Review of Early Infant Diagnosis Programme in Delhi Presented By DR A K Gupta, MD (Pediatrics) Additional Project Director Delhi State AIDS Control Society Govt of Delhi

2 Agenda items This presentation will: Recapitulate Key concepts in diagnosing HIV infection in infants and young children Explain the National algorithms for diagnosing HIV in infants and young children Explain new strategy to ensure enrollment of all new HIV exposed for EID Inform about Scale up of EID programme during Explain Adapting WHO (2010) PMTCT protocol

Recapitulate Key concepts of EID

Children Continue to Be Left Behind Children constitute: 10% of new HIV infections each year o (280,000 out of 2.7 million) 6% of the persons living with HIV o (2 million out of 33 million) 13% of HIV/AIDS deaths each year o (270,000 out of 3 million) o 90% in sub-Saharan Africa Source- UNAIDS,

Why early diagnosis is crucial in Infants ? Rapid HIV progression and higher risk of death in infected infants CD4 and viral load are poor predictors of disease progression in infants Without Anti Retroviral treatment: By age 1, one-third of all HIV-infected children will have Died By age 2, half of all HIV-infected children will have died

Mortality of HIV-infected Infants 6 1 Year = 35% mortality 2 Years = 53% mortality Newell ML Newell ML et al Lancet 2004; 364:

Early Initiation of ART Saves Lives From the Children with HIV Early Antiretroviral Therapy Study (CHER), Violari, NEJM The results of CHER trial demonstrated that early ART in HIV Infected Infants < 12 weeks of age reduced mortality by 76% and HIV progression by 75%.

WHO -new recommendations for starting ART in infants (2010 revised) All infants under 24 months of age with confirmed HIV infection should be started on antiretroviral therapy, irrespective of clinical or immunological stage.

What ART to Start in infants – 2010 revision No infant or maternal ARV exposure MTCT ARV Exposure Sd NVP or NNRTI containing ART Non NNRTI exposure Unknown infant maternal MTCT Exposure NVP triple ART PI triple ART # NVP triple ART # If no PI is available use NVP triple ART

10 Goals of Early Infant Diagnosis To identify the HIV-infected child early, prior to the development of clinical disease during the first months of life. The goal is NOT to exclude infection in infants. Diagnosis should be early enough so interventions and Anti Retroviral treatment can be started Start ART in all confirmed HIV Infected infants irrespective of clinical or immunological status to reduce pediatric mortality and morbidity

1. Rapid HIV Antibody Tests 2. RNA PCR 3. DNA PCR 4. Point of Care Tests (P24 assay) Methods of Early Infant diagnosis

12 Antibody Detection in 77 HIV-Exposed, Uninfected Infants in South Africa Moodley D, PIDJ 1995;14:850 Rapid Ab can be used to exclude infection around months of age

13 DNA PCR for Infant Diagnosis Dunn D, AIDS 1995, 9:F7 At 4-6 weeks of age sensitivity of DNA PCR is %

DNA PCR assays are preferred for EID over quantitative RNA PCR because: (1) DNA assays require whole blood, which is easier to obtain than the plasma required for RNA assays, and (2) DNA assays have greater sensitivity than RNA assays if mothers or infants received antiretroviral drugs for PMTCT. However, RNA PCR can be used for viral load monitoring after established diagnosis. Limitations of RNA PCR for Infant Diagnosis

HIV p24 antigen is produced at high levels within the first few weeks of infection but quickly becomes bound to specific antibodies which make it unable to be detected by standard antigen-detection serological tests. Heat treatment of the sample dissociates p24 from these complexes (the ultrasensitive method). It is a sensitive and highly specific marker for HIV infection Result Time – 1 hour (Northwestern University) Limitations- Testing at Multiple sites, Extensive Trainings, Monitoring, Does Not Eliminate the Need to Improve Lab Systems, More Stock outs Point-of-Care Testing for Early Infant Diagnosis

Process of Enrollling Exposed Infant for EID

EID Reporting Forms & Registers 1. Consent Form 2. HIV DNA PCR Test requisition cum Result Form (TRRF Form) 3. HIV DNA PCR Specimen Delivery checklist 4.Exposed Infant/Child Referral form (ICTC-ART/ART to ICTC) 5. ICTC HIV Exposed Infant /child Card 6.DBS Kit Monthly Stock report site level 7.Critical Call out Form for HIV-1 DNA PCR WBS result 8. HIV-1 DNA PCR Monthly specimen receipt and report dispatch log 9. Corrective action log 10. ICTC HIV Exposed Infant/ Child Register 11 ARTC HIV exposed Infant/ Child Register

