Hepatitis C | Triple-Drug Cocktail in the Works for Hepatitis C Therapy

Drugs that are specific to the hepatitis C test soon go to the clinic, giving more hope to patients, but vaccine is still elusive

people infected with the hepatitis C virus (HCV) face a long road of drug treatment, in the best case, can cure their infections and allow their livers to recover from a liver disease associated with HCV, whose symptoms range from scarring and cancer to organ failure. Unfortunately, almost half of patients treated for the most common strain of HCV, the standard antiviral drugs fail to remove the virus. And even in cases where the drug regimen is effective, flu symptoms, depression and anemia are common side effects during the treatment period 48 weeks

Here is the crux of the current dilemma of treatment.: when John McHutchison, a liver specialist at the Duke Clinical Research Institute (DCRI) in Durham, NC, discuss with patients whether to start treatment for their HCV infections chronic, tells that they would get a 40 percent chance of curing their infection. The system contains two specific HCV antiviral drugs called interferon and ribavirin. However, it also tells his patients today in about 18 months new treatments might be available to improve your chances. “Many of them who have not responded to our current treatment are waiting for these new drugs [HCV],” he says.

The World Health Organization estimates that about 170 million people worldwide have chronic infection of their bodies-resulting HCV have not been able to fight the acute onset and are therefore the risk of developing potentially fatal liver disease. Approximately 3.2 million people in the US They are chronically infected with HCV, according to the US Centers for Disease Control and Disease Prevention. In the US patients are between 38 and 41 percent chance of responding to the combination of interferon and ribavirin, depending on the level of virus in their bodies, as well as the doses of drugs. McHutchison says the likelihood of responding to HCV treatment is higher among European patients Americans, but as low as 25 percent among African Americans, due to differences in mutations in immune genes among these groups.

How long as McHutchison of patients and others will have to wait for new HCV drug depends on the success of drug candidates currently in Phase III clinical trials on a large scale. The strategy of these drugs is directly undermine the ability of HCV to replicate within cells. In contrast, the non-specific interferon stimulates the immune system (the mechanism of ribavirin is not understood well). One of the new HCV drugs, when administered in combination with interferon and ribavirin, the percentage of patients who are cured of the virus to 60 and reduces total processing time. If the drug, called telaprevir, performs well in Phase III trials are underway, could be approved for patients before 2011, says McHutchison, who runs trials with telaprevir.

Although it is in an earlier, a second class of drugs for HCV in clinical development stage could also be part of the treatment strategy. Instead of going after the virus itself, these compounds inhibit the native molecules for the patient. The right kind of cell target “should be mandated by the virus, and then has to be dispensable for the host for the duration of treatment,” says Henrik Orum, scientific director of Santaris Pharma in Denmark. Orum group showed that a type of RNA called microRNA molecule could be that kind of goal in a study that was published on December 3 in Science . Whereas this microRNA is required for HCV replication does not appear that the absence of adverse effects to the host.

Of course, the best way to deal with HCV infection is to prevent altogether.T. Jake Liang, head of the Disease Investigation Branch liver at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), says that even if HCV therapy became an effective cure for all “, there are still cases of new infections through various means, “such as intravenous drug use, sexual and close personal contact, and contaminated medical instruments or products. Because injection drug use is also a major risk factor for HIV, between 50 and 90 percent of injecting drug users who are HIV-positive are also infected with HCV. Co-infection with HIV accelerates the progression of liver disease associated with HCV, and may compromise the effectiveness of HCV treatment.

In the long run, Liang says, drug treatment is more expensive and complicated than vaccination, adding that it is difficult for developing countries to pay the cost of treatment of 48 weeks in the currently it runs to $ 20,000 in the US with current vaccine candidates for HCV in the early stages of clinical trials, however, the anti-HCV drugs is likely to beat the vaccines on the market.

Attack front HCV

The precursors among new medicines adapted to contain HCV infection are telaprevir and boceprevir. Both drugs are currently in your past, or Phase III trials. If the tests are successful, companies that developed them submitted to the Food and Drug Administration US for your approval. Telaprevir, designed by Vertex Pharmaceuticals in Cambridge, Mass., And boceprevir, Schering-Plough in Kenilworth, N.J., also share a similar mechanism of action and effectiveness. Eric Lawitz, president and medical director of Alamo Medical Research in San Antonio, Tex., Expects boceprevir, as telaprevir, should increase the number of patients who respond to interferon and ribavirin by 20 percent. McHutchison Lawitz worked with the DCRI in some of the early clinical studies of telaprevir.

