Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be ...evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines. We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%-4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3-3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1-10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1-13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1-8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7-5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV. Please see later in the article for the Editors' Summary.
The early initiation of antiretroviral therapy (ART) in HIV-1-infected infants reduces mortality and prevents early CD4 T-cell loss. However, the impact of early ART on the immune system has not been ...thoroughly investigated in children over five years of age or adolescents. Here, we describe the levels of naive CD4 and CD8 T lymphocytes (CD4/CD8T
), reflecting the quality of immune reconstitution, as a function of the timing of ART initiation (early (<6 months) versus late (≥24 months of age)).
The ANRS-EP59-CLEAC study enrolled 27 children (5-12 years of age) and nine adolescents (13-17 years of age) in the early-treatment group, and 19 children (L-Ch) and 21 adolescents (L-Ado) in the late-treatment group. T lymphocytes were analyzed by flow cytometry and plasma markers were analyzed by ELISA. Linear regression analysis was performed with univariate and multivariate models.
At the time of evaluation, all patients were on ART and had a good immunovirological status: 83% had HIV RNA loads below 50 copies/mL and the median CD4 T-cell count was 856 cells/µL (interquartile range: 685-1236 cells/µL). In children, early ART was associated with higher CD8T
percentages (medians: 48.7% vs. 31.0%,
= 0.001), and a marginally higher CD4T
(61.2% vs. 53.1%,
= 0.33). In adolescents, early ART was associated with low CD4T
percentages and less differentiated memory CD8 T cells. CD4T
and CD8T
levels were inversely related to cellular activation and gut permeability.
In children and adolescents, the benefits of early ART for CD8T
were clear after long-term ART. The impact of early ART on CD4T
appears to be modest, because pediatric patients treated late respond to HIV-driven CD4 T-lymphocyte loss by the
production of T
cells in the thymus. Our data also suggest that current immune activation and/or gut permeability has a negative impact on T
levels.
ClinicalTrials.gov, identifier NCT02674867.
Abstract
Objectives
Because NRTIs can have fetal toxicities, we evaluated a perinatal NRTI-sparing strategy to prevent perinatal HIV transmission. Our primary objective was to determine the ...proportion maintaining a viral load (VL) of <50 copies/mL up to delivery on darunavir/ritonavir monotherapy, without requiring treatment intensification.
Methods
In a one-arm, multicentre Phase 2 clinical trial, eligible patients in the first trimester of pregnancy on ART with plasma VL < 50 copies/mL received maintenance monotherapy with darunavir/ritonavir, 600/100 mg twice daily. VL was monitored monthly. ART was intensified in the case of VL > 50 copies/mL. Neonates received nevirapine prophylaxis for 14 days.
Results
Of 89 patients switching to darunavir/ritonavir monotherapy, 4 miscarried before 22 weeks’ gestation, 2 changed treatment for elevated liver enzymes without virological failure, and 83 were evaluable for the main outcome. Six had virological failure confirmed on a repeat sample (median VL = 193 copies/mL; range 78–644), including two before switching to monotherapy. In these six cases, ART was intensified with tenofovir disoproxil fumarate/emtricitabine. The success rate was 75/83, 90.4% (95% CI, 81.9%–95.7%) considering two patients with VL missing at delivery as failures, and 77/83, 92.8% (95% CI, 84.9%–97.3%) when considering them as successes since both had undetectable VL on darunavir/ritonavir throughout pregnancy. In ITT, the last available VL before delivery was <50 copies/mL in all of the patients. There was no case of perinatal HIV transmission.
Conclusions
Darunavir/ritonavir maintenance monotherapy required intensification in nearly 10% of cases. This limits its widespread use, thus other regimens should be evaluated in order to limit exposure to antiretrovirals, particularly NRTIs, during pregnancy.
Antiretroviral therapy (ART) is remarkably effective in preventing perinatal transmission (PT) of HIV-1. We evaluated the PT rate in a population of women with widespread access to ART before ...conception.
The analysis included 14 630 women with HIV-1 who delivered from 2000 to 2017 at 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.
PT decreased between 3 periods, from 1.1% in 2000-2005 (58/5123) to 0.7% in 2006-2010 (30/4600) and to 0.2% in 2011-2017 (10/4907; P < .001). Restriction of the analysis to the 6316/14 630 (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 = .007). Among women treated at conception, if maternal pVL was undetectable near delivery, no PT was observed regardless of the ART combination 95%CI 0-0.07 (0/5482). Among women who started 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 with a detectable pVL near delivery, PT was 1.08% 95%CI 0.49-2.04 (9/834). We also qualitatively described 10 cases of transmission that occurred during the 2011-2017 period.
