Effects of preterm birth on HIV acquisition risk and antiretroviral prophylaxis safety in HIV-exposed infants in Botswana (PERHAPS)

June 24, 2019

Updated: March 24, 2021

One of the success stories of the Botswana HIV treatment and prevention program lies in the countries prevention of mother-to-child transmission of HIV program (PMTCT).  Currently, over 95% of pregnant women living with HIV are accessing antiretrovirals (ARV) resulting in a mother-to-child (MTCT) transmission rate of <2%, one of the lowest rates in Sub-Saharan Africa. This welcomed achievement, however, means that an increasing number of infants are now exposed to ARVs in utero, potentially contributing to increased preterm birth (PTB) in these population. PTB (birth < 37 weeks gestational age), among HIV-exposed infants in Botswana is approximately 21% in comparison to 13% among HIV-unexposed infants. 

Despite the reduced MTCT among HIV-exposed infants, we do not know if the timing or rate of HIV-acquisition for infants born preterm differs from infants born on or after 37 weeks gestational age. In our own work in an early infant treatment study underway in Botswana, which enrolls infants who test HIV positive at birth and are born ≥ 35 weeks  gestational age for ART initiation within 7 days of birth, 33.3% of the infants enrolled in that study were born between 35-36 weeks gestational age, a prevalence that exceeds the background preterm birth rate of 21% for infants born to HIV-infected women, suggesting that preterm HIV-exposed infants may be at higher risk for in-utero HIV acquisition. An alternate explanation is that HIV infection may lead to PTB, but this potential for reverse causality has also not been explored by comparing the gestational ages of in utero and intrapartum events.

Also, Botswana PMTCT guidelines currently recommend a triple ARV prophylaxis strategy in the first 4 – 6 weeks of life for HIV-exposed infants deemed to be at “high risk” of HIV-acquisition. In these guidelines, PTB is not recognized as a “high risk” characteristic, in and of itself.  Hence in Botswana, preterm HIV-exposed infants, lacking any other risk factor, receive a low-risk HIV prophylactic regimen of single-dose nevirapine within 72 hours of birth and twice daily dosing of Zidovudine for the first 28-30 days of life.

The PERHAPS study was therefore designed to evaluate and explore the relationship that might exist between PTB and 

a) Mother to Child HIV Transmission (MTCT) 

b)  Antiretroviral prophylaxis toxicity, in Botswana. 

Specifically, the study aims to be able to  

  1. Describe the prevalence and timing (in-utero versus peripartum) of MTCT in HIV exposed infants delivered preterm vs those delivered at term in the setting of ART.
  2. Assess the hematologic safety of ARV prophylaxis among HIV-exposed infants born preterm in the first month of life, evaluating for anaemia and/or neutropenia

Funded by the European and Developing Countries Clinical Trials Partnership (EDCTP – TMA2017CDF-1906), researchers at BHP led by Dr Gbolahan Ajibola, will try to provide answers to the research questions raised. The project which started November 2018, will last for 18 months.

Findings from this study will quantify the extent to which PTB confers an increased risk of mother to child transmission of HIV (MTCT) as well as provide information on the efficacy and safety of prophylactic ARV regimens in preterm infants, potentially informing public policy relative to testing and prophylaxis strategies for preterm HIV-exposed infants.

Summary of Findings

  • Low MTCT rate.
  • High ART coverage in pregnant WLHIV. 
  • High preterm delivery rate of 19% in WLHIV in a setting of high ART coverage 
  • No difference in HIV acquisition rate in HIV exposed infants delivered preterm vs term overall (0.8% vs 0.6%), at birth (0.2% vs 0.3%) and at 14-34 days post-delivery (0.6% vs 0.3%).
  • Trend towards higher rates of peripartum HIV acquisition among infants delivered preterm as against no increase at all in those delivered term (0.2% – 0.6%).
  • Nonuse of antiretroviral by women during pregnancy being the only measured covariate in our cohort that was independently predictive of HIV acquisition in children born to WLHIV.
  • Significant increase in odds of severe anemia in infants born preterm when compared with those born full term. 
  • Significant increase in odds of severe neutropenia in infants born preterm when compared with those born at term.
  • No difference in proportions of infants with severe anemia and neutropenia amongst those who took AZT vs NVP for prophylaxis.
  • No significant independent predictor of severe anemia identified.
  • Younger age at randomization (< 28 days), enrolled in an urban site. (Gaborone) versus peri-urban site and formula feeding from birth remained. significant independent predictors of severe (grade 3/4) neutropenia.

Limitations

  • Very low MTCT rate which could have reduced adequate power in detecting a true difference in risk of HIV acquisition between HIV exposed infants delivered preterm vs those delivered term.
  • Analysis was limited to 34 days post-delivery which could have led to underestimation of peripartum HIV acquisition rates in our cohort.

Conclusion

  • In settings with low MTCT rates attributable to widespread use of triple ART regimen in pregnancy as in Botswana, there was no observed increase HIV acquisition risk overall, in-utero and peripartum among HIV-exposed infants born preterm vs those born at term. However, as MTCT rates decreases across most program with a potential rise in preterm delivery rates, it might me more prudent to look at findings from pooled data across several programs which will provide more power to detect any differential risk of HIV-acquisition.
  • AZT and NVP equally safe and effective as infant prophylaxis with very few severe hematologic effect observed overall.