Using Nevirapine to Prevent Mother-to-Child HIV Transmission During Breastfeeding

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00074412
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), National Institute on Drug Abuse (NIDA) (NIH), National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 2,026
• Locations: 5
• Arms: 2
• Duration (Months): 58
• Patients Per Site: 405.2
• Patients Per Site Per Month: 7

Study Details

Study Description

Brief Summary

The many benefits of breastfeeding are well documented. However, because of the risk of mother-to-child transmission (MTCT) of HIV from an HIV infected mother to her infant, there is considerable concern over the practice, especially in developing countries. The purpose of this study is to determine the safety and effectiveness of the anti-HIV drug nevirapine (NVP) in preventing MTCT of HIV in breastfeeding infants born to HIV infected women in South Africa, Tanzania, Uganda, and Zimbabwe.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Nevirapine; Drug: Nevirapine placebo	Phase 3

Detailed Description

Breastfeeding provides general health, growth, and development benefits to an infant and significantly decreases the risk of certain acute and chronic diseases. Breastfeeding also decreases financial burden on the mother by decreasing the need for infant formula and health care for the infant. However, clinical evidence has shown that HIV can be readily transmitted through breast milk, although the risk of HIV MTCT over time while breastfeeding has been difficult to determine. Given the many advantages of breastfeeding and the significant obstacles to substituting formula for breast milk in developing countries, there is an urgent need to make breastfeeding by HIV infected women safe. This study will evaluate the safety and efficacy of an extended NVP regimen for prevention of MTCT of HIV through breastfeeding.

This study will last approximately 3.5 years. Mother/infant pairs will be enrolled over a period of 18 to 24 months. During the third trimester of pregnancy, HIV infected participants will receive HIV counseling and the intrapartum/neonatal two-dose NVP prophylaxis regimen to prevent MTCT. Mothers will also be given infant feeding options counseling and information on administering the study drug to the infant. Infants who were randomly assigned to receive a placebo and older than 6 weeks of age as of 08/10/07 OR to receive NVP will continue their treatment assignment. Infants who were randomly assigned to receive a placebo and are 6 weeks of age or less as of 08/10/07 will receive open-label NVP through Day 42 of life. For all other participants, all randomized infants will receive extended NVP through 6 weeks (Day 42) of life. All eligible infants will be randomly assigned to one of two groups at Week 6 following birth. The first group will receive extended NVP treatment; the second group will receive nevirapine placebo. Randomized infants will receive the extended NVP or NVP placebo through the first 6 months of life or until cessation of breastfeeding, whichever occurs earlier. Mothers will be instructed to begin giving their infants their assigned intervention starting at Day 3 to Day 7 postpartum. All mothers and infants outside of the study will be offered the local standard of care antiretroviral (ARV) regimen for the prevention of MTCT, but these ARVs will not be provided by the study.

Follow-up evaluations will be conducted at Weeks 2 and 6 and Months 3, 6, 12, and 18 for mothers, and at Weeks 2, 5, 6, and 8 and Months 3, 4, 5, 6, 9, 12, and 18 for infants. Study visits will include physical examinations, blood tests (including HIV tests), and medical histories. Study participants will be followed for up to 3.5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 2026 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Prevention
• Official Title: A Phase III Trial to Determine the Efficacy and Safety of an Extended Regimen of Nevirapine in Infants Born to HIV-Infected Women to Prevent Vertical HIV Transmission During Breastfeeding
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 2A For infants: extended treatment with NVP	Drug: Nevirapine; 10 mg/ml oral suspension taken once daily up to 6 months of age. Dosage will increase throughout study.; Other Names: NVP
Placebo Comparator: 2B For infants: extended treatment with NVP placebo	Drug: Nevirapine placebo; Oral suspension taken once daily up to 6 months of age; Other Names: NVP placebo

Outcome Measures

Primary Outcome Measures

1. HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study [At Month 6]

2. Frequency and Severity of Adverse Reactions Among Participating Infants [6 weeks through 18 months]

   For those infants who were randomized at 6 weeks and who initiated study drug we looked at the frequency and severity of adverse reactions through 18 months of study. The severity of all AEs was graded according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. The term severity is described as the intensity grade or level for specific event (i.e. mild, moderate, severe, or life-threatening). Severity is not the same as seriousness.

