F34 HIV infection in infants and children

Introduction

In Hong Kong, the number of known HIV infections in children has remained small. Perinatal transmission is an important and preventable mode of HIV infection in children. Early identification of HIV-infected pregnant women prior to delivery could effectively reduce perinatal transmission of HIV infection. The proportion of infections occurring by perinatal route is estimated to be approximately 25% to 40% among children who are not breastfed. Mathematical modelling suggests that much of HIV infection occurs relatively late in gestation. The absolute risk for intrauterine transmission is estimated to be approximately 5% or 6%, and for intrapartum transmission, approximately 13% to 18%. Despite the introduction of Universal Antenatal HIV Testing Programme (UATP) and Rapid HIV testing in Hong Kong in 2001 and 2008 respectively, there were still few newborns failing the preventive measure as a result of late presentation or maternal HIV infection acquired after antenatal HIV screening. On the other hand, transmission among adolescent men sex with men (MSM) population is increasing in recent years. The real situation may be underestimated because of the poor link to medical care in this high risk population. HIV infected adolescent MSM will be a new challenge to us in the near future.

Advances in HIV treatment are changing the landscape of HIV/AIDS in the clinical setting. Prior to effective viral suppressive therapy, majority of the perinatal infected infants developed marked immunosuppression and AIDS-defining conditions and become symptomatic in two peaks, either by approximately one year or seven years of age. Pneumocystis jiroveci pneumonia (PCP), HIV encephalopathy, developmental delay or regression, failure to thrive and recurrent bacterial infections were commonly observed problems. Today, effective highly active antiretroviral therapy (HAART) makes it possible for children in Hong Kong to experience prolonged viral suppression and live essentially free of opportunistic infections.

This chapter summarises a standard approach in the management of infants and children infected with HIV, based on scientific research and international experience and recommendations.[1-4] The main sources of references for the tables are those numbered 2, 3, 5, 6, 7, 8. Since research in children usually lags behind that in adults, some recommendations are extrapolated from adult data.

Principles of paediatric HIV management

The guiding principles of effective management of paediatric HIV infection are:

1. Newborns exposed to HIV infected mothers should be evaluated as soon as possible after birth for the diagnosis of HIV infection.
2. Postnatal antiretroviral therapy should be completed according to the perinatal prophylaxis regimen chosen for the mother.
3. Prophylaxis against PCP should be commenced at 4 to 6 weeks of age for infants born to an HIV-infected mother if the presumptive exclusion criteria for infection are not satisfied.[5]
4. Early treatment of HIV-infected infants regardless of clinical and immunologic parameters is the preferred approach for reducing early mortality.[6]
5. Childhood immunisation is an important part of the management programme for HIV infected children, the practice of which is similar to that for healthy infants and children with slight adjustment.
6. HAART should be used in the management of HIV-infected children.
7. A multispecialty, multidisciplinary approach is needed for the comprehensive care of HIV-infected children. Life-long continuous care is recommended.
8. Recommendations for therapy and management will have to be updated frequently as the management of HIV infection in infants, children and adolescents is rapidly evolving and becoming increasingly complex.
9. A mechanism should be in place to enhance the local knowledge base in HIV management in children, and the exposed children (infection or otherwise) to antiretroviral treatment.
10. HIV- and antiretroviral-exposed but uninfected children should be followed.

Diagnosis of HIV infection in infants born to HIV infected mothers

Virologic assays which directly detect HIV should be used to diagnose HIV infection in infants younger than 18 months. RNA PCR tests are preferable to DNA PCR tests as the former have higher sensitivity for the detection of non-subtype B HIV which predominates in our locality. Testing is recommended in infants with known perinatal HIV exposure at age of 2-3 weeks, 1-2 months, and 4-6 months. Additional testing at birth (within 48 hours) is optional and should be considered for infants at high risk of HIV infection such as late maternal presentation, high maternal HIV load. For infants receiving combination antiretroviral prophylaxis (or short term empirical HIV treatment), additional RNA PCR test should be considered 2 to 4 weeks after cessation of antiretrovirals.

Presumptive exclusion of HIV infection

HIV infection can be presumptively excluded in a non-breastfed infant born to an HIV infected mother if:

1. 2 or more negative virologic tests, with one test obtained ≥14 days of age and one obtained at ≥4 weeks of age; OR
2. one negative virologic test obtained at ≥8 weeks of age; OR
3. one negative HIV antibody test obtained ≥6 months of age.

