module 4 hiv infection & art in children

USAID APHIA IINAIROBI/CENTRAL

Management of HIV infected Children


HIV in Children

Unit 1: Epidemiology and HIV transmission in ChildrenUnit 2: Natural history of HIV in Children Unit 3: Diagnosis and Staging of HIV in ChildrenUnit 4: HIV – Related Conditions: Prevention and

TreatmentUnit 5: Antiretroviral Therapy in Children


Objectives

• To outline the epidemiology of HIV in children• To describe various modes of HIV transmission to children.• To discuss the natural disease progression of HIV in children.• Outline diagnostic criteria for paediatric HIV – laboratory as well as

clinical.• To impart knowledge on prevention and treatment of common HIV

related conditions in HIV infected children• To describe how and when to provide antiretroviral therapy in

children, , including initiation, pre-ART preparation, monitoring, when to change/withdraw ART.



Unit 1 Epidemiology and HIV transmission in Children


Objective of Unit 1

• To outline the epidemiology of HIV in children• To describe various modes of HIV transmission to

children.


Epidemiology - Kenya

• 1 million live births in Kenya annually• 8% born to HIV infected mothers• Without PMTCT 30% of these become infected• About 24,000 neonates acquire HIV annually• About 12,000 (50%) die within first 2 years• HIV has had a negative impact on infant survival


Modes of HIV transmission in Children

• Mother to child transmission-95%• Sexual –Adolescent, abuse• Transfusion of infected blood• Unsterile injection procedure (2.5% in adults as

well as children)• Scarification and other traditional practices


Modes of HIV transmission to Children

• Mother to child transmission – 95% of paediatric infections– Intrauterine– During delivery– During breastfeeding


Mother to Child HIV Transmission

30% babies born to HIV+ womenbecome infected through MTCT

5% intrauterine

10-20% during delivery

10-20% via breastfeeding


Modes of HIV transmission to Children

• Horizontal transmission - < 5% of paediatric infections– Sexual transmission– Transfusion of blood and blood products– Exposure to other body fluids– Use of contaminated needles and other skin

piercing/cutting instruments (circumcision, uvulectomy).



Unit 2: Natural history of HIV in Children


Objective of Unit 2

• To discuss the natural disease progression of HIV in children.

• Outline diagnostic criteria for paediatric HIV – laboratory as well as clinical.


Natural history – patterns of disease progression in African children

HIV disease progresses at differing rates in children• Rapid progressors (25 – 30%):

– Develop AIDS and die within 1 year. – Disease acquired in-utero or perinatally.

• Intermediate progressors (50 – 60%):– Children who develop symptoms early in life.– Deteriorate and die by 3 to 5 years.

• Slow progressors (5 – 25%):– Long-term survivors who live beyond 8 years of age.


Natural history – patterns of disease progression in African children

• Slow Progressors

– Low viral loads at birth

– Stable CD4 counts for 2-10 years slow declinethen

– Growth stunting

– Opportunistic infections after 2-10 years as disease progresses

– Encephalopathy rare, growth stunting common

• Rapid Progressors– High viral load at birth

– Rapidly declining CD4

– Low Birth Weight

– Chronically unwell first year• Persistent or recurrent diarrhea• Recurrent bacterial and fungal

infections• Severe encephalopathy before

18 months


Natural History – Immunological changes

Immunologic Parameters

• Absolute CD4 count higher in healthy children than in adults.

• Absolute CD4 count slowly decline to adult levels by age 6

• CD4 percentage does not change with age.

• In children < 6 yr CD4 percentage is the preferred immunological parameter for monitoring disease progression.



Age-related Decrease in CD4+ Number

0

2000

4000

6000

Age in Months

CD

+ N

umbe

r/m

m3

5th percentile

95th percentile

4 12 24 6090



Age-related Decrease in CD4+ Percentage

0

20

40

60

80

Age in Months

CD

4+

% 5th percentile

95th percentile

4 12 24 6090


Natural History – Viral load patterns in children

The HIV viral load (RNA) pattern in perinatally infected infants differs from infected adults.

In infants Viral load (RNA levels):• Increase to high levels >100,000 to millions of copies/ml by

2 months of age.• Remain high through outthe first year of life.• Decline slowly over the next few years to eventually achieve

a “set point” after age 5 years.



Unit 3 Diagnosis and Staging of HIV in Children


Diagnosis and Staging of Paediatric HIV -scope

• I: Clinical presentation of Paediatric HIV• II: Diagnosis:

– Clinical diagnosis – Laboratory diagnosis

• III: Staging– Clinical staging– Immunological staging


I: Clinical presentation of HIV in Children

• Understand common clinical presentations of progressive paediatric HIV infection

• Compare between common paediatric conditions and clinical signs of paediatric HIV


Clinical suspicion of HIV

• First do an initial clinical assessment of child and suspect HIV,

• Certain clinical conditions, if present, point to high probability of HIV infection in the child


Clinical signs & conditions suggestive of HIV infection in a child (1)

• Oesophageal candidiasis• Herpes zoster (shingles) • Invasive salmonella infection• Pneumocystis jiroveci pneumonia (PCP)• Extrapulmonary cryptococcosis• Lymphoma• Kaposi’s sarcoma


Clinical signs & conditions suggestive of HIV infection in a child (2)

• Recurrent severe bacterial infection• Persistent or recurrent oral thrush• Parotid enlargement• Generalized lymphadenopathy• Hepatosplenomegaly (non-malaria areas)• Persistent or recurrent fever• Neurologic dysfunction• Persistent generalized dermatitis


Clinical signs & conditions Common in both HIV+ and HIV- children

• Otitis media - persistent or recurrent• Diarrhoea – persistent or recurrent• Severe pneumonia• Tuberculosis• Failure to thrive


Entry points for HIV diagnosis

HIV exposed &/or infected children can be identified by actively seeking to test them in health services where they and their parents seek care.