Secondary Outcome Measures

1. Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms [At Months 6 and 18]

2. Relative Rates of HIV Infection in the Two Arms [At Month 18]

3. Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms [At Month 18]

4. Frequency and Duration of Maternal Plasma and Breast Milk NVP-resistant HIV Strains and the Relationship With HIV Transmission [Throughout study]

5. Relationship Between Maternal Plasma and Breast Milk RNA Levels and the Risk of MTCT [Throughout study]

6. Frequency and Duration of NVP-resistant HIV Strains in Plasma of HIV-infected Infants [Throughout study]

7. Rates of Disease Progression as Defined by CD4 Counts, HIV-1 RNA PCR, and Mortality in Infected Infants in the Two Arms [Throughout study]

8. NVP Concentrations in Infants Determined to be HIV-infected and in a Sample of HIV-uninfected Infants [Week 8 and Month 3]

   Samples for NVP concentration were selected from the Version 3.0 infants who were randomized to NVP at 6 weeks and whose mothers were not on 3 or more antiretrovirals at the time of randomization. All infants HIV-infected by 6 months who met this criteria were selected and matched to HIV-uninfected infants who also met this criteria in a 1:3 ratio. NVP concentrations were measured by high liquid chromatographic/mass spectroscopy from the aforementioned infants plasma samples collected at week 8 and month 3. Median NVP concentrations were compared

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Note: As of 08/10/07, the arm assignments for current and new participants have changed. Please see the above description for this trial for more information.

Inclusion Criteria for Mothers:

• 18 years of age or older

• HIV infected

• In third trimester of pregnancy, or at most 3 days post-delivery

• If baby is not yet born, planning to deliver at a facility where the study is being conducted

• Plan to breastfeed

Exclusion Criteria for Mothers:

• Complications with this pregnancy

• Serious medical condition that would interfere with the study (e.g., that would prevent breastfeeding or adherence to the follow-up schedule), as judged by the on-site clinician

Inclusion Criteria for Infants:

• Born to an HIV infected mother who is eligible for the study

• Weighed at least 2000 grams (4.4 lbs) at birth

• Blood sample obtained from the infant for HIV-1 DNA PCR, CBC with differential, and ALT

• Infants in a multiple birth are eligible only if both/all infants are eligible for the study and assigned to the same study group

• Able to breastfeed (e.g., mother and infant alive with no condition apparent that would prevent breastfeeding)

Exclusion Criteria for Infants:

• HIV DNA PCR positive at birth

• ALT of Grade 2 or higher at birth

• Hemoglobin, absolute neutrophil count, or platelet count of Grade 3 or higher at birth

• Skin rash of Grade 2B (urticaria), Grade 3, or above

• Confirmed or suspected clinical hepatitis

• Serious illness or condition that would interfere with compliance with study procedures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CAPRISA Umlazi CRS	Umlazi	KwaZulu-Natal	South Africa
2	Muhimbili University of Health and Allied Sciences (MUHAS) CRS	Dar es Salaam		Tanzania
3	Makerere University- JHU Research Collaboration {MUJHU CARE LTD} CRS	Kampala	Mpigi	Uganda
4	Seke North CRS	Chitungwiza		Zimbabwe
5	St Mary's CRS	Chitungwiza		Zimbabwe

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• National Institute on Drug Abuse (NIDA)
• National Institute of Mental Health (NIMH)

Investigators

• Study Chair: Hoosen M. Coovadia, MD, MBBS, Centre for HIV Networking (HIVAN), Nelson Mandela School of Medicine, University of Natal
• Study Chair: Laura Guay, MD, Johns Hopkins University
• Study Chair: Wafaie Fawzi, MD, PhD, Department of Nutrition, Harvard School of Public Health
• Study Chair: Yvonne Maldonado, MD, Stanford University
• Study Chair: Daya Moodley, MSc, PhD, Department of Obstetrics and Gynaecology, Nelson R Mandela School of Medicine, University of Natal

Study Documents (Full-Text)

None provided.

