PEDIATRIC HIV INFECTION

Human retroviral infections include two distinct groups: human T lymphocytic viruses (HTLV-1 and 2) and human immunodeficiency viruses (HIV-1 and 2). HTLV infections have been found associated with leukemia, lymphomas, myelopathy and tropical spastic paraparesis; while HIV infections are responsible for the current AIDS pandemic, discussed here.

Since the first case reports in 1981, HIV/AIDS pandemic has been the major global challenge to recent medicine. In India, first case, a sex worker, was reported from Madras in 1986 while first HIV-infected child was diagnosed in Mumbai in 1987.

Magnitude of problem: While HIV/AIDS pandemic began from North America and Africa, it spread rapidly throughout the world. In recent years, infection is decreasing due to social and therapeutic interventions, though continues to be a major public health problem in India.

Currently ~38 million people are estimated to living with HIV / AIDS (PLHA) globally, including ~23 lakhs in India (NACO 2021) pediatric HIV/AIDS infection in India accounts for lt;5% of total cases (~76000 children lt;15 years, NACO 2021) with a declining trend in recent years due to effective perinatal transmission prevention program. Children living with HIV (CLHIV) is the new term used instead of HIV infected children.

Virology: Causative virus was isolated by Luc Montagnier in France and Robert Gallo in USA during 1982-83, but named as Human immunodeficiency virus or HIV in 1986.

Two distinct but structurally related types of HIV virus have been identified in human disease—HIV-1, responsible for gt;90% cases; and HIV-2, which is less common (lt;3%) and associated with less severe disease. Dual infections occur in ~5-7% cases.

Structurally, HIV virus includes a central cylindrical virion core, surrounded by two major viral envelope proteins—gp120 (outer layer) and gp41 (inner layer).

Modes of transmission: While virus is excreted in various body fluids, it is extremely labile in external environment and adult infection is acquired by direct contact with infected blood during—(a) homo/hetero- sexual intercourse, (b) blood product transfusions, (c) shared IV needles in drug users, or rarely, (d) occu­pational exposure in health care workers.

Unlike adults, gt;95% of HIV infection in children are acquired perinatally (vertical transmission) from infected mothers. Rare horizontal modes of infection in children

TABLE 10.46: Risk factors for perinatal HIV transmission

Maternal factors:

• Severity of infection

- Symptomatic infection (AIDS)

- Low CD4 count

- High viral load

• No anti-retroviral prophylaxis/treatment

• Other less important factors

- Infection with HIV1 viral type

- Primary infection during pregnancy

- Co-existing vitamin A deficiency

Obstetrical factors:

• Postmaturity

• Premature rupture of membranes/chorioamnionitis

• Prolonged labor or interventions, e.g. forceps

• Vaginal delivery

Post-natal factors:

• Breastfeeding

• Maternal breast/nipple problems

include-blood product transfusions, e.g. in thalassemics/ hemophiliacs, sexual abuse and very rarely, IV drug abuse in adolescents.

Perinatal transmission: All infected mothers do not transmit infection to their babies with overall risk of ~30-40% in absence of any interventions, depending on many maternal and obstetric factors (Table 10.46). Perinatal mother to child transmission may be acquired as:

• Peripartum infection (~60%) during the passage of baby through infected vaginal canal, is the commonest mode of infection, specially in instrumental deliveries.

• Transplacental infection (~25%) is rare before 20 weeks of gestation and usually occurs in last trimester due to degenerative placental changes, thus the risk being directly proportional to duration of gestation.

• Postpartum infection (~15%) via breastfeeding usually occurs in early stages of breastfeeding, when breast/ nipple problems are common. Although ingested virus is usually destroyed in gut, it may enter baby's circulation through oral/intestinal mucosal lacer­ations, common in newborns.

Pathogenesis of HIV infection revolves around the special affinity (tropism) of virus towards human cells bearing CD₄ markers on their surfaces, i.e. (a) immunological cells, e.g. T-lymphocytes, monocytes and macrophages, (b) neuronal cells, e.g. dendritic cells, microglia, astro­cytes, etc. and (c) others, e.g. placenta, skin and deeper tissues. Natural history of HIV infection may be divided into four phases:

a. Primary infection: Immediately on entry, the virus infects dendritic neuronal cells (in skin), circulatory CD₄ lymphocytes and gut-associated lymphoid tissue, and replicates rapidly, leading to: (a) destruction of the infected cell (cytopathic effect), (b) further infection of other cells and (c) transport of infected cells to regional lymphoid tissues. This phase is associated with significant decline in CD₄ cells with inversion of CD4/CD8 ratio.

b. Initial viremia after 1-3 weeks with rapid increase in virus infected cells, leads to: (a) dissemination to other tissues, e.g. CNS, (b) rapid fall in CD₄ counts, and (c) reactive lymphoid hyperplasia, clinically presenting as acute retroviral syndrome (flu-like illness) for 2-4 weeks. During above two phases, plasma virus may be detected by culture, antigen tests or molecular methods (PCR) but antibody-tests are negative. (Window period).

c. Latent period due to development of vigorous HIV- specific humoral/cellular immunity after 4-6 weeks of primary infection, which limits the viral replication but does not eliminate the virus. During this phase, CD₄ counts recover and viral load is substantially reduced but ELISA test becomes positive. However, substantial viral population survives in lymph nodes and neuronal cells, which act as sanctuary for residual infection.

d. Progressive immunodeficiency due to slow but continued viral replication within various body cells with CD₄ markers, leads to development of AIDS- indicator illnesses, e.g. opportunistic infections (OIs), HIV encephalopathy, etc. Progression from HIV infection to disease depends on many known and unknown factors, most important being the balance between T-helper (CD₄) and killer/suppressor cell (CD₈) population and ability of the lymph nodes to limit the infection.

