Safety and Efficacy of HIV Hyperimmune Globulin (HIVIGLOB) for Prevention of Mother-to-Child HIV Transmission in HIV-1 infected Pregnant Women and their Infants in Kampala, Uganda (HIVIGLOB/NVP STUDY)

doi:10.1097/QAI.0b013e31822f8914

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2012 December 1.

Published in final edited form as:

J Acquir Immune Defic Syndr. 2011 December 1; 58(4): 399–407.

doi: 10.1097/QAI.0b013e31822f8914

PMCID: PMC3204156

NIHMSID: NIHMS321101

Safety and Efficacy of HIV Hyperimmune Globulin (HIVIGLOB) for Prevention of Mother-to-Child HIV Transmission in HIV-1 infected Pregnant Women and their Infants in Kampala, Uganda (HIVIGLOB/NVP STUDY)

Carolyne Onyango-Makumbi, MBChB, MS,⁽¹⁾ Saad B. Omer, MBBS, MPH, PhD,⁽²⁾ Michael Mubiru, BSc, Dip Med Stat,⁽¹⁾ Lawrence H. Moulton, PhD,⁽³⁾ Clemensia Nakabiito, MBChB, MMed,^(1),⁽⁴⁾ Philippa Musoke, MBChB, FAAP,^(1),⁽⁵⁾ Francis Mmiro, MBChB, FRCOG,⁽¹⁾^* Sheryl Zwerski, RN, MSN, CRNP,⁽⁶⁾ Hans Wigzell, MD,⁽⁷⁾ Lars Falksveden, MD,⁽⁸⁾^* Britta Wahren, MD,⁽⁸⁾ Gretchen Antelman, ScD,⁽⁹⁾ Mary Glenn Fowler, MD, MPH,⁽¹⁰⁾ Laura Guay, MD,^(11),⁽¹²⁾ and J. Brooks Jackson, MD⁽¹⁰⁾

⁽¹⁾Makerere University – Johns Hopkins University Research Collaboration/MU-JHU CARE LTD, Kampala, Uganda

⁽²⁾Rollins School of Public Health, Emory University, Atlanta, GA, USA

⁽³⁾Bloomberg School of Public Health, Johns Hopkins University, Baltimore MD, USA

⁽⁴⁾Mulago National Referral Hospital, Kampala, Uganda

⁽⁵⁾Department of Pediatrics, Makerere University College of Health Sciences, Kampala, Uganda

⁽⁶⁾Division of AIDS, NIAID, NIH, Rockville MD, USA

⁽⁷⁾Karolinska Institute, Stockholm, Sweden

⁽⁸⁾Swedish Institute for Infectious Disease Control, Stockholm, Sweden

⁽⁹⁾International Center for AIDS Care and Treatment Programs, Mailman School of Public Health, Columbia University, New York, NY, USA

⁽¹⁰⁾Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

⁽¹¹⁾George Washington University, School of Public Health and Health Services, Washington, DC, USA

⁽¹²⁾Elizabeth Glaser Pediatrics AIDS Foundation, Washington, DC, USA

Correspondence and Request for Reprints: Dr. Carolyne Onyango-Makumbi, Makerere University – Johns Hopkins University Research Collaboration/MU-JHU CARE LTD, P.O. Box 23491, Kampala, Uganda. Telephone: (256) 414 541044; Fax: (256) 414 543002; Email: carolonyango/at/mujhu.org

^*Deceased

The publisher's final edited version of this article is available at J Acquir Immune Defic Syndr

See other articles in PMC that cite the published article.

Abstract

Background

This phase III randomized clinical trial compared single dose nevirapine (sdNVP) plus HIV immunoglobulin (HIVIGLOB) to sdNVP alone for preventing maternal-to-child transmission (PMTCT) of HIV.

Primary objectives were to determine rates of HIV infection among infants, and to assess the safety of HIVIGLOB in combination with sdNVP in HIV-infected Ugandan pregnant women and their infants.

Methods

Mother-infant pairs were randomized to receive 200mg of NVP to women in labor and 2mg/kg NVP to newborns within 72 hours after birth (sdNVP arm) or to receive sdNVP plus a single intravenous 240ml dose of HIVIGLOB given to women at 36-38 weeks gestation and a single intravenous 24ml dose to newborns within 18 hours of birth (HIVIGLOB/sdNVP arm). Risk of HIV infection was determined using Kaplan-Meier and risk ratio estimates at birth, 2, 6, 14 weeks, 6 and 12 months of age.

