Evolution in the Therapeutics of Respiratory Viral Infections

EVOLUTION IN THE THERAPEUTICS OF RESPIRATORY© by VIRAL author INFECTIONS

ESCMID OnlineS. Tsiodras, Lecture MD, PhD Library Asst Professor of Internal Medicine & Infectious Diseases University of Athens Medical School Respiratory viral infections

Lancet 2011; 377: 1264–75 Lower RTIs - Associations

 Bronchiolitis RSV, hMPV, PIV, adeno

 Wheezing/Asthma RSV, hMPV, rhinovirus

 Croup PIV

 Pneumonia © by flu, author PIV, adeno, RSV ESCMID Pneumonitis Online Tx RSV, Lecture PIV, flu, LibraryhMPV, adeno

Clinical Infectious Diseases 2011;52(S4):S284–S289 VIRAL PNEUMONIAS

Most frequent causes – Influenza – Respiratory syncytial virus (RSV) – Parainfluenza – Human metapneumovirus – Human bocavirus – Rhinoviruses © by author ESCMID– Coronaviruses Online Lecture Library – Adenoviruses – Echo, Coxsackie Lancet 2011; 377: 1264–75 CAP - Viruses vs. Bacteria

ESCMID Online Lecture Library

Lancet 2011; 377: 1264–75 CAP - Viruses vs. Bacteria

Lancet 2011; 377: 1264–75 SPECIFIC PATHOGENS

Neuraminidase (NA)

NA Inhibitors • Oseltamivir • Zanamivir

Matrix protein (M2 ) © by author M2 Inhibitors ESCMID Online Lecture• Amantadine Library • Rimantadine © by author ESCMID Online Lecture Library Influenza & Antivirals

Outcome AM/RM ZNV OSEL

 symptoms YES YES YES Prevent complications ? YES YES

 Abx use ? 28% 24-40%  Hospitalization © by author? ? ~50% Treat complications ? ? ? ESCMID Online Lecture Library  transmission ? (30%) ? ?

?= No placebo-controlled study or not reported © by author ESCMID Online Lecture Library

CID 2010:50 (1 April) • Ling et al © by author ESCMID Online Lecture Library

CID 2010:50 (1 March) • © by author ESCMID Online Lecture Library Influenza in the Community

Mild forms

– Fever, coryza

– General sxs headache, malaise© by, myalgia author/arthralgia & GI Sxs NO evidence of complications –ESCMID Online Lecture Library Influenza in the Community

e.g. >65yrs, chronic dz, pregnancy, BMI>40

e.g. ChemoRx, BMT, SOT, HIV w CD4< 200

Severe forms - Complications – Requiring hospital admission

– Sxs & signs of LRTI hypoxemia, dyspnea, lung infiltrate on CxR © by author – CNS involvement ESCMID Online Lecture Library – exacerbation of underlying medical condition Influenza in the Community

e.g. ChemoRx, BMT, SOT, HIV w CD4< 200

Mild uncomplicated influenza Rx only population at  risk for complications

Complicated© influenza by author or worsening ESCMID OnlineRx Lecture all Library © by author ESCMID Online Lecture Library Adverse effects

Oseltamivir – GI tract nausea vomit – Take w food

? Encephalitis © by author

AllergicESCMID rash Online Lecture Library

? Neuro-psych effects © by author ESCMID Online Lecture Library Relenza® (zanamivir for inhalation) Rotadisk® and Diskhaler® Mouthpiece Piercing Needle

Rotadisk ESCMIDCover Online LectureInhalatio Library n Powder © by author ESCMID Online Lecture Library

CID 2010:50 (1 March) • Oseltamivir Drug - Drug interactions

 Clopidogrel

–  Oseltamivir hydrolysis to active metabolite © by author

ESCMID Online JLecture Pharmac Exp LibraryTher 2006 © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library

Australian influenza report 2011 Emerging Infectious Diseases, Vol. 17, 2011;653-660 • 594 isolates – 238 Interntl 84 pH1N1, 76 A(H3N2), 78 B – 356 USA © by 30 authorpH1N1, 158 A(H3N2), 168 B

ESCMID Online Lecture Library • All A (H3N2) susceptible to NAIs • 1 pH1N1 US oselt R, zana S (H275Y)

© by author • < 1% of 3000 tested viruses were R to NAIs •ESCMIDAll R to adamantanes Online Lecture Library • 1374 viruses tested – 11 A(H1N1)pdm09© byH275Y author mutation oselt R – 1 A(H1N1)pdm09 Y155H mutation oselt/zan R –ESCMID1 A(H3N2)pdm09 Online D151N Lecture mutation Libraryoselt/zan R – 1 B virus I221T mutation oselt R /zan S – All A (H3N2), A(H1N1)pdm09 tested adamantane R

Neuraminidase Inhibitor resistance

 Research level or compassionate use – iv zanamivir, aqueous solution zanamivir – iv oseltamivir – iv peramivir – inh Laninamivir – iv ribavirin © by author ESCMID– Monoclonal OnlineAb Lecture Library – DAS181, favipiravir, nitazoxanide and AVI-7100

Peramivir is the Most Potent in vitro against H1N1 among those studied

© by author ESCMID Online Lecture Library • 108/111 pts Rx – received NAIs – oseltamivir or peramivir© by author • Median t 7 days !!! –ESCMID9.9% within 48 Online hrs Lecture Library • Abxs 71.2% © by author

