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1. PAEDIATRIC HIV (ART, PMTCT&OI’s) Dr Majaliwa June 2021

2. PREVENTION OF MOTHER TO CHILD TRANSMISSION OF HIV (PMTCT) Introduction Worldwide, an estimated 34 million people are living with HIV infection; 3.4 million (10%) are younger than 15 years. Approximately 95% children younger than 15 years acquired HIV infection perinatally O ver 1 million HIV exposed (HIV-E) infants are born to HIV-infected women worldwide every year.

3. PREVENTION OF MOTHER TO CHILD TRANSMISSION OF HIV (PMTCT) Introduction The predominant route of HIV infection in children is MTCT, including intrauterine, intrapartum, and postnatal (breastfeeding) transmission. Maternal, obstetric, fetal, and infant factors contribute to the risk of MTCT Without interventions MTCT is 20 - 45%. The risk of transmission during pregnancy is 10-15 %, during labor and delivery 10-15 % and during breastfeeding 5-20 %.

4. Factors Enhancing HIV Transmission Viral factors Maternal Factors Obstetric and Fetal Factors Postnatal Factors

5. Viral Factors Viral load: (High maternal viral load and low CD4 count ) Virulence of transmitted strain: (HIV-1 is more virulent than HIV-2) Viral strain: (HIV-1 subtype C is more readily transmitted to newborns and infants) Viral resistance: (Pre-existing resistance to available ARV drugs increases the risk of HIV transmission)

6. Maternal Factors High maternal viral load and low CD4 count Placenta infection e.g. malaria Febrile illness Genital tract infection Behavioral factors e.g. unprotected sex Micronutrient and vitamin deficiency e.g. Vit A, Zinc & Selenium Antepartum hemorrhage Pre-mature rupture of fetal membranes Chorioamnionitis

7. Obstetric (Labor and Delivery) and Fetal Factors Prolonged labor Early rupture of membranes > 4hrs before delivery Invasive delivery procedures e.g. episiotomy, artificial rupture of membranes Complicated delivery Breech delivery Forceps delivery Chorioamnionitis Pre-term delivery and low birth weight Intrapartum hemorrhage Twin or multiple pregnancy First born with increased risk compared to subsequently delivered infant(s )

8. Postnatal (Breastfeeding) Factors High maternal viral load and low CD4 count Duration of breastfeeding Mixed feeding Oral disease in the baby e.g. thrush or mouth sores Poor maternal nutritional status Breast disease (abscess, nipple fissures, mastitis)

9. Interventions to Prevent MTCT Comprehensive approach to PMTCT Elements of PMTCT ARVs Obstetric practices Infant feeding practices

10. Measures to Reduce MTCT for HIV Infected (PMTCT) Provision of comprehensive antenatal care Provision of antiretroviral drugs to HIV infected pregnant women Provision of appropriate obstetric care Modification of infant feeding practices

11. Provision of Comprehensive Antenatal Care Infant feeding counseling Support for safer motherhood, including malaria and TB treatment Initiation of ART for HIV-infected women at RCH Linking the family to C&T and support groups Diagnosis and treatment of STIs For HIV positive pregnant women: Clinical evaluation and WHO staging Start Cotrimoxazole preventive therapy (CPT) Provide prompt and adequate treatment of OIs Counsel about how treatment reduces risk of transmission

12. PMTCT Interventions During Labor and Delivery Administer ARV therapy according to National Guidelines Use standard precautions to minimize infection transmission Minimize vaginal examinations Avoid artificial rupture of membranes Avoid unnecessary trauma during delivery e.g. episiotomy, instrumental delivery, routine episiotomy Minimize risk of postpartum hemorrhage

13. PMTCT Interventions After Delivery Avoid nasal suction unless life saving Clean all maternal secretions and blood from the newborn immediately Support infant feeding option chosen by mother If choice is to breastfeed, encourage exclusive breastfeeding for 6 months If replacement feeding is chosen, ensure AFASS is met and provide support Administer immunizations according to National Guidelines For non-breastfed infants, administer vitamin A 50,000IU at birth or on first encounter within 6 months Give ARV prophylaxis as soon as possible according to guidelines Discuss and refer for Family Planning services

14. HIV EXPOSED NEWBORN HIV exposed child is defined as any child born to or who is being breast-fed by an HIV infected mother.

