Create detailed study guide on HIV Infection in children and ART Therapy for both children and adults
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Comprehensive Study Guide: HIV Infection in Children & Antiretroviral Therapy (ART)
Sources: Harrison's Principles of Internal Medicine 22E (2025), Red Book 2021 (AAP), Bradley & Daroff's Neurology in Clinical Practice, Comprehensive Clinical Nephrology 7E
PART 1: HIV VIROLOGY & PATHOGENESIS
1.1 The Virus
HIV is a single-stranded RNA retrovirus (family Retroviridae, genus Lentivirus). Two types exist:
HIV-1: Responsible for the global pandemic. Multiple groups (M, N, O, P); Group M is divided into subtypes/clades (A-K), with subtype C predominating globally.
HIV-2: Less virulent, slower progression, mostly West Africa.
Structure: Icosahedral virion. External spikes formed by a trimeric heterodimer of:
gp120 (surface) - binds CD4+ T cells
gp41 (transmembrane) - mediates membrane fusion
Key enzymes encoded by the pol gene:
Reverse transcriptase
Integrase
Protease
1.2 Replication Cycle (Targets for ART)
Step
Mechanism
Drug Target
1. Attachment
gp120 binds CD4 receptor on host T cell
Entry inhibitors (maraviroc)
2. Co-receptor binding
gp120 binds CCR5 or CXCR4
CCR5 antagonists
3. Fusion
gp41 folds to merge viral/cell membranes
Fusion inhibitors (enfuvirtide)
4. Reverse transcription
RNA -> DNA via reverse transcriptase
NRTIs, NNRTIs
5. Integration
Proviral DNA integrated into host genome by integrase
INSTIs
6. Protein processing
Viral polyproteins cleaved by protease
Protease inhibitors
7. Budding
New virions released
(Maturation inhibitors, experimental)
Harrison's Principles of Internal Medicine 22E, pp. 1600-1603
1.3 Cellular Tropism
Primary target: CD4+ T helper lymphocytes (the immune orchestrators)
Also infect: macrophages, dendritic cells, microglia (CNS)
CD4 molecule is the primary receptor; CCR5 is the predominant co-receptor in early/transmitted infection, CXCR4 in late/advanced disease
The cell-to-cell spread is also facilitated by DC-SIGN (C-type lectin on dendritic cells) which captures HIV and passes it to CD4+ T cells
PART 2: HIV EPIDEMIOLOGY
Global Burden (2023 Data)
~39.9 million people living with HIV worldwide
120,000 new HIV infections in children <15 years in 2023 (down from 300,000 in 2010 - a dramatic improvement due to PMTCT programs)
630,000 AIDS deaths in 2023, including 76,000 children <15 years
30.7 million people (77% of all PLHIV) accessing ART as of December 2023
84% of pregnant women with HIV had access to ART to prevent MTCT in 2023
Eastern/Southern Africa: home to >50% of global PLHIV (20.8 million)
South Africa: highest number of PLHIV globally (7.7 million)
Harrison's Principles of Internal Medicine 22E, pp. 1609-1611
PART 3: HIV INFECTION IN CHILDREN
3.1 Routes of Acquisition in Children
A. Perinatal / Vertical Transmission (most common in children)
Occurs in utero (15-20%), during labor/delivery (60-70%), or via breastfeeding (10-20%)
Without any intervention, MTCT rate is 15-45%
Maternal viral load is the dominant predictor of transmission risk; a 2025 meta-analysis confirms a direct linear relationship (PMID: 40652949)
With effective ART + prophylaxis, MTCT can be reduced to <1-2%
B. Blood-borne (rare in developed countries)
Transfusion of unscreened blood products
Contaminated needles
C. Sexual transmission
In adolescents (consensual or non-consensual)
Post-pubertal routes same as adults
3.2 Diagnosis of HIV in Children
Critical principle: Maternal HIV antibodies passively cross the placenta and persist in the infant until ~18 months. Therefore, antibody tests CANNOT diagnose HIV in infants <18 months.
Diagnostic Algorithm by Age
Children < 18 months: Use virologic (NAAT) tests only
Test
Details
HIV-1 DNA PCR
Detects proviral DNA in peripheral blood mononuclear cells; detects 1-10 copies
HIV-1 RNA PCR (qualitative/quantitative)
Detects plasma viral RNA; equally recommended alongside DNA PCR
Performance
Identifies 25-58% of infected infants in week 1; 60% by 1 month; 90-100% by 2-3 months
Recommended virologic testing schedule (Red Book 2021):
At birth (within 48 hours)
At 14-21 days of age
At 1-2 months of age
At 4-6 months of age
A positive virologic test should be confirmed immediately with a repeat test. Two positive results = confirmed HIV infection.
