Module 4 hiv infection & art in children

Management of HIV infected Children

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

Management of HIV infected Children 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+ women become 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).

Management of HIV infected Children 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.

Natural History – Immunological changes

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.

Management of HIV infected Children 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 clinics HIV positive parents should be encouraged to bring all their children in for testing Confirmation 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 < 3 rd centile (below “very low weight curve” in card Enlarged lymph nodes in 2 or more of the following sites (neck, axilla, groin) Oral thrush

Laboratory Diagnosis There are two types of laboratory tests for HIV diagnosis: Antibody tests-detect antibody toHIV Virologic tests-detect HIV virus or antigen

Laboratory Diagnosis Child >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 Diagnosis Child < 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 Diagnosis Virologic tests Virologic test – detect HIV virus in blood Is 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 Severe (AIDS) 4 C Moderate 3 B Mild 2 A Asymptomatic 1 N Stage WHO CDC

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/mm 3 ), or thrombocytopenia (<30,000/mm 3 ) 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.

Exercise on Clinical Staging 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?

Exercise on Clinical Staging 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) <2000 <2500 <3000 <4000 By total lymphocyte count <200 <350 <750 <1500 By CD4 count <15% <15% <20% <25% By CD4% 5yr+ 36-59 months 12-35 months < 12 months Severe immuno-suppression

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 <250 < 500 < 1500 By CD count <15% <20% <25 % By CD4% > 5 years (60 months) CD4 % 18 months-59 months CD4 % < 18 months CD4 % Severe immunosuppression

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

Computing Total Lymphocyte Count If Total WBC =4.0 X 10 9 /litre and differential Lymphocyte count is 50%, What is the total lymphocyte count? (Give the TLC in two different units – per litre and per mm 3 ).

Computing Total Lymphocyte Count Answer TLC = 50% of 4.0 x 10 9 i.e. 2.0 x 10 9 /litre. Divide by 10 6 to convert TLC to per mm 3 Above example, TLC = (2.0 x 10 9 ) 10 6 = 2000/mm 3

Computing CD4% CD4% = Absolute CD4 count per mm 3 x 100 Total lymphocyte count per mm 3 OR = Absolute CD4 count per litre x 100 Total lymphocyte count per litre

Management of HIV infected Children 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 Do clinical assessment-suspect HIV Do clinical staging (WHO) Do HIV test-<18 months-PCR, >18 months-antibody test Do CD4 test If Cd4 Not available, do Total Lymphocyte Count (TLC) 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

* IPV an alternative for children with symptomatic HIV ** Pending further studies WHO/UNICEF Recommendations for HIV Infected Children No** Yes Yellow fever As for uninfected children Yes Yes Hepatitis B 6 and 9 months Yes Yes Measles 0, 6,10,14 wks Yes Yes OPV* 6,10,14 wks Yes Yes DPT Birth No Yes BCG Optimal timing of immunization Symptomatic HIV Asymptomatic HIV Vaccine

Immunization of HIV infected infants Use National immunization guidelines (KEPI guidelines) Measles give 1 st 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 (paO 2 < 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 weeks OR IV Pentamidine 4mg/kg/day OD x 21 days Add 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

Katindi – 6 years Full blown AIDS Weight 14kg, height 90cm Started 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?

Management of HIV infected Children 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 emergency Take time to counsel, prepare, educate the family Counsel 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 ART Do 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 Nucleoside reverse transcriptase inhibitors (NRTI) Non-nucleoside reverse transcriptase inhibitors (NNRTI) 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 1 st line regimen AZT (or d4T) + 3TC +LPV/r ( Kaletra)

ART and Tuberculosis Rifampicin interacts with Nevirapine and most protease inhibitors If 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

