12. PEDIATRIC HIV....................pptx

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1. Pediatric HIV AIDS and opportunistic infections By- Dr Ermias ( pediatrician ) 2024 GC

2. EPIDEMIOLOGY In 2022, the WHO estimated that 2.6 million children younger than 19 years of age worldwide were living with HIV-1 infection, with 270,000 new infections annually. Nearly 90% of these children 0-9 years of age live in sub-Saharan Africa. From 2010-2022, there has been a 58% reduction in infection in children 0-9 years of age, Over the same period there has been a 46% reduction in new cases 10-19 years of age.

3. Epidemiology Notably, there were still 100,000 deaths worldwide of children <19 years of age with HIV in 2020. As of 2022, an estimated 13.9 million children have been orphaned by AIDS (i.e., having at least one parent die from AIDS). Children experience more rapid disease progression than adults, with up to half of untreated children dying within the first 2 years of life.

4. Epidemiology in Ethiopia In 2020, there were an estimated 622,326 People Living with HIV (PLHIV) in Ethiopia of whom 7% (44,138) were aged less than 15 years old, 72,561(17%) were young people ( 15-24) According to the EDHS done in 2016, the national adult (15-49) HIV prevalence is 0.96 %; the urban prevalence was 2.9%, which is seven times higher than that of the rural (0.4%). National HIV Related Estimates and Projections (2020), also shows that the HIV prevalence varies from region to region ranging from less than 0.15% in Ethiopia Somali to 4.13% in Gambella .

5. ART coverage adults (age >15) has reached 80.5 % coverage for children remains low (40.03%) ( age <15) . According to EPHI 2020/21 report, the national viral load testing coverage was 74.5%, with a suppression rate of 95%.

6. ETIOLOGY HIV-1 and HIV-2 are Retroviridae , Lentivirus genus. HIV-1 common causes of human disease HIV-2 differs from HIV1 in its accessory genes Less virulent, less progressive causes infection in several monkey species Common in western Africa

7. Transmission sexual contact parenteral exposure to blood vertical transmission from pregnant individual to child The primary route of infection in the pediatric population (<15 years) is vertical transmission .

8. Rates of vertical transmission of HIV have varied in high- and low -resource countries; US and Europe have documented transmission rates in untreated pregnant individuals of 12–30% , Africa and Haiti have been higher (25–52%), likely because of more advanced disease and the presence of co-infections. Perinatal treatment of HIV-infected pregnant persons with antiretroviral drugs has dramatically decreased the transmission rate to <2% .

9. Vertical transmission of HIV can occur B efore delivery (intrauterine ) Accounts 20 %-30% positive viral culture or PCR within the first week of life. early onset of symptoms and rapid progression to AIDS

10. D uring delivery (intrapartum) majority of transmissions likely occur (70-80 % ) do not demonstrate detectable virus until after 1 week of age mechanism of transmission appears to be mucosal exposure to infected blood and cervicovaginal secretions in the birth canal intrauterine contractions during active labor/delivery may also increase the risk of late microtransfusions

11. A fter delivery (postpartum through breastfeeding ) the least-common route of vertical transmission in resource-rich nations but is responsible for as much as 40% of perinatal infections in resource-limited countries The risk of an infant acquiring HIV through breastfeeding is 15–20% over 2 years without parental cART or infant prophylaxis. 29–53% in those who acquire HIV postnatally

12. WHO recommends that in resource-limited countries where other diseases (diarrhea, pneumonia, malnutrition) substantially contribute to a high infant mortality rate, the benefit of breastfeeding outweighs the risk for HIV transmission, HIV-infected persons in developing countries should exclusively breastfeed their infants for at least the first 6 months of life, ideally with parent on suppressive ART Recently, infant feeding recommendations for breastfeeding persons with HIV in resource-rich settings have evolved as well, given that the risk of transmission via breastfeeding from an individual on suppressive cART is very low (<1%)

13. Other routes of transmission to children Transfusions of infected blood sexual transmission is infrequent, but a small number of cases resulting from sexual abuse have been reported. Sexual contact is the major route of transmission in the adolescent population (≥13 years), accounting for the vast majority of cases. Infection via shared needles with IV drug use is seen in this population, but much less frequently. premasticated feedings

14. Risk of Transmission depends pregnant parent viral load at delivery (the additional benefit of CS is negligible if the viral load is <1,000 copies/Ml) It should be noted that rarely (≤0.1%), transmission may occur with viral loads <50 copies/mL preterm delivery (<34 weeks’ gestation ) low antenatal CD4 count.

