Paediatric European Network for Treatment of AIDS (PENTA) Guidelines for Treatment of Paediatric HIV-1 Infection 2015

Optimizing Health in Preparation for Adult Life

A Bamford; A Turkova; H Lyall; C Foster; N Klein; D Bastiaans; D Burger; S Bernadi; K Butler; E Chiappini; P Clayden; M Della Negra; V Giacomet; C Giaquinto; D Gibb; L Galli; M Hainaut; M Koros; L Marques; E Nastouli; T Niehues; A Noguera-Julian; P Rojo; C Rudin; HJ Scherpbier; G Tudor-Williams; SB Welch

Disclosures

HIV Medicine. 2018;19(1):e1-e42. 

In This Article

Diagnosis, Baseline Investigations and Pretreatment Monitoring

  • If a mother is diagnosed with HIV infection, all children potentially at risk of infection should be tested for HIV irrespective of age.

  • Children under 18 months of age at risk of perinatally acquired HIV infection should be tested using blood DNA or RNA PCR with subsequent confirmatory repeat PCR if positive.

  • PEP should be given for 4–6 weeks to all babies born to HIV-infected mothers according to local guidelines.

  • Babies born to HIV-infected mothers should have an HIV RNA PCR test at birth and at least two further separate PCR tests (the first 2 weeks after cessation of PEP, and the second at least 6 weeks after cessation of PEP). For babies at high risk of transmission, an additional PCR test midway through PEP is recommended.

  • Breast feeding is not recommended. In circumstances in which the mother is choosing to breast feed against recommendations, the baby should have regular screening PCR tests. Two negative HIV RNA PCR tests (2 and 6 weeks after cessation of breast feeding) are required to confirm that the baby is not infected.

  • Children over 18 months of age can be tested using serological assays with subsequent confirmatory PCR if positive or equivocal.

  • A negative serological test in children who have had positive HIV RNA PCR does not exclude ongoing HIV infection.

  • A detailed history of any possible previous ART given to the child and/or mother (or other likely source of infection) should be documented.

  • The genotypic HIV resistance profile should be documented at baseline.

  • The HLA B*5701 genotype should be confirmed negative before using ABC.

  • Clinical assessment should be carried out 3−4-monthly in children who are stable off ART, with frequency of laboratory monitoring dictated by age, clinical status and proximity to thresholds for ART initiation (minimum 6-monthly HIV VL and CD4 count).

  • Local guidelines for BCG immunization of babies of HIV-infected mothers should be followed. HIV-exposed infants at low risk of HIV transmission (maternal VL < 50 copies/ml at or after 36 weeks of gestation) with high risk of TB exposure may receive BCG vaccination at birth, prior to definitive diagnosis/exclusion of HIV infection.

Confirmation of HIV Diagnosis

Optimal treatment of HIV infection in children depends upon timely diagnosis. This requires early HIV testing of all infants born to HIV-infected women and prompt testing of infants or older children at risk or with symptoms or signs of HIV infection. Infants born to women with HIV infection will be HIV antibody positive because of transplacental transfer of maternal antibodies. An HIV PCR test is needed to confirm or exclude the diagnosis. Either HIV RNA or DNA PCR may be used, depending on local availability.[8–12] PEP should be given for 4–6 weeks to all babies born to HIV-infected mothers according to local guidelines. A PCR test should be performed at birth. At least two positive PCR tests on separate samples from the baby (not the umbilical cord) are required to confirm an HIV diagnosis. A repeat test should be carried out as soon as possible after any positive PCR test in an infant to avoid delay in confirming the diagnosis and initiating treatment. Up to 62% of HIV-infected neonates may have a negative initial PCR test in the first 48 hours of life.[12] PCR tests become more reliable 14–21 days after birth. The purpose of the initial test at birth is thus to allow rapid identification of those that are already positive so that a confirmatory test and treatment can be initiated without delay. Later tests are essential for excluding HIV infection in babies who test negative at birth.

In the absence of breast feeding, at least two separate negative HIV RNA PCRs after stopping PEP are required to confirm that an exposed baby is uninfected (the first 2 weeks after cessation of PEP, and the second at least 6 weeks after cessation of PEP). For babies born with high risk of transmission, an additional PCR test midway through PEP is recommended to allow earlier identification of infected infants. The use of fourth-generation point-of-care antibody/antigen testing for diagnosis of HIV infection in children under 18 months of age is not recommended in view of low sensitivity for distinguishing between HIV infection and positive serology from maternal antibody.[13] Some less prevalent HIV subtypes may escape detection by PCR (e.g. HIV A, C-H and O).[14] Those using PCR for diagnosis should know the sensitivity of the assay being used for the likely subtype being tested for. Expert advice should be sought if there is any doubt about the interpretation of results. However, initiation of ART in infants should not be unduly delayed by referrals to an expert centre.