Results

Intent-to-treat analysis included 198 HIVIGLOB/sdNVP and 294 sdNVP mother-infant pairs. At 6 months of age, the primary endpoint, there was no statistically significant difference in HIV transmission in the HIVIGLOB/sdNVP arm versus the sdNVP arm (18.7% vs.15.0%; RR =1.240 [95% CI: 0.833-1.846]; p= 0.290). Similarly, the proportion of serious adverse events in the HIVIGLOB/sdNVP and sdNVP arms, respectively for mothers (18.9% vs. 19.3%; p= 0.91) and infants (62.6% vs. 59.5%; p=0.51), were not significantly different.

Conclusion

Giving mother-infant pairs an infusion of peripartum HIV hyperimmunoglobulin in addition to sdNVP for PMTCT was as safe as sdNVP alone, but was no more effective than sdNVP alone in preventing HIV transmission.

Keywords: HIV, HIVIGLOB, sdNVP, breastfeeding, PMTCT, Uganda

INTRODUCTION

The majority of pediatric human immunodeficiency virus type 1 (HIV) infections are due to maternal-to-child transmission (MTCT). Globally, about 370,000 children became HIV-infected in 2009 with more than 90% living in sub-Saharan Africa [1]. Vertical transmission may occur in utero, during parturition or via breastfeeding. Without intervention, rates of MTCT of HIV are estimated to range from 25% to 48% in resource poor settings where breastfeeding is common [2].

The majority of breast milk transmission occurs during the first 6 weeks of life with an estimated absolute cumulative risk of 14-16%, with 63% occurring by 6 weeks and 75% occurring by 6 months, based on trial data from Kenya [3]. Analyses from the SAINT study in South Africa showed high rates of early transmission at age 8 weeks for formula-fed versus breastfed infants [4]. Data from Malawi show a monthly hazard rate of 0.7% from 1-5 months post partum, 0.6% from 6-11 months post partum and 0.3% from 12-17 months post partum [5]. These data indicate an increased rate of early transmission, followed by a lower but ongoing risk of transmission associated with prolonged breastfeeding.

Given the protective effects of breastfeeding on overall infant survival, it is critical to test interventions that can target both early and later breast milk transmission. Extensive trials of short course antiretroviral (ARV) therapy to prevent MTCT of HIV have been shown to reduce in utero and intrapartum transmission of HIV-1 in resource limited settings [4, 6-9]. Although the ARV regimens were effective in reducing HIV transmission, these benefits diminished over time with continued breastfeeding and showed the need to supplement short course regimens to prevent MTCT of HIV [7, 10, 11].

Several studies, both observational and clinical trials, suggest that use of either maternal triple ARV prophylaxis [12-17] during the breastfeeding period or extended infant prophylaxis [18-22] are promising public health interventions that decrease the risk of HIV transmission among HIV-infected breastfeeding women who do not yet require treatment for their own health. The World Health Organization now recommends use of either one of the two approaches [23], however the benefits and relative risks of these two strategies have not been directly compared.

A combined approach using both perinatal ARVs and immune globulin interventions has also been proposed [24]. This approach would take advantage of host immunity and potent drugs that attack the HIV life cycle during the high risk period shortly after delivery. In Uganda, a passive immunoprophylaxis perinatal phase I/II trial was conducted to assess the safety, tolerance, pharmacokinetics and virologic and immunologic changes associated with the use of Ugandan HIV hyperimmune globulin (HIVIGLOB) in HIV-infected pregnant Ugandan women and their infants [25]. The product was prepared by collecting whole blood units from asymptomatic Ugandan HIV-1 antibody positive blood donors with CD4 cell counts greater than 500 cells/uL. Plasma was separated and shipped frozen to the Swedish Institute for Infectious Disease Control in Stockholm, Sweden for fractionation into intravenous HIV-1 hyperimmune globulin rendered noninfectious for HIV-1. The product was found to have a 10-35 fold reduction in infectivity against a number of different primary subtype isolates, including three subtype B, one C, one E, and two Ugandan A isolates [25].

This phase III randomized trial was undertaken to assess whether this same HIVIGLOB product plus sdNVP (HIVIGLOB/sdNVP) given to mothers and infants would provide additional benefit over sdNVP alone for prevention of peripartum HIV transmission. The second objective of the study was to assess the safety and tolerance of HIVIGLOB/sdNVP compared with sdNVP alone.