15. PATHOGENESIS HIV infection affects most of the immune system and disrupts its homeostasis When HIV replication reaches a threshold (usually within 3-6 weeks from the time of infection), a burst of plasma viremia occurs. This intense viremia causes acute HIV infection , which can present similar to influenza or mononucleosis (fever, rash, pharyngitis, lymphadenopathy, malaise, arthralgia, fatigue, cytopenias , elevated liver enzymes) in 50–70% of infected adolescents and adults

16. With establishment of a cellular and humoral immune response within 2-4 months, the viral load in the blood declines substantially, and patients enter a phase characterized by a lack of symptoms and a return of CD4 cells to only moderately decreased levels. untreated infants with vertically acquired HIV who have viral loads that are much higher, resulting in faster CD4 count declines and earlier onset of significant immunodeficiency.

17. Three distinct patterns of disease are described in children R apid progression Approximately 15–25% of HIV-infected newborns onset of AIDS and symptoms during the first few months of life median survival time of 6-9 months if untreated. In resource-limited settings, the majority of HIV-infected newborns will have this rapidly progressing disease course.

18. Most children in this group have detectable virus in the plasma in the first 48 hours of life. This early evidence of viral presence suggests that the newborn was infected in utero. The viral load rapidly increases, peaking by 2-3 months of age (median: 750,000 copies/mL) and staying high for at least the first 2 years of life

19. Slower progression 60 to 80% of perinatally infected newborns in highresource settings present with a of disease , median survival time of 6 years have a negative PCR result in the first week of life and are therefore considered to be infected intrapartum . the viral load rapidly increases, peaking by 2-3 months of age (median: 100,000 copies/mL) and then slowly declines over a period of 24 months.

20. Long-term survivors or long-term nonprogressors occurs in <5% of perinatally infected children have minimal or no progression of disease with relatively normal CD4 counts and very low viral loads for longer than 8 years. Mechanisms for the delay in disease progression include effective humoral immunity and/or CTL responses , host genetic factors (e.g., human leukocyte antigen profile ) infection with an attenuated (defective-gene) virus.

21. Elite survivors or elite suppressors no detectable virus in the blood and may reflect different or greater mechanisms of protection from disease progression . both groups warrant long-term close follow-up because later in their course they may begin to progress with their disease

22. Absolute CD4 cell depletion may be less dramatic because infants normally have a relative lymphocytosis. A value of 750 CD4 cells/ μL in children younger than 1 year of age is indicative of severe CD4 depletion and is comparable to <200 CD4 cells/ μL in adults. CNS involvement is more common in pediatric patients than in adults. Macrophages and microglia play an important role in HIV neuropathogenesis , and data show that astrocytes may also be involved.

23. Diagnostic approaches Voluntary counselling and Testing (VCT) Provider initiated HIV testing and counseling (PITC) All forms of testing should adhere to the five C’s: consent, confidentiality, counselling, correct test results and connections to care and Tx and prevention services

24. Tests for children All infants born to HIV-infected individuals test antibody-positive at birth because of passive transfer of HIV antibody across the placenta Most uninfected infants without ongoing exposure (i.e., who are not breastfed) lose antibodies against HIV between 6 and 18 months of age and are known as seroreverters .

25. < 18 months virological testing DNA PCR at six weeks of age or at the earliest opportunity thereafter. > 18 months serological testing demonstration of IgG antibody to HIV.

