BIOGRAPHY
Dr. Rebecca Zash, MD is an Assistant Professor at Harvard Medical School and faculty in the division of infectious disease (ID) at Beth Israel Deaconess Medical Center in Boston. She is also a Research Associate at the Harvard TH Chan School of Public Health and the Botswana Harvard AIDS Institute Partnership. Dr. Zash is an adult ID specialist, consulting on patients with general infectious diseases and also the director of the ID-OB/GYN outpatient clinic. Dr. Zash's research is focused in Botswana where she studies the impact of HIV and antiretroviral medications on pregnancy and lactation. Rebecca is a member of the US DHHS Perinatal HIV Guidelines committee and the sub-Saharan Congenital Anomalies Network.

Objectives:
Neonatal combination antiretroviral (cART) is recommended in situations at high-risk of vertical transmission, however, the maternal viral load at time of delivery (dVL) for which neonatal cART is warranted is not clear. The objective of this study was to describe cART use and risk of vertical transmission across different risk categories.

Methods:
Data were analyzed from mother-infant pairs (MIPs) in the Canadian Perinatal HIV Surveillance Program between 1997-2020. Infants were categorized as high-risk (dVL ≥1000c/ml, or maternal cART <4 weeks prior to delivery), medium-risk (dVL detectable and <1000c/ml, and maternal cART ≥4 weeks prior to delivery), and low-risk (dVL undetectable, and maternal cART ≥4 weeks prior to delivery). Neonatal ART regimens and HIV transmission risk was compared between groups.

Results:
Out of 2891 MIPs included in the analysis, 813 (28.1%) were considered high-risk, 196 (6.8%) medium-risk and 1882 (65.1%) low-risk. An equal proportion of high and medium-risk infants received cART (25.7% vs. 26.6%) vs. 5.8% of low-risk infants. There were 55 transmissions events; this included 49 (6.2%) of those in the high-risk, 1 (0.5%) in the medium-risk, and 5 (0.3%) in the low-risk category (p<0.001). In the high-risk group, transmissions occurred in 22.6% of children without any ART, 12.6% of those on cART, 3% on dual therapy, and 1.9% on single therapy (p<0.001); whereas in low and medium-risk groups, transmissions occurred in only 4.8% and 2.1% of children receiving cART. There were no transmissions among children receiving single, dual or no ART in both low and medium-risk groups.

Conclusion:
While cART was equally prescribed in both high and medium-risk situations, the benefits in the medium-risk group are not clear. These data suggest that efforts may be better directed towards ensuring access to cART in high-risk situations, and limiting cART exposure in others.

Background:
Providing comprehensive infant feeding guidance to families affected by HIV is complex and requires a multidisciplinary approach. While exclusive formula feeding remains the preferred recommendation for infants born to women living with HIV (WLWH) in high-income countries and is the current recommendation in Canadian guidelines, a more nuanced approach that includes the informed decision to breastfeed under certain circumstances is emerging in many resource-rich countries.

Methods:
The Canadian Pediatric & Perinatal HIV/AIDS Research Group (CPARG) hosted a CIHR-funded meeting in 2016 to develop consensus among multidisciplinary providers around counselling and recommendations for infant feeding. After presentations by adult and pediatric health care providers, basic scientists, and community-based researchers, a subgroup drafted summary evidence-informed recommendations. Along with revisions among CPARG members, a community consultation was solicited by WLWH who were known to the authors from Ontario, Quebec and British Columbia. A legal review was also conducted to ensure understanding of the criminalization potential and concern of HIV transmission and exposure.

Results:
The Canadian consensus guidelines continue to support formula feeding as the recommended method of infant feeding as it eliminates any residual risk of postnatal HIV transmission. A comprehensive approach to counselling WLWH, and families, is outlined to assist providers in effectively communicating current evidence to support fully informed in their decision making. The community review highlighted important considerations including the imperative for unbiased, woman-centred counselling, as well as supports and resources needed for implementing effective formula feeding in addition to funded formula programs. The legal review provided clarifying language around child protection services involvement and the need to provide referral to legal resources or information upon request.

