The Pharmaceutical Journal Vol 265 No 7121 p684-685
November 04, 2000 News feature

Issues in viral diseases

By C. Bellingham

Last week, as supplies of influenza vaccine ran out in parts of the United Kingdom, Clare Bellingham attended a viral diseases meeting organised by Roche. Treatments for HIV, hepatitis C and influenza infection were covered at the event which was held at Roche’s Welwyn Garden City site on October 25

There were a number of diseases for which no drug treatments existed, said Professor Jonathan Knowles (head of global pharmaceutical research, Roche). He believed that viruses were a major risk factor for these diseases and that, in the future, antivirals might be used to treat them. Susceptibility to such viruses was determined by genetics, he said. Use of genetics would bring changes to therapeutic practice: it could be used to predict susceptibility to disease and to side effects from drugs which would allow rationalisation of prescribing.
Three infections known to be caused by viruses were discussed at the meeting: influenza, hepatitis C and HIV.

Influenza — the virus with two faces
Influenza was a unique virus with two faces: epidemic and pandemic, said Professor John Oxford (professor of virology, St Bartholomew’s and Royal London school of medicine).
Occasionally and unpredictably, the virus presented its pandemic face, as it had in 1889, 1918, 1957 and 1968. A long time had elapsed since 1968 and virologists had deduced that another pandemic was expected within the next few years.
Although epidemics are less dramatic, in the end, the toll could be worse, particularly for elderly populations. Last year had been an epidemic year. According to the National Office of Statistics, during the winter of 1999/2000, 20,000 people had died from influenza in England. “These are the two faces of ’flu — the mega face, the pandemic face of 1918, and the ensuing drift years of epidemics,” he said.
The 1918 influenza pandemic was a “forgotten plague” that had killed over 40 million people worldwide. What was it in the genetic structure of the influenza virus that could make a person ill and even die, Professor Oxford asked. This was a basic question in virology that was being applied to the 1918 influenza virus, he said. To assess the genetic component, the genetic structure of the virus before, during and after the outbreak needed to be compared. This information could be used to assess the virulence of newly discovered influenza viruses (such as the new virus discovered in Hong Kong 18 months ago). If the part of the gene that explained the virulence of the 1918 pandemic was known, then, if a new virus had that sequence, a pandemic plan could be put into action. Equally, it would be possible to study how long pandemics took to evolve. If they were slow to evolve then it would give time to manipulate vaccinations appropriately.
Professor Oxford had been part of an expedition to Spitzbergen in the Arctic circle which exhumed the bodies of coal miners who died of 1918 influenza and were buried in permafrost. Samples had been taken from six bodies. Research on the virus samples had revealed that it was an influenza A of human clade, rather than being avian or swine in origin. So far, two genes had been examined — the haemaglutinin and neuraminidase genes which were both perfectly normal and were not, as had been predicted, the genes which could explain the virulence of the virus. A further six genes were to be examined, he said.

Neuraminidase inhibitors

T he development of the neuraminidase inhibitors would have a significant impact in the area of influenza treatment, Professor Oxford said. To some extent, influenza was preventable with these drugs or they could, at least, speed up recovery. There were two neuraminidase inhibitors on the market and a further two in the pipeline.
A change in culture was needed among doctors so that neuraminidase inhibitors were used, he added.
Speaking to The Journal following the Roche meeting, Professor Oxford said that the critical issues with neuraminidase inhibitors were right diagnosis and speed of drug administration. Influenza had to be diagnosed correctly through symptom recognition (temperature, aches and cough) and surveillance indicating that ’flu was in the area. Speed was important because neuraminidase inhibitors had to be administered within 36 hours of symptom onset.
There is potential for pharmacists to play a role in supply of neuraminidase inhibitors, perhaps under patient group direction. Asked his opinion on this, Professor Oxford said that while he could not comment on specific details, he could see no problem with the principle of pharmacist-supply. As long as a doctor was “in the equation”, pharmacist-supply or nurse-run clinics were both possibilities and, in the long term, he supported the idea of over-the-counter supply of neuraminidase inhibitors.
Guidance from the National Institute for Clinical Excellence (NICE) on the use of the neuraminidase inhibitor zanamivir is expected to be released soon.

Influenza vaccine

Despite reports last week that many parts of the country had ran out of influenza vaccine, a spokesperson for the Department of Health told The Journal on October 30 that the Government’s campaign was “on course”. However, the spokesperson admitted that supplies from one of the vaccine manufacturers, Solvay, had been delayed. Sixty-five per cent of Solvay’s supply had been distributed but the remainder would not be delivered until the week ending November 10. The DoH says that this will be in time for people to be vaccinated before the full onset of the ’flu season. The delays were connected with problems associated with growing the virus.
Professor Oxford said at the Roche meeting that he thought that this year, the Department of Health was taking influenza more seriously than ever before. Its immunisation campaign was more targeted than in the past and it planned to vaccinate over 10 million people. Influenza was not just a human virus, there was a huge reservoir in animals so it was “impossible to eradicate”. Vaccines should be kept as a cornerstone for those at risk and it would be a mistake to vaccinate the whole population because it would drive the vaccine into antigenic change, he said.
Commenting on schemes which allow vaccinations against influenza to be given in the pharmacy, Professor Oxford told The Journal that the scenario was a good one. It was a big problem to persuade people to be vaccinated and if pharmacy-based vaccination helped, it was “all the better”.

