722 women were enrolled into the HIVIGLOB/NVP trial of which 228 were assigned to the six week extended NVP (SWEN) arm [20
]. Of the remaining 494 women, 204 were randomly assigned to the HIVIGLOB/sdNVP arm and 290 were assigned to the sdNVP arm (). Of the 204 women randomized to the HIVIGLOB/sdNVP arm, only 173 (85%) women received the HIVIGLOB infusion. Twenty six women delivered prior to or missed their HIVIGLOB infusion date; 3 withdrew from the study prior to infusion; 1 had an intrauterine fetal death diagnosed at her infusion appointment and 1 was diagnosed with severe malaria, preventing infusion. One participant assigned to the sdNVP arm withdrew from participation prior to delivery.
There were 199 live births (including twins) and 5 stillbirths in the HIVIGLOB/sdNVP arm, whereas 297 live births (including twins) and 2 stillbirths were delivered to women randomized to the sdNVP arm. Four infants did not receive their HIVIGLOB infusion; two early neonatal deaths and two maternal refusals. Analysis included 198 infants in the HIVIGLOB/sdNVP arm and 294 infants in the sdNVP arm who had an evaluable infection status at 6 months.
Maternal characteristics including age, proportion of Caesarean section deliveries, proportion that received sdNVP at onset of labor, maternal CD4 cell counts and viral load were similar in the two groups (). Infant characteristics including gender, proportion receiving sdNVP at birth and proportion breastfeeding at given time points did not differ significantly between the two study groups ().
Comparison of Maternal and Infant Characteristics by Study Regimen*
Frequency of breastfeeding
Reported breastfeeding was 100% at 1 week and 63-65% at 14 weeks in both study groups (). There was a substantial reduction in breastfeeding after 14 weeks, with proportions of any breastfeeding at 6 months of 33.1% in the HIVIGLOB/sdNVP arm and 31% in the sdNVP arm and (p= 0.64). Rates of exclusive breastfeeding among those still breastfeeding at 6 months were 41.7% in the HIVIGLOB/sdNVP arm and 37.2% in the sdNVP arm (p = 0.59). By 12 months, the proportion of babies receiving any breast milk was 13.1% in the HIVIGLOB/sdNVP arm and 9.9% in the sdNVP arm.
Risk of HIV Transmission
There was a significant difference in the proportion of children with HIV infection detected at birth in the HIVIGLOB/sdNVP arm (9.1% - 18 infections) compared with the low rate found in the sdNVP control arm (4.1% - 12 infections), [RR = 2.3, 95% CI: 1.100- 4.500, p=0.030] (, ). The difference persisted throughout the study period, however it was no longer statistically significant by the 6 week time point. The difference in the proportion of children with HIV infection at 6 months, the primary endpoint, was not statistically significant between the HIVIGLOB/sdNVP arm and the sdNVP arm (18.7% vs. 15.0%, RR = 1.240, 95% CI: 0.833 – 1.846, p= 0.290). Secondary analyses in the modified intent-to-treat population (infants uninfected at birth) showed that there were no statistically significant differences in the proportion of children with HIV infection between the two arms at any of the study time points ().
Risk of HIV Transmission, Death and HIV Transmission or Death among all Live-Born Infants and Infants Uninfected at Birth by Study Regimen
Kaplan-Meier Estimates of Infant HIV Transmission, Death and HIV Transmission or Death among all Live-Born Infants
After adjusting for study arm, maternal baseline viral load (VL) of >100,000 copies/ml led to more than a fivefold overall increase in risk of transmission [HR = 5.360, 95% CI: 2.606-11.024, p= 0.000], while maternal baseline VL of 10,001 – 100,000 copies/ml led to more than a twofold overall increase in risk of transmission [HR = 2.451, 95% CI: 1.170 – 5.136, p= 0.018] when compared to maternal baseline VL of ≤10,000 copies/ml .
Risk of Death
Two mothers died during the eight week study participation period. One death in the HIVIGLOB/sdNVP arm was due to advanced HIV disease associated with wasting, puerperal sepsis and gastroenteritis and the other death in the sdNVP arm was due to cryptococcal meningitis.
There were 28 infant deaths during the 12 month follow-up period: 14 in the HIVIGLOB/sdNVP arm and 14 in the sdNVP arm (). Risk of infant mortality in the HIVIGLOB/sdNVP arm was statistically similar to that in the sdNVP arm at all time points (, ). At 6 months, risk of mortality was 5.6% (HIVIGLOB/sdNVP arm) versus 3.4% (sdNVP arm) [RR= 1.630, 95% CI: 0.706-3.767, p= 0.253]. Reasons for death included respiratory conditions (10), gastroenteritis (6), other infections (3), malnutrition (2), sudden infant death syndrome (2), anemia (2) and other (3). These conditions were responsible for a similar proportion of deaths in both arms (data not shown). There was a significantly reduced overall risk of infant mortality among women with CD4 cell counts >350 cells/mm3 compared to those with CD4 cell counts < 200 cells/mm3, [HR = 0.405, 95% CI: 0.167-0.981, p= 0.045]. Overall risk of infant death was not different in women with CD4 cell counts 201- 350 cells/mm3 compared with women who had lower CD4 cell counts [HR = 0.682, 95% CI: 0.247-1.884, p= 0.461]. Overall risk of infant death adjusted for study arm was not associated with maternal baseline VL.
Secondary modified intent-to-treat population showed that there were no statistically significant differences in the proportion of children who died at any of the study time points ().
Risk of HIV Transmission or Death
The cumulative risk of infant HIV transmission or death was significantly lower in the sdNVP arm (9.9%) than in the HIVIGLOB/sdNVP arm (17.2%) at 2 weeks [RR = 1.834, 95% CI: 1.061 – 3.169, p= 0.030] (). A similar trend was observed at all the other time points (6 and 14 weeks, 6 and 12 months) however, the difference in risk at these time points was not significant (). Secondary analyses for transmission or death showed no significant difference in risk at all time points ().
The number of women experiencing serious adverse events (i.e. grade 3 and 4 AEs) was balanced between the two groups with at least one grade 3 or 4 AE reported in 38 (19.3%) in the HIVIGLOB/sdNVP arm and 54 (18.9%) women in the sdNVP arm, (p= 0.91). Complications of pregnancy and childbirth were the most frequent cause of maternal SAEs in both groups, followed by laboratory abnormalities. Fifty-six mothers had at least one AE considered related to the HIVIGLOB infusion and all involved vital sign changes common with immunoglobulin infusions, such as changes in blood pressure, heart rates, and respiratory rates. One woman had a grade 3 AE that was considered definitely related to HIVIGLOB that necessitated permanent discontinuation of the infusion. All other women who experienced an infusion related AE completed the infusion. All infusion related events resolved with no complications.
There were no differences in the number of infants experiencing at least one grade 3 or 4 SAE between the two arms, 124 (62.6%) in the HIVIGLOB/sdNVP arm and 175 (59.5%) in the sdNVP arm, p=0.51. The majority involved common illnesses in the study population such as malaria, pneumonia, gastroenteritis, and laboratory abnormalities. Fifteen infants had grade 3 events considered definitely or probably related to the HIVIGLOB infusion; 6 infusions were permanently discontinued, 4 were temporarily held then restarted, 4 were continued and 1 event occurred after completion of the infusion. All of these events resolved without complications. Fourteen infants had serious adverse events considered possibly related to the HIVIGLOB infusion. Eight events occurred during the infusion (1 permanent discontinuation, 2 temporarily held, 5 no change in infusion) and the remaining 6 occurred after the infusion was completed.