Chief, Division of Infectious Diseases
Brigham and Women's Hospital
Harriet Ryan Albee Professor of Medicine
Harvard Medical School
Daniel R. Kuritzkes, MD, has disclosed that he has received consulting fees from Gilead Sciences, GlaxoSmithKline, Merck, and ViiV Healthcare and funds for research support from AbbVie, Gilead Sciences, Merck, and ViiV Healthcare.
The 2018 IDWeek and Glasgow meetings featured the latest research on HIV infection. In light of recent concerns related to an interim report from Botswana suggesting a potential association between dolutegravir (DTG) exposure at conception and risk of neural tube defects (NTD), I was particularly interested in new reports providing additional information on ARV drug safety during pregnancy.
The Backdrop: Tsepamo
As a reminder, the Tsepamo study is an ongoing comprehensive survey of birth outcomes among women in Botswana with interim findings presented at AIDS 2018. One of the study’s primary aims is to assess potential relationships between NTDs and ARV drug exposure, particularly efavirenz (EFV), from the time of conception. An unplanned interim analysis requested by the WHO in preparation for their guideline updates demonstrated an unexpected association between DTG exposure at the time of conception and NTDs; among 596 cases with DTG exposure at conception, there were 4 cases of NTDs, resulting in a rate of 0.67% (vs 0.12% with non–DTG-containing ART exposure at conception). The rate of NTDs among women who initiated DTG during pregnancy was 0.03% (1/3104). This difference in risk based on time of initial DTG exposure would be consistent with a neural tube–specific effect as formation of the neural tube occurs very early in pregnancy. It is unclear at this time if the signal reflects a true association or if it is an artifact resulting from a limited data set. Therefore, the study is expanding surveillance from 8 to 18 maternity wards in Botswana, covering approximately 72% of total births in the country and an estimated 1226 additional pregnancies with DTG exposure at conception. The next formal analysis is anticipated to occur after March 31, 2019.
Which ART Regimens Have Been Proven Safe During Early Pregnancy?
Findings from the Tsepamo interim analysis highlight important gaps in our knowledge and understanding of the safety of ART during pregnancy, particularly at the time of conception. Indeed, this gap extends beyond ART to many pharmacologic therapies primarily because pregnant women are almost always excluded from clinical trials of investigational drugs. Clinicians and women with HIV are thus left selecting among different options with few available data to inform their decisions. For example, interim DHHS perinatal recommendations (December 2018) note that it is unclear at this point if the potential association between DTG and NTDs could be a class effect for all INSTIs, yet raltegravir is a recommended ARV agent during pregnancy. Although raltegravir has been widely used for some time during pregnancy, there have been no analyses published to date that look specifically at the effect of raltegravir exposure at the time of conception on birth outcomes.
New Fall 2018 Data
Although we are likely a long way from having a clear indication of the safest regimens for treating HIV through conception and pregnancy, during the fall 2018 HIV conference season, I was reassured to see that researchers are continuing to delve into this question and to work toward providing a stronger foundation for evidence-based medicine in this setting. At IDWeek 2018, investigators from the SMARTT longitudinal, observational cohort study reported the results of an analysis evaluating the incidence of neurologic complications among HIV-exposed but uninfected children with in utero ARV drug exposure. Neurologic cases, defined as microcephaly, febrile seizures, seizure disorders, ophthalmologic disorders, or other neurologic conditions, were identified in 287 (6.3%) of 3747 evaluable infants and children. This study is interesting because it looked not only at birth outcomes but also at conditions that may have developed over time after birth. In the primary analysis, there was no statistically significant association between risk of neurologic diagnosis and EFV or DTG exposure. However, a sensitivity analysis identified a significant association between exposure to EFV at conception (vs no EFV exposure) and risk of neurologic diagnosis (adjusted relative risk: 1.88; 95% CI: 1.07-3.29; P < .05). The association for EFV was statistically significant across 4 out of 6 sensitivity analyses. There were no statistically significant associations with DTG exposure, and the single NTD case identified did not have exposure to DTG. One limitation of this analysis is the small proportions of cases with EFV (4.5%) or DTG (2.6%) exposure.
A second study this fall reporting on birth outcomes with ARV drug exposure looked specifically at 2 other INSTIs: elvitegravir and the most recently approved INSTI bictegravir. This analysis presented at Glasgow 2018 included both prospective and retrospective exposure reports. Among 155 prospectively reported cases involving preconception or first-trimester elvitegravir exposure at any time during pregnancy, no NTDs occurred. Among the overall 630 pregnancies with elvitegravir exposure at any time during pregnancy, there were 2 retrospectively identified cases of NTDs, providing no evidence of an increased risk. Only 25 bictegravir-exposed pregnancies were included in the analysis owing to the recent availability of this drug, and no cases of NTDs were identified. It is worth noting that US guidelines recommend against elvitegravir/cobicistat use during pregnancy because inadequate drug levels and virologic breakthrough have been reported during the second and third trimesters, and they do not currently recommend bictegravir based on insufficient data in pregnancy.
Although both data sets described here provide some reassurance on the safety of INSTIs during early pregnancy, the numbers of exposed cases are still too low to draw firm conclusions.
When considering potential associations between adverse pregnancy outcome risk and ARV drugs, it is important to keep in mind that HIV treatment during pregnancy is critically important for both maternal health and to prevent transmission to the infant. As in any healthcare decision, potential risks need to be weighed based on the magnitude of those risks and alongside the benefits of a given treatment option—all of which must be considered in consultation with the patient. We certainly need more data, and we eagerly await the next report from Tsepamo. In the meantime, we need to be sure we involve women in decisions related to their HIV treatment and provide them with the available data to inform their healthcare choices.
How are you counseling women who wish to become pregnant regarding ART options and available safety data in early pregnancy? Please share your thoughts in the comments box.