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.
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.
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.
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).
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.
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
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.
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.
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.
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
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
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.
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.
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).
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).
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.