8.1     Many people—though, on the strength of our evidence, not enough—know that some infections (e.g. salmonella, pneumonia, meningitis) are caused by bacteria, others (e.g. common cold, influenza, AIDS) by the simpler organisms called viruses. It is possible to vaccinate against some viral diseases; but until recently, most could not be treated (exceptions included herpes simplex, herpes zoster and influenza), so the question of resistance did not arise. However, since resources were poured into AIDS research in the 1980s, enormous progress has been made in understanding and treating viral infection; some new antiviral drugs are on the market, and more are undergoing clinical trials (Q 588). Like bacteria, viruses are adept at developing resistance to drugs.

  8.2     Viruses are different from bacteria in some important respects. They cannot reproduce, unless they are inside a "host cell". They have no plasmids by which to transfer DNA among themselves; so, when resistance to an antiviral arises, it does so through mutation within the viral genome followed by the selective pressure of the drug. Viruses replicate very fast, giving frequent opportunities for resistant mutants to be generated. Different viruses have different "error rates" in the process of replication; HIV has such a high error rate that the viral population within any infected individual is very heterogeneous, and very likely to contain at least a few viral particles resistant to any single drug (Q 582). For more detail, see the evidence of Dr Deenan Pillay (p 278), Head of the new PHLS Antiviral Susceptibility Reference Laboratory in Birmingham.

  8.3     In some cases, says Dr Pillay, the mutation which makes a virus resistant also disables it by comparison with the "wild type"; so, whereas in the presence of the drug the resistant type thrives, in its absence the resistant type is at a disadvantage. Therefore, in such cases, where a virus is transmitted to a person not previously infected and therefore not previously treated with drugs, the strain which establishes itself is the wild type, not the resistant type (QQ 586, 591; cp SKB p 478). However, "It is now becoming clear that some mutations associated with drug resistance do not actually cause resistance, but rather compensate for the loss of fitness consequent on the resistance mutation, thus generating a virus which can compete with wild type. The risk of transmission and spread of drug resistant viruses is therefore a real one, and requires close monitoring" (Pillay p 279). SmithKline Beecham tell the same story (p 479): there is no significant transmission of resistant viruses, but this "may reflect the relative infancy of anti-viral therapy".

Prudent use of antivirals

  8.4     "A good antiviral agent almost by definition will generate resistance" (Q 602). As Dr Pillay explained, it is therefore necessary to use antivirals in such a way as to suppress the viral population as much as possible. He is chairing a BSAC working party, which is working on evidence-based protocols and diagnostic criteria for using antivirals; and he called for an expansion of clinical virology in hospitals (Q 611). Against HIV, as in the case of TB, giving drugs in combination is proving effective against the emergence of resistance (Q 613).[68]

  8.5     Acyclovir, an antiviral against herpes simplex type one (cold sores), is already available over-the-counter in the United Kingdom for topical application.[69] Dr Pillay reported that this has so far given rise to very little resistance (Q 611).[70] However he expressed some general concern[71]: "There is no doubt that there is the potential, with the increasing amount of drugs around in the population...that may change the virus in ways we are currently unaware of" (Q 599). He called for thorough surveillance and research before more antivirals are considered for licensing for sale OTC, and for special caution if antivirals emerge for common and highly transmissible viruses such as the common cold (Q 616).

Surveillance

  8.6     As Dr Pillay explained to us (Q 594), surveillance of viral resistance is in its infancy. The PHLS Antiviral Susceptibility Reference Unit in Birmingham, of which he is the Head, was set up in 1996. It is the only service of its kind in the world, based at one of the few laboratories capable of conducting the necessary tests (Q 609). A start has been made on surveillance of herpes simplex, using a network of sentinel laboratories and targeting immuno-compromised patients; with regard to other viruses, "we are in a state of development". As noted above, methods, definitions and breakpoints for susceptibility testing of antibiotics are still a matter of debate; for antivirals, none at all have yet been validated or agreed (Q 594).

  8.7     CDC in the USA, and a European network based in Holland, are working to develop surveillance of resistance in HIV (Q 595). Dr Pillay said, "The more there is an international effort in this, the better" (Q 604).

Research

  8.8     According to Dr Pillay (QQ 623-632), "Antiviral research and research into basic mechanisms of viruses are going on apace, funded by the MRC, the Wellcome Trust and all the cancer charities". The NHS R&D Budget has also been forthcoming. However, the MRC has terminated its directed programme for HIV, and "it is extremely difficult to get HIV funding now through the MRC"; and HIV research is not supported by the Wellcome Trust or the major cancer charities. Dr Pillay also has difficulty raising funds for targeted research in support of surveillance; the funding bodies expect such work to be paid for by industry.

69   Acyclovir can also be given systemically, eg in herpes simplex encephalitis; this preparation is not available OTC. Back

70   The rate of resistance is consistently low in the immunocompetent, but more frequent in the immunocompromised (SKB p 478). Back

71   Cp Greenwood p 411. Back