Natural course of perinatal infection in children is faster than in adults due to:

• Higher viral load due to sustained exposure in intra­uterine, peripartum and postnatal period.

• Large and expanding CD₄ cell-pool in growing baby, facilitating viral multiplication

• Relative immaturity of HIV-specific immune res­ponses, to limit the infection

Consequently, HIV infection in children progresses rapidly, with shorter latent period and development of symptomatic disease within few months or years. If not diagnosed and treated, 35% of HIV infected children die by first birthday and 60% by three years.

Clinical presentation of HIV infection in perinatally infected children depends on the age, immune status, presence of co-existing diseases, e.g. malnutrition and tuberculosis and probably, the timing of infection. Four recognized variations in clinical course of perinatal infection are:

• Early progressors (50-60%), which present in early infancy with severe bacterial illnesses or Pneumocystis

carinii pneumonia (PCP) and usually do not survive beyond infancy. These children are probably infected in utero, during early gestation.

• Intermediate or slow progressors (30-40%), which present in late infancy or soon after, with failure to thrive, chronic diarrhea, recurrent infections, encephalopathy and opportunistic infections (OI). These children are probably infected in late gestation or during vaginal delivery.

• Long-term survivors or non-progressors (5-15%), presenting beyond 3-5 years of age with signs of relatively preserved immunity, e.g. lymphadenopathy, hepatosplenomegaly, lymphocytic interstitial pneumonitis (LIP) and chronic parotitis.

• Elite controllers (lt;1%) which are least common but most fortunate children, who remain asymptomatic with undetectable viral load (lt; 50 copies/ ml) without antiretroviral therapy.

Clinically, HIV infection in children may begin as non­specific illnesses with abnormal course or with typical AIDS indicator illness. Some important presentations are as follows:

• Failure to thrive is the commonest presentation in Indian children. However, Wasting syndrome, seen in adults, is not as common in children and diagnosis requires presence of three features: (a) failure to thrive,

(b) chronic diarrhea/enteropathy, and (c) prolonged pyrexia.

• Respiratory manifestations are second commonest manifestations, presenting as: (a) recurrent/persistent upper respiratory infections, e.g. sinusitis or otitis media, (b) recurrent/serious lower respiratory infections, e.g. bacterial/PCP pneumonia, or (c) chronic lung disease, e.g. tuberculosis or lymphocytic interstitial pneumonitis (LIP).

P. carinii (P. Jirovecii) pneumonia (PCP) is the commonest OI in infants and ~70% cases present lt;1 year of age with acute/ sub-acute onset of fever, respiratory distress and progressive hypoxemia. X-ray findings vary from diffuse interstitial infiltrates or ground-glass appearance in early disease to nodular lesions in late stages.

Lymphocytic interstitial pneumonitis (LIP) is a common chronic lung disease in HIV-infected children, usually without significant immunosuppression. An association with Epstein-Barr virus has been postulated. Most cases present in 3-5 years age group, with insidious cough, dyspnea, wheeze, progressive hypoxemia and digital clubbing (d/d bronchiectasis). Confirmation requires lung biopsy, though chronic lung disease, X-ray findings (diffuse lace-like reticulonodular pattern) and exclusion of tuberculosis point towards the LIP.

• GIT manifestations vary from: (a) upper GIT mani­festations, e.g. oral/esophageal candidiasis, recurrent herpes stomatitis, (b) lower GIT manifestations, e.g. chronic diarrhea, and (c) accessory manifestations, e.g. chronic parotitis, hepatosplenomegaly and coexis­ting hepatitis.

Chronic diarrhea, the commonest GIT manifesta­tion, may be due to: (a) HIV enteropathy, i.e. primary HIV infection of gut, (b) common infections, e.g. bacterial, viral, giardia, amebiasis, etc., (c) local gut OIs, e.g. candidiasis, Cryptosporidium, Isospora, etc., and (d) systemic OIs, e.g. CMV, Mycobacterium avium intracellulare (MAC), etc. Frequently associated with failure to thrive (Wasting syndrome), it may accelerate progression of HIV disease.

Candidiasis, the commonest OI of GIT, present as persistent oral or esophageal thrush, dysphagia due to esophageal candidiasis, or chronic diarrhea due to intestinal candidiasis.

• CNS involvement may be due to primary HIV encephalopathy or secondary to OIs, e.g. bacterial meningitis/abscess, tubercular meningitis, and toxoplasmosis. Unlike adults, cryptococcal meningitis and CNS tumors are less common in HIV-infected children.

