Pediatric HIV and AIDS

• Human Immunodeficiency Virus (HIV) is a lentivirus that targets and alters the immune system, increasing the risk and impact of other infections and diseases.
• Without treatment, it might progress to an advanced disease stage known as Acquired Immune Deficiency Syndrome (AIDS).
• Current trends in the management of HIV infection have led to a substantial decrease in the incidence of new HIV infections and AIDS in children.
• Globally, there has been an estimated 58% decline in newly infected children since 2001.
• These advancements have dramatically increased the ability to prevent and control this menace.

Where did HIV come from?

• Scientists identified a type of chimpanzee in West Africa as the source of HIV infection in humans.
• They believe that Simian Immunodeficiency Virus (SIV) most likely transmitted to humans and mutated into HIV.
• Over decades, the virus spread slowly across Africa and later into other parts of the world.

HIV History

• The earliest known case in a human was detected in a blood sample of a man in Kinshasa, Republic of Congo.
• June 1981 – 5 cases of Pneumocystis carinii pneumonia were described in homosexual men in Los Angeles.
• December 1982 – Vertical transmission of HIV was reported in 4 infants.
• March 1983 – The virus was discovered, initially termed HTLV-III/LAV; 5 cases were reported in Africa.
• 1985 – Report of an infant infected with HIV through breastfeeding.

The Whirlwind Before Some Calm

• HIV ravaged the world, especially in resource-limited countries.
• Panic spread across countries, with infected people being stigmatized, and an increasing number of AIDS orphans.
• Death became a common occurrence, either due to the disease process or suicides by those who succumbed to social pressures, until the advent of Highly Active Antiretroviral Therapy (HAART) in 1986.

Burden

• More than 90% of adults and children with HIV infection live in sub-Saharan Africa, where the disease continues to have a devastating impact.
• Children experience more rapid disease progression than adults, with up to 50% of untreated children dying within the first 2 years of life.

Why Africa?

• Ignorance
• Poverty
• Accessibility
• Co-infections
• Some sociocultural practices
• Conflict and wars
• Despite the decline, the HIV incidence rate still remains unacceptably high. These are some of the challenges peculiar to Africa that hinder efforts to curb this scourge. Nigeria, for instance, has the 6th largest tuberculosis burden in the world.

Transmission

• Sexual contact:
  • Homosexual
  • Heterosexual
• Parenteral exposure to blood
• Percutaneous route
• Vertical transmission (90-95%) - the primary route in children:
  • Intrauterine
  • Intrapartum
  • Breastfeeding

Virology

• There are 2 types of HIV:
  • HIV-1, which is found worldwide and is responsible for the global pandemic.
  • HIV-2, found mainly in West Africa, Mozambique, and Angola. It is less pathogenic and makes little or no contribution to pediatric AIDS.

HIV Structure

• An outer double lipid layer derived from the host cell membrane
• Surface glycoprotein (gp 120)
• Transmembrane protein (gp 41)
• The core (capsid) is made of several proteins: P24 (the main protein), P17, P9, and P7

HIV Genome

• 2 copies of single-stranded RNA
• 3 major sections:
  • GAG region
  • POL region
  • ENV region

HIV Genome

• GAG region - codes for viral core proteins:
  • P24
  • P17
  • P9
  • P6
• POL region - codes for viral enzymes:
  • Reverse Transcriptase (RT)
  • Integrase (IN)
  • Protease
• ENV region - codes for viral envelope proteins:
  • gp120
  • gp41

HIV Replication

• Binding and Internalization
• Reverse Transcription & DNA incorporation
• Transcription & translation of viral genes
• Assembly and budding

Binding

• HIV binds to cells via interaction between the HIV envelope glycoprotein and the host cell receptors (CD4 molecule) and co-receptors.
• The receptors are the CD4 antigen found on some lymphocytes, macrophages, monocytes, glial cells of the brain, fibroblasts, dendritic cells, and Langerhans cells.
• The major co-receptors are CCR5 and CXCR4 (and CCR3).
• Other proposed methods include:
  • Non-neutralizing antiviral antibodies
  • Complement factors
  • Mannose-binding protein
  • DC-specific C-type lectin

Fusion

• The HIV envelope protein gp120 binds to the host cell receptors and co-receptors on the outside of the cell.
• Insertion of gp41 into the cell membrane of the host cell.
• Fusion of the two membranes.

