Trial of Three Neonatal Antiretroviral Regimens for Prevention of Intrapartum HIV Transmission

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ClinicalTrials.gov Identifier:
NCT00099359
First received: December 10, 2004
Last updated: October 26, 2012
Last verified: February 2011
Results First Received: April 25, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Prevention
Conditions: Disease Transmission, Vertical
Vertical Human Immunodeficiency Virus Transmission
HIV Infections
Interventions: Drug: Zidovudine
Drug: Nevirapine (NVP)
Drug: Epivir (3TC)
Drug: Nelfinavir (NFV)

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The first subject was enrolled on 02/27/2004 and the study ended 02/28/2011. A total of 17 sites in Brazil, South Africa, Argentina and the U.S. participated in the study.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Arm A (ZDV Only) Standard of care ( Zidovudine only). 12 mg PO BID if BW>2000 grams ; 8 mg PO BID if BW</= 2000 grams
ARM B (ZDV + NVP)

Standard of care (Zidovudine) plus Nevirapine (NVP)

NVP, first dose initiated within 48 hrs of birth, second dose 48 hrs (+ 4 hours) after the first dose, and third dose 96 hours (+ 4 hours) after the second dose :

12 mg PO per dose if BW > 2000 grams, 8 mg PO per dose if BW < 2000 grams

ARM C (ZDV + 3TC + NFV)

Standard of Care (Zidovudine) plus 2 weeks of Epivir (3TC) and Nelfinavir (NFV) 3TC, given for 2 weeks: 6 mg po bid if BW > 2000 grams 4 mg po bid if BW < 2000 grams AND

NFV, given for 2 weeks:

200 mg po bid if BW > 3000 grams 150 mg po bid if BW > 2,000 – 3000 grams 100 mg PO BID if BW < 2000 grams


Participant Flow:   Overall Study
    Arm A (ZDV Only)     ARM B (ZDV + NVP)     ARM C (ZDV + 3TC + NFV)  
STARTED     581     580     574  
COMPLETED     527     515     506  
NOT COMPLETED     54     65     68  
Death                 11                 15                 17  
Withdrawal by Subject                 19                 19                 23  
Lost to Follow-up                 15                 24                 24  
moved out of area                 9                 7                 4  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Arm A (ZDV Only) Standard of care ( Zidovudine only). 12 mg PO BID if BW>2000 grams ; 8 mg PO BID if BW</= 2000 grams
ARM B (ZDV + NVP)

Standard of care (Zidovudine) plus Nevirapine (NVP)

NVP, first dose initiated within 48 hrs of birth, second dose 48 hrs (+ 4 hours) after the first dose, and third dose 96 hours (+ 4 hours) after the second dose :

12 mg PO per dose if BW > 2000 grams, 8 mg PO per dose if BW < 2000 grams

ARM C (ZDV + 3TC + NFV)

Standard of Care (Zidovudine) plus 2 weeks of Epivir (3TC) and Nelfinavir (NFV) 3TC, given for 2 weeks: 6 mg po bid if BW > 2000 grams 4 mg po bid if BW < 2000 grams AND

NFV, given for 2 weeks:

200 mg po bid if BW > 3000 grams 150 mg po bid if BW > 2,000 – 3000 grams 100 mg PO BID if BW < 2000 grams

Total Total of all reporting groups

Baseline Measures
    Arm A (ZDV Only)     ARM B (ZDV + NVP)     ARM C (ZDV + 3TC + NFV)     Total  
Number of Participants  
[units: participants]
  581     580     574     1735  
Age  
[units: weeks]
Mean ± Standard Deviation
       
Gestational Age in Weeks     39  ± 1.7     39  ± 1.5     39  ± 1.7     39  ± 1.7  
Gender  
[units: participants]
       
Female     298     303     281     882  
Male     283     277     293     853  
Region of Enrollment  
[units: participants]
       
United States     4     4     4     12  
Puerto Rico     0     1     1     2  
Argentina     10     6     11     27  
Brazil     409     408     402     1219  
South Africa     158     161     156     475  



  Outcome Measures
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1.  Primary:   Infant HIV Infection Status   [ Time Frame: 3 months ]

Measure Type Primary
Measure Title Infant HIV Infection Status
Measure Description Intrapartum HIV infection at 3 Months
Time Frame 3 months  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All infants with HIV-1 test results except infants infected at birth (i.e. in utero infections) were included in these analysis.