15. T ransmission risks High-risk infants are Born to a mother with established HIV infections who has received <4 weeks of ART at the time of delivery Born to a mother with established HIV infection with viral load >1000 copies/ml in the 4 weeks before delivery Born to a mother with incident HIV infection during pregnancy or breast-feeding Identi fi ed for the first time during the postpartum period, with or without a negative HIV test prenatally.

16. Management of HIV exposed Child Prophylaxis for HIV exposed infants: Nevirapine (NVP) syrup should be given immediately after birth to all HIV exposed newborns for the first 6 weeks of life In high-risk infants, additional AZT syrup should be given for the first 6 weeks of life. -After 6 weeks continue with daily NVP alone up to 12 weeks of life. NB: Infant prophylaxis is most effective when given as soon as possible after birth ( within 6 to 12 hours) Infants identif i ed beyond the age of 4 weeks should not be given ARV prophylaxis

17. Management of HIV exposed Child Infant Nevirapine (NVP) dosing recommendations From Birth to 6 weeks NVP Premature/LBW <2000 g 2mg/kg once a day Birth weight 2000 – 2499 g 10mg once a day Birth weight 2500 g 15mg once a day

18. Management of HIV exposed Child Infant Zidovudine (AZT) dosing recommendations From Birth to 6 weeks NVP From Birth to 6 weeks AZT Premature/LBW <2000 g 4mg/kg twice a day Birth weight 2000 – 2499 g 10mg twice a day Birth weight 2500 g 15mg twice a day

19. Management of HIV exposed Child Do DBS (dried blood spot) collection at 6 weeks for DNA PCR (polymerase chain reaction) and again six weeks after complete cessation of breastfeeding From 6 weeks of age until HIV infection is excluded: give cotrimoxazole syrup 6 – 8 mg/kg Give immunizations according to standard for all newborns

20. Cotrimoxazole prophylaxis Give Co-trimoxazole 6-8mg/kg by PO once daily to the following: - All exposed infants until HIV infection is excluded from 4-6 weeks of age All children under 5 years old confirmed to be HIV infected regardless of symptoms or CD4

21. Management of HIV exposed Child Feeding: Women living with HIV are advised to exclusively breastfeed their newborn first 6 months of the life. R eplacement feeding with commercial infant formula can be used if it is acceptable, feasible, affordable, sustainable and safe (AFASS). Mother should choose from these two options (best if decision was already taken before delivery).

22. Antiretroviral therapy (ART) The principal aim of ART is to prevent morbidity and mortality in people with HIV and AIDS by durably suppressing viremia to undetectable levels, and thereby reconstituting and maintaining the immune capacity. ART has dramatically reduced HIV-associated morbidity and mortality and has transformed HIV disease into a chronic, manageable condition

23. Goals of ARV Therapy in Children Promote optimal growth and development Preserve, enhance, or reconstitute the immune system therefore reducing OIs Suppress HIV-replication and prevent disease suppression Reduce morbidity and mortality and improve quality of life Reduce HIV transmission

24. HIV life cycle 1 st step = attachment of the virus particle to receptors on the cell surface, attachment to CD4 +  T cells and other co-receptors present on CD4+ T cells: these are CXCR4 and CCR5. On the surface of the HIV virus this interaction is mediated by glycoprotein 120 (which forms a trimeric envelope complex gp 160, together with gp 41).  Conformational change in gp120 allows for secondary interaction with CCR5.  The distal tips of gp41 are inserted into the cellular membrane

