HIV infection in children O.O.Bogomolets National Medical University department of pediatric infection diseases HIV infection in children Yevtushenko V.

Definitions HIV – human immunodeficiency virus. AIDS - acquired immune deficiency syndrome. Opportunistic infection - an infection by a microorganism that normally does not cause disease but becomes pathogenic when the body's immune system is impaired and unable to fight off infection.

Etiology There are two subtypes of HIV: HIV-1 (distributed worldwide) and HIV-2 (primarily confined to West Africa). HIV is a member of the genus Lentivirus, part of the family of Retroviridae

International Statistic Approximately 34 million people living with HIV in 2011 (WHO). 2.5 million people became newly infected in 2011. 1.7 million died of AIDS-related causes, including 230 000 children.

Adults and children estimated to be living with HIV, 2007

Routes of transmission Sexual contact (most frequent in adults). Via blood and blood products. Mother-to-child (about 90% of cases of HIV in children) - during pregnancy, during delivery, or through breast milk.

Mother-to-child transmission Commonest route of HIV spreading in children. The risk of transmission before or during birth is around 20% (without appropriate treatment) and in those who also breastfeed 35%.

Pathophysiology HIV produces cellular immune deficiency characterized by the depletion of helper T lymphocytes (CD4+ cells). The loss of CD4+ cells results in the development of opportunistic infections and neoplastic processes.

Timeline of untreated HIV-infection. From Wikipedia, based on an original from Pantaleo et al (1993).

Classification

Stages of HIV-infection Incubation period (2 wks – 6 mth); Primary infection (2-4 weeks); Latency (2 wks – 20 yrs); AIDS.

Primary infection Symptoms: Fever Fatigue Lymphadenopathy Pharyngitis Maculopapular rash Myalgia/arthralgia Anorexia Mucocutaneous ulceration Headache, retroorbital pain Neurologic symptoms (e.g., aseptic meningitis, radiculitis, myelitis, cranial nerve palsies)

WHO clinical staging of established HIV infection HIV-associated symptoms WHO clinical stage Asymptomatic 1 Mild symptoms 2 Advanced symptoms 3 Severe symptoms 4

WHO clinical staging for children Clinical stage 1 Asymptomatic Persistent generalized lymphadenopathy Clinical stage 2 Unexplained persistent hepatosplenomegaly Papular pruritic eruptions Fungal nail infection Angular cheilitis Lineal gingival erythema Extensive wart virus infection Extensive molluscum contagiosum Recurrent oral ulcerations Unexplained persistent parotid enlargement Herpes zoster Recurrent or chronic upper respiratory tract infections

WHO clinical staging for children (continuation) Clinical stage 3 Unexplainedi moderate malnutrition or wasting not adequately responding to standard therapy Unexplained persistent diarrhoea (14 days or more) Unexplained persistent fever (above 37.5°C intermittent or constant, for longer than one month) Persistent oral candidiasis (after first 6–8 weeks of life) Oral hairy leukoplakia Acute necrotizing ulcerative gingivitis or periodontitis Lymph node tuberculosis Pulmonary tuberculosis Severe recurrent bacterial pneumonia Symptomatic lymphoid interstitial pneumonitis Chronic HIV-associated lung disease including brochiectasis Unexplained anaemia (<8 g/dl), neutropaenia (<0.5 × 109 per litre) and or chronic thrombocytopaenia (<50 × 109 per litre)

WHO clinical staging for children (continuation) Clinical stage 4 Unexplained severe wasting Pneumocystis pneumonia Recurrent severe bacterial infections Chronic herpes simplex infection and Cytomegalovirus infection Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs) Extrapulmonary tuberculosis and Disseminated non-tuberculous mycobacterial infection Kaposi sarcoma Central nervous system toxoplasmosis Extrapulmonary cryptococcosis (including meningitis) Disseminated endemic mycosis (coccidiomycosis or histoplasmosis) Chronic cryptosporidiosis, isosporiasis Cerebral or B-cell non-Hodgkin lymphoma HIV encephalopathy and progressive multifocal leukoencephalopathy Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy

Stage of immunosupression associated with HIV WHO immunological staging (2006)   Stage of immunosupression associated with HIV Age-related CD4 values <11 months (% CD4+) 12-35 months 36-59 months >5 years (absolute number per mm3 or %CD4+) Absent or insignificant >35 >30 >25 >500 Mild 30-35 25-30 20-25 350-499 Moderate 15-20 200-349 Severe <25 <20 <15 <200 or <15%

Who should be tested for HIV?