METHODS

Study Population

HIV-seropositive pregnant women who presented for antenatal care were recruited from Mulago National Referral Hospital PMTCT program in Kampala, Uganda from July 2004 to May 2006. These women were offered the local standard of care for PMTCT of HIV (primarily sdNVP) and provided infant feeding counseling consistent with Uganda’s Ministry of Health guidelines at the time of the study [26, 27]. Women who chose to breastfeed were offered study participation if they met other eligibility criteria.

Eligibility Criteria

Inclusion criteria included documentation of HIV-1 infection by Western blot, pregnancy of 32-36 weeks gestation, age ≥18 years, intention to breastfeed, hemoglobin ≥7.5 g/dl, creatinine <1.5 mg/dl, SGPT < 5 times upper limit of normal and provision of informed consent. All live born infants of enrolled women were eligible for inclusion in the trial.

Study Design

The HIVIGLOB/NVP study was a phase III randomized, three arm, partially blinded clinical trial that compared the efficacy of either HIVIGLOB/sdNVP or extended daily infant NVP dosing until 6 weeks of age to the sdNVP regimen alone (i.e. maternal sdNVP at labor onset, newborn sdNVP within 72 hours of birth followed by 6 weeks of daily multivitamins as study drug placebo) for the prevention of perinatal and breast milk associated HIV transmission. Only results from the analysis of the efficacy of the addition of HIVIGLOB to the sdNVP regimen given to HIV infected pregnant women and their infants compared to the sdNVP regimen alone are presented here. Details of the evaluation of the efficacy of the extended infant NVP regimen including merged results from similar trials in India and Ethiopia are reported elsewhere [20, 21].

Randomization

At enrollment participants were given a study-specific identification number that was linked to a pre-assigned randomization arm known only by the study pharmacist. A computer-generated block randomization scheme created the treatment allocation for the trial. As part of the larger phase III trial, the original design was to enroll 300 mother-infant pairs into the sdNVP arm, 300 pairs into the extended daily infant NVP arm and 200 pairs into the HIVIGLOB/sdNVP arm allowing for a 3: 3: 2 ratio. Changes to the enrollment numbers were subsequently made following a recommendation by the data and safety monitoring board (DSMB) to merge data from Uganda, Ethiopia and India to allow for rapid accrual to answer the question on efficacy of extended infant NVP. The remaining participants in the Uganda trial were re-randomized into a ratio of 5: 4: 1 to allow for complete and timely enrollment into all arms and to ensure sufficient numbers of participants randomized to the sdNVP and HIVIGLOB/sdNVP arms.

Study Drug Regimens

All women in the HIVIGLOB/sdNVP arm and the sdNVP only arm were given 200mg of NVP to take at the onset of labor; and all newborns were given NVP syrup (2mg/kg) within 7 days of birth. In the HIVIGLOB/sdNVP arm, women also received a single intravenous (IV) infusion of 240ml (approximately 200mg/kg) of HIVIGLOB at 36-38 weeks gestation. Infants born to these mothers received a single IV infusion of 24ml (approximately 400mg/kg) of HIVIGLOB preferably within 18 hours of birth but could receive the dose up to 6 weeks of age if the baby was not well enough to receive the infusion earlier, if delivered outside of Mulago Hospital or for any other delay in availability of the infant. The infant infusion was given via peripheral vein using an auto-syringe in the Mulago Hospital special care unit with continuous monitoring. The 200 mg/kg dosage for the mothers was based on the dosage chosen for a US perinatal trial (PACTG 185) and the 400mg/kg dosage for the infants was based on findings from the phase I/II study [24, 25].

Study Follow-up and Procedures

Medical history, physical examination and routine laboratory tests were done for women at 36 weeks of gestation, labor and delivery, and 2 and 6 weeks post partum. For infants, evaluations were conducted at birth, weekly for the first 6 weeks, then at weeks 10 and 14, and at 6, 12 and 18 months. The HIVIGLOB/NVP trial was originally designed to follow-up infants through 18 months of age, but funding constraints necessitated early closure with follow-up reduced to 12 months of age for approximately 100 children who had not yet completed their 18 month final visit. Counseling on infant feeding was conducted at every scheduled visit. All infants received co-trimoxazole (CTX) prophylaxis against pneumocystis jirovecii pneumonia from 6 weeks of age until they were determined to be HIV-uninfected after breastfeeding cessation. Children identified as being HIV-infected continued with CTX prophylaxis. All women and any infants with confirmed HIV infection were referred to HIV clinics for care and treatment.