Dried blood spot (DBS) a. Whole blood from pricking skin, Dried on filter paper b. Easy to store & Easy to transport c. Required supplies for DBS collection Gloves Pen Lab forms DBS card Lancet or glucolet Disinfectant for skin Gauze or cotton wool

Procedure for heel prick 1.Warm the area 2.Wash hands, put on gloves 3.Position baby with foot down 4.Clean area, dry 30 sec 5.Press lancet into foot, prick skin 6.Wipe away first drop 7.Allow large drop to collect 8.Touch blood drop to card 9.Fill entire circle with drop 10.Fill at least 3 circles 11.Clean foot, no bandage <5kg infants 5-10kg infants Overhead 4-5

Fill at least 3 circles

Valid DBS specimen Overhead 4-34

Invalid DBS specimen: circles not filled clotted/layered Scratched/abraded Not Dried before sending Serum Ring around

How to dry DBS Don’t touch or smear the blood spots. Allow the specimen to air dry horizontally for at least 3 hours. Keep away from direct sunlight, dust, and bugs. Do not heat, stack or allow DBS to touch anything during the drying process. Lay them on a flat surface or drying rack.

Insert into sealable plastic bag (no more than 10 samples per bag) Add desiccant packets (minimum 10 packets per bag) Add humidity card, press air out of bag, and seal bag Keep packaged DBS (in sealable plastic bags) refrigerated until transported to reference laboratory. Shipping HOW TO PACKAGE & TRANSPOPRT DBS CARD

1. DBS a. Sample Collection between 10 AM to 1 PM on every weekday and packaged and stored at ICTC/PPTCT bewteen 2-8 degree C b. Transport to Reference Lab NCDC- on 2 nd and 4 th Tuesday of the month. c.NCDC to send report by courier so as to reach site within 7 days of reciept of sample. 2. Whole Blood Collection a. Sample Collection on 2 nd & 4 th Tuesday of the calender month and transport to Ref Lab NCDC on same day, maintain temperature of 2-25 degree C but do not freeze. b. NCDC should send report back to ART centre within 4 days of receipt of sample. NACO Laboratory Guidelines for Diagnosis of HIV in Children < 18 months

26 Age at which DNA PCR test is Recommnded by WHO in HIV Exposed Infants At 4-6 weeks of life or At first visit (if >6 weeks of age) Why at six weeks of age? The sensitivity of the test is > 96% Testing at this 4-6 weeks of age should identify all babies infected in during pregnancy, labor & delivery and during early breast feeding It correspond to first immunizations visit Cotrimoxazole prophylaxis is initiated at this age.

In 2007: only 8% of HIV exposed infants tested in 1 st 2 months of life only 4 % started on co-trimoxazole Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector, WHO/UNAIDS/UNICEF 2008

1. A large no. (40-50%) of HIV exposed infants never enter EID cascade 2. Missed opportunity for infants born to mothers with unknown HIV status Approach to enroll them: Referring symptomatic infants & children for early infant diagnosis Missed Opportunties for Early Infant Diagnosis

Signs & Symptoms of HIV-Infection in Infants/Children Low weight and/or growth failure Pneumonia, including PCP Oral candidiasis (thrush) after 6 weeks of age Lymphadenopathy Parotid gland swelling Recurrent ear infections Persistent diarrhoea Tuberculosis

Exclusive Breastfeeding Risk of transmitting HIV to the infant during breastfeeding is greater when: – The woman has a high viral load or low CD4 count (new infection or advanced HIV disease) – The woman has mastitis, a breast abscess, nipple sores or other breast problem – The infant or child has ulcers or open sores in the mouth – The child is mixed fed

Risks Associated with Mixed Feeding Mixed feeding in first 6 months increases risk of HIV - If breastfed infant is given formula, risk doubles - If breastfed infant is given solid foods the risk of HIV infection is eleven times as high as the exclusively BF infant

Exclusive Breastfeeding: Early Cessation To minimize risk of MTCT, HIV-infected mothers should discontinue breastfeeding when infant is 6 months of age, if replacement feeding is AFASS Transition from breast milk to replacement feeding should take place over 2-3 days to 2-3 weeks

36 Cotrimoxazole Preventive Therapy Pneumocystis Jiroveci Pneumonia (PCP) is a severe and rapidly progressive pneumonia in HIV infected infants – Peak incidence is between 3-6 months Prophylactic cotrimoxazole therapy significantly reduces the risk of PCP, other bacterial infections and malaria and reduces infant deaths.

