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

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 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 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 HBV coinfection irrespective of immune status.

Children Under 1 Year of Age

ART should be started as soon as possible in all HIV-infected children under 1 year of age irrespective of clinical or immunological status.[4,6] Evidence for this comes from the South African randomized controlled Children with HIV Early Antiretroviral Therapy (CHER) trial,[36,37] which showed a 4-fold reduction in mortality among asymptomatic infants starting ART before 3 months of age compared with those starting at a CD4 percentage < 25% or WHO stage 3 or 4. In addition, in Europe, a 4-fold reduction in HIV progression/mortality was observed among infants starting ART at less than 3 months of age compared with later in a large infant cohort meta-analysis [European Infant Collaboration (EIC)].[38]

Additional CHER trial substudies have added further evidence of the clinical,[23,39] immunological[40] and neurodevelopmental[41] benefits of early ART initiation in infants. Data from European cohorts have also shown that virological, clinical and immunological benefits from early treatment are sustainable outside the trial setting.[42,43] Further analysis of laboratory parameters from the EIC has demonstrated an association between early infant ART, more rapid control of viraemia and a higher CD4 count up until 12 months of age.[44]

Universal treatment of all infants with HIV infection, although challenging, is an achievable goal. The risks of drug resistance and early toxicity are markedly outweighed by improvements in short-term mortality and disease progression, especially prevention of irreversible HIV encephalopathy.

Infants should be reviewed at a minimum of monthly intervals up to 6 months of age in order to increase ART dosing in line with growth. Symptomatic infants presenting with severe illness (including opportunistic infections) should start ART as soon as possible. Debate remains about whether ART should be started immediately or deferred until treatment for the presenting illness has started and the child is clinically stable. There is no evidence to inform this, and it is recommended that ART be started as soon as the child is stable (ideally within 2 weeks of diagnosis). Expert pharmacist advice should be obtained if there is a complex treatment for a coinfection (e.g. TB) as drug interactions may interfere with effectiveness and/or cause side effects. See Section 10 below for further specific information on coinfection.

Children Over 1 Year of Age – General Principles

Starting ART is recommended in all children over 1 year of age with HIV-related symptoms, and in asymptomatic children with CD4 counts or percentages below or approaching recommended age-related thresholds. Starting ART should also be considered in those with a high HIV RNA VL (> 100 000 copies/ml), as they are more likely to progress rapidly to symptoms or have a rapid fall in CD4 values.[45–47]

The evidence for clinical benefit of ART in children with AIDS/CDC category C disease is so strong that parental refusal to treat is a child protection issue. CDC clinical category B covers a wide range of disease severity. A retrospective study from the USA demonstrating a significant reduction in rate of progression of disease adds further weight to the recommendation that children with category B or C disease should be treated irrespective of their CD4 count/percentage.[48] PENTA now recommends that treatment should be initiated for all children in WHO stage 3 or 4 (CDC category B or C) and considered in all children with HIV-related symptoms (WHO stage 2; CDC category A).

CD4-guided treatment thresholds in asymptomatic children are based predominantly on analysis of paediatric and adult cohort data and extrapolation from the adult Simple Trial Comparing Two Strategies for Management of Anti-Retroviral Therapy (SMART study).[47,49–52] Only one randomized trial [Pediatric Randomised Early versus Deferred Initiation in Cambodia and Thailand (PREDICT)] has addressed the question of when to start ART in children over 1 year of age. Thai children aged 1–12 years (median age 6.4 years), with CD4 percentage 15–24%, were randomized to start immediate ART or defer ART until the CD4 percentage dropped below 15%. Rates of progression and death were unexpectedly low in both groups during 144 weeks of follow-up. As a result, the study was underpowered to detect a difference in the primary endpoint of AIDS-free survival. Analysis of secondary endpoints did, however, demonstrate better height-for-age Z scores in the immediate treatment group.[53]

The evidence for absolute age-related CD4 thresholds for starting ART remains as for the PENTA 2009 guidelines, as follows.