Babies of HIV-infected women may subsequently become infected after initial negative tests if they are breast-fed. Breast feeding is not recommended in high-income countries, where alternative feeding is safe and practical. If in exceptional circumstances an uninfected baby is breast-fed, the mother should be on effective ART. Two confirmatory PCR tests, 2 and 6 weeks after cessation of breast feeding and PEP, are required to confirm that the baby is not infected. It is important to note that HIV-infected children who have commenced ART may become seronegative by standard commercial testing after loss of passively acquired maternal antibodies, especially after early ART initiation (< 3–6 months of age).[15] A negative serological test in this context does not exclude ongoing HIV infection as the HIV DNA PCR test remains positive.

Infants and children > 18 months of age who present with symptoms consistent with HIV infection and unknown maternal HIV status should initially have an HIV antibody test. If this is positive, they will require a confirmatory PCR test. It is recommended that all previously untested children of HIV-infected women should be tested for HIV whatever their age, as infected children may remain asymptomatic throughout childhood and adolescence.[16] All siblings at risk of perinatally acquired infection (irrespective of age) should also have an HIV test. Adult physicians and family doctors should routinely ask all HIV-infected men and women in their care if they have children and refer those at risk for testing.[17]

Baseline Assessments Once Diagnosis has Been Confirmed

Once a diagnosis of HIV infection has been confirmed, children should be assessed clinically, including assessment of growth and development, to allow staging of HIV infection according to WHO (or CDC) classifications.[4,6]

To plan future ART, it is important to document whether the child has been exposed to previous ART, in utero, through breast feeding, as PEP or as therapy (e.g. in their country of origin). If available, the antiretroviral history of the mother or other source case should also be documented. In view of the possibility of transmitted drug resistance[18,19] and unreported prior ART exposure, HIV genotypic resistance testing is recommended at baseline (including reverse transcriptase, protease and integrase resistance testing when available). If available, the results of resistance testing of the source case, as close as possible to the time of transmission, should also be documented. Baseline viral co-receptor [C-C chemokine receptor type 5 (CCR5)] tropism testing is not indicated, as CCR5 receptor antagonists are not currently recommended as first-line therapy. Other baseline investigations after HIV diagnosis include measurements of HIV RNA VL and CD4 lymphocyte percentage and absolute count, tests for other vertically transmitted or postnatally acquired infections [infections with HBV, HCV, toxoplasma, cytomegalovirus (CMV), syphilis, TB and Chagas (in those at risk)], full blood count, haemoglobinopathy screen (in risk groups), bone profile, and tests of liver and renal function. Baseline echocardiography in those at risk of cardiomyopathy should be considered. HLA B*5701 testing, where available, is recommended at baseline prior to starting ABC.[20] See baseline investigations at http://www.chiva.org.uk for further guidance.

A full vaccine history should be taken and if necessary serology performed to confirm immunity and to aid in decision making around catch-up and boosting.[21] Local BCG practices for babies of HIV-infected mothers should be followed. In areas of low TB incidence or if there is high risk of HIV transmission, BCG vaccination should be postponed until an infant is confirmed as HIV negative. HIV-exposed infants at low risk of HIV transmission (maternal VL < 50 copies/ml at or after 36 weeks of gestation) with high risk of TB exposure may receive BCG vaccination at birth, prior to definitive diagnosis/exclusion of HIV infection.[22] The very low risk of HIV transmission with an undetectable maternal VL means that in these circumstances the risk of severe TB from not vaccinating is greater than the risk of HIV-related BCG complications. In resource-poor settings with high TB prevalence, BCG vaccination is given to all infants prior to determination of HIV status. Early ART in this context has been shown to minimize the risk of BCG-related complications.[23]

In those presenting outside the neonatal period, a baseline chest radiograph allows assessment for respiratory complications, including lymphoid interstitial pneumonitis and TB. Infants and children with advanced HIV disease should have an ophthalmic examination for evidence of retinitis, and a blood CMV PCR test (if available). Infants and children with evidence of neurological involvement should undergo baseline neuroimaging. Additional baseline immunological assessment for evidence of TB infection is recommended [tuberculin skin test (TST) and/or interferon gamma release assay (IGRA)].

Children not yet requiring ART (see treatment criteria below) should have clinical monitoring at intervals of no longer than 3–4 months. Routine monitoring should include clinical examination and measurement of growth parameters. Monitoring for HIV disease progression and complications using CD4 count/percentage and VL, renal and liver function and urinalysis is recommended on a 6-monthly basis, and should be performed more frequently in younger children and those approaching treatment thresholds. Annual assessment of neurodevelopment, blood pressure, nutrition (including lipids) and puberty is also recommended. Vitamin D should be assessed and managed according to local guidelines as in HIV-uninfected children. Less frequent assessment of these parameters has been suggested in adult guidelines.[2] However, in view of the possibility of more rapid disease progression in children, the frequency of laboratory monitoring should remain as recommended above for children not receiving ART.

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