Study Endpoints

The primary endpoint was HIV infection status at 6 months of age among live-born infants but also included the rate of infection at birth, 2 weeks, 6 weeks, 14 weeks, 6 months, 12 months, and 18 months of age, regardless of HIV infection status at birth. Infant HIV infection status was determined using the Roche Amplicor Version 1.5 qualitative DNA PCR assay or quantitative HIV-1 RNA PCR assay (Roche Diagnostics Corporation, Indiana, USA). A positive diagnosis was based on two independent positive PCR tests at different time points or if one test was positive and there was no subsequent sample available. HIV RNA PCR tests were considered positive if viral load was over 5,000 copies per mL based on a modification of the Pediatric ACTG definition for infant HIV diagnosis, generally requiring at least 10,000 HIV RNA copies per mL to be deemed positive [28]. Infants who died or were lost to follow-up after only one positive PCR or antibody test were classified as infected. Secondary endpoints included death as well as HIV transmission or death at 2, 6 and 14 weeks and 6, 12, and 18 months. Safety was assessed by evaluation and grading of adverse events (AEs) according to the Division of AIDS (DAIDS) Toxicity Tables for Grading Severity of Adverse Experiences, April 1994. AEs in mothers were documented from enrollment to 8 weeks post partum; among infants, AEs were collected from birth through 14 weeks of age, and thereafter only serious AEs (SAEs) were documented.

Statistical Analysis

Only the HIVIGLOB/sdNVP efficacy component of this trial with follow-up to 12 months is presented. Intent-to-treat analysis (primary analysis) included all live-born infants with an evaluable infection status at 6 months. Risk of HIV infection and/or death was determined using Kaplan-Meier and risk ratio (RR) estimates and the z-test was used to compute p values for the risk ratios. In the analysis of HIV transmission, infants were censored at the time of study termination, last HIV determination, or death. A similar approach was used for the endpoints involving death and HIV transmission or death (complement of infection-free survival). The secondary modified intent-to-treat analysis excluded infants HIV positive at birth (infants with unknown birth status were included in the modified intent-to-treat analysis). AEs were compared across the two arms using an exact test. Statistical analyses were performed using Stata 10 [29] and statistical significance of comparisons and associations was evaluated at α=0.05. The DSMB provided ongoing and interval review of efficacy and safety data from this study.

Ethical Considerations

The study was approved by the national AIDS Research Committee in Kampala, Uganda and Western Institutional Review Board in Olympia, Washington, USA.

RESULTS

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 (Figure 1). 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.

FIGURE 1

HIVIGLOB/NVP TRIAL PROFILE

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 (Table 1). 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 (Table 1).

Table 1

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 (Table 1). 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] (Table 2, Figure 2). 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 (Table 2).

Table 2

Risk of HIV Transmission, Death and HIV Transmission or Death among all Live-Born Infants and Infants Uninfected at Birth by Study Regimen

Figure 2

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 (Table 2). Risk of infant mortality in the HIVIGLOB/sdNVP arm was statistically similar to that in the sdNVP arm at all time points (Table 2, Figure 2). 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 (Table 2).

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] (Table 2). 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 (Figure 2). Secondary analyses for transmission or death showed no significant difference in risk at all time points (Table 2).

Safety

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.

DISCUSSION

This study assessed the relative safety and efficacy of an HIV hyperimmune globulin product combined with peripartum antiretrovirals compared to a peripartum antiretroviral strategy alone in HIV infected pregnant women and their breastfeeding infants for the prevention of peripartum transmission of HIV-1 infection. The proportions of breastfeeding infants were similar between the two arms throughout the duration of the study. The low rates of breastfeeding which were observed at 12 months reflect the recommendations from the Ugandan Ministry of Health PMTCT guidelines at the time which recommended that HIV infected women breastfeed for 3-6 months following delivery. This is reflected in the results which show that the proportion of breastfeeding infants was high at and prior to 14 weeks of age when the efficacy of the HIVIGLOB infusion was most likely to be effective.