Reporting Groups
  Description
ARM A (ZDV - Standard of Care)

ZDV (standard of care), given for 6 weeks:

12 mg PO BID if birthweight (BW) > 2000 grams 8 mg PO BID if BW < 2000 grams

ARM B (ZDV + NVP) plus NVP, first dose initiated within 48 hrs of birth, second dose 48 hrs (+ 4 hours) after the first dose, and third dose 96 hours (+ 4 hours) after the second dose : 12 mg PO per dose if BW > 2000 grams, 8 mg PO per dose if BW < 2000 grams
ARM C (ZDV +3TC+NFV)

ZDV (standard of care) plus 3TC, given for 2 weeks:

6 mg po bid if BW > 2000 grams 4 mg po bid if BW < 2000 grams AND

NFV, given for 2 weeks:

200 mg po bid if BW > 3000 grams 150 mg po bid if BW > 2,000 - 3000 grams 100 mg PO BID if BW < 2000 grams


Measured Values
    ARM A (ZDV - Standard of Care)     ARM B (ZDV + NVP)     ARM C (ZDV +3TC+NFV)  
Number of Participants Analyzed  
[units: participants]
  566     562     556  
Infant HIV Infection Status  
[units: participants]
  24     11     12  


Statistical Analysis 1 for Infant HIV Infection Status
Groups [1] All groups
Method [2] multiple comparison
P Value [3] .046
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Hochberg’s modified Bonferroni method was used to adjust the significance level for comparisons between arms.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Overall comparison of 3 KM curves using an extension of the M-H test was performed. Results indicated a significant difference therefore a 2nd stage analysis was done to compare each pair of transmission rates, using 2-sample Mantel-Haenzel tests.



2.  Primary:   Participants With Serious Adverse Events   [ Time Frame: through age 6 months. ]

Measure Type Primary
Measure Title Participants With Serious Adverse Events
Measure Description Serious Adverse Events by System Organ Class=Blood and lymphatic system disorders
Time Frame through age 6 months.  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
ARM A (ZDV Only) ZDV only
ARM B (ZDV + NVP) ZDV + NVP
ARM C (ZDV + 3TC/NFV) ZDV + 3TC/NFV

Measured Values
    ARM A (ZDV Only)     ARM B (ZDV + NVP)     ARM C (ZDV + 3TC/NFV)  
Number of Participants Analyzed  
[units: participants]
  566     562     556  
Participants With Serious Adverse Events  
[units: participants]
  86     59     110  


Statistical Analysis 1 for Participants With Serious Adverse Events
Groups [1] All groups
Method [2] Chi-squared
P Value [3] .0001
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



3.  Secondary:   Infant HIV-1 Infection Status   [ Time Frame: birth ]

Measure Type Secondary
Measure Title Infant HIV-1 Infection Status
Measure Description In utero HIV-1 infection rate
Time Frame birth  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Arm A (ZDV Only) Standard of care ( Zidovudine only). 12 mg PO BID if BW>2000 grams ; 8 mg PO BID if BW</= 2000 grams
ARM B (ZDV + NVP)

Standard of care (Zidovudine) plus Nevirapine (NVP)

NVP, first dose initiated within 48 hrs of birth, second dose 48 hrs (+ 4 hours) after the first dose, and third dose 96 hours (+ 4 hours) after the second dose :

12 mg PO per dose if BW > 2000 grams, 8 mg PO per dose if BW < 2000 grams

ARM C (ZDV + 3TC + NFV)

Standard of Care (Zidovudine) plus 2 weeks of Epivir (3TC) and Nelfinavir (NFV) 3TC, given for 2 weeks: 6 mg po bid if BW > 2000 grams 4 mg po bid if BW < 2000 grams AND

