1. 1 Natural History of HIV Infection in Children HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. 2 Learning Objectives By the end of this session, participants should be able to: Describe the characteristic, structure of HIV Describe the and transmission route of HIV Describe the HIV life cycle Explain HIV pathogenesis Describe the natural history of HIV disease progression in children

3. 3 Basic Concepts

4. 4 HIV Virology HIV: Human Immunodeficiency Virus HIV is an RNA virus HIV is a “ retrovirus ”: replication occurs from RNA to DNA using the enzyme “ reverse transcriptase ” the DNA created is then integrated into the host cell genome (T lymphocyte) further HIV virus is then produced using this DNA complex Two types: HIV1 and HIV2

5. 5 HIV Virion HIV virion taken with electronic microscope p24 Source of pictures: wikipedia

6. 6 CD4 Cell – Definition CD4 cell is one type of T-Lymphocyte HIV binds with receptors on the CD4 cell to enter and infect the cell After infection, the number of CD4 cells gradually declines over time

7. 7 CD4 Count - Definition The CD4 cell count is the number of CD4 cells in a cubic millimeter of blood The CD4 cell count indicates extent of HIV-induced immune damage

8. 8 Viral Load – Definition The viral load is the amount of HIV in the blood The level of HIV in the blood indicates the magnitude of HIV replication and rate of destruction of CD4 cells The viral load test measures the amount of HIV RNA in the plasma

9. 9 How is HIV Transmitted? Blood/Parentally IV drug use Occupational exposure (needle sticks) Unprotected sexual contact with infected partner/s Heterosexual or homosexual Perinatally (mother to child) During pregnancy and labor Through breastfeeding

10. 10 Transmission Activity

11. 11 Estimated HIV Risk for a Single Exposure to HIV Source Blood Transfusion Mother to child IDU needle sharing Occupational needle stick Receptive anal sex Receptive vaginal sex Insertive anal sex Insertive vaginal sex Receptive oral sex Insertive oral sex (CDC, MMWR, 2005) 90% 25-35% 0.67% 0.3% 0.5% 0.1% 0.065% 0.05% 0.01% 0.005%

12. 12 What Characterizes HIV Transmission? HIV is spread only through exposure to certain bodily fluids: Blood Semen Vaginal secretions Breast milk In order for HIV to be spread, infected fluids need to be exposed to: a mucous membrane (vagina, eye, mouth) broken skin blood (needle stick, infusion) HIV is difficult to transmit even through risky behaviors

13. 13 How is HIV not Spread? HIV is NOT transmitted through casual contact such as: Hugging or kissing Coughing or sneezing Sharing utensils, cups or bowls Sharing toilets Swimming pools Insect bites

14. 14 How Does HIV Infect the Human Cell?

15. 15 1 2 3 4 5 6 7 Reverse tran- scriptase HIV RNA

16. 16 HIV Pathogenesis

17. 17 What Happens after HIV Virus Enters the Bloodstream? Virus: enters dendritic cells and macrophage and is carried to regional lymph nodes, and: infects CD4 cells produces virions, which in turn infect other CD4 cells also goes into other body compartments Virus causes deaths of massive number of memory CD4 cells (impairing ability to fight infections later on)

18. 18 Pathogenesis of HIV-infection: Compartments Dendritic cells, macrophage

19. 19 Pathogenesis of HIV-infection (1) Rapid HIV virus production results in: depletion of CD4 lymphocytes and a weakened immune system HIV may also lay dormant in the host cell after integration into host DNA (the reservoir) These viruses are not affected by ARVs

20. 20 Pathogenesis of HIV-infection (2) Two main types of injury caused by HIV Direct injury encephalopathy peripheral neuropathy cardiomyopathy nephropathy Indirect injury Immuno-suppression: opportunistic infections malignancies Immuno-dysregulation: Autoimmune: thyroid dysfunction, psoriasis

21. 21 Natural History of HIV Infection in Children

22. 22 Natural History Untreated HIV infection

23. 23 Bimodal Progression of AIDS and Deaths in HIV-infected Children 1 year5 year Deaths10 - 35%40 – 50% AIDS25 – 30%40 – 43% Immune suppression10 -20%>50% AIDS Deaths

