DCH 2015

HIV / TB / other ID updates

Dr James Nuttall

Paediatric Infectious Diseases Unit

Red Cross War Memorial Children’s Hospital & University of Cape Town

james.nuttall@uct.ac.za

Readings on HIV/TB/other ID

• Child Health for All – a manual for Southern Africa, 5th edition (2012)– Chapters 16, 40-43, 46, 47, 50

• Handbook of Paediatrics, 7th edition (2010)– Chapter 9: Immunization and infections

– Chapter 10: HIV infection

– Other sections relevant to ID (newborn, CNS, immunodeficiency)

• Coovadia’s Paediatrics and Child Health - a manual for health professionals in developing countries, 6th edition (2009)

– Chapters 14-18, 21

• The two websites listed below include up-to-date disease fact sheets and vaccine information for vaccine-preventable diseases and other infectious diseases of childhood. Suggested minimum topics to cover include: all diseases on SA national immunisation programme as well as rubella, chickenpox, influenza, rabies, typhoid, cholera, schistosomiasis, malaria & selected parasites.

– http://www.cdc.gov/ncidod/diseases/children/diseases.htm

– http://www.who.int/topics/en/

• Various presentations in pdf format relating to HIV & TB from HIV TB symposia from 2010 - 2013 available at www.paediatrics.uct.ac.za under “Clinical Services” then “Infectious Diseases”, scroll to bottom of page

• Various presentations in pdf format on different paediatric topics from GP Paediatric Update 2013 available at www.uctpaediatriccourses.ac.za under “Past Events” then “download presentations”

Update on Paediatric HIV infection

• Dynamic, rapidly evolving field: research, policy, practice

– Prevention of mother to child transmission (PMTCT)• Pregnancy: less complexity: universal cART before/during pregnancy,

breastfeeding (but adherence, treatment failure etc)

• HIV-exposed infant: increasing complexity: intensified testing & prophylaxis in high-risk transmission scenarios

– Diagnosis of HIV infection• timing, technologies, linkage to treatment

– Combination antiretroviral therapy (cART)• Timing of initiation (neonates, CD4 thresholds), regimens, adherence,

drug resistance testing, new drugs, drug interactions, HIV/TB co-infection

National consolidated guidelines for the prevention of

mother-to-child transmission of HIV (PMTCT) and the

management of HIV in children, adolescents and

adults

24 December 2014

What’s new in the paediatric guidelines

http://bit.ly/12m3XUS

What’s new in PMTCT guidelines

http://bit.ly/1ytjLDa

Terminology & definitions

• HIV exposure– An infant born to a mother with HIV infection and indicated by the presence of HIV antibodies

in blood of a child <18 months of age

– Ingestion of breastmilk from a woman with HIV infection (HIV antibodies in blood of infant may be absent)

– Exposure to certain other body fluids of an HIV-infected person (e.g. following sexual abuse)

• “Seroreversion”– Absence of HIV antibodies in a child known to be HIV exposed

• HIV infection– <18 months of age: PCR or viral load (x2 )

– ≥18 months of age: antibody tests (rapid tests, x2)

• HIV exposed uninfected (HEU)– PCR negative HIV exposed child

– Seroreversion

Steps to starting ART in Children

• Confirm HIV diagnosis & provide counseling

• Assess and manage opportunistic illnesses & malnutrition if present

• Clinical & immunological staging: criteria for starting ART (>5yrs of age)

• Social criteria for starting ART: identification of reliable caregiver

• Further counseling: treatment literacy & treatment readiness

• Baseline investigations

• Appropriate drug regimen (protocols)

When to initiate ART?WHO 2013

Paediatric Antiretroviral Therapy (ART)

SA NDOH 2015

• Eligibility– Children less than 5 years of age:

• All

– Children ≥5 years to 15 years:

• Clinical Stage 3 or 4 OR CD4 <500 cells/µl

• Fast-track initiation (within 1-2 weeks of eligibility)– Children <1 year of age

– Stage 4 HIV disease

– MDR or XDR – TB

– CD4 <15% OR <200 cells/µl

Social requirements for ART

Mandatory:

• a reliable, responsible adult to at least administer medication

Desirable:

• Treatment “ready” i.e. clinic attendance, adequate counselling and demonstration of medication.