Cotrimoxazole Prophylactic Therapy The CPT should be given from 6 weeks onwards to the weight of the infant/Child. Give CPT until HIV has been ruled out and mother is no longer breast feeding In BF - dispersed in expressed breast milk. In RF- disperse in 1-2 TSF of boiled water Weight( Kg)Child dispersible tablets( 20mg TMP/100mg smx) X Once daily <51 tablet tablet tablet tablet

38 Cotrimoxazole Prophylaxis CTX is generally very well tolerated in children – Check for tolerance and adherence at every visit Side effects and toxicities are more common in – Adults > children – Advanced disease > early stages of disease – HIV-infected > HIV-exposed children If a child develops severe reaction to CTX Dapsone can be used for prophylaxis (2mg/kg/dose daily, maximum 100mg daily)

Reviw of Performance of EID programme during  What proportion of pregnant women testing HIV+ get their HIV- exposed infants tested and at what age?  How long does it take for an EID sample to reach the lab, and for the result to reach the site? the family?  Among HIV-exposed infants receiving EID testing, what percent of mothers/caregivers receive their infant’s result?  Among all confirmed HIV-infected infants, what proportion initiates ART and at what age?  Among those initiated ART, proportion initiated correct regimen as per National Guidelines?

Why PI Containing ART Regimen for Nevirapine (NNRTI) Exposed HIV Infected Children? 1.When HIV-1 is transmitted despite PMTCT with > 2 ARV drugs, or mother's ART, prevalence of NRTI or NNRTI resistance in infant HIV will be > 30%. 2.When HIV-1 is transmitted despite PMTCT with NVP alone, the prevalence of major mutations associated with NNRTI resistance in infant HIV will be 50% or greater 3.NNRTI Resistance may decrease with time by 20% in many infants after a long period of non-exposure to ARVs. Source- Diane Bennett et al, Global AIDS Programme, CDC Atlanta

1. Diagnostic testing at 4 to 6 weeks of age for all HIV‐exposed infants, with quick turnaround of test results for immediate initiation if needed. 2. Universal treatment with ART for all infants and children under 2 years of age, regardless of CD4 count or clinical stage with 2 NRTI + 1 NNRTI 3. Infants who have been exposed to maternal or infant NVP or other NNRTIs should be started on protease inhibitors (PIs). WHO 2010 Revised Guidelines for EID and ART

Issues and Challenges Ensuring entry of all HIV exposed infants in the EID cascade Ensuring testing at 6 weeks of age of all HIV exposed infants to serve the very purpose of EID Training of pediatric providers on PICT and referral of symptomatic cases who missed opportunity of EID. Reducing Turn Around Times of DNA PCR testing- change in national guideline of only 2 days /month of sending samples to reference lab. Better coordination between ICTC and ART centers regarding NVP exposure status Improving follow up of BF first DBS negative exposed infants Early Initiation of ART in confirmed HIV infected infants before signs / symptoms of HIV develop i.e by 12 weeks of age

1. Adherence to CPT ? 2. Infant Feeding Counseling ? Supply Chain Management has not been a problem in Delhi Other issues

Scale up of EID programme during

Existing DBS collection facility in Delhi S. No.Designated DBS collection sites 1.LNJP (PPTCT) 2.Dr. Hedge war Hospital (PPTCT) 3.Sucheta Kriplani Hospital (PPTCT) 4.Mrs. GLM Hospital (PPTCT) 5.Hindu Rao Hospital (PPTCT) 6.DAD Dispensary, Ashok Vihar 7.Kasturba Hospital (PPTCT) 8.GTB Hospital (PPTCT) 9.SDN Hospital (PPTCT)

S. No.Designated DBS collection sites 10.Dr. B.S.A. Hospital (PPTCT) 11.BJRM Hospital 12.Maharishi Balmiki Hospital 13.AIIMS (PPTCT) 14.NDMC, Palika Maternity Home 15.Safdarjung Hospital(PPTCT) 16.RTRM Hospital (PPTCT) 17.GGS Hospital(PPTCT) 18.ASB Hospital 19.DDU Hospital (PPTCT)

