Zika Virus Infection (1 of 7)

1 Patient presents w/ signs, symptoms & history suggestive of Zika virus infection

2 3 DIAGNOSIS No ALTERNATIVE Is Zika virus DIAGNOSIS conﬁ rmed?

Yes

A Patient/Partner education B Pharmacological therapy • Analgesic, Antipyretic C Prevention • Protection from mosquito bite • Prevention from sexual transmission • Prevention from unintended pregnancy • Preventive measures among pregnant women & their partners • Caretakers, family members & visitors of a person w/ Zika virus infection • Preventive measures in healthcare setting & among healthcare professionals • HIV & Zika virus infection • Community control measures © MIMS

Not all products are available or approved for above use in all countries. Speciﬁ c prescribing information may be found in the latest MIMS.

B1 © MIMS 2019 Zika Virus Infection (2 of 7)

1 ZIKA VIRUS INFECTION

• Zika virus infection is an arboviral & a notiﬁ able disease • All healthcare professionals are encouraged to report suspected cases to the state & local health departments to facilitate the diagnosis & mitigate the risk of transmission Etiology • Zika virus is an icosahedral, enveloped, single-stranded RNA virus that comes from the Flaviviridae family & genus Flavivirus

- Its lipid envelope is covered w/ dense projections consisting of membrane & glycoproteins ZIKA VIRUS INFECTION Mode of Transmission • It can primarily be transmitted in humans through a bite of Aedes aegypti & Aedes albopictus mosquitoes - Other Aedes species that can transmit infection are Aedes africanus, Aedes luteocephalus, Aedes vittatus, Aedes furcifer, Aedes hensilli & Aedes apicoargenteus - ese mosquito vectors breed in domestic water-holding containers - ey are aggressive daytime biters - Peak biting hours: Early in the morning & late afternoon/evening - Feed both indoors & outdoors especially near dwellings - Main reservoirs of the virus: Nonhuman & human primates - During outbreaks, anthroponotic transmission (human-to-vector-to-human) may occur • Other possible modes of transmission: - Perinatal - Sexual (anal, vaginal & oral) - May be transmitted from male-to-male, male-to-female- & female-to-male sex partners - At present, female-to-female transmission has not been documented - Women infected w/ Zika may pass the virus through vaginal fl uid & menstrual blood - Blood transfusion - Organ transplantation - Laboratory exposure Epidemiology • First identifi ed in the Zika forest of Entebbe in Uganda in 1947 in a Rhesus monkey & isolated in humans in 1952 in Uganda & Tanzania • It was in 2007 that the fi rst outbreak happened in the Yap Islands of Micronesia that aff ected >70 of the population aged 3 years old & above • In 2013 to 2014, the second outbreak occurred in French Polynesia which aff ected ⅔ of the population - 3 of the donated blood samples tested were positive for Zika virus • Countries & territories that are known to have local mosquito-borne transmission of Zika virus are: East Timor, Ecuador, El Salvador, Fiji, French Guiana, Grenada, Guadeloupe, Guatemala, Guyana, Haiti, Honduras, Indonesia, Jamaica, Kosrae (Federated States of Micronesia), Laos, Malaysia, Maldives, Marshall Islands, Martinique, Mexico, Myanmar, New Caledonia, Nicaragua, Palau, Panama, Papua New Guinea, Paraguay, Peru, Philippines, Saba, Samoa, Saint Barthélemy, Saint Kitts & Nevis, Saint Lucia, Saint Martin, Saint Vincent & Grenadines, Singapore, Saint Eustatius, Saint Maarten, Suriname, ailand, Tonga, Trinidad & Tobago, Turks & Caicos, United States, Venezuela, Vietnam, Anguilla, Antigua & Barbuda, Argentina, Aruba, Bahamas, Barbados, Belize, Bolivia, Bonaire, Brazil, British Virgin Islands, Brunei, Cambodia, Cape Verde, Cayman Islands, Colombia, Costa Rica, Cuba, Curaçao & Dominica & Dominican Republic • It was in early 2015 that Zika virus was fi rst identifi ed in Brazil - is was also when the Zika virus has rapidly spread throughout the Americas • In mid to late 2015, cases of microcephaly & Guillain-Barré syndrome were increased & reported in northern Brazil • In May 2015, the fi rst local transmission of Zika virus in the Western Hemisphere was reported by World Health Organization (WHO) • In February 2016, the Zika virus infection was declared by the World Health Organization (WHO) as an international health emergency • On September 7, 2016, the fi rst Zika infection in pregnancy was reported in Malaysia Signs & Symptoms • Zika virus infection is mild & self-limiting • Incubation period is 3-14 days • May present w/: - Arthralgia (eg particularly on the small joints of the hands & feet) & muscle pain - Skin rash (eg fi ne & diff usely distributed maculopapular rashes on the face, trunk, extremities, palms & soles) - Conjunctivitis - Headache - Acute onset of mild or low-grade fever - Retro-orbital pain • Symptoms may appear on the 1st week of illness, last for up to 2-7 days & occur for 2 weeks, though some individuals w/ Zika virus infection may be asymptomatic • © MIMS May overlap w/ other arboviral infections but presence of maculopapular & immune-mediated rash predominates Risk Factor • Zika virus transmission & infection are increased in patients w/ Guillain-Barré syndrome

