herpesviruses, influenza by elibrary escmid

ANTIVIRAL TREATMENT:

HERPESVIRUSES, INFLUENZA

Prof. Mojca Matičič, MD, PhD

Clinic for Infectious Diseases and Febrile IllnessesUniversity Medical Centre Ljubljana

Faculty of Medicine, University of Ljubljana

Ljubljana: April 15, 2019

© ESCMID eLibrary by a

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The extent of the pipelines

Antibiotics

Antivirals

Antibiotics

Antifungals


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Viral infections

• Clinical course depends on:

virus patogenity

patient immunity

• Infection: acute

chronic

latent (clinically inactive) → reactivation


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Treatment of viral infections

• Usually symptomatic

Antivirals used for:

• Treatment: for clinically overt disease

• Pre-emptive treatment: for prevention of disease in increased replication of latent viruses

• Supressive treatment: for prevention of reactivation of latent viruses© ESCMID eLibrary by a

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Antiviral drugs

Viruses:

• replicate intracellulary

• to synthesize viral particles they employ: - host cell enzymes - host cell macromolecules - host cell organelles

Antiviral drugs:

• discrimination between host functions and viral functions© ESCMID eLibrary b

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Antiviral drugs

NO “MAGIC BULLET”

Main problems:

• toxicity

• efficacy

• resistance© ESCMID eLibrary by a

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Medications against viral infections

• Antivirals:

prevent viral replication intracellularly nucleos(t)ide analogues, protease inhibitors, integrase inhibitors etc

• Immunomodulators:

enhance or change host immune response to viruses immunoglobulins, interferons, biological therapy (anti TNF, anti-CD20, anti-CD52 etc)

• In 2019: over 50 antivirals for systemic usenew or updated giudelines for their use© ESCMID eLibrary b

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VIRAL INFECTIONS treated with SYSTEMIC ANTIVIRALS

Against: HIV (33)

herpesviruses: HSV-1, HSV-2, VZV, CMV

influenza viruses

hepatitis B virus (HBV), hepatitis C virus (HCV)

respiratory syntitial virus (RSV)

other viruses: EBV, HHV-6

parvo B19,

enteroviruses, adenoviruses,

human polioma viruses BK, JC

HPV© ESCMID eLibrary by a

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Human herpesviruses

Common characteristics: lifelong infection

latency

reactivation

oncogeneity

NOT curable!

Clinical sindromes related to herpesvirus infections:Syndrome HSV-1 HSV-2 VZV CMV EBV HHV-6 HHV-7 HHV-8

Gingivostomatitis + + - - - - - -

Genital lesions + + - - - - - -

Keratokonjuktivitis + + + - - - - -

Retinitis + + + + - - - -

Skin lesions + + + + + + + +

Ezophagitis + + + + - - - -

Pneumonitis + + + + + + - -

Hepatitis + + + + + + - -

Meningitis + + + - + + - -

Encephalitis + + + + + + + -

Mononucleosis - - - + + + - +?

Hemolytical anemia - - + + + -

Peripartal infection + + + + - + - +


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Antiviral drugs used for herpesvirus infections

VIRUS Antivirals

HSV and VZVinhibitors

aciclovirvalaciclovirpenciclovir*famciclovir

brivudinidoksuridin*trifluridin*vidarabin*

CMVinhibitors

ganciclovirvalganciclovir

foscarnetcidofovir

fomiversen**HSV = virus herpes simplex; VZV = virus varicella-zoster; CMV = citomegalovirus

*: topical; **intravitreal


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Aciclovir

• Guanozine derivative• Patented in 1974; approved for medical use in 1981

• Oral/intravenous/topical administration

• In vitro: most potent against HSV-1half as potent against HSV-210th as potent against VZV

• Most commonly used in HSV infections

• Very well tolerated• Favourable safety profile

AE: renal disfunction

• Pregnancy: at high doses chromosomal breakageNO fetal abnormalities

NO MORE abnormalities compared to the newborns in general population


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Valaciclovir

• L-valine ester of aciclovir (prodrug form of aciclovir)

• Oral administration

• Enhanced absorbtion after oral administration

• Bioavailability: 3-5x ↑ compared to acyclovir

• Concentration-time curve:

1g tid PO valcyclovir = 5 mg/kg tid IV acyclovir

• Very well tolerated


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• Guanosine analogue

• Prodrug form of penciclovir with improved oral bioavailability (77%↑)


• Intracellular concentrations of penciclovir triphosphate are higher than acyclovir triphosphate

• Penciclovir is not metabolized, but is eliminated unchanged in urine

• Adjustment of the famciclovir dose is required in patients with creatinine clearance of <60 ml/min.

