Edge

How to defeat a virus

Many viruses have found ways to escape the body's defence system. The slyest of the lot is the Hepatitis-C virus. The virus sabotages the protective system of millions of infected people by making trillions of new viruses every day, for years. Aashruti Kak finds out what is being done to beat the silent killer

The Hepatitis-C virus (HCV) was first identified in 1989. However, this dreadful disease has been spreading unknowingly since the early 1960s, mainly through blood transfusions. Reliable blood tests became available only in 1992. Besides, more recently, the increased prevalence of intravenous drug use and other unrecognisable transmission routes have added to the spread of the disease. For example, the practice of self-inflicted injury as a part of the religious rites by certain religious communities and some tribals has also increased the spread of the disease in India. Dr Samir Shah, Consultant Hepatologist and Gastroenterologist, Jaslok Hospital and Research Centre and Breach Candy Hospital, says, "Indirectly, you can come to know whether you are infected or not through the blood donor data because anybody who goes to donate blood is automatically checked for HCV and HIV. And around 0.6 to 0.9 per cent of blood donors test positive for HCV in the process. These are apparently healthy people, so you can extrapolate." He further says, "Mortality will depend whether the infected people go out to develop liver disease, because not all would develop that condition. It is a very slow virus which affects the liver over 20-40 years. Around 20 percent of the infected will not develop liver disease."

Existing Approved Therapies

The standard treatment for HCV is the combination therapy with PEGylated interferon-alpha and ribavirin. But unfortunately, the treatment, the only available one, is inadequately efficient, has poor tolerability, and involves a huge expense. Prashant Tewari, Managing Director, USV, says, "Interferon-alpha is the only known drug to induce sustained HCV clearance and cause an improvement in liver histology. IFN-alpha monotherapy is limited by adverse side effects such as severe flu-like syndrome, leucopoenia and thrombocytopenia. Besides, a Sustained Virological Response is achieved in only 15 per cent of patients." He goes on to say, "The combination with ribavirin yields an Systemic Vascular Resistance in 35-40 per cent of patients. PEGylated interferon is more effective than Interferon-alpha. Yet, overall 50 per cent of treated patients do not experience significant long-term benefits from the current PEGylated interferon and ribavirin-based combination therapy." Hence, there is an urgent need for new treatment options that are more potent and less toxic.

The fact that there is a considerable drop out rate due to adverse side effects in patients on the treatment just makes it worse. "We do have good treatments, but either the treatment may not work because the person does not respond or the person comes too late with liver failure; then the treatments are useless. If the patient reacts adversely to the treatment, then we have to discontinue it. There is no other alternative left," says Shah. It becomes even more difficult to treat patients in case of corresponding illnesses. Shah elaborates, "If the patient has got kidney disease, then we cannot use ribavirin because the haemoglobin is already low and ribavirin causes a further drop in RBCs. And when the main drug is taken away, the injection (interferon-alpha) does not work well in the absence of the tablets. If the patient has got both HIV and Hepatitis C then there is double problem."

What Would Work?

"Since the current therapeutic regimens (interferon monotherapy IFN- in combination with ribavirin and PEGylated interferon) do not yield adequate Sustained Virological Response, and considering the rapid spread of the virus, protecting the unexposed population is also critical. These facts make the development of an HCV vaccine an obvious necessity," says Tewari. Shah, on the other hand, thinks that therapies and vaccines have to go hand in hand, "Even if you develop a vaccine, it would protect person at risk, but what about the people who already have the virus. We need to have what you call a therapeutic vaccine, a vaccine which treats." He explains, "The final treatment is the body's own defence mechanism. So, if we can by some way alter the defence mechanism, the body will be able to fight out the virus, then it becomes a therapeutic vaccine." There are two types of vaccines available—a prophylactic vaccine, which boosts the immune system so that the person does not get the virus, and a therapeutic vaccine, which stimulates the body's immune system to clear the virus.

"Lot of new compounds are being developed, many of them being oral candidates with polymerase and protease inhibitors and so on. But alone they do not work as of now," says Shah. "That's the whole idea. If we can have two or three molecules that can be combined, we can have only one tablet rather than an injection," he adds.