B2 © MIMS 2019 • • TestsSerologic • • Trioplex Real-Time Assay (PCR) RT-Polymerase Reaction Chain • • • • • RNA NAT Women forPregnant • • • • RNA Nucleic Acid Test (NAT) Women forNon-Pregnant Tests Laboratory • • infection: virus Zika w/suspected ofpatients history theclinical in points Important History • • • Ultrasound • • - orCSF inserum IgMantibodies Detects - MAC-ELISA) Immunosorbent (Zika Assay Capture Enzyme-Linked IgMAntibody Zika - ofsymptoms the onthe onset 4th after are day positive upto12weeks eIgMantibodies - the end towards ofthe ofillness 1stweek Develop - virus-specifiZika antibodies c IgM&neutralizing &amnioticfl inurine RNA virus forthe ofZika qualitative used detection Also uid (EDTA) wholeblood human sera, or cerebrospinal fl uid (CSF) forthe &diff qualitativeUsed detection foundin &chikungunyavirus dengue erentiation Zika, from ofRNA refl as For known test asubsequent whoare IgMpositive, those NATex RNA included shouldbe transmission w/activevirus inareas especially ofpregnancy trimester tohave onthe pregnantpatients IgMtesting 1st&2nd asymptomatic are care, advised ofthe obstetric part As &are IgMpositive exposed being from whopresent ≥2weeks forthose forcare Recommended - exposure the from possible date oflast samples 2-12weeks within &urine serum both NAT RNA For on isrecommended testing pregnant patients asymptomatic whotraveledareas, inhigh-risk tested may be also Wholeblood - IgM-positive out tobe whoturned exposure after 2-12weeks transmission&were evaluated activeZika without who liveinareas NAT ofexposure RNA pregnant women w/<2weeks asymptomatic isrecommended forthose &urine ofserum ofsymptoms the onset after forupto2weeks is recommended NAT RNA &urine of the testing serum For virus, symptomatic pregnant women to Zika whohave exposure testing (IgM) antibody usingthe immunoglobulin M analyzed further shouldbe If the then isnegative, result collected the serum indicative ofcurrent infection &is inany result If there are needed ofthe ispositive samples noadditionaltests that collected, have been ofsymptoms the <14days onset samples after collected conducted onurine Should be - ofsymptoms the from onset NAT 2weeks RNA performed shouldbe earlier inpatients who are symptomatic detected may be virus inZika eRNA toys) ofsex or sharing anal,oral&/ vaginal, (may be virus recent contactUnprotected toZika sexual whohas exposure w/aperson transmission ofrecent virus travelHistory toplaces w/activeZika date &place oftravel the well patient's as as activities features, onclinical based shouldbe infection virus w/Zika ofapatient diagnosis suspected epreliminary management decisions formaking basis sole as used itshouldnottobe thus, infection; virus out Zika donotrule results Negative weeks at abnormalities 19 intrauterine retardation &CNS at growth detect 18weeks can First ultrasound trimester Reproductive-aged &pregnant women are the tothe susceptible effReproductive-aged most adverse infection virus ofZika ects infection virus w/Zika neuropathy) associated complications ofneurologic risk &children (egAdults Guillain-Barré are at increased

