Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study.

OBJECTIVE: Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada. DESIGN: The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies. SETTING: Paediatric HIV clinics. POPULATION: Live-born infants born in Canada to WLWH between 2007 and 2017. METHODS: Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites. MAIN OUTCOME MEASURES: Congenital anomalies. RESULTS: Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%). CONCLUSION: Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies. TWEETABLE ABSTRACT: Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.

Muscle power in children, youth and young adults who acquired HIV perinatally.

OBJECTIVES: To compare muscle power between youth who acquired HIV perinatally and HIV unexposed uninfected (HUU) youth. METHODS: We assessed muscle power (relative to body mass, Pmax/mass), muscle force normalized to body weight (Fmax/BW), force efficiency, jump height (Hmax) and velocity (Vmax) during a single two-legged jump with hands on waist on a force platform (Leonardo) in HIV+ youth (n=35, 9-21 y). Thirty-three and 22 participants returned at 12- and 24-months, respectively. We compared age- and sex-specific z-scores in the HIV+ youth to those in HUU controls (n=716, 9-21 y) adjusting for height and muscle cross-sectional area (MCSA, by pQCT). RESULTS: At baseline, z-scores for Pmax/mass, Fmax/BW and Vmax were less than 1 standard deviation lower than HUU after adjusting for height and MCSA (p⟨0.05). Pmax/mass z-score was negatively associated with level of immunosuppression (p=0.013), but this relationship was not significant after adjusting for height and MCSA (p=0.07). Z-scores for all mechanography outcomes remained stable over time in HIV+ youth. CONCLUSION: Small deficits in muscle power were apparent in children and youth who acquired HIV perinatally, and the trajectory of muscle power did not change over two years. Further study is needed to identify effective strategies to improve dynamic muscle function in this population.

Bone geometry and strength are adapted to muscle force in children and adolescents perinatally infected with HIV.

OBJECTIVES: To determine if bone health is compromised in perinatally HIV-infected youth. METHODS: We assessed BMC at the proximal femur, lumbar spine and total body using DXA in perinatally HIV-infected youth (n=31; 9-18y). Using pQCT, we assessed muscle CSA, total and cortical bone area, cortical BMD and thickness and strength strain index at the tibial shaft. Thirty and 18 participants returned at 12- and 24-months, respectively. We calculated age- and sex-specific z-scores for the HIV-infected youth using data from a healthy cohort (n=883; 9-18y). RESULTS: At baseline, height and MCSA were reduced in HIV-infected youth (-0.79 to -0.23, p<0.05). BMC z-scores adjusted for height and lean mass were lower than controls at all sites except the lumbar spine (-0.57 to -0.27, p<0.05). Bone area and strength z-scores were not different from zero after adjusting for tibial length and MCSA. In contrast, cortical BMD z-scores were greater in HIV-infected youth (0.46, p=0.011). Z-scores for all bone outcomes showed positive trends over time in HIV-infected youth. CONCLUSION: Although HIV infection may be associated with bone mass deficits during growth, bone geometry and strength appear adapted to muscle force. Further, deficits in bone mass may dissipate over time in this population.

ADC mapping of chronic cerebral hypoperfusion induced by carotid artery stenosis.

BACKGROUND: Carotid artery stenosis is associated with the occurrence of acute and chronic ischemic lesions that increase with age in the elderly population. Diffusion Imaging and ADC mapping may be an appropriate method to investigate patients with chronic hypoperfusion consecutive to carotid stenosis. This non-invasive technique allows to investigate brain integrity and structure, in particular hypoperfusion induced by carotid stenosis diseases. The aim of this study was to evaluate the impact of a carotid stenosis on the parenchyma using ADC mapping. METHODS: Fifty-nine patients with symptomatic (33) and asymptomatic (26) carotid stenosis were recruited from our multidisciplinary consultation. Both groups demonstrated a similar degree of stenosis. All patients underwent MRI of the brain including diffusion-weighted MR imaging with ADC mapping. Regions of interest were defined in the anterior and posterior paraventricular regions both ipsilateral and contralateral to the stenosis (anterior circulation). The same analysis was performed for the thalamic and occipital regions (posterior circulation). RESULTS: ADC values of the affected vascular territory were significantly higher on the side of the stenosis in the periventricular anterior (P<0.001) and posterior (P<0.01) area. There was no difference between ipsilateral and contralateral ADC values in the thalamic and occipital regions. CONCLUSIONS: We have shown that carotid stenosis is associated with significantly higher ADC values in the anterior circulation, probably reflecting an impact of chronic hypoperfusion on the brain parenchyma in symptomatic and asymptomatic patients. This is consistent with previous data in the literature.

Serious toxicity associated with continuous nevirapine-based HAART in pregnancy.