NFV, given for 2 weeks:

200 mg po bid if BW > 3000 grams 150 mg po bid if BW > 2,000 - 3000 grams 100 mg PO BID if BW < 2000 grams


Measured Values
    Arm A (ZDV Only)     ARM B (ZDV + NVP)     ARM C (ZDV + 3TC + NFV)  
Number of Participants Analyzed  
[units: participants]
  581     580     574  
Infant HIV-1 Infection Status  
[units: participants]
  37     28     28  


Statistical Analysis 1 for Infant HIV-1 Infection Status
Groups [1] All groups
Method [2] multiple comparison
P Value [3] .2432
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



4.  Secondary:   Participant Deaths   [ Time Frame: through age 6 months ]

Measure Type Secondary
Measure Title Participant Deaths
Measure Description No text entered.
Time Frame through age 6 months  
Safety Issue Yes  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Arm A (ZDV Only) Standard of care ( Zidovudine only). 12 mg PO BID if BW>2000 grams ; 8 mg PO BID if BW</= 2000 grams
ARM B (ZDV + NVP)

Standard of care (Zidovudine) plus Nevirapine (NVP)

NVP, first dose initiated within 48 hrs of birth, second dose 48 hrs (+ 4 hours) after the first dose, and third dose 96 hours (+ 4 hours) after the second dose :

12 mg PO per dose if BW > 2000 grams, 8 mg PO per dose if BW < 2000 grams

ARM C (ZDV + 3TC + NFV)

Standard of Care (Zidovudine) plus 2 weeks of Epivir (3TC) and Nelfinavir (NFV) 3TC, given for 2 weeks: 6 mg po bid if BW > 2000 grams 4 mg po bid if BW < 2000 grams AND

NFV, given for 2 weeks:

200 mg po bid if BW > 3000 grams 150 mg po bid if BW > 2,000 - 3000 grams 100 mg PO BID if BW < 2000 grams


Measured Values
    Arm A (ZDV Only)     ARM B (ZDV + NVP)     ARM C (ZDV + 3TC + NFV)  
Number of Participants Analyzed  
[units: participants]
  581     580     574  
Participant Deaths  
[units: participants]
  11     15     17  


Statistical Analysis 1 for Participant Deaths
Groups [1] All groups
Method [2] Chi-squared
P Value [3] 0.49
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.



5.  Secondary:   3TC and NFV Pharmacokinetics   [ Time Frame: through age 14 days ]

Measure Type Secondary
Measure Title 3TC and NFV Pharmacokinetics
Measure Description Descriptive study of 3TC and NFV pharmacokinetics during first two weeks of life using weight band dosing regimen in a subset of enrolled infants.
Time Frame through age 14 days  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
This was a descriptive study. A total of 26 infants were analyzed with 14 at age 4-7 days and 12 at 10-14 days.Plasma samples were collected prior to first AM dose and then at 1,2,4,8 and 12 hours.

Reporting Groups
  Description
ARM C (ZDV + 3TC/NFV) Standard ZDV for 6 weeks combined with 2 weeks of 3TC and NFV. NFV and 3TC plasma concentrations were measured by validated HPLC assays with lower detection limit of 0.04 micrograms/mL.

Measured Values
    ARM C (ZDV + 3TC/NFV)  
Number of Participants Analyzed  
[units: participants]
  26  
3TC and NFV Pharmacokinetics  
[units: ug*h/mL]
Median ( Full Range )
 
(NFV-AUC-12h) 4-7 day     20.7  
  ( 3.4 to 183.5 )  
(NFV-AUC-12h) 10-14 day     25.5  
  ( 1.7 to 41.7 )  
(3TC-AUC-12 h) 4-7 day     4.0  
  ( 2.9 to 15.6 )  
(3TC-AUC-12h) 10-14 day     7.9  
  ( 2.7 to 14 )  

No statistical analysis provided for 3TC and NFV Pharmacokinetics



6.  Secondary:   Risk Factors for Perinatal HIV-1 Transmission   [ Time Frame: through age 3 months ]

Measure Type Secondary
Measure Title Risk Factors for Perinatal HIV-1 Transmission
Measure Description Risk factors to be assessed include maternal HIV-1 RNA levels at delivery, maternal syphilis and other infections, obstetrical factors such as duration of membrane rupture, and adherence to neonatal medication.
Time Frame through age 3 months  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All available demographic and clinical variables were tested for association with transmission rate. All variables that were significant at p ≤ 0.20 were included in the multivariable regression model. Variables that were not significant were then removed from the model. The backward elimination method was used to select the final model.