Entry

• The virus particle leaves its membrane behind (uncoating).
• The core of the virus is released into the cytoplasm of the host cell.
• Release of viral enzymes.

Reverse Transcription

• For the virus to multiply, the viral (single-stranded) RNA must first be converted into (double-stranded) DNA.
• This is done by the viral enzyme reverse transcriptase.

Integration and Replication

• The viral DNA is integrated into the host cell DNA by integrase.

Assembly and Maturation

• Viral DNA is transcribed into mRNA (messenger RNA) with the help of the host’s enzymes.
• mRNA is transported to the cytoplasm where it is translated into protein precursors.
• Among the strands of messenger RNA produced by the cell are complete copies of HIV genetic material. These assemble with newly made HIV proteins and enzymes to form new viral particles, which are then released from the cell.
• The enzyme protease plays a vital role at this stage of HIV's life cycle by chopping up long strands of protein into smaller pieces, which are used to construct mature viral cores.

Budding

• The provirus particles push through the cell membrane by budding, taking the lipid bilayer with them to form raw virus particles.
• This forms a mature virus, which is then ready to infect a new cell.

• Development of Quasi-Species: HIV rapidly mutates, creating diverse viral populations within the host, which helps it evade the immune system.
• High Turnover of Virus and Role of Cytokines: The virus replicates quickly, and cytokines (immune signaling molecules) play a role in this process.
• CD4 Cells Depletion: HIV targets and depletes CD4+ T cells, which are crucial for immune function.
• Deterioration of the Immune System: The loss of CD4+ T cells leads to a weakened immune system, making the body more susceptible to infections and diseases.

• The clinical manifestations of HIV infection vary widely among infants, children, and adolescents:
  • Asymptomatic
  • Non-specific
  • Recurrent infections
  • Opportunistic infections
  • Dermatological manifestations
  • CNS manifestations
  • Hematology/Oncology manifestations
  • AIDS defining illnesses
• Clinical staging is used along with immunologic criteria to determine when to initiate and how to monitor therapy.

Adults and adolescents	Children
Clinical Stage 1
Asymptomatic Persistent generalized lymphadenopathy Performance scale 1: asymptomatic, normal activity	Asymptomatic Persistent generalized lymphadenopathy Performance scale 1: asymptomatic, normal activity
Clinical Stage 2
Weight loss, <10% of body weight Minor mucocutaneous manifestations (seborrhoeic dermatitis, fungal nail infections, recurrent oral ulcerations and angular chelitis) Herpes zoster within the last five years Recurrent upper respiratory tract infection (i.e. bacterial sinusitis) And/or performance scale 2: symptomatic, normal activity	Unexplained persistent hepatosplenomegaly Papular pruritic eruptions Extensive wart virus infection Extensive molluscum contagiosum Recurrent oral ulcerations Unexplained persistent parotid enlargement Linear gingival erythema Herpes zoster Recurrent/chronic upper respiratory tract infection (otitis media, otorrhoea, sinusitis, tonsillitis) Fungal nail infections And/or performance scale 2: symptomatic, normal activity
Clinical Stage 4
HIV wasting syndrome Pneumocystis Jirovecii Pneumonia (PCP) Toxoplasmosis of the Central Nervous System Cryptococcus, extrapulmonary Cytomegalovirus disease of an organ other than liver, spleen or lymph node e.g retinitis Herpes simplex virus infection, mucocutaneous (>1 month) or visceral Progressive multifocal leucoencephalopathy Any disseminated endemic mycosis Candidiasis of esophagus, trachea and bronchi Lymphoma Kaposi's sarcoma HIV encephalopathy Extrapulmonary tuberculosis and/or perfomance scale 4: bedridden>50% of the day during last month Atypical disseminated leishmaniasis Disseminated non-tuberculous mycobacterial infection Chronic cryptosporidiosis	Unexplained severe wasting, stuntingb or severe malnutrition not responding to standard therapy Pneumocystis pneumonia Recurrent severe bacterial infections (e.g. empyema, pyomyositis, bone or joint infection but excluding pneumonia) Chronic Herpes simplex infection (oro-labial or cutaneous of >1 month, or visceral at any site) Extra-pulmonary TB Kaposi's sarcoma Oesophageal candidiasis (or candida of trachea, bronchi or lungs) Central nervous system toxoplasmosis (after the neonatal period) HIV encephalopathy CMV infection; retinitis or infection affecting another organ with onset >1 month) Extra-pulmonary cryptococcosis (including meningitis) Disseminated endemic mycosis (extra-pulmonary histoplasmosis, coccidiomycosis) Chronic cryptosporidiosis (with diarrhoea)