• Able to travel to and attend ARV centre monthly and without difficulty

• Disclosure to household or friend

Certainly advisable…

• “Assistant caregiver” identified and included in work-up

• “Back-up” plan in case of crisis

• Know maternal CD4 count and assess general health. Refer or treat if indicated

What ART regimen to startWHO 2013

1st line ART regimens for infants & children(SA NDOH 2015)

All infants & children under 3 years (or <10kg) ABC + 3TC + LPV/r

Children ≥3 years (and ≥10kg) * ABC + 3TC + EFV

Currently on d4T-based regimen 1. Change d4T to ABC if viral load is

undetectable

2. If viral load >1000 copies/ml, manage as

treatment failure

3. If viral load between 50-1000 copies/ml,

consult with expert for advice

(* Children ≥3 years and exposed to NVP for 6 weeks or longer (PMTCT)

should be initiated on ABC + 3TC + LPV/r)

Baseline investigations before starting ART

Prior to initiation of ART Purpose

Full blood count If <8 g/dl start ART & discuss with specialist

CD4 count (if not done in last 6 mths) Baseline assessment

Cholesterol & triglycerides if on PI regimen Baseline assessment

Creatinine if on TDF regimen If abnormal, refer for specialist opinion

ALT (if jaundiced or on TB Rx) To assess for liver dysfunction

Neurocognitive developmental assessment With appropriate available tool

Urine dipsticks, serum phosphate (if on TDF) Baseline assessment

Staying on ART

Four main aspects requiring on-going

monitoring are:

– Adherence & support

– Treatment efficacy: clinical, CD4, viral load

– Drug toxicity and adverse events

– Developmental and psychosocial progress

Assessment & support

of caregivers

• Pre-ART

– Screening form

– 3 counselling sessions

– Home visit if necessary

– Child support grants

– Secondary caregiver

(treatment partner)

– Practical demonstration of

ARV drug regimen

• On ART

– Interview with caregivers

– Return of medications / pill

counts & demonstration

– Support groups

– Assistance with disclosure

– Referral of mother / father /

siblings for HIV testing / care

/ ART

– Referral to community-based

services where possible

Monitoring treatment efficacy on ART

On ART Purpose

Height, weight, head circumference (<2

years) and development

To monitor growth and

developmental stage

Clinical assessment To monitor response to ART, and

exclude adverse effects

CD4: ALL at mth 4 and mth 12, then

1-5 years: 6 mthly

> 5 years: If CD4 < 200 cells/mm3 repeat

6 mthly until two consecutive CD4’s > 200

cells/mm3

To monitor response to ART, stop

co-trimoxazole prophylaxis as per

national guidelines

VL: All: at mth 4 and 12, then

- children <5 years: 6 mthly

- children 5 years to 15 years: 12 mthly

To monitor viral suppression

response to ART

To identify treatment failure and

problems with adherence

2nd-line ART regimens

1st line regimen 2nd line regimen

PI-based

ABC + 3TC + LPV/r

d4T + 3TC + LPV/r

Unboosted PI-based regimen

Rifampicin while on LPV/r

Consult with expert for advice

NNRTI-based

ABC + 3TC + EFV (or NVP)

d4T + 3TC + EFV (or NVP)

AZT + 3TC + LPV/r

AZT + ABC + LPV/r

1st line regimen 2nd line regimen

TDF-based regimen AZT + 3TC + LPV/r

d4T-based regimen TDF + 3TC (or FTC) + LPV/r

Infants & children

Adolescents & adults

2nd line ART after PI-based 1st line

1st line “3rd drug” 2nd line “3rd drug” Comment

LPV/rtv “Refer”

No standard

recommendation

Consider new

generation boosted PI

(DRV) +/or NNRTI (e.g.

etravirine) +/or

integrase inhibitor (e.g.

raltegravir)