These drugs target HCV-protease enzymes of the virus. When the virus infects a cell genome RNA is translated into a long polyprotein. HCV protease, along with some cellular proteases, should split this polyprotein in different viral proteins that can perform other jobs in the viral cycle, such as making more copies of the viral genome life. laboratory strains harboring mutations HCV protease paralyzing can not replicate in cells in a petri dish and can not establish an infection in chimpanzees, the animal model for the study of HCV. Because of the importance of HCV protease, Vertex scientists and Schering designed small molecules based on the structure of the protease protein, which will fit the active site of the protease. Next, they tested for their ability to disarm the enzyme. The winners were telaprevir and boceprevir.

In the most recent clinical trial phase II, a team of researchers, including McHutchison, found that 61 percent of patients receiving treatment three times telaprevir with interferon and ribavirin responded to treatment compared to 41 percent in the control group received the usual schedule of 48 weeks of interferon and ribavirin. Treatment response meant that the patient had undetectable levels of virus for at least 24 weeks after the end of treatment, indicating that could be cured of HCV. Also, instead of 48 weeks, patients were on triple therapy for 12 weeks followed by 12 weeks of double therapy (interferon and ribavirin). The study results were published in the April 30 edition of The New England Journal of Medicine.

The drawback of triple therapy, however, are its side effects. Rash was the most common, as well as an overall high degree of nausea and anemia associated with dual therapy. Because of such effects, 21 percent of the triple-therapy group withdrew from the study, compared with 11 percent in the control group.

McHutchison attributes the success of the triple down the level of virus therapy to the fact that “we are only attacking viral replication otherwise.” But there could be some overlap between the action of protease inhibitors and Interferon. With cleavage of the viral polyproteins, which benefits the virus, HCV protease also cleaves cellular proteins involved in the immune response, which may compromise the patient’s immunity. Interferon treatment restores part of the innate immune response. And, if a protease inhibitor is added to the treatment mixture, which may avoid some of the destruction of the host immune response.

As is the problem with any drugs HCV protein, viruses have emerged that are resistant to protease inhibitors is directed. Because patients harbor a smorgasbord of species of HCV, it could not easily be a few in the population that are able to grow despite protease inhibitors, causing a so-called “viral breakthrough.” This heterogeneity is due to the fact that HCV at a high speed and the viral polymerase replicates, making copies of the RNA genome, is prone to error. In fact, studies have estimated that the value of gene replication of one day, all sites in the viral genome mutates at least once.

In the recent phase II study of telaprevir, viral breakthrough occurred in 7 percent of patients receiving triple therapy. “[But] hope is that most of [viruses that break through will] respond to interferon and ribavirin,” said Lawitz medical Alamo.

protease inhibitors could be just the beginning of anti-HCV drugs are added to the treatment regimen. Compounds that inhibit HCV polymerase currently in Phase II trials and, if all goes well, could reach the market about a year after protease inhibitors. Although it would be less likely for a viral species have mutations that made resistant to both protease inhibitors and polymerase, the idea is that HCV strains resistant to multiple drugs may still arise as HIV strains have spite ofantiretroviral therapy.

inhibit indirectly HCV infection

To reduce the risk of viral resistance and give patients infected with HCV another treatment option, scientists are looking for inhibit cellular molecules that are important for HCV replication. In 2006 scientists discovered that HCV needs a microRNA, a regulatory RNA that does not get translated into protein, in order to replicate. Although this microRNA called miR-122, binds directly to the viral genome it is not entirely clear how miR-122 helps the virus replicate.

Based on the dependence of HCV in the miR-122, Santaris scientists decided to try a technology that also have been developed to treat various cancers, such as leukemia and solid tumors. The team called SPC3649 synthesized a RNA molecule is designed to base pair with miR-122 and has a blocking chemical modification at one of its two possible confirmations. Blocking the molecule allows miR-122 join more efficiently, thereby avoiding the miR-122 binding HCV RNA.