The study demonstrated that there was no significant difference in HIV transmission rates at 6 months (primary endpoint) and 12 months of age in Ugandan mother – infant pairs who each received a single infusion of HIVIGLOB in addition to the standard sdNVP regimen for PMTCT compared to the standard sdNVP regimen alone. While there was no demonstrable difference in treatment efficacy, the study also showed that that there were no significant differences in mortality or serious AEs between the two arms. The majority of the infant deaths were due to infections common in children in Uganda and were unrelated to the receipt of the HIVIGLOB infusion.

Our trial findings do not support a role for use of HIVIGLOB to help reduce peripartum or early breast milk transmission of HIV-1 among breastfed HIV-1 exposed infants. These results are similar to those of the PACTG 185 trial of a hyperimmune product, HIVIG, to reduce peripartum transmission in a non-breastfeeding population in the United States (US), which failed to demonstrate efficacy due to the overall low rate of transmission in both study arms [24]. However, there was a trend toward decreased transmission in women with low CD4 count in the US study, which was not found in this study. It had been hypothesized that the addition of HIVIGLOB to sdNVP would be a promising intervention strategy for various reasons. The presence of antibodies to specific HIV-1 V3 loop peptides has been negatively correlated with vertical transmission in some earlier studies [30, 31]. Likewise, the presence of neutralizing antibodies in the serum of HIV-1 infected women appears to correlate with delivery of uninfected children [32]. It was hoped that preparation of HIVIGLOB from the plasma of multiple asymptomatic HIV-1 infected Ugandan blood donors would have the potential to provide both group specific and type specific neutralizing antibodies, gp120/CD4 blocking antibodies and V3 loop antibodies to the diverse strains of HIV-1 found in Uganda [33].

While there are no data at present to show what viral subtypes the women in the study had, it is possible that the HIVIGLOB product did not demonstrate broadly neutralizing antibody activity against Ugandan subtype isolates, particularly subtype D, which is the second most common subtype in the Ugandan population. Antibody responses are often very specific to the individual viral strain with which one is infected and may not have activity against other strains of viruses. It is also possible that the antibodies in the HIVIGLOB solution were able to neutralize the strains used in the laboratory but may have had less neutralizing activity against individual strains found in the mothers participating in the trial. It is also possible that the concentration of the HIVIGLOB antibodies present in cord blood, vaginal fluids or breast milk was not sufficient to inhibit virus at the different time points for viral transmission to infants. Giving the maternal dose of HIVIGLOB several weeks prior to delivery may have allowed selection of viral escape mutants such that subsequent administration of HIVIGLOB to the baby did not confer protection against maternal virus at delivery and during the early breastfeeding period. Passive immunization with a broadly reactive monoclonal antibody cocktail just to the infant may possibly be a better option in preventing early HIV transmission after birth.

Interpretation of the comparative efficacy of the HIVIGLOB product is complicated by the unanticipated low rate of HIV infection at birth in the sdNVP control arm in this study. At 4.1%, the sdNVP birth infection rate was significantly lower than the HIVIGLOB/sdNVP arm (9.1%) and the birth transmission rates seen with the same sdNVP regimen in the third arm of this trial (9.6%) and the HIVNET 012 study at the same trial site (8.1%) [6, 20]. There were no identifiable differences in the characteristics of the mothers or infants across the study arms to account for this unbalanced infection rate at birth. Kaplan-Meier estimates excluding infants infected at birth showed no significant difference in HIV infection risk between the arms at any other time point including the primary endpoint at 6 months. Although there is a theoretical risk of early enhanced transmission due to high dose HIV antibody via immune complexes, we believe it is unlikely that the addition of the HIVIGLOB product led to an increased risk of transmission compared to the sdNVP arm alone since the transmission rate in the HIVIGLOB arm was similar to the transmission rate in the sdNVP arm at six weeks of age. The fact that 26 women delivered prior to or missed their HIVIGLOB infusion raises the possibility of selection bias. However, the two study groups in the final analysis were similar in terms of maternal and infant characteristics - which is reassuring in terms of the internal validity of this study.

In conclusion, the theoretical plausibility of the benefit of adding passive immunotherapy with HIV immune globulin to sdNVP for further reduction in peripartum and early HIV-1 transmission through breast milk was not evident from this trial. Further studies using novel broadly neutralizing monoclonal antibodies may yield critical information on the ultimate contribution of passive immunotherapy to the prevention of mother-to-child transmission.