Famciclovir


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Brivudin

IC50 activity in vitro

• Bromovinildeoksiuridin

• Competitive inhibitor of viral DNA polymerase


• Once daily

• In vitro:

BVD 200-1000 times more potent in inhibition of VZV replicationcompared to ACV

• Indication: Shingles

in immunocompetent patients© ESCMID eLibrary by a

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Brivudin

IC50 activity in vitro

• Bromovinildeoksiuridin

• Competitive inhibitor of viral DNA polymerase


• Once daily

• In vitro:

BVD 200-1000 times more potent in inhibition of VZV replication compared to ACV

• Indication: Shingles in immunocompetent patients


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HSV infectionsSystemic treatment options

• acyclovir

• valacyclovir

• famciclovir

Rescue treatment:

• foscarnet

• cidofovir


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HSV-1, HSV-2Systemic antiviral treatment efficacy

• Primary: acyclovir IV/PO speeds healing of lesions valacyclovir PO reduces virus shedding

• Recurrent:acyclovir PO speeds healing of lesionsvalacyclovir PO

• Immunocompromised:speeds healing of lesions

acyclovir IV

reduces virus shedding

• Labial herpes:valacyclovir 2g bid, 1 day reduces duration by 1 day

Fife KH. Sex Transm Dis 1997; 24: 481-6. Bodsworth NJ. Genitourin Med 1997: 73: 110-6.

CDC. MMWR 2010; 59(RR-12): 15-6.


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HSV-1, HSV-2Indications for systemic TREATMENT

• genitalni herpes: primary infection recurrences

• orofacialni herpes • ophtalmic herpes• herpes encephalitis• neonatal herpes• mucocutaneous herpes in immunocompromised • Other herpetic syndromes

eccema herpeticum, erythema multiforme hepatitis, proctitis, esophagitis, pneumonitis systemic infection

GPs


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HSV-1, HSV-2Indications for systemic TREATMENT

• genitalni herpes: primary infection recurrences

• orofacialni herpes • ophtalmic herpes• herpes encephalitis• neonatal herpes• mucocutaneous herpes in immunocompromised • Other herpetic syndromes

eccema herpeticum, erythema multiforme hepatitis, proctitis, esophagitis, pneumonitis systemic infection© ESCMID eLibrary b

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Genital herpesIndications for CHEMOPROPHYLAXIS

• Immunocompetent patients:

recurrent herpes (≥6 recurrences per year)

• Immunodefficient patients:

recurrent herpes solid organ/bone marrow Tx

HIV/aidshaematological malignances© ESCMID eLibrary b

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Treatment regimens for HSV infection

HSV

encephalitis aciclovir intravenous 10-15 mg/kg x 3; 14-21 daysimmunocompromised–

systemic infectionsaciclovir intravenous 10-15 mg/kg x 3; 14-21 days

neonatal herpes aciclovir intravenous 10-15 mg/kg x 3; 14-21 days

genital herpes

primary

(treatment)

aciclovir orintravenous 5 mg/kg x 3; 5-10 days

oral 200 mg x 5; 7-10 days

valaciclovir or oral 500 mg x 2; 7-10 days

famciclovir oral 250 mg x 3; 7-10 days

recurrent

(treatment)

aciclovir or oral 200 mg x 5; 5 days or

800 mg x 2; 5 days

valaciclovir or oral 500 mg x 2; 3 days

famciclovir oral 1000 mg x 2; 1 days

recurrent

(chemo-

prophylaxis)

aciclovir or oral 200 mg x 1-5 or

400 mg x 2; several months

valaciclovir or oral 500-1000 mg x 1; several months

famciclovir oral 125-250 mg x 2; several months

immuno-

compromised –

mucocutaneous

herpes

treatment

aciclovir orintravenous 5 mg/kg x 3; 7 days

oral 500 mg x 5; 10 days

valaciclovir or oral 1000 mg x 3; 7 days


chemo-

prophylaxis

aciclovir ororal 200 mg x 2; prolonged

intravenous 5 mg/kg x 2; prolonged

valaciclovir or oral 1000 mg x 3; prolonged

famciclovir oral 500 mg x 2; prolonged

labial herpes

(recurrent)

