A Review and Analysis of Outcomes from Prevention of Mother-to-Child Transmission of HIV Infant Follow-up Services at a Pediatric Infectious Diseases Unit of a Major Tertiary Hospital in Nigeria: 2007-2020

1.1. Background of the Study

The high burden of mother-to-child transmission of Human Immunodeficiency Virus (HIV) in sub-Saharan Africa including Nigeria is due to high rates of heterosexual transmission, high prevalence of HIV in women of reproductive age, high total fertility rate, characteristically prolonged breastfeeding culture, sub-optimal infection prevention measures during labor and delivery, and limited access to general HIV prevention interventions.1 According to the National Agency for the Control of AIDS (NACA), Nigeria accounted for 37,000 of the world’s 160,000 new cases of babies born with HIV in 2016.2 A high burden of infection in women naturally translates to an increase in that of infants and young children as vertical or mother-to-child transmission (MTCT) accounts for upwards of 90% of infections. MTCT can occur during pregnancy, birth, or through breastfeeding. Without any interventions during these stages, MTCT rates range between 15% and 45%, increasing with the duration of breastfeeding.3 However, the risk of MTCT can be reduced to less than 2% with a package of evidence-based interventions which constitute prevention of mother-to-child transmission (PMTCT) strategies.3 PMTCT services are offered to women of childbearing age living with or at risk of HIV to maintain their health and prevent their infants from acquiring HIV. These services include preventing unwanted pregnancies among women living with HIV; safe childbirth practices; life-long antiretroviral (ARV) drug therapy to mothers once their status is ascertained, irrespective of CD4 cell counts; ARV prophylaxis to infants from birth; infant feeding counseling and appropriate choices; early infant virologic diagnosis of HIV post-partum and during the breastfeeding period.3

Since PMTCT commenced in 2001 in Nigeria, the National PMTCT guidelines, in collaboration with the World Health Organization, have undergone frequent evidence-based modifications. Maternal ARV therapy moved from ‘when pregnant only’ for those not immunosuppressed to ‘lifelong irrespective of CD4 counts’ and ‘treat all.’ Infant feeding moved from mandatory ‘no breastfeeding’ to ‘exclusive breastfeeding in the first 6 months of life, then appropriate complementary foods plus continued breastfeeding until 12 months, in a bid to enhance child survival.4-6 Nigeria has a prevalence of 1.4%, and currently takes the fourth position among countries battling with HIV.7,8 However, prevalence varies in the constituent states (highest in Akwa Ibom 5.5%, Benue 5.3%, Rivers 3.8%, Taraba 2.9%, Anambra 2.4%, lowest in Katsina and Jigawa 0.3% each, among others).7,8 Anambra is one of the states with a high prevalence of HIV, and the Nnamdi Azikiwe University Teaching Hospital (NAUTH), Nnewi is the largest center offering HIV care in the state. NAUTH was one of the first PMTCT centers in Nigeria and has continued to expand its service delivery to a vast clientele covering Anambra and neighboring states, such as Imo, Benue, Enugu, and Delta. An initial review of the Early Infant Diagnosis services in the center,9 yielded an MTCT rate of 3.6% in spite of PMTCT. Since then, breastfeeding has been encouraged, more so with prolonged duration up to age 12 months, and most mothers are accessing ARVs.

1.2. Objectives of the Study

The objective of this study was to audit the PMTCT infant follow-up services offered by the Pediatric Infectious Diseases Unit of NAUTH over a 14-year period (January 2007 – December 2020).

1.3. Specific Aims and Hypothesis

Specifically, the study: a) determined the MTCT rate in the milieu of maternal and infant ARV drugs; b) assessed the impact of infant feeding on the rate of MTCT; c) assessed if sociodemographic factors such as the timing of infant ARV, initial PCR test and gender affected PMTCT outcomes. It was hypothesized that maternal and infant ARV administration, infant feeding options, and timing of initial PCR tests would affect PMTCT outcomes.

2.1. Study Location

Nnamdi Azikiwe University Teaching Hospital (NAUTH) is located in Nnewi, the industrial hub of the southeast of Nigeria. It is a tertiary health facility that provides services for Anambra and surrounding communities in Imo, Delta, and Enugu States. NAUTH is one of the largest centers for HIV Care in Nigeria. Organized HIV Care Services commenced in this center by 2001. Moreover, the program received support from the President’s Emergency Plan for AIDS Relief (PEPFAR) under the auspices of the Institute of Human Virology (IHVN) domiciled in Nigeria from 2005. However, in 2013 IHVN was replaced by Family Health International (FHI), which has continued to support the activities. The PCR Laboratory has been analyzing dried blood spot samples for Early Infant Diagnosis (EID) of HIV and Viral load assays since 2007. The infant follow-up clinic is manned by pediatricians, pediatric resident doctors, medical officers, well-trained nurses, and counselors.