Definitive exclusion of HIV infection

HIV infection can be definitively excluded in a non-breastfed infant born to an HIV infected mother if:

1. 2 or more negative virologic tests, with one obtained at ≥1 month of age and one ≥4 months of age; OR
2. 2 negative HIV antibody tests from separate specimens obtained ≥6 months of age.

If the patient has received HA ART, consider additional RNA PCR test 2 to 4 weeks after cessation of antiretrovirals.

Documentation of loss of maternal HIV antibodies between 12 and 18 months is recommended to definitively confirm the absence of HIV infection in a child born to an HIV infected mother. A positive HIV antibody after 18 months of age indicates HIV infection.

Care of infant born to an HIV infected mother

Antiretroviral prophylaxis therapy (postnatal arm of perinatal prophylaxis)

All infants born to HIV infected women should receive postnatal antiretroviral (ARV) drugs to reduce perinatal transmission of HIV. A 6-week course of oral zidovudine (ZDV) alone is recommended to all HIV-exposed infants whose mothers have received standard antepartum and intrapartum ART prophylaxis. A 4-week course may be considered for babies having low risk of acquiring infection and whose mothers have a low HIV viral load.

Infants born to HIV infected women who have not received adequate antepartum ARV drugs and detectable viral load should receive prophylaxis with ZDV given for 6 weeks combined with 3 doses of nevirapine (NVP) (at birth begun as soon after birth as possible, 48 hours later and 96 hours after 2nd dose).

When mothers have very high HIV viral load or with known ARV drug resistant viruses, a multi-ARV regimen may be considered. In these situations, a paediatric HIV/AIDS specialist should be consulted for advice.

In Hong Kong, breastfeeding by one’s HIV-infected mother is contraindicated since there are safe alternatives to breast milk.

Laboratory monitoring

Complete blood picture (CBP) and differential count should be performed on the newborn as a baseline evaluation before administration of ZDV. Anaemia is the primary short-term complication of the 6-week ZDV regimen in the neonate. Repeat measurement of haemoglobin is required during and after the completion of the regimen. Infants who have anaemia at birth or who are premature warrant more intensive monitoring.

Serum lactate should be checked if an infant develops severe clinical symptoms of unknown etiology, especially neurologic symptoms.

CD4+ T lymphocyte count and percentage should be monitored at 1 and 3 months of age and then continued at 3-month-interval if the presumptive exclusion criteria for infection is not satisfied.

Prophylaxis for Pneumocystis jirovecii pneumonia (PCP) and Mycobacterium avium complex (MAC)

PCP used to be the most common AIDS presenting illness in children before the days of effective antiretroviral therapy.[7] It occurs most often between 3 and 6 months of age when many HIV-exposed infants have not yet been identified as being infected. All infants born to HIV-infected women should begin prophylaxis at 4-6 weeks of age, regardless of CD4+ T lymphocyte counts or percentage if the presumptively exclusion criteria for HIV infection is not satisfied.[Box 34.1(A)] The drug regimens are shown in Box 34.2.

Prophylaxis should be discontinued for children who are determined to be not infected with HIV. Both primary and secondary prophylaxis can be discontinued in children older than 1 year of age if they have been on HAART for at least 6 months and have achieved age-appropriate CD4 count and percentage levels above the threshold for PCP prophylaxis for at ≥3 months. Prophylaxis should not be discontinued in children <1 year of age. If prophylaxis is discontinued, it should be reinitiated if the CD4 count or percentage decreases to below age-appropriate threshold. Children who have secondary prophylaxis discontinued should be thoroughly evaluated if they have signs and symptoms suspicious of PCP, regardless of CD4 counts or percentages.

Mycobacterium avium complex (MAC) was the second most common opportunistic infection (OI) in children. HIV-infected children having advanced immunosuppression should receive prophylaxis. The drug regimens are shown in Box 34.1(B). Primary prophylaxis can be discontinued in patient aged ≥2 years receiving HAART ≥6 months and have achieved age-appropriate CD4 count and percentage levels above the threshold for MAC prophylaxis for at ≥3 months.

The management of newborns from HIV infected mothers is summarised in the clinical pathway in Algorithm 34 towards the end of this chapter.[8]

Care of HIV infected infant or children

The following practice applies to all newly diagnosed HIV infected children:

Complete and detailed medical history and physical examination

Depending on the individual situation, baseline assessment of the child and family may be done in the in-patient setting. This approach has several advantages: more time can be spent during the initial encounter between the family and the medical team; the family can familiarise themselves with the medical team and the hospital; doctors and nurses can observe the social dynamics of the family; and the initiation of ARV drugs can be supervised and monitored.