HIV-Associated Clinical Disease	WHO Clinical Stage
Asymptomatic	1
Mild	2
Severe	3
Advanced	4

HIV Infection Stage* Based on Age-Specific CD4+ T-Lymphocyte Count or CD4+ T-Lymphocyte Percentage of Total Lymphocytes
Stage
	Age on Date of CD4+ T-Lymphocyte Test
	<1		1-5 Yr		≥6 Yr
	CELLS/μL	%	CELLS/μL	%	CELLS/μL	%
1	≥1,500	≥34	≥1,000	≥30	≥500	≥26
2	750-1,499	26-33	500-999	22-29	200-499	14-25
3	<750	<26	<500	<22	<200	<14

*Stage is based primarily on the CD4+ T-lymphocyte count. The CD4+ T-lymphocyte count takes precedence over the CD4+ T-lymphocyte percentage, and the percentage is considered only if the count is missing.

From Centers for Disease Control and Prevention: Revised surveillance case definition for HIV infection—United States, 2014. MMWR 63(No. RR-3):1-10, 2014.

Infections

• Bacterial Infections
  • Multiple or recurrent
  • Mycobacterium Avium complex or Mycobacterium kansasii, disseminated or extrapulmonary
  • Mycobacterium tuberculosis of any site (pulmonary, disseminated, or extrapulmonary)
  • Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
  • Salmonella septicemia, recurrent
• Fungal Infections
  • Candidiasis of bronchi, trachea, or lungs
  • Candidiasis of esophagus
  • Coccidioidomycosis, disseminated or extrapulmonary
  • Cryptococcosis, extrapulmonary
  • Histoplasmosis, disseminated or extrapulmonary
  • Pneumocystis jiroveci (previously known as Pneumocystis carinii) pneumonia
• Parasitic Infections
  • Cryptosporidiosis, chronic intestinal (>1 month duration)
  • Toxoplasmosis of brain, onset at age >1 month

Neoplasms

• Cancer
  • Cervical cancer, invasive
  • Kaposi sarcoma
  • Lymphoma, Burkitt (or equivalent term)
  • Lymphoma, Immunoblastic (or equivalent term)
  • Lymphoma, primary, of brain

Viral Infections

• Cytomegalovirus (CMV)
  • Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month
  • Cytomegalovirus retinitis (with loss of vision)
• Herpes Simplex Virus
  • Chronic ulcers (>1 month duration)
  • Bronchitis, pneumonitis, or esophagitis (onset at age >1 month)

Neurological Disorders

• HIV-Related Encephalopathy
  • Encephalopathy attributed to HIV
  • Progressive multifocal leukoencephalopathy

General Conditions

• Recurrent Pneumonia
  • Pneumonia, recurrent
• Wasting Syndrome
  • Wasting syndrome attributed to HIV

• Rapid Progressors
  • 25-30% (In developing countries)
  • Onset of symptoms in the first few months of life
  • Median survival of 6-9 months
  • Die by age 1 year
  • Usually acquire the infection in utero or during the early perinatal period
• Slower Progression of the Disease
  • 50-60%
  • Perinatally infected
  • Median age of survival 6 years
• Long Term Survivors
  • 5-25% of perinatally infected children
  • Minimal or no progression of the disease
  • Relatively normal CD4 count
  • May live beyond 8 years

