Other pregnancy studies IAS 2019
Although eclipsed by Tsepamo and other presentations evaluating dolutegravir (DTG)-associated neural tube defect risk,  there were several interesting related oral and poster abstracts at IAS 2019 focusing on pregnancy and maternal infant health.
One session was actually entitled “HIV and pregnancy, beyond dolutegravir” (webcast for those who missed it). 
Data from Lesotho – where almost a third of women of reproductive age are living with HIV – showed that in the ART era women with HIV still remain at a higher risk for adverse pregnancy outcomes. 
An analysis from South Africa – which is currently in the midst of twin epidemics of HIV and obesity – looked at the impact of HIV and body weight on pregnancy outcomes and found that these differed between women living with and without HIV. 
The South African analysis was conducted among women who mostly received efavirenz (EFV)-based ART. Recent data suggest significant weight gain among non-pregnant adults living with HIV after starting DTG-based ART.  Data from Tsepamo showed greater weight gain among pregnant women receiving DTG compared with EFV.  But neither group experienced as much weight gain as HIV negative pregnant women.
Another secondary analysis from Tsepamo compared in utero transmissions between regimens and found no difference in rates between women receiving DTG- and EFV-based ART. 
Despite global transition to DTG-based ART, EFV is likely to remain an alternative first-line ART for a while. Isoniazid (INH) is recommended as TB preventive therapy for everyone (including pregnant women) living with HIV in TB-endemic low- and middle-income countries. Pharmacokinetic data from IMPAACT P1078 showed pregnancy increased plasma EFV clearance while INH decreased plasma EFV exposure, particularly in intermediate and slow metabolisers. 
Adverse pregnancy outcomes among women living with HIV in Lesotho
Despite almost universal ART and most women starting treatment before pregnancy, adverse birth outcomes remained elevated among women living with HIV compared with HIV negative women in the Integrated Management Team to Improve Maternal-Child Outcomes (IMPROVE) study. 
HIV prevalence is very high in Lesotho: about 30% among women aged 15–59. Despite ART, elevated adverse pregnancy outcomes have been reported in both low- and high-income countries among pregnant women living with HIV compared with those without HIV.
IMPROVE is a cluster randomised study of facility-based interventions to improve maternal child health services.
Women attending their first antenatal visit were enrolled 2016–17 from 12 health facilities in the Maseru District and followed regularly for 12–24 months after delivery.
A total of 1004 pregnant women were enrolled in the study: 614 and 390 with and without HIV. All HIV positive women received ART; most (89%) received tenofovir disoproxil fumarate (TDF)/lamivudine (3TC)/EFV.
Delivery outcome data was available for 906 women: 564 (92% of enrolled) HIV positive women and 342 (88% of enrolled) HIV negative women.
At baseline, women living with HIV were older with median age 28 vs 23 years; they had fewer years of education and were less likely to be enrolled during their first pregnancy than HIV negative women.
In multivariate analysis (adjusted for maternal age, estimated gestational age at enrollment, gravidity and education) adjusted odds ratio (AOR) for any adverse outcome (intrauterine loss, preterm, low birth weight, birth defect) for HIV positive vs negative women was 2.29 (95% CI 1.41 to 3.72), p=0.001. This difference was significant for individual outcomes, intrauterine loss (p=0.013) and low birth weight (p=0.002) but not for preterm delivery.
In a subset of women with syphilis, adjusted odds of adverse pregnancy outcomes remained higher in women living with HIV.
There were no significant differences in any adverse outcomes between women who started ART preconception vs during pregnancy.
Associations between weight and adverse pregnancy outcomes and HIV status in South Africa
Among HIV negative women, being obese or underweight might have increased the likelihood of adverse pregnancy outcomes in a South African study, conducted 2013 to 2014.  But women with HIV at normal BMI were at higher risk of adverse pregnancy outcomes, including low birth weight (LBW) and small for gestational age (SGA).
The study was a secondary analysis of a trial evaluating integrating postpartum services into ART care, conducted in Guguletu, a township outside Cape Town.