OBJECTIVE: This study was designed to determine the safety of nevirapine (NVP)-based highly active antiretroviral therapy (HAART) in a cohort of HIV-positive pregnant women. DESIGN: This was a prospective cohort study of HIV-positive pregnant women. POPULATION AND SETTING: All HIV-positive women treated with HAART during pregnancy from January 1997 to February 2004 at the British Columbia (BC) Women's Hospital in Vancouver, BC, Canada. METHODS: Demographic and clinical data were collected to compare antiretroviral drug toxicities in women treated antenatally with NVP-based or non-NVP-based HAART. Multivariate analyses were then used to investigate determinants of toxicity. RESULTS: From 1997 to 2004, 103 HIV-positive pregnant women received HAART. Equivalent numbers of women were initially treated with NVP-based (54%) and non-NVP-based (46%) HAART. The groups did not differ by clinical or demographic parameters and duration of HAART exposure was similar between groups. Toxicities necessitating treatment discontinuation were observed in 6 of 56 NVP-exposed women (2 cases each of grade 2, 3, and 4 toxicity) compared with 1 of 47 in the non-NVP-exposed women. First time use of NVP approached significance as a predictor for toxicity, with a toxicity rate of 12.5% (6/48) observed among those taking NVP for the first time (adjusted OR 2.68, 95% CI 0.49-14.6). CONCLUSION: Continuous NVP use in pregnancy resulted in a relatively higher rate of toxicity, and all cases of NVP toxicity occurred in women exposed to NVP for the first time during pregnancy.

Growing up: perspectives of children, families and service providers regarding the needs of older children with perinatally-acquired HIV.

Children with perinatally-acquired HIV are living into adolescence and adulthood. As this is a relatively new phenomenon, there is a paucity of research highlighting the complex issues that arise for these children. This qualitative case-study examines the needs of a select group of older children (9-16 years old) with perinatally-acquired HIV in the province of British Columbia, Canada through focus groups and interviews conducted with ten HIV-infected children, 11 family members and 11 service providers. The needs of this population are diverse, reflecting its heterogeneity. However, participants consistently highlighted issues of stigma, sexual health and mental health as major areas of current and future concern. Continued support, education and future planning in these areas are necessary for older HIV-infected children as they transition out of childhood.

The perianeurysmal environment: influence on saccular aneurysm shape and rupture.

PURPOSE: The purpose of this study was to evaluate whether interactions between intracranial cerebral saccular aneurysms and the perianeurysmal environment (PAE), in the form of contact constraints, influence aneurysm shape and risk of rupture. METHODS: A total of 190 consecutive aneurysms during a 34-month period were retrospectively analyzed. Of these, 124 were ruptured (group 1) and 66 were unruptured (group 2). Pretreatment high-resolution CT angiography was available for each aneurysm and was the determinant inclusion criterion. Aneurysm size and location, type of hemorrhage, initial Glasgow Coma Scale rating, World Federation of Neurological Societies grade, Fisher grade, and presence of concomitant aneurysms were recorded. Contact constraints between aneurysms and anatomical structures of the PAE were identified for each aneurysm and further subdivided into balanced or unbalanced depending on whether contact constraints occurred symmetrically on the aneurysm wall. Regular or irregular shape was recorded and correlated to contact constraints. RESULTS: Compared with unruptured aneurysms, ruptured aneurysms were found to be larger and more irregular, to develop more contact constraints with the PAE, and to show higher rates of unbalanced contact constraints. Ruptured aneurysms had a tendency to be found in locations of a constraining PAE. Irregular shape was positively correlated with the presence of an unbalanced contact constraint, even in the absence of obvious contour deformations from an imprint of an adjacent structure. CONCLUSION: The existence of contact constraints between intracranial saccular aneurysms and the PAE were shown to influence shape and risk of aneurysm rupture. Modifications of wall shear stress by contact constraints are discussed. Analysis of contact constraints between aneurysm and the PAE could be considered additional parameters in the assessment of risk of aneurysm rupture.

White matter lesions in watershed territories studied with MRI and parenchymography: a comparative study.