More Information

Publications

• Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Owor M, Ducar C, Deseyve M, Mwatha A, Emel L, Duefield C, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Gigliotti M, Bray D, Mmiro F. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet. 2003 Sep 13;362(9387):859-68.
• Mitchla Z, Sharland M. Current treatment options to prevent perinatal transmission of HIV. Expert Opin Pharmacother. 2000 Jan;1(2):239-48. Review.
• Mofenson LM. Advances in the prevention of vertical transmission of human immunodeficiency virus. Semin Pediatr Infect Dis. 2003 Oct;14(4):295-308. Review.
• Piwoz EG, Ross J, Humphrey J. Human immunodeficiency virus transmission during breastfeeding: knowledge, gaps, and challenges for the future. Adv Exp Med Biol. 2004;554:195-210. Review.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00074412
• Other Study ID Numbers: HPTN 046; 10142
• First Posted: Dec 15, 2003
• Last Update Posted: Aug 23, 2022
• Last Verified: Jul 1, 2013

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): HIV Seronegativity; Treatment Experienced; Treatment Naive
• Additional relevant MeSH terms: HIV Infections; Nevirapine

Study Results

Participant Flow

Recruitment Details	HIV-infected pregnant women were recruited from antenatal clinics at DAIDS Clinical Trials Sites in Zimbabwe, South Africa, Uganda & Tanzania between May 14, 2008 & January 20th 2010. 1700 mother/infant pairs were enrolled & infants were given daily doses of Nevirapine for 6 weeks at which point there were randomized to placebo or extended NVP.
Pre-assignment Detail	Infants were excluded from randomization if in first 42 days: had a positive HIV-1 DNA PCR, breastfeeding was discontinued, never initiated or permanently discontinued open-label NVP, certain graded abnormal labs, skin rash grade2B or higher, clinical hepatitis, serious illness/condition that prevented compliance, or use of rifampin/ketoconazole.

Arm/Group Title	Placebo	Nevirapine
Arm/Group Description	For infants: extended treatment with NVP placebo	For infants: extended treatment with NVP
Period Title: Overall Study
STARTED	763	759
Week 8 Visit	759	759
Month 3 Visit	759	755
Month 4 Visit	758	752
Month 5 Visit	756	750
Month 6 Visit	748	748
Month 9 Visit	741	741
Month 12 Visit	733	735
COMPLETED	681	675
NOT COMPLETED	82	84

Baseline Characteristics

Arm/Group Title	Nevirapine	Placebo	Total
Arm/Group Description	For infants: extended treatment with NVP	For infants: extended treatment with NVP placebo	Total of all reporting groups
Overall Participants	759	763	1522
Age (Count of Participants)
<=18 years	759 100%	763 100%	1522 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex/Gender, Customized (participants) [Number]
Ambiguous	1 0.1%	0 0%	1 0.1%
Male	363 47.8%	398 52.2%	761 50%
Female	395 52%	365 47.8%	760 49.9%
Region of Enrollment (participants) [Number]
Tanzania	98 12.9%	99 13%	197 12.9%
Uganda	259 34.1%	261 34.2%	520 34.2%
South Africa	171 22.5%	171 22.4%	342 22.5%
Zimbabwe	231 30.4%	232 30.4%	463 30.4%
Categorical Infant Birthweight (g) (participants) [Number]
Missing	0 0%	1 0.1%	1 0.1%
2000-2499	50 6.6%	52 6.8%	102 6.7%
2500-2999	214 28.2%	211 27.7%	425 27.9%
3000-3499	329 43.3%	336 44%	665 43.7%
>=3500	166 21.9%	163 21.4%	329 21.6%

Outcome Measures

1. Primary Outcome

Title	HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study
Time Frame	At Month 6

Outcome Measure Data

Analysis Population Description

All infants who were randomly allocated to either treatment or placebo at 6 weeks of age under version 3.0 of the protocol were included in the analysis of the primary endpoint, HIV infection at 6 months. 127/1700 infants were enrolled but excluded from randomization at 6 weeks for various reasons as mentioned in the flow-through.