neutralization testing (PRNT) testing neutralization or inconclusive, conﬁ it should be equivocal positive, to be If the is presumed test plaque-reduction by rmed © IgMantibodies foranti-Zika virus tested samples be these that itisrecommended For ofsymptoms, samples ≥14days the that from serum onset collected have been MIMS Zika Virus Infection(3of7)

COMPLICATIONS 2 DIAGNOSIS B3 syndrome, myelitis, myelitis, syndrome, © MIMS 2019

ZIKA VIRUS INFECTION • • • • • • • • • • • • atrophy ofthe &cortical corpus callosum inning orhypoplasia &malformation - ofthe cerebellum, Hypoplasia brainstem ordermis - - fever Dengue as: such (congenital syndrome) fetus &may their to theor may defects birth developing cause pass infection Zika may have virus complications ormiscarriage birth preterm stillbirth, such as Zika by womenPregnant infected - infection &asymptomatic syptomatic after Congenital malformations develop contractures Limb &hypertonia - fl Extra-axial uid - Intracranial calcifications - Ventriculomegaly - Microcephaly - - - &chikungunya have vector similar manifestations &mosquito Zika Both - Chikungunya may present infections w/headache Both - - Group AStreptococcus (GAS) - virus Patients have w/Zika similarsymptoms w/Rickettsia - Rickettsia infection virus which isabsent rash generalized inpatients precede w/Zika Koplikspots - w/fever, conjunctivitis presents Also &lymphadenitis cough, throat, sore coryza, - Measles smear onperipheral Establishment isthrough ofthe ofparasites diagnosis the visualization - &anemia pain,diarrhea abdominal malaise, fever, by myalgia, Characterized &vomiting, nausea - Malaria donotpresent w/jaundice infection virus Patients w/Zika - May present w/fever, rigor, conjunctival suff myalgia, &jaundiceusion, headache - Leptospirosis simple task perform patients oreven Some able w/chikungunya may orwalk tobend notbe - - Rubella are &the usuallymilder symptoms tissueinfections soft notcause does infection virus Zika - - - Parvovirus lymphadenopathy butwithout fever w/low-grade presents also infection virus Zika - - Alphavirus (eg Alphavirus River, Mayaro,Ross Forest, o'nyong-nyong Barmah &sindbis virus) - Adenovirus - Enterovirus - infection: virus that considered may outZika inruling be Other viruses are present maculopapular rashes present may orabsent be whileinZika, inparvovirus Rash -

mosquito vector mosquito have the by same manifestations similarclinical infections &aretransmitted both virus &dengue virus Zika In dengue, the fever is usually high grade, muscle pain is severe & not usually associated w/conjunctivitis ¬usuallyassociated muscle isusuallyhighgrade, painsevere theIn dengue, fever conjunctivitis w/non-bacterial muscle painismild&usuallyassociated isusuallymild´inonset, the fever In Zika, as conjunctivitisas well as &back, knees feet, w/intense joint pain in the hands, ishighassociated the fever In chikungunya, use, burns, varicella virus infection & spontaneous gangrenous myositis) gangrenous &spontaneous infection varicella virus burns, use, drug injection pyoderma, (eg erysipelas, tissueinfections cellulitis, skin&soft Group Astreptococcus causes isnotpresent inZika in Rickettsia echaracteristic presence at ofaneschar the lymphadenopathy tick-bite w/associated siteofinoculation & suboccipital lymph nodes) that concurrently lymph nodes) fever & suboccipital occur w/low-grade &ﬁ wrists the knees, ngers) &lymphadenopathy auricular, posterior (involvement cervical, ofthe posterior involves (primarily arthritis 24 hours, within caudally &extremities tothe generalized that trunk becomes onthe face pinpoint then that &pinkmaculopapular spreads rash begins are coryza, ofrubella Characteristics are characterized by pruritic macules & papules that appear on the trunk, extremities, palms&soles extremities, &papules that macules onthe trunk, appear pruritic by are characterized whilethe rashes onthe ofthe smalljoints hands&feet noted may the arthralgia be infection, virus In Zika © & feet) knees (involvement orarthritis wrists, arthralgia ofthe ofthe smalljoints hands, May present w/acute&symmetric MIMS 3