Children ≥ 18-24 months:
HIV antibody/antigen combination assay (4th generation) can be used
Note: 14% of infants remain seropositive after 18 months, 4.3% after 21 months, 1.2% after 24 months - so some may still need NAAT confirmation
Adults and older children:
FDA-recommended algorithm: 4th generation Ag/Ab combo assay → if reactive, HIV-1/HIV-2 antibody differentiation assay → if indeterminate, HIV-1 NAAT
Intrapartum: Continue maternal ART; IV Zidovudine for high viral load
Postpartum neonatal prophylaxis:
Low-risk infant (mother virologically suppressed): Zidovudine for 4-6 weeks
High-risk infant (mother not on ART, high VL): Zidovudine + Nevirapine + Lamivudine x 6 weeks
Infant feeding: In resource-rich settings, formula feeding is recommended; in resource-limited settings, exclusive breastfeeding with maternal ART is acceptable
Virologic testing at 4-6 weeks, 3 months, 6 months; and at cessation of breastfeeding + 6 weeks after
PART 4: STAGES OF HIV DISEASE (ADULT REFERENCE)
4.1 Acute HIV Syndrome (Fiebig Stages I-VI)
Occurs 3-6 weeks post-infection in 50-70% of individuals
Corresponds to high-level viremia and transient CD4 decline
Symptoms of Acute HIV Syndrome:
General
Neurologic
Dermatologic
Fever
Meningitis
Erythematous maculopapular rash
Pharyngitis
Encephalitis
Mucocutaneous ulceration
Lymphadenopathy
Peripheral neuropathy
Headache / retroorbital pain
Myelopathy
Arthralgias/myalgias
Lethargy/malaise
Anorexia, N/V/D
Harrison's Principles of Internal Medicine 22E, Table 208-10, p. 1628
4.2 Chronic Asymptomatic Phase
CD4 count falls slowly (~50-70 cells/µL per year without treatment)
Plasma viremia at a "set point"; viral replication continues in lymphoid tissue
May last 1-20 years (median ~10 years)
4.3 Advanced HIV Disease / AIDS
CD4 <200 cells/µL in adults/children >5 years = AIDS (CDC definition)
Opportunistic infections and malignancies emerge
Untreated: median survival after AIDS-defining illness was only 26 weeks (pre-ART era)
With ART: a 20-year-old newly diagnosed can expect to live 50+ more years
4.4 Long-term Nonprogressors & Elite Controllers
Long-term nonprogressors: HIV-infected ≥10 years, stable CD4 in normal range, low viremia, no ART - ~5-15% of PLHIV
Elite controllers: <1% of PLHIV; undetectable viral load without ART; robust HIV-specific CD8+ CTL responses; associated with HLA-B57-01 and HLA-B27-05 haplotypes
PART 5: ANTIRETROVIRAL THERAPY (ART) - COMPLETE GUIDE
5.1 Drug Classes and Mechanisms
A. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Mechanism: Competitive inhibitors of reverse transcriptase; incorporated into viral DNA causing chain termination (lack a 3'-OH group)
Drug
Common Name
Dose
Key Toxicity
Lamivudine
3TC
150 mg BID or 300 mg QD
Flare of hepatitis B on discontinuation
Emtricitabine
FTC, Emtriva
200 mg QD
Skin discoloration; hepatitis B flare
Abacavir
ABC, Ziagen
300 mg BID
Fatal hypersensitivity in HLA-B*5701+ individuals (fever, rash, N/V/fatigue)
Tenofovir disoproxil fumarate
TDF
300 mg QD
Renal toxicity, osteomalacia, hepatitis B flare on discontinuation
Tenofovir alafenamide
TAF, Vemlidy
25 mg QD
Less renal and bone toxicity than TDF; nausea
Zidovudine
AZT, ZDV
300 mg BID
Bone marrow suppression, anemia, myopathy, lactic acidosis
Screen HLA-B*5701 before prescribing abacavir - positive = contraindicated
TDF preferred over TAF when HBV co-infection is present (greater anti-HBV activity)
B. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Mechanism: Non-competitive, bind allosteric site of reverse transcriptase; conformational change blocks function (do NOT require intracellular phosphorylation)
Drug
Notes
Key Toxicity
Efavirenz (EFV)
CYP450 inducer; once-daily
CNS symptoms (vivid dreams, mood changes), teratogenic in 1st trimester
Nevirapine (NVP)
CD4 cutoffs: avoid if CD4 >250 (women) or >400 (men)
Severe hepatotoxicity and Stevens-Johnson syndrome
Rilpivirine (RPV)
Requires food; not with PPIs
QTc prolongation, depression
Etravirine (ETR)
Active against NNRTI-resistant strains
Rash
Doravirine (DOR)
Fewer CNS effects than EFV
Nausea, fatigue
NNRTI resistance: A single mutation (K103N, Y181C, etc.) can cause high-level resistance - low genetic barrier.