Acknowledgments

The HIVIGLOB/NVP study was sponsored by NIAID/NIH [RO1-AI34235, UO1 AI038576 S and UO1 AI69350-01]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the U.S. National Institutes of Health.

The authors sincerely thank the mothers and children who volunteered and participated in the trial and all the staff of Makerere University-Johns Hopkins University Research Collaboration for their participation in and support of the trial.

Sources of Support: National Institute of Allergy and Infectious Diseases, NIH, USA and the Ugandan Ministry of Health (clinicaltrials.gov number: NCT00639938)

Footnotes

AUTHORS CONTRIBUTIONS C Onyango-Makumbi coordinated the HIVIGLOB/NVP trial, contributed to the data analysis and wrote the manuscript. SB Omer, M Mubiru and LH Moulton provided data management and statistical support for analysis and writing of the manuscript. C Nakabiito contributed to acquisition of data, monitoring of adverse events and writing of the manuscript. H Wigzell, L Falksveden and B Wahren contributed to the study design and HIVIGLOB product development. SL Zwerski, P Musoke, F Mmiro (Principal Investigator), G Antelman, MG Fowler, LA Guay and JB Jackson (Principal Investigator) contributed to protocol development, conduct of the trial including monitoring of adverse events and also with analyses and writing of the manuscript.

CONFLICT OF INTEREST STATEMENT J. Brooks Jackson as Principal Investigator for the trial has full access to all the data and has final responsibility for the decision to submit for publication. None of the authors have any conflicts of interest related to the conduct or reporting of this study.

Presented at the XVII International AIDS Conference, 3-8 August 2008, Mexico City

References

1. UNAIDS. UNAIDS Report on the Global AIDS 2010

2. De Cock KM, Fowler MG, Mercier E, et al. Prevention of mother-to-child HIV transmission in resource-poor countries: Translating research into policy and practice. JAMA. 2000;283:1175–1182. [PubMed]

3. Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: A randomized clinical trial. JAMA. 2000;283:1167–1174. [PubMed]

4. Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis. 2003;187:725–735. [PubMed]

5. Miotti PG, Taha TE, Kumwenda NI, et al. HIV transmission through breastfeeding: A study in Malawi. JAMA. 1999;282:744–749. [PubMed]

6. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single dose nevirapine compared with zidovudine for prevention of mother- to – child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomized trial. Lancet. 1999;354:795–802. [PubMed]

7. The Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa and Uganda [Petra Study]: a randomized, double blind, placebo-controlled trial. Lancet. 2002;359:1178–1186. [PubMed]

8. Wiktor SZ, Ekpini E, Karon JM, et al. Short- Course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Cote d’Ivoire: a randomized trial. Lancet. 1999;353:781–785. [PubMed]

9. Leroy V, Sakarovitch C, Cortina-Borja M, et al. on behalf of the Ghent Group on HIV in Women and Children. Is there a difference in the efficacy of peripartum antiretroviral regimens in reducing mother-to-child transmission of HIV in Africa? AIDS. 2005;19:1865–1875. [PubMed]

10. Jackson JB, Musoke P, Fleming T, et al. 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;362:859–868. [PubMed]

11. Leroy V, Karon J, Alioum A, et al. Twenty- Four month efficacy of a maternal short-course zidovudine regimen to prevent mother-to-child transmission of HIV-1 in West Africa. AIDS. 2002;16:631–641. [PubMed]

12. Thomas T, Masaba R, Ndivo R, et al. PMTCT of HIV among breastfeeding mothers using HAART: the Kisumu Breastfeeding Study, Kisumu, Kenya, 2003-2007. Presented at: 15th Conference on Retroviruses and Opportunistic Infections; Boston, MA. 2008. abstr 45aLB.

13. Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers with triple antiretroviral therapy in Dar es Salaam, Tanzania: the Mitra Plus study. J Acquir Immune Defic Syndr. 2009;52(3):406–416. [PubMed]

14. Peltier CA, Ndayisaba GF, Lepage P, et al. Breastfeeding with maternal antiretroviral therapy or formula feeding to prevent HIV postnatal mother-to-child transmission in Rwanda. AIDS. 2009;23(18):2415–2423. [PMC free article] [PubMed]

15. Palombi L, Marazzi MC, Voetburg A, et al. Treatment acceleration program and the experience of the DREAM program in prevention of mother-to-child transmission of HIV. AIDS. 2007;21(Suppl 4):S65–71. [PubMed]

16. The Kesho Bora Study Group. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora Study): a randomized controlled trial. Lancet Infect Dis. 2011 Jan 13; Epub ahead of print. [PubMed]

17. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362(24):2282–2294. [PMC free article] [PubMed]

18. Vyankandondera J, Lutchers S, Hassink E, et al. Reducing risk of HIV transmission from mother to infant through breastfeeding using antiretroviral prophylaxis in infants (SIMBA). 2nd IAS Conference on HIV Pathogenesis, Treatment and Prevention; Paris, France. 2003. Abstract LB7.

19. Kilewo C, Karlsson K, Massawe A, et al. Prevention of Mother-to-Child Transmission of HIV-1 Through Breast-Feeding by Treating Infants Prophylactically With Lamivudine in Dar es Salaam, Tanzania: The Mitra Study. J Acquir Immune Defic Syndr. 2008;48(3):315–323. [PubMed]

20. Six Week Extended-Dose Nevirapine (SWEN) Study Team. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet. 2008;372(9635):300–313. [PubMed]

21. Omer SB. Six Week Extended Dose Nevirapine (SWEN) Study Team. Twelve-month follow-up of Six Week Extended Dose Nevirapine randomized controlled trials: differential impact of extended-dose nevirapine on mother-to-child transmission and infant death by maternal CD4 cell count. AIDS. 2011;25(6):767–76. [PubMed]

22. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended Antiretroviral Prophylaxis to Reduce Breast-Milk HIV-1 Transmission. N Engl J Med. 2008;359(2):119–129. [PubMed]

23. WHO. Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infections in Infants. Recommendations for a Public Health Approach. 2010 Version.

24. Stiehm ER, Lambert JS, Mofenson LM, et al. Efficacy of zidovudine and human immunodeficiency virus (HIV) hyperimmune immunoglobulin for reducing perinatal HIV transmission from HIV-infected women with advanced disease: results of Pediatric AIDS Clinical Trials Group protocol 185. J Infect Dis. 1999;179(3):567–575. [PubMed]

25. Guay L, Musoke P, Hom D, et al. Phase I/II Trial of HIV-1 Hyperimmune Globulin (HIVIGLOB) for the Prevention of HIV-1 Vertical Transmission in Uganda. AIDS. 2002;16:1391–1400. [PubMed]

26. WHO. New data on the prevention of mother-to-child transmission of HIV and their policy implications. Conclusions and recommendations. WHO technical consultation on behalf of the UNFPA/UNICEF/WHO/UNAIDS Inter-Agency Task Team on Mother-to-Child Transmission of HIV; Geneva. 11-13 October 2000; Geneva: World Health Organization 2001, WHO/RHR/01.28;

27. Ministry of Health, Republic of Uganda. Policy for Reduction of the Mother-To-Child HIV Transmission in Uganda. 2003 May;

28. Read JS. Committee on Pediatric AIDS. Diagnosis of HIV-1 infection in children younger than 18 months in the United States. Pediatrics. 2007;120:1547–1562. [PubMed]

29. Stata Corp. Stata Statistical Software: Release 10. College Station, TX: StataCorp LP; 2003.

30. Rossi P, Moschese V, Broliden PA, et al. Presence of maternal antibodies to human immunodeficiency virus 1 envelope glycoprotein gp120 epitopes correlates with the uninfected status of children born to seropositive mothers. Proc Natl Acad Sci U S A. 1989;86:8055–8058. [PubMed]

31. Devash Y, Calvelli TA, Wood DG, et al. Vertical transmission of human immunodeficiency virus is correlated with the absence of high-affinity/avidity maternal antibodies to the gp120 principal neutralizing domain. Proc Natl Acad Sci U S A. 1990;87:3445–3449. [PubMed]

32. Scarlatti G, Albert J, Rossi P, et al. Mother-to-child transmission of human immunodeficiency virus type 1: correlation with neutralizing antibodies against primary isolates. J Infect Dis. 1993;168:207–210. [PubMed]

33. Oram JD, Downing RJ, Roff M, et al. Nucleotide sequence of a Ugandan HIV-1 provirus reveals genetic diversity from other HIV-1 isolates. AIDS Res Hum Retroviruses. 1990;6:1073–1078. [PubMed]