Multicentre analysis of second‐line antiretroviral treatment in HIV‐infected children: adolescents at high risk of failure

Introduction : The number of HIV‐infected children and adolescents requiring second‐line antiretroviral treatment (ART) is increasing in low‐ and middle‐income countries (LMIC). However, the effectiveness of paediatric second‐line ART and potential risk factors for virologic failure are poorly characterized. We performed an aggregate analysis of second‐line ART outcomes for children and assessed the need for paediatric third‐line ART. Methods : We performed a multicentre analysis by systematically reviewing the literature to identify cohorts of children and adolescents receiving second‐line ART in LMIC, contacting the corresponding study groups and including patient‐level data on virologic and clinical outcomes. Kaplan–Meier survival estimates and Cox proportional hazard models were used to describe cumulative rates and predictors of virologic failure. Virologic failure was defined as two consecutive viral load measurements >1000 copies/ml after at least six months of second‐line treatment. Results : We included 12 cohorts representing 928 children on second‐line protease inhibitor (PI)‐based ART in 14 countries in Asia and sub‐Saharan Africa. After 24 months, 16.4% (95% confidence interval (CI): 13.9–19.4) of children experienced virologic failure. Adolescents (10–18 years) had failure rates of 14.5 (95% CI 11.9–17.6) per 100 person‐years compared to 4.5 (95% CI 3.4–5.8) for younger children (3–9 years). Risk factors for virologic failure were adolescence (adjusted hazard ratio [aHR] 3.93, p < 0.001) and short duration of first‐line ART before treatment switch (aHR 0.64 and 0.53, p = 0.008, for 24–48 months and >48 months, respectively, compared to <24 months). Conclusions : In LMIC, paediatric PI‐based second‐line ART was associated with relatively low virologic failure rates. However, adolescents showed exceptionally poor virologic outcomes in LMIC, and optimizing their HIV care requires urgent attention. In addition, 16% of children and adolescents failed PI‐based treatment and will require integrase inhibitors to construct salvage regimens. These drugs are currently not available in LMIC.     

Variability in the management of adhesive small bowel obstruction in children

BackgroundThis study assessed inter-hospital variability in operative-vs-nonoperative management of pediatric adhesive small bowel obstruction (ASBO).MethodsA multi-institutional retrospective study was performed examining patients 1–21 years-of-age presenting with ASBO from 2010 to 2019 utilizing the Pediatric Health Information System. Multivariable mixed-effects logistic regression was performed assessing inter-hospital variability in operative-vs-nonoperative management of ASBO.ResultsAmong 6410 pediatric ASBO admissions identified at 46 hospitals, 3,239 (50.5%) underwent surgery during that admission. The hospital-specific rate of surgery ranged from 35.3% (95%CI: 28.5–42.6%) to 74.7% (66.3–81.6%) in the unadjusted model (p < 0.001), and from 35.1% (26.3–45.1%) to 73.9% (66.7–79.9%) in the adjusted model (p < 0.001). Factors associated with operative management for ASBO included admission to a surgical service (OR 2.8 [95%CI: 2.4–3.2], p < 0.001), congenital intestinal and/or rotational anomaly (OR 2.5 [2.1–3.1], p < 0.001), diagnostic workup including advanced abdominal imaging (OR 1.7 [1.5–1.9], p < 0.001), non-emergent admission status (OR 1.5 [1.3–1.8], p < 0.001), and increasing number of complex chronic comorbidities (OR 1.3 [1.2–1.4], p < 0.001). Factors associated with nonoperative management for ASBO included increased hospital-specific annual ASBO volume (OR 0.98 [95%CI: 0.97–0.99], p = 0.002), older age (OR 0.97 [0.96–0.98], p < 0.001), public insurance (OR 0.87 [0.78–0.96], p = 0.008), and presence of coinciding non-intestinal congenital anomalies, neurologic/neuromuscular disease, and/or medical technology dependence (OR 0.57 [95%CI: 0.47–0.68], p < 0.001).ConclusionsRates of surgical intervention for ASBO vary significantly across tertiary children's hospitals in the United States. The variability was independent of patient and hospital characteristics and is likely due to practice variation.Level of evidenceIII     

A novel Online‐to‐Offline (O2O) model for pre‐exposure prophylaxis and HIV testing scale up

