Trial Outcomes & Findings for Trial of Three Neonatal Antiretroviral Regimens for Prevention of Intrapartum HIV Transmission (NCT NCT00099359)

NCT ID: NCT00099359

Last Updated: 2012-12-04

Results Overview

Intrapartum HIV infection at 3 Months

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1735 participants

Primary outcome timeframe

3 months

Results posted on

2012-12-04

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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
Overall Study STARTED	581	580	574
Overall Study COMPLETED	527	515	506
Overall Study NOT COMPLETED	54	65	68

Reasons for withdrawal

Reasons for withdrawal
Measure	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
Overall Study Death	11	15	17
Overall Study Withdrawal by Subject	19	19	23
Overall Study Lost to Follow-up	15	24	24
Overall Study moved out of area	9	7	4

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A (ZDV Only) n=581 Participants 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) n=580 Participants 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) n=574 Participants 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 n=1735 Participants Total of all reporting groups
Age Continuous Gestational Age in Weeks	39 weeks STANDARD_DEVIATION 1.7 • n=5 Participants	39 weeks STANDARD_DEVIATION 1.5 • n=7 Participants	39 weeks STANDARD_DEVIATION 1.7 • n=5 Participants	39 weeks STANDARD_DEVIATION 1.7 • n=4 Participants
Sex: Female, Male Female	298 Participants n=5 Participants	303 Participants n=7 Participants	281 Participants n=5 Participants	882 Participants n=4 Participants
Sex: Female, Male Male	283 Participants n=5 Participants	277 Participants n=7 Participants	293 Participants n=5 Participants	853 Participants n=4 Participants
Region of Enrollment United States	4 participants n=5 Participants	4 participants n=7 Participants	4 participants n=5 Participants	12 participants n=4 Participants
Region of Enrollment Puerto Rico	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants
Region of Enrollment Argentina	10 participants n=5 Participants	6 participants n=7 Participants	11 participants n=5 Participants	27 participants n=4 Participants
Region of Enrollment Brazil	409 participants n=5 Participants	408 participants n=7 Participants	402 participants n=5 Participants	1219 participants n=4 Participants
Region of Enrollment South Africa	158 participants n=5 Participants	161 participants n=7 Participants	156 participants n=5 Participants	475 participants n=4 Participants

PRIMARY outcome

Timeframe: 3 months

Population: All infants with HIV-1 test results except infants infected at birth (i.e. in utero infections) were included in these analysis.

Intrapartum HIV infection at 3 Months

Outcome measures

Outcome measures
Measure	ARM A (ZDV - Standard of Care) n=566 Participants 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) n=562 Participants 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) n=556 Participants 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
Infant HIV Infection Status	24 participants	11 participants	12 participants

PRIMARY outcome

Timeframe: through age 6 months.

Serious Adverse Events by System Organ Class=Blood and lymphatic system disorders

Outcome measures

Outcome measures
Measure	ARM A (ZDV - Standard of Care) n=566 Participants 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) n=562 Participants 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) n=556 Participants 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
Participants With Serious Adverse Events	86 participants	59 participants	110 participants

SECONDARY outcome

Timeframe: birth

In utero HIV-1 infection rate

Outcome measures

Outcome measures
Measure	ARM A (ZDV - Standard of Care) n=581 Participants 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) n=580 Participants 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) n=574 Participants 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
Infant HIV-1 Infection Status	37 participants	28 participants	28 participants

SECONDARY outcome

Timeframe: through age 6 months

Outcome measures

Outcome measures
Measure	ARM A (ZDV - Standard of Care) n=581 Participants 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) n=580 Participants 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) n=574 Participants 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
Participant Deaths	11 participants	15 participants	17 participants

SECONDARY outcome

Timeframe: through age 3 months

Compare HIV-1 RNA levels; CD4+ lymphocyte counts; and rates of genotypic and phenotypic resistance among the three treatment regimens.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: through age 14 days

Population: 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.

Descriptive study of 3TC and NFV pharmacokinetics during first two weeks of life using weight band dosing regimen in a subset of enrolled infants.

