Background
Antiretroviral therapy (ART) is remarkably effective to prevent perinatal transmission (PT) of HIV-1. We evaluated the PT rate in a population of women with widespread access to ART before conception.
methods
The analysis included 14630 women living with HIV-1 delivering from 2000 to 2017 in centers participating in the nationwide prospective multicenter French Perinatal Cohort (ANRS-EPF). PT was analyzed according to time period, timing of ART initiation, maternal plasma viral load (pVL), and gestational age at birth. No infants were breastfed and all received neonatal prophylaxis.
results
PT decreased between the three periods, from 1.1% in 2000-2005 (58/5123), to 0.7% in 2006-2010 (30/4600), and 0.2% in 2011-2017 (10/4907; p < 0.001). Restricting the analysis to the 6316/14630 (43%) women on ART at conception, PT decreased from 0.42% (6/1434) in 2000-2005 to 0.03% (1/3117) in 2011-2017 (p = 0.007). Among women treated at conception, if maternal pVL was undetectable near delivery, no PT was observed whatever the ART combination, [95%CI 0-0.07] (0/5482). Among women starting ART during pregnancy and with undetectable pVL near delivery, PT was 0.57% [95%CI 0.37-0.83] (26/4596). Among women treated at conception but having a detectable pVL near delivery, PT was 1.08% [95%CI 0.49-2.04] (9/834). We also qualitatively described the 10 cases of transmission occurring during the 2011-2017 period.
conclusion
In a setting with free access to ART, monthly pVL assessment, infant ART prophylaxis, and in the absence of breastfeeding, suppressive ART initiated before pregnancy and continued throughout the pregnancy can reduce perinatal transmission of HIV to almost zero.
Background
We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases.
Methods
We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.
Results
No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5).
Conclusions
Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
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