Infants exposed to an antiretroviral regimen of tenofovir, emtricitabine and efavirenz (Atripla) from conception experienced fewer adverse birth outcomes compared to other three-drug regimens, according to a study of births in Botswana between 2014 and 2016, presented on Tuesday at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.
The Tsepamo study, an observational analysis of approximately 45% of all births in Botswana from August 2014 to August 2016, provides important information on the safety of various regimens in common use in sub-Saharan Africa, Asia and Eastern Europe, where the vast majority of HIV-exposed infants are found.
“Our data for the first time show that there really could be differences [in birth outcomes] between regimens,” said Dr Rebecca Zash of Beth Israel Deaconess Medical Center, Boston, presenting the findings at a press conference.
World Health Organization (WHO) guidelines recommend all individuals with HIV including pregnant and breastfeeding women start combination antiretroviral therapy (ART) regardless of clinical or immune status. After lengthy investigations of the possible harmful effects of efavirenz on the foetus, which found no increased risk of birth abnormalities in cohort studies, WHO recommended in 2013 that efavirenz-containing regimens should be provided regardless of pregnancy status.
A wide range of regimens remain in use and an increasing number of women start ART before pregnancy. Disconcertingly, there is still limited evidence about the severity and extent of the risks of foetal exposure, yet the benefits of ART clearly outweigh the risks. Previous studies have looked at risks associated with single agents rather than combinations, or have looked at the effect of ART exposure in comparison to no exposure.
A recent systematic review and meta-analysis covering the period from June 1980 to June 2016 regarding the timing of ART and adverse pregnancy outcomes included just eleven studies. Women who started ART before conception were significantly more likely to deliver preterm or very preterm or have low birth weight infants.
The aim of the Tsepamo study is to evaluate adverse birth outcomes with in utero exposure to different ART regimens, the first study of its kind. It is a planned two-year analysis of a four-year birth outcomes surveillance study.
WHO-recommended first-line regimen of tenofovir, emtricitabine and efavirenz (TDF/FTC/EFV) was compared with the other four most common ART regimens in Botswana, namely:
- tenofovir/emtricitabine/nevirapine (TDF/FTC/NVP)
- zidovudine/lamivudine/nevirapine (ZDV/3TC/NVP)
- tenofovir/emtricitabine/lopinavir/ritonavir (TDF/FTC/LPV/r)
- zidovudine/lamivudine/lopinavir/ritonavir (ZDV/3TC/LPV/r).
Botswana presents an ideal setting: it has a high HIV prevalence (22%), a 90% uptake of ART and over 95% of women deliver in health facilities. For the purpose of comparison, a variety of regimens are in use among women at the time of conception.
In 2012 Botswana moved from Option A (ZDV/3TC/NVP) to Option B (TDF/FTC/EFV). While dolutegravir was introduced in May 2016 for all adults and pregnant women, it is not captured in this interim analysis.
The study team abstracted data from all consecutive births at or above 24 weeks of gestational age at eight maternity wards in geographically diverse government hospitals in Botswana.
Outcomes included: stillbirth, preterm delivery (under 37 weeks), very preterm delivery (under 32 weeks), small for gestational age, very small for gestational age, neonatal death and two combined endpoints of any adverse outcome and severe birth outcomes. For a single birth the adjusted risk ratio (aRR) of each outcome was determined to evaluate the effect of HIV and ART exposures adjusting for maternal age, number of pregnancies and education.
The study population comprised 47,027 births, of which 11,932 were HIV-exposed and 5780 were in mothers taking ART at the time of conception:
- almost half of the women (2503) were taking TDF/FTC/EFV
- 24% (1403) were taking ZDV/3TC/NVP
- 13% (775) were taking TDF/FTC/NVP
- 4% (237) were on TDF/FTC/LPV/r
- 3% (169) were on ZDV/3TC/LPV/r.
Women on TDF/FTC/EFV tended to be younger, while those on ZDV/3TC/NVP had less education and were more likely to have had five or more prior pregnancies. All had relatively high CD4 cell counts ranging from 478 to over 600 cells/mm3.
Combined adverse birth outcomes were more common among all HIV-exposed infants compared to HIV-unexposed infants (34% vs 24%, p < 0.001). The relative risk of each adverse birth outcome was calculated for each regimen in comparison to TDF/FTC/EFV.
Overall rates for adverse and severe birth outcomes were very high; 36% and 12% respectively for those exposed to TDF/FTC/EFV. For exposure to all other regimens they ranged from 42 to 48% for adverse birth outcomes and from 18 to 23% for severe birth outcomes.
Outcomes for preterm birth ranged from 19% for TDF/FTC/NVP exposure to 30% for ZDV/3TC/LPV/r exposure. The risk for very preterm birth was more than double among those exposed to ZDV/3TC/LPV/r, aRR: 2.2 (95%CI: 1.3-3.8) and the risk of very preterm birth was also significantly higher among infants exposed to ZDV/3TC/NVP (aRR 1.4, 1.1-2.0) when compared to TDF/FTC/EFV.
A similar pattern of increased risk for non-efavirenz-based regimens held true for infants born small for gestational age; when compared to TDF/FTC/EFV, infants exposed to other regimens were between 40 to 80% more likely to be born small or very small for gestational age.
Stillbirths were fewest among those exposed to TDF/FTC/EFV while those exposed to ZDV/3TC/NVP had more than twice the risk (aRR: 2.3; 95% CI: 1.6-3.3).
Similar results were seen for neonatal death; the rate was lowest among those exposed to TDF/FTC/EFV (1.2%). For those exposed to ZDV/3TC/NVP the risk was almost double, aRR: 1.9 (95% CI: 1.1-3.3), while among those exposed to ZDV/3TC/LPV/r the risk was four times greater, aRR: 4.0 (95% CI: 1.8-9.2).
Dr Zash concluded that expanded monitoring of pregnancy outcomes in different settings is needed especially as new antiretrovirals become available. Further research is needed to understand the mechanisms of adverse birth outcomes, notably in populations with high CD4 cell counts and where HIV is well controlled.
Zash R et al. Adverse birth outcomes differ by ART regimen from conception in Botswana. Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 25, 2017.