Seek expert advice

and genotyping to

inform choice of

regimen. Avoid

empirical use of

NNRTI + 2 NRTIs as

may lead to rapid

virological failure

• If LPV/r is 1st PI, virus usually remains susceptible to LPV even in setting of

treatment failure. Exceptions include co-treatment with rifampicin,

breaking/crushing of Aluvia tablets

• NRTI cross-resistance, 3TC resistance, and archived NNRTI resistance following

NVP exposure in PMTCT programme may impact on potency of 2nd line regimen

Van Zyl GU et al. Pediatr Infect Dis J 2009;28(12):1125-7

Taylor BS et al. AIDS Res Hum Retroviruses 2011;27:945-56

Frange P et al. Pediatr Infect Dis J. 2011

Genotypic resistance testing:Important principles

• Only useful for detecting resistance to drugs currently being taken by patient (or within 4 weeks of stopping them)

• Helps to exclude drugs from a future regimen, may not indicate which drugs will work

• Viral load must be >1000 copies/ml & won’t detect resistance in minor variants (<20% of viral population)

• Interpretation may be difficult and requires expertise

• Expensive (±R2000): few guidelines on optimal use of resistance testing in large treatment programmes

3rd-line ART regimens

Failing any 2nd –line regimen

Refer for specialist opinion.

Regimen based on genotype resistance testing, expert opinion and

supervised care

Access to 3rd –line ART will be managed centrally by the National

Department of Health

HIV-TB co-infection in children

• HIV testing of all children diagnosed with TB / starting TB treatment (provider-initiated testing)

• Co-trimoxazole prophylaxis

• All children with HIV/TB co-infection are eligible to start ART

– Generally start ART 2-8 weeks after TB treatment

– Stage 4 disease (extra-pulmonary TB) or MDR/XDR-TB are criteria for fast-track ART (within 2 weeks)

• ART regimens may require modification of drugs and dosages

• Adherence support & monthly ALT monitoring

Combining anti-TB treatment & ART in children

– Rifampicin is a powerful inducer of hepatic metabolism (cytochromep450 system)

– The NNRTI and PI group of antiretroviral drugs are also metabolised by the cytochrome p450 system

– When rifampicin is used in combination with NVP or PI drugs, potentially sub-therapeutic plasma levels of NVP or PI may result putting the patient at risk of developing HIV resistance mutations and antiretroviral treatment failure

– Efavirenz plasma levels are not significantly affected by rifampicin in most patients so dose adjustment is not routinely recommended

– In children on lopinavir/ritonavir (Kaletra® or Aluvia®)-based ART and rifampicin-based TB treatment, additional ritonavir added to lopinavir/ritonavir is recommended (“super-boosting”)

TB (separate lecture)

Other ID

Contraindications to vaccination

• Absolute– Anaphylaxis to previous vaccination contraindicates repeat vaccination with same vaccine

• Pertussis vaccine (DTP or DTaP)– Anaphylaxis or encephalopathy within 7 days

– Precautions: convulsions within 3 days, persistent screaming for >3hrs, collapse or shock-like state within 48hrs, fever>40.5 within 48hrs

– Egg allergy• MMR not contraindicated

• Influenza avoid

• Yellow fever avoid

• Relative– Immunosuppression

• Malignancy, cytotoxic drugs, prolonged high dose corticosteroids, radiotherapy

– Previous plasma or immunoglobulin• Defer MMR for 3 months

• ‘False contraindications’

HPV vaccine

• Cervarix (2) / Gardasil (4)

• 2 vs 3 doses

• National campaign

• Cancer / anogenital warts

• Consent

A theoretical frameworkInfectious/communicable diseases

Exposure • Route of transmission: contact, droplet, airborne, vector

• Risk factors for infection include duration & intensity of exposure,

organism factors, host factors

↓

Incubation period (disease-specific)↓

Infection• Clinical: prodromal / “seroconversion” illness or asymptomatic/latent infection

• Laboratory: specific immunological response (±isolation of organism)

↓

Disease• Clinical diagnosis: pattern recognition / clinical case definition

• Laboratory diagnosis: specific immunological response, isolation of

organism/genetic material, sensitivity & specificity of tests

Routes of transmission

• Contact– Direct (e.g. STI)

– Indirect (e.g. faecal-oral)

• Droplet (e.g. influenza, streptococcus, pertussis, diphtheria)– Large droplets, contact with mucous membranes

• Airborne (e.g. TB, measles, varicella)– Small droplets, inhaled

• Vehicle / Vector– Biological (e.g. mosquito in malaria)

