Maintenance darunavir/ritonavir monotherapy to prevent perinatal HIV transmission, ANRS-MIE 168 MONOGEST study.

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.

Rilpivirine in HIV-1-positive women initiating pregnancy: to switch or not to switch?

BACKGROUND: Safety data about rilpivirine use during pregnancy remain scarce, and rilpivirine plasma concentrations are reduced during second/third trimesters, with a potential risk of viral breakthroughs. Thus, French guidelines recommend switching to rilpivirine-free combinations (RFCs) during pregnancy. OBJECTIVES: To describe the characteristics of women initiating pregnancy while on rilpivirine and to compare the outcomes for virologically suppressed subjects continuing rilpivirine until delivery versus switching to an RFC. METHODS: In the ANRS-EPF French Perinatal cohort, we included women on rilpivirine at conception in 2010-18. Pregnancy outcomes were compared between patients continuing versus interrupting rilpivirine. In women with documented viral suppression (<50 copies/mL) before 14 weeks of gestation (WG) while on rilpivirine, we compared the probability of viral rebound (≥50 copies/mL) during pregnancy between subjects continuing rilpivirine versus those switching to RFC. RESULTS: Among 247 women included, 88.7% had viral suppression at the beginning of pregnancy. Overall, 184 women (74.5%) switched to an RFC (mostly PI/ritonavir-based regimens) at a median gestational age of 8.0 WG. Plasma HIV-1 RNA nearest delivery was <50 copies/mL in 95.6% of women. Among 69 women with documented viral suppression before 14 WG, the risk of viral rebound was higher when switching to RFCs than when continuing rilpivirine (20.0% versus 0.0%, P = 0.046). Delivery outcomes were similar between groups (overall birth defects, 3.8/100 live births; pregnancy losses, 2.0%; preterm deliveries, 10.6%). No HIV transmission occurred. CONCLUSIONS: In virologically suppressed women initiating pregnancy, continuing rilpivirine was associated with better virological outcome than changing regimen. We did not observe a higher risk of adverse pregnancy outcomes.

Lipodystrophy among HIV-infected patients: a cross-sectional study on impact on quality of life and mental health disorders.

BACKGROUND: Lipodystrophy (LD) is a frequent adverse event of combination antiretroviral therapy (ART) and occurs mainly in patients exposed to first-generation antiretroviral drugs. The aim of this study was to explore and measure the interaction between LD, mental health, and quality of life of human immunodeficiency virus (HIV) positive individuals seen in a metabolic clinic. METHODS: We conducted a single-site cross-sectional study including all HIV-infected patients attending the LIPO group and metabolism day clinic at the University Hospitals of Geneva, Switzerland between January 31, 2008 and November 28, 2013. Data on LD were prospectively collected using the HIV Outpatient Study (HOPS) score, the Lipodystrophy Case Definition (LDCD), ART regimens, anthropometric measures, imaging, and standardized questionnaires. Quality of life was evaluated using a visual analog scale of 0-100. Depression and anxiety were assessed using the Beck Depression Inventory and the State Trait Anxiety Inventory scales, respectively. RESULTS: One hundred ninety-four patients (54.6% male; 45.4% female; median age, 50 years) on successful ART (median CD4 cell count, 569.0 cells/mm(3); median viral load, 20 copies/mL) were evaluated. Among these, 62.7, 63.5 and 35.5% of patients reported at least one body site affected by fat hypertrophy, atrophy or both, respectively. Using the LDCD score conservative definition, including imaging and biological values, 57.8% were diagnosed with LD. Of these, 39.7% suffered from severe/very severe LD. Depression was reported by 35.6% of individuals; 51.9% had anxiety symptoms and 49.5% reported poor quality of life (defined as being inferior to 50% on a scale from 0 to 100%). LD (odds ratio (OR = 5.22, 95% confidence interval (CI) 1.07-25.37, p-value: 0.040), depression (OR = 4.67, 95% CI 1.08-20.31, p-value 0.040), and anxiety (OR = 7.83, 95% CI 1.91-32.03, p-value 0.004) all affected significantly the quality of life. CONCLUSIONS: LD, depression and anxiety were frequent features among HIV-infected individuals seen in the metabolic clinic and significantly impacted on their quality of life.

Is bone mineral mass truly decreased in teenagers with a first episode of forearm fracture? A prospective longitudinal study.