It evaluated 877 women with singleton, live births: 464 women without HIV and 413 with HIV. Those living with HIV received TDF/emtricitabine (FTC) or 3TC/EFV; 96% started ART during pregnancy.
Women were enrolled at first antenatal visit and were followed for 12 months postpartum.
At baseline women were a median 28 years of age with median gestational age of 20 weeks; 22% were pregnant for the first time; 7% vs 25% without and with HIV reported hazardous alcohol use and 22% vs 33% respectively stage 1 or 2 hypertension. Obesity was common: 40% of women were obese; 36% and 45% of those living with and without HIV.
Overall, 10.6% of infants were preterm; 10.8% were LBW; 11.4% were SGA and 10.8% were large for gestational age (LGA); 33.9% were caesarean deliveries.
Women living with HIV had fewer caesarean deliveries than those without HIV: 30.4% vs 37.8%. They also had fewer LGA infants: 6% vs 16.2%.
But they had a more preterm and LBW infants: 11.6% vs 9.4% and 12.5% vs 9% among women living with and without HIV respectively.
Obesity was associated with caesarean delivery: overall RR 1.69 (95% CI 1.29 to 2.22), without HIV RR 1.65 (95% CI 1.15 to 2.38) and with HIV RR 1.70 (95% CI 1.14 to 2.54).
There were no associations between any BMI category and preterm birth, overall or by HIV status.
Birth weight increased with pre-pregnancy BMI: overall mean 11.36 (95% CI 5.96 to 16.76), without HIV mean 11.81 (95% CI 4.11 to 19.52) and with HIV mean 9.92 (95% CI 2.16 to 17.68).
There was a trend towards women with higher BMI being less likely to have a LBW. No underweight HIV negative women had a LGA baby. Obese HIV negative women were more likely to have an LGA infant. For women living with HIV obesity seemed to be protective. But the investigators noted that only 8 obese women with HIV had an LGA infant (28 LGA infants overall among women living with HIV). And most LGAs occurred among normal weight women. Similarly, underweight women without HIV were more likely to have a SGA infant, but not women with HIV.
In summary, the investigators concluded that there was no evidence of association between pre-pregnancy BMI category and preterm birth or LBW. Obesity was associated with LGA and underweight with SGA, among women living without HIV but not among women living with HIV.
Weight gain among pregnant women in Botswana
Women living with HIV starting DTG during pregnancy in Tsepamo gained more weight between 18 and 36 weeks’ gestation compared with those starting EFV. This was most apparent among women with higher pre-ART pregnancy weight. Notably, neither group gained as much weight as HIV negative women. 
Women starting DTG and EFV had similar baseline characteristics, including pre-pregnancy weight and weight at ART initiation. Compared to EFV, the adjusted mean weekly weight gain was 0.05 (95% CI 0.03 to 0.07) kg/week higher and the adjusted mean 18-week weight gain was 1.12 (95% CI 0.67 to 1.57) kg higher for DTG.
The weight gains in both ART groups were less than the weight gains in HIV negative women. Differences in weight gain by ART regimen were greater among women weighing more than 80 kg and were attenuated among women weighing less than 50 kg before starting ART.
In utero vertical transmission with dolutegravir- and efavirenz-based ART in Botswana
In utero vertical transmission is rare in Botswana and an analysis linking the Early Infant Treatment Study (EIT) and Tsepamo study surveillance found no difference in the rate between women receiving DTG/TDF/FTC and EFV/TDF/FTC. 
The risk was highest when ART was started in the third trimester regardless of regimen.
The EIT screened HIV-exposed infants for HIV DNA before 96 hours of life from April 2015 to July 2018. Maternal ART and start date were available for infants who could be linked to the Tsepamo surveillance database.
In Botswana, as of May 2016, the majority of adults, including pregnant women, started DTG-based ART. But those already receiving other regimens continued to do so.
Forty (0.38%) of 10,622 HIV-exposed screened infants were HIV positive: 12/2849 (0.42%) from before and 28/7773 (0.36%) after the transition to DTG.
