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

Stopping Treatment and Treatment Interruptions

  • 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.

It is now clear that immune activation is a key component of HIV immunopathogenesis, and is characterized by polyclonal B- and T-cell activation, increased T-cell turnover, high levels of apoptosis and raised proinflammatory cytokines and chemokines. Immune activation drives CD4 decline, immunosenescence and immune exhaustion. The aetiology of HIV-related immune activation is multifactorial but includes immune responses to HIV and other reactivated chronic viral infections, direct T-cell activation by HIV components, depletion of CD4 regulatory T cells and translocation of microbial products across the gut mucosa.[202]

Many studies have shown that levels of immune activation are reduced but not normalized by ART, and it is the ongoing inflammation that may underlie the noninfectious complications of HIV infection such as heart and brain disease. Indeed, the SMART trial, a large randomized CD4 cell count-driven treatment interruption study in adults, was stopped early because of higher rates of non-AIDS-related complications and deaths (cardiovascular, liver and renal) in the treatment interruption arm as a result of presumed increased levels of immune activation off ART.[51] Largely because of the SMART trial results, treatment interruptions are no longer recommended in adult patients.

In view of these studies in adults, studying treatment interruptions in children has been difficult. However, earlier ART initiation in children and commencement of ART in all those diagnosed during infancy increase the importance of addressing the question of whether children can undergo periods off ART safely. There are many reasons why children may have superior responses to intermittent therapy than adults. These include the much lower short-term risk of cardiovascular complications in children, and the benefit of a more active thymus, which facilitates improved capacity for immune reconstitution.

In a paediatric feasibility trial, PENTA 11, assessing clinical, immunological and virological data for planned treatment interruption (PTI) in older children with a median age at entry of 9 years, there were no deaths or serious clinical events in the treatment interruption arm.[203] By 2 years after the end of the trial, when the majority of children were back on ART, there was no difference in immunological recovery or viral suppression in the treatment interruption and continuous arms.[204] Independent predictors of attaining a higher CD4 percentage after re-start of ART were higher baseline CD4 percentage prior to PTI and higher CD4 percentage prior to re-start of ART. Although the PENTA 11 trial showed some evidence of immune reactivation during PTI,[205] this did not translate into clinical events. Reassuringly, there was no difference in height or weight gain and no difference in developmental test scores between the two arms. In addition, most carers and children reported better quality of life during PTI, and the clinicians were more likely to re-start ART after PTI with simpler regimens and FDCs.[204]

Can treatment be interrupted after starting early ART in infants? The CHER trial in South Africa showed that it is safe to stop ART at 1 or 2 years of age where clinical, virological and immunological parameters do not meet criteria for ART. However, most of the children who stopped ART at 1 or 2 years of age needed to re-start in a median time of 33 weeks or 70 weeks, respectively.[36] Nevertheless, nearly a third of children who stopped ART at 2 years of age were still off ART at the end of the 6-year trial. Unfortunately, the study had no comparator continuous treatment arm to ascertain whether it is more advantageous to stay on continuous ART beyond 2 years of age. A small randomized trial in young Kenyan children, with a median age of 30 months, comparing continuous versus interrupted treatment after 2 years of ART, was stopped early because a high proportion required to re-start ART: 66% by 3 months post interruption and 86% by 18 months.[206] So, at present, ART interruption cannot be routinely recommended even after ART has been started in infancy.

Despite the recommendation for continuous therapy, unplanned treatment interruptions in children as a result of adherence difficulties or side effects of ART are common.[207] Interruption of treatment occurred in nearly a quarter of children and young people in the Adolescent Master Protocol study in the USA.[207] In the light of such frequent unplanned treatment interruptions, strategically planned treatment interruptions may be preferable. Where possible, this should be done safely to avoid development of resistance to classes of drugs that could be used again in the future. The options are a 'staggered stop', where the NRTI backbone is continued for at least 7–10 days after stopping the NNRTI to cover the 'tail', or a 'replacement stop', where the NNRTI is replaced by a boosted PI before discontinuing the PI and NRTIs simultaneously. There are no randomized comparisons of these strategies; however, evaluation of emergent resistance mutations in the SMART trial showed higher rates of follow-up resistance mutations in patients undertaking a simultaneous or staggered stop compared with a replacement stop (although this did not reach statistical significance).[208] A replacement stop is therefore preferable. The EFV 'tail' may be longer compared with that of NVP because of the longer half-life, and therefore the replacement stop may need to be longer (21 days of the PI and NRTIs).[209]

Further studies of treatment interruptions in adults and children may give better understanding of their place in the management of HIV infection in children and young people. The results of the Botswana/Baylor Antiretroviral Assessment trial as well as a 5-year follow-up on immunological and neurodevelopmental outcomes in PENTA 11 are awaited. Further research is needed to ascertain whether PTI can reduce unplanned interruptions in older children and young adults and be advantageous in terms of reduction of resistance, preservation of future treatment options and improvement of quality of life.

Might the case be different following early ART for primary infection? The results of the Short Pulse Anti Retroviral Therapy at HIV Seroconversion (SPARTAC) trial in adults, comparing short-term ART initiated during primary HIV infection (ART for 48 weeks or 12 weeks) versus standard of care (no ART), showed that a 48-week course resulted in delayed decline of CD4 count and lower VL off treatment as compared with standard care. Disappointingly, time off treatment was not significantly longer than the 48-week treatment period and the increase in CD4 count on long-term ART was similar across all three groups. In contrast to the SMART trial, there were no adverse effects on clinical outcomes.[51,210] Adult case series from prospective observational cohort studies and the results of the Agence Nationale de Recherche sur le SIDA (ANRS) Virological and Immunological Studies in Controllers after Treatment Interruption (VISCONTI) study suggest that some patients with different genetic characteristics and characteristic CD8 cell response to HIV, after prolonged treatment of primary HIV infection, can control HIV replication post treatment interruption for at least several years.[211,212] It appears that restricting the pool of HIV-infected cells by very early treatment might decrease long-lived viral reservoirs,[213] which may be essential for successful control without therapy.[212]

In addition to these adult studies, there is a case report of ART-free 'HIV remission' for over 2 years in a child who was started on ART at 36 hours after birth,[214] and a more recent report of an infected infant on continuous ART treatment from 4 hours of age with undetectable proviral DNA by 6 days of life.[215] Although the first patient has now been reported as having detectable VL and has commenced ART,[216] these reports together provide a proof of concept that in some individuals, after early treatment of primary infection, a prolonged treatment interruption may be possible with preservation of control of HIV replication. The phenomenon of post-treatment HIV controllers is rare and treatment interruption cannot be applied to routine management of children. Extensive research is being undertaken to identify correlates for prolonged remission in post-treatment controllers.

In summary, routine treatment interruptions cannot be recommended at present and starting ART currently means lifelong therapy. In circumstances where unplanned treatment interruption is unavoidable, it needs to be done safely, as outlined above. Strategic treatment interruption may be considered in individual circumstances of problematic adherence in order to avoid resistance and preserve future treatment options.

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