26. Staging

27. WHO staging

28. Advanced HIV Disease

29. When to Start ART in Children

30. The ARV drugs The following principles form the basis for cART 1. Uninterrupted HIV replication causes destruction of the immune system and progression to AIDS. 2 . The magnitude of the viral load predicts the rate of disease progression , and the CD4 cell count reflects the risk of opportunistic infections and HIV infection complications. 3 . cART , which includes at least three drugs with at least two different mechanisms of action, should be the initial treatment . 4 . The goal of sustainable suppression of HIV replication is best achieved by the simultaneous initiation of combinations of antiretroviral drugs to which the patient has not been exposed previously and to which the patient’s virus does not have cross resistance. 5 . Drug-related interactions and toxicities should be minimized as much as possible. 6 . Adherence to the complex drug regimens is crucial for a successful outcome

31. Reverse Transcriptase Inhibitors prevent the HIV enzyme from converting single-stranded HIV RNA into HIV DNA : a.Nucleoside /nucleotide RT inhibitors (NRTIs) eg . Zidovudine , lamivudine and emtricitabine , abacavir , emtricitabine , tenofovir b. Non -nucleoside RT inhibitors ( NNRTIs ) Efavirenz,Etravirine,Nevirapine

32. Protease Inhibitors Block protease enzyme which prevents new virus particles assembly Atazanavir, indinavir , lopinavir /ritonavir , ritonavir

33. Integrase Inhibitors Block the HIV enzyme integrase , which the virus uses to integrate its genetic material into the host cell DNA Raltegravir , Dolutagravir

34. Fusion Inhibitors Entry/Co-receptor inhibitors

35. What ART regimen to start with (first-line ART)

36. Immune Reconstitution Inflammatory Syndrome (IRIS) spectrum of clinical signs and symptoms thought to be associated with immune recovery brought about by a response to ART. In patients with advanced HIV disease the risk of IRIS is high, it even goes higher when CD4 count gets below 50 cells/mm3. IRIS may present in two different ways : paradoxical IRIS , when an opportunistic infection or tumor diagnosed before ART initially responds to treatment but then deteriorates after ART starts unmasking IRIS , in which initiating ART triggers disease that is not clinically apparent before ART.

37. The most serious and life-threatening forms of paradoxical IRIS are due to TB, Cryptococcus, Kaposi’s sarcoma and hepatitis. BCG vaccine– associated IRIS (localized and systemic) may occur in some HIV infected infants. IRIS is generally self-limiting, and interruption of ART is rarely indicated

38. Opportunistic infections The most common serious infections in HIV-infected children are bacteremia , sepsis, and bacterial pneumonia, accounting for more than 50% of infections in these patients. Meningitis , urinary tract infections, deep-seated abscesses, and bone/joint infections occur less frequently. Milder recurrent infections, such as otitis media, sinusitis , and skin and soft tissue infections, are very common and may be chronic with atypical presentations

39. Co- trimoxazole preventive therapy (CPT)

40. Tuberculosis TB is the most frequent life-threatening OI and a leading cause of death among HIV infected people. accounting for 30% of the AIDS-related deaths reported in 2019. TB increases HIV replication through the process of immune activation leading to increased viral load and this results in a more rapid progression of HIV disease . On the other hand, HIV increases susceptibility to be infected with M. Tuberculosis, the risk of progression to TB disease and the incidence and prevalence of TB. The lifetime risk of HIV positive individuals to develop TB is 50%, the annual risk is 10%. The WHO recent estimation indicates the risk of developing active TB disease is 18 times higher in PLHIV.

41. Pneumonia bacteremia accompanying pneumonia is increased compared with individuals who are not HIV infected. Bacterial pneumonia occurs during the whole spectrum of HIV disease but tends to be more severe and recurrent as the CD4 counts drops significantly. If not treated promptly, extra pulmonary complications like empyema, meningitis, pericarditis, hepatitis and arthritis can follow. Streptococcus pneumonia and Hemophilus influenzae are the most common etiologies of community acquired pneumonia

42. Pneumocystis pneumonia caused by Pneumocystis jiroveci classified as a fungus but also shares biologic characteristics with protozoa . It commonly occurs when patients have significant immune suppression ( CD4 percentage < 14 %).

43. insidious onset of low grade fever, dry cough, and dyspnea exacerbated by exertion. P/E reveals fever, tachypnea, tachycardia and scattered rales in the lungs, but examination of the lungs can appear normal in some patients. In children highest incidence is seen between 2-6 months of age and is characterized by abrupt onset of fever, tachypnea, dyspnea and cyanosis

44. Presumptive diagnosis of PCP is based on clinical judgement and typical chest X-ray findings revealing a perihilar interstitial infiltration with tendency to spread outwards . Note that the chest X-ray can be normal in 20% of patients . Definitive diagnosis of PCP is based on demonstration of the organism from an induced sputum sample using special stains like Giemsa or methylamine silver stains

45. Use Trimethoprim 15-25 mg/kg, three or four times daily for 21 days . In severely ill patients and extensive chest X-ray findings add prednisolone - 2mg/kg per day for the first 7 - 10 days followed by a tapering regimen for the next 10 - 14 days.