penciclovir or topical 1% ointment: for 2h in the morning; 4 days

valaciclovir or oral 2000 mg x 2; 1 day


herpetic keratitis

aciclovir or oral 200 mg x 5; 7-10 days

valaciclovir oral 500 mg x 2; 10 days

+

aciclovir or topical 3% ointment: 5x daily

trifluridin or topical1 gtt, 1% ocular solution:every 2 h during

daytime

vidarabin topical 3% ointment: 5xdailyTomažič J, Strle F, et al. Infekcijske bolezni. 2nd ed. Ljubljana, SZD 2017; p. 76-7.


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HSV-1, HSV-2Resistance to acyclovir

Prevalence:• immunocompetent patients: 0,3 % (USA) - 0,7 %(UK)

0,19 % (11 large trials)

• herpes keratitis patients: 6,4 %

• HIV/aids patients: 3,5-7 %

• solid organ Tx patients: 2,5-10%

• allogenic bone marrow Tx patients: 30%

Treatment options: RESCUE ONLY!

• foscarnet IV

• cidofovir IV (not well controlled studies)

Morfin F, Trouvenet J. J Clin Virol 2003; 26: 29-37. Chilukuri S, Rosen T. Dermatol Clin 2003; 21: 311-20. Pirat J, Boivin S. Antimicrobial Agents Chemother 2011; 55: 459-72.


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VZVChickenpox

Serious compications in:

• adults (50x ↑ than children)

• newborns

• immunocompromised

• pregnancy

• chronic pulmonary diseases

• chronic skin diseases© ESCMID eLibrary by a

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ChickenpoxSystemic treatment options

VZV HSV

• acyclovir : 5x800 mg PO 5-7 days 5x200mg

• acyclovir : 3x10 mg/kg IV 10 days 3x 5 mg/kg

• valacyclovir : 3x1000 mg PO 5-7 days 2x500 mg

• famciclovir

Aciclovir : VZV vs HSV

higher doses and more frequent dosing for VZV than for HSV (VZV less sensitive)


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ChickenpoxSystemic treatment efficacy

Immunocompetent host:

- children: ↓ fever duration temperature↓ no. of lesions (247 vs. 347)speeds healing (2.7 days vs. 3.2 days)

- adolescents: ↓ fever duration ↓ time of new lesion development (for 0.5 days)

- adults: ↓ fever duration (for 1.8 days)speeds healing ↓ general symptoms

Immunocompromised host:

- Systemic treatment prevents dissemination of the disease

Balfour HH, 1990; Dunkle LM, 1991; Wallace MR, 1992; Walsh JB,1996; Dunkle LM, 2001; Balfour HH, 2001.


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CHICKENPOXAvtiviral treatment guidelines

• Indications: >18 yearssecondary contacts 12-17 yearspregnant womenpatients with complicationsimmunocompromised

• Treatment should be started within 48 hours of the onset of skin lesions(except for immunocompromised patients)

• Pregnant women should be warned on Category 3 treatmentrecommendation

• Acyclovir IV in highly impaired immunity: HIV/aids, haematologicalmalignancies, high dose citostatic treatment, TX

• Acyclovir PO or valacyclovir PO in moderately impaired immunity: solidtumors, corticosteroid therapy, low dose citostatic treatment


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Treatment regimens for CHICKENPOX

Imunity Patients Antivirals Mode of application

Dosing Treatment duration

normal

<12 years symptomatic / / /

12-18 yearsprimary contact symptomatic / / /

secondary

contact

aciclovir p.o. 5x800mg 5-7days

>18 years

valaciclovir or p.o. 3x1000mg 5-7days

famciclovir or p.o. 3x500mg 5-7days

aciclovir p.o. 5x800mg 5-7days

newborns aciclovir i.v. 10mg/kg/8h 5-7days

pregnant women aciclovir p.o. 5x800mg 5-7days

complications aciclovir i.v. 10mg/kg/8h 10 days

deficient

Immune deficiency: mild /

moderate:•solid tumor in remission,

•corticoid treatment

•moderate dosing of citostatics

valaciclovir or p.o. 3x1000mg ≥7days

famciclovir or p.o 3x500mg ≥7days

aciclovir p.o 5x800mg ≥7days

Immune deficiency: severe

• HIV/aids,

•stemcell carcinoma,

•high dosing of citostatics,

•treansplant recipients

aciclovir i.v. 10mg/kg/8h 7-10days

complications aciclovir i.v. 10mg/kg/8h

aciclovir resistant viral strains foscarnet i.v. 40-60mg/kg/8h ≥14days

Tomažič J, Strle F, et al. Infekcijske bolezni. 2nd ed. Ljubljana, SZD 2017; p. 76-7.