Initial Evaluation

• Confirmation of HIV Infection
• Clinical Evaluation of the Child
  • Detailed history and physical examination
  • Determination of immunization status
  • Anthropometry (weight, height/length, MUAC, head circumference)
  • Neuro-developmental assessment
• Immunological Evaluation of the Child (CD4+ count/CD4+%)
• Review of other laboratory results
• Development of child-specific adherence strategy

Diagnosis

• Index of Suspicion
• Indirect Testing
  • Antibody assay
    • Serial
    • Parallel
• Presumptive Diagnosis
• Current Trends in Diagnosis
  • Early infant diagnosis
  • Diagnosis in older children
    • Indirect
    • Direct

Presumptive Diagnosis in Early Infants

• Infant is Confirmed HIV Antibody Positive
  • Any Stage 4 or AIDS-indicator condition
  • Recurrent bacterial infections
• Other Factors That Support the Diagnosis
  • Recent HIV-related maternal death
  • Advanced HIV disease in the mother

Current Trends in Diagnosis

• HIV RNA PCR
  • Detects viral RNA
  • Lower sensitivity and specificity than DNA PCR in infants
  • May be affected by antiretroviral therapy
• HIV Culture
  • Just as sensitive as HIV DNA PCR
  • More expensive, risky
  • Long turnaround time
• P24 Antigen
  • Least sensitive of all tests
  • Should not be used for diagnosis, especially in infants under 1 month
  • High false positive rate but newer test: Ultrasensitive p24 Ag [Up24 Ag] is more sensitive
• Surrogate Markers
  • Neopterin
  • Beta-2 microglobulin
  • HIV DNA PCR
    • Highly sensitive
    • Preferred method in infants < 18 months
  • Reverse Transcriptase-PCR
    • Detects and quantifies the amount of HIV RNA in plasma

Current Recommendations on Diagnosis

• Age < 18 Months
  • Rapid Test
  • DBS at 4-6 weeks
  • DBS 6 weeks after cessation of breastfeeding
  • Presumptive diagnosis in the absence of virological tests *
• Age > 18 Months
  • Rapid Test
• Breastfeeding Child *
  • Direct virological test

Provider-Initiated HIV Testing and Counselling (PITC)

• Offered to all children seen in health services because:
  • Features of HIV infection are often non-specific
  • HIV disease progresses faster with higher mortality
  • The “three C’s” – Consent, Counselling, and Confidentiality must be observed
• Adopts an “opt-out” approach: Caregivers and adolescents must specifically decline after pre-test information if they don’t want testing.

Ancillary Investigations

• Immunological Tests
  • CD4 Count / %CD4 Count
  • Viral Load
• Microbiological Tests
  • Tuberculin Skin Test
  • Sputum/Gastric Aspirate for AAFB
  • Gene Expert
  • Blood Culture
  • CSF Analysis
  • Swab MCs
  • HBV & HCV Screen
• Radiological and Imaging
  • Chest X-ray
• Biochemical Tests
  • Liver Function Tests (LFT)
  • Electrolytes/Urea/Creatinine (E/U/Cr)
  • Complete Blood Count (CBC)
  • Serum Lipids
  • Serum Amylase
• Urine and Stool Tests
  • Urinalysis
  • Stool Studies

Goals of Antiretroviral Therapy

• Eradication of HIV
• Reduction of HIV-associated morbidity
• Prolong duration and quality of survival
• Restore and preserve immunologic function
• Prevent HIV transmission

Treatment Modalities

• HAART Therapy
  • Eligibility criteria
  • Classes of ART
  • Choosing a regimen
  • Adherence
  • Monitoring
  • Treatment success
  • Treatment failure
  • 2nd line drugs
  • Complications of therapy
• WHO “Treat-All” Recommendation (Geneva 2015)
  • No limitations on eligibility (28 million – 37 million)
  • All populations, age groups, and stages
  • Proposed benefits and limitations
    • Avert 21 million AIDS-related deaths
    • Avert 28 million new infections by 2030
  • Expanded offer of pre-exposure prophylaxis
  • New sets of targets for 2030 (90:90:90)
    • 90% of PLWHA being aware of their infection
    • 90% of those diagnosed receiving HAART
    • 90% of those on HAART having no detectable virus in their blood