C. Protease Inhibitors (PIs)
Mechanism: Inhibit HIV protease enzyme, preventing cleavage of viral polyprotein precursors into functional proteins; result = non-infectious immature virions
3TC/FTC (M184V - but this mutation also reduces viral fitness)
5.7 Long-Acting ART Regimens (2025 Update)
Injectable regimens for treatment:
Cabotegravir LA + Rilpivirine LA (CAB/RPV - Cabenuva): Monthly or every-2-month IM injections; used in virologically suppressed adults; EACS guidelines 2025 endorse this as a maintenance option (PMID: 41088922)
Injectable PrEP:
Cabotegravir LA (CAB-LA) for PrEP: every-2-month IM injection; highly effective
Oral ultra-long-acting:
Lenacapavir (LEN): SC injection every 6 months (capsid inhibitor); for highly treatment-experienced patients with multi-drug-resistant HIV
Paradoxical worsening as recovering immune system mounts response to previously subclinical pathogens
Unmasking IRIS: New opportunistic infection revealed as immune system recovers
Paradoxical IRIS: Known infection previously treated worsens after ART initiation
Risk highest with CD4 <50 at ART start, rapid CD4 recovery
High-risk OIs for IRIS: TB, MAC, CMV, Cryptococcus, KS (especially Kaposi's in HHV-8-endemic countries)
Management: Continue ART; treat underlying OI; steroids for severe reactions (except when infection not controlled)
5.9 Special Populations
Pregnancy:
ART mandatory throughout pregnancy
DTG + TDF + FTC is preferred (neural tube defect risk with DTG in periconception very low; benefits outweigh risks)
Avoid EFV in 1st trimester
Zidovudine IV during labor if VL >1,000 copies/mL near delivery
Renal Impairment:
Avoid TDF in eGFR <50; substitute TAF
Dose-adjust NRTIs (TDF, 3TC, FTC, AZT) based on GFR
Dose-adjust based on pharmacokinetics
Hepatic Impairment:
Use NRTIs with caution (lactic acidosis/hepatosteatosis risk especially with stavudine/ddI)
HBV co-infection: do NOT use single-agent anti-HBV therapy (use TDF or TAF-containing regimen to prevent HBV resistance; discontinuing ART containing anti-HBV agents can cause hepatitis flare)
Child-Pugh C: Avoid protease inhibitors; some INSTIs may be used with monitoring
HIV-TB Co-infection:
Rifampin induces CYP3A4 - significantly reduces PI and some NNRTI levels
Preferred ART with rifampin: Efavirenz (with standard dose) or Dolutegravir (with doubled dose to 50 mg BID)
Rifabutin substituted for rifampin when using PIs
PART 6: OPPORTUNISTIC INFECTION PROPHYLAXIS (Summary)
OI
Indication
Preferred Agent
PCP
CD4 <200 (adults) or all HIV+ children <5 yrs
Co-trimoxazole (TMP-SMX)
Toxoplasma encephalitis
CD4 <100 + IgG positive
Co-trimoxazole (also covers PCP)
MAC (Mycobacterium avium complex)
CD4 <50 (if not on ART)
Azithromycin weekly
Cryptococcus (secondary prophylaxis)
After treatment of cryptococcal meningitis
Fluconazole (until CD4 >200 for 3+ months on ART)
CMV (secondary prophylaxis)
After CMV retinitis treatment
Valganciclovir
Prophylaxis can be stopped when CD4 count rises above threshold on ART (sustained ≥3-6 months):
PCP prophylaxis can stop when CD4 >200 for >3 months
Toxoplasma prophylaxis can stop when CD4 >200 for >3 months
MAC prophylaxis can stop when CD4 >100 for >3 months
PART 7: AIDS-DEFINING MALIGNANCIES
Three AIDS-defining cancers:
Kaposi's Sarcoma (KS): Caused by HHV-8; mucocutaneous violaceous lesions; visceral involvement (GI, lung, lymph nodes). In children: unusual presentation without skin lesions - prominent firm lymphadenopathy, cytopenias. IRIS-KS can occur post-ART especially in children from HHV-8-endemic countries.
Non-Hodgkin Lymphoma (NHL): Often high-grade B-cell lymphomas (Burkitt's, immunoblastic, primary CNS lymphoma). Treatment: chemotherapy ± rituximab + effective ART. Survival improved significantly with ART era.
Invasive Cervical Cancer: HPV-associated; more aggressive in HIV.
Sources consulted: Harrison's Principles of Internal Medicine 22E (2025, McGraw Hill) pp. 1600-1660; Red Book 2021: Report of the Committee on Infectious Diseases (AAP) pp. 695-716; Comprehensive Clinical Nephrology 7E; Bradley & Daroff's Neurology in Clinical Practice; EACS Guidelines v13.0, 2025 (PMID: 41088922). HIV vertical transmission meta-analysis: Lancet 2025 (PMID: 40652949).
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