25. HIV life cycle 2 nd step = Fusion = gp41 undergoes significant conformational change; folding in half and forming coiled-coils. This process pulls the viral and cellular membranes together, fusing them. This results into endocytosis and therefore an entrance into host cells. 3 rd step = Uncoating = This is the removal of protein envelopes to expose the viral genome

26. HIV life cycle 4 th step = Reverse transcription = this is mediated by the enzyme  reverse transcriptase which converts the positive-sense single-stranded RNA genome from the attached viral proteins and copies it into a complementary DNA (cDNA) molecule. This is now ready to incorporated into the host genome machinery. 5 th step = Integration = incorporation of viral DNA into host DNA, Its carried out by viral enzyme called  integrase

27. HIV life cycle 6 th step = Transcription = When the host cell receives a signal to become active, the provirus uses a host enzyme called RNA polymerase/Transcriptase to create copies of the HIV genomic material, as well as shorter strands of RNA called messenger RNA (mRNA). The mRNA is used as a blueprint to make long chains of HIV proteins. 7 th step = Translation = mRNAs are exported from the nucleus into the cytoplasm, where they are translated into the regulatory proteins (which encourages new virus production)

28. HIV life cycle 8 th step =Assembly =An HIV enzyme called protease cuts the long chains of HIV proteins into smaller individual proteins. As the smaller HIV proteins come together with copies of HIV's RNA genetic material, a new virus particle is assembled. 9 th step = Budding =The newly assembled virus pushes out ("buds") from the host cell. During budding, the new virus steals part of the cell's outer envelope. This envelope, which acts as a covering, is studded with protein/sugar combinations called HIV glycoproteins. These HIV glycoproteins are necessary for the virus to bind CD4 and co-receptors. The new copies of HIV can now move on to infect other cells.

29. Types of Antiretroviral Drugs (ART) The recommended ART drugs in Tz guidelines fall into five main categories: a) Nucleotide reverse transcriptase inhibitors (NtRTIs) b) Nucleoside reverse transcriptase inhibitors (NRTIs) c) Non-nucleoside reverse transcriptase inhibitors (NNRTIs) d) Protease inhibitors (Pls) e) Integrase strand transfer inhibitors (INSTI)/ Integrase inhibitors Other antiretroviral drugs used elsewhere include: f) Fusion inhibitors e.g. Enfuvirtide (ENF) g) Chemokine receptor inhibitors/ CCR5 inhibitors e.g. Maraviroc

30. Nucleoside reverse transcriptase inhibitors (NRTIs) This group of drugs is the mainstay of antiretroviral therapy in the country. The primary mechanism of action of this class is inhibition of viral RNA-dependent DNA polymerase (reverse transcriptase) enzyme by direct incorporation into the viral DNA Available drugs in Tanzania include Zidovudine (AZT) Lamivudine (3TC) Emtricitabine (FTC) Abacavir (ABC)

31. Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) R esemble nucleoside analogues (NRTI’s). The mechanism of action involves selectively inhibiting viral reverse transcriptase enzyme. It is converted by cellular enzymes to the diphosphate, which is the inhibitor of HIV reverse transcriptase. Available drugs in Tanzania include Tenofovir disoproxil fumarate (TDF) Tenofovir alafenamide (TAF)

32. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) NNRTIs act by disrupting the reverse transcription of viral RNA into DNA that is then incorporated in the cell’s nucleus U nlike the NRTIs, they are not directly incorporated into the viral DNA; instead they inhibit replication directly by binding to the enzyme reverse transcriptase They bind to HIV reverse transcriptase at a site adjacent to the active site , inducing a conformational change that results in enzyme inhibition a) 1st generation NNRTIs Nevirapine (NVP) Efavirenz (EFV) - Resistance to these drugs develops rapidly, especially when used alone b) 2nd generation NNRTIs Etravirine (ETR) -Has b etter resistance profile and a higher genetic barrier to the development of resistance.