Classes of ART

• Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
• Protease Inhibitors (PIs)
• New ART Classes
  • Entry Inhibitors (HIV Fusion Inhibitors)
  • Integrase Inhibitors
  • Chemokine Receptor Antagonists
  • Maturation Inhibitors

Trade Name	Abbrev	Drug
Epivir	3TC	Lamivudine*
HIVID *	ddC	Zalcitabine
Retrovir	AZT	Zidovudine*
Viread	TDF	Tenofovir*
Zerit	d4T	Stavudine*
Ziagen	ABC	Abacavir*

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Abbrev	Drug
DLV	Delavirdine
EFV	Efavirenz*
NVP	Nevirapine*
ETV	Etravirine

Non-nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Abbrev	Drug
TPV	Tipranavir
APV	Amprenavir
IDV	Indinavir
SQV	Saquinavir
LPV/r	Lopinavir/ritonavir*
RTV	Ritonavir*
ATV	Atazanavir
FPV	Fosamprenavir
NFV	Nelfinavir*
DRV	Darunavir

Receptor Blockers

• Maraviroc (CCR5 receptor blocker)

Entry Inhibitor

• Enfurvitide

Integrase Inhibitors

• Raltegravir

Maturation Inhibitors

• Beviramat

Recommended first-line ART regimens for adults, adolescents, pregnant, breastfeeding women and children
First-line ART	Preferred first-line	Alternative first-line regimens	Special Circumstances
Adults and Adolescents	TDF + 3TC (or FTC) + DTG	TDF + 3TC (or FTC) + EFV 400	TAF + 3TC (or FTC) + DTG ABC + 3TC + DTG AZT + 3TC + EFV 400

Recommended First-line ART regimen for Children
Weight (Kg)	Age (years)	Preferred First Line Regimen	Alternative First Line Regimen	Special Circumstances
Neonates
< 3kg	< 1 month	AZT + 3TC + DTG* or RAL	AZT + 3TC + LPV/r**	AZT+3TC+NVP
Infants & Children
< 20kg	< 6years	ABC +3TC + DTG	ABC+3TC +LPV/r AZT + 3TC +LPV/r ABC (or AZT) +3TC+ RAL***	ABC + 3TC +EFV**(or NVP) AZT + 3TC + EFV (or NVP)
20 – 30kg	6-10years	ABC+3TC+DTG Or TDF****(TAF)***** + 3TC +DTG	ABC+3TC +LPV/r ABC +3TC + RAL	AZT + 3TC + LPV/r (or RAL)

* DTG 50mg is recommended from four weeks of age and weighing ≥3kg, raltegravir (RAL) is recommended for use in neonates from birth to 4 weeks of age
** LPV/r liquid can be used from two weeks of age (corrected gestational age of 42 weeks) at 1ml 12 hourly
*** RAL is used for children aged 4 weeks to 3 years
**** TDF is used from children with weight ≥ 25kg
***** TAF can be used in children aged 6years and above weighing ≥ 25kg
Note: Refer to National HIV/ART and STIs Guidelines for dosing of ARVs. AZT should be administered in instances of poor tolerability or administration challenges with DTG/s particularly in settings where the rapid acquisition of maternal treatment/viral load is unlikely and children at very high risk of carrying or INSTI resistance.

Routine Monitoring of Children on ART

• 2 weeks after commencement of therapy
• Monthly for the first 3 months
• Thereafter every 3 months except otherwise indicated

Evaluation in Follow-Up Clinics

• Clinical Evaluation:
  • Growth monitoring using growth chart
  • Physical examinations
  • Developmental assessment
  • Immunization status
  • Nutritional assessment
  • Psychosocial assessment
  • Adverse ARV effects
  • Review ARV dosages for every 10% increase in body weight

Laboratory Evaluation

• CD4+ count every 3 months (except otherwise indicated)
• Viral load at 6 months (where available)
• FBC at one month and every 3 months (except otherwise indicated)
• LFTs at baseline and AST and ALT plus bilirubin levels every 3 months unless otherwise indicated (for patients on NVP, these should be done after 1 month of commencement)
• E/U, creatinine, and urinalysis at baseline then every 3 months unless otherwise indicated
• Serum lipid profile and amylase at baseline, at 3 months, and thereafter as indicated, where possible

