New data presented at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) show that the integrase inhibitor dolutegravir (Tivicay, DTG) is more effective than efavirenz (Sustiva, Stocrin, EFV) at achieving viral suppression among women who present for treatment during late-term pregnancy.
Specifically, the DolPHIN-2 study initiated antiretroviral therapy (ART) treatment in HIV-positive women in Uganda and South Africa who were at least 28 weeks pregnant, randomly assigning the women to receive dolutegravir or efavirenz plus a background NRTI treatment. The primary endpoint was viral suppression, measured by a viral load of less than 50 copies/mL.
Ultimately, 268 women were randomly assigned to receive treatment. All of those women were included in the safety analysis, but only 237 were included in the efficacy analysis. At delivery, viral suppression was significantly more likely in the dolutegravir arm, with 74% of women on a dolutegravir regimen achieving viral suppression at delivery compared to only 43% of women in the efavirenz arm. The results were highly significant, with a risk ratio of 1.66 in favor of the dolutegravir arm (95% confidence interval 1.32-2.08).
"The DolPHIN-2 study was primarily designed to evaluate the responses between DTG and EFV," said Saye Khoo, M.D., MRCP, DTM&H, professor of molecular and clinical pharmacology at the University of Liverpool, speaking during an oral abstract session at CROI.
"To that end, we showed superiority in virological suppression in the DTG arm compared to EFV," Khoo said. "DTG was, moreover, very well tolerated."
Importantly, though there were more stillbirths and mother-to-child transmissions in the dolutegravir arm, none of these events were thought to be related to the drug itself. This study offers a reassuring sign that dolutegravir and efavirenz are safe during late-stage pregnancy, though there is still lingering doubt about the effects if given during the first or second trimester.
In 2018, an unscheduled analysis of the Tsepamo study in Botswana found a link between dolutegravir and neural tube birth defects, prompting multiple federal agencies to issue warnings. Later that year, a separate study was published that found efavirenz use during pregnancy to be associated with a 60% increase in the risk of neurological conditions in children. This finding also prompted public health warnings.
While the effect of integrase inhibitors during early-stage pregnancy still needs to be explored, the new data presented at CROI offer compelling evidence for initiating dolutegravir over efavirenz in women who are seeking care for the first time during late-stage pregnancy.
Initiating ART during late pregnancy is notoriously risky, associated with a greater likelihood of mother-to-child transmission and worse rates of viral suppression. The DolPHIN-2 study clearly demonstrates that dolutegravir led to faster rates of viral suppression -- a finding that was consistent across other characteristics, such as CD4 count.
Viral load at less than 1,000 copies/mL at the time of delivery was also more likely among women on dolutegravir, with 93% of the dolutegravir arm hitting this endpoint compared to only 83% in the efavirenz arm (risk ratio 1.11, 95% confidence interval 1.00-1.23).
There were no differences between the drugs in terms of how well they were tolerated in the mothers, and no major difference in laboratory tests other than a modest change in creatinine, a side effect that is already known to be associated with dolutegravir.
Among the 270 live births, there was no meaningful difference in gestational age at delivery (39.8 weeks in both arms), or in the number of births at less than 34 weeks (4.76% in the dolutegravir arm and 5.13% in the efavirenz arm) or less than 37 weeks (16.67% versus 15.38%, respectively).
However, there were four stillbirths -- all in the dolutegravir arm. The causes of death in these cases were determined to be maternal syphilis, uterine rupture, fetal distress, and presumptive tuberculosis.
"In all cases, [stillbirths] were thought to be unrelated to DTG," Khoo said.
The dolutegravir arm also included all three cases of mother-to-child transmission, with researchers concluding these were all probably in-utero transmissions.
Meanwhile, last year's finding of neural tube defects meant researchers were on the lookout for any sort of congenital disabilities. The DolPHIN-2 study collected data for a wide range of newborn characteristics, even superficial ones such as birth marks and umbilical hernias. Excluding those two outcomes, congenital anomalies were seen in 17 infants -- 8 in the dolutegravir arm and 9 in the efavirenz arm.
Notably, there were no neural tube defects in either arm. We may see additional data from the DolPHIN-2 study, as researchers will continue to monitor mothers and infants up to 72 weeks postpartum.
There were several presentations looking at the role of integrase inhibitors in pregnancy at CROI this year. A separate study presented at CROI found that the integrase inhibitor raltegravir (Isentress) bested efavirenz among pregnant women who initiated treatment at 28 weeks' gestation or later. At delivery, 98% of the raltegravir group had a viral load of less than 200 copies/mL compared to 84% of the efavirenz group, according to research presented by Mark H. Mirochnick, M.D., professor of pediatrics and chief of the division of neonatology at Boston University School of Medicine/Boston Medical Center.