Dual bNAb Treatment in Children

This study will evaluate the impact of two broadly neutralizing antibodies, VRC01LS and 10-1074, on the maintenance of HIV suppression in a cohort of early-treated children in Botswana.

The primary objectives are as follows:

1. To conduct an interventional clinical trial to determine the safety, pharmacokinetics, dosing and antiviral efficacy of up to 24 weeks of maintenance VRC01LS and 10-1074 immunotherapy in early-treated HIV-1 infected children in Botswana.
2. To evaluate effects of treatment with VRC01LS and 10-1074 on the size and cellular composition of residual viral reservoirs.
3. To investigate the influence of VRC01LS and 10-1074 treatment on the magnitude and quality of antiviral innate and adaptive immune responses.

The study includes 4 steps: the pharmacokinetics (PK) Step, Step 1, Step 2, and Step 3. In the PK Step, antiretroviral treatment (ART) is continued and 12 study participants will undergo safety and PK testing, 6 for each bNAb used in the study (10-1074 and VRC01LS). In Step 1, ART is continued and dual bNAb treatment occurs, with PK confirmation of dual bNAb dosing for the first 6 participants in Step 1. In Step 2, ART is withdrawn and dual bNAb maintenance treatment occurs. In Step 3, dual bNAbs will be discontinued and participants will be re-started on ART.

Participants will be in the study for a minimum of 56 weeks, and a maximum of 98 weeks for those who start in the PK step and continue through the study.

• ART (Drug): ART will not be provided by the study. Participants will continue to receive their ART regimen they were receiving prior to enrolling in the study.
• VRC01LS (Biological): Administered by intravenous (IV) infusion
• 10-1074 (Biological): Administered by intravenous (IV) infusion

Primary outcomes

• Frequency of Treatment-associated Adverse Events (AEs) [Number of Participants With Treatment-associated Adverse Event(s) of Any Grade] [Measured until 30 days after study completion for each participant]
• Severity of Treatment-associated AEs (Number of Participants With Grade 3 or Higher Related AEs) [Measured until 30 days after study completion for each participant]: Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table). The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with Grade 1 indicating a mild event, Grade 2 indicating a moderate event, Grade 3 indicating a severe event, Grade 4 indicating a potentially life-threatening event, and Grade 5 indicating death.
• Proportion of Children Who Maintain HIV-1 Plasma RNA Less Than 400 Copies/mL, After Initiating VRC01LS and 10-1074 Infusions and Stopping ART [Measured through Week 24 of Step 2]: Based on laboratory evaluations
• Proportion of Children Who Maintain HIV-1 Plasma RNA Less Than 40 Copies/mL, After Initiating VRC01LS and 10-1074 Infusions and Stopping ART [Measured through Week 24 of Step 2]: Based on laboratory evaluations

Secondary outcomes

• VRC01LS or 10-1074 Concentrations in Plasma [Measured through Week 12 (PK Step)]: Median pre-dose trough (28 days post previous dose) based on laboratory evaluations
• Median Trough Concentration of VRC01LS or 10-1074 in Plasma 28 Days After the Third Dose [Measured through Week 12 (PK Step)]: Based on laboratory evaluations
• VRC01LS and 10-1074 Concentrations in Plasma for Each Time Point [Measured through Week 32 following Step 1 entry]: Based on laboratory evaluations
• Proportion of Children With Trough VRC01LS and 10-1074 Concentrations Below Defined Trough Ranges [Measured through Week 32 following Step 1 entry]: Based on laboratory evaluations
• Height Z-scores of Virally Suppressed Children Receiving bNAbs [Measured through Week 24 (Step 3)]: World Health Organization (WHO) standardized Z-scores will be evaluated for changes over time: WHO Length/height-for-age z-score (0-19 yrs), Change from Step 1, Day 0 to Step 3, Week 24. A z-score of 0 corresponds to the population mean. Scores above 0 indicate a participant's height is above the mean, while a score below 0 indicates a participant's height is below the mean. A positive change in z-score corresponds to a higher z-score at the second timepoint compared to the first.
• Weight Z-scores of Virally Suppressed Children Receiving bNAbs [Measured through Week 24 (Step 3)]: WHO standardized Z-scores will be evaluated for changes over time: WHO Weight-for-age z-score (0-10 yrs), Change from Step 1, Day 0 to Step 3, Week 24. A z-score of 0 corresponds to the population mean. Scores above 0 indicate a participant's weight is above the mean, while a score below 0 indicates a participant's weight is below the mean. A positive change in z-score corresponds to a higher z-score at the second timepoint compared to the first.

