Download The priorities for antiviral drug resistance

Journal of Antimicrobial Chemotherapy (2007) 60, Suppl. 1, i57 – i58
doi:10.1093/jac/dkm159
The priorities for antiviral drug resistance surveillance and research
Deenan Pillay1,2*
1
2
Department of Infection, University College London, London W1T 4JF, UK;
Centre for Infections, Health Protection Agency, Colindale, London NW9 5HT, UK
The number of available antiviral drugs is growing fast. The emergence of drug-resistant viruses is
well documented as a cause for drug failure. Such viruses also carry the potential for transmission,
the risks for which vary according to specific viral transmission dynamics. This potential is best
described for HIV and influenza. Resistance to the new generation of hepatitis C virus inhibitors is also
likely to become a cause for concern. The priorities for future action to limit resistance include application of sophisticated surveillance mechanisms linked to detailed virological data, development of
optimal treatment regimens (e.g. combination therapies) to limit emergence of resistance, and a focus
on prevention strategies to prevent transmission.
Keywords: HIV, influenza, hepatitis C, herpes, transmission
Introduction
The last 10 years has witnessed a major growth in the availability of specific antiviral compounds, currently standing at more
than 30 within the UK. This has been fuelled by antiretroviral
drug development (25 of the above drugs are targeted at HIV),
although other targets include the herpes viruses, hepatitis B
virus (HBV), hepatitis C virus (HCV) and influenza virus. In
general, these drugs inhibit key, virally encoded enzymes of the
virus in question, such as polymerase and protease. Only one
drug to date, ribavirin, appears to have broad antiviral specificity, with a mode of action which may include an effect on
viral genome replication fidelity.1
As will be noted from the above list, drugs are mainly targeted against chronic infections. This is because persistent
infections provide a larger ‘window of opportunity’ for drugs to
impact on the natural history of infection, compared with acute
viral diseases. In addition, it is easier to monitor antiviral
efficacy through surrogate markers (such a blood viral load).
Long-term therapy is a more attractive economic proposition for
the pharmaceutical industry than a treatment course of a few
days. Of note, antiviral drug therapy does not clear (eradicate)
virus for viruses which establish latency, such as HIV and HBV,
and therefore the aim of the therapy is to reduce virus-associated
morbidity through inhibiting replication.2 In contrast, treatment
of acute infections requires a different paradigm. As acute infections are, in the main, self-limiting, the cost – benefit of intervention is more difficult to demonstrate. For instance, what is
the ‘value’ ascribed to an antiviral-induced reduction of pyrexia
by 1 day for a mild respiratory infection? In addition, the
window of opportunity for intervention is shorter; the efficacy
of neuraminidase inhibitors for influenza is only demonstrable
when drug is started within 24 – 48 h of first symptoms.3 This
makes widespread use of such drugs untenable within current
healthcare systems, which require general practice consultation,
and diagnosis prior to drug prescription. It is for this reason
that influenza pandemic plans include discussion of syndromic
treatment following the identification of circulating pathogenic
viruses through surveillance mechanisms.4
Resistance to antivirals
Antiviral therapy is very effective. For instance, it has transformed HIV from a death sentence to a chronic infection, albeit
requiring lifelong treatment. Nevertheless, drug resistance has
been documented against virtually all licensed drugs. Such resistance is caused by specific mutations, or sets of mutations in the
viral genome, leading to an alteration of viral enzyme interaction
with drug. The mechanisms of resistance nevertheless vary. For
instance, HIV resistance to the nucleoside analogue reverse transcriptase inhibitors may be mediated through a reduction in drug
binding to the enzyme, or, in contrast, an increased rate of drug
dissociation from the enzyme following binding.5 Such differences underpin the cross-resistance patterns observed for specific
sets of mutations. For HIV, over 50 key resistance mutations can
be identified, which may be present in isolation or in combination with others. This almost infinite number of permutations
is a major challenge for using genotypic data to estimate which
new drugs are likely to be effective.6 Drugs with different resistance and cross-resistance patterns are also available for HBV, the
herpes viruses [herpes simplex virus (HSV), cytomegalovirus
(CMV) and varicella-zoster virus] and influenza, thus providing
the rational and clinical utility of undertaking resistance testing
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*Tel: þ44-208-327-6237; Fax: þ44-208-327-6019; E-mail: [email protected] or [email protected]
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# The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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Pillay
at the time of failure of first-line therapy. Efficacy of therapy is
increasingly monitored virologically, for instance, blood viral
load (HIV, HBV, HCV and CMV), and thus the potential emergence of resistance can be identified at an early stage. The incidence of resistance emerging on first-line therapy is highly
variable between viruses and between specific drug regimens.