  1. Analysis of adult data
    Data from the SMART trial clearly showed that adults with CD4 counts between 250 and 350 cells/μL have significantly better outcomes on ART than off ART.[51] Adult (US and European) guidelines strongly recommend ART initiation at CD4 cell counts below 350 cells/μl.[2,3,5,6]

  2. Comparison of child and adult data
    Comparison of the short-term risks of disease progression in pre-ART adult seroconverters in the Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) cohort collaboration and in children aged 5 years and older in the paediatric HIV Paediatric Prognostic Markers Collaborative Study (HPPMCS) cohort showed that the short-term risk of disease progression was very similar in young adults (around 20 years old) and children aged 5 years and older.[52] Absolute CD4 count, rather than percentage, should therefore be used to determine treatment thresholds in children from the age of 5 years. These should follow the same CD4 threshold recommendations for treatment recommended in adult guidelines.

  3. Analyses of child data
    Analyses from the HPPMCS cohort demonstrated that CD4 counts are highly prognostic of disease progression at all ages after infancy.[49] However, to obtain a uniform progression risk with the thresholds for adults and children aged 5 years and over, thresholds between 1 and 5 years of age would have to change approximately every 6 months or less. This would require too many age bands for a workable guideline, and the historical data on which progression risks are based are not robust enough to warrant ignoring the importance of practical guidance and the desirability of general concordance with other international guidelines. Therefore, only two age bands between 1 and 5 years have been selected. CD4 count as well as CD4 percentage thresholds should be taken into account. In the HPPMCS data, 10–20% of CD4 percentages and CD4 counts are discordant in terms of ART initiation thresholds adopted for these PENTA guidelines. However, these values are frequently concordant on a subsequent blood sample. If consistent discordance is observed, and particularly if the count is below the threshold although the percentage is not, then initiation of ART is strongly recommended.[54]

The prognostic significance of plasma HIV RNA for short-term risk of disease progression is much weaker than CD4 count or percentage.[45–47,50] However, ART is recommended in asymptomatic children with VL persistently above 100 000 copies/ml, even if they do not meet CD4 count criteria.

Rapid clinical, virological or immunological failure may occur, but, in general, ART does not need to be started quickly except in infants or in an older child seriously ill with advanced HIV disease. Time spent preparing and educating the family, particularly about adherence, is very important. Starting ART needs to be supported and promoted by the caregivers if it is to succeed. It is preferable not to start ART at the first clinic visit. Older children should preferably know why they are taking treatment, and timing of full or partial naming of HIV diagnosis in relation to starting ART is an important consideration. These CD4 thresholds are for children without coinfection. See Section 10 for guidance in the context of HBV/HCV, TB and opportunistic infections.

Children Aged 1–3 Years

As in the previous PENTA guidelines,[1] CD4 thresholds for absolute indication to start treatment outside the infant period are based on data extrapolated from adults and analysis of HPPMCS data. The age bands (1−< 3, 3−< 5 and ≥ 5 years) provide harmony with DHHS guidelines (which are also largely based on HPPMCS data)[4] but contrast with new WHO guidelines which group all children aged 1–5 years together. The PENTA 2009 guidelines defined thresholds based on an individual child's risk of progression to AIDS or death over the subsequent 1 year (derived from HPPMCS data using the on-line PENTA calculator available at http://www.hppmcs.org/). The absolute treatment thresholds aimed to maintain the overall risk of mortality below 2% and the AIDS progression risk below 5% (acknowledging that progression risk is higher and more variable in the first few years after infancy). The ongoing success of ART means that we should continue to expect better clinical outcomes for children, and in 2015 these rates of disease progression are no longer deemed acceptable. Looking more closely at the calculated risks, using a threshold of < 1000 cells/μl and < 25%, between 1 and 3 years, risk of progression at these thresholds increases dramatically at younger ages (Table 2). For these reasons, while we recommend keeping the 2009 CD4 thresholds in this age range, it is also recommended that ART should be considered in all children aged 1–3 years in order to minimize risk of progression and death and to minimize potential deleterious effects of ongoing viral replication on the child's rapidly developing brain and immune system.