Sex: All, ages: 96 Weeks to 7 Years

Inclusion Criteria for PK Step*:

* On ART for at least 96 weeks
* Greater than or equal to 96 weeks and less than 5 years of age at enrollment
* HIV RNA less than 40 copies/mL for at least 24 weeks prior to entry
* Ability to remain in close study follow-up for at least 12 weeks
* Willingness to receive IV infusions of bNAbs
* Willingness to provide signed informed consent (by the parent/guardian)

  * *It is anticipated that all children in PK Step will be from Early Infant Treatment (EIT) Study (NCT02369406); however, up to 4 HIV+ children outside the PK Study (age range 2-5 years) may participate in the PK Step if otherwise eligible and if EIT children are unavailable.

Inclusion Criteria for Entry into Step 1 (followed by participation in Steps 2-3):

* EIT Study participant (NCT02369406)
* On ART for at least 96 weeks
* Greater than or equal to 96 weeks and less than 7 years of age at enrollment
* HIV RNA less than 40 copies/mL for at least 24 weeks prior to entry
* Ability to remain in close study follow-up for at least 56 weeks
* Willingness to receive IV infusions of bNAbs
* Willingness to provide signed informed consent (by the parent/guardian)

Exclusion Criteria:

* Medical condition making survival for at least 32 weeks unlikely
* Active tuberculosis or malignancy
* Actively breastfeeding
* Previous receipt of VRC01/VRC01LS or 10-1074 (except during the PK Step)

Participant flow

Outcome results

• Frequency of Treatment-associated Adverse Events (AEs) [Number of Participants With Treatment-associated Adverse Event(s) of Any Grade] (Primary), Count of participants, Participants: Group PK-A: ART + VRC01LS 4; Group PK-B: ART + 10-1074 1; Steps 1-3 Participants (ART + 10-1074 + VRC01LS) 19
• Severity of Treatment-associated AEs (Number of Participants With Grade 3 or Higher Related AEs) (Primary), Count of participants, Participants: Group PK-A: ART + VRC01LS 0; Group PK-B: ART + 10-1074 0; Steps 1-3 Participants (ART + 10-1074 + VRC01LS) 1
• Proportion of Children Who Maintain HIV-1 Plasma RNA Less Than 400 Copies/mL, After Initiating VRC01LS and 10-1074 Infusions and Stopping ART (Primary), Count of participants, Participants: Steps 2 Participants (10-1074 + VRC01LS) 11
• Proportion of Children Who Maintain HIV-1 Plasma RNA Less Than 40 Copies/mL, After Initiating VRC01LS and 10-1074 Infusions and Stopping ART (Primary), Count of participants, Participants: Steps 2 Participants (10-1074 + VRC01LS) 10
• VRC01LS or 10-1074 Concentrations in Plasma (Secondary), Median, mcg/mL: Group PK-A: ART + VRC01LS 223.3 (157.9 to 253.3); Group PK-B: ART + 10-1074 155.2 (91.3 to 318.6)
• Median Trough Concentration of VRC01LS or 10-1074 in Plasma 28 Days After the Third Dose (Secondary), Median, mcg/mL: Group PK-A: ART + VRC01LS 156.9 (125.8 to 201.4); Group PK-B: ART + 10-1074 258.3 (122.4 to 467.3)
• VRC01LS and 10-1074 Concentrations in Plasma for Each Time Point (Secondary), Median, mcg/mL: Steps 1-3 Participants (ART + 10-1074 + VRC01LS) 154.4 (83.7 to 257.2)
• Proportion of Children With Trough VRC01LS and 10-1074 Concentrations Below Defined Trough Ranges (Secondary), Count of participants, Participants: Steps 1-3 Participants (ART + 10-1074 + VRC01LS) 0
• Height Z-scores of Virally Suppressed Children Receiving bNAbs (Secondary), Mean, change in score on a scale: Steps 1-3 Participants (ART + 10-1074 + VRC01LS) 0.18 (0.07 to 0.30)
• Weight Z-scores of Virally Suppressed Children Receiving bNAbs (Secondary), Mean, change in score on a scale: Steps 1-3 Participants (ART + 10-1074 + VRC01LS) 0.09 (0.04 to 0.22)

Adverse events

Time frame: Measured until 30 days after study completion for each participant. Each column reports events occurring during that specific step.

Serious adverse events by term

Other adverse events by term

24 more terms not shown.