Attention should be paid to clinical symptoms commonly seen in HIV infection, e.g., failure to thrive, developmental delay, lymphadenopathy, hepatomegaly, splenomegaly, candidiasis. The HIV related symptoms in children is detailed in Box 34.3. If the child is the first member of the family diagnosed with HIV infection, both parents and other siblings should also be counselled and evaluated for HIV infection.

Baseline and follow-up investigations

The main investigations are T cell subset enumeration and viral load measurement. Other investigations are also included in this section.

1. T-cell subsets
   CD4+ T lymphocyte absolute number and percentage are surrogate markers of disease progression in HIV infection and should be monitored every 3 to 4 months. This marker can be monitored less frequently (every 6-12 months) in virologically and immunologically stable patients who are adherent to therapy. CD4 percentage is preferred for monitoring immune status in children <5 years, whereas absolute CD4 count can be used in older children. Monitoring should be performed more frequently if there is clinical or immunologic deterioration. Profound decrease in CD4 counts in the first year of life signifies rapid progression of HIV disease and indicates the immediate need for highly active antiretroviral therapy (HAART). Infected infants who have a thymic defect lymphocyte immunophenotypic profile (CD4 count <1900/μL and CD8 count ≥850/μL) during the first 6 months of life also have a more rapid HIV disease progression.[9] The immunological classification system for HIV infection in children is in Box 34.4.

Box 34.4. Staging of HIV diseases, from Centers for Disease Control and Prevention: Revised Surveillance Case Definition for HIV Infection-United States, 2014. MMWR 2014;63(No. RR-3):1-10. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6303a1.htm

	Age on date of CD4 test
	≤12 months	1-<6 years	≥6 years
	Cell/μL	Cell/μL	Cell/μL
Stage 1	≥1500 (≥34)	≥1000 (≥30)	≥500 (≥26)
Stage 2	750-1499 (26-33)	500-999 (22-29)	200-499 (14-25)
Stage 3	<750 (<26)	<500 (<22)	<200 (<14)

2. HIV viral load
   The dynamics of HIV RNA burden observed in infants is very different from that of adults. Perinatally infected infants exhibit primary HIV viraemia in the first month of life. Against the background of a relatively immature system, they exhibit an extremely high plasma viral load, commonly greater than 10⁶ copies/mL plasma by HIV RNA PCR. Over time the viral load tends to decrease. In general, elevated HIV RNA viral load after the first month of life correlates with rapid disease progression, especially if CD4 percentage is <15%, although some children with high HIV RNA levels in the first year do not progress as rapidly. HIV RNA should be measured every 3 to 4 months in an infected child, and more frequently if there is virologic or clinical deterioration or when there is a change of antiretroviral therapy.

   Biological variation in HIV RNA levels within one person, also known as blip, is well documented in adults. This biological variation may be greater in infected infants and young children. In general, only changes greater than 0.7 log copies/mL (fivefold) in children under 2 years and those greater than 0.5 log copies/mL (threefold) in children older than 2 years should be considered significant. Unless confirmed by a second testing, no alternation in therapy should be made base on a change in viral load.

