This study was carried out to evaluate the HIV-free survival rate at 18 months and associated factors among HIV exposed infants enrolled and followed up in two tertiary health facilities in Gulu district, northern Uganda under the PMTCT option B+ program.
HIV-free survival
The overall HIV-free survival rate in the current study among exposed infants enrolled within the recommended first 2 months of life was 94.6%, while 5.4% of the infants were either HIV-infected (2.5%) or died 2.8%) (Figure 2). This was calculated only among infants with complete data. Nonetheless, this highlights the impact of the current effort to eliminate mother-to-child transmission of HIV implemented initially as PMTCT option B+, and now as test and treat or treat all (mothers tested and if HIV positive, initiated on lifelong ART regardless of CD4 count or clinical stage, and infants were given ARV prophylaxis from birth for 6 or 12 weeks depending on risk classification while mothers are encouraged to exclusively breastfeed for at least 6 months). The 18-months HIV-free survival rate in the study setting only marginally falls short of the >95% HIV-free survival rate recommended among breastfeeding populations, and is lower than the 95.9% HIV-free survival rate reported in a community-based survey in Swaziland (13). However, the rate in the current study compares well with the 93.2% 24-month HIV-free survival under similar Option B+ program in Rwanda (14) and is higher than the pooled estimates of 89.8% and 85.8% for 12-month and 24-month HIV-free survival respectively as reported by Chikhungu et al (2016) in a systematic review of 18 studies evaluating HIV-free survival among breastfed infants of HIV positive women on ART (15). The above differences could largely be explained by the differences in the duration of breastfeeding and maternal ART; timing of measurements of HIV-free survival (12 months vs 18 months vs 24 months), and the guidelines or PMTCT approaches used in the different studies. Notwithstanding, these findings seem to lay credence to the effectiveness of option B+ over the earlier approaches towards the elimination of mother-to-child transmission (eMTCT) of HIV among breastfeeding population in developing countries.
The mortality rate of 2.8% in the current study was generally low but higher than the 1.1% reported in Mma Bana trial in Botswana (16), a difference possibly explained by the fact that infants in the Mma Bana trial breastfed for a shorter duration of 6 months (median 5.8 months).
Factors associated with HIV-free survival
There was a significantly higher HIV-free survival rate for infants enrolled in Lacor (a private not for profit faith-based facility) as compared to those enrolled in GRRH (a public health facility), and this was statistically significant (OR=6.56). The treatment facility also remained a statistically significant predictor of HIV-free survival on multivariate analysis with an 88% increase in HIV-free survival rate for infants enrolled in Lacor as compared to those enrolled in GRRH (Table 3). We supposed this could relate to the fact that infants followed up in Lacor hospital were more likely to be enrolled slightly earlier into care (mean age 1.55[SD 0.26]) –a factor positively associated with HIV-free survival, compared to those in GRRH (mean age 1.58[SD 0.20]). This is valid and is in accord with the WHO recommendation for early infant diagnosis and a finding by Berhan et al (2014) in Ethiopia where infants with delayed DNA PCR tests had a 30% excess risk of mother-to-child transmission of HIV compared to those tested early (17). However, this difference could be as a result of several factors – both infant/caregiver factors as well as healthcare factors which were beyond the scope of this study to explore.
Similarly, there was a statistically significant likelihood of being discharged HIV negative and survival among the female gender compared to males, who in contrast were more likely to become infected or die. In the multivariate analysis, there was a 77% increased chance of HIV-free survival if an infant was of a female compared to being male. The difference in outcome among HIV exposed infants by gender has not been well explained in previous studies. However, one plausible view could relate to the fact that an increased risk of morbidity and mortality among young males, in general, has long been advanced, albeit with no well understood scientific explanations (18, 19). In the context of HIV therefore, this could translate to faster disease progression in males compared to female infants.