Arm/Group Title	Nevirapine	Placebo
Arm/Group Description	For infants: extended treatment with NVP	For infants: extended treatment with NVP Placebo
Measure Participants	759	763
# of HIV infections at 6 months	8 1.1%	18 2.4%
# of Infants at risk for HIV infection at 6 months	700 92.2%	699 91.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nevirapine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	6 month Rate of Cum. HIV Infection (%)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 0.3 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	6 month Rate of Cum. HIV Infection (%)
	Estimated Value	2.4
	Confidence Interval	(2-Sided) 95%; 1.3 to 3.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Nevirapine, Placebo
	Comments	Assuming the cumulative HIV infection rate in placebo group would be 4.2% (2.6 at 6 wk. & 6.7 at 6 mon.), we estimated 1500 mother/infant pairs would provide 90% power to detect a reduction in HIV infection from 4.2% to 1.4% at 6 mon. with a Pearson χ² test statistic and a one-sided false positive error rate of 0.025. Rate of cumulative infection was calculated using Kaplan-Meier method and rates between extended NVP group and placebo were done with the Z statistic.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments	P-value has not been adjusted for interim analysis or multiple testing. A priori threshold for statistical significance was 0.05.
	Method	Z-test
	Comments
Method of Estimation	Estimation Parameter	Z statistic
	Estimated Value	1.973
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Frequency and Severity of Adverse Reactions Among Participating Infants
Description	For those infants who were randomized at 6 weeks and who initiated study drug we looked at the frequency and severity of adverse reactions through 18 months of study. The severity of all AEs was graded according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. The term severity is described as the intensity grade or level for specific event (i.e. mild, moderate, severe, or life-threatening). Severity is not the same as seriousness.
Time Frame	6 weeks through 18 months

Outcome Measure Data

Analysis Population Description

A total of 1519 infants, 758 in the NVP arm and 761 in the placebo arm, initiated study product and were thus included in the analysis for the frequency and severity of adverse reactions.

Arm/Group Title	Nevirapine	Placebo
Arm/Group Description	For infants: extended treatment with NVP	For infants: extended treatment with NVP placebo
Measure Participants	758	761
Measure Adverse Events	2014	1964
Death	26	30
Life-Threatening	87	87
Severe	375	332
Moderate	694	677
Mild	832	838

3. Secondary Outcome

Title	Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms
Time Frame	At Months 6 and 18

Outcome Measure Data

Analysis Population Description

There were 1522 infants randomized at 6 weeks of birth to either the extended Nevirapine arm (759) or the placebo arm (763).

Arm/Group Title	Nevirapine	Placebo
Arm/Group Description	For infants: extended treatment with NVP	For infants: extended treatment with NVP placebo
Measure Participants	759	763
Number of Infants Alive and HIV-free at 6 months	689 90.8%	683 89.5%
Number of Infants Alive and HIV-free at 18 months	629 82.9%	616 80.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nevirapine
	Comments	The cumulative rate of HIV-free survival at 6 months in the extended NVP arm was calculated using the Kaplan-Meier method; while the 95% CI was calculated using Greenwood's formula.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cum. Rate of HIV-free Survival 6mon (%)
	Estimated Value	97.7
	Confidence Interval	(2-Sided) 95%; 96.6 to 98.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	The cumulative rate of HIV-free survival at 6 months in the placebo arm was calculated using the Kaplan-Meier method; while the 95% CI was calculated using Greenwood's formula.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cum. Rate of HIV-free Survival 6mon (%)
	Estimated Value	96.8
	Confidence Interval	(2-Sided) 95%; 95.5 to 98.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Nevirapine, Placebo
	Comments	The cumulative rates of HIV-free survival at 6 months were compared between the two groups using a Z-statistic.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.274
	Comments	P-value was not adjusted for interim analysis or multiple testing.
	Method	Z-test
	Comments
Method of Estimation	Estimation Parameter	Z statistic
	Estimated Value	1.095
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Nevirapine
	Comments	The cumulative rate of HIV-free survival at 18 months in the extended NVP arm was calculated using the Kaplan-Meier method; while 95% confidence intervals were calculated using Greenwood's formula.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cum. Rate of HIV-free Survival 18mon (%)
	Estimated Value	94.5
	Confidence Interval	(2-Sided) 95%; 92.9 to 96.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	The cumulative rate of HIV-free survival at 18 months in the placebo arm was calculated using the Kaplan-Meier method; while the 95% confidence interval was calculated using Greenwood's formula.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cum. Rate of HIV-free Survival 18mon (%)
	Estimated Value	93.3
	Confidence Interval	(2-Sided) 95%; 91.5 to 95.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Nevirapine, Placebo
	Comments	The cumulative rates of HIV-free survival at 18 months were compared between the two groups using a Z statistic.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.323
	Comments	P-value was not adjusted for interim analysis or multiple testing.
	Method	Z-test
	Comments
Method of Estimation	Estimation Parameter	Z statistic
	Estimated Value	0.988
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Relative Rates of HIV Infection in the Two Arms
Time Frame	At Month 18

Outcome Measure Data

Analysis Population Description

A total of 1527 infants were randomized to either placebo or extended NVP. 5 of these infants were later found to be infected at the time of randomization (2 in NVP and 3 in Placebo). Thus, only 1522 infants were included in the analysis.