33. Protease Inhibitors (PIs) PIs competitively inhibit the HIV protease enzyme whose activity is critical for the terminal maturation of infectious virions. This inhibition prevents the maturation of virions capable of infecting other cells. These drugs are usually boosted with a small dose of ritonavir (also a PI) to enhance therapeutic drug concentration and hence increase efficacy of the drug, reduce food restrictions, dose and frequency of administration. Boosted PIs have a high genetic barrier to resistance. The newer PIs such as Darunavir have an advantage of having a better resistance profile, a higher genetic barrier to the development of resistance and a broad spectrum of activity against PI resistant viruses. Are effective after failure of a first generation PI-based regimen due to resistance 1st generation PIs include Atazanavir (ATV) and Lopinavir (LPV). -Ritonavir (Used as a booster with other PIs) 2nd generation PIs include Darunavir (DRV)

34. Integrase Strand Transfer Inhibitors (INSTI) (Integrase inhibitors) This group of drugs acts by inhibiting integrase enzyme which facilitates integration of viral pro-DNA into the host cell Drugs under this class that are recommended in Tz include: Dolutegravir (DTG) Raltegravir (RAL)

35. Entry inhibitors Include CCR5 Antagonist e.g. Maraviroc Blocks the CCR5 receptor on the T-Cell to prevent viral attachment. It selectively binds to human CCR5 receptor on the cell membrane, thus blocking the interaction of the HIV gp120 and the CCR5 receptor for CCR5-tropic HIV. However, it does not block viral entry of CXCR4 tropic HIV or HIV that uses both CCR5 and CXCR4 for cell entry. Prior to the prescription of Maraviroc, viral tropism testing must be performed to confirm that the patient’s virus only uses the CCR5 co-receptor.

36. Fusion inhibitors Disrupt binding, fusion, and entry of HIV virions into a human cell. B inds to gp41 prevents conformational change and disrupts membrane attachment and fusion. Example: Enfuvirtide (Injectable ARTs…Subcutaneously)

37. Initiating Antiretroviral therapy (ART)

38. Antiretroviral therapy (ART)

39. Antiretroviral therapy (ART)

40. Antiretroviral therapy (ART)

41. Antiretroviral therapy (ART)

42. Antiretroviral therapy (ART)

43. Changing ART in children and adolescents U15 Reasons include Drug toxicity and Treatment Failure DRUG TOXICITY The principles for changing ARVs and the managing drug toxicity in children and adolescents are similar to those applied to adults. When toxicity is related to an identifiable drug in the regimen, the offending drug should be replaced with another drug that does not have the same side effect

44. Changing ART in children and adolescents TREATMENT FAILURE 1. Virological treatment failure Viral load is the most reliable method to detect early treatment failure. Virological treatment failure is recognized if the child or the adolescent is adherent to the current ART regimen, for six months or more and has two consecutive viral load measurements over 1000 copies/ml at three months apart.

45. Changing ART in children and adolescents 2. Immunological treatment failure If adherence is good, immunological criteria indicating that a change to second-line therapy is warranted where/when HVL test is not available includes the following:

46. 3. Clinical Rx failure: Changing ART Clinical treatment failure is a new or recurrent clinical event indicating advanced or severe immunodeficiency (WHO clinical stage 3 and 4 with exception TB) after six months of effective treatment.

47. ARV TOXICITY

48. ARV Toxicities

49. ARV Toxicities

50. WHO Clinical staging of HIV

51. WHO Clinical staging of HIV

52. Opportunistic Infections Definition : Infections caused by organisms that would not cause disease in a child with a well-functioning immune system Infections that occur more frequently and severe in people with weakened immune system

53. Mgt of OIs

54. Mgt of OIs

55. Mgt of OIs

56. Mgt of OIs

57. Mgt of OIs

58. Mgt of OIs

59. Mgt of OIs

60. Mgt of OIs

61. Mgt of OIs

62. Prophylactic Treatment of Common OIs in HIV/AIDS

63. Prophylactic Treatment of Common OIs in HIV/AIDS

64. TB Preventive therapy

65. END