The results that Santaris group saw in HCV infected chimpanzees, published Nov. 30 in science, encouraged scientists to conduct Phase I SPC3649 trials are currently underway. They found that the level of HCV collapsed in the four chimpanzees chronically infected that SPC3649 injected weekly for 12 weeks. These results do not resolve, however, if SPC3649 can erase a chronic infection because the virus levels rebounded after scientists discontinued treatment. “Future studies in human patients are investigated that point,” says Orum, who is the project leader, adding that “12 weeks is a relatively short period of time to eradicate HCV virus.”

Before SPC3649 as a potential HCV drug can be tested in humans, the team Orum has to deal with its security. This Phase I trial tested four different negative HCV-doses of SPC3649 in healthy patients, should shed light on this issue when completed in the first half of 2010. Since the miR-122 normally regulates cholesterol levels, the effect secondary is more likely that it would disrupt cholesterol-particles both “good” (HDL) and varieties “bad” (LDL). In chimps SPC3649 reduced cholesterol levels by 40 percent, he says Orum not affect your health and is similar to the effect of cholesterol-lowering drugs, namely statins. Overall, it does not expect that inhibition of a miRNA could completely alter a cellular process. “MicroRNAs do not act like switches on / off, act as fine tuners of physiological pathways,” he says.

If SPC3649 helps eradicate the virus in humans, doctors would have reduced the fear of the virus developing resistance. For this, a virus would have to arise that it has acquired a different mode of replication, which would probably involve multiple mutations. If the virus were able to adapt to replicate without miR-122, “would very likely that mutations have been collected during the [period of miR-122] repression that have repopulated chimpanzees,” says Orum. “With direct acting drugs [such as protease inhibitors], which collect escape mutants with days of treatment.”

The search for a vaccine

Groups working to develop a vaccine against HCV have a number of obstacles to contend with. “Basically we face the same problems as people trying to develop a vaccine against HIV,” says Liang NIDDK. These groups face “all the same problems,” added Liang, who is trying to demonstrate efficacy for the first time in chimpanzees-of its own vaccine candidate.

These problems are of three types, as Liang explained: The first is that the envelope proteins lining the outer membrane of the virus do a poor job of stimulating an antibody response in the host. This poor immunogenicity is probably part of the reason, Liang says, that HCV is the only RNA virus (although HIV has an RNA genome, is considered a retrovirus) that is able to persist in the host and cause chronic infection. Second, any vaccine would protect against viral species mix in a patient by finding a region of the envelope protein that is important enough to be conserved among different species. Finally, the virus has developed strategies to evade the immune response, for example, by repressing interferon response of the host

However, there are several vaccines are in clinical trials, although in the early safety trials . Liang says it is probably possible to finally find regions of envelope proteins that are conserved among different species. Another question will be how to deliver to the hosts. While some groups, such as the development team vaccines Novartis Pharmaceuticals, are testing these fragments of proteins in solution, Liang and his colleagues are trying to ride on “virus-like particles.” “We believe that the virus-like particles mimic much better than soluble proteins virus,” says Liang.

If any of these candidate vaccines reach large-scale clinical trials, scientists will then face the next hurdle: how to test them in the general population. Because HCV prevalence is low in the US, testing the ability of a vaccine to prevent infection would probably require thousands of American volunteers or conduct testing in high incidence areas, such as China, India or Egypt. Liang said that many groups involved in the development of HCV vaccines probably first test its vaccine as a therapeutic vaccine to treat people with chronic HCV infection.

Even if one candidate vaccine is a success, it could take years to prove its effectiveness, allowing time for anti-HCV drugs to finish moving through the development pipeline to market . Lawitz of Alamo predicts that “in 2011 three drugs are the standard treatment [for HCV].” The addition of telaprevir and other pending anti-HCV drugs to the armory would make more personalized treatment of HCV, similar to how antiretroviral treatment for HIV has become.

McHutchison expected in early 2010, people who are diagnosed with HCV will be tested to see which mutations they have in the genes that predict immune response to treatment with interferon and ribavirin. People who carry the least likely to respond to current treatment, those of African American descent, may want to hold off the most promising treatments like telaprevir. On the other hand, “if you are genetically predisposed to having [a higher] opportunity, perhaps only need eight to 12 weeks [on therapy],” says McHutchison.

He adds: “To be able to go to tell [to a patient that you have a 40 percent chance of clearing the virus] to sit back and say we’re going to have to try for six months and you have the opportunity of two-thirds is a very different conversation.”

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