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

Summary of Recommendations

Diagnosis, Baseline Investigations and Pretreatment Monitoring

  • If a woman is diagnosed with HIV infection, all of her 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 polymerase chain reaction (PCR) with subsequent confirmatory repeat PCR if positive.

  • Post-exposure prophylaxis (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 with 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 a positive HIV RNA PCR test 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 human leucocyte antigen (HLA) B*5701 genotype should be confirmed negative before using abacavir (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 viral load (VL) and CD4 count].

  • Local guidelines for bacillus Calmette−Guérin (BCG) immunization of babies of HIV-infected mothers should be followed. HIV-exposed infants at low risk of HIV transmission (maternal VL < 50 HIV-1 RNA 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.

Prophylaxis Against Opportunistic Infections

  • Prophylaxis against Pneumocystis jirovecii pneumonia (PJP) should be given to all HIV-infected infants from age 1 month and to older children with low CD4 counts: in children aged 1–4 years, CD4 count < 500 cells/μL or < 15%; in children aged ≥ 5 years, CD4 count < 200 cells/μl or < 15%. Co-trimoxazole is the drug of first choice (see drug table in Supplementary Table S1 for dosing).

  • Routine primary prophylaxis against other infections is not recommended.

When to Start ART

ART is recommended:

  • in all children under 1 year of age;

  • in all children with significant disease [WHO stage 3 or 4 or Centers for Disease Control and Prevention (CDC) stage B or C];

  • in asymptomatic children over 1 year of age based on age-specific CD4 count thresholds;

  • to be initiated before the CD4 count reaches the CD4 treatment threshold;

  • in those with hepatitis C virus (HCV) or active TB coinfection.

ART should be considered:

  • in asymptomatic children over 5 years of age at CD4 counts of 350–500 cells/μl, to potentially optimize CD4 count in adulthood;

  • in children with high VL (> 100 000 copies/ml);

  • in asymptomatic children aged 1–3 years irrespective of immune status and VL;

  • in sexually active adolescents, to minimize the risk of onward transmission;

  • in the presence of any significant HIV-related clinical symptoms;

  • in hepatitis B virus (HBV) coinfection irrespective of immune status.

Which ART Regimen to Start as First-line Therapy

  • Children should start effective (at least three drugs) ART, usually a dual or triple nucleoside reverse transcriptase inhibitor (NRTI) backbone together with either a ritonavir-boosted protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI).

  • Children exposed to nevirapine (NVP) during failed prevention of mother-to-child transmission (PMTCT) (or in whom perinatal NVP exposure cannot be excluded) should be started on a boosted PI-containing regimen as transmitted resistance may lead to failure of NVP-containing ART.

  • Children aged < 3 years not exposed to NVP during failed PMTCT may be initiated on either NVP or ritonavir-boosted lopinavir (LPV/r)-containing ART. We recommend that NVP should be given together with three NRTIs [ABC, lamivudine (3TC) and zidovudine (ZDV)] in all infants and in children aged 1–3 years with VL > 100 000 copies/ml or signs of central nervous system (CNS) involvement as an induction-maintenance strategy, unless any of these drugs are contraindicated (such as ABC in HLA B*5701-positive children).

  • In children aged > 3 years, either NNRTI or boosted PI-based ART is acceptable for initial therapy. Factors such as availability of age-appropriate formulations, palatability, dosing frequency and adherence should be considered when choosing NNRTIs or boosted PIs.

  • The preferred NNRTI is NVP in children aged < 3 years not exposed to NVP during failed PMTCT, and efavirenz (EFV) in children aged > 3 years. The preferred PI in children aged < 6 years is LPV/r, in children aged 6−12 years it is ritonavir-boosted atazanavir (ATV/r), and in children aged > 12 years it is ATV/r or ritonavir-boosted darunavir (DRV/r).

  • Integrase inhibitor (INSTI)-based ART may be an alternative regimen in children over age 12 years.

  • The preferred first-line NRTIs are ABC/3TC in children aged < 12 years, and tenofovir/emtricitabine (TDF/FTC) or ABC/3TC (if VL < 100 000 copies/ml) in children aged > 12 years.

  • Age, HLA B*5701 genotype, previous drug exposure, resistance profile, coinfections, available formulations and likely adherence should be taken into account when choosing a first-line regimen.

  • See Table 4 (later) for details of recommended first-line ART regimens.

Adherence and HIV Knowledge

  • Adherence to treatment is paramount and should be discussed at each clinic visit.

  • Every effort should be made to simplify a regimen to support adherence (e.g. using once-daily regimens, FDCs, and 'forgiving' regimens with higher barriers to resistance). Simple adherence aids should be used when appropriate.

  • Children should know of their HIV diagnosis before adolescence.

  • Monitoring for psychological, neurocognitive and mental health issues should be routine, allowing early supportive and therapeutic intervention.

Monitoring on ART

  • The aim of ART is to achieve an undetectable VL (< 50 copies/ml) and CD4 reconstitution.

  • Laboratory monitoring for drug toxicity should be performed initially within 2–4 weeks of starting a new drug, then at least every 6 months if there are no ongoing toxicity concerns.