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 pregnancy can reduce PT of HIV to almost zero.
The ANRS-EP38-IMMIP study aimed to provide a detailed assessment of the immune status of perinatally infected youths living in France. We studied Gag-specific CD4 and CD8 T-cell proliferation and the ...association between the proliferation of these cells, demographic factors and HIV disease history. We included 93 youths aged between 15 and 24 years who had been perinatally infected with HIV. Sixty-nine had undergone valid CFSE-based T-cell proliferation assays. Gag-specific proliferation of CD4 and CD8 T cells was detected in 12 (16%) and 30 (38%) patients, respectively. The Gag-specific proliferation of CD4 and CD8 T cells was more frequently observed in black patients than in patients from other ethnic groups (CD4: 32% vs. 4%, P = 0.001; CD8: 55% vs. 26%, P = 0.02). Among aviremic patients, the duration of viral suppression was shorter in CD8 responders than in CD8 nonresponders (medians: 54 vs. 20 months, P = 0.04). Among viremic patients, CD8 responders had significantly lower plasma HIV RNA levels than CD8 nonresponders (2.7 vs. 3.7 log10 HIV-RNA copies/ml, P = 0.02). In multivariate analyses including sex and HIV-1 subtype as covariables, Gag-specific CD4 T-cell proliferation was associated only with ethnicity, whereas Gag-specific CD8 T-cell proliferation was associated with both ethnicity and the duration of viral suppression. Both CD4 and CD8 responders reached their nadir CD4 T-cell percentages at younger ages than their nonresponder counterparts (6 vs. 8 years, P = 0.04 for both CD4 and CD8 T-cell proliferation). However, these associations were not significant in multivariate analysis. In conclusion, after at least 15 years of HIV infection, Gag-specific T-cell proliferation was found to be more frequent in black youths than in patients of other ethnic groups, despite all the patients being born in the same country, with similar access to care.
Background. Children born at the start of the human immunodeficiency virus (HIV) epidemic and infected during the perinatal period are now young adults living with the virus. Naive T-lymphocyte ...restoration is essential for the maintenance of a diverse T-cell receptor repertoire and for immunity to pathogens. Methods. The ANRS-EP38-IMMIP study included 93 patients infected with HIV type 1 (HIV-1) during the perinatal period. Naive CD4 (CD4 N ) and CD8 (CD8 N ) T lymphocytes and CD4 recent thymic emigrants (CD4 RTE ) were quantified in the peripheral blood by flow cytometry. Wilcoxon tests, Pearson correlation coefficients, and linear regressions were used to study their associations with HIV disease parameters. Results. Median CD4 N , CD8 N , and CD4 RTE percentages were 56% (interquartile range IQR, 44–64), 31% (IQR, 22–44), and 79% (IQR, 74–83), respectively. The three T-lymphocyte subsets were positively correlated with CD4 T-cell count. Patients aviremic at the time of the study tended to have a lower CD4 N percentage (55% vs 58%; P = .10), a significantly higher CD8 N percentage (39% vs 22%; P < .0001), and a significantly lower CD4 RTE percentage (77% vs 81%; P = .003) than viremic patients. In aviremic patients, CD4 N percentages were positively associated with cumulative viremia over the last 10 years (r = 0.335; P = .01) and were significantly higher in patients harboring X4R5 viruses than in those harboring R5 viruses (61% vs 44%; P = .001). Conclusions. After at least 15 years of HIV infection, perinatally infected youths had preserved CD4 N and CD4 RTE levels. This persistence of high levels of thymic activity potentially compensating for the deleterious effects of current and past HIV replication is remarkable.
Following an alert on neural tube defects and dolutegravir, we sought to evaluate if the exposure integrase strand transfer inhibitors (INSTIs) at conception was associated with birth defects or ...other adverse pregnancy outcomes.
In the prospective national French Perinatal Cohort (EPF), we studied birth defects and other perinatal outcomes by matching each pregnant woman exposed to INSTIs with a pregnant woman exposed to darunavir/ritonavir receiving the same backbone of nucleoside reverse transcriptase inhibitors and matched for other characteristics such as age, geographic origin, centre and year of delivery.
