CHAPTER 8 ANTIVIRAL DRUGS |
8.1 Many peoplethough,
on the strength of our evidence, not enoughknow 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
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
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).
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.
Dr Pillay reported that this has so far given rise to very
little resistance (Q 611).
However he expressed some general concern:
"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).
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).
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.
According to SmithKline Beecham, "The duration of therapy
has been too short to draw any definitive conclusions on the propensity
of the virus to become resistant to all three agents" (p 479). Back
Acyclovir can also be given systemically, eg in herpes simplex
encephalitis; this preparation is not available OTC. Back
The rate of resistance is consistently low in the immunocompetent,
but more frequent in the immunocompromised (SKB p 478). Back
Cp Greenwood p 411. Back