Children Aged 3–5 Years

As mentioned above, the levels of risk deemed acceptable in previous versions of the PENTA guidelines (2% mortality and 5% AIDS) should be lowered in the light of the ongoing success of ART, and the absolute CD4 threshold for ART initiation in children aged 3–5 years has been increased to 750 cells/μl and 25% accordingly (Table 3). This is in line with current US and WHO guidance.[4,6]

Children Aged > 5 Years

For older children, the recommended absolute threshold for ART initiation remains at a CD4 count of 350 cells/μl, in line with current European adult guidelines.[2,3] However, ART should be considered below 500 cells/μl, in line with current US and WHO guidelines, in order to potentially optimize ultimate CD4 count in adulthood (see below). Treatment should certainly be initiated before the CD4 count reaches 350 cells/μl rather than letting it fall below this value. The ongoing Strategic Timing of Antiretroviral Treatment (START) trial comparing ART initiation at > 500 cells/μl versus < 350 cells/μl will report in 2016.

Other Indications for ART Initiation Irrespective of Immunological or Virological Status

  • Coinfection with HCV or TB

  • Autoimmune manifestations (e.g. thrombocytopenia)

  • Malignancy

  • Growth or puberty delay

  • Neurocognitive delay

  • Prevention of transmission in sexually active adolescents

  • Pregnancy

  • Primary infection (e.g. after nosocomial or sexual transmission)

  • Child and family wish to start treatment (following full discussion of risk/benefit)

Consideration for Starting Antiretroviral Therapy to Optimize Immune Function in Adulthood

The aim of treatment in paediatric HIV infection should extend beyond survival to maximizing long-term outcomes and quality of life. Current treatment goals should thus include normal growth and physical, pubertal, neurological and psychological development and immune reconstitution, while minimizing long-term drug toxicity and viral drug resistance. To date, studies with such long-term outcome data have been lacking, but in the field of immune reconstitution, mathematical models may allow us to begin to use predicted long-term outcomes for treatment initiation decisions.

A number of studies indicate that, even with good adherence, long-term immunity may remain suboptimal after starting ART. The reasons for this are likely to be multifactorial and include: a depleted/inadequate immunological memory for childhood infections and vaccinations; destruction/skewing of B- and T-cell repertoires; and persistently low CD4 counts in relation to healthy age-matched children (reviewed in[55]). Mathematical modelling of data from large European and African cohorts indicates that CD4 cell recovery depends strongly on both the age and CD4 count at ART initiation.[56,57] The important predictions from these studies are as follows.

  1. Children under 5 years of age have very good potential for recovering their CD4 counts, even when counts are low at ART initiation.

  2. In contrast, with every year that passes after the age of 5 years, the potential for long-term CD4 count recovery to the normal range diminishes (Figure 1).

Figure 1.

Predicted long-term CD4 count following antiretroviral therapy (ART) initiation at thresholds of 250, 350, 500, 750 and 1000 cells/μL (curves), using models derived from the AntiRetroviral Research for Watoto (ARROW) study. Delaying treatment in children younger than 5 years (to the left of the vertical line) results in relatively small differences in long-term expected CD4 count. In contrast, children aged over 5 years (right of the vertical line) are predicted to experience a steady deterioration in long-term CD4 count as ART is initiated at increasingly older ages (and a constant CD4 threshold). Dashed lines show that a 6-year-old delaying treatment until the age of 13 years, with a CD4 count of 350 cells/μL throughout, may expect the long-term CD4 count to be lowered by 151 cells/μL: from 770 to 619 cells/μL.

Current PENTA guidelines recommended a uniform threshold for children over 5 years old and continuing at the same threshold through adulthood (CD4 count < 350 cells/μl). These mathematical projections raise the concern that this approach may substantially compromise long-term CD4 recovery in adulthood, particularly for children older than 10 years at ART initiation. The reasons for the effects of age and initial CD4 count on immune reconstitution are only partially understood. They are likely to be attributable to a combination of declining thymic output from its peak at 1 year of age and irreversible immune injury. Whatever the causes, it would appear logical to strive to initiate ART at combinations of age and CD4 counts that are most likely to achieve a better long-term reconstitution.