BACKGROUND: Forearm fractures are common in the pediatric population and are mostly treated by cast immobilization. The purposes of this study were first to determine whether forearm fractures in adolescents are associated with abnormal bone mineral density (BMD) or content (BMC) at the time of fracture, and second, to quantify the bone mineral loss at various sites due to cast-mediated immobilization. METHODS: This longitudinal case-control study recruited 50 adolescents (age, 12.8 ± 1.8 y) who underwent cast-mediated immobilization for a forearm fracture and 50 healthy controls (13.0 ± 1.8 y). Using 2 dual-energy x-ray absorptiometries, BMD and BMC were measured at various skeletal sites (total body, lumbar spine, total upper limb, and forearm) at fracture time and at cast removal. RESULTS: At the fracture time, BMD/BMC Z-scores at the lumbar spine and areal BMD at the peripheral wrist were not different among the injured and the healthy subjects. At cast removal, significant BMD decreases were observed in adolescents with fracture at the level of the radial and the ulnar diaphyses (-5.6% and -3.8%, respectively) and the total upper limb (-5.6%) compared with the noninjured side. Significant decreases in the BMC values were observed at the level of the radial diaphysis (-6.4%), ultradistal ulna (-10.2%), total upper limb, and total ulna (-8.2% and -4.9%, respectively). CONCLUSIONS: These data demonstrate that total body, lumbar spine, or wrist bone mineral mass and density (BMC and BMD) are not reduced at the fracture time in adolescents sustaining a first episode of upper limb fracture when compared with healthy subjects. These findings suggest that forearm fractures are not related to osteopenia in youth. In addition, cast-mediated immobilization results in a significant bone mineral loss at the upper limb, which may explain the increased risk of sustaining a second fracture. Finally, bone callus formation may interfere when assessing bone mineral mass after cast removal and may lead to an erroneous underestimation of bone mineral mass decrease. LEVEL OF EVIDENCE: Level IV.

Measles seroprevalence in human immunodeficiency virus-infected adults born in the era of measles vaccination.

OBJECTIVE: Widespread use of the measles vaccine should lead to the elimination of this disease. Here, we study the seroprevalence of measles in a cohort of adults living with HIV born after the introduction of measles vaccine in France and attempt to identify risk factors for the absence of serum measles antibody. DESIGN: In this multi-centre cross-sectional study, adult outpatients born after 1980 were screened for the presence of measles IgG antibody. Demographic and clinical data were obtained from the standardized electronic medical record system. Univariate and multivariate logistic regressions were performed to identify factors associated with the absence of measles antibodies. RESULTS: Between April 2019 and April 2020, 648 participants were enrolled. The median age was 33 years, 53.6% were born outside of France, and 74% were considered as socially deprived. Plasma HIV RNA was undetectable in 86% of patients. Among 603 evaluable patients, measles serology was positive in 87.2%. Only 81.8% of the patients with documented vaccination tested positive for measles IgG. Younger age was significantly associated with the absence of measles serum antibodies ( P  = 0.004 for each 10-year lower), as was birth in France ( P  < 0.001) and absence of social vulnerability ( P  = 0.04). CONCLUSION: The current study revealed a low seroprevalence of measles compared with that previously reported in France 6 years earlier and to the expected rate to achieve herd immunity. Checking vaccination record should be systematically carried out in patients living with HIV to fill the immunity gaps.

Clinical, behavioral and biomarker predictors of PCSK9 levels in HIV-infected patients naïve of statin therapy: A cross-sectional analysis from the Swiss HIV cohort.

BACKGROUND AND AIMS: Better characterization of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) profile is currently needed to tailor appropriate lipid-lowering strategies in HIV patients. METHODS: HIV-infected individuals aged ≥ 40 years and naive of statin therapy included in the Swiss HIV cohort study were screened for PCSK9 levels with a routine blood sample collection in 2014 at the Geneva University Hospitals. An exploratory linear regression model was built including clinical (age, sex, ethnicity, cardiovascular risk factors, body mass index, low CD4 defined as ≤200 cells/µl, leucocytes, lymphocytes, platelet, antiretroviral therapy), behavioral (tobacco and marijuana smoking, alcohol use and physical activity) and biomarker (CRP, TNF-α, IL-8, Il-10 and MCP-1) to investigate association with continuous PCSK9 levels. RESULTS: We studied 239 HIV-infected individuals who met inclusion criteria and available PCSK9 levels with a mean age of 49 years. 35 subjects (14.6%) reported marijuana consumption, of whom 20 (57.1%) reported daily consumption and 15 (6.3%) occasional use. PCSK9 levels were correlated with low-density lipoprotein-cholesterol (LDL-C). Our exploratory model identified marijuana consumption (p=0.023) and low CD4 values (p=0.020) as significantly associated factors with higher PCSK9 levels. No association was found with Framingham risk score. Patients with marijuana consumption had significantly higher levels of PCSK9 with a dose-response effect (p < 0.001); the association persisted after adjustment for the calculated Framingham risk score (p=0.003) and additional adjustment for clinical variables (p=0.027). CONCLUSIONS: In HIV-infected individuals naïve of statin treatment, marijuana consumption and low CD4 values are associated with higher PCSK9 levels independently of clinically relevant confounding factors.