Hopes in HIV treatment

There were three main therapeutic approaches offering hope in HIV infection, said Dr Mary Graves (director of biology and head of viral diseases, Roche Discovery, Welwyn). First, new drugs were being developed that worked in the same way as existing drugs but targeted specific resistant viruses. Another approach was to find new drugs that acted on a different part of the viral lifecycle, specifically viral entry into the cell. Finally, attempting to use the host immune system to help control infection by strategic treatment interruptions was being studied. This method involved patients stopping antiretroviral drugs which led to the immune system “kicking in”, she said. When the viral load rebounded, drugs were started again until viral load became undetectable when the process was repeated. Benefits had been seen in a small number of patients, she said.
Blocking entry of HIV into cells was discussed by Dr Nick Cammack (head of virology, Roche Discovery, Welwyn). The area offered significant promise for the treatment of HIV, particularly for patients who had infection resistant to existing antiretrovirals. The events in HIV entry into host human cells were well defined, he said. First, the virus attached itself to the cell by binding to CD4 molecules, after which the HIV envelope underwent a conformational change. Next, the HIV bound to a chemokine co-receptor and, finally, it fused with the cell membrane. Entry inhibitors targeted one of these areas. Inhibitors that were currently being developed fell into three classes — attachment inhibitors, co-receptor inhibitors and fusion inhibitors. There was a “huge amount of activity” in the development of co-receptor inhibitors, he said, for example, inhibitors of the co-receptors CCR-5 and CXCR-4. An example of a fusion inhibitor was the peptide T-20 which had been approved for phase III clinical trials by the Food and Drug Administration a couple of weeks ago, he said. Earlier phase II trials of T-20 had shown a “good drop” in viral load over the trial period.

Hepatitis C — an underestimated disease

There were a number of outcomes following infection with hepatitis C virus (HCV), said Professor Howard Thomas (Imperial College school of medicine, St Mary’s hospital, London). Fifteen per cent of patients had an acute infection that spontaneously resolved but the majority, 85 per cent, went on to develop chronic infection. Of the group that developed chronic HCV, there was a varying degree of scarring and more than 20 per cent developed cirrhosis. Liver cancer and death could follow cirrhosis, and the process from acute infection to death could take 30 years.
An understanding of the role that genetics played in HCV infection would help to determine which patients needed therapy, which would remain asymptomatic and which would have a negative response to treatment. This was particularly important because of the treatment costs for HCV, said Professor Thomas.
Genetic determinants could be both viral and human. Women infected with HCV had better outcomes than men. It was also known that a particular viral genotype progressed more rapidly than others. However, there were other suggested genetic associations that were currently being investigated. A genetic association had been suggested for susceptibility to disease, disease progression and response to treatment. His vision for the future was that genetic profiling could be used to determine a patient’s prognosis and their response to antiviral therapy so that therapy could be targeted for responders.
Interferon alpha was one of the current treatments for hepatitis C. There were three patterns of response to treatment. Around 30 per cent of patients had no response at all. The rest had a rapid fall in HCV, and in 40 per cent this was a sustained response. However, the remainder had a break-through in response resulting in a rise in HCV levels. This was explained by a change in the viral population in which there was selection for an interferon-resistant virus. A region in the HCV had been identified as an interferon sensitivity determining region (ISDR) which, in Japanese populations, had been used successfully as a predictor of response to therapy but had proved less useful in European populations. In people who had had a sustained response after treatment was stopped, their T-cells recovered and there was an adequate host immune response. Relapse could occur because the host immune recovery was inadequate. It was also possible that there was a secondary site of infection which might explain relapse.
There were four HCV genotypes. Treatment with interferon was most successful for patients infected with HCV genotype 3. Genotype 1 gave the poorest response. The time needed to treat HCV also varied between the genotypes. Genotypes 2 and 3 had equal responses at 24 and 48 weeks indicating that therapy was only needed until 24 weeks. A greater response was seen after 48 weeks than 24 for genotype 1 so a longer treatment period was indicated. The main driver for future therapeutic success was improving response in HCV genotype 1 patients. This genotype was the predominant strain in many countries. One approach was to improve the pharmacokinetics of interferon through pegylation. Pegylation improved the properties of proteins, said Dr Mary Graves (director of biology and head of viral diseases, Roche Discovery Welwyn). It involved the addition of a long polymer (polyethylene glycol, PEG) to a protein which protected the protein from the body’s systems and improved its performance. Therapy with pegylated interferon resulted in more stable blood levels, with less peaks and troughs, than unmodified interferon. Pegylated interferon gave a four-fold increase in response in HCV genotype 1 and a two-fold increase in other genotypes compared with unmodified interferon, Professor Thomas said. Pegylated interferon might offer a prospect of improving the current treatment success rate of 40 per cent, he added.
Another goal was to control the development of fibrosis and cancer in response to HCV, said Professor Thomas. Interferon was antifibrotic and preliminary studies had suggested that it might also reduce the incidence of carcinoma. In terms of vaccination, a prophylactic vaccine was a “long way off”, he said. Current candidates were, at best, only partially adequate. They reduced the rate of progression to persistent infection but could not prevent infection itself.

NICE guidance
In guidance released on October 31, the National Institute for Clinical Excellence (NICE) recommended the use of interferon alpha and ribavirin as combination therapy for moderate to severe chronic hepatitis C in patients over the age of 18. It says that interferon alpha monotherapy should only be considered when ribavirin is contraindicated and adds that pegylated interferon monotherapy was not considered in the guidance.
Schering-Plough, manufacturer of interferon and ribavirin, comments that currently fewer than 1,000 patients in the UK receieve combination therapy. The guidance indicates that about 7,000 patients should be treated.

Mrs Bellingham is on the staff of The Pharmaceutical Journal