What to expect. Neonatal HIV management. Background 3/9/2017. ID Update in Children Background. The straightforward.

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1 What to expect Background Neonatal HIV management Prof. Nicolette du Plessis Paediatric Infectious Diseases University of Pretoria The straightforward The difficult The impossible In the absence of cart, HIV-related mortality peaks at 2-3 months of age in South Africa. Background Early HIV diagnosis and early cart early infant mortality by 76% HIV progression by 75% Bourne D, Thompson M, Brody L, et al. Emergence of a peak in early infant mortality due to HIV/AIDS in South Africa. AIDS 2009;23: Other benefits of early cart improved neurodevelopmental outcomes incidence of IRIS chronic otorrhoea preservation response infant vaccinations size of latent HIV reservoir early control of HIV viraemia EARLY (IU & IP) transmission in 100 HIV-infected infants 6 wk PCR Birth PCR In utero Intrapartum Postnatal HIV+ 70 HIV+ Laughton B, Cornell M, Grove D, et al. Early antiretroviral therapy improves neurodevelopmental outcomes in infants. AIDS 2012;26(13): Rabie H, Violari A, Duong T, et al. Early antiretroviral treatment reduces risk of bacille Calmette-Guerin immune reconstitution adenitis. Int J Tuberc Lung Dis 2011;15(9): Hainline C, Taliep R, Sorour G, et al. Early antiretroviral therapy reduces the incidence of otorrhea in a randomised study of early and deferred antiretroviral therapy: evidence from the Children with HIV Early Antiretroviral Therapy (CHER) Study. BMC Res Notes 2011;4:48 Penisieroso S, Cagigi A, Palma P, et al. Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children. Proc Natl Acad Sci USA 2009;106: Persaud D, Palumbo P, Ziemniak C, et al. Dynamics of the resting CD4(+) T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age. AIDS 2012;26(12): ID Update in Children

2 Problem Drug classes and names Term/Preterm considerations NRTI Abacavir (ABC) Not FDA approved <3 months Lamivudine (3TC) Didanosine (d4t) Not FDA approved <3 months, but generally well tolerated. May contribute to haematological toxicity, esp AZT+3TC Short-term use in neonatal cart when AZT is contraindicated or haematological toxicity has occurred Zidovudine (AZT) Standard paediatric AZT dose (240 mg/m 2 /dose twice daily): Haematological toxicity (particularly in premature neonates) Concurrent meds may cause BM suppression (e.g. ganciclovir, co-trimoxazole) Monotherapy with IV AZT as treatment in HIV-infected neonates is not recommended. NNRTI* Nevirapine (NVP) No 14-day lead-in dose Close monitoring for rash and liver function test abnormalities is required. Protease inhibitors (PI)** LPV/r (Kaletra) LPV and/or the inactive ingredients propylene glycol and ethanol: cardiac toxicity, elevated lactate level, neuromuscular toxicity, acute renal failure. PMA 42 weeks. Integrase inhibitor Raltegravir (RAL) Raltegravir oral suspension approved by the FDA in infants >4 weeks of age and >3 kg body weight. In SA, RAL suspension is not MCC registered. In the SA public sector, RAL has been restricted for use in third-line ART regimens. *Efavirenz, etravirine and rilpivirine are not approved for use in neonates and are not recommended **Nelfinavir not currently recommended for treatment in children <2 years of age. Atazanavir, darunavir, fosamprenavir, indinavir, full-dose ritonavir, saquinavir and tipranavir are not approved for use in neonates. How many drugs? 4 rather than 3 ARV drugs Could improve outcomes Young infants commonly have VL regimen potency virological suppression immunological recovery long-term treatment efficacy Available studies heterogeneous in nature difficult to compare directly 3 drug regimens have remained the standard-of-care in most guidelines Luzuriaga K, Mcmanus M, Mofenson L, et al. for the PACTG 356 Investigators. A trial of three antiretroviral regimens in HIV-1-infected children. N Engl J Med 2004;350: The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord. Early antiretroviral therapy in HIV-1-infected infants, : treatment response and duration of first-line regimens. AIDS 2011;25: Kekitiinwa A, Cook A, Nathoo K, et al. Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV (ARROW): a 5-year openlabel randomised factorial trial. Lancet 2013;381: ID Update in Children