NRTIs I No food restrictions Syrup stable at 15-25 o x 1mth Not to be used with d4T Dose adjustment in Renal/Hepatic Failure Bone marrow suppression (anemia and/or neutropenia) 240mg/m 2 /dose BD; >12yrs, 300mg BD HIV encephalopathy: 300mg/m 2 /dose BD Syrup 10mg/ml, 240ml; Caps/Tab 100mg, 300mg; Inj. IV 10mg/ml, 5ml; FDCs Zidovudine Store solution at 25-25 0 C for </= 1mth No food restrictions Dose adjustment in Renal Failure Well tolerated May be associated with hepatitis 4mg/kg/dose BD, >12yrs or 60kg+ 150mg BD Oral solution 10mg/ml, 100mls, 240mls; Tablets 150mg FDCs Lamivudine Reconstituted syrup needs refrigeration </= 1mth; Not to be used with AZT No food restrictions Dose adjustment in Renal Failure Peripheral neuropathy; lipodystrophy 1mg/kg/dose BD Max: 30 mg Syrup 1mg/ml, 200ml; Caps 15, 20,30mg FDCs Stavudine Comments Adverse effects Dose Formulation Drug

NRTIs II Take on empty stomach (>1/2 hour pre or> 2hour post meal) Pancreatitis Peripheral neuropathy GI intolerance 100-120 mg/m 2 /dose BD Dispersible buffered tablets 25/100/200mg/400mg Chewable/dissolved in water/apple juice Didanosine Not recommended in combination with ddI, if used, close monitoring needed Take with meal Well tolerated Renal impairment reported 300 mg OD Tabs 300mg FDC with Emtricitabine Tenofovir 1.Not to be used in children< 3mths 2.No food restrictions 3.Educate patient/carer re: hypersensitivity reaction 3. DO NOT re-challenge after reaction Hypersensitivity reactions (i.e. rash, fever, GI and RT symptoms) 8mg/kg/dose BD, max 300mg BD. Over 37.5kg or over 16 years: 300mg BD Oral solution 20mg/ml, 240ml; Tablets 300mg Abacavir Comments Adverse effects Dose Formulation Drug

NNRTIs Avoid high fat meal as increases absorption, drug levels and side effects CNS disturbances Teratogenic (DO NOT use in pregnancy) Hepatitis 10-14kg: 200mg, 15-19kg: 250mg, 20-24kg: 300mg; 25-32.5kg: 350mg 33-39kg:400mg > 40kg: 600mg Capsules 50mg/200mg/600mg Syrup 30mg/ml., 180ml Efavirenz Store suspension at room temperature. Need to monitor LFTs in first few months Educate 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. RASH Hepatoxicity 4mg/kg OD for 14 days, then 7mg/kg BD for <8yrs. For >8 years 4mg/kg BD max 200mg Oral Suspension 10mg/ml, 100mls, 240ml Tablets 200mg Nevirapine Comments Adverse effects Dose Formulation Drug

PIs Separate from buffered ddI by 2hours Take on empty stomach (1 hr pre or 2hr post meals) No food effect when taken with RTV Kidney stones (take >2litres fluid/day) Inc indirect bilirubin Class side effects 800 mg TDS OR 800mg with RTV BD 200, 333, 400mg capsules Indinavir Food increases levels by 2-3X. Take with meals, preferably high fat meal Diarrhea Class side effects 55-75mg/kg/dose BD, max 1250mg BD Or 750mg TDS 250 mg capsules 50mg/g oral powder Nelfinavir Refrigerate reconstituted solution. Stable for 30 days. Give with food. Moderate fat meal increases bioavailability. Storage at <25 O C for up to 2 months GI Intolerance Taste perversion Hepatitis Class side effects 7-15kg-0.15ml/kg BD 15-40kg-0.125ml/kg BD > 40kg: 3 capsules BD (400/100) Capsules 133.3mg/33.3mg Oral solution 80mg/20mg per ml Lopinavir/ritonavir (Kaletra TM ) Used as PI booster. Refrigeration required if solution or caps kept for > 30 days Oral solution contains alcohol 12%. GI Intolerance Taste perversion. transaminases, CPK uric acid Class side effects Now used predominantly as a mini-dose for purposes of “boosting” other PIs 100 mg capsule Syrup 80mg/ml Ritonavir Comments Adverse effects Dose Formulation Drug

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

Indications for change of therapy – treatment failure 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)

Indications for change of therapy – treatment failure 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 2 nd 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 Studies Patient MO

MO 6 months old History Persistent diarrhoea Recurrent mouth sores Weight loss Mother had TB 1 year ago Two previous hospitalizations with pneumonia Q 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 immunosuppressed? 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 Diseases Case - Katindi

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

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

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