HIV testing should be also routinely offered and recommended to the following patients: all patients presenting for healthcare where HIV, including primary HIV infection, enters the differential diagnosis (see table of indicator diseases and section on primary HIV infection) all patients diagnosed with a sexually transmitted infection all sexual partners of men and women known to be HIV positive all men who have disclosed sexual contact with other men all female sexual contacts of men who have sex with men all patients reporting a history of injecting drug use all men and women known to be from a country of high HIV prevalence (>1%*) all men and women who report sexual contact abroad or in the UK with individuals from countries of high HIV prevalence.

Clinical indicator diseases for pediatric HIV infection ENT Chronic parotitis; Recurrent and/or troublesome ear infections Oral Recurrent oral candidiasis; Poor dental hygiene Respiratory Pneumocystis Recurrent bacterial pneumonia; CMV pneumonitis; Lymphoid interstitial pneumonitis; Tuberculosis; Bronchiectasis Neurology HIV encephalopathy; Developmental delay; meningitis or encephalitis; Childhood stroke Dermatology Kaposi’s sarcoma Severe or recalcitrant dermatitis; Multidermatomal or recurrent herpes zoster; Recurrent fungal infections; Extensive warts or molluscum contagiosum Gastroenterology Wasting syndrome; Unexplained persistent hepatosplenomegaly; Persistent cryptosporidiosis; Hepatitis B infection; Hepatitis C infection Oncology Lymphoma; Kaposi’s sarcoma Haematology Any unexplained blood dyscrasia including: thrombocytopenia, neutropenia, lymphopenia Ophthalmology Cytomegalovirus retinitis; Any unexplained retinopathy Other Recurrent bacterial infections (e.g. meningitis, sepsis, osteomyelitis, pneumonia etc.); Pyrexia of unknown origin

Etiologic spectrum of opportunistic infections Bacterial infections Mycobacterium tuberculosis Mycobacterium avium complex Salmonella, Campylobacter, E. coli, Pseudomonas, Kledsiella. Staphylococcus, Streptococcus, Hemophillus pneumoniae Mycotic infections Candida, Aspergillus Cryptococcus neoformans, Pneumocystis carinii Histoplasma capsulatum, Coccidioides immitis Protozoan infection Toxoplasma gondii Cryptosporidium Isospora belli, Microsporidia Viral infection Herpes viruses: HSV, VZV, EBV, CMV, HHV-6, HHV-7, HHV-8, Papovaviruses 21

Kaposi's sarcoma

Herpes zoster 23

Candidiasis 24

Pneumocystis pneumonia

Which test to use?

HIV-infection examination Serological test for HIV-antibodies, Enzyme Immunoassay (EIA) Immunoblot analyses (Western blot) PCR (proviral DNA), Viral load Viral antigens (p24 with EIA) viral RNA detection For immunodeficiency stage - level of CD4 cells In case of positive EIA –make it twice, confirmation by Western blot. Also other methods are available: looking for viral antigens (p24 with EIA), viral RNA or whole virus detection-using PCR tests. Could be usefull in early stages of the disease when antibodies and not present yet and also in terminal stages when antibody level is to low. 27

Who should be treated?

Age related indication Indication for Anti Retroviral Treatment (ART) Clinical stage Level of CD4+ -Т-lymphocytes Age related indication <12 months >12 months IV Any Start ART III Immunosupression Start ART depend on grade of immusupression and opportunistic diseases II Start ART depend on grade of immusupression І

Goal of ART Virologic criteria: inhibition of viral replication (decreasing viral load) Immunologic criteria: restoring and preserving of immune response Clinical criteria: decline incidence of opportunistic infections Epidemiologic criteria: decreasing infection transmission Social criteria: life quality improvement, decreasing mortality rate, increasing life span

Which medication to use?

ARV drugs NRTI - Nucleoside Reverse Transcriptase Inhibitors (e.g. abacavir, tenofovir) NNRTI - Non-nucleoside Reverse Transcriptase Inhibitors (e.g. efavirenz, nevirapine) PI - Protease Inhibitors (e.g. lopinavir, sequinavir) EFI - Entry and Fusion Inhibitors (e.g. enfuvirtide) II - Integrase Inhibitors (e.g. raltegravir)

Treatment regimes in children 1 NNRTI + 2 NRTI or 1 PI + 2 NRTI Duration - lifelong

How to prevent HIV on individual level?

Prevention of sexual transmission Reduction in number of sexual partners Using barrier contraception Treatment of concurrent sexually transmitted diseases (STDs) Testing of self and partner for HIV and other STDs

Prevention of vertical transmission Maternal testing Effective control of maternal infection Prenatal antiviral therapy and treatment of mother and infant during labor, delivery, and the neonatal period Cesarean delivery Avoidance of breastfeeding

Postexposure prophylaxis (occupational) Percutaneous superficial injury or small volume splash: Known HIV status – antiretroviral prophylaxis Unknown HIV status or unknown source – prophylaxis not recommended Percutaneous deep injury or large volume splash: Known HIV status or HIV risk factor – antiretroviral prophylaxis