{TITLE}

Unfortunately, very little information is available on particular drugs in development. Most are still in the laboratory stages of development and have yet to be tested in humans. Here is an overview:

Preventing Cellular Infection

Before the virus can infect a cell, HCV must first successfully bind to the cell’s membrane. Based on their experiences with other viruses—including rhinovirus, influenza virus, picornavirus, and, we kid you not, the Semliki Forest virus and the foot and mouth disease virus (FMDV)—researchers have stumbled upon several possible approaches that may prevent the binding of HCV to liver cells (hepatocytes). These compounds, which include neutralizing antibodies and fusion inhibitors, are barely out of the test tube, so information about how effective they may be is extremely limited.

Viral Enzyme Targets

Once inside a cell, HCV uses several of its own enzymes to help itself replicate. Thus, finding drugs that stop these enzymes from functioning is a primary goal for many researchers. It is likely that these drugs will be used in combination, both with interferon and each other, in clinical trials.

Protease inhibitors, as their name implies, attack the HCV protease enzyme. Similar to HIV’s protease enzyme, HCV protease snips large strands of the virus into smaller pieces during the replication process, allowing them to form into new virus.

Two HCV protease inhibitors have been approved for people living with hepatitis C and are currently in clinical trials for people coinfected with HIV and HCV: Vertex Pharmaceuticals' Incivek (telaprevir) and Merck's Victrelis (boceprevir). People who combined these drugs with the standard treatment were far more likely to have a sustained response than people receiving only standard treatment. Encouragingly, the HCV protease inhibitors have substantially increased treatment response rates in people living with HCV genotype 1.

Other HCV protease inhibitors are in development, including compounds that are active against HCV strains resistant to Incivek and/or Victrelis, in addition to agents that only need to be taken once a day (Victrelis and Incivek require three-times-daily dosing).

There are also polymerase inhibitors, which are somewhat similar to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV. They bind to the polymerase enzyme that helps copy viral RNA. A number of HCV polymerase inhibitors are in early stages of research. Researchers hope one day to combine these newer drugs together, perhaps without the need for interferon or ribavirin.

Helicase is another enzyme used by HCV and is primarily responsible for unwinding the virus’ RNA once it is inside a cell. As this is an important step in the life cycle of HCV, helicase inhibitors may prove to be effective treatments. Researchers have recently determined the three-dimensional structure of helicase—an important discovery for pharmaceutical companies hoping to produce compounds that will work against it.

Three other classes of drugs include replicase inhibitors, antisense molecules, and ribozomes. Replicase inhibitors are being developed to halt the production of new HCV RNA. Antisense molecules are receiving much attention, as they have shown to be effective for the treatment of other viral infections, such as CMV. As a potential treatment against HCV, these drugs prevent the virus from producing necessary proteins and prevent HCV RNA from functioning properly. Ribozymes do the opposite of protease inhibitors. They cleave RNA at critical places needed by HCV to replicate.

Immune Therapies

Over the past few years, much has been learned about the role of the immune system and its inability to control HCV in the majority of people infected with the virus. People who are either able to clear the virus or control HCV replication for many years have an abundance of "type 1" T-cells (Th1), while people who gradually see their HCV viral load increase and experience liver damage mostly have "type 2" T-cells (Th2). The difference? Th1 T-cells produce vital proteins, called cytokines and chemokines, which program other immune system cells to seek and destroy HCV-infected cells. Th2 T-cells, on the other hand, produce antibodies that can prevent necessary immune system cells from doing their job correctly. The reason for this phenomenon is not known, but one thing is for sure: Th1 T-cells are the ones to have.

One of the advantages of interferon therapy is its ability to shift the immune response in people with chronic viral infections from Th2 to Th1. Some of the other immune-based therapies slated for development include cytokine therapies—particularly those that boost Th1 cytokines, such as interleukin-2 (IL-2) and interleukin-12 (IL-12), and those that block Th2 cytokines, including IL-10 and tumor necrosis factor (TNF)—and therapeutic vaccines. Other types of interferon are also being studied.

In addition to experimental treatments, researchers are still trying to understand why some people respond well to HCV treatment while others don't, apart from the known factors such as HCV viral load and degree of fibrosis. One relatively new discovery is that people who carry two copies of a gene that makes an immune signalizing protein called IL-28 are far more likely to respond to HCV treatment than people who do not have both gene copies. Experts have not begun recommending that people get tested for these genes before starting treatment, but the test might ultimately be used in the clinic if further research confirms its benefit.

If you would like to find out if you are eligible for any clinical trials involving new treatments for HCV, there is an interactive web site run by the U.S. National Insitutes of Health (AIDSinfo.nih.gov). They have "health information specialists" you can talk to at their toll-free number at 1-800-HIV-0440 (1-800-448-0440).