2.2. Subjects, Interventions, and Data collection

The study population consisted of mother-infant pairs who were seen at the infant follow-up arm of the NAUTH Nnewi PMTCT program. The majority of the mothers were enrolled during pregnancy and benefited from antenatal PMTCT interventions as well as follow-up for their infants. However, some infants who were enrolled in the infant follow-up program at different ages after delivery had not benefited from PMTCT intervention in utero and sometimes neither the infant post-exposure prophylaxis.

HIV-positive women were enrolled in the PMTCT program at different stages of pregnancy depending on the gestational age at initial presentation. The mothers were offered ART interventions for PMTCT, infant feeding counseling, support, and modified obstetric care. The infants were commenced on post-exposure prophylaxis as soon as possible (within 72 hours of life). Maternal and Infant ARV prophylaxis was based on Nigeria’s National Guidelines for HIV prevention and treatment. Over the years, the guidelines were reviewed in line with prevailing evidence and WHO recommendations. This resulted in variations in maternal/infant ARV prophylaxis received. Generally, the infants received syrup nevirapine and or zidovudine, the duration of which depended on the risk of MTCT.

Over the years, infant feeding practices varied according to the National Guidelines. During the “pre-rapid advice” era (prior to the implementation of the 2009 WHO guideline), HIV-infected mothers were required to practice either EBF or replacement feeding during the first six months of their infant’s life depending on their ability to meet the AFASS criteria. (Breastmilk substitute must be Acceptable, Feasible, Affordable, Sustainable, and Safe). Subsequently, breastfeeding was promoted as the preferred infant feeding option for HIV-positive mothers in Nigeria. All breastfeeding mothers were on ARVs during the period of breastfeeding. Avoidance of mixed-feeding was emphasized at each follow-up visit. Free infant formula was not provided for mothers who chose to formula-feed. The infants also received co-trimoxazole prophylaxis for Pneumocystis jiroveci pneumonia, early infant diagnosis (EID) using HIV DNA PCR technique on DBS sample, and monitoring for vaccination, developmental and nutritional status. EID was done at 6 weeks of age and 6 to 8 weeks after all cessation of exposure to breastmilk. Those who tested positive were immediately linked to HIV treatment services. However, if the infants were healthy and had an HIV-negative rapid test at 18 months of age, they were discharged from the unit.

At enrollment, each mother-infant pair had a proforma completed documenting demographic data, birth details, use of ARV prophylaxis in mother and infant, infant feeding practice, etc. Subsequently, the mother-infant pairs were seen on scheduled appointments during which their health, nutritional, vaccination, developmental, and HIV status were assessed and documented both electronically and in physical folders. Tracking was done through phone calls after each missed appointment to ensure continued engagement in care. The list of those who were lost to follow-up was handed over to the Home-Based Care Unit at intervals for continued tracking and home visits where feasible. Data were abstracted from the electronic record of the subjects which was prospectively updated at each clinic visit.

2.3. Study Variables

The dependent variable was final HIV status (by DNA PCR [<18 months] and rapid tests [at ≥18 months), while the independent variables were maternal or infant ARV prophylaxis, infant feeding practice, the timing of DNA PCR test, and gender of the infant.

Mother-infant pairs were recruited at various infant ages into the Infant Follow-Up arm of PMTCT of HIV at the Pediatric HIV Unit of Nnamdi Azikiwe University Teaching Hospital, Nnewi, from January 2007 to December 2020. Mothers-infant pairs may or may not have received all components of the NAUTH PMTCT package depending on the timing of presentation.

2.4. Statistical Analysis

Data were analyzed using Statistical Package for Social Sciences (SPSS) version 21 (IBM Corp., Armonk, NY). The characteristics of the infants were presented as categorical variables in frequency tables. The primary outcome was the HIV status of the infants that were discharged from the HIV-exposed infant follow-up program. The association between the primary outcomes (HIV positive, HIV negative, or inconclusive HIV status) and infants’ characteristics were examined using the Chi-square test. Factors significantly associated with the final outcome in bivariate analysis were further analyzed using multinomial logistic regression analysis. A P-value less than 0.05 was considered statistically significant. Ethics approval was obtained from the Research and Ethics Committee of NAUTH, Nnewi, Anambra state. All data obtained during the study was kept confidential.