• Sick children services• PMTCT clinics• MCH clinics• TB clinics• Adult HIV clinicsHIV positive parents should be encouraged to bring all their children in

for testingConfirmation of HIV diagnois provides an entry point for appropriate care

for the child and the family.


IMCI definition of symptomatic HIV infection

Presence of 3 or more of the following:• TB in any parent in the last 5 years• Pneumonia (now or previously)• 2 or more episodes persistent diarrhoea (>14 days)• Growth faltering or weight < 3rd centile

(below “very low weight curve” in card• Enlarged lymph nodes in 2 or more of the following sites

(neck, axilla, groin)• Oral thrush


DIAGNOSIS OF PEDIATRIC HIV


Laboratory Diagnosis

There are two types of laboratory tests for HIV diagnosis:

Antibody tests-detect antibody toHIVVirologic tests-detect HIV virus or antigen


Laboratory DiagnosisChild >18 months

Child > 18 months:• A positive HIV antibody test confirms HIV

infection as maternal antibodies have cleared

• A negative HIV antibody test rules out HIV infection in non breast feeding child


Laboratory DiagnosisChild < 18 months

Child < 18 months, HIV Antibody (Ab) may come from:• Maternal Ab passively transferred to infant

– Maternal Ab may persist in her infant up to 18 months– Ab test is +ve in ALL children born to HIV+ women, including those

that are NOT infected (gives false +ve results)• Infant generated Ab if infant is HIV infected.

A positive HIV Ab test at this age is therefore not diagnostic, only shows child has been HIV exposed


Laboratory DiagnosisVirologic tests

Virologic test – detect HIV virus in bloodIs ideal method of HIV diagnosis in child under 18 months

• Various types:- RNA PCR - most available, also gives viral load- DNA PCR – not widely available- P24 antigen (immune-complex dissociated)

• When to do virologic test:– Not BF: test at age 1 month repeat 3 months later– BF: wait until 3 months after cessation of BF to confirm final HIV

status.


When to do PCR for HIV diagnosis of Child < 18 months

• 30 % become infected through MTCT– 5 % intrauterine-PCR +ve in first week of life– 15% during delivery-PCR +ve by age 1 month– 10% via breast feeding-Do PCR 1 month after

stopping breast feeding


When to do PCR for HIV diagnosis of child <18 months

• If child NOT breast feeding:– Do PCR from 4 to 6 weeks, repeat after 3 month

• If child IS breast feeding:– Do PCR from age 1 month

• If positive at 1 month, encourage mother to continue BF• If negative, encourage mother to consider stopping BF early (IF

REPLACEMENT FEEDING IS AFFORDABLE, ACCESIBLE, FEASIBLE, SAFE AND SUSTAINABLE)


Interpretation of laboratory diagnosis

• Diagnostic Gold standard- is to perform two tests to confirm or rule out HIV infection

• 2 positive virological tests performed on blood samples taken on 2 separate dates confirms HIV infection.

• 2 or more negative virological tests at age >1 month, one of which is performed at age >4 months in a non- breastfed infant rules out HIV infection.

• Remember, if breast feeding wait 1 month after cessation of breastfeeding.


HIV Diagnosis before age 18 month without virologic test

• The infant is confirmed as being HIV antibody-positive• Diagnosis of any AIDs-indicator can be made

or• The infant is symptomatic with two or more of the following:

– Oral candidiasis /thrush– Severe pneumonia– Severe sepsis

Other factors supporting HIV infection in infant include:– recent maternal death or advanced HIV disease in mother. – CD% <20%

Confirmation of the diagnosis of HIV infection should be sought as soon as possible.


DIAGNOSIS - summary

• In children < 18 months HIV is diagnosed by 2 positive virological tests performed on blood samples taken on 2 separate dates.

– HIV is excluded by 2 or more negative virological tests at >age 1 month, one of which is performed at age >4 months in a non-breastfed infant

– If BF wait 3 months after cessation of BF

• Antibody tests: 2 or more antibody tests after 18 months confirm or exclude diagnosis.

• Presumptive severe HIV infection Child who needs ART should be made where PCR is not available and HIV diagnosis should be confirmed as soon a spossible or at age of 18 months


STAGING PEDIATRIC HIV

Clinical and Immunological


Clinical Staging

TWO international clinical staging systems:

World Health Organization (WHO)Four stages – 1, 2, 3, 4

Centres for Disease Control (CDC)Four stages – N, A, B, C


Clinical Staging

Stage WHO CDC

Asymptomatic 1 N

Mild 2 A

Moderate 3 B

Severe (AIDS) 4 C


WHO Clinical Staging – stage 1

Stage I• Asymptomatic• Persistent generalized lymphadenopathy (PGL)


WHO Clinical Staging - stage 2

• Papular pruritic eruptions• Seborrheic dermatitis• Fungal nail infections• Angular cheilitis• Linear gingival erythema• Extensive HPV or molluscum infection (>5% of body area/face)• Recurrent oral ulcerations (>2 episodes/g mos)• Parotid enlargement• Hepatosplenomegaly • Herpes zoster (>1 episode/12 mos)• Recurrent or chronic upper respiratory infection (URI): otitis media,

otorrhea, sinusitis (>2 episodes/6 mos)


WHO Clinical Staging – Stage 3

• Unexplained moderate malnutrition (-2SD or Z score) not responding to standard therapy

• Unexplained persistent diarrhea (>14 days)• Unexplained persistent fever (intermittent or constant, >

1mo)• Oral candidiasis (outside neonatal period)• Oral hairy leukoplakia• Pulmonary tuberculosis, TB lymphadenitis• Severe recurrent presumed bacterial pneumonia


WHO Clinical Staging – Stage 3 (continued)

• Acute necrotizing ulcerative gingivitis/periodontitis• Lymphoid interstitial pneumonitis (LIP)• Unexplained anemia (<8g/dL), neutropenia

(<1000/mm3), or thrombocytopenia (<30,000/mm3) for >1 mo.