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VZVShingles (Herpes zoster)

Complications:• Dissemination: skin

pneumonitis, hepatitis

meningo/encephalitis

• Dermatological: bacterial superinfection

granulomatous dermatitis

erythema multiforme

• Due to localisation: otic

ophtalmic

anogenital

• Postherpetic neuralgia © ESCMID eLibrary by a

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ShinglesSystemic antiviral treatment efficacy

• Shortens healing process of acute disease

• Alleviates pain

• Alleviates/prevents acute and chronic complications(postherpetic neuralgia!)

Am J Clin Dermatol 2005; 6: 317-25.

Dworkin RH. Clin Infect Dis 2007; 44: S1-26.


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ShinglesSystemic antiviral treatment

Indications: >50 years of agesevere pain/several vesicles at any age zoster on head/neckimmunocompromisedatopic dermatitiseccema

Effective: given within 48-72 hours by rash onset>72 hours: ophtalmic HZ

immunocompromisedsevere acute pain

Am J Clin Dermatol 2005; 6: 317-25.

Dworkin RH. Clin Infect Dis 2007; 44: S1-26.


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Imunity Patients AntiviralsMode of application Dosing

Treatment duration

preserved

<50 years

Pain: no / mild symptomatic / / /

Pain: moderate / severe

valaciclovir or p.o. 3x1000mg 7days

famciclovir or p.o. 3x500mg 7days

brivudin or p.o. 1x125mg 7days

aciclovir p.o. 5x800mg 7days

>50 years



brivudin or p.o. 1x125mm 7days


Zoster ophtalmicus / zoster oticus(any age)




deficient

Immune deficiency: mild / moderate:•solid tumor in remission,

•after immunosupressive treatment

aciclovir or p.o. 5x800mg 7days


famciclovir p.o 3x500mg 7days

Immune deficiency: severe

•leukemia / lymphome

•immunosupressive therapy

•trensplant recipients

aciclovir i.v. 10mg/kg/8h 7-10days

HIV/aids:•zoster in one dermatoma

(not face)

aciclovirali p.o. 5x800mg 7-10days

valaciclovir p.o. 3x1000mg 7-10days

• zoster with complications

(face, multiple dermatomas, etc)aciclovir i.v. 10mg/kg/8h 10-

14(21)days

disseminated disease aciclovir i.v. 10mg/kg/8h 10-

14(21)days

aciclovir resistant viral strains foscarnet i.v. 40-60

mg/kg/8h

≥14days

Treatment regimens for ZOSTER



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CMVAntiviral treatment

DNA polymerase inhibitors:• Ganciclovir

• Valganciclovir

• Foscarnet

• Cidofovir

• Brincidofovir

Viral terminase inhibitor: NEW!• Letermovir© ESCMID eLibrary b

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Ganciclovir• synthetic analogue of 2′-deoxy-guanosine

• DNA polymerase inhibitor

• absorption of the oral form is very limited

• 90% of plasma ganciclovir is eliminated unchanged in the urine

• a half-life of 2–6 hours

Indication: primarily CMV (symptomatic immunocompromised pts)

Administration:

- IV

- slow-release formulations (implantate) – intravitreous

- topical ophthalmic gel (acute HSV keratitis)

AE: bone marrow supression (↓ Leu, ↓Tr)

Resistant strains: rarely occur (genes: DNA polymerase, UL97)

usually sensitive for foscarnet and cidofovir


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Valganciclovir

• L-valyln ester of gancyclovir

• Good resorbtion

• 60% bioavailability

• Oral administartion

• Indications: CMV infection

- treatment (900 mg/day bid)

symptomatic immunocompromised pts

- pre-emptive treatment (900 mg/day bid)

- chemoprophylaxis (900 mg/day qd)


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Foscarnet

• phosphonoformic acid


• only IV

• efficacy: same as ganciclovir

• Indication: CMV retinitis in HIV/aids pts

CMV - failure of ganciclovir (resistant virus, neutropenia)

HSV, VZV - ONLY rescue treatment !