Introduction : PrEP awareness and uptake among men who have sex with men (MSM) and transgender women (TG) in Thailand remains low. Finding ways to increase HIV testing and PrEP uptake among high‐risk groups is a critical priority. This study evaluates the effect of a novel Adam's Love Online‐to‐Offline (O2O) model on PrEP and HIV testing uptake among Thai MSM and TG and identifies factors associated with PrEP uptake. Methods : The O2O model was piloted by Adam's Love ( www.adamslove.org ) HIV educational and counselling website. MSM and TG reached online by PrEP promotions and interested in free PrEP and/or HIV testing services contacted Adam's Love online staff, received real‐time PrEP eCounseling, and completed online bookings for receiving services at one of the four sites in Bangkok based on their preference. Auto‐generated site‐ and service‐specific e‐tickets and Quick Response (QR) codes were sent to their mobile devices enabling monitoring and check‐in by offline site staff. Service uptake and participant's socio‐demographic and risk behaviour characteristics were analyzed. Factors associated with PrEP uptake were assessed using multiple logistic regression. Results : Between January 10th and April 11th, 2016, Adam's Love reached 272,568 people online via the PrEP O2O promotions. 425 MSM and TG received eCounseling and e‐tickets. There were 325 (76.5%) MSM and TG who checked‐in at clinics and received HIV testing. Nine (2.8%) were diagnosed with HIV infection. Median (IQR) time between receiving the e‐ticket and checking‐in was 3 (0–7) days. Of 316 HIV‐negative MSM and TG, 168 (53.2%) started PrEP. In a multivariate model, higher education (OR 2.30, 95%CI 1.14–4.66; p = 0.02), seeking sex partners online (OR 2.05, 95%CI 1.19–3.54; p = 0.009), being aware of sexual partners’ HIV status (OR 2.37, 95%CI 1.29–4.35; p = 0.008), ever previously using post‐exposure prophylaxis (PEP) (OR 2.46, 95%CI 1.19–5.09; p = 0.01), and enrolment at Adam's Love clinic compared to the other three sites (OR 3.79, 95%CI 2.06–6.95; p < 0.001) were independently associated with PrEP uptake. Conclusions : Adam's Love O2O model is highly effective in linking online at‐risk MSM and TG to PrEP and HIV testing services, and has high potential to be replicated and scaled up in other settings with high Internet penetration among key populations.     

HIV viral suppression and longevity among a cohort of children initiating antiretroviral therapy in Eastern Cape,South Africa

Introduction

There are limited data on viral suppression (VS) in children with HIV receiving antiretroviral therapy (ART) in routine care in low‐resource settings. We examined VS in a cohort of children initiating ART in routine HIV care in Eastern Cape Province, South Africa.

Methods

The Pediatric Enhanced Surveillance Study enrolled HIV‐infected ART eligibility children zero to twelve years at five health facilities from 2012 to 2014. All children received routine HIV care and treatment services and attended quarterly study visits for up to 24 months. Time to VS among those starting treatment was measured from ART start date to first viral load (VL) result <1000 and VL <50 copies/mL using competing risk estimators (death as competing risk). Multivariable sub‐distributional hazards models examined characteristics associated with VS and VL rebound following suppression among those with a VL >30 days after the VS date.

Results

Of 397 children enrolled, 349 (87.9%) started ART: 118 (33.8%) children age <12 months, 122 (35.0%) one to five years and 109 (31.2%) six to twelve years. At study enrolment, median weight‐for‐age z‐score (WAZ) was −1.7 (interquartile range (IQR):−3.1 to −0.4) and median log VL was 5.6 (IQR: 5.0 to 6.2). Cumulative incidence of VS <1000 copies/mL at six, twelve and twenty‐four months was 57.6% (95% CI 52.1 to 62.7), 78.7% (95% CI 73.7 to 82.9) and 84.0% (95% CI 78.9 to 87.9); for VS <50 copies/mL: 40.3% (95% CI 35.0 to 45.5), 63.9% (95% CI 58.2 to 69.0) and 72.9% (95% CI 66.9 to 78.0). At 12 months only 46.6% (95% CI 36.6 to 56.0) of children <12 months had achieved VS <50 copies/mL compared to 76.9% (95% CI 67.9 to 83.7) of children six to twelve years (p < 0.001). In multivariable models, children with VL >1 million copies/mL at ART initiation were half as likely to achieve VS <50 copies/mL (adjusted sub‐distributional hazards 0.50; 95% CI 0.36 to 0.71). Among children achieving VS <50 copies/mL, 37 (19.7%) had VL 50 to 1000 copies/mL and 31 (16.5%) had a VL >1000 copies/mL. Children <12 months had twofold increased risk of VL rebound to VL >1000 copies/mL (adjusted relative risk 2.03, 95% CI: 1.10 to 3.74) compared with six to twelve year olds.

