldi among others, is a medication used to treat hepatitis C. It is taken by mouth.

<span class="mw-page-title-main">Simeprevir</span> Chemical compound

Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.

<span class="mw-page-title-main">Ledipasvir</span> Hepatitis C drug

Ledipasvir is a drug for the treatment of hepatitis C that was developed by Gilead Sciences. After completing Phase III clinical trials, on February 10, 2014, Gilead filed for U.S. approval of a ledipasvir/sofosbuvir fixed-dose combination tablet for genotype 1 hepatitis C. The ledipasvir/sofosbuvir combination is a direct-acting antiviral agent that interferes with HCV replication and can be used to treat patients with genotypes 1a or 1b without PEG-interferon or ribavirin.

<span class="mw-page-title-main">Ledipasvir/sofosbuvir</span> Medication used to treat hepatitis C

Ledipasvir/sofosbuvir, sold under the trade name Harvoni among others, is a medication used to treat hepatitis C. It is a fixed-dose combination of ledipasvir and sofosbuvir. Cure rates are 94% to 99% in people infected with hepatitis C virus (HCV) genotype 1. Some evidence also supports use in HCV genotype 3 and 4. It is taken daily by mouth for 8–24 weeks.

<span class="mw-page-title-main">Gamal Esmat</span>

Gamal Esmat is a professor at Endemic Medicine and Hepatogastroenterology Department, Cairo University. He was vice president of Cairo University for Graduate Studies and Research.

Elbasvir/grazoprevir, sold under the brand name Zepatier, is a fixed-dose combination for the treatment of hepatitis C, containing elbasvir and grazoprevir. It is used to treat chronic hepatitis C virus (HCV) genotypes 1 or 4 infection in both treatment-naïve and treatment-experienced patients.

<span class="mw-page-title-main">Sofosbuvir/daclatasvir</span> Combination drug

Daclatasvir/sofosbuvir is a two-drug combination for the treatment of hepatitis C. It is given as a single daily pill containing daclatasvir, a viral NS5A inhibitor, and sofosbuvir, a nucleotide inhibitor of the viral RNA polymerase NS5B.

<span class="mw-page-title-main">Discovery and development of NS5A inhibitors</span>

Nonstructural protein 5A (NS5A) inhibitors are direct acting antiviral agents (DAAs) that target viral proteins, and their development was a culmination of increased understanding of the viral life cycle combined with advances in drug discovery technology. However, their mechanism of action is complex and not fully understood. NS5A inhibitors were the focus of much attention when they emerged as a part of the first curative treatment for hepatitis C virus (HCV) infections in 2014. Favorable characteristics have been introduced through varied structural changes, and structural similarities between NS5A inhibitors that are clinically approved are readily apparent. Despite the recent introduction of numerous new antiviral drugs, resistance is still a concern and these inhibitors are therefore always used in combination with other drugs.

<span class="mw-page-title-main">Narlaprevir</span> Chemical compound

Narlaprevir, is an inhibitor of NS3/4A serine protease, intended for the treatment of chronic hepatitis C caused by genotype 1 virus in combination with other antiviral drugs.

<span class="mw-page-title-main">NS5B inhibitor</span> Class of pharmaceutical drugs

Non-structural protein 5B (NS5B) inhibitors are a class of direct-acting antivirals widely used in the treatment of chronic hepatitis C. Depending on site of action and chemical composition, NS5B inhibitors may be categorized into three classes—nucleoside active site inhibitors (NIs), non-nucleoside allosteric inhibitors, and pyrophosphate analogues. Subsequently, all three classes are then subclassified. All inhibit RNA synthesis by NS5B but at different stages/sites resulting in inability of viral RNA replication. Expression of direct-acting NS5B inhibitors does not take place in cells that are not infected by hepatitis C virus, which seems to be beneficial for this class of drugs.