COMPLICATIONS (CONT'D) ALTERNATIVE DIAGNOSIS Zika Virus Infection(4of7) B4 - Hearing loss Hearing - Visual defects - myelination Delayed - brainparenchymal volume Decreased - Polymicrogyria -

ZIKA VIRUS INFECTION • Bite Mosquito from Protection • • • &Analgesics Antipyretics • • • • of Principles erapy • • • Transmission Sexual from Prevention • • - - - to: Patients are advised - the ofhemorrhage risk outinorder todecrease ruled been has dengue &nonsteroidal anti-infl toavoid takingAspirin Patients advised are also until (NSAIDs) drugs ammatory &acidosis bleeding Avoid since may &other gastritis, these cause salicylates Aspirin &painrelief forfever Paracetamol isused donefrequently shouldbe monitoring function &respiratory signs For vital exam, including optimalcare neurologic syndrome, patients w/Guillain-Barre present) are advised fl increased rest, which care, bed includes Supportive uid intake (only ofanalgesic &painare &use when fever transmission &toreduce local infected becoming inorder from of illness toprevent the other mosquitoes the during fi especially tomosquito exposure further from patients protected shouldbe Infected days rst few ere isnospecifi &symptomatic treatment supportive are given thus, infection; virus c treatment forZika - transmission virus & outcome risk counseled of Zika on the possible should be men & women (pregnant or non-pregnant) Both - Wear &pants toavoid light-colored skinexposure &longsleeves clothing, - virus hightransmissionofZika w/known Avoid orinareas areas going tomosquito-infested - - - - Pregnant women are advised to abstain from sex forthe sex remainder toabstain from ofher pregnancy Pregnant women are advised - virus: transmission ofZika are toprevent sexual recommended measures efollowing his orher partner to stilltransmitthe heorshecan infection isasymptomatic, that ifthepartner It sexual noted even shouldbe ordeveloped recognized have been virus consultation chickungunya Seek ofdengue, &Zika ifsymptoms - closed screens &door windows Use airconditioning &keep when indoors - takingfolicacidsupplementFor advised pregnant, toget for28days shouldbe patients whoare trying - man's ittakeaninfected longwill It forhow semen the toclear virus isstillunknown - the from illness hisrecovery manafter inthe semen ofaninfected stillpersists ofthe virus eRNA - formen isrecommended because: period Longer precautionary -

active Zika virus transmission virus active Zika inorhave who have w/ forthose traveled wholived partners toareas especially Use condoms sex, during sex) & use ofdental sheets) &use sex) dams(latex orpolyurethane tofi start from maleorfemale condoms used oruse sex (tobe anal&oral vaginal, timeduring nish, every toabstain from advised transmissionare also virus w/activeZika inanarea been has partner whose Couples transmission & other mosquitoes from being infected being from transmission &other mosquitoes on theAvoid fi especially bitten mosquito being by to prevent local days (viremic phase) of illness rst few the ofhaving prematureminimize risk closure ofthe ductus arteriosus inorder to toavoid takingNSAIDs agearePregnant women advised at ofgestation (AOG) ≥32weeks sex having unprotected 6months before ofsymptoms at theSymptomatic least from towait onset men are advised Use nets (w/ or without treated insecticide) & insect repellents when outdoors (eg when repellents outdoors DEET, &insect insecticide) treated (w/orwithout Use nets orIcaridin) IR3535 sex having unprotected before ofsymptoms the onset after 8weeks atSymptomatic least towait women are advised sex having unprotected before 6months exposure at date the least from ofpossible towait last men are advised Asymptomatic onthe diff evidence ere isnodocumentation agood about men erence &asymptomatic symptomatic between sex having unprotected before exposure date the from ofpossible last 8weeks at least towait women are advised Asymptomatic -