• HIV-related cardiomyopathy• HIV-related nephropathy


WHO stage 4 – all ages

Conditions where a presumptive diagnosis can be made using clinical signs or simple investigations:

• Unexplained severe wasting or severe malnutrition not adequately responding to standard therapy

• Pneumocystis pneumonia• Recurrent severe presumed bacterial infections (2 or > episodes within one year

e.g. empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia )

• Chronic orolabial or cutaneous Herpes simplex infection (of more 1 month duration)• Extrapulmonary tuberculosis (except TB adenitis)• Kaposi's sarcoma• Oesophageal Candida • CNS Toxoplasmosis • HIV encephalopathy


WHO stage 4 – all ages (continued)

Conditions where confirmatory diagnostic testing is necessary:• CMV infection (CMV retinitis or infection of organ other than liver, spleen,

or lymph nodes onset at age 1 month or more) • Cryptococcal meningitis (or other extrapulmonary disease)• Any disseminated endemic mycosis(e.g. extra-pulmonary Histoplasmosis,

Coccidiomycosis, Penicilliosis)• Cryptosporidiosis • Isosporiasis• Disseminated non-tuberculous mycobacteria infection • Candida of trachea, bronchi or lungs• Acquired HIV related recto-vesico fistula


WHO-Presumptive severe HIV infection: Child < 18 months requiring ART- when PCR testing not available

• The infant is confirmed as being HIV antibody-positive• Diagnosis of any AIDs-indicator can be made

or• The infant is symptomatic with two or more of the following:

– Oral candidiasis /thrush– Severe pneumonia– Severe sepsis

Other factors supporting HIV infection in infant include:– recent maternal death or advanced HIV disease in mother. – CD% <20%

Confirmation of the diagnosis of HIV infection should be sought as soon as possible.


Exercise on clinical staging

• Case 1:• Tooto is 4 yrs old, presents with oral thrush,

recurrent pneumonia, fever for 2 weeks, and weighs 14kgs.

• Qtn: Whatis Toto’s WHO clinical stage?


Exercise on Clinical Staging

• ANSWER: WHO stage 3 based on the oral thrush and recurrent pneumonia.



• Case 2:• Abba is 10 months and presents with severe oral thrush

and sepsis requiring one month hospitalization. She recently lost her mother. There is no PCR available for virological diagnosis but her HIV antibody test is positive.

• Qtn: What is her WHO clinical stage?



• Answer: We make a presumptive HIV stage 4 clinical diagnosis in this child based on her positive HIV ELISA and recent death of her mother.

• She is presumptive stage 5 based on age less than 18 months, oral thrush and severe sepsis.


Immunological Staging

Differences in CD4 counts between adults and children

• CD4 counts are normally high in healthy young children

• Decline to adult levels by age 6 years• CD4% dose not change with age


Indicators of severe Immunosuppresion (WHO 2006)

Severe immuno-suppression

< 12 months 12-35 months 36-59 months 5yr+

By CD4% <25% <20% <15% <15%

By CD4 count <1500 <750 <350 <200

By total lymphocyte count

<4000 <3000 <2500 <2000


NASCOP 2007- classification of severe immunosuppresion in children

• WHO proposed immune staging 2006 more complex than previous immune staging

• To maintain simplicity and continuity NASCOP opted to retain three age-group classification (<18 months, 18 months-5 years and above 5 years) when making ART decisions for ART initiation in children


Immunological Staging Using CD4 percentage

Severe immunosuppression

< 18 monthsCD4 %

18 months-59 monthsCD4 %

> 5 years (60 months)CD4 %

By CD4%<25 % <20% <15%

By CD count< 1500 < 500 <250


Total Lymphocyte Count (TLC)

• Where one cannot perform CD4 assays, TLC provides a rough guide to level of immunosuppression.

• As CD4 count drops, TLC also drops• Only useful for baseline evaluation for

immunosuppression.


Computing Total Lymphocyte Count

TLC = Lymphocyte percentage per litre x 100 White cell count per litre

TLC = Lymphocyte percentage per mm3 x 100 White cell count per mm3



• If Total WBC =4.0 X 109/litre and differential Lymphocyte count is 50%, What is the total lymphocyte count?

(Give the TLC in two different units – per litre and per mm3).



AnswerTLC = 50% of 4.0 x 109

i.e. 2.0 x 109/litre.

Divide by 106 to convert TLC to per mm3

Above example, TLC = (2.0 x 109) 106 = 2000/mm3


Computing CD4%

CD4% = Absolute CD4 count per mm3 x 100 Total lymphocyte count per mm3

OR = Absolute CD4 count per litre x 100 Total lymphocyte count per litre



Unit 4 HIV – Related Conditions:Prevention and Treatment


Diagnosis – combining lab and clinical criteria

• May not have access to PCR as is not widely available or affordable.

• You can still make a diagnosis in child < 18 months combining simple lab and clinical parameters.