Market for a Hep-C Vaccine

HCV has infected more than 170 million people globally and can establish a chronic infection in up to 85 percent of cases. This is five times more than HIV-infected individuals. Hep-C is the most common cause of hepatocellular carcinoma and the primary reason for liver transp-lantations among adults. All drugs have side-effects and troubles, and every disease has victims who want treatment at any cost. Too much focus on these can make you lose sight of significant things like the safety and efficacy of the developing drug over existing therapies, and whether there is a market for it. Currently there are no true therapeutic vaccines available, though research on several Hep-C candidates is ongoing worldwide. "However, according to estimates the total market of currently available Hep-C therapies is about $3 billion annually, which is expected to quadruple by 2015" says Tewari. Hence, the market for a Hep-C vaccine is highly competitive with several other companies developing drugs.

In India, USV seems to be the only company which is working towards the development of a Hep-C vaccine for Indian genotype of the virus. But it is too early to say anything as the animal tests are yet to commence. "We do not know of any other Indian company currently into Hep-C vaccine development. In the international scene, a number of major pharma companies like Merck, Chiron, Novartis and Institut Pasteur are known to have ongoing Hep-C vaccine programmes," says Tewari. There are other international companies as well that have been, and are working on developing a Hep-C vaccine.

However, Shah says, "We are currently working on a clinical trial for a vaccine, which is a part of a global clinical trial. It is for a new compound known as albuferon, which is albumin bound to interferon. It's an international trial with more than 2,000 patients under trial. We are looking at the safety and efficacy compared to the standard of care." Shah, who is also the Secretary of the National Liver Foundation (NLF)—a non-profit organisation promoting awareness and prevention of liver diseases—says that NLF has taken 15 patients free of charge, who cannot afford treatment at all, with Roche giving donations to sustain the treatments.

Confronting Fears

Development of a vaccine meets with many obstacles. Due to very high degree of genetic variability, HCV can be classified into six main genotypes; there are more than 30 subtypes throughout the world. Chimpanzees remain the only animal model for HCV infection, but they are an endangered species and difficult to work with because of high costs and other restrictions. Tewari says, "Even though HCV infection generates antibodies, none of these seem capable of resolving the infection. One reason might be that the virus does not appear to circulate as free virions—virus particles that are inert carriers of the viaral genome—but is always found in association with lipoprotein particles or immune complexes."

Vast majority of infec-tions in Western countries are due to genotypes 1a, 1b and 3a, whereas infections in western Africa are due to genotype 2. In Central Africa, such as the Demo-cratic Republic of Congo and Gabon, genotypes 1 and 4 are prevalent, while in Southern and Eastern Asia, genotypes 3 and 6 are common. Such wide genetic variability poses a major challenge for the develop-ment of a vaccine. Genotype 1 and 3 are commonly found in India. Of these, type 1 is more common in the South, whereas type 3 and its variants are predominant in North India. These genotypes may vary radically in their biological effects from each other, in terms of replication, mutation rates, type and severity of liver damage, and detection and treatment options, which are not yet understood.

In America, genotype 1 is quite predominant (90 per cent) and it is this type which does not respond so well to treatment. "We are lucky that way because the predominant type of the virus that we have is easily treatable. The duration of the treatment is also short, so the treatment lasts for six months instead of one year compared to genotype 1. The response rate is almost 80-90 percent in genotype 3 compared to 40-50 percent in genotype 1," Shah adds. Another major problem is that the virus becomes resistance to anti-retrovirals in a short time because it constantly changes its structure and mutates naturally, hence escaping the body's natural defence mechanism. And that is how it survives in the body. "How do you plan to kill a virus? You do that by blocking its multiplication. Now, if the virus keeps on changing its structure, the company has already spent millions of dollars trying to attempt to block one step, while it has already changed its structure," laments Shah.

Despite significant progress in the field of biotechnology, reliable diagnostic procedures; an alternative animal model other than the chimpanzee, an efficient cell culture that can support long-term replication of the virus and effective therapeutic strategies are still lacking. "Are we being a bit impatient? Remember, diseases like diabetes have been known for centuries; however, the real pathogenetic factor for the disease (insulin resistance) was realised only about 20 years ago. Further, therapies based on the pathogenetic factor (insulin sensitisers) are still being introduced." He further says, "In comparison, HCV was first identified only in 1989. Since then, considerable progress has been made to introduce drugs that could be used to manage the disease." He concludes, "Let us not forget that the development time for any novel drug is about 12-15 years, if not more."

aashruti.kak@expressindia.com