© area high-risk Avoid for6months sex having unprotected w/their whohave malepartners traveled toamoderate- to MIMS Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing A B PATIENT/PARTNER EDUCATION PHARMACOLOGICAL THERAPY Zika Virus Infection(5of7) C PREVENTION B5 © MIMS 2019

ZIKA VIRUS INFECTION • • • • • Professionals &AmongHealthcare Setting Healthcare in Measures Preventive • • • • Virus &Visitors Family Infection ofaPerson Members w/Zika Caretakers, • • • • • Women AmongPregnant Measures Preventive & Partners eir • • Unintended Pregnancy from Prevention • • • Transmission Sexual from Prevention (Cont'd) - Pregnant personnel - For are nowork given restrictions personnel, healthcare asymptomatic - infection virus w/Zika professional Healthcare the toadhere personnel tothe Advise forallpatients standard precautions - - Occupational exposure - - Presence of body fl Presence ofbody on: &based assessed uids &other materials shouldbe infectious - setting &delivery Labor fl mucous For membranes, exposed w/copiousushing &cleansing amounts ofwater done must be - fl Wounds &body to blood that exposed have been w/soap &water immediately washed uids shouldbe - - transmission disease from professionals allhealthcare Use toprotect standard precaution usingasterilant &disinfectant reprocessed must be All devices Use isnotnecessary ofbleach - fl &body For blood clothes w/soiled the clothes w/detergent remove &wash immediately uids, Wash care providing immediately after handrub analcohol-based handsw/soap &water oruse Avoid fl touching body skin w/exposed forthose especially &contaminated surfaces, blood uids, conception attempt they before ofsymptoms forwomen the from onset 6months 8weeks forat least &atto wait least men are advised symptoms, For transmission&have w/activeviral developed men &women wholiveinareas virus w/Zika toavoid infected being preventive measures Advise traveling transmission) incountries &its w/adjacent virus that borders Zika information have about limited transmissionor (eg infection local virus ofZika non-essential travel toplacesConsider postponing w/reports - transmission virus Pregnant women shouldavoid tohave traveling Zika known inareas bites Prevent mosquito pregnancy Women shouldhave access tosafe&eff want todelay they contraceptive oravoidective incase methods discussed must intentions be &timingofpregnancy pregnancy lifeplans, Reproductive - infection virus ofZika w/high-risk areas consultation toseek planningonhaving ababy, before Patients in couples are those advised living especially - onthe ofpregnancy 1stprenatal &2ndtrimester tested Should visit be - advised For w/activetransmission,consultation inanarea pregnant women wholived is professional w/ahealthcare isrecommended 3-4weeks every Ultrasound - advised shouldbe virus forZika testing oftraveling, 2weeks within symptoms For ordidnotdevelop pregnantwomen whohave traveled w/activetransmission&whodeveloped inanarea whoisasymptomatic toapartner exposure having sexual after symptoms who developed &those sexually virus toZika exposed whohave those been especially All pregnant patients tested, shouldbe

