ENABLE

The challenge

An estimated 130,000 babies become infected with HIV every year. Such infants are at very high risk of death – mortality within the first 12 months after diagnosis is around 10%. This largely reflects poor control of viral replication: good virological suppression is seen in only 25–35% of infants after a year, and baseline viral load is the biggest risk factor for death.

These figures persist despite the availability of antiretroviral drugs suitable for young infants. Supplementary interventions to provide additional protection to this vulnerable group could therefore have a major impact.

The project

The ENABLE project is evaluating whether broadly neutralising antibodies (bnAbs) against HIV could make the virus undetectable in young children living with HIV. In very rare cases, HIV infection generates antibodies that are active against a wide range of different strains of HIV. Methods have been developed to isolate these antibodies and to manufacture them in large quantities so that they can be used to block infection.

The ENABLE project is assessing whether two bnAbs in clinical development (ePGT121v1-LS and VRC07-523-LS), given on diagnosis and after 3, 6 and 9 months, can provide an additional layer of protection against infection in young infants. These antibodies have been engineered so that they persist for longer in the bloodstream, offering protection for up to 3 months.

The project is carrying out a phase II/III trial at eight sites in Cameroon, Mozambique and South Africa, comparing standard antiretroviral treatment with an enhanced approach that also includes bnAb administration. The trial will compare viral suppression at 12 months in the two groups, as well as factors such as overall mortality and safety.

In addition, the project will analyse multiple patient and viral markers to determine whether any associated with protection. These include various markers of different types of immune response as well as viral mutations and levels of key biomolecules. Pharmacokinetic studies will track bnAb levels in a subset of children, to determine whether therapeutic levels are maintained and the levels associated with treatment failure.

Consultations will also be organised to explore the acceptability of bnAb use in children and to identify any barriers or facilitators that might affect take up or implementation of a new intervention.

Impact

The ENABLE project will generate key evidence on whether an innovative new intervention can protect newly diagnosed children with HIV. It will:

• Show whether bnAbs can offer additional protection beyond standard antiretroviral therapy.
• Identify biomarkers associated with successful responses or inadequate control, to inform the refinement of treatment strategies.
• Assess the acceptability of the approach among caregivers and identify any factors that could delay implementation.

If bnABs are shown to improve the virus control, they could protect young infants through a window of vulnerability, and ultimately enable them to survive and thrive into adulthood.