Arm/Group Title	Nevirapine	Placebo
Arm/Group Description	For infants: extended treatment with NVP	For infants: extended treatment with NVP placebo
Measure Participants	759	763
# of infants with HIV infection at 18 months	16 2.1%	23 3%
# of infants @ risk for HIV infection at 18 months	664 87.5%	663 86.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nevirapine
	Comments	The cumulative rate of HIV infection at 18 months in the extended NVP arm was calculated using the Kaplan-Meier method; while the 95% confidence interval was calculated using Greenwood's formula.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	18 mon. Rate of Cum HIV Infection (%)
	Estimated Value	2.2
	Confidence Interval	(2-Sided) 95%; 1.1 to 3.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	The cumulative rate of HIV infection at 18 months in the placebo arm was calculated using the Kaplan-Meier method; while the 95% confidence interval was calculated using Greenwood's formula.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	18 mon. Rate of Cum. HIV Infection (%)
	Estimated Value	3.1
	Confidence Interval	(2-Sided) 95%; 1.9 to 4.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Nevirapine, Placebo
	Comments	The cumulative rates of HIV infection at 18 months were calculated using the Kaplan-Meier method and were compared between arms using a Z statistic.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.280
	Comments	P-value was not adjusted for interim analysis or multiple testing.
	Method	Z-test
	Comments
Method of Estimation	Estimation Parameter	Z statistic
	Estimated Value	1.081
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Time Frame	At Month 18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nevirapine	Placebo
Arm/Group Description	For infants: extended treatment with NVP	For infants: extended treatment with NVP placebo
Measure Participants	759	763
# Infant Deaths at 18 months	26 3.4%	30 3.9%
# Infants at risk of death at 18 months	678 89.3%	684 89.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nevirapine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cumulative Mortality Rate at 18mon (%)
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; 2.0 to 7.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cumulative Mortality Rate at 18mon (%)
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; 2.7 to 5.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Nevirapine, Placebo
	Comments	The cumulative rates of mortality at 6 months, as calculated by Kaplan-Meier, were compared between the two groups using a Z-statistic.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.805
	Comments	P-value was not adjusted for interim analysis or multiple testing
	Method	Z-test
	Comments
Method of Estimation	Estimation Parameter	Z statistic
	Estimated Value	-0.247
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Nevirapine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cumulative Mortality Rate at 6mon (%)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; 0.4 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Cumulative Mortality Rate at 6mon (%)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 0.3 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Nevirapine, Placebo
	Comments	The cumulative mortality rates at 18 months, as calculated by Kaplan-Meier, were compared between the two groups using a Z statistic.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.719
	Comments	P-value was not adjusted for interim analysis or multiple testing.
	Method	Z-test
	Comments
Method of Estimation	Estimation Parameter	Z statistic
	Estimated Value	-0.360
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Nevirapine, Placebo
	Comments	We compared the cumulative mortality rates, as calculated using Kaplan-Meier, between the two study groups over all 18 months of the study follow-up using a log-rank test.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.611
	Comments
	Method	Log Rank
	Comments

