Polly Clayden, HIV i-Base
Maternal antiretroviral therapy (ART) of efavirenz, tenofovir and emtricitabine was associated with lower risk of adverse birth outcomes compared with other regimens, among infants exposed to ART from conception in Botswana.
Rebecca Dash presented these findings at CROI 2017 on behalf of investigators from the Tsepamo study. The aim of the study was to compare birth outcomes with in-utero exposure from conception to the five most common ART regimens used in Botswana between August 2014 and August 2016.
She showed data from a planned two-year analysis of a four-year birth outcomes surveillance conducted at eight maternity wards in government hospitals across the country, representing about 45% of all births in Botswana. Data were extracted from all consecutive births at 24 weeks or more gestational age, using obstetric records.
Botswana provided an ideal setting to do this analysis. There is high HIV prevalence (about 22%), high uptake of ART in pregnancy (about 90%) and the majority of women (over 95%) deliver in a healthcare facility. Due to changes in national guidelines there was also a variety of regimens at conception to compare.
Since 2012, Botswana guidelines have recommended tenofovir, emtricitabine and efavirenz (TDF/FTC/EFV) for adults with CD4 <350 cells/mm3 and all pregnant women (WHO Option B). Women who were stable on previously recommended regimens (WHO Option A) were not switched. By 2014 when the study started, TDF/FTC/EFV could be compared with the four other most common regimens: tenofovir/emtricitabine/nevirapine (TDF/FTC/NVP), zidovudine/lamivudine/nevirapine (AZT/3TC/NVP), tenofovir/emtricitabine/lopinavir/ritonavir (TDF/FTC/LPV/r), and zidovudine/lamivudine/lopinavir/ritonavir (AZT/3TC/LPV/r).
Of note in May 2016, Botswana switched to Treat all with a dolutegravir-based regimen for all adults including pregnant women but these births were not captured in this two-year interim analysis.
Outcomes included stillbirth, neonatal death (<28 days), preterm birth (<37 weeks), very preterm birth (<32 weeks), small for gestational age (<10th%), very small for gestational age (<3rd%) and two combined endpoints of any adverse outcome and any severe adverse outcome.
Between August 2014 to August 2016, there were 47,124 births of which 47,027 (98.8%) were included in the analysis; 11,932 (25%) were to HIV positive women. Almost half, 5780 (48%) started ART before conception, while receiving the following regimens:
- TDF/FTC/EFV: 2,503 (43%)
- TDF/FTC/NVP: 775 (13%)
- AZT/3TC/NVP: 1,403 (24%)
- TDF/FTC/LPV/r: 237 (4%)
- AZT/3TC/LPV/r: 169 (3%)
The remaining women received other 3-drug, non-standard or unspecified ART, or changed/stopped ART.
Women on TDF/FTC/EFV tended to be younger than those on all other regimens. They had fewer weeks from HIV diagnosis to conception as well as weeks on ART before conception. Those receiving AZT/3TC/NVP had less education. They were also more likely to have had five or more previous pregnancies as were women on LPV/r regimens. Among approximately 25% women with documented CD4 count, median values were quite high, ranging from 478 cells/mm3 for women on TDF/FTC/EFV to above 600 cells/mm3 for women receiving LPV/r-based regimens. Very few women had low CD4 counts <200 cells/mm3.
Overall rates for adverse birth outcomes and severe adverse outcomes were extremely high (as much as 48% and 23% respectively with LPV/r-based regimens) in the group of ART-exposed infants from conception. TDF/FTC/EFV was associated with the lowest risk for combined adverse birth outcomes, p<0.001. See Table1.
|Severe adverse outcome||12%||18%||21%||20%||23%|
|Adverse outcome aRR (95%CI)||ref||1.2 (1.0–1.3)||1.3 (1.2–1.4)||1.3 (1.1–1.5)||1.2 (1.0–1.5)|
|Severe adverse outcome aRR (95%CI)||ref||1.4 (1.2–1.7)||1.7 (1.4–2.0)||1.6 (1.2–2.1)||1.2 (1.4–2.6)|
Adjusted for maternal age, educational attainment and gravida.
Preterm birth was very common in this group of women and ranged from 19–30%. Women receiving TDF/FTC/EFV had a lower risk for preterm birth than those receiving a LPV/r-based regimen or AZT/3TC/NVP. Women receiving TDF/FTC/EFV had the lowest risk for very preterm birth. The risk was more than double among those receiving AZT/3TC/LPV/r (which had the highest rate): 4.1% vs 9%, aRR 2.2 (95%CI: 1.3 to 3.8).
The investigators found similar results for small for gestational age and very small for gestational age outcomes: range 17–29% and 7.3–14%, respectively. TDF/FTC/EFV had the lowest risk for both outcomes except for small for gestational age among AZT/3TC/LPV/r exposures.
There were fewer stillbirths among women exposed to TDF/FTC/EFV. AZT/3TC/NVP was associated with more than twice the risk of still birth: 2.4% vs 6.1%, aRR 2.3 (95%CI: 1.6 to 3.3).
Results were again similar for neonatal death. The lowest rate was seen with TDF/FTC/EFV exposure. The risk was almost double with AZT/3TC/NVP: 1.2% vs 2.2%, aRR 1.9 (95%CI: 1.1 to 3.3). And it rose to four times greater with AZT/3TC/LPV/r: 4.4%, aRR 4.0 (95%CI: 1.8 to 9.2).
The investigators performed several sensitivity analyses. CD4 count in pregnancy, time on ART or time with HIV before pregnancy did not substantially change the associations between ART regimens and either total or severe birth outcomes.
The investigators rightly emphasised the importance of expanded monitoring of pregnancy outcomes in different settings particularly as new antiretrovirals become available. More research is badly needed to better understand the mechanisms of adverse birth outcomes, which in this study occurred frequently in women with fairly high CD4 counts and well-controlled HIV.
As dolutegravir-based ART became the recommended adult first-line in Botswana since May of last year (including for pregnant women starting ART), there is heightened interest in data from this programme. To date information about the drug in pregnancy is scarce, and trial results will not be available for two years or more.
The first dolutegravir data from Botswana (notably for women starting in pregnancy not before conception) should be analysed in June–July of this year, when the investigators get to approximately 800 exposures. This should provide outcomes from enough women for a reasonably tight 95%CI around rates of adverse pregnancy outcomes (and also avoid biased reporting of women who deliver earlier ie who have preterm delivery).
At present, women on legacy regimens in Botswana are not switched from these until after delivery, but this might change in 2017–2018. If the government of Botswana does change its policy and switches women to dolutegravir, the investigators will try to capture this in their surveillance data and see if the adverse outcomes can be mitigated by such a switch. Such data would really help isolate the potential drug effect, if outcomes improve (assuming dolutegravir is similar to efavirenz, and not like nevirapine or lopinavir/r, which currently is unknown).
Zash R et al. Adverse birth outcomes differ by ART regimen from conception in Botswana. CROI 2017. 13–17 February 2017. Seattle, Washington. Oral abstract 25.