Better virologic outcomes with efavirenz vs lopinavir/ritonavir in pregnant women and no difference in risk of preterm birth

Polly Clayden, HIV i-Base

Efavirenz was associated with superior virologic outcomes compared to lopinavir/ritonavir (LPV/r) in a Ugandan study of ART-naive pregnant and breastfeeding women, according to data presented at CROI 2014. The risk of preterm birth was no different between women randomised to LPV/r- or EFV-based ART in this cohort.

Deborah Cohan from the University of California presented findings from secondary analyses of the PROMOTE study in an oral presentation on behalf of researchers from Kampala, Uganda and the United States. [1]

PROMOTE was an open label, randomised study conducted at Tororo District Hospital and HIV clinics in Tororo, rural Eastern Uganda set up to look at risk of placental malaria between women receiving two ART regimens. The study enrolled HIV positive pregnant women who were ART-naïve and between 12-28 weeks gestation. All women received daily trimethoprim-sulfamethoxazole and bednets.

Women received either LPV/r or EFV with AZT/3TC from enrollment until one year of breastfeeding. The LPV/r dose was increased from the standard 400/100 mg twice daily to 600/150 mg at 30 weeks gestation.

A total of 389 women were enrolled in the study: 195 in the EFV and 194 in the LPV/r arms. There were respectively 187 and 190 women at delivery and 173 and 175 completed the study.

There were no significant differences between the two arms at enrollment: mean age was 29 years and gestational age 21 weeks, two thirds of the women had three or more live children. The women’s median pre-ART CD4 count was 370 cells/mm3, mean pre-ART viral load was 61,611 copies/mL and 95% were WHO stage 1. About 40% were diagnosed with HIV in this pregnancy.

Dr Cohan noted that there was considerable incidence of malnutrition in this cohort with a median BMI of 21.8 in both arms.

For virologic efficacy the primary analysis was a non-inferiority comparison with 80% power to exclude a significant difference between study arms of 11% at delivery and 24 weeks – in both cases the 95% confidence interval did not indicate inferiority.

But when the investigators looked at the pattern of viral suppression at different time points, compared to LPV/r, women on EFV were significantly more likely to achieve viral suppression (<400 copies/mL) by delivery: 98% vs 86%, p <0.0001. There were no differences in suppression at 8 weeks post ART or 24 and 48 weeks post partum; about 90% of women achieved viral suppression at these time points.

There was significantly more virologic failure in the LPV/r vs EFV arm: odds ratio 0.51(95% CI 0.31 to 0.82), p=0.0062 (n=374).

Women receiving LPV/r had greater CD4 count increase at delivery and 24 weeks post partum vs EFV: respectively +57 vs -7 cells/mm3, p=0.002, and +178 vs +109 cells/mm3, p<0.01.

There was no difference in grade 3 or 4 adverse events between the arms (one per arm). Unsurprisingly grade 1 or 2 gastrointestinal adverse events were significantly more likely for women on LPV/r vs EFV. There were no reports of increased CNS adverse events with EFV but it was suggested that the questionnaire might not have been specific enough to pick these up.

The HIV transmission rate was 0.5% (2/374) – one in utero and one breastfeeding transmission in LPV/r arm.

HIV-free infant survival was similar between arms LPV/r vs EFV: 92.9% vs. 97.2%, p=0.10.

A poster from the same group, authored by Catherine Koss and colleagues looked at potential risk factors for preterm birth (<37 weeks, very preterm <32 weeks) in this cohort. [2]

Gestational age was calculated by last menstrual period and ultrasound at enrollment. Stillbirths and spontaneous abortions were excluded from the analysis.

The investigators reported, among 356 live-born singleton deliveries, the prevalence of preterm birth was 15.4% and of very preterm birth 1.7%.

Multivariate analysis, controlling for time since HIV diagnosis and ART regimen, revealed maternal gestational weight gain <0.1 kg/week vs > to be significantly associated with preterm birth: aHR 2.21 (95% CI 1.28 to 3.83), p=0.005.

There was a trend toward increased risk of preterm birth with gestational age at ART initiation of 24 to 28 weeks vs 12 to 23 weeks: aHR 1.69(95% CI 0.97 to 2.87), p= 0.065.

Neither placental malaria nor antiretroviral regimen was a risk factor for preterm birth.

Comment

These results support the WHO guidelines preferred regimen for pregnant women.

The increased LPV dose might not have been necessary and – as noted – the additional gastrointestinal events in the LPV/r arm come as no surprise. CNS events need to be monitored more carefully as this is now a component of the WHO preferred regimen for the vast majority of people receiving first-line ART including pregnant women.

References:

Cohan D et al. Efficacy and safety of LPV/r versus EFV in HIV+ pregnant and breast-feeding Ugandan women. 21st Conference on Retroviruses and Opportunistic Infections (CROI), 3-6 March 2014, Boston. Oral abstract 69.
http://www.croiwebcasts.org/console/player/22143
Koss CA et al. Risk factors for preterm birth in pregnant women randomised to lopinavir- or efavirenz-based ART. 21st Conference on Retroviruses and Opportunistic Infections (CROI), 3-6 March 2014, Boston. Poster abstract 867.
http://croiconference.org/sites/all/abstracts/867.pdf