• Results publication: Capparelli EV, Ajibola G, Maswabi K, Holme MP, Bennett K, Powis KM, Moyo S, Mohammed T, Maphorisa C, Hughes MD, Seaton KE, Tomaras GD, Mosher S, Taylor A, O'Connell S, Narpala S, Mcdermott A, Caskey M, Gama L, Lockman S, Jean-Philippe P, Makhema J, Kuritzkes DR, Lichterfeld M, Shapiro RL; Tatelo Study Team. Safety and Pharmacokinetics of Intravenous 10-1074 and VRC01LS in Young Children. J Acquir Immune Defic Syndr. 2022 Oct 1;91(2):182-188. doi: 10.1097/QAI.0000000000003033. PMID 36094485
• Results publication: Shapiro RL, Ajibola G, Maswabi K, Hughes M, Nelson BS, Niesar A, Pretorius Holme M, Powis KM, Sakoi M, Batlang O, Moyo S, Mohammed T, Maphorisa C, Bennett K, Hu Z, Giguel F, Reeves JD, Reeves MA, Gao C, Yu X, Ackerman ME, McDermott A, Cooper M, Caskey M, Gama L, Jean-Philippe P, Yin DE, Capparelli EV, Lockman S, Makhema J, Kuritzkes DR, Lichterfeld M. Broadly neutralizing antibody treatment maintained HIV suppression in children with favorable reservoir characteristics in Botswana. Sci Transl Med. 2023 Jul 5;15(703):eadh0004. doi: 10.1126/scitranslmed.adh0004. Epub 2023 Jul 5. PMID 37406137
• Results publication: Banga J, Nelson BS, Ajibola G, Mohammed T, Maphorisa C, Boleo C, Moyo S, Batlang O, Sakoi-Mosetlhi M, Maswabi K, Holme MP, Powis KM, Lockman S, Hughes MD, Makhema J, Kuritzkes DR, Litcherfeld M, Shapiro R. Predictive markers for sustained viral suppression on dual bNAbs during ART interruption in children. J Acquir Immune Defic Syndr. 2025 Mar 26:10.1097/QAI.0000000000003663. doi: 10.1097/QAI.0000000000003663. Online ahead of print. PMID 40136003
• Results publication: Sakoi-Mosetlhi M, Ajibola G, Haghighat R, Batlang O, Maswabi K, Pretorius-Holme M, Powis KM, Lockman S, Makhema J, Litcherfeld M, Kuritzkes DR, Shapiro R. Caregivers of children with HIV in Botswana prefer monthly IV Broadly Neutralizing Antibodies (bNAbs) to daily oral ART. PLoS One. 2024 Mar 27;19(3):e0299942. doi: 10.1371/journal.pone.0299942. eCollection 2024. PMID 38536810
• Results publication: Niesar A, Lancien M, Hong S, Naasz C, Ajibola G, Maswabi K, Sakoi-Mosetlhi M, Batlang O, Moyo S, Mohammed T, Maphorisa C, Carrere L, Roseto I, Hartana CA, Tan TS, Gao C, Parsons E, Hua R, Pretorius Holme M, Lockman S, Powis KM, Carrington M, Makhema J, Yu XG, Kuritzkes DR, Shapiro RL, Lichterfeld M. Immune correlates of HIV-1 rebound during broadly neutralizing antibody treatment in young children. J Clin Invest. 2026 Feb 16;136(4):e193912. doi: 10.1172/JCI193912. eCollection 2026 Feb 16. PMID 41697750
• Results publication: Ajibola G, Nelson BS, Niesar A, Hong S, Lancien M, Holme MP, Hughes MD, Yin DE, Jean-Philippe P, Moyo S, Batlang O, Sakoi M, Maphorisa C, Mohammed T, Lockman S, Makhema J, Kuritzkes DR, Lichterfeld M, Shapiro RL. Long-Term Clinical, Immunologic, and Viral Reservoir Outcomes in Children Treated With VRC01LS and 10-1074 Monoclonal Antibodies in the Tatelo Study. Clin Infect Dis. 2026 Feb 25;82(2):e278-e285. doi: 10.1093/cid/ciaf568. PMID 41078080

• Study Protocol (PDF, 2021-07-19)
• Statistical Analysis Plan (PDF, 2022-09-27)
• Informed Consent Form: PK Step (PDF, 2018-12-20)
• Informed Consent Form: Steps 1 to 3 (PDF, 2020-05-19)

• Roger Shapiro, MD, MPH, Principal investigator, Harvard School of Public Health (HSPH)
• Daniel Kuritzkes, MD, Principal investigator, Brigham and Women's Hospital
• Mathias Lichterfeld, MD, PhD, Principal investigator, Brigham and Women's Hospital/Massachusetts General Hospital