Principal Investigator - Dr. Jennifer Jao, MD, MPH
- To assess the early longitudinal metabolic effects including insulin sensitivity in HIV-exposed uninfected (HEU) children compared to HIV-unexposed uninfected (HUU) children.
- To determine differences in the effects of neonatal zidovudine (AZT) vs. nevirapine (NVP) prophylaxis on early longitudinal changes in insulin sensitivity in the first 3 years of life.
- To assess mechanisms underlying early longitudinal metabolic effects of in utero HIV/ARV exposure including specific alterations in intermediary metabolism and mitochondrial dysfunction.
Study Design: This study is a prospective cohort study with a nested randomized component.
Study Population: The study population consists of pregnant women living with HIV and HIV-uninfected pregnant women and their children in Gaborone, Botswana.
Study Size: A total of 300 women living with HIV/child dyads and 150 HIV-uninfected pregnant woman/child dyads will be evaluated for the study aims.
Study Duration: Pregnant woman/fetus dyads were enrolled antenatally at 16-36 weeks gestational age and are being followed through the child’s third year of life. The entire study duration will be 5 years.
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases.
Dolutegravir (DTG) is associated with lower rates of gestational diabetes (GDM) compared to Efavirenz (EFV). Pregnant women living with HIV (WLHIV) on antiretroviral therapy (ART) in Botswana were not at increased risk of GDM compared with women without HIV. Among WLHIV, the risk of GDM was lower with DTG- than with EFV-based ART. Further studies with larger cohorts are warranted to confirm these findings.
Fetal biometry is similar between in utero HIV/Dolutegravir (DTG)-exposed, in utero HIV/Efavirenz (EFV)-exposed, and HIV-unexposed fetuses. In this small Botswana cohort, there does not appear to be a substantial association between in utero HIV/antiretroviral exposure and fetal biometry or between in utero DTG vs. EFV exposure and fetal biometry. While these results are reassuring and support continued use of these regimens in pregnancy, larger studies with serial ultrasounds are needed to validate these findings.
HIV-exposed uninfected (HEU) infants have higher Homeo-static Model Assessment-Insulin Resistance (HOMA-IR) compared to HIV-unexposed uninfected (HUU) infants. Preliminary data on HOMA differences by various exposure groups for the study show that HEU newborns had lower insulin sensitivity compared to those HUU from birth to 1 month of life. Future studies to evaluate the long-term significance of this early life metabolic alteration are warranted.
Mitochondrial proton leak is higher in HIV-exposed uninfected (HEU) vs. HIV-unexposed uninfected (HUU) infants. In preliminary data analyses, we evaluated mitochondrial function by Seahorse among an initial n=69 infants at 1 month of age (n=39 HEU, n=30 HUU). While mitochondrial respiration and ATP production were similar between groups, median proton leak was higher in HEU compared to HUU infants (10.3 vs. 6.4 pmoles/min, p<0.01). The inverse correlation between proton leak and HOMA-IR trended towards significance (rho= -0.23, p=0.06). In subgroup analysis of HEU infants, there were no differences in mitochondrial function parameters between infants randomized to zidovudine (AZT) vs. nevirapine (NVP) prophylaxis, though, the sample size was small.