46. Central Nervous System The incidence of CNS involvement in perinatally infected children is as high as 50–90% in resource-limited settings. Manifestations may range from subtle developmental delay to progressive encephalopathy with loss or plateau of developmental milestones, cognitive deterioration, impaired brain growth resulting in acquired microcephaly , and symmetric motor dysfunction. Encephalopathy may be the initial manifestation of the disease or may present much later when severe immune suppression occurs .

47. Older children may exhibit behavioral problems and learning disabilities. Associated abnormalities identified by neuroimaging techniques include cerebral atrophy in up to 85% of children with neurologic symptoms, increased ventricular size, basal ganglia calcifications, and, less frequently, leukomalacia.

48. Focal neurologic signs and seizures are unusual and may imply a comorbid pathologic process such as a CNS tumor, opportunistic infection, or stroke. CNS lymphoma may present with new-onset focal neurologic findings, headache, seizures, and mental status changes .

49. Respiratory Tract LIP is the most common chronic lower respiratory tract abnormality occurred in approximately 25% of HIV-infected children, Several studies suggest that LIP is a lymphoproliferative response to a primary EBV infection in the setting of HIV infection . leading to progressive alveolar capillary block over months to years. There is an insidious onset of tachypnea, cough, and mild to moderate hypoxemia with normal auscultatory findings or minimal rales.

50. Progressive disease presents with symptomatic hypoxemia, accompanied by digital clubbing. Diffuse bilateral reticulonodular infiltrate on X-ray with mediastinal lymphadenopathy. It is important to exclude tuberculosis and other infectious etiology It is also associated with a slower immunologic decline Bronchodilators may be helpful in mild to moderate disease. Corticosteroids are usually reserved for children with significant hypoxemia and symptoms of pulmonary insufficiency

51. Cardiovascular System LVH, left vertricular dilation, reduced left ventricular fractional shortening, and/ or heart failure occurred in 18–39% of HIV-infected children in the pre- cART era ; lower nadir CD4 percentage and a higher viral load were associated with lower cardiac function

52. Gastrointestinal and Hepatobiliary Tract Candidiasis,oral or esophageal ulcer (CMV) AIDS enteropathy, a syndrome of malabsorption with partial villous atrophy chronic or recurrent diarrhea with malabsorption, abdominal pain, dysphagia , and failure to thrive

53. Renal Disease Nephropathy is an unusual presenting symptom of HIV infection, more commonly occurring in older symptomatic children Nephrotic syndrome is the most common manifestation of pediatric renal disease

54. Skin Manifestations Seborrheic dermatitis or eczema that is severe and unresponsive to treatment may be an early nonspecific sign of HIV infection . Recurrent or chronic episodes of HSV, herpes zoster, molluscum contagiosum , flat warts, anogenital warts, and candidal infections are common and may be difficult to control.

55. Hematologic and Malignant Diseases Anemia occurs in 20–70% of HIV-infected children The anemia may be a result of chronic infection , poor nutrition, autoimmune factors, virus-associated conditions , or the adverse effect of drugs (zidovudine). Leukopenia occurs in almost 30% of untreated HIV-infected children , and neutropenia often occurs. Multiple drugs used for treatment or prophylaxis for opportunistic infections, such as TMP-SMX, and ganciclovir, or zidovudine . Thrombocytopenia has been reported in 10–20% of patients. The etiology may be immunologic (i.e., circulating immune complexes or antiplatelet antibodies) or, less commonly, from drug toxicity, or idiopathic.

56. Malignant diseases have been reported infrequently in HIV-infected children, representing only 2% of AIDS-defining illnesses. NHL (including Burkitt lymphoma), primary CNS lymphoma, and leiomyosarcoma are the most commonly reported neoplasms among HIV-infected children