– Mechanical

Natural history (“clinical timetable”)

e.g. measles

Incubation period & prodromal periodIncubation period Disease Prodromal period

Short (1-7 days) Cholera Nil

Diphtheria Nil

Influenza Nil

Meningococcal disease Nil

Scarlet fever Nil

Intermediate (7-14 days) Measles 3-7 days

Pertussis Usually 5-7 days (up to 21 days)

Polio 3-36 days

Tetanus Nil

Typhoid Nil

Long (14-21 days) Chickenpox 0-2 days

Mumps 0-1 day

Rubella 0-2 days

15-40 days Hepatitis A 2-5 days

60-180 days Hepatitis B 2-5 days

Disease Period of communicabilityMeasles 4 days before rash until 4 days after onset of rash (immunocompromised patients may be

contagious for duration of illness)

Rubella Approximately a week before onset of rash until 5-7 days after onset of rash

Erythema infectiosum Approximately a week before onset of rash until appearance of the rash

Varicella zoster virus Primary infection: 1-2 days before rash until all lesions have crusted (usually 5-7 days after

onset of rash). Reactivation disease: onset of rash until all lesions have crusted

Meningococcal disease Until 2 days after start of antibiotic treatment

Scarlet fever Until rash fades & desquamation starts

Viral gastroenteritis Rotavirus is present in stools for several days before and several days after onset of clinical

disease

Hepatitis A Most infectious from 1-2 weeks before onset of jaundice until 1 week after onset of

jaundice.

Influenza From a few days before symptoms begin until 5-7 days after onset of symptoms. Very

young children and individuals with severe disease (e.g. viral pneumonia) may be

infectious for >10 days after onset of symptoms and severely immunocompromised

individuals may shed virus for weeks to months.

Pertussis Most infectious during the catarrhal stage and for the first 2 weeks after onset of cough.

Other factors influencing communicability include age, immunisation status, and

appropriate antimicrobial therapy.

Mumps Until parotid swelling subsides

Recommendations on when children with selected infectious

diseases are no longer regarded as infectious and may return to

school or other teaching institution

Disease Isolation Period

Measles 5 days from start of rash

Rubella 7 days from start of rash

Chickenpox Until all skin lesions have crusted, usually 5-7 days after start

of rash

Meningococcal

disease

2 days after start of antibiotic treatment

Scarlet fever Until rash fades and desquamation starts

Hepatitis A 7 days from onset of jaundice

Pertussis 5 days from starting effective antibiotic therapy or 3 weeks

after onset of paroxysmal cough

Influenza Until apyrexial and feeling better or until 5-7 days after onset

of symptoms

Describing an infectious disease e.g. malaria

• Disease name– Malaria

• Identification – clinical & laboratory tests

– Clinical syndrome incl. fever, travel history, v & d, cough, tachypnoea, lethargy. Non-specific tests: anemia, acidosis, thrombocytopenia, hypoglycemia. Specific tests: thick and thin blood smears, rapid antigen tests

• Infectious agent– Plasmodium falciparum, also P. ovale, vivax,

malariae, knowlesi

• Occurrence– Specific geographical areas incl. tropics,

subtropics etc

• Reservoir– humans

• Mode of transmission– Via bite of insect vector: female Anopheles

mosquito

• Incubation period– Usu. 7-21 days

• Period of communicability– While parasitaemia is present

• Susceptibility & resistance– All in non or hypo-endemic areas. Reduced by

physical measures & chemoprophylaxis, seasonal variation. Increased susceptibility to severe malaria in children <5 years & preg. Women. Relative resistance to severe disease in Hb’opathies & rbc abN

• Methods of control– Preventive measures – individuals &

groups• Avoid areas, physical measures to avoid

bites, insecticides, chemoprophylaxis (no vaccine)

– Control of patient, contacts & immediate environment

• Drug Rx of individuals, no contact prophylaxis or isolation etc

– Epidemic measures• Endemic to many parts of world,

environmental measures eg. Draining swamps etc , better prophylaxis and treatment, vaccine research

– Disaster implications• Nil

– International measures• Co-operation across national borders

– Bioterrorism measures• N/A

Infection Prevention & Control (IPC)

• Based on the epidemiology of infections (“how often diseases occur in different groups of people & why”)

