Latency and Early Neonatal Provision of Antiretroviral Drugs Clinical Trial (LEOPARD)

• ClinicalTrials.gov Identifier: NCT02431975
• Recruitment Status: Completed
• First Posted: May 1, 2015
• Last Update Posted: August 4, 2020
• Sponsor: Columbia University
• Collaborators: National Institutes of Health (NIH); University of Witwatersrand, South Africa; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Louise Kuhn, Columbia University

Study Description

Brief Summary:

The investigators propose a non-randomized clinical trial of 60 HIV-infected infants identified within 48 hours of birth and their mothers to investigate the consequences of very early ART on the establishment and maintenance of the viral reservoir.

The first phase (early ART initiation within 48 hours of birth) will examine the trajectory i.e. changes over time of the viral reservoir and detection of HIV-specific antibody responses in infants testing HIV-positive within 48 hours of birth and initiating early ART.

Secondary pathogenesis aims will test whether markers of neonatal immune quiescence are associated with the extent of seeding and rate of decline of the viral reservoir when ART is started at a young age and investigate whether markers in infant stool samples can be used as a non-invasive method of defining relevant immune and HIV-specific parameters associated with viral reservoir size.

The investigators hypothesize that developmental characteristics of newborn immunity may make this period the optimal time to begin ART and influence the seeding of the viral reservoir.

Condition or disease	Intervention/treatment	Phase
HIV	Drug: Nevirapine; Drug: Zidovudine; Drug: Lamivudine; Drug: LPV/r	Phase 4

Detailed Description:

Prevention of mother-to-child transmission (PMTCT) programs using antiretrovirals (ARVs) have had tremendous success in sub-Saharan Africa. However, HIV transmission continues to occur because (1) implementation of PMTCT is incomplete and (2) ARV interventions are not 100% effective in blocking infection. Thus the challenge of providing treatment to HIV-infected children is far from over. The capacity of early ART treatment to favorably influence the viral reservoir and potentially lead to post-treatment cessation viral control needs to be described in the population of infants, and to identify useful public health strategies.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 73 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Latency and Early Neonatal Provision of Antiretroviral Drugs Clinical Trial
• Actual Study Start Date: August 2015
• Actual Primary Completion Date: April 30, 2020
• Actual Study Completion Date: April 30, 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: Early ART; All infants enrolled in the trial, regardless of maternal PMTCT regimen, will be initiated on a triple ARV regimen consisting of nevirapine (NVP), zidovudine (ZDV) and lamivudine (3TC) presumptively based on the initial positive result. This regimen will be continued to 42 weeks post menstrual age (PMA). At this time, infants will be switched to LPV/r, ZDV and 3TC to be continued to 104 weeks or longer unless otherwise preferred by the treating clinician or if any clinical or laboratory contraindications are identified.

Drug: Nevirapine; Standard medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medication. The initial dose of NVP will be 6 mg per kg per dose orally twice daily until 42 weeks gestational age (2 weeks of age for infants born at term) which is the dosing selected by the NIH International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network.; Other Names: NVP; Viramune; Drug: Zidovudine; An antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretroviral. ZDV will be dosed as per standard guideline and routine practices.; Other Names: ZDV; Retrovir; Drug: Lamivudine; An antiretroviral medication used to prevent and treat HIV/AIDS. It is effective against both HIV-1 and HIV-2. 3TC will be dosed as per standard guideline and routine practices.; Other Names: 3TC; Epivir; Drug: LPV/r; Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir. LPV/r will be dosed as per standard guideline and routine practices.; Other Name: Ritonavir-boosted lopinavir

Outcome Measures

Primary Outcome Measures :

1. Percent of patients with initial viral suppression [ Time Frame: 24 weeks ]
   Suppression is defined as patients with plasma HIV RNA <50 copies/mL.

Secondary Outcome Measures :

1. Percent of patients maintaining viral suppression [ Time Frame: Between 24 and104 weeks ]
   Suppression is defined as patients with plasma HIV RNA <50 copies/mL.
2. Prevalence of CD4 percentage greater than 30 [ Time Frame: By 24 weeks and sustained through 104 weeks ]
   Patients that reached a normal CD4% level.
3. Prevalence of growth along curve within one standard deviation or upward trend [ Time Frame: Up to 104 weeks ]
   By comparing viral growth curves.
4. Prevalence of detection of specific HIV antibody classes [ Time Frame: 24 and 104 weeks ]
   HIV antibody detection
5. Size of the viral reservoir (copies/million cell) [ Time Frame: Up to 104 weeks ]
   Quantification of viral reservoir

Eligibility Criteria

• Ages Eligible for Study: up to 48 Hours (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Point of care (POC) or laboratory-based test positive on a sample collected within 48 hours of birth.
• Mother willing and able to provide informed consent.

Exclusion Criteria:

• Expressed intention to leave the Johannesburg area permanently.
• Co-morbidities, birth defects or other conditions which in the opinion of the clinical team have a greater than 50% risk of mortality in the first days of life.
• Co-morbidities or conditions which in the opinion of the clinical team advise against initiation of ART within the first 48 hours of life.
• Active (uncontrolled) maternal psychiatric illness.

Contacts and Locations

Locations

South Africa

Rahima Moosa Mother and Child Hospital

Johannesburg, Gauteng, South Africa

Sponsors and Collaborators

Columbia University

National Institutes of Health (NIH)

University of Witwatersrand, South Africa

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Louise Kuhn, PhD; Columbia University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kuhn L, Paximadis M, Da Costa Dias B, Shen Y, Mncube S, Strehlau R, Shiau S, Patel F, Burke M, Technau KG, Sherman G, Loubser S, Abrams EJ, Tiemessen CT. Predictors of Cell-Associated Human Immunodeficiency Virus (HIV)-1 DNA Over 1 Year in Very Early Treated Infants. Clin Infect Dis. 2022 Mar 23;74(6):1047-1054. doi: 10.1093/cid/ciab586.

Kuhn L, Strehlau R, Shiau S, Patel F, Shen Y, Technau KG, Burke M, Sherman G, Coovadia A, Aldrovandi GM, Hazra R, Tsai WY, Tiemessen CT, Abrams EJ; LEOPARD Study Team. Early antiretroviral treatment of infants to attain HIV remission. EClinicalMedicine. 2020 Jan 7;18:100241. doi: 10.1016/j.eclinm.2019.100241. eCollection 2020 Jan.

• Responsible Party: Louise Kuhn, Professor of Epidemiology, Department of Epidemiology, Columbia University
• ClinicalTrials.gov Identifier: NCT02431975
• Other Study ID Numbers: AAAO5011; U01HD080441 ( U.S. NIH Grant/Contract )
• First Posted: May 1, 2015
• Last Update Posted: August 4, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Contact PI Non-identifying data
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Based on availability of resources
• Access Criteria: Scientific justification

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Louise Kuhn, Columbia University:

HIV; infant; antiretroviral therapy, highly active; antiretroviral agents

Additional relevant MeSH terms:

Ritonavir; Lopinavir; Lamivudine; Zidovudine; Nevirapine; HIV Protease Inhibitors; Viral Protease Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Antimetabolites; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 Enzyme Inducers