• MAJOR TOXICITY:

renal impairment !!! (Ca, K, P, Mg)

• Cross-resistance with gancyclovir possible© ESCMID eLibrary b

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Cidofovir

• citosyne derivate


• only IV

• long half-life time: 5mg/kg once a week for 2 weeks

followed by maintainance 5mg/kg /2 wks

• MAJOR TOXICITY: renal impairment !!!

Indications:

• Primarily CMV

• HSV, VZV - ONLY rescue treatment

BRINCIDOFOVIR: lyposomal prodrug of CIDOFOVIR

1000x more potent than cidofovir against CMV

oral, high blood levels, NOT nephrotoxic© ESCMID eLibrary b

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CMV infection

prophylaxis valganciclovir oral 900 mg once daily; 3-6 mths

pre-emptive treatment

valganciclovir or

oral 900 mg x 2; untill 2 x negative viremia

ganciclovir intravenous 5 mg/kg x 2; untill 2 x negative viremia

treatment

ganciclovir or

intravenous5 mg/kg x 2; at least 14 d;Followed by maintainance 5 mg/kg/d

valganciclovir or oral900 mg x 2; at least 14 d;Followed by maintainance 900 mg/d

foscarnetor

intravenous90 mg/kg x 2 or 60 mg/kg x 3; at least 14 d;Followed by maintainance: 90-120 mg/d

cidofovir intravenous

5 mg/kg, 1 x weekly; 2 weeks;Followed by 1x per 2 weeksGood hidrationAdd probenecid

fomivirsen intravitreal1. day and 15. day: 330 mg;Followed by maintainance 330 mg /mth

Treatment regimens forCMV infection



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letermovir

Existing CMV antivirals

• Existing CMV antivirals & brincidofovir are inhibitors of viral DNA polymerase

• inhibits the synthesis of viral DNA

• act early in the virus lifecycle

• Letermovir is a novel viral terminase inhibitor

• prevents proper DNA cleavage into unit-length genome and packaging of these genomes into

procapsids

• blocks viral replication without inhibiting the synthesis of HCMV DNA or viral proteins

• prevents the formation of infectious virions

• acts late in the virus lifecycle

letermovir


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EBVAntiviral treatment

• Indication: PTLD

HPS

• Treatment: ganciclovir?

rituximab?

other?© ESCMID eLibrary b

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INFLUENZA pandemics

151.700 –575.400

ECDC, 2009.


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INFLUENZA pandemics

151.700 –575.400


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INFLUENZAProportion of vaccinated persons

aged >65 years in Europe

European Centre for Disease Prevention and Control. Seasonal influenza vaccination andantiviral use in EU/EEA Member States – Overview of vaccine recommendations for 2017–2018 and vaccinationcoverage rates for 2015–2016 and 2016–2017 influenza seasons. Stockholm: ECDC; 2018.


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Amantanes - target M2 ion channel protein of influenza A virus:- Amantadine and rimantadine - active against influenza A virus (not influenza B virus!)

- high levels of resistance (>99% in H3N2 and H1N1) NOT recommended for antiviral treatment or chemoprophylaxis

Neuraminidase inhibitors - active against both influenza A and B viruses:

– oral oseltamivir phosphate (Tamiflu®)

– inhaled zanamivir (Relenza®)

– intravenous peramivir (Rapivab®)

Endonuclease inhibitor (cap-dependent):- oral baloxavir marboxil (Xofluza®) - approved 2018 in Japan, USA

INFLUENZAAntiviral agents

https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm


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INFLUENZAAntiviral agents

Amantanes - target M2 ion channel protein of influenza A virus:- Amantadine and rimantadine - active against influenza A virus (not influenza B virus!)

- high levels of resistance (>99% in H3N2 and H1N1) NOT recommended for antiviral treatment or chemoprophylaxis

Neuraminidase inhibitors - active against both influenza A and B viruses:

– oral oseltamivir phosphate (Tamiflu®)

– inhaled zanamivir (Relenza®)

– intravenous peramivir (Rapivab®)

Endonuclease inhibitor (cap-dependent):- oral baloxavir marboxil (Xofluza®) - approved 2018 in Japan, USA



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INFLUENZAUnlicensed/unauthorised antivirals available for compassionate use

(emergency/experimental/research) in Europe, season 2017/18



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INFLUENZAThe benefit of antiviral treatment

Clinical trials and observational data:

• early antiviral treatment can shorten the duration of fever and illness symptoms

• may reduce the risk of some complications (e.g., otitis media in young children, pneumonia, and respiratory failure)

• early treatment of hospitalized adult influenza patients with oseltamivir has been reported to reduce death in some observational studies

• in hospitalized children, early antiviral treatment with oseltamivir has been reported to shorten the duration of hospitalization in observational studies.