Conclusion:
The Canadian infant feeding consensus guideline is designed to inform and enable better care for WLWH and their babies. Ongoing evaluation of these guidelines as new evidence emerges will be important.

Each year, ~1.1 million children are exposed in utero to ARVs, but their safety is not fully characterized during pregnancy. The Tsepamo study suggests that exposure to dolutegravir (DTG) from conception may be detrimental. Our objective was to characterize the effects of InSTI exposure on human embryonic stem cells (hESCs), with respect to cellular health, and markers of pluripotency and differentiation.

H9 (n=6) and CA1S (n=3) hESCs were exposed to 0.1% DMSO or DTG, cabotegravir (CAB), bictegravir (BIC), or raltegravir (RAL) at 0.01X-1XCmax (peak plasma concentrations). After three days, hESCs were assessed for viability, apoptosis, and for the markers of differentiation SSEA-3, and TRA-1-60 via flow cytometry. HESCs exposed to 0.5XCmax (n=3) were analyzed for expression of differentiation genes by RT-qPCR. Measures were compared between InSTIs and DMSO by paired t-tests.

H9 hESCs exposed to ≥0.5XCmax DTG, CAB, or BIC exhibited ≥2-fold decreased proliferation (p≤0.04). Exposure to DTG or BIC at 1XCmax severely reduced viability (p<0.001) and increased apoptosis (p≤0.001). Similar cell toxicity trends were seen in CA1S hESCs exposed to ≥0.5XCmax DTG, CAB, or BIC. H9 hESCs exposed to ≥0.5XCmax DTG, CAB, or BIC showed decreased SSEA-3 (≥20%, p≤0.02) and TRA-1-60 (≥20%, p≤0.03) expression and increased early mesendoderm lineage gene expression. CA1S hESCs exposed to ≥0.5XCmax DTG or CAB showed ≥75% decrease in SSEA-3, but no effect on TRA-1-60 or differentiation marker gene expression. In both hESC lines, RAL did not induce any cytotoxicity or differentiation, regardless of dose exposure.

Even at sub-pharmacological concentrations, some InSTIs induce cytotoxicity and differentiation in hESCs. Given their common use by women of reproductive age, it is imperative to elucidate their long-term safety in the context of pregnancy. Our data also indicate that RAL shows a safer profile in this model, a reassuring finding that warrants further investigation.

Background: Many factors influence pubertal onset including in utero exposures to medications and infections. We investigated associations of in utero antiretroviral exposures and maternal HIV severity with pubertal status at age 9 years in children who are HIV exposed but uninfected (CHEU).
Methods: CHEU in the Surveillance Monitoring for ART Toxicities study of the Pediatric HIV/AIDS Cohort Study with a Tanner stage (TS) assessment at age 9 (4mo) were included. Puberty was defined as present when TS2 for each indicator (girls: breasts/pubic hair; boys: testicular volume/pubic hair). Exposures of interest were: protease inhibitor (PI) exposure at 30 weeks’ gestation, maternal CD4 and HIV viral load in pregnancy, and child body mass index (BMI) >95th percentile at 9 years. Log-binomial regression models were fit to estimate relative risks.
Results: 227 CHEU were included (114 girls, 113 boys). 77% were exposed to PIs at 30 weeks’ gestation. A higher proportion of females (34.2% breast, 31.9% pubic hair, 27.4% both) than males (16.8% testicular volume, 13.3% pubic hair, 12.4% both) had attained TS2. Factors associated with the child having begun puberty differed by sex (Table). Among males, CHEU with PI exposure were less likely to have reached TS2, while higher maternal viral load in pregnancy increased the likelihood of reaching TS2.
Conclusions: Maternal HIV viral load in pregnancy was associated with presence of puberty at age 9 in males, but not in females. Further confirmatory and mechanistic studies are warranted.