Summary of approach to diagnosis

1. Do clinical assessment-suspect HIV2. Do clinical staging (WHO)3. Do HIV test-<18 months-PCR, >18 months-antibody test4. Do CD4 test5. If Cd4 Not available, do Total Lymphocyte Count (TLC)6. Make final diagnosis and stage child’s disease


Unit 4: HIV related conditions

• OBJECTIVE: To impart knowledge on prevention and treatment of common HIV related conditions in HIV infected children


HIV-related Diseases

Infections that complicate HIV disease in children include:

• Infections that are commonly seen even in HIV uninfected children

• Opportunistic infections – rare in HIV negative children – more common with advancing immune compromise.


HIV-related Diseases (cont)

• Other clinical problems not commonly seen in other children– Lymphoid interstitial pneumonitis– Malignancies– HIV encephalopathy


Respiratory Infections in HIV infected children

• Respiratory infections are the most common causes of hospital admissions

• Aetiology mainly S. pneumoniae, H. influenzae, non- typhoid Salmonella– These pathogens are also the common causes of bacteraemia and

meningitis in children with HIV.• Treatment is the same as in HIV negative children but duration

may need to be longer.• Prevention

– Immunization – pneumococcal vaccine – Cotrimoxazole


Infections causing diarrhoea in HIV infected Children

• Acute, persistent and chronic diarrhoea are important causes of morbidity in children with HIV

• Etiologies include organisms commonly seen in HIV negative children as well as opportunistic pathogens.– Rotavirus– E coli– Samonella– candida


Infections causing diarrhoea in HIV infected children

• Opportunistic pathogens.– Cryptosporidium– Microsporidium– Isospora belli– Cytomegalovirus (CMV)– Herpes simplex virus (HSV)


Measles

• Severe illness in children with HIV infection, particularly those with advanced immunodeficiency

• May occur in early infancy in HIV infected children

• Severe cases can occur without the typical rash and may be complicated by pneumonia or encephalitis.

• High case fatality, should be treated in hospital.


Measles

• Management should include 2 doses of vitamin A calculated based on the age of the child– 50,000 IU if aged <6 months; 200,000 IU in children

aged 12 months to 1 year• Immunization should be given to HIV infected

children at 6 months and repeated at 9 months.


Septicemia and Meningitis

• Fever may be the only presenting symptom of serious infection

• HIV infected children with fever need careful clinical and laboratory assessment to identify the cause of fever, and intensive follow-up

• Treatment should follow local guidelines• Treatment failure is more frequent.• Prevention: immunisation (Hib, pneumococcal)


Skin infections

• Bacterial – impetigo, cellulitis, abscess

• Fungal skin infections; more common, extensive and more difficult to treat, than in the non immunocompromised.

• Viral –molluscum contagiosum.

• Parasites - scabies


Multiple skin

abscesses

Photo courtesy of

Israel Kalyesubula


Malaria

• May be associated with more severe disease with HIV infected children due to:

• Pre-existing anaemia• Malnutrition• Low immunity• Co-morbidity – septicaemia


Summary

Characteristics of common childhood infections in HIV infected children:

• Same pathogens as non HIV-infected children• Severe Disease• Recurrence• Higher case fatality rates


Opportunistic Infections

• Prevalence and severity of opportunistic infections increase with HIV disease progression

• Often occult and non-localizing• Unusual organisms• Unusual presentation


Prevention of Opportunistic Infections

• The two broad strategies for prevention include chemoprophylaxis and immunization.


Immunization of HIV Infected Child

Broad issues in the immunosuppressed child:• Some live vaccines can result in severe vaccine

associated disease- BCG• Immune response to vaccines may be reduced• Immune response may not be sustained


World Health Organization/UNICEF recommendations

For the Immunization of HIV-infected children and women of childbearing age


Vaccine Asymptomatic HIV Symptomatic HIV

Optimal timing of immunization

BCG Yes No Birth

DPT Yes Yes 6,10,14 wks

OPV* Yes Yes 0, 6,10,14 wks

Measles Yes Yes 6 and 9 months

Hepatitis B Yes Yes As for uninfected children

Yellow fever Yes No**

* IPV an alternative for children with symptomatic HIV** Pending further studies

WHO/UNICEF Recommendations for HIV Infected Children


Immunization of HIV infected infants

• Use National immunization guidelines (KEPI guidelines)• Measles give 1st dose at 6 months; repeat at 9 months whether

symptomatic or not• BCG and Yellow fever vaccines: contraindicated in full blown

AIDS

• Avoid missed opportunities for HIV infected children who are sick


Chemoprophylaxis

This involves administering daily an antimicrobial drug to prevent disease by specific opportunistic organisms:

• Given against PCP, TB and Cryptococcosis• Aim of chemoprophylaxis includes

– Primary prevention: prevention of the first episode– Secondary prevention: prevention of recurrence after an initial

episode of an opportunistic infection


TB Chemoprophylaxis

This should be given to the following:• Neonate whose mother is diagosed with PTB

• All contacts under 5 years of age in a household with an adult with open TB– Need to first exclude active TB disease in the child.