Reporting Groups
  Description
Infected Infants infected after birth
Uninfected Infants uninfected after birth

Measured Values
    Infected     Uninfected  
Number of Participants Analyzed  
[units: participants]
  47     1544  
Risk Factors for Perinatal HIV-1 Transmission  
[units: participants]
   
Treatment Arm C (ZDV+3TC/NFV)     12     516  
Treatment Arm B (ZDV+NFV)     11     523  
Treatment Arm A (ZDV only)     24     505  
Illegal Substance Abuse during pregnancy     7     130  


Statistical Analysis 1 for Risk Factors for Perinatal HIV-1 Transmission
Groups [1] All groups
Method [2] Regression, Logistic
P Value [3] 0.05
Odds Ratio (OR) [4] 0.50
95% Confidence Interval ( 0.24 to 1.01 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Adjusted Odds ratio for treatment arm C (ZDV+3TC/NFV) association with Intrapartum Infection Status with Treatment Arm A (ZDV only) as reference group
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Risk Factors for Perinatal HIV-1 Transmission
Groups [1] All groups
Method [2] Regression, Logistic
P Value [3] 0.01
Odds Ratio (OR) [4] 0.39
95% Confidence Interval ( 0.19 to 0.82 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Adjusted odds ratio for association of treatment arm B (ZDV+NVP) with intrapartum infection status with Treatment Arm A (ZDV only) as reference.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 3 for Risk Factors for Perinatal HIV-1 Transmission
Groups [1] All groups
Method [2] Regression, Logistic
P Value [3] 0.03
Odds Ratio (OR) [4] 2.51
95% Confidence Interval ( 1.08 to 5.86 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Adjusted odds ratio for association of illegal substance use during pregnancy and intrapartum HIV infection status with "NO" being reference group.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 4 for Risk Factors for Perinatal HIV-1 Transmission
Groups [1] All groups
Method [2] Regression, Logistic
P Value [3] <0.0001
Odds Ratio (OR) [4] 2.28
95% Confidence Interval ( 1.56 to 3.35 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Adjusted odds ratio for the association of continuous log10 viral load with intrapartum infection status
[4] Other relevant estimation information:
  No text entered.



7.  Secondary:   NVP Pharmacokinetics   [ Time Frame: 14 days ]

Measure Type Secondary
Measure Title NVP Pharmacokinetics
Measure Description Descriptive study of NVP pharmacokinetics during first two weeks of life using weight band dosing in a subset of enrolled infants.
Time Frame 14 days  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
ARM B (ZDV + NVP) NVP concentrations were measured in 14 infants immediately before the 3rd dose, 4 hours post dose, 1 day post dose, 3-5 days post dose and 7 days post dose.

Measured Values
    ARM B (ZDV + NVP)  
Number of Participants Analyzed  
[units: participants]
  14  
NVP Pharmacokinetics  
[units: ng/mL]
Median ( Full Range )
 
NVP conc prior to 3rd dose     362  
  ( 165 to 1728 )  
NVP peak conc (Cmax) post 3rd dose     2286  
  ( 1241 to 3811 )  
NVP conc 3-5 day post 3rd dose     459  
  ( 73 to 1747 )  
NVP conc 7 day post 3rd dose     76  
  ( 25 to 652 )  

No statistical analysis provided for NVP Pharmacokinetics



8.  Secondary:   Clinical Covariates of HIV-1 Infection   [ Time Frame: through age 3 months ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


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