In 2016 the World Health Organization added dolutegravir, an integrase inhibitor, to its HIV treatment guidelines as an alternative first-line ART for adults and adolescents over 12 years of age.
Due to its potency, improved tolerability and higher barrier to drug resistance dolutegravir provides better clinical benefits compared to another integrase inhibitor, raltegravir (the safety in pregnancy of the latter is discussed below). Switching to dolutegravir from an efavirenz-based first-line ART, the most common regimen used in pregnancy in high-burden countries, may also be cost-effective because relatively less active pharmaceutical ingredient is needed to make it.
So, many countries are moving to a dolutegravir-based ART as a first-line recommended regimen.
However, the lack of a sufficient evidence base for safety and efficacy of dolutegravir (among other new antiretrovirals) means its introduction as the preferred first-line option is being approached cautiously in many low- and middle-income countries. Importantly, more evidence is needed on safety during pregnancy and breastfeeding.
In 2016 Botswana changed first-line ART from the efavirenz-based regimen to the dolutegravir-based option including for pregnant women.
At the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) this year Dr Zash presented findings from a two-year analysis of a study (Tsepamo) showing that an efavirenz-based regimen in pregnancy was safer than four older ART regimens. The differences in birth outcomes were significant with a 6 to 12% lower prevalence for any adverse outcomes and a 6 to 11% lower prevalence for severe adverse outcomes.
With the change in Botswana national guidelines Dr Zash and her colleagues were able to perform a dolutegravir analysis within the Tsepamo study.
Outcomes comprised combined endpoints of any adverse outcomes that included: stillbirth, preterm birth [less than 37 weeks], SGA [small for gestational age – below the 10th percentile weight-for-gestational age], or neonatal death [less than 28 days old]; and severe adverse outcomes that included: stillbirth, neonatal death, very preterm birth [less than 32 weeks] and very SGA [below the 3rd percentile weight-for-gestational age].
Maternal characteristics including age, education, occupation, parity, alcohol/tobacco use, history of adverse birth outcomes, delivery site, gestational age at presentation for antenatal care and CD4 count were very similar in women starting either the dolutegravir- or efavirenz-based regimen.
ART was started at a median of 19 weeks (IQR: 15-25) and 21 weeks (IQR: 16-27) into the pregnancy among those on the dolutegravir- and efavirenz-based regimens, respectively.
Comparison of women taking dolutegravir/tenofovir/emtricitabine (DTG/TDF/FTC) (who delivered from November 2016 to April 2017) with those taking efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) (who delivered from August 2014 to 2016) showed no significant differences in stillbirth, neonatal death, preterm or very preterm birth, SGA or very SGA.
Just over a third in both the DTG/TDF/FTC (n = 845) and EFV/TDF/FTC (n = 4593) groups had a combined endpoint of any adverse birth outcomes, 291 (34%) and 1606 (35.%), respectively, (adjusted relative risk (aRR): 1.0, 95% CI: 0.9-1.1).
Eleven per cent of infants in both groups had a combined endpoint of severe adverse outcomes, 92 and 519 in the DTG/TDF/FTC and EFV/TDF/FTC groups, respectively, (aRR: 1.0, 95%: CI: 0.8-1.2).
Just over 2% experienced stillbirth, 18 (2.1%) and 105 (2.3%) among those on the dolutegravir- and efavirenz-based regimens, respectively, aRR: 0.9, 95% CI: 0.6-1.5). Neonatal death occurred in 1.3% in both groups.
The findings for preterm birth are similar, 18% and 19% among infants born to mothers starting dolutegravir- and efavirenz-based regimens in pregnancy, respectively and 4% for very preterm births for both regimens.
Similarly, 19% of women on both regimens had an infant SGA while 6% and 7% of women on dolutegravir- and efavirenz-based regimens, respectively, had an infant that was very small for its gestational age (very SGA).
Among the infants of the 512 women (116 DTG/TDF/FTC and 396 EFV/TDF/FTC) who started ART in the first trimester only one major congenital abnormality was identified, namely skeletal dysplasia in an efavirenz-exposed infant. This is very preliminary given the small number.
Dr Zash concluded while these findings are very reassuring further studies are needed to look at the safety of dolutegravir exposure from conception, congenital abnormalities, combinations with other antiretroviral backbones and maternal viral load at delivery.