3 Patient VW The straightforward February 2016 Term delivery, 2.5kg Maternal history FDC since October 2015 Syphilis (partially treated) Suspected tuberculosis ruled out Admitted to HCU after delivery Baby Started NVP Pen G for congenital syphilis (RPR titre 64) TB work up Progress patient VW TB ruled out mother and baby Continued with Pen G Maternal demise day 5 of life Birth HIV PCR Results Day 0 Day 6 Syphilis & HIV Primary syphilis facilitates both the transmission and the acquisition of HIV infection: causes transient increases in the viral load decreases in the CD4 cell count How these transient changes affect the overall course of the HIV disease or the risk for syphilis transmission remains unknown Clinical Infectious Diseases 2007; 44: ID Update in Children

4 Management Stopped NVP Complete Pen G Started cart on day 14 AZT + 3TC + Kaletra Switch ABC + 3TC + Kaletra (3/12) Last visit Caregivers: grandmother and aunt Compliance questionable at times 11mo: wt= 8.43kg Asymptomatic Pearls of wisdom Nothing is straightforward in HIV The difficult Patient PN October/November 2014 Late-preterm delivery 37 weeks, 2.09kg Mother: cart for 3 months Baby: Birth PCR Started NVP Discharged home ID Update in Children

5 Breastfeeding in the context of new recommendations for Prevention of Mother-to-Child Transmission of HIV in South Africa Preterm and low birth weight neonates MTCT by breastfeeding: HIV-infected women avoided BF 2012 BHIVA guidelines: permitted it (tight controlled) 1999: significantly post-natal HIV transmission if breastfeeding is exclusive 2010 SA PMTCT: supportive of more breastfeeding by HIV-infected women and their infants but stopped short of adopting breastfeeding as the program s default feeding choice Higher risk of perinatal HIV transmission Increased susceptibility to enteral acquisition of HIV Birth before adequate passive transfer of maternal neutralizing antibodies may reduce protection against postnatal HIV infection. Human milk feeding is critical to better outcomes in HIVexposed preterm neonates: May risk HIV transmission despite ARV prophylaxis 4 weeks Progress patient PN Compliment infant PEEP and maternal cart to further reduce transmission risk: Heat-treatment Donor breast milk ID Update in Children

6 Progress patient PN Currently 2y5m old; wt=10.1kg Previous meningitis ND delay (gross motor & speech)* Treatment failure *patient still on AZT Pearls of wisdom The impossible Transmitted resistance important consideration in infant HIV management Patient RM May/June 2016 Preterm ELBW, 24/40 580g Mother: 20yr, unbooked Writing Matric Believes boyfriend cheated and got HIV Want to study interior design Baby: Birth PCR ID Update in Children

7 Progress patient RM Monocytes and neutrophils Smaller pool Impaired ability to kill pathogens Lower cytokine production Limits T cell activation Reduces ability to fight intracellular bacteria and viruses IU inflammation risk for early onset sepsis Medical interventions ANC CS immunosuppressive (febrile responses, lymphocyte proliferation, cytokine production) Respiratory support (chronic inflammatory lung disease) C/S (infant colonization and establishment of microbiome) NNJ Renal impairment Deranged transaminases PDA Anemia with recurrent bloodtranfusions Suspected NEC MRSA Sepsis CMV disease Clinical and Experimental Immunology 140(2005): Frontiers in Neuroscience 7(2013) Progress patient RM cart Started at day g AZT + 3TC + NVP Pancytopenia/jaundice/anemia Progress patient RM Currently 8mo old; wt=3.65kg Stable, no new symptoms Changed day 79 (1.52kg) 35 weeks PMA ABC + 3TC + Kaletra Holgate et al. described the use of Kaletra -based cart in 8 HIV-infected premature neonates treated between 2006 and 2011 in Cape Town. The median gestational age at birth was 31 weeks (range 27-33), median age at initiation of LPV/r-based cart was 26.5 days (range 5-96), median corrected gestational age at cart initiation was 34.1 (range ) and median dose of LPV/r at time of measuring LPV levels was 287 mg/m 2 /dose or 23.1 mg/kg (range ; ). Pearls of wisdom Nothing is impossible in HIV Thank you ID Update in Children