New DBS Collection Facilities S. No.DBS collection sitesUnique DNA Infant code First 10 digits of codeYearS. No. at ICTC 001 onwards 1.LBS Hospital (PPTCT)DNADLEAS RML Hospital(PPTCT)DNADLNEW Bhagwan Mahaveer HospitalDNADLNWS Sanjay Gandhi Memorial HospitalDNADLNWS Satyavadi Raja Harischandra HospitalDNADLNWS Pt. Madan Mohan Malviya HospitalDNADLSOU Dada Dev Matrey Avum Shishu ChikitsalayaDNADLSWS National center for Disease ControlDNADL NOR

Strategy to Address the issues

1. ICTC/PPTCT Counselor should conduct proper counsleing of mother at the time of starting CPT at 6 weeks of age. ART Counselor should also check for adherence to CPT. 2.Monitor for CPT adherence - DBS Negative infants by ICTC Counselor and WB PCR reactive infants initaited ART by ART Counselor 3.Provide stock sufficient till the next imunization visit (10 weeks, 14 weeks). After 14 weeks provide CPT for 2 months and call mother every 2 months to receive supply. Inform mother when CPT will be discontinued. Ensuring Adherence to CPT

Infant feeding counseling should be done at 3 crtitical steps: a. Within 24 hours of birth of HIV exposed baby b. At 6 weeks of age at the time of EID c. At about 6 months of age (weaning in BF infants) Infant feeding Counselling- is it really happening ?

Day 1-3 : Ensure first DBS DNA PCR test at 6 weeks of age & Send sample to NCDC within 2 days (ICTC/PPTCT) Day 31/32: ART Centre call parents to start ART in confirmed HIV +ve infants within 7 days ie < =12 weeks of age Day-10 Ensure result of DBS test is collected within 7 days of test (ICTC/PPTCT) Day-17 Ensure infant reaches ARTC for Whole Blood Test (ICTC/PPTCT) Day -17/18: Ensure whole blood sample is collected and sent to NCDC on same day Day 23/24: ARTC to ensure that result of Whole blood test is collected on 4th day of submitting sample.

Improving Follow-up Swaziland Expérience (2010)-Makaria Reynolds et al 26 Initiated ART 12 LTFU 8 Died 4 Refused 50 HIV Infected Not coming For ART Contacted Active Follow up through Phone Calls Phone calls were effective Staff invested significant time in calling patients Many clients had incorrect information recorded Some infants had died 52

Getting Results to Families ICTC/ARTC Counselor must ensure following: Emphasize parent /caregivers the need of prompt follow up for diagnosis and treatment Record correct contact information of parent / caregiver Contact families for follow-up by phone call and if reqd. home visit, may also take help of ORWs. DSACS will provide travel allowance. Record in Register when result was provided to /parent caregiver. Add program indicators on % PCR results given to families and percent of PCR positive initiating treatment 53

New WHO PMTCT Protocol

PPTCT regimens for pregnant women with CD4 > 350 cells/mm 3

PPTCT Option-B, triple ARV prophylaxis for women ARV Prophylaxis and dosing AntepartumIntra-partumPost-partum TDF 300mg once daily 3TC 150mg twice daily EFV 600mg once daily Start at 14 weeks or as soon as possible thereafter Continue triple ARV prophylaxis Continue triple ARV prophylaxis until 1 week after all infant exposure to breast milk has ended * * When the Option-B regimen is stopped, stop EFV and continue with 7-day TDF+ 3TC tail

ARV prophylaxis for pregnant women presenting in active labour with no prior ARV prophylaxis Maternal StatusIntra-partumPost-partum Presenting in active labour, no prior ARV prophylaxis sd-NVP 200 mg once at onset of labour with AZT 300 mg + 3TC 150 mg at onset of labour and every 12 hours until delivery AZT 300 mg + 3TC 150 mg twice daily x 7 days

Protocol PPTCT-3: ARV prophylaxis for women presenting directly in labour

Infant Age NVP Daily Dose (10mg/ml formulation) Birth to 6 weeks Birth weight 2.0 to 2.5 kg 1ml once daily Birth weight>2.5 kg 1.5ml once daily >6 weeks to 6 months2ml once daily >6 months to 9 months3ml once daily >9 months to end of breast feeding4ml once daily Dosing schedule for infant NVP prophylaxis