INH 5-10mg/kg/day for 6 months


Pneumocystis Pneumonia

• Caused by a fungus, Pneumocystis jiroveci*, that is commonly found in the environment

• Commoner under the age of 1 year and in severely immunosuppressed children

• Major cause of morbidity and mortality in HIV infected children• Clinical presentation:

Tachypnoea– Dyspnoea– Low grade fever or afebrile– Cough– Hypoxemia (paO2 < 90%)– Clear chest or fine crepitations– Poor response to standard antibiotics


Investigations

• Chest X-ray: hyperinflation, diffuse infiltrates or may be normal

• Sputum induction or nasopharyngeal aspirate: stain with Silver or Immunofluorescent stain

• Bronchoalveolar lavage: bronchial wash specimen stain as above

• Diagnosis should be made clinically and empirical treatment should be started


Management of PCP

• Supportive – Oxygen/ventilatory support– Maintain and monitor hydration– Nutritional support– Continue therapy for bacterial pneumonia

• Definative treatment – Co-trimoxazole


PCP Treatment

• Cotrimoxazole I.V (or oral if IV not available)– Trimethoprim (TMP): 15-20 mg/kg/day in 3-4 doses– Sulphamethoxazole (SMX): 75-100 mg/kg/day in 3-4 doses

• Infuse each dose over 1 hour • After acute symtoms subside, change from I.V. to oral• If I.V. formulation not available, give oral form

– Duration of treatment: 3 weeksOR

• IV Pentamidine 4mg/kg/day OD x 21 daysAdd prednisone 2mg/kg for 7-14 days in severely ill children (taper off)


PCP Prophylaxis

• Co-trimoxazole prophylaxis– All HIV exposed infants until HIV infection excluded– All HlV infected children– All children who are possibly HIV infected as per IMCI

guidelines• Dose 25mg SMX / 5mg TMP per kg O.D. (30mg

cotrimoxazole/kg o.d.)

OR• Dapsone 2mg/kg p.o daily


Cotrimoxazole reaction and management


Candidiasis

• Oral candidiasis a frequent OI• May extend to oesophagus and disseminate

when CD4 severely depressed• Oesophageal candidiasis assoc with difficulty in

swallowing/dysphagia


Treatment of Candidiasis

Oral thrush:• Clotrimazole mouth paint 10-20 drops p.o qid 7 days (after

feeds) or until thrush clears.• Or clotrimazole 10 mg troches (older children only) Or:• 0.25%-0.5% gentian violet solution • 2% miconazole gel, 2.5 ml (young child) or 5 ml (older

child) two times a day


Treatment of Candidiasis

Oesophageal candidiasis:• Oral ketoconazole , 3-6mg/kg/day for 7 days OR• Oral fluconazole 3-6 mg/kg/day for 2-3 weeks or

until resolution of symptoms.


Photo courtesy of Israel Kalyesubula


Coccidioidomycosis


Katindi – 6 years

Full blown AIDSWeight 14kg, height 90cmStarted on co-trimoxazole 5 ml once daily

Q1 Is the dose appropriate?


Katindi

• Katindi developed severe Steven Johnsons reaction to the cotrimoxazole

Q 2 How will you manage her?Q3 After stabilized, how is it possible to

continue to give her prophylaxis against PCP?


Katindi

While you are deciding what to do about her prophylaxis, she presents in casualty with

• Severe cough of 1 weeks duration• Afebrile, Cyanosis• RR 90/min• Clear chest

Q4 What is the diagnosis?Q5 How will you treat her?



Unit 5 Antiretroviral Therapy in Children


Unit 5 Antiretroviral Therapy in Children• Objective: To describe how and when to provide antiretroviral therapy in children, , including initiation, pre-ART preparation, monitoring, when to change/withdraw ART.


Antiretroviral Therapy

Will cover the following:• Indications for ART initiation• National ART Regimens• Monitoring• Indications for change or withdrawal of ART• National second line regimens• ART and tuberculosis


Criteria for ART Initiation

There are two broad criteria to consider prior to ART initiation

• Medical criteria

• Psychosocial criteria


Criteria for ART Initiation

Medical criteria• WHO stage 3 or 4 disease (irrespective of CD4 counts or %).• Low CD4 count or percentage as follows (irrespective of WHO stage):

– Child < 18 months – CD4 < 25% or absolute CD4 count < 1500– Child 18 months to 5 years – CD4 < 20% or absolute CD4 count < 500– Child older than 5 years – CD4 < 15% or absolute CD4 count < 250

• Recurrent hospitalizations (> 2 admissions in previous year) for HIV-related disease, or prolonged hospitalization (> 4 weeks) in previous year.


Criteria For ART Initiation

Psychosocial criteria• An identifiable parent or guardian who is able to understand the

regimen, and consistently administer the child’s medication.• Adolescent – disclosure of HIV diagnosis before ART initiation

recommended where possible• Ability to regularly attend the HIV clinic appointments.• Sustainable long-term access to antiretroviral drugs (either

through programs providing ART, or financially able to purchase ARV drugs).


Preparing a Child for ART

Prior to initiating ART, the following preparations should take place

• Medical Preparation

• Counseling Preparation


Preparing a Child for ART (2)

Medical Preparation• Baseline tests to check haematological, liver and kidney

function:– Full blood count (resources limited, do Hb)– Liver function tests (resources limited, do alanine transaminase

or ALT)– Renal function tests (resources limited, do serum creatinine)

• Do baseline CD4 if possible• Do baseline viral load (RNA PCR – this is optional if

resources limited)


Preparing a Child for ART (3)

Medical Preparation (continued)• Baseline clinical assessment including weight, height,

surface area.• If current TB suspected, investigate for TB (If TB

confirmed, consider delaying ART initiation until child completes 2-4 weeks of anti TB treatment)

• Initiate co-trimoxazole prophylaxis • Treat any inter-current illnesses


Prior to starting ARV in children

Start in haste, repent at leisure!!Starting ART is never an emergencyTake time to counsel, prepare, educate the familyCounsel the caregiver on:• Cost – drugs, monitoring tests, food security• Adherence to therapy – strict time scheduling• Support, support, support. Child can’t do it alone.• Older child – disclosure to child• Goals, limitations and side effects of ARTDo careful social assessment of family situation prior to starting

therapy.


Prior to starting ARV in children- cont..

