Nevirapine Dosing in Neonates for Prophylaxis of Mother-to-Child-Transmission (MTCT) of HIV Infection

The purpose of this study is to determine whether the current dose of nevirapine recommended in the Ontario Ministry of Health vertical transmission prevention protocol achieves therapeutic drug levels in newborn infants at high risk of HIV infection.

Study Overview

• Status: Completed
• Conditions: HIV; Human Immunodeficiency Virus; Vertical Infection Transmission

Detailed Description

Although nevirapine (NVP) is often given as part of combination antiretroviral therapy (cART) at our institutions for prevention of vertical transmission (VT) in high risk infants, the optimal prophylactic dose of nevirapine is unknown. The National Institute of Health (NIH) guidelines currently recommend a single 2 mg/kg dose of nevirapine given to the infant within 72 hours of birth, however, this dose is not being used in practice given the controversies previously described with single-dose nevirapine. In the absence of any guidance to inform the multiple daily dosing of nevirapine for prophylaxis of VT, we are currently using the treatment dose for infants >15 days of age of 150 mg/m2 once daily for 14 days, then increasing to 150 mg/m2 twice daily for 14 days. This is analogous to the treatment dosing of triple antiretrovirals (ARVs) that is given for occupational post-exposure prophylaxis. Nevirapine is given for 4 weeks total with zidovudine (AZT) and lamivudine (3TC), followed by 2 additional weeks of AZT and 3TC to prevent the development of nevirapine resistance from its long half life. Stopping all 3 drugs simultaneously would result in a period of functional NVP monotherapy, resulting in a risk of NVP resistance should the infant become infected despite prophylaxis. Since the dose of nevirapine being used in our clinic populations for prevention of VT is higher than has been previously studied in neonates, it is important to evaluate the safety and efficacy of this dosing regimen, using therapeutic drug monitoring.

• Study Type: Observational
• Enrollment (Actual): 27

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada
      • Children's Hospital of Eastern Ontario
    • Toronto, Ontario, Canada, M5G1X8
      • The Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 days (Child)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The patients in this study are newborn infants clinically prescribed combination antiretroviral treatment with nevirapine for prevention of mother-to-child HIV transmission. These infants are routinely referred to the SickKids and CHEO HIV clinics in Toronto and Ottawa, respectively, for ongoing management. The majority of referrals are from Mount Sinai Hospital and St. Michael's Hospital in Toronto, and the Ottawa General Hospital in Ottawa.

Description

Inclusion Criteria:

• Newborn infants prescribed combination antiretroviral treatment with nevirapine for prevention of mother-to-child HIV transmission. These infants are routinely referred to the Hospital for Sick Children (SickKids) and Children's Hospital of Eastern Ontario (CHEO) HIV clinics in Toronto and Ottawa, respectively, for ongoing management. The majority of referrals are from Mount Sinai Hospital and St. Michael's Hospital in Toronto, and the Ottawa General Hospital in Ottawa.
• Voluntary informed consent by the legal guardian

Exclusion Criteria:

• Infants born prior to 32 weeks gestational age;
• Infants with life-threatening medical conditions;
• Infants unable to take oral medication;
• Infants born to women considered at high risk of harboring nevirapine resistance mutations in whom Kaletra (lopinavir/ritonavir) is a therapeutic option (e.g. term neonates) will be excluded and prescribed Kaletra rather than nevirapine

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Nevirapine; The patients in this study are newborn infants clinically prescribed combination antiretroviral treatment with nevirapine for prevention of mother-to-child HIV transmission.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of nevirapine trough (Cmin) plasma levels that are above or below the target range for prophylaxis	Weeks 1, 2, and 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Final dose of nevirapine	Final dose of nevirapine required to achieve target plasma trough concentrations at week 4	Week 4
Derived pharmacokinetic parameters	Derived pharmacokinetic parameters volume of distribution (Vd)(L/kg), elimination rate (ke), clearance (mL/kg/hr), Cmin (ug/L), Cmax (ug/L), Tmax (hrs), and Area under the Curve (AUC)	Week 4
Association between nevirapine levels and incidence of adverse effects	Number of adverse events among patients with therapeutic vs. supratherapeutic nevirapine levels	Weeks 1, 2 and 4
Association between patient characteristics and differences in nevirapine levels	Patient characteristics that may explain differences in nevirapine levels including chronologic and gestational age, weight, and ethnic background.	Baseline, Week 1, 2 and 4
Rate of vertical transmission of HIV		18 months

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: Unity Health Toronto; Children's Hospital of Eastern Ontario; Mount Sinai Hospital, Canada; Canadian Foundation for AIDS Research (CANFAR)
• Investigators: Principal Investigator: Ari Bitnun, MD, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: June 5, 2014
• First Submitted That Met QC Criteria: June 14, 2014
• First Posted (Estimate): June 18, 2014

Study Record Updates

• Last Update Posted (Estimate): November 18, 2015
• Last Update Submitted That Met QC Criteria: November 17, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: HIV; pediatric; prevention; prophylaxis; nevirapine
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome
• Other Study ID Numbers: 1000029134