• Clinical benefit is greatest when antiviral treatment is administered early, especially within 48 hours of influenza illness onset in clinical trials and observational studies.



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INFLUENZA Antiviral medications

recommended for treatment and chemoprophylaxis



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INFLUENZA Dosing of antiviral treatment and chemoprophylaxis


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INFLUENZAIndications for treatment

• hospitalized• severe, complicated, or progressive illness• at higher risk for influenza complications

• children <2 years• adults ≥65 years• people with chronic pulmonary (including asthma), cardiovascular (except

hypertension alone), renal, hepatic, hematological (including sickle cell disease), and metabolic disorders (including diabetes mellitus), or neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle, such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury)

• people with immunosuppression, including that caused by medications or by HIV infection

• women who are pregnant or postpartum (within 2 weeks after delivery)• people younger than 19 years old who are receiving long-term aspirin- or

salicylate-containing medications• people who are extremely obese• residents of nursing homes and other chronic care facilities.



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INFLUENZARecommendations for treatment of

suspected or laboratory confirmed influenza, season 2017/18 in Europe



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INFLUENZARecommendations for treatment

of suspected or laboratory confirmed influenza, seasons 2014/15 and 2017/18 in Europe


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INFLUENZAIndications for chemoprophylaxis

• Neuraminidase inhibitor s: 70 - 90% effective in preventing influenza

• Widespread or routine use of antiviral medications for pre-exposure or post-exposure chemoprophylaxis NOT recommended

• Indications for chemoprophylaxis for those not vaccinated and being exposed to person with influenza:

– people at high risk of influenza complications during the first two weeks following vaccination

– people at high risk for complications from influenza who cannot receive influenza vaccine due to a contraindication

– people with severe immune deficiencies or others who might not respond to influenza vaccination, such as people receiving immunosuppressive medications

• Indication to control outbreaks among high risk people in institutional settings, such as long term care facilities, is recommended.

• Antiviral chemoprophylaxis generally is not recommended if more than 48 hours have elapsed since the first exposure to a person with influenza.



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INFLUENZARecommendations for prophylaxis

following exposure to of suspected or laboratory confirmed influenza, season 2017/18 in Europe



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INFLUENZARecommendations for prophylaxis

following exposure to of suspected or laboratory confirmed influenza, seasons 2014/15 and 2017/18 in Europe



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Koszalka P et al. Influenza Other Respir Viruses 2017;11(3):240-246. doi: 10.1111/irv.12446.

INFLUENZA Antiviral agents currently in late-phase clinical trials


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CONCLUSIONS

• Treatment of viral infections usually symptomatic

• Systemic antiviral treatment for: HIV (31)

herpesviruses: HSV-1, HSV-2, VZV, CMV

hepatitis B virus (HBV)

hepatitis C virus (HCV)

respiratory syntitial virus (RSV)

influenza A and B virus, H1N1

• Follow the indications

• Special population for antiviral therapy: immunocompromised patients© ESCMID eLibrary by a

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Literature

• https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm

• https://www.ncbi.nlm.nih.gov/books/NBK47401/

• http://www.idpublications.com/journals/pdfs/avres/avres_mostcited_1.pdf

• https://journals.lww.com/transplantjournal/Fulltext/2018/06000/The_Third_International_Consensus_Guidelines_on.13.aspx

• http://www.bloodjournal.org/content/131/26/2899

• https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-human-herpesvirus-6-infection-in-adults

• https://www.idsociety.org/globalassets/idsa/practice-guidelines/2018-seasonal-influenza.pdf


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https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6403a1.htm

https://www.ncbi.nlm.nih.gov/books/NBK47401/

http://www.idpublications.com/journals/pdfs/avres/avres_mostcited_1.pdf

https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-treatment-of-human-herpesvirus-6-infection-in-adults

https://www.idsociety.org/globalassets/idsa/practice-guidelines/2018-seasonal-influenza.pdf

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