Brain aging affects an increasing segment of the population and the role of chronic cerebrovascular disease is considered to be one of the main parameters involved. For this purpose we compared retrospectively MRI data with digitized subtraction angiography (DSA) data in a group of 50 patients focusing onto the watershed area of the carotid artery vascular territories. In order to evaluate the presence of white matter lesions (WML) in the hemispheric watershed areas, coronal fluid-attenuated inversion-recovery or axial T2 weighted MRI images of patients with symptomatic cerebrovascular insufficiency areas were compared with the capillary phase of DSA studies in anterior-posterior projection. Presence of cerebrovascular occlusive disease was evaluated on DSA using North American symptomatic carotid endarterectomy trial criteria and including evaluation of collateral vascular supply. Pathological MRI findings in the region of the watershed territories correlated overall in 66% of cases with a defect or delayed filling on DSA. In the case of asymmetrical MRI findings, there was a pathological finding of the capillary phase in the watershed area in 92% of DSA studies. Hypoperfusion in the capillary phase of the watershed area as seen on DSA correlated with the stenosis degree of the concerned carotid artery. Our findings suggest that asymmetrical findings of WML in the watershed areas as seen on MRI are caused by hemodynamic effect and a differentiation between small vessel disease and a consequence of distant stenosis may be possible under such conditions.

Cardiac and autonomic evaluation in a pediatric population with human immunodeficiency virus.

BACKGROUND: Cardiac involvement in children with human immunodeficiency virus (HIV) infection is a well-known entity and occurs clinically more often in patients with advanced acquired immunodeficiency syndrome (AIDS). Autonomic dysfunction is less known, especially in children. HYPOTHESIS: The aim of this study was to asses the prevalence of cardiovascular abnormalities in a pediatric population with HIV. We also aimed to evaluate whether autonomic involvement occurs in the same population and is dependent on echocardiographic abnormalities. METHODS: The occurrence of echocardiographic abnormalities was evaluated in 22 children with HIV infection, and five noninvasive tests were performed to evaluate the presence of autonomic dysfunction. RESULTS: We found cardiac lesions in four children (18%), consisting of pericardial effusion in three children, wall motion abnormalities in three children, and acute aortic endocarditis in one child. All cardiac abnormalities were found at Stage C by Center for Disease Control (CDC) revised classification. We also found left ventricular filling pattern abnormalities consisting of E-wave maximal velocity decrease and prolonged deceleration time compatible with diastolic dysfunction. One of the five autonomic tests (Valsalva maneuver) was significantly altered, even in patients without abnormal echocardiography, suggesting mild autonomic dysfunction. CONCLUSION: The study demonstrated a high prevalence of cardiac lesions in children with HIV infection and indicated the presence of autonomic dysfunction even when there are no echocardiographically detected abnormalities.

Detection of virus in vertically exposed HIV-antibody-negative children.

BACKGROUND: HIV-infected mothers can transmit their infection to their children in utero or at delivery (vertical transmission). There have been cases of children who were reported as acquiring infection vertically and later clearing the infection. We report the frequency of this phenomenon in a European cohort study. METHODS: In four centres of the European Collaborative Study of children born to HIV-infected mothers, 299 children became HIV-antibody-negative and 264 of these had been followed up with virus culture and PCR for viral DNA at least once. FINDINGS: Nine of the 264 children were positive by virus culture or PCR, and subsequently seroreverted. Two of the nine tested virus-positive after they became antibody-negative. Six cases were virus-positive early in life and became negative thereafter, which is consistent with clearance of infection. The pattern was less clear in the other three. The nine cases had had their last virus test at age 16-101 months. All nine children had been bottlefed only. Eight had been delivered vaginally. The children had no HIV-related symptoms and received no anti-HIV treatments. Based on only those children who had two or more positive virological tests, we estimate that 2.7% (6/219) cleared or "tolerated" the virus. INTERPRETATION: The detection of virus or viral DNA in "uninfected" children born to HIV-infected mothers was rare and was not associated with clinical disease or immunological abnormalities. The timing of samples will affect the documentation of clearance since, in uninfected children of HIV-positive mothers who cleared the virus, viraemia was intermittent. Current paediatric opinion is to inform parents of children who serorevert that the child is not HIV-infected.

Quantitation of HIV-1 in whole blood of infected children.

OBJECTIVE: To validate the technique of HIV-1 culture from whole blood for the quantitation of viral load in infected children. PATIENTS: Forty-three HIV-1-infected children were followed in two paediatric centres. METHODS: Quantitative HIV-1 cultures from unfractionated whole blood using an end-point dilution technique were compared with simultaneous quantitative cultures of peripheral blood mononuclear cells (PBMC) and plasma. RESULTS: Good sensitivity (93%) of the methods used was confirmed. A close correlation (r = 0.80) was observed between HIV-1 titres measured directly from whole blood and those expected from PBMC and plasma titres. The mean whole blood viral load was higher in patients with more severe signs of disease, but the difference did not reach statistical significance. The whole blood viral titres measured sequentially at monthly intervals remained within one dilution of each other in 16 of the 22 patients studied. CONCLUSION: In this study, the quantitation of HIV-1 in unfractionated blood allowed for a reliable and sensitive measurement of the whole blood viral load in infected children.

Normal immune function and inability to isolate virus in culture in an individual with long-term human immunodeficiency virus type 1 infection.