Outcome measures

Outcome measures
Measure	ARM A (ZDV - Standard of Care) n=26 Participants 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
3TC and NFV Pharmacokinetics (NFV-AUC-12h) 4-7 day	20.7 ug*h/mL Full Range 46.57 • Interval 3.4 to 183.5	—	—
3TC and NFV Pharmacokinetics (NFV-AUC-12h) 10-14 day	25.5 ug*h/mL Full Range 13.10 • Interval 1.7 to 41.7	—	—
3TC and NFV Pharmacokinetics (3TC-AUC-12 h) 4-7 day	4.0 ug*h/mL Full Range 4.50 • Interval 2.9 to 15.6	—	—
3TC and NFV Pharmacokinetics (3TC-AUC-12h) 10-14 day	7.9 ug*h/mL Full Range 4.12 • Interval 2.7 to 14.0	—	—

SECONDARY outcome

Timeframe: through age 3 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	ARM A (ZDV - Standard of Care) n=47 Participants 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) n=1544 Participants 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
Risk Factors for Perinatal HIV-1 Transmission Treatment Arm C (ZDV+3TC/NFV)	12 participants	516 participants	—
Risk Factors for Perinatal HIV-1 Transmission Treatment Arm B (ZDV+NFV)	11 participants	523 participants	—
Risk Factors for Perinatal HIV-1 Transmission Treatment Arm A (ZDV only)	24 participants	505 participants	—
Risk Factors for Perinatal HIV-1 Transmission Illegal Substance Abuse during pregnancy	7 participants	130 participants	—

SECONDARY outcome

Timeframe: 14 days

Descriptive study of NVP pharmacokinetics during first two weeks of life using weight band dosing in a subset of enrolled infants.

Outcome measures

Outcome measures
Measure	ARM A (ZDV - Standard of Care) n=14 Participants 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
NVP Pharmacokinetics NVP conc prior to 3rd dose	362 ng/mL Interval 165.0 to 1728.0	—	—
NVP Pharmacokinetics NVP peak conc (Cmax) post 3rd dose	2286 ng/mL Interval 1241.0 to 3811.0	—	—
NVP Pharmacokinetics NVP conc 3-5 day post 3rd dose	459 ng/mL Interval 73.0 to 1747.0	—	—
NVP Pharmacokinetics NVP conc 7 day post 3rd dose	76 ng/mL Interval 25.0 to 652.0	—	—

Adverse Events

ARM A (ZDV Alone)

Serious events: 219 serious events

Other events: 492 other events

Deaths: 0 deaths

ARM B (ZDV + NVP)

Serious events: 211 serious events

Other events: 482 other events

Deaths: 0 deaths

ARM C (ZDV + 3TC/NFV)

Serious events: 252 serious events

Other events: 480 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	ARM A (ZDV Alone) n=581 participants at risk ZDV, 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) n=580 participants at risk ZDV, given for 6 weeks: 12 mg PO BID if birthweight (BW) \> 2000 grams 8 mg PO BID if BW \< 2000 grams AND 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) n=574 participants at risk ZDV, given for 6 weeks: 12 mg PO BID if birthweight (BW) \> 2000 grams 8 mg PO BID if BW \< 2000 grams AND 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
Blood and lymphatic system disorders Anaemia NOS	49.2% 286/581 • Number of events 451 • through 6 months AE data collected from study entry to off study period	46.6% 270/580 • Number of events 402 • through 6 months AE data collected from study entry to off study period	50.0% 287/574 • Number of events 456 • through 6 months AE data collected from study entry to off study period
Blood and lymphatic system disorders neutropenia	38.7% 225/581 • Number of events 294 • through 6 months AE data collected from study entry to off study period	20.5% 119/580 • Number of events 261 • through 6 months AE data collected from study entry to off study period	42.5% 244/574 • Number of events 334 • through 6 months AE data collected from study entry to off study period
Infections and infestations oral candidiasis	27.9% 162/581 • Number of events 188 • through 6 months AE data collected from study entry to off study period	29.3% 170/580 • Number of events 194 • through 6 months AE data collected from study entry to off study period	27.2% 156/574 • Number of events 177 • through 6 months AE data collected from study entry to off study period
Investigations Aspartate Aminotransferase Increased	57.7% 335/581 • Number of events 439 • through 6 months AE data collected from study entry to off study period	54.7% 317/580 • Number of events 429 • through 6 months AE data collected from study entry to off study period	56.6% 325/574 • Number of events 418 • through 6 months AE data collected from study entry to off study period

Additional Information

Margaret Camarca, Project Director

Westat

Phone: 301-517-4128

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place