The Priorities for Antiviral Drug Resistance Surveillance and Research

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*

1Department of Infection, University College London, London W1T 4JF, UK; 2Centre for Infections, Health Protection Agency, Colindale, London NW9 5HT, UK Downloaded from https://academic.oup.com/jac/article/60/suppl_1/i57/999663 by guest on 27 September 2021

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 appli- cation 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 when drug is started within 24–48 h of first symptoms.3 This makes widespread use of such drugs untenable within current The last 10 years has witnessed a major growth in the availa- healthcare systems, which require general practice consultation, bility of specific antiviral compounds, currently standing at more and diagnosis prior to drug prescription. It is for this reason than 30 within the UK. This has been fuelled by antiretroviral that influenza pandemic plans include discussion of syndromic drug development (25 of the above drugs are targeted at HIV), treatment following the identification of circulating pathogenic although other targets include the herpes viruses, hepatitis B viruses through surveillance mechanisms.4 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 Resistance to antivirals drug to date, ribavirin, appears to have broad antiviral speci- ficity, with a mode of action which may include an effect on Antiviral therapy is very effective. For instance, it has trans- viral genome replication fidelity.1 formed HIV from a death sentence to a chronic infection, albeit As will be noted from the above list, drugs are mainly tar- requiring lifelong treatment. Nevertheless, drug resistance has geted against chronic infections. This is because persistent been documented against virtually all licensed drugs. Such resist- infections provide a larger ‘window of opportunity’ for drugs to ance is caused by specific mutations, or sets of mutations in the impact on the natural history of infection, compared with acute viral genome, leading to an alteration of viral enzyme interaction viral diseases. In addition, it is easier to monitor antiviral with drug. The mechanisms of resistance nevertheless vary. For efficacy through surrogate markers (such a blood viral load). instance, HIV resistance to the nucleoside analogue reverse tran- Long-term therapy is a more attractive economic proposition for scriptase inhibitors may be mediated through a reduction in drug the pharmaceutical industry than a treatment course of a few binding to the enzyme, or, in contrast, an increased rate of drug days. Of note, antiviral drug therapy does not clear (eradicate) dissociation from the enzyme following binding.5 Such differ- virus for viruses which establish latency, such as HIV and HBV, ences underpin the cross-resistance patterns observed for specific and therefore the aim of the therapy is to reduce virus-associated sets of mutations. For HIV, over 50 key resistance mutations can morbidity through inhibiting replication.2 In contrast, treatment be identified, which may be present in isolation or in combi- of acute infections requires a different paradigm. As acute infec- nation with others. This almost infinite number of permutations tions are, in the main, self-limiting, the cost–benefit of inter- is a major challenge for using genotypic data to estimate which vention is more difficult to demonstrate. For instance, what is new drugs are likely to be effective.6 Drugs with different resist- the ‘value’ ascribed to an antiviral-induced reduction of pyrexia ance and cross-resistance patterns are also available for HBV, the by 1 day for a mild respiratory infection? In addition, the herpes viruses [herpes simplex virus (HSV), cytomegalovirus window of opportunity for intervention is shorter; the efficacy (CMV) and varicella-zoster virus] and influenza, thus providing of neuraminidase inhibitors for influenza is only demonstrable the rational and clinical utility of undertaking resistance testing

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...... i57 # The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected] Pillay at the time of failure of first-line therapy. Efficacy of therapy is assess the clinical correlates of resistance will be required. increasingly monitored virologically, for instance, blood viral Secondly, planning for a future influenza pandemic has focused load (HIV, HBV, HCV and CMV), and thus the potential emer- on the stockpiling and use of one particular neuraminidase inhibi- gence of resistance can be identified at an early stage. The inci- tor, oseltamivir. In view of the potential risk of emergence and dence of resistance emerging on first-line therapy is highly spread of resistant viruses, as described earlier, consideration variable between viruses and between specific drug regimens. needs to be given to the use of combination therapy, and the rel- For instance, some drugs have a higher ‘genetic barrier’ to resist- evant in vitro, animal and clinical studies to support a combi- ance than others.7 Despite the current availability of antiviral nation therapy approach are urgently required.13 agents, there continues to be a requirement for new drugs within In summary, the emergence of antiviral drug resistance is vir- existing classes, as well as new classes of drugs, to deal with the tually inevitable. This provides a major clinical, laboratory and ever expanding number of patients infected with drug-resistant public health challenge. We have already learnt the potential for viruses. We have recently demonstrated that the mortality of HIV spread of these viruses from experience with HIV. A coordinated