• When and how to administer the drugs• Possible adverse effects and how to recognize and deal with

them• Possibillity of immune reconstitution inflammatory syndrome

(initially getting worst before getting better)

• Donot overemphasize the last two issues-Don't scare guardian


Goals of ARV Therapy

• Maximal and durable suppression of HIV replication.

• Restoration and preservation of immune function.

• Reduce HIV related Morbidity & Mortality.• Improve quality of life.


Special Considerations for Children and ARVs

Choose drugs that:• Do not have to be timed around meals• Have acceptable taste• Suspensions/syrups are stable at room temperature if patient

does not own a refrigerator. • Children older than 6 years may take tablet and capsule

formulations• Some capsule formulations may be opened and capsule content

mixed with food or drink.• Some chewable tablets may be crushed and mixed with food or

drink.


Types of Antiretroviral Drugs

1. Nucleoside reverse transcriptase inhibitors (NRTI)

2. Non-nucleoside reverse transcriptase inhibitors (NNRTI)

3. Protease inhibitors (PI)


Antiretroviral Agents

• NRTI Nucleoside Reverse Transcriptase Inhibitor

– Zidovudine (AZT,ZDV)– Didanosine (ddI)– Zalcitabine (ddC)– Stavudine (D4t)– Lamivudine (3TC)– Abacavir (ABC)– Emtricitabine (FTC)

• Nucleotide analogues– Tenofovir (Viread)

• NNRTI Non-Nucleoside Reverse Transcriptase Inhibitor

– Nevirapine (NVP)– Delavirdine (DLV)– Efavirenz (EFV)


Antiretroviral Agents

• PI- Protease Inhibitors

– Saquinavir (SQV)– Ritonavir (RIT)– Indinavir (IDV)– Nelfinavir (NFV)– Amprenavir (APV)– Lopinavir/ritonavir (LPV/r)– Atazanavir (ATZ)

• Fusion inhibitors– Enfuvirtide (T-20)

Entry inhibitors-Maraviroc


Kenya national recommended 1st line ART in children

Always give three drugs (triple therapy). National first line regimen – use 2 NRTIs and 1 NNRTI

Age < 3 years• Zidovudine (ZDV) + Lamivudine (3TC) + Nevirapine (NVP)

Age > 3 years• ZDV + 3TC + Efavirenz (EFV) or NVP.

These can be taken with or without food, taste is acceptable, and all are stable at room temperature.

If child very anaemic, ZDV may be substituted by stavudine (D4T)


First line regimen in NVP-exposed child

Child exposed to single dose Nevirapine for PMTCT may have NVP resistant virus. Avoid NNRTI in their 1st line regimen

• AZT (or d4T) + 3TC +LPV/r (Kaletra)


ART and Tuberculosis

Rifampicin interacts with Nevirapine and most protease inhibitorsIf possible, complete anti-TB therapy before ART initiation. If child too sick to wait, and anti-TB therapy must be given with ART

use the following regimen:• Child < 3 yr – Replace NVP with Abacavir. After completing anti-

TB therapy revert to NVP• Child > 3 yr – Two NRTIs with Efavirenz


Dosages of ARV drugs

• Many are calculated using surface area• S.A = sq root of ([wt x ht] / 3600)• Others calculated using weight for age- charts• Failure to compute dosage correctly leads to

under- or over-dosing• Suboptimal dose – resistance• Overdose – toxicity


Drug Formulation Dose Adverse effects

Comments

Stavudine Syrup 1mg/ml, 200ml;Caps 15, 20,30mgFDCs

1mg/kg/dose BDMax: 30 mg

Peripheral neuropathy; lipodystrophy

•Reconstituted syrup needs refrigeration </= 1mth;•Not to be used with AZT•No food restrictions•Dose adjustment in Renal Failure

Lamivudine Oral solution 10mg/ml, 100mls, 240mls;Tablets 150mgFDCs

4mg/kg/dose BD, >12yrs or 60kg+ 150mg BD

Well toleratedMay be associated with hepatitis

•Store solution at 25-25 0C for </= 1mth•No food restrictions•Dose adjustment in Renal Failure

Zidovudine Syrup 10mg/ml, 240ml; Caps/Tab 100mg, 300mg;Inj. IV 10mg/ml, 5ml; FDCs

240mg/m2/dose BD; >12yrs, 300mg BDHIV encephalopathy: 300mg/m2/dose BD

•Bone marrow suppression (anemia and/or neutropenia)

No food restrictionsSyrup stable at 15-25o x 1mthNot to be used with d4TDose adjustment in

Renal/Hepatic Failure

NRTIs I



Comments

Abacavir Oral solution 20mg/ml,

240ml; Tablets 300mg 8mg/kg/dose BD, max 300mg BD. Over 37.5kg or over 16 years: 300mg BD

Hypersensitivity reactions (i.e. rash, fever, GI and RT symptoms)

1.Not to be used in children< 3mths2.No food restrictions3.Educate patient/carer re: hypersensitivity reaction3. DO NOT re-challenge after reaction

Tenofovir Tabs 300mgFDC with Emtricitabine

300 mg OD Well tolerated Renal impairment reported

Not recommended in combination with ddI, if used, close monitoring needed

Take with meal

Didanosine Dispersible buffered tablets25/100/200mg/400mg Chewable/dissolved in water/apple juice

100-120 mg/m2/dose BD

•Pancreatitis •Peripheral neuropathy•GI intolerance

Take on empty stomach (>1/2 hour pre or> 2hour post meal)

NRTIs II



Comments

Nevirapine Oral Suspension 10mg/ml, 100mls, 240mlTablets 200mg

4mg/kg OD for 14 days, then 7mg/kg BD for <8yrs. For >8 years 4mg/kg BD max 200mg

•RASH•Hepatoxicity

Store suspension at room temperature.Need to monitor LFTs in first few monthsEducate patient/carer about rash.