For instance, some drugs have a higher ‘genetic barrier’ to resistance than others.7 Despite the current availability of antiviral
agents, there continues to be a requirement for new drugs within
existing classes, as well as new classes of drugs, to deal with the
ever expanding number of patients infected with drug-resistant
viruses. We have recently demonstrated that the mortality of HIV
patients with multidrug resistance appears to be 3-fold the rate
for the UK HIV cohort as a whole,8 thus justifying the urgent
search for drugs against novel targets.
assess the clinical correlates of resistance will be required.
Secondly, planning for a future influenza pandemic has focused
on the stockpiling and use of one particular neuraminidase inhibitor, oseltamivir. In view of the potential risk of emergence and
spread of resistant viruses, as described earlier, consideration
needs to be given to the use of combination therapy, and the relevant in vitro, animal and clinical studies to support a combination therapy approach are urgently required.13
In summary, the emergence of antiviral drug resistance is virtually inevitable. This provides a major clinical, laboratory and
public health challenge. We have already learnt the potential for
spread of these viruses from experience with HIV. A coordinated
approach is required to ensure that the clinical benefit afforded
by these drugs is maintained.
Transparency declarations
Transmission of resistant viruses
One of the consequences of antiviral drug resistance is the
potential for resistant viruses to be transmitted to others. This is
obviously the most common case for viruses with relevant transmission dynamics, and for which resistance is common. For
instance, the increasing number of new HIV infections through
sexual transmission will inevitably include infections from those
with existing resistance (and on therapy). Similarly, the high
infectivity of influenza will ensure transmission of resistant
strains at times of widespread implementation of therapy. In
contrast, most HBV infections worldwide occur through the vertical (mother to child) route; since treatment of women in pregnancy is uncommon (and if so, is likely to reduce the risk of
transmission) and therefore transmission of resistance is less
likely at a population level. Transmission of drug-resistant HSV-1
or CMV is also very rare, as a large proportion of the population
is already infected as well as the fact that emergence of resistance
is limited to the highly immunosuppressed population. Virtually
all data on transmitted resistance thus refer to HIV.
Surveillance of antiviral resistance
Approximately 10% of new HIV infections in the UK are with
viruses with at least one major resistance mutation.9 The detrimental impact of this on future drug therapy has led to widespread
implementation of resistance testing prior to starting therapy, in
order that first-line treatment can be individualized depending on
these transmitted resistance patterns.10 It is self-evident that surveillance systems to monitor resistance in untreated individuals
(i.e. transmitted resistance) are essential. Indeed, as antiretroviral
therapy is rolled out to the developing world, the WHO has
initiated a global laboratory network to monitor the emergence of
resistance in treated and untreated HIV-infected individuals.
Future developments
There are two future developments requiring a research and surveillance response. First, a number of new drugs specifically targeting HCV polymerase and protease are likely to enter clinical
practice.11,12 Unlike the current drug combination of ribavirin
and interferon, these drugs will rapidly select for drug-resistant
variants, particularly if used as single agents. The laboratory
capacity to assess resistance and cross-resistance and studies to
Dr Pillay has undertaken consultancy for Gilead Sciences,
Bristol-Myers Squibb, GlaxoSmithkline, Roche and Boehringer
Ingelheim.
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