ESCMID OnlineHuman Lecture monoclonal antibody Library CR8020 w broad neutralizing activity against most group 2 viruses, including H3N2 and H7N7 Science, 2011: 843-850 © by author ESCMID Online Lecture Library

Science, 2011: 843-850 © by author ESCMID Online Lecture Library Science, 2011: 843-850 Figure 8. The pockets on the predicted structures explored by AutoDock based on a subunit:

Cui W, Wang K, Ruan J, Qi Z, et al. (2012) The Molecular Mechanism of Action of the CR6261-Azithromycin Combination Found through Computational Analysis. PLoS ONE 7(5): e37790. doi:10.1371/journal.pone.0037790 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037790 Rhinovirus Therapeutics

• Antivirals – Pleconaril • 3C protease inhibitors (e.g. nasal spray of ruprintrivir) – AAC 2003; 47(12): 3907-16. • Interferon alpha-2b for prophylaxis – N Engl J Med 1986; 314:71. • Soluble ICAM-1 (Tremacamra© by author) – JAMA 1999; 281:1797 • ESCMIDVLDL and LDL receptorOnline fragments Lecture Library – J Virol 1998; 72:10246 Rhinoviruses

Thibaut HJ et al. Biochemical pharmacology. 2012;83(2):185-92 Rhinoviruses

Wide range of clinical manifestations

Several serotypes  respiratory dz

Pharyngitis common © by author ESCMID Online Lecture Library Enterovirus

• Several targets for inhibition of viral replication

– viral 3C protease© by author ESCMID– the putative Online2C helicase Lecture Library – the 3D RNA-dependent RNA polymerase

• Inhibitors against host cell factors, IVIG Enteroviruses

Thibaut HJ et al. Biochemical pharmacology. 2012;83(2):185-92 Parainfluenza virus

• Croup (types 1, 2), laryngitis • Pneumonia (type 3) in children 6 m – 3 yrs • Pneumonia in immunocompromised – BMT units (type© 3 )by author • Rx: ribavirin, ? NAIs, recombinant sialidase ESCMID Online Lecture Library fusion protein (DAS 181)

The Journal of infectious diseases 2010; 202(2): 234-41. Transplant infectious disease 2012; 14(4): 427-33. RSV Alveolar obstruction

 Syncytia formation

 Inflammatory cell infiltrate

© by author Sloughing of respiratory ESCMID Online Lecture epitheliumLibrary Prevention • Palivizumab = Synagis – RSV-F protein-specif. humanized monoclonal Ab • Impairs fusion & resp epithelium entry, NO role in Rx – Children < 2 yrs &  risk • Prematurity, bronchopulmonary© by author dysplasia, neuromuscular dz, congenital heart disease, CLD, immunodeficiency – ESCMIDChildren w recurrent Online wheezing Lecture that had Library RSV infxn –  cost

Motavizumab

Pediatr Res 70: 186–191, 2011 RSV Rx

 Supportive, Abx if mixed bacterial infection

 RSV IG

 Ribavirin

Monoclonal Ab against G protein

. Experimental data, mice

Small molecules

. BMS-433771, TMC353121, JNJ-2408068, VP14637

Lundin et al., 2010; Haynes LM JID 2009; Miao C J Gen Virol. 2009; Collins P et al. J. Immunol. 2009;183 (10), 6338–6345, PLoS One. 2012;7(12):e51485. © by author ESCMID Online Lecture Library

PNAS 2010 ; 107;8800-05 © by author ESCMID Online Lecture Library © by author ESCMID Online Lecture Library Human Metapneumovirus

 Epi & clinical picture similar to RSV

 Max incidence between 4-6 months of age

 Frequent coinfection w RSV © by author  Frequently mild or asymptomatic infection ESCMID Online Lecture Library J. Williams et al. NEJM 2004;350:5 Xepapadaki P et al. J Clin Virol 2004 Jul;30(3):267-70 HMPV in immunosupression

Transpl Infect Dis 2011: 13: 324–328 Human Metapneumovirus Rx

ESCMID Online Lecture Library

Transpl Infect Dis 2011: 13: 324–328 Virology Journal 2012, 9:105

ADENOVIRUS

 51 serotypes

– Pharyngo-conjunctivitis / association w pools

– Immunocompromised, BMT (60 % mortality)

– Military recruits - CAP 10-20% © by author Rx: Ribavirin ± IVIG, Cidofovir, Vidarabine ESCMID Online Lecture Library Transplantation 2007; 13(1): 74-81 Bone Marrow Transplant. 2013 Mar 18 SARS

 Ribavirin  NA  Protease inhibitors – Lopinavir/ritonavir – Nelfinavir © by author Human interferons  Statins ESCMID Online Lecture Convalescent Library serum  Monoclonal Abs Other Coronaviruses

Els Keyaerts et al. AAC 2009;53:3416-3421 New coronavirus - MERS-CoV

• ? interferons (types I and III)

– MERS-CoV ->50 to 100 times more sensitive to interferon-alpha (IFN-α) Rx than SARS-CoV

mBio.00611-12 19 February 2013 mBio vol. 4 no. 1 e00611-12 J Gen Virol. 2013 Apr 25. New coronavirus - MERS-CoV

 Herpesviruses – VZV, HSV • Immunocompromised, pregnancy,HIV – CMV  Systemic dz © by author ESCMID– Measles, Hantavirus Online Lecture Library  Others… Bocavirus, Parechovirus ? Mimivirus