& mucous membranes skin orabraded chapped object, stick orcutw/asharp ofthe toneedle on the personnel potential exposure advised shouldbe however, managers virus; allfacility &supervisors w/Zika May forpatients care infected of the patient onthe presenting symptoms For based given may work restrictions personnel, symptomatichealthcare be have been exposed to Zika virus toZika exposed have been ﬂEvaluation body ofblood, that personnel inallhealthcare &excretions required must be secretions uids, the possible pathogens including ZIKA, HIV &hepatitis HIV pathogensthe possible including ZIKA, for all assessed should immediatelybe & personnel reported it should be occurred, has exposure If possible infectious agentsinfectious ﬂAll body mucous excretions, &non-intact membranes considered skinmust as be secretions, blood, uids, recommended If traveling consultation delayed orprevented, be totravel cannot prior w/ahealthcare professional is pregnancy anytime during tested shouldbe they w/Zika, If pregnantwomen associated present w/symptoms Application equipment protective (PPE) ofpractices &personal - Nature performed ofthe oractivity procedure - Type ofanticipated contact - ofthe Condition patient - - Blood, semen & vaginal secretions are associated w/ the transmission of Zika virus w/the transmissionofZika are associated secretions semen &vaginal Blood, -

ZIKA VIRUS INFECTION • (Cont'd) Professionals &AmongHealthcare Setting Healthcare in Measures Preventive • Vaccination • Control Measures Community • Virus Infection &Zika HIV • • (Acetaminophen) Paracetamol - ofpatient'sDisinfection room - infection virus forthe worldwide prevention ofZika developed are vaccines being At several present, should collaborate transmission density the &preventing further &participate inreducing vector development agencies & social tourism facilities, healthcare government & health organizations, Schools, all infections for closely monitored immunosuppression shouldbe &have severe w/Zika coinfected adults HIV-infected used shouldbe devices &disinfected Onlysterilized - splashes from the Protect eyes - setting indentistry Prevention ofexposure usingasterilant &disinfectant reprocessed must be Alldevices - properly &packed sterilized dried, cleaned, shouldbe &devices Instruments - &devices ofequipments Reprocessing - &ﬂ ofthe Dailycleaning surfaces cleaning after used shouldbe disinfectant &ahospital isadvised oors - - - All dosage recommendations are for non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults non-elderly for are recommendations dosage All

or known to have Zika virus tohave Zika or known materials cleaning orpractices theofpatients incleaning are rooms required whoare suspected No special Vaccine Center Research trial clinical isundergoing II phase the by National Diseases' Institute &Infectious ofAllergy developed vaccine being Zika A DNA-based textiles the soiled usingthe cloths managed for workers standard precaution shouldbe handling towels &wash linens, Bed several mRNA-based Zika vaccines are being evaluated indiff evaluated are vaccines being Zika mRNA-based several erent trials Iclinical phase A purifi the by Walter developed Army & Institute ofResearch, ZPIC Reed vaccine called inactivated ed Institute is in phase I Institute isinphase the National by US Institutes of Health & the Butantan developed vaccine being A live-attenuated Zika Drug Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed © MIMS 120-250 mg PO 4-6hrly 120-250mgPO 1-5 yr: 4-6hrly 250-500mgPO 6-12 yr: Susp: Oral 4doses/day dose: childn Max 6-8hrly PO wt <3 mth:10mg/kgbody 6-8hrly 60-120mgPO 3 mth-1yr: 6-8hrly 120-250mgPO 1-5 yr: 6-8hrly Up to500mgPO 6-12 yr: Childn: 4g/day adultdose: Max 4-6hrly 0.5-1gPO Adults: Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing Please see the end of this section for the reference list. reference the for section this of end the see Please C ANALGESIC &ANTIPYRETIC Zika Virus Infection(7of7) Dosage Dosage Guidelines PREVENTION (CONT'D) B7 • • Instructions Special • Reactions Adverse days >3 days orifpaincontinues for>5 for persists Monitor patients iffever dependency disorders &alcoholhematological or hepatic orrenal impairment, CV Use w/ caution inpatients w/known &agranulocytosis) neutropenia pancytopenia, leukopenia, (thrombocytopenia, reactions & usuallymildhematological inchildn); rare &angioedema adults in hypotension dyspnea, (urticaria, reactions hypersensitivity Occasional Remarks © MIMS 2019

ZIKA VIRUS INFECTION