Direct-acting antiviral agents for the treatment of hepatitis C

This is the fourth in my series on progress towards eliminating hepatitis C infection and disease. Read more about hepatitis C part 1, part 2 and part 3.

Previous articles in this series have outlined the seriousness and uncontrollable nature of hepatitis C. In the absence of a vaccine, control and treatment of hepatitis C, as for HIV/AIDS, depends on the use of antiviral drugs. medicine. Recent advances in the development of several highly active anti-hepatitis C drugs are triumphs of modern medicine. These drugs usher in an era of effective treatment and even eradication of hepatitis C both nationally and globally. Later in this series, I will describe how these drugs were used to eradicate his hepatitis C infection and how that success will be replicated in other countries.

history

The first effective treatment for hepatitis C infection, alpha interferon, was introduced in 1986. Rather than acting directly on the virus itself, interferon activates the host’s antiviral immune defenses. This early version of immunotherapy had some clinical benefit but little benefit against more advanced hepatic C-induced liver disease. Treatment with α-interferon is associated with serious adverse events such as hair loss, periodontal disease, and flu-like symptoms.

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In the mid-1990s, the drug ribavirin was added to the treatment regimen. Interferons act by activating the immune system, whereas ribavirin interferes with viral replication, presumably by inhibiting polymerases. The combination of the two drugs resulted in sustained suppression of infection in up to half of the treated patients. Drug combinations are not equally effective against all her hepatitis C strains. The addition of ribavirin increased the effectiveness of alpha-interferon therapy, but added the risk of serious side effects such as thyroid problems, anemia, and psychosis.

The next generation of hepatitis C drugs emerged in the early 2000s in the form of long-acting pegylated alpha-interferon. Pegylation is the process of increasing the molecular size of interferon by adding polyethylene glycol molecules. The larger the interferon molecule, the slower the drug absorption rate and the longer the drug stays in the body. These long-acting pegylated interferons showed higher response rates than previous interferon therapy, especially when combined with ribavirin. It also required fewer injections than interferon monotherapy, which reduces side effects.

One of the major drawbacks of early hepatitis C drugs was their varying efficacy across different hepatitis C virus subtypes. In the United States, approximately 75% of chronic hepatitis C infections are caused by hepatitis C genotype 1, 15-20% by genotypes 2 or 3, and less than 5% by genotypes 4, 5, or 6. triggered. Combination therapy with alpha-interferon and ribavirin increased the efficacy of interferon monotherapy from approximately 15% to 40%, although responses varied by hepatitis C virus genotype. Only an average of 30% of subtype 1 patients were able to achieve a sustained viral response, whereas his 70% of subtype 2 and 3 patients were able to achieve a sustained viral response. The efficacy of the combination of long-acting pegylated alpha-interferon and ribavirin also varied by genotype. Patients with genotypes 1 and 4 responded the least to treatment, with only about half of patients with these subtypes achieving a sustained viral response. There was a sustained viral response rate of 10% and half of the duration of treatment.

current medicine

As the need for more radical hepatitis C treatments grew, pharmaceutical companies began investing in developing new types of drugs. This is a drug that can provide a more sustained viral response across all genotypes. This new generation of drugs, called direct-acting antivirals, are designed to attack specific molecular targets known to be involved in hepatitis C virus replication. In 2011, the first direct-acting antiviral drugs for hepatitis C, telaprevir (developed by Vertex Pharmaceuticals and Johnson & Johnson) and boceprevir (developed by Merck), were approved by the Federal Food and Drug Administration. These first-generation direct-acting antivirals produced more durable virologic responses, shorter treatment durations, and fewer side effects, especially in patients with genotype 1. Today’s direct-acting antiviral drugs are even more effective and are classified according to which part of the hepatitis C virus replication cycle they target (Figure 1). There are three classes of direct-acting antiviral drugs: NS3/4A protease inhibitors, inhibitors targeting NS5A replicase factors, and inhibitors targeting NS5B RNA polymerase.

NS3/4A protease inhibitors target the NS3/4A protease enzyme, which the virus needs to make the proteins it needs for self-replication. These agents are primarily used to treat hepatitis C virus genotype 1, but are sometimes used in combination with other agents to attack the virus from multiple sites of replication. Compared to other classes of direct-acting antivirals, NS3/4A have longer regimens, more side effects, and a higher potential for hepatitis C virus resistance. NS3/4A protease inhibitors currently approved for the treatment of hepatitis C include glazoprevir, paritaprevir, voxilprevir, and glecaprevir.

NS5A is a multifunctional protein important for viral genome replication. NS5A inhibitors work by blocking the virus’ ability to assemble new virions. These inhibitors are effective against all viral genotypes but are sometimes poorly tolerated and susceptible to resistance. These agents are also known to work more effectively when combined with alpha-pegylated interferon or ribavirin. Generic names for NS5A protein inhibitors include Elbasivr, Ledipasvir, Ombitasvir, Velpatasvir, and Pibrentasvir.

NS5B is a membrane-anchored enzyme that initiates the synthesis of the hepatitis C virus RNA genome. NS5B inhibitors stop hepatitis C virus replication by blocking the function of the enzyme. These drugs work well across all genotypes, are generally well tolerated, and are least susceptible to viral resistance. there is.

Combinations of direct-acting antiviral drugs

As with interferon therapy, optimal treatment with direct-acting antivirals includes consideration of the patient’s genotype and comorbidities such as advanced cirrhosis and co-infection with hepatitis B or HIV. Also, as with previous treatments, many direct-acting antivirals are more effective when combined with other antivirals. and gain resistance to the agents used in the attack. When used in combination with other antivirals, including ribavirin, direct-acting antivirals can inhibit multiple replication targets and enhance efficacy. The market for these new combination drugs was also very lucrative. In 2011, Gilead acquired pharmaceutical company Pharmasset for his $11 billion and produced Harvoni, his first hepatitis C combination drug approved in 2014. Harvoni He combines two direct-acting antiviral therapies (ledipasvir and sofosbuvir) and is the first FDA-approved regimen. No additional pegylated interferon injections and ribavirin were needed.

In the absence of a prophylactic hepatitis C vaccine, direct-acting antiviral drugs have proven to be highly effective in treating active hepatitis C virus infection. However, timely and appropriate treatment for hepatitis C remains an important part of disease eradication. The next part of this series describes a clinical protocol for hepatitis C screening and direct-acting antiviral therapy.