6. Secondary Outcome

Title	Frequency and Duration of Maternal Plasma and Breast Milk NVP-resistant HIV Strains and the Relationship With HIV Transmission
Time Frame	Throughout study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Relationship Between Maternal Plasma and Breast Milk RNA Levels and the Risk of MTCT
Time Frame	Throughout study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Frequency and Duration of NVP-resistant HIV Strains in Plasma of HIV-infected Infants
Time Frame	Throughout study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Rates of Disease Progression as Defined by CD4 Counts, HIV-1 RNA PCR, and Mortality in Infected Infants in the Two Arms
Time Frame	Throughout study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	NVP Concentrations in Infants Determined to be HIV-infected and in a Sample of HIV-uninfected Infants
Description	Samples for NVP concentration were selected from the Version 3.0 infants who were randomized to NVP at 6 weeks and whose mothers were not on 3 or more antiretrovirals at the time of randomization. All infants HIV-infected by 6 months who met this criteria were selected and matched to HIV-uninfected infants who also met this criteria in a 1:3 ratio. NVP concentrations were measured by high liquid chromatographic/mass spectroscopy from the aforementioned infants plasma samples collected at week 8 and month 3. Median NVP concentrations were compared
Time Frame	Week 8 and Month 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Regardless of seriousness, severity or relatedness all AEs occurring in infants after enrollment (birth) and throughout the duration of the study (18 months) must be recorded.
Adverse Event Reporting Description	Non-serious adverse events occurring in an infant between randomization and 8 months of life will be collected on a case report form. Further, Serious AEs and AEs that meet the DAIDS expedited reporting criteria will be reported through case report forms throughout the entire 18 month follow-up period.
Arm/Group Title	Nevirapine		Placebo
Arm/Group Description	For infants: extended treatment with NVP		For infants: extended treatment with NVP placebo
All Cause Mortality
	Nevirapine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nevirapine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	152/758 (20.1%)		141/761 (18.5%)
Blood and lymphatic system disorders
Aneamia	1/758 (0.1%)	1	4/761 (0.5%)	4
Cardiac disorders
Cardipulmonary failure	0/758 (0%)	0	1/761 (0.1%)	1
Congenital, familial and genetic disorders
Cerebral palsy	1/758 (0.1%)	1	0/761 (0%)	0
Congenital absence of bile ducts	1/758 (0.1%)	1	0/761 (0%)	0
Sickle cell anaemia	3/758 (0.4%)	4	2/761 (0.3%)	2
Sickle cell anaemia with crisis	1/758 (0.1%)	1	1/761 (0.1%)	1
Eye disorders
Blindness	0/758 (0%)	0	1/761 (0.1%)	1
Gastrointestinal disorders
Diarrhoea	6/758 (0.8%)	6	5/761 (0.7%)	5
Gastrointestinal haemorrhage	0/758 (0%)	0	1/761 (0.1%)	1
Inguinal hernia	0/758 (0%)	0	1/761 (0.1%)	1
Intussusception	0/758 (0%)	0	1/761 (0.1%)	1
Vomiting	0/758 (0%)	0	1/761 (0.1%)	1
General disorders
Death	4/758 (0.5%)	4	2/761 (0.3%)	2
Oedema	1/758 (0.1%)	1	0/761 (0%)	0
Pyrexia	1/758 (0.1%)	1	0/761 (0%)	0
Sudden infant death syndrome	0/758 (0%)	0	1/761 (0.1%)	1
Hepatobiliary disorders
Hyperbilirubinaemia	0/758 (0%)	0	1/761 (0.1%)	1
Immune system disorders
Anaphylactic reaction	1/758 (0.1%)	1	0/761 (0%)	0
Infections and infestations
Abscess	0/758 (0%)	0	1/761 (0.1%)	1
Abscess bacterial	1/758 (0.1%)	1	0/761 (0%)	0
Arthritis bacterial	1/758 (0.1%)	1	0/761 (0%)	0
Bacteraemia	1/758 (0.1%)	1	1/761 (0.1%)	1