HIV encephalopathy develops in gt;40% survivors beyond infancy due to direct viral infection and cytopathic damage to neuronal cells and usually presents in 2^nd year of life with: (a) regression of milestones/cognitive function, (b) microcephaly, and (c) progressive symmetrical spastic paresis with gait abnormalities. cerebral atrophy and basal ganglia calcification are common on neuroimaging.

• Skin manifestations are seen in ~30% cases at some time, and include recurrent impetigo, severe scabies, molluscum contagiosum, herpes simplex or varicella­zoster infections. Kaposi sarcoma, a common skin tumor in HIV-infected adults, is extremely rare in children.

• Hemato-oncological manifestations include mode- rate/severe anemia, thrombocytopenic purpura and malignancies, e.g. non-Hodgkin's or CNS lymphomas.

• Opportunistic infections (OIs) are hallmark lesions in AIDS, though causative pathogens vary with the severity of immunosuppression and CD₄ counts (Table 10.47). Four commonest OIs in Indian children are severe/recurrent bacterial infections, candidiasis, PCP and tuberculosis.

Tuberculosis is the commonest co-infection in HIV- infected children, present in ~40-50% cases. Dissemi- nated/extrapulmonary tuberculosis is more common than pulmonary disease. Diagnostic confirmation may be difficult due to false-negativity of tuberculin test in immunocompromised state, non-specific X-ray find­ings, and usually AFB-negative disease in children. A tuberculin test of gt;5 mm is considered as positive in HIV-infected children.

¹superficial#8725;mucocutaneous disease ²invasive disease,

RBI: Recurrent bacterial infections

• Non-infective systemic lesions are rare in children and include cardiomyopathy, nephropathy and hepatitis (usually due to co-HBV/HCV infection).

Diagnosis: Possibility of HIV infection should be suspected in children with:

• Known HIV infection or high-risk behavior in parents,

• History of multiple transfusions,

• High-risk for sexual abuse, e.g. street-children, and

• Presence of clinical indicators for HIV disease.

These cases require laboratory screening after appro­priate pretest counseling of parents.

While many diagnostic tests are available for HIV infection, the choice differs according to the age of child. Diagnosis of HIV in children gt;18 months rests on detection of IgG antibodies against HIV by ELISA/ rapid tests as follows:

• Two positive HIV-antibody tests done sequentially using different principles/antigens but using same serum/plasma sample in a symptomatic child, or

• Three positive HIV-antibody tests done sequentially using different principles/antigens but using same serum/plasma sample in an asymptomatic child. Indeterminate results (two positive and one negative test in asymptomatic child) must be tested again on a second sample after 14-28 days.

Currently used rapid tests detect both-HIV1 and HIV-2. Samples, which are reactive for both HIV-1 and HIV-2 or to HIV-2 with only one kit, need confirmation from a reference laboratory.

Other diagnostic tests, e.g. Western blot test, viral cultures and p24 antigen assays are rarely used in practice.

Diagnosis in children lt;18 months cannot rely on the antibody testing due to transplacental transfer of IgG antibodies from seropositive mother, which may persist till 6-12 months. Diagnosis in these cases rests on detection of total nucleic acid of virus by polymerase chain reaction (PCR-TNA). It is a qualitative test to both DNA and RNA, superior to the previously used DNA- PCR with high sensitivity (99%) and specificity (99%) after 6 weeks of age.

An infant is considered as HIV positive if two PCR tests are positive and HIV Negative if two PCR tests are negative, of which at least one is done after 4-6 months of age.

All perinatally exposed infants, born to a seropositive mother must be tested as per early infant diagnosis (EID) guidelines, recommended by NACO 2021, discussed later.

Presumptive diagnosis is rarely necessary at present due to wide availability of diagnostic facilities. However, in cases where the final confirmation is getting delayed due to some reasons, presumptive diagnosis can be made for the purpose of initiating ART provided: (a) child is HIV-antibody positive and (b) have any of two of the following: (a) oral thrush, (b) severe pneumonia, (c) severe sepsis, or (d) any AIDS indicator illness, e.g. PCP, cryptococcal meningitis, severe wasting, Kaposi sarcoma or extrapulmonary tuberculosis, etc.

Prevention of HIV infection in children largely revolves around prevention of perinatal or parent to child transmission (PPTCT) with four-pronged strategy: (a) Primary prevention to reduce the general HIV prevalence, (b) Prevention of unintended pregnancies,

(c) Prevention of mother to child transmission, and (d) care and support to HIV positive mothers.

NACO guidelines 2021 recommends that:

• Universal HIV testing of pregnant mothers with opt­out option: All pregnant women attending antenatal care must be offered HIV counseling and testing, with an opt-out option, i.e. choice to refuse it. However, those who opt­out of HIV testing must be re-counselled to explore reasons for the same, address any misunderstanding and encourage to reconsider her decision. However, no mother should be tested without her consent.

• Anti-retroviral therapy to HIV infected mothers:

All HIV-positive pregnant women including those presenting in labour and breastfeeding should be initiated on a triple-drug ART regardless of CD₄ count and clinical stage (Treat all), for preventing mother to child transmission and should continue lifelong ART. Preferred regimen for this purpose is PO Tenofovir (300 mg) + Lamivudine (300 mg) + Dolutegravir (50 mg), once a day. While it is important to obtain blood samples for CD4 count and baseline tests before initiating ART, initiation of therapy should not be delayed for want of results.

