Background

Several milestones are recommended for ending the global HIV epidemic by 2030, including the elimination of mother to child HIV transmission. This is defined by the WHO as a rate of <50 new paediatric HIV infections per 100 000 live births and a transmission rate <5% in breastfed infants, maintained for at least 1 year.1 As one of the countries with the highest burden of HIV in the world, South Africa has a well-established prevention of mother to child transmission (PMTCT) programme.2 South Africa’s national PMTCT guideline changed from single-dose nevirapine (NVP) for the mother to zidovudine (AZT) monotherapy from 28 weeks of gestation in 2008. In 2010, infants were able to receive 6 weeks of NVP prophylaxis, instead of a single dose within 72 hours of birth. These two changes drastically improved the vertical transmission rates. Between 2003 and 2012, HIV transmissions from mother to child in South Africa decreased from occurring in 23.2% of mother–infant pairs to 2.4% of pairs.2

Based on clinical and programme evidence demonstrating the benefit of a single, standardised regimen for PMTCT, the WHO updated the PMTCT programme to include options B and B+ to augment option A in 2012.3 Option A encouraged mothers to use AZT from 14 weeks’ gestation, single-dose nevirapine (NVP) at birth, and 7 days of AZT/lamivudine (3TC) postpartum for the mother, with daily NVP for the infant until breastfeeding cessation, or until 4–6 weeks of age if the mother is receiving antiretroviral therapy (ART) or is not breastfeeding. Option B was simplified to ART for the mother from 14 weeks’ gestation until birth or the cessation of breastfeeding, and the use of NVP for the infant until 4–6 weeks of age. While NVP prophylaxis for the infant remains the same for option B+, the mother however remains on lifelong ART.3 South Africa began implementation of option B+ in 2015, together with birth PCR testing for infants. We report here on the mother to child transmission of HIV in a cohort of infants born to women enrolled in a PMTCT programme at two public health clinics in Durban, South Africa between 2013 and 2018. These mothers and infants were a cohort of HIV-exposed, breastfeeding infants enrolled into a clinical trial examining the current relevance of the WHO cotrimoxazole prophylaxis guideline in a non-malaria area.4

HIV transmission

During the study period, eight (0.85%) infants were found to have acquired an HIV infection. Four infants (0.42%) tested positive for HIV at the 10-week PCR, which is indicative of either intrapartum or very early postnatal infections (hereafter referred to as ‘birth transmissions’), and the other four infants (0.42%) tested positive at the 12-month visit, which is indicative of postnatal breastfeeding transmission (table 1).

While the main study cohort is not very different compared with the cohort with those lost to follow-up excluded, we compare the seroconverter group with the group that excludes those lost to follow-up. In the HIV seroconverter group, 5/8 (62.5%) of the infants were female and 5/8 (62.5%) were delivered via vaginal birth. Infant birth weight for seroconverters was not different when compared with the main study cohort. Maternal age was 29.0 years (IQR: 26.0–34.0) in the main cohort and 28.5 years (IQR: 25.8–33.6) in the HIV seroconverter cohort. When stratified by mode of transmission, maternal age was 27.5 years (IQR: 25.0–30.0) in the birth transmission group compared with 30.0 years (IQR: 26.8–33.3) in the breastfeeding transmission group. The maternal CD4 captured was the most recent test result prior to birth on maternal recall. Unsurprisingly, maternal CD4 was lower in the HIV seroconverter group compared with the main study cohort, respectively (228 cells/mm³ (IQR: 145.5–262.5) vs 460 cells/mm³ (IQR: 324.0–601.5)). Stratified by mode of transmission, maternal CD4 was 195.5 cells/mm³ (IQR: 94.5–240.0) in the birth transmission group versus 233 cells/mm³ (IQR: 181.0–322.0). If we compare mothers whose CD4 was <350 cells/mm³, 25% of the main cohort fell into this category, compared with 7/8 (88%) of the HIV transmission cohort (100% of birth and 75% of breastfeeding transmissions).

While HIV transmission in this cohort was low, it was similar to South African district health data, which also reported vertical birth transmission of under 1%. The national average for birth transmissions in South Africa has steadily declined from 4.3% in 2015/2016 to 0.7% in 2018/2019 (0.6% for the province of KwaZulu-Natal).5 A meta-analysis of six studies in low-income settings in which mothers started ART before or during their most recent pregnancy, estimated a 6-month postnatal HIV transmission rate of 1.08%, with higher rates from mothers who commenced ART later in pregnancy.6 Similarly, the breastfeeding vertical transmission rate in this cohort was also low, but comparable to other studies. The Promoting Maternal Infant Survival Everywhere (PROMISE) Study in southern Africa reported a 0.7% breastfeeding transmission rate when mothers were on ART.7