patients with multidrug resistance appears to be 3-fold the rate approach is required to ensure that the clinical benefit afforded Downloaded from https://academic.oup.com/jac/article/60/suppl_1/i57/999663 by guest on 27 September 2021 for the UK HIV cohort as a whole,8 thus justifying the urgent by these drugs is maintained. search for drugs against novel targets. Transparency declarations Transmission of resistant viruses Dr Pillay has undertaken consultancy for Gilead Sciences, One of the consequences of antiviral drug resistance is the Bristol-Myers Squibb, GlaxoSmithkline, Roche and Boehringer potential for resistant viruses to be transmitted to others. This is Ingelheim. 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 References sexual transmission will inevitably include infections from those with existing resistance (and on therapy). Similarly, the high 1. Crotty S, Cameron SE, Andino R. RNA virus error catastrophe: infectivity of influenza will ensure transmission of resistant direct molecular test by using ribavirin. Proc Natl Acad Sci USA 2001; strains at times of widespread implementation of therapy. In 98: 6895–900. contrast, most HBV infections worldwide occur through the ver- 2. Ghani A, de Wolf F, Ferguson N et al. Surrogate markers for tical (mother to child) route; since treatment of women in preg- disease progression in treated HIV infection. J Acquir Immune Defic Syndr 2001; 28: 226–31. nancy is uncommon (and if so, is likely to reduce the risk of transmission) and therefore transmission of resistance is less 3. Gubavera LV, Kaiser L, Hayden F. Influenza virus neuraminidase inhibitors. Lancet 2000; 355: 827–3. likely at a population level. Transmission of drug-resistant HSV-1 4. Colizza V, Barrat A, Barthelemy M et al. Modeling the worldwide or CMV is also very rare, as a large proportion of the population spread of pandemic influenza: baseline case and containment inter- is already infected as well as the fact that emergence of resistance ventions. PLoS Med 2007; 4: e13. is limited to the highly immunosuppressed population. Virtually 5. White KL, Margot NA, Ly JK et al. A combination of decreased all data on transmitted resistance thus refer to HIV. NRTI incorporation and decreased excision determines the resistance profile of HIV-1 K65R RT. AIDS 2005; 19: 1751–60. Surveillance of antiviral resistance 6. Rhee SY, Taylor J, Wadhera G et al. Genotypic predictors of human immunodeficiency virus type 1 drug resistance. Proc Natl Acad Approximately 10% of new HIV infections in the UK are with Sci USA 2006; 103: 17355–60. 9 viruses with at least one major resistance mutation. The detrimen- 7. Nijhuis M, van Maarseveen NM, Lastere S et al. A novel tal impact of this on future drug therapy has led to widespread substrate-based HIV-1 protease inhibitor drug resistance mechanism. implementation of resistance testing prior to starting therapy, in PLoS Med 2007; 4: e36. order that first-line treatment can be individualized depending on 8. Grover D, Allen L, Edwards SG et al. Predictors of death, and these transmitted resistance patterns.10 It is self-evident that sur- response to therapy in patients with multi (three)-class drug resistant veillance systems to monitor resistance in untreated individuals (MDR) HIV in the UK. Antiviral Therapy 2005; 10: S7. (i.e. transmitted resistance) are essential. Indeed, as antiretroviral 9. Cane P, Chrystie I, Dunn D et al. Time trends in primary resist- therapy is rolled out to the developing world, the WHO has ance to HIV drugs in the United Kingdom: multicentre observational initiated a global laboratory network to monitor the emergence of study. BMJ 2005; 331: 1368. resistance in treated and untreated HIV-infected individuals. 10. Gazzard B, Bernard AJ, Boffito M et al. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006). HIV Med 2006; 7: 487–503. 11. Reesink HW, Zeuzem S, Weegink CJ. Rapid decline of viral RNA Future developments in hepatitis C patients treated with VX-950: a phase Ib, placebo- controlled, randomized study. Gastroenterology 2006; 131: 997–1002. There are two future developments requiring a research and sur- 12. Le Pogem S, Kang H, Harris SF et al. Selection and characteri- veillance response. First, a number of new drugs specifically tar- zation of replicon variants dually resistant to thumb- and palm-binding geting HCV polymerase and protease are likely to enter clinical nonnucleoside polymerase inhibitors of the hepatitis C virus. J Virol 11,12 practice. Unlike the current drug combination of ribavirin 2006; 80: 6146–54. and interferon, these drugs will rapidly select for drug-resistant 13. The Royal Society and the Academy of Medical Sciences variants, particularly if used as single agents. The laboratory 2006. Pandemic Influenza: Science to Policy. http://www.royalsoc.ac. capacity to assess resistance and cross-resistance and studies to uk/displaypagedoc.asp?id=22903 (4 April 2007, date last accessed).

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