3. HIV resistance testing
   Testing for resistance is recommended prior to initiation of therapy in all treatment naive children. Resistance testing should be performed when a change of antiretroviral therapy regimen is being considered for a child who has virologic failure.
4. Other laboratory investigations
   Baseline assessment includes CBP with differentials, liver and renal function tests, lipid, amylase, lipase levels, lactic dehydrogenase and quantitative immunoglobulins. Baseline antibody titres should be considered for toxoplasma, cytomegalovirus (CMV), Epstein-Barr virus, varicella-zoster virus, herpes simplex virus (HSV), hepatitis B and C, hepatitis A (particular for adolescent MSM) and syphilis. Initial titres drawn at the neonatal period would reflect the immune status of the mother. Repeat testing should be done at 12 months of age and then annually if they are negative. The results provide information about these children’s exposure and susceptibility to specific infection. For example, CMV negative HIV infected children should receive CMV negative blood in the case of transfusion and if unavailable, leukofiltered blood should be used if possible. For older children, functional antibodies against common antigens could be assessed. This is usually achieved by measuring their immune status after routine immunisation, e.g. IgG against measles and tetanus. Since primary CMV infection in the first month of life has been associated with an increase in HIV replication, urine culture for CMV may also be obtained in the first 6 months of age.
5. Other evaluations
   • Chest X-ray – A baseline chest x ray should be obtained and then annually even in asymptomatic children. This test identifies mediastinal enlargement, lung lesions, lymphoid interstitial pneumonitis (LIP) and cardiomegaly. Patient with chronic lung changes should also have oxygen saturation measured at every visit.
   • Cardiac assessment – HIV cardiomyopathy starts early in life. A study on HIV-infected children using ECG has shown that subclinical cardiac abnormalities are common and may be persistent and often progressive. A baseline and annual cardiac assessment that includes at least a CXR and an ECG is recommended.
   • Neurodevelopmental assessment – For older children, as well as young infants with neurologic deficits, imaging of the brain (MRI or CT) should be performed at baseline for evaluation of possible brain atrophy. Older children are referred for a baseline neurodevelopmental assessment by a neurologist. Infants can be referred after 6 months of age if there are no neurologic symptoms, and earlier if they are symptomatic.
   • Psychosocial assessment – The diagnosis of HIV infection in a child is very devastating for a family. Since the care of an HIV-infected child is a chronic issue, clinicians should aim to establish a long-term relationship with the patient and the family. The establishment of trust and rapport greatly improves adherence to medical treatment. The family should be assessed by the medical social worker for addressing their social service need or financial support. Members of the family should be offered referral to a clinical psychologist. Referral to non-government organisations in the field of HIV care should also be considered. These organisations provide invaluable integrated services including home care nursing, physiotherapy, counselling and activities to families of HIV-infected individuals.

Prevention of opportunistic infections (OI)

Caregivers should be advised to avoid consumption of raw or undercooked meat, seafood or poultry, unpasteurised milk products as well as food prepared under doubtful hygiene conditions to decrease the risk of enteric infection. They should also be advised of the potential risks of infection from pets, e.g. cats that can transmit toxoplasma and bartonella, and turtles and reptiles that can transmit salmonella. Exposure to young farm animals should also be avoided to reduce the risk of cryptosporidiosis. HIV infected children should not drink or swim in lake or river water to reduce the risk of Cryptosporidium or Giardia infection. Practice of good hand-washing and personal hygiene should be emphasised.

For PCP and Mycobacterium avium complex (MAC) prophylaxis, please refer to Box 34.1a, Box 34.1b and Box 34.2.

Immunisation

HIV-exposed and infected infants and children should receive standard paediatric immunisations with a few adjustments.

BCG
The recommendation of BCG vaccine is based on a risk assessment between disseminated BCG infection in HIV-infected infants immunised with BCG and the high prevalence of tuberculosis in our locality. In Hong Kong BCG is recommended, but with the availability of virologic testing, the vaccination can be deferred till 4 months of age when HIV infection is definitely excluded.

MMR
Measles-mumps-rubella (MMR) vaccination is recommended for HIV-exposed and HIV-infected children who are not severely immunocompromised (CDC immune category 3).

Varicella vaccine
HIV infected children aged 1-8 years in CDC Stage 1 or 2, or aged >8 years with CD4 ≥200/μL may be considered for varicella immunisation. Due to lack of data on safety for the new combination MMR-V vaccine, monovalent vaccine should be used.

Rotavirus vaccine
Because of the limited safety and efficacy data in the use of rotavirus vaccine in HIV-infected children, the balance between the potential risk and benefits of this live-attenuated vaccine should be considered. Recommendation from the US favours the use of the vaccine. In HIV-exposed infants, if presumptive exclusion of HIV infection can be made before the age for the first dose (maximum age is 14 weeks and 6 days), rotavirus vaccine immunisation may be considered.

Influenza vaccine
Influenza vaccine should be given seasonally and repeated annually for children who are at least 6 months of age and are infected, or living with persons who are infected with HIV. Nasal live attenuated influenza vaccine should not be used.

Hepatitis A vaccine
There is a high rate of hepatitis A infection among MSM population in Hong Kong and some other cities/countries. Adolescent MSM is recommended to receive a 2 dose regimen if they are confirmed non-immune to the virus.

Nutrition

HIV-infected children require high-energy, high-protein, nutrient-dense diets. For early intervention, all infants and children diagnosed of HIV infection should receive a baseline nutritional assessment within 3 months of diagnosis with follow-up every 1 to 6 months depending on the child’s status and condition. Wasting syndrome can be a significant problem in HIV infected children, accounting for 17% of the reported AIDS-defining condition in the US in 1994.