About half, 5064 (47.8%), could be linked to the Tsepamo database. Of linked infants, 1235 (24.4%) were exposed to DTG/TDF/FTC, 2411 (47.6%) to EFV/TDF/FTC and 1418 (28.0%) to other or no ART.
Overall there was no difference in transmission rates between women receiving DTG-based (0.65%) or EFV-based ART (0.37%): OR 1.74 (95% CI 0.58 to 5.08). Nor among those starting DTG-based (0.80%) or EFV-based ART (0.91%) in pregnancy: OR 0.88 (95% CI 0.29 to 2.71).
Vertical transmissions mostly (4 of 8 with DTG, 6 of 9 with EFV) occurred after starting ART and less than 90 days before delivery. There were in 4/17 (23.5%) transmissions among women with undetectable viral load (<40 copies/mL) at delivery – all 4 women were receiving DTG.
Efavirenz and isoniazid pregnancy pharmacokinetics
Pregnancy increased plasma EFV clearance but INH decreased plasma EFV exposure, especially in intermediate and slow metabolisers, in IMPAACT P1078 a trial designed to look at safety of INH preventative therapy in pregnancy. [8,9]
This was a phase 4, double-blind placebo-controlled pharmacokinetic (PK) study that randomised women to start 300 mg INH daily for 28 weeks either in pregnancy (immediate arm) or at 12 weeks postpartum (deferred arm).
Pregnant women 14–34 weeks’ gestation, living with HIV, receiving or starting ART, were enrolled from TB-endemic areas in Africa, Asia, and Haiti.
PK sampling was either intensive (before INH/placebo dosing and 1, 2, 4, 6, 8, 12 hours after), or sparse (approximately 2 hours post dose) at 2 weeks or more after recruitment and at 12–21 weeks postpartum.
EFV concentrations from 21 intensively sampled and 767 sparsely sampled women were included. At enrolment, median weight, age, and gestational age at enrollment were: 67 kg, 29 years and 28 weeks respectively.
CYP2B6 slow, intermediate and normal metabolisers had oral clearances of: 2.74, 9.90 and 14.1 L/h, respectively.
After adjustment for CYP2B6 genotype and weight, pregnancy increased EFV clearance by 17% (p< 0.001). INH decreased EFV clearance by 8% in normal metabolisers and 14% in slow and intermediate metabolisers (p< 0.001) both during pregnancy and postpartum.
Unless stated otherwise, all references are to the programme and abstracts of the 10th IAS Conference on HIV Science. Mexico City, Mexico (IAS 2019), 21–24 July 2019.
- Clayden P. Dolutegravir neural tube defect risk declines but still slightly higher than with other antiretrovirals. HTB. 24 July 2019.
- HIV and pregnancy, beyond dolutegravir. IAS 2019, Mexico City. Session TUB01
- Tukei VJ et al. Adverse pregnancy outcomes among HIV-positive women in the era of universal antiretroviral therapy (ART) remain elevated compared with HIV-negative women in Lesotho. IAS 2019, Mexico City. Oral abstract TUAB0102.
- Bengtson A et al. Dual epidemics: The impact of HIV and obesity on pregnancy outcomes among women in South Africa. IAS 2019, Mexico City. Poster abstract TUAB0105.
- Clayden P. Dolutegravir-based first-line non-inferior to efavirenz-based ART but associated with substantial weight gain: results from the ADVANCE study. HTB. 23 August 2019.
- Caniglia et al. Weight gain during pregnancy among women initiating dolutegravir in Botswana. IAS 2019, Mexico City. Poster abstract LBPEB14.
- Davey S et al. In utero mother-to-child transmission (MTCT) in Botswana does not differ between efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) and dolutegravir/tenofovir/emtricitabine (DTG/TDF/FTC). IAS 2019, Mexico City. Poster abstract LBPEC30.
- Gausi K et al. Impact of isoniazid and pregnancy on efavirenz pharmacokinetics in women living with HIV. IAS 2019, Mexico City. Poster abstract WEPEB281.
- Clayden P. Isoniazid preventive TB therapy in pregnancy and postpartum: recommendations now need to be re-evaluated. HTB. 16 April 2018.