Conclusions

We found suboptimal VS among South African children initiating treatment and high proportions experiencing VL rebound, particularly among younger children. Greater efforts are needed to ensure that all children achieve optimal outcomes.

     

Factors associated with retention in Option B+ in Malawi: a case control study

Introduction : There are limited data on factors associated with retention in Option B+. We sought to explore the characteristics of women retained in Option B+ in Malawi, with a focus on the role of HIV disclosure, awareness of partner HIV status, and knowledge around the importance of Option B+ for maternal–child health. Methods : We performed a case‐control study of HIV‐infected women in Malawi initiated on antiretroviral therapy (ART) under Option B+. Cases were enrolled if they met criteria for default from Option B+ (out of ART for >60 days), and controls were enrolled in approximately 3:1 ratio if they were retained in care for at least 12 months. We surveyed socio‐demographic characteristics, HIV disclosure and awareness of partner HIV status, self‐report about receiving pre‐ART education, and knowledge of Option B+. Univariate logistic regression was performed to determine factors associated with retention. Multivariate logistic regression model was used to evaluate the relationship between HIV disclosure, Option B+ knowledge, and retention after adjusting for age, schooling, and travel time to clinic. Results : We enrolled 50 cases and 153 controls. Median age was 30 years (interquartile range (IQR) 25–34), and the majority (82%) initiated ART during pregnancy at a median gestational age of 24 weeks (IQR 16–28). Ninety‐one per cent of the cases (39/43) who started ART during pregnancy defaulted by three months postpartum. HIV disclosure to the primary sex partner was more common among women retained in care (100% versus 78%, p < 0.001). Odds of retention were significantly higher among women with: age >25 years (odds ratio (OR) 2.44), completion of primary school (OR 3.06), awareness of partner HIV status (OR 5.20), pre‐ART education (OR 6.17), higher number of correct answers to Option B+ knowledge questions (OR 1.82), and support while taking ART (OR 3.65). Pre‐ART education and knowledge were significantly correlated (r = 0.43, p < 0.001). In multivariate analysis, awareness of partner HIV status (OR 4.07, 95% confidence interval (CI) 1.51–10.94, p = 0.02) and Option B+ knowledge (OR 1.60, 95% CI 1.15–2.23, p = 0.004) remained associated with retention. Conclusions : Interventions that address partner disclosure and strengthen pre‐ART education around the benefits of ART for maternal and child health should be evaluated to improve retention in Malawi's Option B+ programme.     

The vulnerability of men to virologic failure during antiretroviral therapy in a public routine clinic in Burkina Faso

Introduction

Gender differences in antiretroviral therapy (ART) outcomes are critical in sub-Saharan Africa. We assessed the association between gender and virologic failure among adult patients treated in a public routine clinic (one of the largest in West Africa) in Burkina Faso.

Methods

We performed a case-control study between July and October 2012 among patients who had received ART at the Bobo Dioulasso Day Care Unit. Patients were eligible if they were 15 years or older, positive for HIV-1 or HIV-1+2, and on first-line ART for at least six months. Cases were all patients with two consecutive HIV loads >1000 copies/mL (Biocentric Generic or Abbott Real Time assays), or one HIV load >1000 copies/mL associated with immunologic or clinical failure criteria. Controls were all patients who only had HIV loads <300 copies/mL. The association between gender and virologic failure was assessed using a multivariate logistic regression, adjusted on age, level of education, baseline CD4+ T cell count, first and current antiretroviral regimens and time on ART.

Results

Of 2303 patients (74.2% women; median age: 40 years; median time on ART: 34 months), 172 had virologic failure and 2131 had virologic success. Among the former, 130 (75.6%) had confirmed virologic failure, 38 (22.1%) had viro-immunologic failure, and four (2.3%) had viro-clinical failure. The proportion of men was significantly higher among the cases than among the controls (37.2% vs. 24.9%; p<0.001). Compared to controls, cases were also younger, more immunodeficient at ART initiation, less likely to receive a protease inhibitor-based antiretroviral regimen and had spent a longer period of time on ART. After adjustment, male gender remained strongly associated with virologic failure (odds ratio 2.52, 95% CI: 1.77–3.60; p<0.001).