Disclosure

Children who know their HIV status have higher self-esteem than children who are not aware of their diagnosis, and patients who have disclosed to their children experience less depression than those who do not. There is no arbitrary age of disclosure but the American Academy of Pediatrics recommends disclosure to school age children. However, concrete guidelines are not available. The appropriate time should be determined jointly with the parents and when the child is deemed mature enough. Ongoing support should be provided to the parents and children before, during and after the disclosure is made.

Antiretroviral therapy

Goals and principles of HAART

The immediate goal of therapy should be complete viral suppression. With the implementation of universal testing of pregnant women for HIV infection, most HIV infants can be diagnosed in the first month of life. Provided that the child carers are committed to adherence to long-term therapy, early treatment of these recently infected infants offers the best chance for complete viral suppression and reduced early mortality. Initiating therapy very early in primary infection may also prevent the spread of HIV to long-lived reservoirs like memory CD4+ T lymphocytes. The goals of antiretroviral therapy therefore include: (a) life prolongation; (b) prevention of disease progression; (c) maintenance or improvement of quality of life, (d) prevention of emergence drug-resistance mutants, (e) reducing the risk of sexual transmission to discordant partners in adolescents who are sexually active, and (f) reducing the risk of perinatal transmission in adolescent females who become pregnant.

Recent studies had suggested that CD4 cell counts provided greater prognostic value over CD4 percentage for short term disease progression for children aged <5 years as well as in older children. Thus a preference for absolute CD4 count over CD4 percentage is used for deciding the timing for commencement of antiviral treatment.

The following are criteria for initiating the use of antiretroviral treatment in infants and children:[Box 34.5]

1. Urgent treatment should be provided for HIV-infected infants <12 months of age, regardless of clinical status, CD4 percentage, or viral load. Based on results of the CHER Trial, early commencement of ART before 12 weeks of age in asymptomatic MTCT infants have a 75% reduction in early mortality.[6] However, the issues associated with adherence should be addressed and thorough discussion with caretakers should be made before initiation of therapy. With more clinical evidence available, the administration of a three-drug combination ARV regimen to newborns at highest risk of HIV acquisition is now considered. Empiric HIV therapy is intended to be early treatment for a newborn who is later confirmed to have acquired HIV, but also serves as ARV prophylaxis against HIV acquisition for those newborns who are exposed to HIV in utero, during the birthing process, or during breastfeeding and who do not acquire HIV.
2. Urgent treatment should also be provided for all children ≥12 months with Stage 3-defining opportunistic illness, or 1 to <6 y with CD4 <500/μL, or ≥6 y with CD4 <200/μL.
3. Treatment should be offered to all children ≤12 months, regardless of symptoms, viral load or CD4 counts.

The regimen

When antiretroviral treatment is indicated, HAART should be prescribed.[Box 34.6] The treatment should only be given by paediatricians experienced in HIV care. The regimen chosen should be effective in achieving a sustained viral suppression and the side effects should be tolerable. The antiretroviral regimen for infected infants of mother who have received antiretroviral treatment should not be routinely chosen on the basis of maternal regimen. However, genotypic mutations conferring resistance have been documented in US infants with perinatal antiretroviral exposure.[10] Resistance testing prior to initiation of therapy in all treatment-naive children is recommended.

The recommended regimen includes either a non- nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase inhibitor (INSTI) plus a dual-nucleoside reverse transcriptase inhibitors (NRTI) backbone (Box 33.6). In children having sustained virological suppression, their current HAART can be modified to once-daily dosing regimen to facilitate adherence.

While waiting for more clinical trials of antiretroviral drugs on children, some information regarding the efficacy of these drugs can be extrapolated from trials involving adults. The absence of clinical trials addressing paediatric-specific manifestations of HIV infection does not preclude the use of any approved antiretroviral drug in children. All antiretroviral drugs approved for treatment of HIV infection may be used for children when indicated – irrespective of labelling notations.

For selected ARV drugs, therapeutic drug monitoring (TDM) or checking pharmacogenetic markers may be indicated to minimise possible side effect.[Chapter C13] Examples include checking HLA B*5701 for abacavir use in non-Chinese patient, or TDM monitoring and checking CYP2B6 for efavirenz use in infants. Consultation with paediatric HIV expert is advised for details and arrangement.

References