Elsevier

The Lancet Infectious Diseases

Volume 15, Issue 9, September 2015, Pages 1108-1114
The Lancet Infectious Diseases

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Early antiretroviral therapy in children perinatally infected with HIV: a unique opportunity to implement immunotherapeutic approaches to prolong viral remission

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Summary

From the use of antiretroviral therapy to prevent mother-to-child transmission to the possibility of HIV cure hinted at by the Mississippi baby experience, paediatric HIV infection has been pivotal to our understanding of HIV pathogenesis and management. Daily medication and indefinite antiretroviral therapy is recommended for children infected with HIV. Maintenance of life-long adherence is difficult and the incidence of triple-class virological failure after initiation of antiretroviral therapy increases with time. This challenge shows the urgent need to define novel strategies to provide long-term viral suppression that will allow safe interruption of antiretroviral therapy without viral rebound and any associated complications. HIV-infected babies treated within a few days of birth have a unique combination of a very small pool of integrated viruses, a very high proportion of relatively HIV resistant naive T cells, and an unparalleled capacity to regenerate an immune repertoire. These features make this group the optimum model population to investigate the potential efficacy of immune-based therapies. If successful, these investigations could change the way we manage HIV infection.

Introduction

Study of the pathogenesis and management of HIV in paediatric populations has contributed pivotally to the collective understanding of the pathogen, from use of antiretroviral therapy to prevent mother-to-child transmission1 to the possibility of cure suggested by the circumstances surrounding the Mississippi baby.2 Babies infected vertically with HIV and treated within a few days after birth represent a unique opportunity to study novel approaches to HIV management and particularly therapeutic vaccines. These babies have a very small viral reservoir, rarely exhibit HIV-specific immunity, but still seem to maintain normal immune development.3, 4 The unique combination of a very small pool of integrated viruses,5 a very high proportion of relatively HIV resistant naive T cells,6 and an unparalleled capacity to regenerate an immune repertoire7, 8 makes this group the optimum model population to investigate the potential efficacy of immune-based therapies.

Infants born with HIV infection have access to potent combinations of antiretroviral therapy, so that increasing numbers of children are surviving to adolescence and older. Despite this optimistic outlook, several questions still need to be addressed (panel 1). An estimated 3–4 million children are living with HIV, more than 90% of whom are in sub-Saharan Africa, and almost all of these infections were acquired through mother-to-child transmission. As a result of widespread use of preventive interventions such as the administration of antiretroviral drugs to mothers and their babies, elective caesarean section, and bottle feeding, vertical HIV transmission has diminished to less than 2% from mother to baby in resource-rich countries. Similar results have been achieved in resource-poor settings, in which these strategies have also been implemented. Although new HIV infections in children declined by 53% from 2001 to 2012 because of the effective implementation of techniques to prevent mother-to-child transmission, about 250 000 HIV-infected infants are still newly infected every year.9 Antiretroviral therapy has very effectively prevented mortality when initiated in infancy10 and international guidelines now recommend initiation of antiretroviral therapy in all infants younger than 12 months infected with HIV, irrespective of clinical and immunological variables.11 Thus, research can now focus on the effect of viral reservoirs in different antiretroviral therapy regimens started in early life. In terms of long-term viral control, evidence is growing to suggest that regimens containing lopinavir, if tolerated, started within the first year of life might be better than nevirapine regimens.12 Moreover, a potential role for the use of integrase inhibitors during infancy has been suggested.13 How the use of different or novel combinations of antiretroviral drugs will affect viral reservoirs is still unclear.

Section snippets

What did we learn from the Mississippi baby?

The Mississippi baby led scientists to think that very early and aggressive antiretroviral therapy in vertically infected infants could be sufficient to ensure HIV remission, defined as a prolonged period of undetectable plasma viraemia without antiretroviral therapy. The attempt to replicate this case with very early antiretroviral therapy (started within 48 h after birth) represents the objective of the IMPAACT1115 trial14 announced by the National Institute of Health. The Mississippi baby

Virological and immunological benefits of early antiretroviral therapy in children

Emerging evidence suggests that the use of early antiretroviral therapy not only reduces HIV-1 related mortality but also preserves immune function and long-term control of viral production. Early antiretroviral therapy restricts the number of long-lived CD4 T cells that harbour HIV-1 DNA and viruses that are competent of replication.4, 26 Importantly, early treatment also preserves the predominant naive CD4 cell populations and restricts the generation of memory cells. Data in early treated

Therapeutic HIV vaccine research in early treated children

Reasons to implement therapeutic HIV vaccine research in children are summarised in panel 2. Life-long drug treatment for antiretroviral therapy is recommended for the paediatric population.36 Maintenance of life-long adherence to the therapy is difficult, the risk of viral resistance, and as yet unknown long-term toxic effects, represent major concerns. Children infected vertically with HIV have a progressively increased risk of developing triple-class virological failure after 5 years of

Immunotherapeutic strategies tested in HIV-infected adults

Several immunological strategies have been proposed to achieve viral remission without antiretroviral therapy. These include passive immunisation with broadly neutralising antibodies, which have been tested in primates,42 in infected human beings,43 and with a selected potent human monoclonal anti-CD4 binding site.44 Another passive immunisation strategy targets the infected cell with a combination of antiretroviral drugs and monoclonal antibodies.45 These approaches could reduce viral loads in

Early treated children with perinatal HIV-infections as unique models to evaluate therapeutic HIV vaccine

A major limitation of the adult cohorts studied so far is the absence of a uniform population to analyse in terms of timing of antiretroviral therapy, in addition to the immunological and virological status of the participants. Immunological impairment that occurs during the early phases of the infection and pre-existing immunity to HIV can severely bias the interpretation of immunological results, as described by Robb and Kim.70 Children vertically infected with HIV and treated with

Present scenario and future perspectives of therapeutic HIV vaccines in childhood

Only five randomised clinical trials of HIV vaccine have been done in paediatric settings in the past 20 years and only one in the specialty of therapeutic vaccination (table).72, 73, 74, 75, 76 Two prophylactic HIV-1 vaccines in exposed infants were safe and immunogenic in phase 1 trials.72, 73 These vaccines can induce robust and durable env-specific IgG responses, including antibodies (anti-V1V2 IgG) associated with a reduced risk of HIV-1 acquisition in the RV144 adult vaccine trial.77 Of

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