Rule of 95% includes that: (a) gt;95% pregnant mothers are registered with at least one antenatal care check-up, (b) gt;95% of pregnant women are tested for HIV, and (c) gt;95% of HIV positive pregnant women are on ART.

• Antiretroviral prophylaxis to HIV-exposed baby, as discussed later in section of management of a HIV- exposed infant.

TABLE 10.48: Universal safety precautions

Personal protection

• Handwashing with soap and running water

• Use of gloves/gowns and masks during procedures

• Use of long handle wet-mops and gloves by cleaners

Recyclables - disinfection

• Gloves: dip in 1% hypo* (20 min) before autoclaving

• Linen: Soak in 2-4% hypo* (30 min), before laundry

• Instruments: Heat sterilization for min 30 minutes

Waste disposal

• Sharps: Dispose in metal container, filled with 1% hypo*

• Biomed waste: Dispose in buckets filled with 4% hypo*

• Spilt blood: Cover with 4% hypo* (10 min) gt; mopping

Hypo: Sodium hypochlorite solution

Prevention of HIV infection also involves minimizing the risk of transfusion-related infections by appropriate screening of blood-products and preventing health­care facility exposures by observing universal safety precautions (Table 10.48).

Management of HIV in children, for the sake of discussion, may be broadly divided into:

• Management of a HIV-exposed child

• Management of a HIV-infected child or child with advanced disease

Management of a HIV-exposed child, i.e. child born to a seropositive mother, while still awaiting confirmation of infection in him/herself, involves following compo­nents: (1) immediate care at birth, (2) infant feeding, (3) antiretroviral prophylaxis, (4) immunization and vita­min A supplementation, (5) cotrimoxazole prophylaxis, (6) growth and development assessment, (7) early infant diagnosis, and (8) regular follow-up and counseling.

1. Immediate care at birth: Care of HIV-exposed infants in delivery room should follow standard neonatal care including the following precautions:

± Baby's mouth and nostrils should be wiped as soon as the head is delivered.

± Baby should be handled with gloves until all blood/maternal secretions have been washed off.

± Cord should be clamped soon after birth, and milking should be avoided. It should be covered with gloved hand and gauze before cutting to avoid blood splattering.

± Initiate feeding within the first hour of birth according to the preferred and informed choice.

2. Early infant feeding: Feeding should be initiated within the first hour of birth in accordance with the preferred and informed choice of the mother.

As the virus is excreted in breast milk, breastfeeding increases the risk of mother to child transmission by 15-20% and ideal intervention would be not to breastfeed the baby. However, this issue should be viewed in conjunction with potential risks of top feeding, e.g. diarrhea and malnutrition, as well as economical considerations. Risk of HIV transmission via breast milk can be minimized by interventions, e.g. antiretroviral therapy to all seropositive mothers and prophylaxis to their babies. NACO guidelines 2021 recommend that:

± All pregnant women should be counselled in antenatal period about advantages and risks of feeding options, i.e. exclusive breastfeeding (EBF) or exclusive replacement feeding (ERF), to assist in informed decision making.

± EBF is the preferred option for first 6 months and should continue even when complementary feeding is initiated, till nutritionally adequate diet can be provided without breastfeeding and may continue till 24 months as in general population.

± ERF is an option only if breastfeeding is not possible (maternal death, severe illness, twins) or in cases of individual mother's informed choice. However, AFASS criteria must be fulfilled in ERF cases (acceptable, feasible, affordable, sustainable and safe), in addition to the easy access to health services. Use of bottle for ERF should be strictly avoided due to risk of diarrhea.

± Mixed feeding increases the risk of transmission and should be avoided at all cost. Top feeds are known to alter gut mucosal barrier, which may facilitate viral entry from breast milk. However, current evidence suggests that in continued presence of maternal ART, mixed feeding is also rendered safe and may be preferred over no breastfeeding at all. Hence, while EBF is still recommended during first 6 months, practicing mixed feeding is not a reason to stop breastfeeding in the presence of ART.

± If mother plans to return to work, she can be reassured that shorter duration of breastfeeding is still better than never breastfeeding at all.

± Complementary feeding should be started at 6 months with similar principles as for other children. However, HIV-infected children need additional 10% calories if growing well, 20-30% calories if having poor weight gain and 50-100% calories if having SAM.

3. Antiretroviral prophylaxis to HIV-exposed baby: NACO guidelines 2021 recommends that all infants born to HIV-infected women must receive ART prophylaxis as follows:

± Low-risk infant born to mothers with suppressed viral load (lt;1000 copies/ml) done any time after 32 weeks of gestation, should receive single drug prophylaxis with Nevirapine (NVP) for minimum 6 weeks. Syp NVP (10 mg/ml) should be given

a single oral daily dose of 15 mg lt;6 weeks of age (10 mg in infants lt;2.5 kg), 20 mg in 6 weeks- 6 months of age, 30 mg in 6-9 months age and 40 mg above 9 months.