Does Changing Antiretroviral Therapy in the First Trimester of Pregnancy for Safety Concerns Have an Impact on Viral Suppression?

OBJECTIVE: To determine whether changing antiretroviral therapy (ART) during pregnancy because of concern about fetal risks led to poorer virological outcomes. METHODS: All pregnancies in women with HIV-1 infection enrolled in the national multicenter prospective French Perinatal cohort at 14 week gestation or more were included between January 2005 and December 2015, if the mother was on ART at conception with a plasma viral load <50 copies/mL. The reasons for a change in the ART were analyzed according to treatment guidelines at the time of the pregnancy and defined as for safety concerns in the absence of reported maternal intolerance. Virological and pregnancy outcomes were studied by survival analysis and logistic regression adjusted for a propensity score established for each patient according to baseline characteristics. RESULTS: Of 7079 pregnancies in the overall cohort, 1797 had ART at conception with a viral load <50 copies/mL before 14 week gestation. Of these, 22 changed regimens in the first trimester for intolerance, and 411 of the remaining 1775 (23%) solely for safety concerns. The proportion of change was higher when the initial treatment was not recommended in the national guidelines (OR adjusted: 23.1 [14.0-38.2]), than when it was an alternative option (ORa: 2.2 [1.3-3.7]), as compared to recommended first-line regimens. Treatment changes for safety concerns did not lead to poorer virological control, compared with pregnancies without such changes (19.3% vs. 15.6%, HRa: 1.0 [0.7-1.4]). CONCLUSIONS: Changing ART early in pregnancy to regimens considered safer for pregnancy, and neonatal health did not have a destabilizing effect on viral suppression.

Angiotensin II activates the Smad pathway during epithelial mesenchymal transdifferentiation.

Epithelial to mesenchymal transdifferentiation is a novel mechanism that promotes renal fibrosis and here we investigated whether known causes of renal fibrosis (angiotensin II and transforming growth factor beta, TGFbeta) act through this pathway. We infused angiotensin II into rats for 1 day and found that it activated the Smad pathway which persisted for up to 2 weeks in chronically infused rats. Renal TGF-beta mRNA expression was increased at 3 days and its protein at 2 weeks suggesting Smad pathway activation occurred earlier than TGF-beta upregulation. In cultured human tubuloepithelial cells, angiotensin II caused a rapid activation of Smad signaling independent of TGF-beta however, Smad-dependent transcription after 1 day was TGF-beta mediated. Two weeks of angiotensin II infusion activated genes associated with epithelial mesenchymal transdifferentiation. Stimulation with angiotensin II for 3 days caused transdifferentiation of the cultured epithelial cells by TGF-beta-mediated processes; however, early changes were independent of endogenous TGF-beta. Smad7 overexpression, which blocks Smad2/3 activation, diminished angiotensin II-induced epithelial mesenchymal transdifferentiation. Our results show that angiotensin II activates the Smad signaling system by TGF-beta-independent processes, in vivo and in vitro, causing renal fibrosis.

Developmental delay and behavioral disorders in 59 HIV-exposed uninfected infants.

BACKGROUND: Antiretroviral therapy (ART) in HIV pregnant women has led to a dramatic decrease in the rate of HIV mother-to-child transmission but this benefit is counterbalanced with adverse effects related to in utero and neonatal exposure to ART. In 2013, some parents described neurodevelopmental disorders in their children. METHODS: A standardized letter was sent to the 133 women who delivered in Nantes hospital from 01/01/2003 to 31/12/2012 (167 births). RESULTS: Response rate was 33%. Over a 10-year period, 7 children had behavioral disorders and/or cognitive/developmental delay, 1 child had developmental delay + growth retardation and 2 experienced cancer. CONCLUSIONS: We found a significant association between neurodevelopmental disorders, preterm birth and exposure to 3 nucleoside reverse transcriptase inhibitors (NRTIs). Further studies are needed and long-term follow-up into adulthood should continue.

Is acute idiopathic pericarditis associated with recent upper respiratory tract infection or gastroenteritis? A case-control study.