24. 24 Patterns of HIV Disease Progression in Children (1) 10-25% of infants develop profound immunosuppression and AIDS usually within the first 2 years of life Rapid progressors About 75% children have a slower progression to AIDS with a mean time of 5-6 years Slow progressors Some children remain asymptomatic for a long time without ART Long-term non- progressors

25. 25 Patterns of HIV Disease Progression in Children (2) Long-term non-progressors: Prevalence: about 2%, similar to adults Definition: Age ≥10 Never have CDC category B/C disease (=WHO stage 3/4) CD4 > 25% Never been on ARV except AZT Source: Warszawski et al. Clinical Infectious Diseases 2007; 45:785–94

26. 26 What are Risk Factors for Disease Progression in Children? In utero or perinatal transmission High viral load and advanced disease in mother Stage III/IV conditions, esp. encephalopathy Low CD4 cells/percentage High plasma viral load

27. 27 Risk Factors for Disease Progression in Children NOTE: Normal CD4 or low VL does not have predictive value in young children < 2, i.e. those with normal CD4 or low VL can still develop severe disease and die. This is the basis for treating all HIV-infected children under 2 y.o regardless of clinical and immunological stage

28. 28 Common OIs/Conditions in Vietnamese Children Respiratory infections, including PCP Tuberculosis Oral candidiasis Diarrhea PPE/dermatitis Herpes varicella zoster Otitis media Hepatosplenomegaly Failure to thrive  Infants may be symptomatic in the 1 st year, after that, the majority of them tend to be: asymptomatic or only with mild symptoms  Below is the list of common OIs/conditions:

29. 29 Plasma Viremia in Vertically HIV-infected Infants Time Viral Load (Copies/ ml Birth – 6 months ≥10 6 18 months 10 5 -10 5.5 5 years≤ 10 5 Copies/ml Viral load 6 months Viremia is extremely high in the first 6 months, then gradually declines

30. 30 CD4 Percentage/Count: Which to Use? AgeParameter to use Comment < 5 y.o CD4 percentage (%) is preferred  the absolute CD4 count is generally not used due to: high inter-measurement variability and age-related decline  CD4% is more constant ≥ 5 y.oCD4 count  the CD4 count pattern is similar to that of adults in this age group

31. 31 Role of CD4 Percentage/Count CD4 is extremely useful for: when to start prophylactic medications when to start ARV treatment monitoring response to treatment predicting risk for OI’s

32. 32 Natural History of HIV infection treated with ART

33. 33 HIV infection treated with ART Combination ART is associated with improvement in: virologic, immunologic, and clinical health for HIV-infected adults and children

34. 34 Brady MT, Oleske JM, Williams PL, et al. Declines in mortality rates and changes in causes of death in HIV-1- infected children during the HAART era. J Acquir Immune Defic Syndr 2010; 53:86. 7.2 0.8 Between 1994 and 2000, the mortality rate decreased 7.2 to 0.8 deaths per 100 person-years; mortality rate was inversely associated with HAART treatment Declines in mortality rates in HIV infected children during the HAART era

35. 35 Ciaranello AL, Chang Y, Margulis AV, et al. Effectiveness of pediatric antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis. Clin Infect Dis 2009; 49:1915. 70 % of children attained virologic suppressionincrease of 13.7 percent in CD4 percentage Effectiveness of pediatric antiretroviral therapy in resource-limited settings

36. 36 Key Points After infecting CD4 cells, HIV multiplies rapidly, resulting in: depletion of CD4 lymphocytes weakened immune system 3 patterns of HIV disease progression in children are : Rapid progressors Slow progressors Long-term non-progressors In infants infected perinatally, viremia is extremely high in the first 6 months, then gradually declines

37. 37 CD4 count is the best way to: Determine degree of immune suppression Make treatment decisions Monitor for treatment response Combination ART is associated with improvement in: Virologic Immunologic Clinical health for HIV-infected children. Key Points

38. 38 Thank you! Questions?