<span class="mw-page-title-main">Interferon Lambda 4</span> Protein-coding gene in the species Homo sapiens

Interferon lambda 4 is one of the most recently discovered human genes and the newest addition to the interferon lambda protein family. This gene encodes the IFNL4 protein, which is involved in immune response to viral infection.

References

  1. 1 2 "Overview-Hepatitis C". National Health Service, UK. 21 June 2018.
  2. ↑ González-Grande R, Jiménez-Pérez M, González Arjona C, Mostazo Torres J (January 2016). "New approaches in the treatment of hepatitis C". World Journal of Gastroenterology. 22 (4): 1421–32. doi: 10.3748/wjg.v22.i4.1421 . PMC   4721977 . PMID   26819511.
  3. ↑ Falade-Nwulia O, Suarez-Cuervo C, Nelson DR, Fried MW, Segal JB, Sulkowski MS (May 2017). "Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review". Annals of Internal Medicine. 166 (9): 637–648. doi:10.7326/M16-2575. PMC   5486987 . PMID   28319996.
  4. ↑ "Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure". Food and Drug Administration. 28 February 2022.
  5. ↑ Smith-Palmer, Jayne; Cerri, Karin; Valentine, William (December 2015). "Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits". BMC Infectious Diseases. 15 (1). doi: 10.1186/s12879-015-0748-8 . PMC   4299677 .
  6. ↑ Yoshida, Eric M.; Sulkowski, Mark S.; Gane, Edward J.; Herring, Robert W.; Ratziu, Vlad; Ding, Xiao; Wang, Jing; Chuang, Shu‐Min; Ma, Julie; McNally, John; Stamm, Luisa M.; Brainard, Diana M.; Symonds, William T.; McHutchison, John G.; Beavers, Kimberly L.; Jacobson, Ira M.; Reddy, K. Rajender; Lawitz, Eric (January 2015). "Concordance of sustained virological response 4, 12, and 24 weeks post‐treatment with sofosbuvir‐containing regimens for hepatitis C virus". Hepatology. 61 (1): 41–45. doi: 10.1002/hep.27366 .
  7. ↑ Simmons, Bryony; Saleem, Jawaad; Heath, Katherine; Cooke, Graham S.; Hill, Andrew (1 September 2015). "Long-Term Treatment Outcomes of Patients Infected With Hepatitis C Virus: A Systematic Review and Meta-analysis of the Survival Benefit of Achieving a Sustained Virological Response". Clinical Infectious Diseases. 61 (5): 730–740. doi: 10.1093/cid/civ396 . PMC   4530725 .
  8. ↑ van der Meer, Adriaan J.; Veldt, Bart J.; Feld, Jordan J.; Wedemeyer, Heiner; Dufour, Jean-François; Lammert, Frank; Duarte-Rojo, Andres; Heathcote, E. Jenny; Manns, Michael P.; Kuske, Lorenz; Zeuzem, Stefan; Hofmann, W. Peter; de Knegt, Robert J.; Hansen, Bettina E.; Janssen, Harry L. A. (26 December 2012). "Association Between Sustained Virological Response and All-Cause Mortality Among Patients With Chronic Hepatitis C and Advanced Hepatic Fibrosis". JAMA. 308 (24): 2584–2593.
  9. 1 2 Backus, Lisa I.; Belperio, Pamela S.; Shahoumian, Troy A.; Mole, Larry A. (February 2019). "Impact of Sustained Virologic Response with Direct‐Acting Antiviral Treatment on Mortality in Patients with Advanced Liver Disease". Hepatology. 69 (2): 487–497. doi:10.1002/hep.29408.
  10. ↑ Kleandrova VV, Scotti MT, Speck-Planche A (2021). "Indirect-Acting Pan-Antivirals vs. Respiratory Viruses: A Fresh Perspective on Computational Multi-Target Drug Discovery". Current Topics in Medicinal Chemistry. 21 (30): 2687–2693. doi:10.2174/1568026621666211012110819. PMID   34636311.
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