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‘Baby Cure’ Ucwaningo Lwabantwana Study: Towards Paediatric Cure/Remission

The ‘Mississippi baby’ received ART at 30hrs of age, and for more than 2 years she appeared to be cured following ART discontinuation. However, viral replication ultimately re-established detectable virus in the blood. Anecdotal cases such as this child, the ‘Visconti child’, the ‘South African child’, and others, have generated considerable interest in the possibility that children might be different from adults in terms of cure potential. However, viral rebound in the case of the Mississippi child, and in similar cases, suggest that interventions in addition to early ART will be needed to achieve functional cure/remission. Top of this list are broadly neutralising antibody treatments, which have been shown in the SIV-macaque model to bring about eradication of infection or post-treatment control (functional cure) if used early enough.

 

The potential for cure/remission is high among children, for three main reasons. First, ART can be initiated very early after birth following in utero infection. This means a small viral reservoir of narrow diversity. Second, the tolerogenic environment of early life reduces the ability of the virus to rapid establish a large reservoir of infection in the tissues as happens in early adult infection. Third, the virus transmitted across the placental barrier is typically of low replicative capacity (‘low fitness’). Thus there is a window of opportunity in very early paediatric infection in which to initiate ART and reduce the reservoir to a very low level of low diversity, low fitness virus.

 

In 2015 we started a study in KwaZulu-Natal, South Africa, initiating very early ART in infants infected in utero (‘very early’ defined as: within the first 48hrs of life). To date we have enrolled 137 in utero infected infants from 4 study sites in KwaZulu-Natal. These studies have already demonstrated the extraordinary opportunities for cure/remission potential in these children, 12% of enrolled infants having plasma RNA viral loads that are so low that they are undetectable by standard assays. The challenges are also massive, with 25% of children lost to follow up/died/withdrawn from study within the first 6 months. Only two-thirds of enrolees achieve suppression of viraemia on ART by 6 months of age, and half of these will have become viraemic as a result of ART non-adherence within 12 months of viral suppression.

 

Ongoing studies are focused on determining the frequency of Mississippi-like children following very early ART initiation, and the mechanisms by which these arise; defining the paediatric immune responses that can contribute to post treatment control following ART treatment interruption; identifying eligible candidates from among the very early treated children for the bnAb clinical trials planned; and defining the impact of sex differences both in susceptibility to in utero infection (females infants are ~twice as susceptible) and in maintaining post treatment control off ART (see Goulder & Deeks, PLoS Pathogens, 2018).

 

STUDY TEAM

 

Principal Investigators:

Philip Goulder (Oxford), Thumbi Ndung’u (KwaZulu-Natal)

 

Clinical Team

Lab Team   

Clinical coordinator:

  • Jane Millar

Site coordinators & study clinicians:

  • Zodumo Mvo (Edendale)
  • Rowena Fillis (Mahatma Gandhi Memorial Hospital)
  • Jane Millar/Vuyokazi Ntlantsana (Stanger)
  • Nomonde Bengu (Empangeni)

Operations manager:

  • Ken Sprenger

Site paediatricians: 

  • Yeney Graza (Stanger)
  • Jeroen van Lobenstein (Stanger)
  • Malini Krishna (Edendale),
  • Roopesh Bhoola (Edendale)
  • Constant Kapongo (Queen Nandi Hospital, Empangeni)
  • Chinniah Kogielambal (MGMH)

Sisters/Counsellors:

  • Noxolo Mchunu
  • Lihle Mbambo
  • Sizakele Zondi
  • Gugu Hlophe
  • Sjabulile Ngcobo
  • Nongcebo Ndluli
  • Patience Mthetwa
  • Siphiwe Ngema
  • Nomvula Nzuza,
  • Nicky Linda
  • Thandi Sikhakane

Post-docs: 

  • Max Muenchhoff
  • Julia Roider
  • Emily Adland
  • David Malone
  • Nick Grayson
  • Reena DSouza

Research assistants: 

  • Nelisiwe Nxele
  • Anna Csala
  • Ekta Mukhopadhyay