Auto induced metabolism in the first 2-4 weeks with a 2 fold increase in clearance hence higher dosing after 2 weeks.

Efavirenz Capsules 50mg/200mg/600mgSyrup 30mg/ml., 180ml

10-14kg: 200mg, 15-19kg: 250mg, 20-24kg: 300mg; 25-32.5kg: 350mg 33-39kg:400mg> 40kg: 600mg

•CNS disturbances•Teratogenic (DO NOT use in pregnancy)•Hepatitis

•Avoid high fat meal as increases absorption, drug levels and side effects

NNRTIs


Drug Formulation Dose Adverse effects Comments

Ritonavir 100 mg capsuleSyrup 80mg/ml

Now used predominantly as a mini-dose for purposes of “boosting” other PIs

•GI Intolerance•Taste perversion.•transaminases, CPK uric acid•Class side effects

Used as PI booster.Refrigeration required if solution or

caps kept for > 30 days Oral solution contains alcohol 12%.

Lopinavir/ritonavir (KaletraTM)

Capsules 133.3mg/33.3mg Oral solution 80mg/20mg per ml

7-15kg-0.15ml/kg BD15-40kg-0.125ml/kg BD> 40kg: 3 capsules BD (400/100)

•GI Intolerance•Taste perversion•Hepatitis •Class side effects

Refrigerate reconstituted solution. Stable for 30 days.

Give with food. Moderate fat meal increases bioavailability.

Storage at <25OC for up to 2 months

Nelfinavir 250 mg capsules50mg/g oral powder

55-75mg/kg/dose BD, max 1250mg BDOr 750mg TDS

•Diarrhea •Class side effects

Food increases levels by 2-3X. Take with meals, preferably high fat meal

Indinavir 200, 333, 400mg capsules

800 mg TDSOR800mg with RTV BD

•Kidney stones (take >2litres fluid/day)•Inc indirect bilirubin •Class side effects

Separate from buffered ddI by 2hoursTake on empty stomach (1 hr pre or 2hr

post meals)No food effect when taken with RTV

PIs


Clinical Monitoring

• Clinical response – anthropometry, physical exam at every visit– Symptoms improving, static, deteriorating?– Growth (weight, height)– General well-being

• Clinical signs of specific adverse effects (depend on class of drugs)


Laboratory Monitoring

• Response to therapy– CD4 every 6 months (expect rise within 6 months)– Viral load at baseline, month 3 then every 6 months if

affordable (aim at 5-fold drop by 8-12 weeks)• Adverse effects

– FBC, SGPT/ALT at baseline, month 1, then 3 monthly or as appropriate

– Others (lipids, glucose etc) as appropriate for toxicity or inter-current illnesses


When to change or stop ART

1. Toxicity – replace only the offending drug

2. Treatment failure – replace all 3 drugs

3. Poor adherence – if cannot rectify, withdraw ART


When to change ART

Toxicity – replace offending agent only with equivalent drug

• Hb < 7gm/dl• Platelets < 49,000• Neutrophils < 250• Bilirubin 3-7x upper normal• SGPT 10x upper normal• Amylase, lipase: 2-3x upper normal• Neuropathy, severe dermatitis • Lipoatrophy, pancreatitis


Indications for change of therapy – treatment failure

FIRST CHECK ADHERENCE!!

Clinical indications• Progressive neurodevelopmental deterioration• Growth failure • Disease progression – move from one stage to

next



Immunological indications• For kids with CD4 below 15%, decline of ≥ 5

percentile points• Rapid decline in absolute CD4 count (loss of >

1/3 of CD4 cells in < 6 months)



Virological indications

• Persistent increase in viral load (confirmed by 2 tests)


Second line therapy – factors to consider

• Change ALL 3 DRUGS.• Include a Protease inhibitor.• Replace the NRTIs with two new NRTIs• Replace the NNRTI with a PI• IF initial problem was adherence to therapy, must address

this first. If can’t, best to just withdraw therapy altogether


Kenya national recommended 2nd line ART in children

First line• ZDV/3TC/NVP or EFV

• d4T/3TC/NVP or EFV

• ZDV/3TC/Kaletra

Second line• ddI/ABC/LPV/r or ddI

/ABC/NFV

• ddI/ABC/LPV/r or NFV• ddI /ABC/PI/ ritonavir


When To Stop/withdraw ART.

ART should be withdrawn in the following situations:

• Severe adverse effects (lactic acidosis)• Intolerability, inability to take drugs.• Poor adherence• Interruption of drug supply • Patients wish.


Immune Reconstitution Inflammatory Syndrome (IRIS)

• Inflammatory disorders associated with paradoxical worsening /atypical presentation of preexisting infectious processes following the initiation of highly active antiretroviral therapy

• Preexisting infections in individuals with IRIS mat have been previously diagnosed and treated or they may be subclinical and alter unmasked by thr host’s regained capacity to mount inflammatory response


IRIS-cont..

• Systemic or local inflammatory reactions may occur at the site or sites of the pre-existing infection.

• Reaction is usually self-limited, especially if the pre-existing infection is effectively treated.

• Long-term sequelaeand fatal outcomes may rarely occur when neurologic structures are involved.


IRIS

• IRIS appears to be most prevalent in people with• A severely compromised immune system at baseline, • Start of ART soon after of Rx of O.I.• Genetic mutationsof their innate cytokines eg TNF Management:• Antimicrobial agents directed at the underlying infection/

intesification of medications.• Steriods or nonsteroidal anti-inflammatory agents.• Continued use of HAART may be all that is necessary for IRIS to

resolve.