Syrup Zidovudine (ZDV), instead of NVP, is recommended till 6 weeks of age only in setting when NVP will not be effective, i.e. infant born to a mother: (a) with confirmed HIV-2 / dual infection,

(b) who had received single dose of NVP during earlier pregnancy/delivery, and (c) who is on PI- based ART due to treatment failure. Syp Zidovudine (10 mg/ml) should be given twice a day as 5 mg BD (lt;2000 gm), 10 mg BD (2000-2500 gm) and 15 mg BD (gt; 2500 gm).

- High-risk infants (all except as above including mothers not on ART/detected seropositive within 6 weeks of delivery) should receive dual drug prophylaxis with NVP and ZDV for minimum 6 weeks, in dose as above (if on exclusive replacement feeding) or 12 weeks (if on exclusive breastfeeding).

4. Immunization and vitamin A prophylaxis: HIV- exposed children may be infected or not infected. Even infected children are also unlikely to be severely immunosuppressed in early infancy. While live vaccines are generally contraindicated in immuno­compromised states and immune response to may not be optimal in them, HIV-infected children are in fact more susceptible for infections and hence, in higher need of vaccinations. NACO guidelines 2021 recommends that:

All HIV-exposed infants should be immunized as per regular schedule, including vitamin A and live vaccines, e.g. BCG, MR and Rotavirus with following exceptions:

- BCG, if not given at birth and baby has been confir­med as HIV-infected, should be delayed until ART has been started and the infant confirmed to be immunologically stable (CD4 gt;25%).

- Measles containing vaccine (MCV) should not be given in HIV-infected children, only in presence of severe immunosuppression. An additional dose of MCV is recommended to HIV-infected children on ART following immune reconstitution (CD4 count gt;20%). A supplemental dose of MCV may also be considered in HIV-exposed or infected infants gt;6 months, who are not on ART but at a higher risk of measles.

- Rotavirus vaccine is recommended to all HIIV- exposed infants, except in those with confirmed HIV infection with severe immunodeficiency.

- Pneumococcal conjugate vaccine (PCV) should be given at 2, 4 and 6 months with booster at 12-15 months. In addition, HIV infected children gt;2 years of age should also be given pneumococcal polysaccharide vaccine (PPSV23), at least 8 weeks after the last dose of PCV.

- Double-dose schedule for HBV is recommended in HIV-infected children due to poor seroconversion, along with frequent assessment of antibody titers and booster, if required.

- Additional hepatitis A, varicella, influenza and meningococcal vaccines are recommended to HIV infected children, along with human papilloma­virus vaccine in adolescents.

5. Cotrimoxazole prophylaxis: All HIV-exposed infants should get Cotrimoxazole prophylaxis against PCP with 5 mg/kg/d as single oral dose, starting from the age of 6 weeks till 5 years of age. PO Dapsone 2 mg/kg is the alternative drug in children with serious adverse reactions to Cotrimoxazole or G6PD deficiency. It may be discontinued at 5 years only child is in clinical stage I or 2 and CD count is gt;350 cells/mm³ on two occasions, not more than 6 months apart.

6. Growth and developmental assessment: All HIV exposed children should be periodically assessed for growth and development as any other child, using standard reference tools.

7. Early infant diagnosis: NACO recommends use of PCR-TNA on a dried blood spot (DBS) sample of the infant for diagnosis of HIV-1 infection during infancy, (Fig. 10.16) with following considerations:

- First PCR-TNA should be performed at 6 weeks of age (sensitivity is poor before 6 weeks due to window period). A positive test should be confirmed by repeating the same on a second DBS as soon as possible. However, a negative test should be repeated again at or after 6 months to exclude the infection, after pre-screening the child for HIV antibodies by a rapid test.

- In a breastfed infant, due to continuing risk of transmission through breast milk, PCR-TNA should be conducted 6 weeks of age and then at 12 weeks after cessation of breastfeeding (or 18 months of age, whichever is later) to exclude the infection.

- An infant is considered as HIV-positive, if two PCR tests are positive and HIV-negative if two PCR tests are negative, of which at least one is done after 4-6 months of age.

- All infants, irrespective of the PCR results, should also be tested by ELISA/Rapid test at or after 18 months for confirmation.

- An infant is considered as seroreverter, if born to a seropositive mother but has been HIV antibody negative by two tests at 6 and 18 months or one test at 18 months, with no other clinical or laboratory evidence of HIV/AIDS.

Note: In infants gt;6 months, TNA-PCR is performed only if rapid test is positive as maternal

Fig. 10.16: Early infant diagnosis: Testing algorithm for HIV-1 exposed infants lt; 18 months.

antibodies disappear in 74% and 96% of HIV- uninfected exposed children by 9 and 12 months respectively. In a HIV-exposed child, who is anti­body negative at 6 months of age, there are two situations:

± If the infant is not breastfed in the last 3 months, s/he is probably not infected and does not need TNA-PCR testing.

± If the infant continues to receiving breastfeeding, HIV antibody test should be repeated after 3 months of complete cessation of breastfeeding to rule out HIV infection.

All HIV testing should be provided following five essential Cs: Consent, Confidentiality, Counseling, Correct test results and immediate Connection/linkages to services for HIV prevention, treatment and care.

