Erik de Clercq - Böcker

Antiviral chemotherapy has come of age, and, after an initial slow pro­ gress, the development of new antiviral agents has proceeded at a more rapid pace and the perspectives for their clinical use have increased considerably. Now, 25 years after the first antiviral assay (idoxuridine) was introduced in the clinic, it is fitting to commemorate the beginning of the antivirals' era. In its introductory chapter B.E. Juel-Jensen touches on what may be con­ sidered as five of the most fundamental requirements of an antiviral drug : efficacy, relative non-toxicity, easy solubility, ready availability and rea­ sonable cost. Surely, the antiviral drugs that have so far been used in the clinic could still be improved upon as one or more of these five essential demands are concerned. How is all began is narrated by W.H. Prusoff. The first antiviral drugs to be used in humans were methisazone and idoxuridine, the former, which is now of archival interest, in the prevention of smallpox, the latter, which was approved for clinical use in the United States in 1962, for the topical treatment of herpetic keratitis. In terms of potency, also because of solubility reasons, idoxuridine has been superseded by trifluridine in the topical treatment of herpes simplex epithelial keratitis. H.E. Kaufman did not find trifluridine or acyclovir ef­ fective in the treatment of deep stromal keratitis or iritis and he reckons that other antiviral drugs (i.e. bromovinyldeoxyuridine) would not be effec­ tive either.

The International Symposium on Frontiers in Microbiology has been de­ dicated to Prof. P. De Somer, whom I succeeded shortly after his death on 17 June 1985 as Rector of this now more than 560-year old University. When Prof. De Somer became the head of the University he started to remodel it, giving our old Alma Mater a more transparent administrative structure, strengthening its scientific and cultural autonomy, and establishing close links with the most prestigious national and foreign institutions. This made De Somer to one of the greatest, if not the greatest, of rectors in the history of Belgian Universities. He was a great leader, a perfect organizer, a clever negotiator, and a brilliant orator. In his speeches one immediately sensed his intuitive cognition and witty evaluation of the values of life. He knew perfectly well how to persuade the unwilling and to disenchant the illusionist. Sometimes a visionary himself, he would not pursue his ideas unless there was a chance of success. As innovative Prof. P. De Somer was in providing to this University a new face, or should I say facelifting, as international is his reputation as the founder, and, since its inception, only director, of the Rega Institute. Built now more than 30 years ago, the Rega Institute has re­ mained one of the world's leading centers in microbiological research.

Antiviral chemotherapy has come of age, and, after an initial slow pro­ gress, the development of new antiviral agents has proceeded at a more rapid pace and the perspectives for their clinical use have increased considerably. Now, 25 years after the first antiviral assay (idoxuridine) was introduced in the clinic, it is fitting to commemorate the beginning of the antivirals' era. In its introductory chapter B.E. Juel-Jensen touches on what may be con­ sidered as five of the most fundamental requirements of an antiviral drug : efficacy, relative non-toxicity, easy solubility, ready availability and rea­ sonable cost. Surely, the antiviral drugs that have so far been used in the clinic could still be improved upon as one or more of these five essential demands are concerned. How is all began is narrated by W.H. Prusoff. The first antiviral drugs to be used in humans were methisazone and idoxuridine, the former, which is now of archival interest, in the prevention of smallpox, the latter, which was approved for clinical use in the United States in 1962, for the topical treatment of herpetic keratitis. In terms of potency, also because of solubility reasons, idoxuridine has been superseded by trifluridine in the topical treatment of herpes simplex epithelial keratitis. H.E. Kaufman did not find trifluridine or acyclovir ef­ fective in the treatment of deep stromal keratitis or iritis and he reckons that other antiviral drugs (i.e. bromovinyldeoxyuridine) would not be effec­ tive either.

This pUblication contains the Review Lectures presented at a joint NATO Advanced Study Institute and FEES Advanced Study Course held at Les Arcs, Bourg-8aint-Maurice, France, from the 19th June - 2nd July 1983. The Course, entitled "Targets for the Design of Antiviral Agents" was in some ways a sequel to the NATO-FEES Course held at SOGESTA (near Urbino), Italy from the 7th - 18th May 1979 and published as volume A26 in this series. During the subsequent four years, we have witnessed the first of the "new generation" of antiviral compounds, which are more efficacious and less toxic than the "classical" antiviral drugs, reach the clinic and we felt that it w~s the right time to assess the future prospects of this verY important and exciting field. The vast majority of the drugs developed recently have proved active against various members of the herpesvirus family and elsewhere in this publication we learn that the cure for only rather few viral diseases, such as the common cold, influenza and herpes, promises the return on investment required by the pharmaceutical industry. However, the aim of this Course was for eminent virologists to identify possible targets among the various virus classes against which the chemists could then design suitable therapeutic agents. Recent advances with antiherpesvirus drugs have shown that a far greater selectivity and therapeutic index can be obtained than was previously thought to be possible.

HIV infection has been a greater challenge to current medicine than any other viral disease ofmodem times. HIV leads to a persistent infection and the virus has an immense genetic flexibility under selective pressure. During its replica­ tive cycle in patients, HIV accumulates mutations at such a high rate that the selective pressure inflicted on the immune system, or generated by antiviral drugs rapidly triggers the appearance of escape mutants. Currently available drugs, when used singly, are not capable of suppressing virus replication in patients to such a level that the generation of mutations, from which a variant resistant to immune attack or antiviral drugs can be selected, is prevented. This is the main reason why combination therapy, usually of three drugs, has become the standard procedure for the treatment ofAIDS. It is obvious that virus eradication will not readily be achievable, so that drugs have to be taken for a prolonged time or even lifelong so as to keep the viral load as low as possible. Whether the currently used drug combinations will be able to control virus replication in a particular patient for such a pro­ longed period of time depends on many factors, most of which are addressed in the different chapters of this book. The aim of antiviral drug combination therapy for AIDS is ultimately to restore full function of the immune system.

This book is the first to tackle, in a single treatise, a subject that has recently become a discipline in its own right, that of the combination antiretroviral therapy of AIDS. It is aimed at an audience of clinicians, researchers, public health workers, specialists or non-specialists in AIDS and particularly those who want to know how to optimally approach the treatment of AIDS. Combination drug treatment of AIDS is focussed from different angles and perspectives, historical, basic, economic, theoretical, virological, immunological, clinical and practical reasons for therapy failures are examined and strategies to prevent or overcome failing therapies are formulated. This book fills a gap in the current literature on clinical therapeutics. It should be particularly informative to those who want and need to know more about the current treatment of AIDS, with its successes and failures, but also with lessons and guidelines to affront these failures.