  • After starting ART, VL should be checked early (at around 1 month) to confirm that VL is decreasing (this can coincide with toxicity monitoring).

  • VL and CD4 count can then be monitored approximately every 3–4 months once the patient has been established on treatment.

  • Once CD4 cells are reconstituted and VL has been < 50 copies/ml consistently for over 1 year, CD4 parameters can be monitored less frequently (every 6–8 months, i.e. at alternate clinic visits).

  • More frequent clinical and laboratory monitoring is required:

  • in infancy;

  • if adherence is poor;

  • soon after starting or changing therapy (e.g. liver function tests should be performed within 2 weeks);

  • in the context of ongoing drug toxicity;

  • when giving medications with significant drug interactions with ART such as antituberculous therapy.

Drug Toxicities and Interactions

  • Toxicities depend on the individual drugs and ART combination and should be assessed at each clinic visit.

  • Drug interactions should be considered when starting new medications in a child on ART. Use http://www.hiv-druginteractions.org/ to check drug interactions and toxicities.

  • See Table 5 (later) for common ART-associated toxicities.

Coinfections

Hepatitis B virus and hepatitis C virus:

  • Liver disease in children with HBV or HCV coinfection should be managed jointly with paediatric experts in viral hepatitis.

  • HCV coinfection is an indication for starting ART.

  • For HBV coinfection, if treatment of HIV infection is not indicated and there is no evidence of liver disease, HIV treatment should be considered but may be deferred.

Tuberculosis:

  • All HIV-infected children exposed to an individual with infectious TB and all children with evidence of latent TB infection should have preventive TB treatment (once active TB disease has been excluded).

  • In children with active TB disease, TB treatment should be started at TB diagnosis. ART should be started, as soon as practicable, and within 2 and 8 weeks of TB treatment in children with severe and moderate immunosuppression, respectively. ART may be deferred at higher CD4 counts until TB treatment is completed.

  • There is significant interaction between ART and TB therapy. Therapeutic drug monitoring (TDM), where available, should be used in the context of potential significant interactions.

  • Children with TB coinfection should be managed in consultation with an expert in the treatment of paediatric TB. A specialist in drug-resistant TB (DRTB) should be involved in the management of DRTB contacts and cases.

  • See Table 6 (later) for ART choices in children with TB.

Opportunistic infections:

  • We recommend that ART should be initiated as early as possible, apart from in the context of cryptococcal meningitis, where evidence in adults has shown that delaying ART may be associated with reduced mortality.

When to Switch, Resistance Testing and Second and Subsequent ART Regimens

ART regimens may be changed because of treatment failure, because of toxicity or for simplification.

Virological failure – second and subsequent regimens:

  • Switching to second-line therapy following virological failure should occur early (VL > 1000 copies/ml) for those failing on combinations including drugs with a low genetic barrier to resistance [NNRTIs or raltegravir (RAL)].

  • Where there are blips in VL (detectable VL < 400 copies/ml), blood tests should be repeated within 4 weeks to confirm re-suppression.

  • Reinforcement of adherence support, as the main reason for treatment failure, should be prioritized. Switching treatment when there are ongoing problems with adherence may lead to loss of efficacy of further classes of ART.

  • Table 7 (see later) summarizes potential strategies for choosing second-line therapy. If the suggested options are not applicable, seek expert advice.

Resistance testing:

  • Resistance testing should be performed prior to switching regimens when there is virological failure. Resistance testing should be undertaken while the patient is still on the failing regimen. If this is not possible, ideally test for resistance within 4 weeks of stopping the failing regimen.

  • Resistance testing may include reverse transcriptase/protease/integrase/V3 loop/envelope sequencing.

  • The interpretation of resistance results can be guided by the Stanford HIV Drug Resistance Database (http://hivdb.stanford.edu/).

  • Substituting single drugs in a failing regimen without prior resistance testing is not recommended.

Simplification

  • Where possible, regimens should be simplified (once-daily and fixed dose combinations), but switching to NNRTI-based regimens or PI monotherapy is not advised if there are adherence issues.

Stopping Treatment and Treatment Interruption

  • Treatment interruptions cannot be routinely recommended and starting ART currently means lifelong therapy.

  • Judicious use of planned treatment interruptions may be considered in circumstances when ART needs to be stopped such as because of toxicity or adherence difficulties, while the latter is being addressed.

  • Stopping NNRTIs when HIV is fully suppressed requires a replacement or staggered stop to reduce the risk of developing NNRTI resistance as a result of the longer half-life of NNRTIs. A replacement stop is preferable.

Adolescence, Mental Health and Transition

  • Adolescents commencing first-line therapy should be started on boosted PI-based ART and subsequently switch to NNRTI-based ART once adherence has been established and VL is consistently < 50 copies/ml.

  • Multidisciplinary monitoring for signs of psychological distress and mental health disorder should be routine as children progress through adolescence towards transition.

  • Early and ongoing support from clinical psychologists with specialist paediatric knowledge is recommended.

Pipeline and Upcoming Trials

See Table 8.

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