– Where is the organism?• Eliminate the source: identify & treat infectious cases, isolation if

indicated, follow-up of contacts

– How does it spread?• Interrupt transmission: transmission-based precautions

– Who is susceptible?• Increase host resistance

– Active: vaccination

– Passive: breastfeeding, post-exposure prophylaxis / immunoglobulin

Infection Control Precautions for

Health Care settings

• Standard precautions (“universal precautions”)– Hand disinfection

– Gloves & mask when working with blood/body fluids

– Safe disposal of sharps

– Safe disposal of contaminated linen/other waste

• Transmission-based precautions– Contact

– Droplet

– Airborne

My 5 Moments for Hand Hygiene

(WHO)

• Defines the key moments when health care workers

should perform hand hygiene

• Evidence-based, field-tested, user-centred approach

Contact precautions

• Resistant organisms– Methicillin-resistant staphylococcus aureus (MRSA)– Extended spectrum B lactamase (ESBL)-producing Gram negatives– Carbapenem-resistant organisms e.g. Acinetobacter

• Clostridium difficile

• Enteric illnesses (Hepatitis A, Salmonella, Shigella) –especially in children

• Respiratory syncytial virus• Adenovirus

• Private room / cohort

• Limit movement

• Use dedicated equipment (if possible)

Droplet precautions

• Meningococcus

• Haemophilus influenzae B

• Diphtheria

• Pertussis

• Adenovirus

• Mumps

• Influenza

• Separate cubicle if possible, or cohort, or ≥1 metre separation of beds

Airborne precautions

• TB, measles, varicella

• Private room with negative pressure

ventilation

• 6 air changes per hour

• Gloves, gown & particulate filter mask

Disease Who qualifies for post-exposure prophylaxis Recommended prophylaxis

Chickenpox Non-immune contacts

Newborns whose mothers develop varicella from 5 days before to 2 days

after birth.

Varicella zoster immune globulin (VZIG) dosed

according to manufacturer, administered

within 96 hours of exposure OR

Varicella vaccine within 72 hours of exposure.

Vaccine is not indicated for newborns,

children <9 months of age or HIV-infected

children

Meningococcal

disease

Household members and close contacts in day-care centres and hostels.

Hospital contacts only if intense and intimate contact e.g. resuscitation /

intubation

Ceftriaxone: <12 years of age: 125mg, ≥12

years of age: 250mg as single intramuscular

dose OR Ciprofloxacin: <12 years of age:

10mg/kg, ≥12 years of age: 500mg as single

oral dose

Measles Susceptible children (received <2 measles vaccines) Human anti-measles immunoglobulin

(0.25ml/kg, and 0.5ml/kg for those who are

immunocompromised, maximum dose 15ml,

as single intramuscular dose) within 1 week of

exposure

Hepatitis A Household contacts, children and staff in crèche or day-care settings or

other institutional settings, individuals at risk for severe disease e.g.

underlying chronic liver disease

Pooled immunoglobulin dosed according to

manufacturer OR Hepatitis A vaccine (for

healthy individuals 1-40 years of age, who

should also receive booster dose of vaccine 6

months later) within 14 days of exposure

Pertussis Household and other close contacts, vulnerable contacts at high risk of

severe or complicated pertussis disease (including newborn infants born to

symptomatic mothers, infants <1 year of age with incomplete immunisation,

immunocompromised, chronic cardiac or lung disease)

Erythromycin OR azithromycin OR

clarithromycin. (Erythromycin is not

recommended under 1 month of age).

Chemoprophylaxis should start within 21 days

of onset of cough in index case. Refer to

guidelines [Ref 6] for dosing and duration.

Antibiotic Stewardship

Underused

•Morbidity and

mortality

•Litigation

Overused

•Resistance

•Toxicity

•C. difficile

•Appropriate use

•Appropriate choices

•De-escalation

•Formulary guidelines

•Restriction policies

Antimicrobial stewardship & rational

antimicrobial prescribing

• Right drug/s

• Right time

• Right dose

• Right route

• Right duration

Current topics

• Antibiotic stewardship

• Ebola / infection control

• Drug-resistant TB prophylaxis / treatment

• Neonatal HIV diagnosis and treatment

• Neonatal exposure to TB & prophylaxis