8. Follow-up and counseling: All HIV-exposed infants should be followed up at 6 weeks for collect DBS and initiate Cotrimoxazole prophylaxis and then at 10 and 14 weeks and then at 6, 9, 12 and 18 months for growth monitoring, developmental assessment and nutritional counseling, along with early infant diagnosis, ART/Cotrimoxazole prophylaxis and clinical assessment, as required.

Management of a HIV-infected baby, once the diagnosis is confirmed includes: (a) clinical and immunological staging of the disease, (b) baseline assessment for OIs and primary prophylaxis, (c) initiation of Antiretroviral therapy, and (d) periodic follow-up for adherence and side effects as well as clinical/virological/immunological monitoring for early detection and management of treatment failures, (e) diagnosis and management of concurrent OIs, including secondary prophylaxis, (f) nutrition and feeding, and (g) counseling.

1. Clinical and immunological staging of the disease: All HIV-infected children must be assessed clinically in detail, not only for the staging of disease but also for growth and development, nutrition, immunization and presence of co-morbidities, e.g. tuberculosis. Cascade screening of parents and other siblings is also warranted for HIV and other infections.

Current WHO classification for clinical staging of HIV/AIDS in children lt;13 years is given in Table 10.49.

All HIV-infected children must be assessed for CD₄ counts to detect and monitor the extent of immunosuppression. According to CD₄ counts, HIV- infected children are categorized into various stages of the immunosuppression (Table 10.50). CD₄ percentage values are preferred in children lt;5 years than absolute values due to physiologically high cell counts in them.

2. Baseline assessment to identify presence of OIs and primary prophylaxis: All HIV infected children should be assessed for presence of OIs, specially tuberculosis on clinical indicators and relevant investigations.

TABLE 10.49: Clinical classification for HIV infection in children lt;13 years (WHO 2006)

Clinical stage 1 (asymptomatic)

• Asymptomatic

• Persistent generalized Iymphadenopathy

Clinical stage 2 (mild)

• Persistent hepatomegaly*

• Papular pruritic eruptions

• Extensive wart virus infection

• Extensive molluscum contagiosum

• Fungal nail infections

• Recurrent oral ulcerations

• Persistent parotid enlargement*

• Linear gingival erythema

• Herpes zoster

• Recurrent/chronic upper respiratory infections (otitis media, otorrhea, sinusitis, tonsilitis)

Clinical stage 3 (advanced)

• Moderate malnutrition* (no response to treatment)

• Persistent diarrhea* (gt;14 days)

• Persistent fever* (gt;1 month)

• Persistent oral candidiasis (gt;8 weeks of age)

• Oral hairy leukoplakia

• Acute necrotizing ulcerative gingivitis/periodontitis

• Lymph node tuberculosis

• Pulmonary tuberculosis

• Severe recurrent bacterial pneumonia

• Symptomatic lymphoid interstitial pneumonitis (LIP)

• Chronic lung disease, e.g. bronchiectesis

• Unexplained anemia (lt;8 gm/dl), neutropenia (lt;500/mm³) or chronic thrombocytopenia (50,000/mm³)

Clinical stage 4 (severe)

• Severe wasting, stunting, malnutrition*

• Pneumocystis carinii pneumonia

• Recurrent severe bacterial infections, e.g. empyema, bone/ joint infection, meningitis excluding pneumonia

• HSV (orolabial/skin for gt;1 mo or visceral at any site)

• Extrapulmonary TB

• Kaposi sarcoma

• Esophageal candidiasis (or of trachea, bronchi or lungs)

• CNS toxoplasmosis (gt;1 mo age)

• HIV encephalopathy

• CMV retinitis or infection of other organs gt;1 mo age

• Extrapulmonary cryptococcosis (including meningitis)

• Disseminated mycosis, e.g. histoplasmosis

• Chronic cryptospridiosis or Isosporiasis

• Disseminated nontuberculous mycobacterial infection

• Cerebral or B cell non-Hodgkin lymphoma

• Progressive multifocal leukoencephalopathy

• Symptomatic nephropathy or cardiomyopathy

^unexplained

Prophylaxis against OIs may be divided into: (i) primary prophylaxis before the first attack in high-risk cases, and (ii) secondary prophylaxis after the first attack to prevent recurrence.

Primary prophylaxis is indicated with: (a) cotrimo- xazole for PCP and toxoplasmosis as discussed earlier, (b) isoniazid (PO 10 mg/kg/day for 6 months) for tuberculosis in all newly diagnosed cases after

TABLE 10.50: Immunological classification (WHO 2006)

*absolute values (cells/mm³), rest are in %.

excluding active disease. In addition, primary pro­phylaxis is also indicated during the course of disease with (c) Azithromycin (PO 20 mg/kg once a week) for Mycobacterium avium intracellular complex when CD₄ count drops lt;100 cells/mm³, and (d) Ganciclovir (PO 30 mg/kg TDS) when CD₄ count drops lt; 50 cells/mm³.

3. Antiretroviral therapy (ART): Life-long highly active ART (HAART) is the cornerstone of management of HIV infected children, while many antiretroviral drugs are available, safety and efficacy of many is not well established in children, as also lack of child- appropriate formulations.