A detailed, longitudinal study was undertaken to investigate the immunological and virological features of an individual with hemophilia infected with human immunodeficiency virus type-1 (HIV-1) for 10 years without disease. Methods applied to serial samples of peripheral blood included Western blot analysis, neutralizing antibody assays, antibody-dependent cell-mediated cytotoxicity (ADCC) titration, HIV-1 specific cytotoxic T lymphocyte (CTL) assays, viral cultures, and PCR with sequence analysis of viral regulatory genes. Strong antibody responses against HIV-1 antigens as measured by Western blot and ADCC assays have persisted throughout infection. Repeated attempts to isolate HIV-1 using sensitive culture techniques and to demonstrate viremia with standard PCR methods have failed. Using the "booster" PCR technique, a period of viremia in peripheral blood mononuclear cells was demonstrated. Concurrent with detection of circulating virus, titers of neutralizing antibodies and circulating HIV-1-specific CTLs became measurable. Sequencing studies of a portion of the viral genome showed no significant abnormalities of the regulatory genes. In this individual, the combination of low viral load in the peripheral blood and a strong, responsive immune system is associated with long-term, disease-free coexistence with HIV-1 infection.

Early viremia and immune responses in vertical human immunodeficiency virus type 1 infection.

Thirty-three infants born to human immunodeficiency virus type 1 (HIV-1)-seropositive women were evaluated from birth using plasma and peripheral blood mononuclear cell (PBMC) cultures, polymerase chain reaction, and serum p24 antigen assays. Five children were identified as infected. Evidence of infection was found in cord blood and subsequent samples from 2 infected children, suggesting in utero infection. Virologic studies on cord blood and early neonatal specimens from the 3 other infected children were negative but became positive by 8 weeks of age, suggesting either intrapartum transmission or sequestration of virus with subsequent detection. An increase in blood (plasma and PBMC) virus titers consistent with primary viremia was observed in 4 infants between 3 and 16 weeks of age. Blood virus titers subsequently declined in the absence of antiretroviral therapy and in the absence of activated HIV-1-specific cytotoxic T lymphocyte responses or broadly neutralizing antibodies. Confirmation of these results in larger studies may be helpful in the design of clinical trials to interrupt vertical transmission or to modify the course of infection.

Diagnosis of vertical human immunodeficiency virus type 1 infection by whole blood culture.

The qualitative and quantitative performance of a human immunodeficiency virus type 1 (HIV-1) whole blood culture method was assessed for use in the diagnosis of vertical HIV-1 infection. This method requires < 1 mL of whole blood and allows for the quantification of blood virus load. HIV-1 was isolated from 36 (95%) of 38 whole blood specimens from 27 HIV-1-infected children compared with 0 of 16 whole blood specimens from 16 uninfected children. HIV-1 titers were significantly higher in severely symptomatic children (2450 TCID/mL) than in less symptomatic children (179 TCID/mL). This simple quantitative culture assay may be useful for the early diagnosis of vertical HIV-1 infection, the assessment of blood virus load, and the evaluation of antiretroviral therapies.

Quantitation of human immunodeficiency virus in vertically infected infants and children.

We used a quantitative human immunodeficiency virus, type 1 (HIV-1) culture method to determine whether there is a relationship between the amount of replicating virus in the blood of vertically infected children and the relatively short latency period before development of symptomatic disease in these children. HIV-1 titers were determined by end point dilution in the peripheral blood mononuclear cells and the plasma of 30 infected (CDC class P1 and P2), 36 indeterminate (CDC class PO), and 19 uninfected (CDC class P3) infants and children born to HIV-1 seropositive mothers. HIV-1 was recovered from 35 (90%) of 39 PBMC cultures and 23 (60%) of 38 plasma cultures of infected patients not receiving antiretroviral therapy. The mean HIV-1 titers tended to be higher in patients with more advanced disease (P2, D, E, or F: 1760 TCID/10(6) PBMC, 460 TCID/ml plasma) than in asymptomatic or mildly symptomatic patients (P1; P2, A or C: 90 TCID/10(6) PBMC; 60 TCID/ml plasma). A poor correlation between HIV-1 titers and serum p24 antigen levels was found. No correlation was observed between viral titers and relative or absolute numbers of CD4 lymphocytes. Plasma virus titers were lower in 9 patients receiving zidovudine (ZDV) therapy (mean 2 TCID/ml) than in untreated patients of similar clinical status. The viral titers measured in the blood of vertically infected infants and children were on the same order of magnitude as the viral titers measured in HIV-infected adults. We conclude that the relatively rapid progression to symptomatic disease of the majority of vertically infected patients is not due to a higher load of replicating virus in blood.