The overall duration of breastfeeding did not significantly affect the HIV-free survival in the current study. This finding compares well with that reported by Alvarez-Uria et al (2012) in India (20) and Peltier et al (2009) in Rwanda (21) where there was no significant difference in HIV-free survival with breastfeeding status, though HIV-free survival was significantly higher among breastfed than formula-fed children in the two reports. Besides, the Rwandan study estimated HIV-free survival at an earlier time interval of 9 months during a different approach to PMTCT and the infants were breastfed for only 5-6 months (exclusive breastfeeding) followed by rapid weaning. In contrast, Mekonnen A, et al (2017) reported a significantly lower 18 months cumulative probability of HIV-free survival in the breast-fed infants and young children (84%) than formula-fed counterparts (97%) (22).
While the majority (90.5%) of the infants were reported to have had exclusive breastfeeding (EBF), less than one third (29.3%) were exclusively breastfed for at least 6 months as recommended by the national guidelines. The overall rate of exclusive breastfeeding in this study though compares well with that reported by Okafor et al (2014) in Nigeria of 91.8% (23). However, by implication, the fact that only very few mothers (29.3%) in the study setting are exclusively breastfeeding their infants adequately for at least 6 months should be of concern since it could be a precursor of prevailing misinformation and inherent negative perception about breastfeeding in the context of HIV which calls for more awareness and counselling. By and large, exclusive breastfeeding for at least 6 months in the current study was protective and associated with 55% increased chance of HIV-free survival compared to EBF for <6 months, although this was not statistically significant, OR=0.45 (Table 2). The above findings could be attributed to the fact that regardless of breastfeeding duration, maternal ART and timely infant ARV prophylaxis are critical factors in the prevention of mother-to-child transmission of HIV, in line with the current guidelines.
In the current study, the timing of maternal HIV diagnosis and ART initiation did not statistically significantly influence HIV-free survival. Infants of mothers diagnosed before pregnancy were 12% less likely to have an HIV-free survival, while those born to mothers who initiated ART before pregnancy were 37% less likely to have an HIV-free survival. However, the documented HIV transmission rate was lower among infants of mothers initiated on ART before pregnancy (1.7%) compared to the rate among infants of mothers initiated during pregnancy (3.9%). This finding is in keeping with that reported in a Cameroonian study in which the 12-month HIV transmission rate where 51% of women were receiving ART before pregnancy was low at 1.2% (24), and also compares relatively well with that reported in a study by Hoffman et al (2010) where MTCT rate was lower in women who were on HAART before pregnancy compared to women who initiated HAART during pregnancy (25). The similar benefit of prior ART maternal use was reported by Oluwayemi et al (2015) in Nigeria where the risk of transmission was significantly lower among babies whose mothers commenced HAART before pregnancy (3.4%) compared to those whose mothers initiated HAART during pregnancy (5.4%) (26). The above results could be explained by the fact that one of the hypothesized benefits of lifelong ART is protection against HIV transmission in subsequent pregnancies, resulting from greater chances of virologic suppression, as was also suggested by Gill et al (2017) in a Rwandan study where the substantial proportion of women on ART before pregnancy with suppressed viral load (VL) was thought to have contributed to the high effectiveness of PMTCT (14).
Likewise, available evidences also point to the fact that long duration of ART may be associated with high viral load (VL) or viral rebound postpartum which could be associated with increased risk of mother-to-child transmission (14, 27, 28), supporting the importance of VL monitoring during pregnancy and breastfeeding, and continued adherence counselling (14). In the current study, data on maternal viral load suppression was very limited (VL was not widely available in Uganda within the period for which data was collected for this study), making comparison of HIV-free survival based on maternal VL impossible.
Limitations of the Study
Being a retrospective study with the use of secondary data, the information retrieved was incomplete for some infants. Some of the maternal potential factors for vertical transmission could not be exhaustively explored in the study because they were lacking. Secondly, exclusion of cases lost to follow up and those with the unknown outcome or missing data is likely to have created a selection bias, affecting the accuracy of the estimates of survival and therefore the generalizability (external validity) of the study findings. Our estimates may, therefore, be an overestimate or underestimate since some infants with missing data and undocumented outcome were not considered. Our results could, therefore, be skewed since for instance, it is likely that those missing an outcome more frequently died than remained HIV-free and survived