DOLPHIN-2: Dolutegravir Well-Tolerated When Initiated Late in Pregnancy

Initiation of antiretroviral therapy (ART) late in pregnancy is notably associated with a failure to achieve vial suppression prior to delivery of the infant, as well as increased rates of mother-to-child HIV transmission. Now, a study, DOLPHIN-2, has found that dolutegravir is well-tolerated and achieves more rapid virological suppression prior to delivery compared with efavirenz when initiated during a late stage of pregnancy.

The results of the study were presented in a late-breaking oral abstract session at the Annual Conference on Retroviruses and Opportunistic Infections (CROI 2019).

Saye Khoo, MD, professor at the University of Liverpool, and lead presenter of the study spoke with Contagion® about the findings of the study in an exclusive interview (see video).

"Every year around 1.5 million HIV-positive women become pregnant, and of course there is a risk in these women that there is infection passed from mother to child. That risk is most closely mapped onto the viral load — the amount of virus in the blood at the time of delivery – so the beneficial effect of antiretroviral therapy is blunted when treatment is started too late in pregnancy," Dr. Khoo said in the interview, further acknowledging Unitaid as the sponsor of this trial.

DolPHIN-2 is an open label trial in which pregnant women from Uganda and South Africa were randomized 1:1 to initiate either dolutegravir or efavirenz plus 2 nucleoside reverse transcriptase inhibitors from 28 weeks gestation. A total of 268 women were included in the safety data and 237 were included in efficacy analyses by intent-to-treat, of which 122 were enrolled in the dolutegravir arm and 115 in the efavirenz arm.

"Our hypothesis was this new class of drug dolutegravir, which is an integrase inhibitor, would be superior to efavirenz, which is the standard of care, at getting the viral load down when initiated in the third trimester in late pregnancy," Dr. Khoo said.

The primary endpoint of the study was viral load <50cps/mL at delivery (measured up to 14 days post-partum) for efficacy of the drug, as well as the occurrence of drug toxicity in participants and infants.

Each participant’s viral load was measured at baseline, 1 and 4 weeks after initiation, at the point of 36 weeks gestation and delivery, and 6 weeks post-partum.

The investigators note that, at the point of enrollment, there were no differences between dolutegravir and efavirenz in “median gestation (31w), viral loal (log_q0 4.4 vs 4.5 cps/mL), CD4 count (464 vs 412 cells/mL), or other characteristics. The median duration of ART at delivery was 52 vs 59 days (range 0-133 days).”

The study found that viral load <50 cps/mL at delivery was significantly higher in the dolutegravir arm (90/122, 74%) than in the efavirenz arm (49/115, 43%) [adjusted risk ratio and 95% CI, 1.66 (1.32-2.09)].

The investigators observed that this trend was consistent across subgroups of baseline viral load, CD4 cell count, and gestation at initiation, among other characteristics.

A viral load of <1000 cps/mL at delivery was also more likely to be observed in participants in the dolutegravir arm compared with those in the efavirenz arm (93% vs 83%) RR, 1.11 (1.00-1.23).

“Dolutegravir was well-tolerated in pregnancy with no differences with efavirenz in frequency or organ class of severe adverse events,” the investigators write, highlighting that there were no significant differences between median gestational age at delivery “(39.9 weeks for both arms) or births at <34 weeks (4.76% vs. 5.13%) and <37 weeks (16.67% vs 15.38%) gestation respectively.”

Four stillbirths were documented in the study, all of which occurred in the dolutegravir arm. Additionally, 3 cases of mother-to-child-transmission were detected at birth, all from the dolutegravir am, and are considered by the investigators to be likely to be in-utero transmissions.

Seven infant deaths were recorded with 4 occurring in the dolutegravir treatment arm and 3 in the efavirenz group.

Of 270 total live births, congenital anomalies were reported in 17 infants, 8 in the dolutegravir treatment arm and 9 in the efavirenz arm, occurring up to 6 weeks of age. No neural tube defects were observed.

The investigators conclude that dolutegravir is well-tolerated and achieves more rapid virological suppression prior to delivery when compared to efavirenz in a population initiating treatment late in pregnancy. However, late presentation in pregnancy is associated with poor outcomes despite ART and regardless of enrollment in either treatment arm.

"in summary we've shown superiority of dolutegravir over efavirenz in reducing the viral load quickly, which is the best indicator of diminished risk," Dr. Khoo told Contagion® in a separate interview. "That said, we found a number of adverse outcomes we do not think those were related to the drugs that were used but rather to the poor overall prognosis."

The study, “RCT of Dolutegravir vs. Efavirenz-Based Therapy Initiated in Late Pregnancy: DOLPHIN-2,” was announced in a press conference previewing a presentation on Tuesday, March 5, 2019, at CROI 2019 in Seattle, Washington.

This interview is part 1 of a 3-part interview with Dr. Khoo. More clips are to follow.