OBJECTIVES: The aim of this study was to assess the association of a clinical diagnosis of acute idiopathic pericarditis (AIP), and a reported upper respiratory tract infection (URTI) or gastroenteritis (GE) in the preceding month. DESIGN: Patients who were hospitalised with a first diagnosis of AIP were retrospectively compared with a control group of patients admitted with deep vein thrombosis (DVT), matched by gender and age. SETTING: Primary and secondary care level; one hospital serving a population of about 170,000. PARTICIPANTS: A total of 51 patients with AIP were included, of whom 46 could be matched with 46 patients with control DVT. Only patients with a complete review of systems on the admission note were included in the study. MAIN OUTCOME MEASURE: Conditional logistic regression was used to assess the association of a clinical diagnosis of AIP and an infectious episode (URTI or GE) in the month preceding AIP diagnosis. RESULTS: Patients with AIP had more often experienced a recent episode of URTI or GE than patients with DVT (39.1% vs 10.9%, p=0.002). The multivariate conditional regression showed that AIP was independently associated with URTI or GE in the last month preceding diagnosis (OR=37.18, 95% CI=1.91 to 724.98, p=0.017). CONCLUSIONS: This is, to the best of our knowledge, the first study demonstrating an association between a recent episode of URTI or GE and a clinical diagnosis of AIP.

Tobacco-stained fingers: a clue for smoking-related disease or harmful alcohol use? A case-control study.

OBJECTIVE: Tobacco stain on fingers is frequent. However, there is scarce description of this clinical sign. We aimed to explore tobacco stain on fingers as a marker of tobacco-related disease independent of cumulative tobacco exposure, and to find behavioural and environmental characteristics associated with those stains. DESIGN: Case-control study. SETTING: A Swiss community hospital of 180 beds. PARTICIPANTS: 49 adults presenting tobacco-tars staining on fingers were matched to 49 control smokers by age, gender, height and pack-year (PY). OUTCOME MEASURES: Documented smoking-related carcinoma, ischaemic heart disease, peripheral arterial disease, stroke and chronic obstructive pulmonary disease (COPD), also determined by lung function, were compared between groups. Association between harmful alcohol use, mental disorders or unemployment and tar-staining was adjusted for smoking behaviour through conditional logistic regression. RESULTS: Overall cigarette-related disease was high in the case group (84%), and symptomatic peripheral arterial disease was more frequent compared to controls (OR 3.5, CI 95% 1.1 to 14.6). Smoking-related carcinoma, ischaemic heart disease, stroke and COPD were not statistically different for control smokers. Harmful alcohol use was strongly associated with stains and this association persists after adjustment for smoking unfiltered cigarettes, smoking more than one pack of cigarettes in a day and age at smoking onset (adjusted OR 4.6, CI 95% 1.2 to 17.2). Mental disorders and unemployment were not statistically significant. CONCLUSIONS: Patients with tobacco-tar-stained fingers frequently have cigarette-related disease, however statistically not more than control smokers matched for PY, except for symptomatic peripheral arterial disease. This study suggests a link between stained fingers and addictive behaviour or concomitant high alcohol consumption.

Inhibitory effect of interleukin-1beta on angiotensin II-induced connective tissue growth factor and type IV collagen production in cultured mesangial cells.

Connective tissue growth factor (CTGF) is overexpressed in kidney diseases associated with extracellular matrix accumulation. Angiotensin II (ANG II) participates in renal fibrosis by the upregulation of growth factors, including CTGF, and extracellular matrix proteins, such as type IV collagen. During renal injury, ANG II and the macrophage-produced cytokine interleukin-1beta (IL-1beta) may be present simultaneously in the glomerular environment. However, there are no studies about the interaction between ANG II and IL-1beta in renal fibrosis. For this reason, in cultured mesangial cells (MC), we investigated whether IL-1beta could regulate ANG II-mediated collagen accumulation and the mechanisms underlying this process. In MC, CTGF is a downstream mediator of type IV collagen production induced by ANG II. IL-1beta did not increase the production of CTGF and type IV collagen but significantly inhibited ANG II-induced CTGF and type IV collagen overexpression. Moreover, IL-1beta also inhibited type IV collagen upregulation caused by exogenous recombinant CTGF. Matrix metalloproteinase-9 (MMP-9) is the main enzyme involved in type IV collagen degradation. In MC, coincubation of IL-1beta and ANG II caused a synergistic increase in MMP-9 gene expression and activity, associated with type IV collagen inhibition. The described IL-1beta effects were dependent on activation of ERK/MAPK but independent p38-MAPK, JNK, phosphatidylinositol 3-kinase/Akt, and Rho-associated kinase pathways. In summary, these data indicate that IL-1beta inhibited ANG II-mediated type IV collagen production, via CTGF downregulation, and increased type IV collagen degradation, through MMP-9 upregulation. Our in vitro data show that the proinflammatory cytokine IL-1beta abrogates ANG II-induced CTGF production, describing antagonistic activities of proinflammatory cytokines on ANG II actions.