Depending on the mode of action, commonly used ART drugs in children may be classified as: (a) nucleoside reverse transcriptase inhibitor (NRTI), e.g. Zidovudine, Lamivudine, Abacavir, Tenofovir, etc. (b) non-nucleoside reverse transcriptase inhibitor (NNRTI), e.g. Nevirapine, Efavirenz, etc. (c) protease inhibitor (PI), e.g. Lopinavir, Ritonavir, Nelfinavir, etc. and

(d) integrase strand transfer inhibitors (INSTI), e.g. Dolutegravir.

NACO guidelines 2021 recommend following principles for ART in children, as follows:

• When to start? ART should be initiated in all children and adolescents living with HIV, regardless of age, CD4 count and WHO staging. However, initiating ART should be deferred until: (a) acute infections and OIs are treated, if possible, (b) parents have been adequately counselled about the need for adherence and expected side effects.

In cases associated with confirmed or presumptive tuberculosis, antitubercular therapy (ATT) should be initiated about two weeks before the ART, except in tubercular meningitis when r it should be delayed for 4-8 weeks.

Which drugs to use? Standard HAART treatment includes three drugs (Triple drug therapy), though choice depends on the age and weight of the child, previous drug exposure, side effects and feasibility. Fixed drug combinations, especially suitable for child­ren, are preferred over to improve adherence. NACO 2021 guidelines recommends that:

- Children lt;6 years and Wt lt;20 kg should be treated with Abacavir (ABC) + Lamivuduine (LMV) +

TABLE 10.51: Doses and common side effects of recommended ARTs in children

Doses (in mg) for different weight bands

*All doses once a day, except LPV/r, which is to be given twice a day.

For super boosting, add additional Ritonavir 50 mg lt; 6 kg and 100 mg above 6 kg

Lopinavirfritonavir (LPV/r) regimen, in doses as per Table 10.51.

- Children aged 6-10 years and Wt 20-30 kg, should be treated with ABC+ LMV+ Dolutegravir (DTG), in doses as per Table 10.51.

- Children gt;10 years and Wt gt;30 kg should be treated with Tenofovir (TDF)+ LMV+ DTG, in doses as per Table 10.51.

However, children with HIV-TB co-infection should be provided double-dose DTG (given BD rather than OD) and super-boosted LPV/r (ratio 1:1) with additional dose of Ritonavir, till two weeks after the last dose of rifampicin.

Children/adolescent already initiated on ART in childhood should continue with same regimen with weight adjusted dosing as long as they are virologically suppressed.

• How to monitor? All cases on ART should be followed up clinically and for relevant laboratory parameters to assess: (a) general well-being including nutritional and development assessment, (b) change in clinical status, e.g. development of new OIs or immune reconstitution inflammatory syndrome (IRIS, discussed later), and

(c) adherence to the treatment as well as recognition of side effects.

CD4 counts should be repeated every 6 months and viral load after 6 months, 12 months and then annually.

• When to consider treatment failure? Resistance to ART drugs may develop rapidly, but treatment failure should be considered only after fair trial of regimen for minimum 6 months, defined as:

- Clinicalfailure, with a new/recurrent stage IV event, or progressive developmental deterioration or growth failure;

- Immunological failure with:

#9632; CD₄ count fall lt;15% or persists lt;200 cell/mm³ in children 1-3 yrs, or

#9632; CD₄ count falls lt;10% or persists lt; 200 cells/mm³ in children 3-5 yrs, or

#9632; CD₄ counts fall gt;50% from peak on treatment level or persist lt;100 cells/mm³ or falls to CD4 pre-treatment levels, in older children

- Virological failure with two HIV-1 plasma viral load persistently gt;1000 copies/ml after 6 months of ART, despite gt;95% adherence in last 3 months and at least three adherence counseling.

Children with poor clinical response despite adequate virologic and immunologic responses should be carefully evaluated as all such cases may not represent ART failure. Clinical deterioration after initiation of ART may be due to paradoxical worsening of a known OI, or unmasking of previously undiagnosed OI due to IRIS.

• What to change? All cases of treatment failure should be managed only at specialized centers, after excluding a complicating OI or drug side effects.

4. Early detection and management of OIs is the critical aspect of care in HIV-infected child tuberculosis is the commonest co-infection in Indian HIV-infected children and some base-line information to recognize, diagnose, prevent and treat these OIs have been summarized in Table 10.52.

- Cotrimoxazole preventive therapy is indicated in all HIV-infected children (as discussed earlier for HIV- exposed children) with 5 mg/kg/d as single oral dose: (a) from 6 months to 5 years of age irrespective of the clinical or immunological staging, (b) from 5 years onwards, if having CD₄ count lt;350 cell/mm³ or WHO clinical stage 3 or 4 disease, irrespective of CD₄ count. All cases with history of PCP infection should receive CPT as secondary prophylaxis.

- Life-long secondary prophylaxis after first episode/s to prevent recurrence is indicated for:

(a) recurrent serious bacterial infections (gt;2 in a year) with IVIG, (b) PCP with Cotrimoxazole, (c) CMV with Ganciclovir), (d) Toxoplasmosis with Sulfadiazine and pyrimethamine, (e) MAC with Azithromycin and ethambutol, (f) herpes simplex or varicella with Acyclovir.