Bronchiolitis	2/758 (0.3%)	2	4/761 (0.5%)	7
Bronchopneumonia	18/758 (2.4%)	19	20/761 (2.6%)	23
Cellulitis	1/758 (0.1%)	1	0/761 (0%)	0
Cerebral malaria	1/758 (0.1%)	2	0/761 (0%)	0
Febrile infection	0/758 (0%)	0	1/761 (0.1%)	1
Gastroenteritis	45/758 (5.9%)	50	50/761 (6.6%)	58
Gastroenteritis shigella	0/758 (0%)	0	1/761 (0.1%)	1
Giardiasis	0/758 (0%)	0	1/761 (0.1%)	2
Injection site abscess	0/758 (0%)	0	1/761 (0.1%)	1
Lobar pneumonia	3/758 (0.4%)	3	0/761 (0%)	0
Lower respiratory tract infection	6/758 (0.8%)	6	1/761 (0.1%)	2
Malaria	42/758 (5.5%)	50	34/761 (4.5%)	40
Measles	3/758 (0.4%)	3	3/761 (0.4%)	3
Meningitis	2/758 (0.3%)	2	3/761 (0.4%)	3
Meningitis bacterial	3/758 (0.4%)	3	0/761 (0%)	0
Pericarditis tuberculous	1/758 (0.1%)	1	0/761 (0%)	0
Plasmodium falciparum infection	1/758 (0.1%)	1	1/761 (0.1%)	1
Pneumocystis jiroveci pneumonia	1/758 (0.1%)	1	0/761 (0%)	0
Pneumonia	20/758 (2.6%)	21	29/761 (3.8%)	29
Pneumonia bacterial	2/758 (0.3%)	2	2/761 (0.3%)	2
Pulmonary tuberculosis	2/758 (0.3%)	2	2/761 (0.3%)	2
Respiratory tract infection	2/758 (0.3%)	2	0/761 (0%)	0
Sepsis	5/758 (0.7%)	5	9/761 (1.2%)	12
Sepsis neonatal	0/758 (0%)	0	1/761 (0.1%)	1
Tonsilitis	0/758 (0%)	0	1/761 (0.1%)	1
Upper respiratory tract infection	0/758 (0%)	0	1/761 (0.1%)	1
Urinary tract infection	1/758 (0.1%)	1	0/761 (0%)	0
Injury, poisoning and procedural complications
Chemical poisoning	1/758 (0.1%)	1	1/761 (0.1%)	1
Femur fracture	1/758 (0.1%)	1	0/761 (0%)	0
Head injury	1/758 (0.1%)	1	0/761 (0%)	0
Thermal burn	1/758 (0.1%)	1	2/761 (0.3%)	2
Traumatic shock	1/758 (0.1%)	1	0/761 (0%)	0
Investigations
Alanine aminotransferase increased	1/758 (0.1%)	1	1/761 (0.1%)	1
Haemoglobin decreased	1/758 (0.1%)	1	0/761 (0%)	0
Hepatic enzyme increased	1/758 (0.1%)	1	0/761 (0%)	0
Neutrophil count decreased	1/758 (0.1%)	1	2/761 (0.3%)	2
Metabolism and nutrition disorders
Electrolyte imbalance	0/758 (0%)	0	1/761 (0.1%)	2
Kwashiorkor	5/758 (0.7%)	5	9/761 (1.2%)	9
Malnutrition	1/758 (0.1%)	1	0/761 (0%)	0
Marasmus	3/758 (0.4%)	3	4/761 (0.5%)	5
Nervous system disorders
Febrile convulsion	5/758 (0.7%)	5	0/761 (0%)	0
Hydrocephalus	1/758 (0.1%)	1	0/761 (0%)	0
Respiratory, thoracic and mediastinal disorders
Aspiration	1/758 (0.1%)	1	2/761 (0.3%)	2
Pneumonia aspiration	2/758 (0.3%)	2	0/761 (0%)	0
Other (Not Including Serious) Adverse Events
	Nevirapine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	614/758 (81%)		618/761 (81.2%)
Blood and lymphatic system disorders
Anaemia	42/758 (5.5%)	48	51/761 (6.7%)	55
Eye disorders
Conjunctivitis	62/758 (8.2%)	66	43/761 (5.7%)	53
Gastrointestinal disorders
Diarrhoea	57/758 (7.5%)	63	55/761 (7.2%)	65
Infections and infestations
Conjunctivitis bacterial	76/758 (10%)	86	72/761 (9.5%)	80
Gastroenteritis	188/758 (24.8%)	268	208/761 (27.3%)	288
Malaria	122/758 (16.1%)	164	112/761 (14.7%)	160
Oral candidiasis	97/758 (12.8%)	121	79/761 (10.4%)	93
Upper respiratory infection	135/758 (17.8%)	159	187/761 (24.6%)	223
Investigations
Haemoglobin decreased	73/758 (9.6%)	76	64/761 (8.4%)	67
Neutrophil count decreased	145/758 (19.1%)	181	121/761 (15.9%)	153
Skin and subcutaneous tissue disorders
Dermatitis atopic	55/758 (7.3%)	60	37/761 (4.9%)	44

Limitations/Caveats

The rate of maternal highly active antiretroviral therapy use was higher than expected in our study. Thus there were fewer infant infections which decreased the power to detect differences in HIV transmission risks between study groups.

More Information

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Principal Investigators are NOT employed by the organization sponsoring the study.

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