The absolute thresholds for ART initiation represent the lowest CD4 thresholds for ART initiation to prevent disease progression; however, these may not be optimal thresholds for CD4 recovery in adulthood. Although Figure 1 represents extrapolations in time and from available data, it can be used as a guide to help indicate how delay in ART initiation may adversely influence eventual CD4 recovery. With current treatment regimens, which are less toxic and easier to take, there is a theoretical case for starting ART at any CD4 count in older children, especially those over 5 years old.

Another long-term consideration when starting ART in children, irrespective of CD4 count, is the possible benefit of minimizing HIV viral reservoirs in order to optimize the potential for achieving eventual 'functional HIV cure'. Recent reports in both adults and children have indicated that early and sustained full suppression of HIV may limit viral reservoirs[58,59] and that a longer cumulative time spent with ongoing viral replication is associated with a larger viral reservoir.[60] How this may relate to future 'cure' is yet to be determined, but it should also be borne in mind when considering ART initiation in young children who may see the advent of new curative treatments within their lifetime.

We therefore recommend that the CD4 thresholds indicate the lowest limits below which a child should not be allowed to fall before starting treatment. Where resources allow and families are motivated, discussions should be had with children, young people and their families about the option of starting treatment at higher CD4 counts with the aim of optimizing long-term immune recovery, while always balancing possible long-term toxicity effects of ART and the potential for viral drug resistance if adherence is poor. With an increase in the number of indications for ART, and in the context of less robust evidence for clinical benefit, optimal adherence is essential so as not to compromise future treatment options though development of resistance to first-line drugs.

Comparison of PENTA Guidelines With DHHS and WHO Guidelines for HIV-infected Children and Adults

As can be seen from Table 1, PENTA and US guidelines are generally in agreement; however, DHHS guidelines advise that ART initiation should be considered for any child irrespective of immune and clinical status. Furthermore, the CD4 thresholds are higher for children over 5 years of age. This is in line with recent updates to adult DHHS and WHO guidelines, which give a universal ART threshold of 500 cells/μl, while DHSS recommend that asymptomatic adults should be considered for treatment at any CD4 count. The latter is in part based on cohort data demonstrating a possible benefit with respect to non-AIDS-related morbidity for all patients on ART as well as a known decrease in the risk of onward sexual transmission (summarized in[5]).

These most recent changes to the adult US guidelines have been debated extensively; the strength of the evidence on which they are based is relatively weak.[7,61,62] It is the opinion of PENTA that extrapolation of these adult data to guide treatment for children is inadvisable at present. Results of large randomized trials comparing higher versus lower treatment thresholds in adults are expected in 2016 [http://clinicaltrials.gov/show/NCT00867048 (START); http://clinicaltrials.gov/show/NCT00495651 (TEMPRANO)]. This evidence will clarify the wider risks and benefits of starting treatment at higher CD4 counts.

Current European/UK adult guidelines are more conservative.[2,3] The absolute CD4 threshold for ART initiation remains at 350 cells/μl, with a number of exceptions where starting at higher thresholds is indicated (end organ involvement, hepatitis/TB coinfection, pregnancy, discordant couples or primary infection). The PENTA 2015 guidelines are in line with European adult guidance, with the additional option that, for older children, ART initiation at CD4 counts > 350 cells/μl, to optimize immune reconstitution/CD4 count in adulthood, should be considered.

WHO guidelines have harmonized and simplified adult and child recommendations as far as possible, recommending starting ART in all children under 5 years of age, and in older children with CD4 counts < 500 cells/μl. Treatment is recommended for all children under 5 years old for mainly programmatic reasons alongside extrapolation of data from adult cohort studies suggesting clinical benefit to treating irrespective of immune status, while accepting that neither data from PREDICT[53] nor data from a causal modelling study from a large paediatric cohort study[63] indicate clinical benefit. It is suggested that, by simplifying guidance and making treatment universal, access to ART for children will increase in resource-poor settings where it remains inadequate. This is fortunately not as relevant for the majority of European countries, so for this reason universal treatment is still only recommended by PENTA for those under 1 year of age, for whom the evidence-based health benefits are incontrovertible.

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