Possible contributing factors to birth transmissions

Each birth transmission had a possible causal factor. For infant 1, the mother had a partner from Central Africa from whom she contracted the virus. It is therefore possible that she was infected with HIV-2, rather than HIV-1, which does not respond as well to the ARV regimen she was taking, therefore resulting in a detectable viral load. The second infant tested positive with both cytomegalovirus (CMV) and HIV at 10 weeks of age. An active CMV infection could have resulted in the mother having an increased HIV viral load. Reactivation of latent viral infections such as CMV is thought to synergistically favour HIV shedding.8 Infant 3’s mother had initiated ARV treatment some time before pregnancy; despite this, her viral load was high throughout pregnancy. It is unknown if this mother’s viral load was high due to treatment fatigue and therefore non-adherence to her regimen, or due to not responding to her regimen. While adherence would have been probed by peer counsellors, the mother did not report non-adherence to her ART regimen. The mother of the fourth infant who was a birth transmission had no CD4 or VL monitoring prior to birth. Thus, it would have been impossible to assess whether she was responding to treatment sufficiently.

Possible contributing factors to breastfeeding transmissions

Similarly, each of the four infants whose HIV transmission could be attributed to breastfeeding transmissions, had circumstances that likely led to their transmissions. Infant 1 was born to a Zimbabwean mother who decided to return home for 3 months during the study, where she had no access to ARVs, per self-report. This likely led to the increased VL that resulted in the breastfeeding transmission. A second breastfeeding transmission was a Mozambiquan mother who also returned home for 3 months, where she was not adherent to an ARV regimen. Infant 3’s mother missed several ARV clinic visits, and reported non- adherence to her ARV regimen. Infant 4’s mother had a low CD4 count at birth (76 cells/mm³). Despite the birth VL being undetectable, the mother presented with a low, but detectable, VL at 6 months postpartum.

Lessons learnt

While the low vertical transmission rates observed in this cohort show movement towards the elimination of vertical transmission, there is still much work to be done to improve these rates. We believe that several lessons can be learnt from vertical HIV transmission during this 5-year cohort study. Strong and persistent peer counselling (both ART adherence and breastfeeding counselling), together with widespread adoption of option B and option B+, likely contributed to the low mother to child HIV transmission rate observed in this cohort. Both the mothers’ viral load and CD4 count monitoring is critical in the last trimester and at birth to prevent birth transmission and to ascertain whether the mother has responded adequately to her ARV regimen. While viral load test results were not collected for this study, several studies have shown that viral load is linked to vertical transmission.9 Le Roux et al10 showed that infants born to mothers with lower CD4 counts (<350 cells/mm³) had higher morbidity than those born to mothers with higher CD4 counts.10 Hence targeted ART adherence, health and nutrition counselling could be directed towards these mothers. Mothers with a detectable viral load at birth could be provided with additional ARV prophylaxis for the infant, which could be extended until the mothers’ VL is confirmed undetectable. The PROMISE Study showed that it was safe and just as effective at preventing HIV transmission to provide the infant with ARV prophylaxis for up to 12 months of age compared with mothers receiving prophylaxis.7 Additionally, breastfeeding mothers need to have regular VL testing, as recommended, and need to be clearly counselled on these time points and the importance of adhering to them. This will help determine which mothers are either not responding to their ARV regimen or not completely adherent to their regimen, facilitating the necessary steps to protect the infant from HIV transmission. Point-of-care testing for CD4 and viral load would assist in real-time assessment of mother’s health and adherence/response to ART regimen, rather than waiting for lab results to return to the clinic, and are encouraged by the WHO.11

Recommendations

Based on these lessons learnt, we recommend that the following be prioritised in countries where vertical transmission has not reached desired targets:

• Breastfeeding and ARV adherence counselling support for all mothers is critical during this vulnerable time for pregnant and breastfeeding mothers.

• Point-of-care viral load and CD4 testing for mothers in the last trimester, at birth and regularly while breastfeeding would facilitate real-time counselling and adjustment of mothers’ and infants’ prophylaxis regimens.

• Extend infant prophylaxis for mothers who are struggling to adhere to their ARV regimen or who are not responding appropriately, despite treatment adherence. Additionally, infant prophylaxis can be offered for those mothers who are changing to a second-line regimen, until their VL is undetectable.

• Consideration must be given to foreign mothers who may not be able to obtain their ARVs when travelling to visit their home countries and extended (3–6 monthly) supplies should be considered for these mothers if they are stable on their current regimen.

• Regular refresher information sessions with healthcare workers on the extended infant prophylaxis options when mothers are not responding or adherent to their ARV regimens could assist in protecting the vulnerable infants.