HIV Infections
Conditions
Keywords
HIV Seronegativity, Treatment Experienced, Treatment Naive
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.
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.
Interventions
DRUGNevirapine
10 mg/ml oral suspension taken once daily up to 6 months of age. Dosage will increase throughout study.
Oral suspension taken once daily up to 6 months of age
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute on Drug Abuse (NIDA)
National Institute of Mental Health (NIMH)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study | At Month 6 | — |
| 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
| Measure | Time frame |
|---|---|
| Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms | At Months 6 and 18 |
| Relative Rates of HIV Infection in the Two Arms | At Month 18 |
| Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms | At Month 18 |
Countries
South Africa, Tanzania, Uganda, Zimbabwe
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Nevirapine For infants: extended treatment with NVP | 759 |
| Placebo For infants: extended treatment with NVP placebo | 763 |
| Total | 1,522 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 30 | 26 |
| Overall Study | Lost to Follow-up | 52 | 58 |
Baseline characteristics
| Characteristic | Nevirapine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 759 Participants | 763 Participants | 1522 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Categorical Infant Birthweight (g) 2000-2499 | 50 participants | 52 participants | 102 participants |
| Categorical Infant Birthweight (g) 2500-2999 | 214 participants | 211 participants | 425 participants |
| Categorical Infant Birthweight (g) 3000-3499 | 329 participants | 336 participants | 665 participants |
| Categorical Infant Birthweight (g) >=3500 | 166 participants | 163 participants | 329 participants |
| Categorical Infant Birthweight (g) Missing | 0 participants | 1 participants | 1 participants |
| Region of Enrollment South Africa | 171 participants | 171 participants | 342 participants |
| Region of Enrollment Tanzania | 98 participants | 99 participants | 197 participants |
| Region of Enrollment Uganda | 259 participants | 261 participants | 520 participants |
| Region of Enrollment Zimbabwe | 231 participants | 232 participants | 463 participants |
| Sex/Gender, Customized Ambiguous | 1 participants | 0 participants | 1 participants |
| Sex/Gender, Customized Female | 395 participants | 365 participants | 760 participants |
| Sex/Gender, Customized Male | 363 participants | 398 participants | 761 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 614 / 758 | 618 / 761 |
| serious Total, serious adverse events | 152 / 758 | 141 / 761 |
Outcome results
Primary
Frequency and Severity of Adverse Reactions Among Participating Infants
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nevirapine | Frequency and Severity of Adverse Reactions Among Participating Infants | Life-Threatening | 87 Number of Adverse Events |
| Nevirapine | Frequency and Severity of Adverse Reactions Among Participating Infants | Moderate | 694 Number of Adverse Events |
| Nevirapine | Frequency and Severity of Adverse Reactions Among Participating Infants | Severe | 375 Number of Adverse Events |
| Nevirapine | Frequency and Severity of Adverse Reactions Among Participating Infants | Mild | 832 Number of Adverse Events |
| Nevirapine | Frequency and Severity of Adverse Reactions Among Participating Infants | Death | 26 Number of Adverse Events |
| Placebo | Frequency and Severity of Adverse Reactions Among Participating Infants | Mild | 838 Number of Adverse Events |
| Placebo | Frequency and Severity of Adverse Reactions Among Participating Infants | Death | 30 Number of Adverse Events |
| Placebo | Frequency and Severity of Adverse Reactions Among Participating Infants | Life-Threatening | 87 Number of Adverse Events |
| Placebo | Frequency and Severity of Adverse Reactions Among Participating Infants | Severe | 332 Number of Adverse Events |
| Placebo | Frequency and Severity of Adverse Reactions Among Participating Infants | Moderate | 677 Number of Adverse Events |
Primary
HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study
Time frame: At Month 6
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nevirapine | HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study | # of HIV infections at 6 months | 8 participants |
| Nevirapine | HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study | # of Infants at risk for HIV infection at 6 months | 700 participants |
| Placebo | HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study | # of HIV infections at 6 months | 18 participants |
| Placebo | HIV Infection in Infants Determined to be HIV Uninfected at 6 Weeks Enrolled in Each Arm of the Study | # of Infants at risk for HIV infection at 6 months | 699 participants |
95% CI: [0.3, 1.8]Kaplan-Meier Method
95% CI: [1.3, 3.6]Kaplan-Meier Method
Comparison: 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.p-value: 0.049Z-test
Secondary
Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms
Time frame: At Month 18
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nevirapine | Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms | # Infant Deaths at 18 months | 26 participants |
| Nevirapine | Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms | # Infants at risk of death at 18 months | 678 participants |
| Placebo | Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms | # Infant Deaths at 18 months | 30 participants |
| Placebo | Infant Survival Rates (Mortality Regardless of HIV Infection) in the Two Arms | # Infants at risk of death at 18 months | 684 participants |
95% CI: [2, 7.4]Kaplan-Meier Method
95% CI: [2.7, 5.6]Kaplan-Meier Method
Comparison: The cumulative rates of mortality at 6 months, as calculated by Kaplan-Meier, were compared between the two groups using a Z-statistic.p-value: 0.805Z-test
95% CI: [0.4, 2]Kaplan-Meier Method
95% CI: [0.3, 1.8]Kaplan-Meier Method
Comparison: The cumulative mortality rates at 18 months, as calculated by Kaplan-Meier, were compared between the two groups using a Z statistic.p-value: 0.719Z-test
Comparison: 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.p-value: 0.611Log Rank
Secondary
Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms
Time frame: At Months 6 and 18
Population: There were 1522 infants randomized at 6 weeks of birth to either the extended Nevirapine arm (759) or the placebo arm (763).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nevirapine | Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms | Number of Infants Alive and HIV-free at 6 months | 689 participants |
| Nevirapine | Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms | Number of Infants Alive and HIV-free at 18 months | 629 participants |
| Placebo | Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms | Number of Infants Alive and HIV-free at 6 months | 683 participants |
| Placebo | Proportion of Infants Who Are Alive and HIV-uninfected in the Two Arms | Number of Infants Alive and HIV-free at 18 months | 616 participants |
Comparison: 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.95% CI: [96.6, 98.8]Kaplan-Meier Method
Comparison: 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.95% CI: [95.5, 98]Kaplan-Meier Method
Comparison: The cumulative rates of HIV-free survival at 6 months were compared between the two groups using a Z-statistic.p-value: 0.274Z-test
Comparison: 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.95% CI: [92.9, 96.2]Kaplan-Meier Method
Comparison: 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.95% CI: [91.5, 95.1]Kaplan-Meier Method
Comparison: The cumulative rates of HIV-free survival at 18 months were compared between the two groups using a Z statistic.p-value: 0.323Z-test
Secondary
Relative Rates of HIV Infection in the Two Arms
Time frame: At Month 18
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nevirapine | Relative Rates of HIV Infection in the Two Arms | # of infants with HIV infection at 18 months | 16 participants |
| Nevirapine | Relative Rates of HIV Infection in the Two Arms | # of infants @ risk for HIV infection at 18 months | 664 participants |
| Placebo | Relative Rates of HIV Infection in the Two Arms | # of infants with HIV infection at 18 months | 23 participants |
| Placebo | Relative Rates of HIV Infection in the Two Arms | # of infants @ risk for HIV infection at 18 months | 663 participants |
Comparison: 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.95% CI: [1.1, 3.3]Kaplan-Meier Method
Comparison: 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.95% CI: [1.9, 4.4]Kaplan-Meier Method
Comparison: 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.p-value: 0.28Z-test