Module 7

Case StudiesPatient MO


MO

• 6 months old• History

– Persistent diarrhoea– Recurrent mouth sores– Weight loss– Mother had TB 1 year ago– Two previous hospitalizations with pneumoniaQ 1 Do you suspect HIV? If so, why?


MO

• Exam– Weight 3.5kg, height 60cm, wasted, dehydrated, severe

oro-pharyngeal thrush, has not achieved head support.

Q 2 What is his clinical stage? (WHO and CDC)

Q 3 How would you confirm his HIV status?


MO

See his lab tests (MO 1 to MO 3)

Q4 Compute his TLC from the first FBC report (June 2003)

Q 5 Based on his TLC is he immuno-suppressed?

Q 6 Compute his TLC and CD4 % from his CD4 report (July 2003)

Q 7 What is his immunological category?


MO

Q8 Does MO require antiretroviral therapy?

Q9 If yes, which ARV drugs would you prescribe?

Q10 What is his surface area?

Q11 What doses and formulations would you administer?


MO

• M.O. started on antiretroviral therapy

Q 12 Compute his TLC and CD4% in January 2005 after 15 months of ART


Adherence Issues to Consider

• Children depend upon adults to administer drugs• Adherence may be affected by stage of development

(spitting, vomiting, running away)• Providers need to teach families techniques of giving

medicine to young children– Use of syringe for measurement and administration– Crushing of meds– Mixing in fruit juice, other foods– Opening of capsules– Repeat dose if vomited


Case Studies Module 7

HIV-Related DiseasesCase - Katindi


Katindi – 6 years

Full blown AIDSWeight 14kg, height 90cmStarted on co-trimoxazole 5 ml once daily

Q1 Is the dose appropriate?


Katindi

• Katindi developed severe Steven Johnsons reaction to the cotrimoxazol

Q 2 How will you manage her?Q3 After stabilised, how is it possible to

continue to give her prophylaxis against PCP? How


Katindi

While you are deciding what to do about her prophylaxis, she presents in casualty with

• Severe cough of 1 weeks duration• Afebrile, Cyanosis• RR 90/min• Clear chest

Q4 What is the diagnosis?Q5 How will you treat her?


CASE PRESENTATION: SK


CASE SMK BORN JUNE 2002.

• Birth weight 2.6kg. • Apgar score 9/1, 10/5• Second born.• Older sibling male, born in 1999 Nov.


Progress:

•6weeks: 4.2kg. Thrush noted. On breast-milk and formula.

•12weeks: 5.3kg. Not breastfeeding.Mother on undisclosed drugs.

Unwilling to discus her own condition.


• How would you counsel the mother?• What would you like to know from her?


• 18weeks: 6.4kg. Noted to have generalized lymphadenopathy,

• and hepato-splenomegally.• Would you suspect HIV?• How would you proceed?


• Mother on ddI, d4T, EFZ.• 22weeks: 7.2kg. Multiple abscesses, nappy

dermatitis, severe oral thrush, hepatosplenomegally and generalized lymphadenopathy.

• Mother agreed HIV tests for baby.What is the WHO clinical staging?Which tests would you order?


• If mother cannot afford PCR test, what would you do?

• When then is the earliest you can confirm the child’s diagnosis?


• HIV diagnostic test: Viral load by Amplicor HIV-1 monitor version1.5:

• 9,818copies/ml.• WBC 21 300, Lymphocytes 72% (15 336)• Hb. 11.2g/dl, platelets 343.• Comment on these results.• Do they change the child’s clinical stage?


• Mother came for results one month latter.• Child now 7months old. In addition to above symptoms

noted to have parotid enlargement, palpable lymph node in the left cubital area.

• Temp. 38.2C, respiratory rate 74/min. with chest retractions, cyanosed, normal breath sounds.


• What are the possible diagnoses?• What is the child’s clinical stage now?• How would you manage his acute problem?


• Treated with cotrimoxazole and cefprozil.• ARVs to be started when parents ready.


• 8months:8.7kg. Admitted with severe pneumonia. Chest x-ray: bi-basal and perihilar nodular opacities. WBC 16 400, Lymph. 67%. Hb. 10.1g/dl

• CD4 1,889 or 17%.• Viral load 380 000copies/ml.• What is his immunological stage?• Discuss management.


• Started on AZT, 3TC, NVP. co-trimoxazole prophylaxis.

• One month latter, aged 9months: Admitted with fever for one day and refusal to feed.

• Cough had continued since the last admission one month ago.

• Chest x-ray: pneumonia.


• Mantoux test ulcerative• Sputums positive for AAFBS. (three slides)• What do you think is happening? • Discuss management of the patient and the

family. (Mother on ART, father positive but healthy, older sibling’s status not known.)


• Treated with INH, PZA, RFP for 2months. Then INH, RFP for 4months.

• ART changed to AZT, 3TC, ABC.


• 20th. September 2003, age 1year 3months: 11kg. No lymphadenopathy, liver and spleen not palpable. Parotids not enlarged.

• TB treatment over

• What should be done next?


• May 2004: 13kg. Viral load <50copies/ml• CD4 2,330 (16%)• Abacavir not available.

• What are your options?


• Was changed to NVP, AZT, 3TC.• July 2005: 18kg.Viral load <50copies/ml• CD4 20%

• Your comments?• Discuss future plans.

module 4 hiv infection & art in children

Health & Medicine

natural history

natural disease

class side

clinical signs

outline diagnostic

natural history

therapy treatment

paediatric