HOPE ON THE HORIZON

Initial trials with a newly developed cocktail of anti- HIV drugs are giving fresh optimism that the fight against Aids can be won. Liz Hunt investigates

This is the year in which Aids scientists stopped talking about a cure. Instead, a new word crept into their vocabulary, one which in the space of just six months, has triggered a seismic shift in thinking about HIV infection and how it should be managed. "Eradication" was the buzz word of the Eleventh International Aids Conference in Vancouver in July. The results of preliminary clinical trials with a cocktail of drugs, including one of a new class known as protease inhibitors, suggested that the Aids virus, HIV, could be reduced below the level of detection in the blood, and that this could be maintained while drug treatment continued.

Dr David Ho, director of the Aaron Diamond Aids Research Centre in New York, and an internationally-renowned scientist, took this a stage further when presenting the first of a series of ground-breaking studies to an auditorium in Vancouver packed to the rafters with doctors and scientists, Aids lobbyists, patients, and their families. He told them that using mathematical models based on the results to date, it was not "unrealistic" to assume that if suppression of the virus could be maintained for 18 months to three years, HIV may be eradicated entirely from the body.

His views were echoed by Dr Scott Hammer, a researcher at the National Institute of Allergy and Infectious Diseases in Maryland, and member of the US Food and Drug Administration's Anti-Viral Drugs Advisory Committee. A concept which six months ago would have been dismissed as "ludicrous" - the eradication of HIV - was now acceptable and could be tested, he said. Dr Martin Markowitz, who works with Dr Ho, put it graphically: "If you think of HIV as a raging fire ... we put out the fire ... We have turned off viral replication."

British scientists were more cautious. Irritated by the hype that surrounded Ho's theoretical model of HIV eradication, their views seemed almost churlish at the time but are arguably more realistic. Professor Paul Griffiths, a virologist at the Royal Free Hospital in London, said that talk of eradication was dangerous because the small numbers of patients on protease inhibitors had only been treated for a year at most. However, he acknowledges that the drugs are certainly more potent than the first generation antivirals such as zidovudine (AZT). "The data are not there yet to prove it but all the signs are that they will give substantial benefits."

Dr Ian Williams, a senior lecturer in sexually-transmitted diseases at Univer-sity College London Medical School, says that the near-hysteria generated by the new drugs in the American media is "probably justified" - but not because of the eradication theory. "It is too early to say this would be possible. Ho presented a theoretical mathematical model and he was very cautious - but that was ignored in the reporting. What is exciting about these drugs is their potency. The amount of virus in the bloodstream can be reduced to levels that cannot be detected [with current tests]. That isn't generally possible with the nucleoside analogues [zidovudine etc]."

More is probably known about HIV than any other virus, but 15 years of undivided attention from some of the best scientific brains in the world, and billions of dollars-worth of investment, have failed to deliver a cure. Hence the high-profile launch of any new drug for HIV infection or an Aids-related illness. Many - zidovudine is a good example - fail to live up to initial promise.

However, the addition of protease inhibitors to the Aids weaponry does represent significant progress after years in which the virus proved itself an elusive target. The new drugs have allowed doctors to develop a "double whammy" approach to therapy. They hit the virus simultaneously at two different stages of its life cycle. What has been shown is that this approach significantly reduces the amount of virus circulating in the bloodstream - what is known as the viral load. A low-level of viral load is associated with a good prognosis in untreated people and an impoved prognosis in those on anti-HIV drugs. This, according to a recent issue of Aids Treatment Update, has prompted many researchers to argue that "the goal of anti- HIV treatment should simply be to keep viral load as low as possible for as long as possible." Protease inhibitors make that goal much more accessible.

Protease inhibitors work differently to previously available anti-retroviral treatments (HIV belongs to a class of viruses known as retroviruses.) They block the action of HIV protease, an enzyme that is involved in the assembly of new viral particles during replication in infected cells. HIV protease "cuts" polypeptide precursor proteins into smaller functional structural proteins and viral enzymes. Disrupting this normal processing of these precursor proteins results in new virus particles which are immature and non-infectious. They cannot infect other healthy immune-system cells, so the spread of HIV from cell to cell is slowed dramatically.

Zidovudine, the first anti-retroviral which was licensed for use in Britain under the brand name Retrovir, and subsequent nucleoside analogues, 3TC, ddI, ddC, etc, exert their anti-viral effects at an earlier stage in the viral lifecycle. They block an enzyme known as reverse transcriptase which is essential for HIV to establish infection in a cell, and therefore replication. What Ho and fellow doctors have demonstrated is that when triple combination therapy is used, a protease inhibitor and two nucleoside analogues, viral levels in the blood were reduced by 99 per cent in the first few weeks of treatment. The low level of virus on treatment with triple therapy has the added advantage of limiting the emergence of viral resistance.

In Ho's model it is suggested that in this initial phase of treatment it is HIV released from short-lived CD4 cells, the immune system cells most vulnerable to infection by HIV, that is stopped. Over the subsequent weeks of therapy, other infected cells such as macrophages - scavenger cells of the immune system - which live longer than CD4 cells, begin to die off too, and HIV production falls even further to undetectable levels within two months of treatment starting.

However, very low levels of HIV in the blood do not mean that the virus has been eliminated from the body, and there are "sanctuary sites" such as the lymph glands, tonsils, spleen where scientists know the virus will lurk and continue replicating, albeit at a much slower rate. Lymphoid tissue is the ideal environment for the virus because of the millions of CD4 cells present there. In Vancouver doctors reported that lymph tissue from a recently-infected patient who had been treated with combination therapy for more than a year, showed dramatically reduced levels of HIV. Attempts to culture the virus from this tissue failed. But when, with the patient's consent, doctors halted combination treatment to see what would happen, viral load increased rapidly within a few weeks. It fell again to undetectable levels once the drug regimen was resumed.