Among 808 women exposed to INSTIs during pregnancy (raltegravir = 703, dolutegravir = 57 and elvitegravir = 48), we reported a slightly higher rate of birth defects in infants exposed at conception to raltegravir (6.7%) vs. infants exposed to raltegravir later in pregnancy: 2.9% if initiated during pregnancy as first-line, and 2.5% as second-line treatment, P =0.04. When compared with matched controls, raltegravir exposure at conception was not significantly associated with birth defects: 6.4 vs. 2.3%, P = 0.08. There was no cluster of birth defect type and no neural tube defects were observed. Other perinatal outcomes, such as preterm birth and stillbirths, did not differ significantly between raltegravir-exposed women and matched counterparts. No difference in any outcome was observed for elvitegravir/cobicistat or dolutegravir.
We found a nonsignificant trend for an association between exposure to raltegravir at conception and birth defects, which needs to be evaluated by larger prospective surveillance data, as these drugs are increasingly prescribed in women living with HIV.
To identify factors associated with mother-to-child HIV-1 transmission (MTCT) from mothers receiving antenatal antiretroviral therapy.
The French Perinatal Cohort (EPF), a multicenter prospective ...cohort of HIV-infected pregnant women and their children.
Univariate analysis and logistic regression, with child HIV status as dependent variable, were conducted among 5271 mothers who received antiretroviral therapy during pregnancy, delivered between 1997 and 2004 and did not breastfeed.
The MTCT rate was 1.3% 67/5271; 95% confidence interval (CI), 1.0-1.6. It was as low as 0.4% (5/1338; 95% CI, 0.1-0.9) in term births with maternal HIV-1 RNA level at delivery below 50 copies/ml. MTCT increased with viral load, short duration of antiretroviral therapy, female gender and severe premature delivery: 6.6% before 33 weeks versus 1.2% at 37 weeks or more (P < 0.001). The type of antiretroviral therapy was not associated with transmission. Intrapartum therapy was associated with four-fold lower MTCT (P = 0.04) in case of virological failure (> 10 000 copies/ml). Elective cesarean section tended to be inversely associated with MTCT in the overall population, but not in mothers who delivered at term with viral load < 400 copies/ml odds ratio (OR), 0.83; 95% CI, 0.29-2.39; P = 0.37. Among them, only duration of antenatal therapy was associated with transmission (OR by week, 0.94; 95% CI, 0.90-0.99; P = 0.03).
Low maternal plasma viral load is the key factor for preventing MTCT. Benefits in terms of MTCT reduction may be expected from early antiretroviral prophylaxis. The potential toxicity of prolonged antiretroviral use in pregnancy should be evaluated.
A previous study showed that, during the first year of life, the presence of cytotoxic T lymphocytes (CTLs) in human immunodeficiency virus (HIV)–infected children is associated with a lack of rapid ...progression to acquired immunodeficiency syndrome. The goal of the study was to address the role of CTLs in children who survived after age 5 years. Memory HIV-specific CTLs directed against Env, Gag, Nef, and Pol proteins were measured in a group of 47 highly active antiretroviral therapy–naive HIV-infected children. Both Gag- and Pol-specific CTLs were positively correlated with CD4+ T cell counts. Gag-, Nef-, and Pol-specific CTLs were inversely correlated with virus load. The inverse correlation between virus load and Gag-specific CTLs was independent of CD4+ T cell counts. In conclusion, this study showed the beneficial role of HIV-specific CTLs in children who survived after age 5 years
To evaluate the risk of late postnatal HIV-1 infection in nonbreastfed children enrolled in the French ANRS Cohort CO01 (EPF).
The EPF cohort has prospectively enrolled HIV-infected mother/child ...pairs with a low proportion of known breastfeeding (<0.2%). Children were followed until they were 24 months old, with HIV-1 DNA/RNA PCR tests performed at birth, M1, M3 and M6 and a late serology at 18-24 months. This substudy included 4539 children who were uninfected at the age of 6 months in 1984-2005.
Five children were late diagnosed with HIV-1 infection despite negative PCR tests until 6 months. In three cases, the infection was diagnosed between 14 and 18 months. The other infections were diagnosed at 10 and 12 years of age because of AIDS-defining symptoms; their last (negative) serologies were performed at 19 and 9 months, respectively. A phylogenetic study performed in the latest case revealed a strong homology between the mother and child strains. No known mode of viral transmission (including breastfeeding or use of premasticated food) could be found. However, we observed previously reported risk factors for intrafamilial HIV-1 transmission: poor socioeconomic backgrounds and sustained HIV-1 viremia in the mothers during the follow-up of their children.
Late postnatal HIV-1 infection can rarely be diagnosed in the absence of known breastfeeding in high-income countries. Our results highlight the need for a maintained close follow-up of the noninfected children even after 6 months, especially when there are risk factors for intrafamilial viral transmission.
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