Routine Monitoring of Children Who Are Not Yet Eligible for ART

• The evaluation of infants and children who are not yet eligible for ART should be performed every 3 months
• Clinical evaluation
• Immunological evaluation (CD4+ count/CD4+ %)
• Other investigations as clinically indicated

ART Treatment Success

• Reduction of viral load of:
  • At least 1 log by 6-8 weeks after initiation of treatment
  • < 400 cp/ml at 24 months on therapy
  • Sustained < 50 cp/ml
• Undetectable (< 200 RNA copies/ml) viral load by 6 months
• Reduced MTCT
• Improved quality of life
• Reduced morbidity from opportunistic infections

3rd Line Therapy

• Comprehensive assessment
  • Adherence assessment
• Consideration for third line
  • Limited evidence to guide third-line strategies in resource-limited settings
  • Considerations include:
    • Raltegravir/boosted Darunavir/Etravirine
    • Optimized NRTI (dependent on genotype findings)

Supportive Care

• Social support
• Nutrition
• Routine dental evaluation and oral hygiene
• Pain management
• Developmental evaluation
• Immunization
• PCP prophylaxis
• Tuberculin testing
• Hand washing

Psychosocial Support

• Reassurance on being accepted, care, attention, security, love, nurturing, play
• Supportive home environment
• Specific help to overcome individual problems
• Simple, age-appropriate information about loss of loved ones
• Avoid stigmatization

Palliative Care for the Terminally Ill Child

• Most challenging period for parents/caregivers
• Caregivers need assistance to ensure that the child receives dignified end-of-life care at home or in the hospital

• Follows mode of transmission:
  • Parenteral exposure to blood
  • Percutaneous
  • Sexual transmission
  • MTCT (Mother-To-Child Transmission)
• Educate children about potentially risky exposures/behaviours and how to avoid them
• Discuss reduction of potentially risky behaviours as appropriate to their age
• Pre-exposure prophylaxis
• Post-exposure prophylaxis
• Limiting transmission by blood
• PMTCT (Prevention of Mother-To-Child Transmission)

Universal Precaution

• Safe handling and disposal of sharps
• Use of personal protective equipment
• Decontaminating equipment
• Safe disposal of infectious waste material
• Safe environmental practices

Pre-Exposure Prophylaxis (PrEP)

• Providing oral ARVs to uninfected individuals prior to HIV exposure is known as pre-exposure prophylaxis (PrEP)
• PrEP has been demonstrated to be effective among:
  • Men who have sex with men (MSM)
  • Individuals exposed to the virus through heterosexual sex

Post-Exposure Prophylaxis (PEP)

• Occupational hazards
• Victims of sexual assault

Primary prevention of HIV infection among women of reproductive age

• Early diagnosis and treatment of STIs
• STI treatment services present a good opportunity to provide information on:
  • HIV infection
  • Mother-to-Child Transmission (MTCT)
  • Referral for HIV Testing and Counseling (HTC)
  • Condom use and effective contraception for dual protection from HIV and other STIs

Prevent Unwanted Pregnancies Among Women Living with HIV

• Contraception
  • Barrier methods
  • Oral contraceptives
  • Injectables
• Planned pregnancy
• Issues of discordant couples

Prevent HIV Transmission from Women Living with HIV to Their Infants

• Identifying HIV-infected women
• Reducing maternal viral load (VL) with ARV prophylaxis or treatment
• Reducing viral exposure by safer delivery practices
• ARV prophylaxis for the infant
• Reducing infant exposure to the virus through infant-feeding counseling

Follow-Up Visit

• HIV-exposed babies should be seen:
  • Every 2 weeks for the first 6 weeks, then
  • Every 4 weeks until confirmation of HIV status, or
  • As indicated.

Provide Appropriate Treatment, Care, and Support

• To mothers living with HIV:
  • Their health and future
  • The health and nutrition of their children
  • The welfare of their families