"Virus production was clearly being sustained somewhere in the patient's body and currently available treatments may need to be taken for much longer to flush out all the virus from the body," according to Aids Treatment Update. "Alternatively, total elimination of virus may prove to be impossible with anything short of total long-term suppression of replication, because of the 'reservoir' of infection in long-lived cells."

Further investigation of lymphoid tissue from treated individuals is now under way here and in the US, with particular interest in participants of a study first reported in America in January, and updated in Vancouver. People in advanced stages of disease with a high viral load, were given zidovudine, 3TC, and a protease inhibitor called indinavir which has yet to be licensed in Britain. Up to 90 per cent of patients in the trial had undetectable levels of virus in their bloodstream and this effect has been sustained for over a year. The levels of virus in their lymphoid tissue will indicate what long-term treatment with triple combination therapy can achieve.

Only one protease inhibitor, ritonavir (Norvir) has been licensed in Britain so far - the drug used in the Ho study - but two others, indinavir and saquinavir, should be licenced shortly. Saquinavir is less potent than the other two as it is less well-absorbed but beneficial effects are observed when it is used in combination. Dr Williams, who works at the Mortimer Market Health Centre, one of the largest HIV clinics in Britain, says that use of the drugs is increasing in those with advanced HIV disease whose immune systems are severely compromised. As more is known about their long-term safety and effectiveness it is likely they will be used more routinely in patients with earlier disease and who are symptom-free.

But protease inhibitors have a greater therapeutic potential than treating HIV, according to Professor Leslie Benet of the Department of Biopharmaceutical Sciences at the University of California. Last month, At the Pharmacy World Congress in Jerusalem, he spoke of the possibilities for their role in cancer management. Protease inhibitors in laboratory tests appear to slow the spread of cancer, known as metastases. Tumour spread is believed to occur when protease enzymes produced by cancer cells, called metalloproteinases, degrade the matrix of tissue which supports the tumour and isolates it from surrounding healthy cells. By blocking these enzymes with protease inhibitors, this process is curtailed. Dr Jonathan Waxman, a consultant oncologist at the Royal Post-Graduate Medical School at Hammersmith Hospital in London, is enthusiastic, but also has some of the reservations of British Aids scientists over unwarranted hype.

This issue surfaced last year over a drug called Marimastat, for which startling claims were made after it had been used to treat less than 100 patients with cancer for about a month. British Biotech, an Oxford-based research company which developed the drug, used the concentration of "cancer antigens" in the patient's bloodstream as an indication of efficacy. In 33 per cent of those taking the drug for 28 days, levels of certain specific antigens either fell or were stable. In a further 26 per cent, the levels rose but less quickly than before treatment. This, according to Dr Waxman, shows very little and would certainly not be accepted by any drug regulatory authority. Despite this, the company's share price soared from pounds 10 to pounds 16.75 in the space of a day, putting an estimated pounds 800m value onto a company which had never made a profit.

Dr Waxman believes that future cancer therapies will almost certainly include protease inhibitors, and that progression to metastatic cancer - the cause of most cancer deaths - could be limited. "They are a very interesting group of drugs. But cancer is a big story and this is just a paragraph in that story," he says. !

AIDS: HYPE AND FACTS

Aids has failed spectacularly to live up to expectations - at least as far as British newspapers are concerned. From the early 1980s when headlines linking blood, gay sex, death, the wrath of God and global epidemics were the daily fare, coverage has dwindled to the odd "news in brief" item marking some scientific advance, or another potential treatment with exotic origins. Bluebells and daffodils are the latest flora under investigation.

There was a brief revival of interest in Aids during the early 1990s when the Sunday Times, under editor Andrew Neil, promoted in an uncritical fashion the theory of a few maverick scientists and conspiracy-theory journalists that HIV did not cause Aids. But essentially, the science and the social issues associated with the disease had run their course in newspaper coverage. HIV had failed to make the sizeable impact on heterosexuals in Britain that its advance publicity had promised. Remember the icebergs and tombstones of the first Govern-ment advertising campaign in 1987? Its status in terms of public health was downgraded and HIV/Aids was incorporated into general health education messages on sexually-transmitted diseases while grants to Aids organisations were cut.

Almost a decade on, heterosexual transmission still accounts for a tiny, albeit a growing, minority of the 12,976 Aids cases and 27,088 HIV positive people that have been reported in Britain since 1982. The majority of heterosexuals contracted HIV abroad or during sex with members of the so-called high-risk groups, including intravenous drugs users, prostitutes, bisexuals and gay men. The next big Aids story will be "the cure," and only that will rouse newsdesks from Aids fatigue.

About three years ago, the editors of the most of the national daily papers and broadcast organisations stopped sending journalists to the annual International Aids Conference, which for so many years had been a must on the news diary. They were reluctant to fund a trip that resulted in little of relevance to their readers. Journalists themselves didn't mind too much either; the conference had become a tedious, overblown event. It had degenerated into a mixture of vociferous Aids activism, pure science and complex molecular biology that passed most of us by. And so when an important breakthrough in the treatment of HIV infection actually arrived, triple combination therapy with the new class of protease inhibitor drugs - the story of the 1996 Conference in Vancouver - we were caught napping. A flick through the cuttings reveals woefully poor coverage.