5. Nutrition and feeding: Considering the higher nutritional needs in HIV infected children due to poor nutritional status and impaired immune system with high-risk of infections, WHO recommends that

TABLE 10.52: Common opportunistic infections in HIV infected children

Alt: Alternative therapy, OPC: Oropharyngeal candidiasis, VZIG: Varicella-zoster immunoglobulin, IVIG: Intravenous immunoglobulin, Hib: H. influenzae B, PYM: Pyrimethamine, SDZ: Sulfadiazine, LCV: Leucovorin

1. PO Cotrimoxazole 5 mg/kg of (TMP) OD.

2. IV/PO Cotrimoxazole 15-20 mg/kg/d q6hr + IV Dexamethasone 0.3-0.5 mg/kg QID 21 days.

3. IV Immunoglobulin 400 mg/kg/month.

4. PO Clarithromycin 15 mg/kg/d q12hr or PO Azithromycin 20 mg/kg/week.

5. PO Clarithromycin or Azithromycin (as above) + PO Ethambutol 15-20 mg/kg/d q24hr or PO Ciprofloxacin 20-30 mg/kg/d q12-24hr.

6. PO Clarithromycin 7.5-10 mg/kg/d q12hr or PO Azithromycin 10-12 mg/kg/d q24hr + PO Ethambutol 15-20 mg/kg/d q24hr with/without PO/IV ciprofloxacin 20-30 mg/kg/d or IV/IM Amikacin 5-30 mg/kg/d.

7. PO Fluconazole 3-6 mg/kg OD (in severe recurrent mucocutaneous candidiasis/esophageal candidiasis).

8. IV Fluconazole 3-6 mg/kg OD x 21 days.

9. IV Amphotericin B 0.5-1.5 mg/kg OD ? 2-3 weeks after clinical recovery and last positive culture.

10. IV Amphotericin B 0.7-1.5 mg/kg OD + PO Flucytosine 100 mg/kg/d q6hr ? 2 weeks followed by IV/PO Fluconazole 10-12 mg/kg/d q12hr ? 10 weeks.

11. PO Ganciclovir 30 mg/kg TDS or IV Ganciclovir 5 mg/kg OD 5 days a week.

12. IV Ganciclovir 5 mg/kg BD ? 2-3 weeks. IV Foscarnet 60 mg/kg TDS 14-21 days

13. IV Acyclovir 10 mg/kg TDS ? 7-14 days (in severe disease) or PO Acyclovir 20 mg/kg TDS ? 7 days (in mild disease). IV Foscarnet 120 mg/ kg/day q8hr ? 7 days.

14. PO Acyclovir 80 mg/kg/d q6-8hr.

15. PO Sulphadiazine 80-100 mg/kg/d q6-12hr + PO Pyrimethamine 1 mg/kg OD + Leucovorin (Folinic acid) 5 mg/d alternate day.

16. PO Suphadiazine 25-50 mg/kg QID + Pyrimethamine 2 mg/kg OD ? 2 day gt;1 mg/kg/d + 2-6 mo gt;1 mg/kg/Alt. day ? total 6 mo + Leucovorin 10-25 mg/kg OD.

17. PO Nitazoxanide 100-200 mg BD ? 3 days (200 mg BD in children gt;3 years). PO Azithromycin 5 mg/kg OD ? 10 days (10 mg/kg on Day 1)

18. PO Cotrimoxazole 20 mg/kg/d of TMP q6hr ? 10 days than q12hr ? 3 days.

these children need high-energy, caloric-dense food as follows:

- Caloric requirements should be enhanced by 20­30% in CLHIV with symptomatic HIV or episode of OI, while those with growth faltering may need up to 50-100% additional calories.

- Proteins should supply 12-15% of the energy intake to maintain and/or recover lean body mass.

- Micronutrient supplementation is needed as per RDA.

- Issues related to early infant feeding have been already discussed earlier. Breastfeeding can be continued till 2 years.

6. Counseling is a vital component of HIV care and parents should be counselled at all available opportu­nities for treatment adherence, regular follow-up, timely reporting for opportunistic infections, proper nutrition, etc. Older children and adolescents need age-appropriate disclosure and counseling to ensure treatment adherence.

Immune reconstitution inflammatory syndrome (IRIS) is a collection of signs and symptoms resulting from the ability to mount an immune response to antigens or organisms associated with immune recovery on HAART. It may develop in ~10% cases after starting ART, specially in those with severe immunosuppression.

Clinically, most cases present within 2-12 weeks of initiating ART with unexpected deterioration of clinical status due to unmasking or worsening of sub-clinical co-infections, e.g. tuberculosis, HBV, HCV, MAC and cryptococcal disease.

Diagnosis depends on the high index of suspicion and differentiation from a new OI due to treatment failure may be difficult.

Treatment involves management of unmasked OI. ART should be continued, if possible. Steroids, e.g. prednisolone 0.5-1.0 mg/kg/d ? 5-10 days may be used in severe or life-threatening cases to suppress exaggerated inflammatory response. In most cases the symptoms resolve after a few weeks.

10.28