3.1. Sociodemographic Characteristics

A total of 3,784 mother-infant pairs were enrolled. The infants had a male to female ratio of 1.04:1. Nearly two-thirds (62.5%) of infants were never breastfed. Among the 1,419 infants who were breastfed, 1,053 (74.2%) received breastmilk for 6 months or less. The majority (3,145 [83.1%]) of mothers and infants (3,240 [85.6%) received some form of ARVs for PMTCT. Both mother and infant in a mother-infant dyad received ARVs in 80.6% of cases. Mothers were mostly on the combination of Nevirapine or Efavirenz/Lamivudine/Zidovudine. The prophylaxis given to the infants is shown in Table 1. The majority of the infants received either single dose Nevirapine plus 6 weeks of Zidovudine (sdNVP, 6wkZDV) [40.22%] or 6 weeks of Nevirapine (6wkNVP) [43.71%]. There was no gender-based difference in the outcome.

3.2. Maternal and Infant ARV Therapy and MTCT Rate

Infants who did not receive any form of ARVs for post-exposure prophylaxis (PEP) were significantly more likely to have MTCT of HIV. This was higher where mothers received no ARVs compared to infants of mothers who received any form of ARVs (52.1% vs. 9.3%) (see Table 2). Table 3 shows that 3,337 mother-baby pairs received some form of ARV Prophylaxis, out of which 74 (2.2%) babies turned out HIV positive. This was further reduced to 1.4% (44/3,048) where both mother and infant pairs benefited from PMTCT interventions according to the National Guidelines. In other words, the true PMTCT failure rate at the NAUTH center is 1.4%. The MTCT rates were 1.4%, 9.3%, 24.1%, and 52.1% for both mother and infant, mother only, infant only and none received ARV prophylaxis respectively.

3.3. Infant Feeding and MTCT Rate

Breastfed infants who did not benefit from any form of ARV prophylaxis significantly had a higher rate of MTCT compared to their never breastfed counterparts (57.9% vs. 34.8%). However, among infants who received ARV prophylaxis, there was a slight difference in the MTCT rate between the breastfed (2.5%) and never breastfed (2.1%). Infants who were mixed-fed were significantly more likely to become infected via MTCT.

Table 4 shows that among the ARV-naïve mother-infant pairs MF in the first 6 months resulted in 61.7% MTCT as against 35.5% in those not mixed-fed. The MTCT rate was reduced to 28.6% in the mixed-fed and 1.4% in the non-mixed fed where both mothers and infants received ARVs.

After multinomial logistic regression analysis factors that remained significantly associated with being HIV-negative were maternal ARV prophylaxis for PMTCT (p<0.001, OR 7); ARV prophylaxis for infants (p<0.001, OR 4).

3.4. Age of Infant at Initial DNA PCR Test and PMTCT Outcomes

The younger the age at the first PCR test, the more likely it is that PMTCT interventions were accessed and also final outcome being HIV negative. However, this also meant a higher tendency for loss to follow up, especially among the breastfed infants (Table 5).

3.5. Failed PMTCT Cases

Two infants turned out to be HIV positive after an initial negative test, following cessation of breastfeeding. One of the infants had the initial negative test at 8 weeks and after EBF for 3 months retested positive. The mother had received ARVs for 3 years before conception and all through pregnancy, however, her adherence to the program was poor. The second infant had the initial negative test at 3 months (after having been mix-fed (MF) from birth) but when retested at 8 months, after a total of 6 months of breastfeeding the result was positive. The mother had received ARVs in the index pregnancy only. Both infants had ARV prophylaxis. Table 6 gives the characteristics of the infants with PMTCT failure.

Among the infants who became HIV positive despite any form of PMTCT intervention for mother-baby pair, 97.3% had a positive initial DNA PCR. Approximately two-thirds had the initial PCR test after the recommended 6-8 weeks (62.2%). The majority were never mix-fed (87.8%) and approximately two-thirds were never breastfed (63.5%). Both mothers and infants in each pair received ARV prophylaxis for PMTCT in 60.8% of cases. Only 27% of their mothers were on ARVs before index pregnancy, and more than half (54.1%) of the MTCT occurred during the era of sdNVP + 6wkZDV use for infant PEP.

4.1 Limitations of the Study

The inability to incorporate maternal viral load results due to logistic difficulties is a limitation. There was an appreciable number of inconclusive outcomes, especially among the infants that were breastfed beyond six months due to a high rate of loss to follow-up. Tracking the lost mother-infant dyads proved an insurmountable task with limited communication support and a lack of home visits.