Conclusions

Men on ART appeared more vulnerable to virologic failure than women. Additional studies are needed to confirm the poorer prognosis of men in this setting and to determine the causes for their vulnerability in order to optimize HIV care. From now on, efforts should be made to support the adherence of men to ART in the African setting.     

Adherence to antiretroviral therapy for HIV in sub‐Saharan Africa and Asia: a comparative analysis of two regional cohorts

Introduction : Our understanding of how to achieve optimal long‐term adherence to antiretroviral therapy (ART) in settings where the burden of HIV disease is highest remains limited. We compared levels and determinants of adherence over time between HIV‐positive persons receiving ART who were enrolled in a bi‐regional cohort in sub‐Saharan Africa and Asia. Methods : This multicentre prospective study of adults starting first‐line ART assessed patient‐reported adherence at follow‐up clinic visits using a 30‐day visual analogue scale. Determinants of suboptimal adherence (<95%) were assessed for six‐month intervals, using generalized estimating equations multivariable logistic regression with multiple imputations. Region of residence (Africa vs. Asia) was assessed as a potential effect modifier. Results : Of 13,001 adherence assessments in 3934 participants during the first 24 months of ART, 6.4% (837) were suboptimal, with 7.3% (619/8484) in the African cohort versus 4.8% (218/4517) in the Asian cohort (p < 0.001). In the African cohort, determinants of suboptimal adherence were male sex (odds ratio (OR) 1.27, 95% confidence interval (CI) 1.06–1.53; p = 0.009), younger age (OR 0.8 per 10 year increase; 0.8–0.9; p = 0.003), use of concomitant medication (OR 1.8, 1.0–3.2; p = 0.044) and attending a public facility (OR 1.3, 95% CI 1.1–1.7; p = 0.004). In the Asian cohort, adherence was higher in men who have sex with men (OR for suboptimal adherence 0.6, 95% CI 0.4–0.9; p = 0.029) and lower in injecting drug users (OR for suboptimal adherence 1.6, 95% CI 0.9–2.6; p = 0.075), compared to heterosexuals. Risk of suboptimal adherence decreased with longer ART duration in both regions. Participants in low‐ and lower‐middle‐income countries had a higher risk of suboptimal adherence (OR 1.6, 1.3–2.0; p < 0.001), compared to those in upper‐middle or high‐income countries. Suboptimal adherence was strongly associated with virological failure, in Africa (OR 5.8, 95% CI 4.3–7.7; p < 0.001) and Asia (OR 9.0, 95% CI 5.0–16.2; p < 0.001). Patient‐reported adherence barriers among African participants included scheduling demands, drug stockouts, forgetfulness, sickness or adverse events, stigma or depression, regimen complexity and pill burden. Conclusions : Psychosocial factors and health system resources may explain regional differences. Adherence‐enhancing interventions should address patient‐reported barriers tailored to local settings, prioritizing the first years of ART.     

Icariin improves the sexual function of male mice through the PI3K/AKT/eNOS/NO signalling pathway

We aimed to investigate the effect and mechanism of icariin on male sexual function. Forty‐eight Crl:CD1(ICR) male mice were randomly divided into control, low‐, medium‐ and high‐dose icariin group (intragastric administration of 50, 100 and 200 mg/kg/d for 21 days). Mating experiment was then performed at a ratio of 1: 3 (male: female). The mating behaviours of male mice were recorded. The genital indexes and serum testosterone, nitric oxide (NO), hypothalamic dopamine (DA) and 5‐ hydroxy tryptophan (5‐HT) concentrations were measured. The expression of endothelial nitric oxide (eNOS), phosphatidylinositol tallow alcohol 3‐kinase (PI3K) and phosphorylated protein kinase (p‐AKT) in penile tissue was detected by Western blot. All icariin groups exhibited shorter capture latency and ejaculation latency, increased number of capture and ejaculation, higher capture and ejaculation rate, and higher testicular and prostate indexes compared with controls (p < .001). These groups had higher serum testosterone and NO concentrations (p < .001), hypothalamic DA and 5‐HT levels, and eNOS, PI3K and phosphorylated AKT expressions in penile tissue (p < .05). The effect of icariin was dose‐dependently increased. Our study suggests that icariin improves the sexual function of male mice, which might be associated with the hypothalamic–pituitary–gonadal axis and the PI3K/AKT/eNOS/NO signalling pathway.     

Safety and immunogenicity of adjuvanted recombinant subunit herpes zoster vaccine in lung transplant recipients

Lung transplant recipients are at high risk for herpes zoster and preventive measures are a significant unmet need. We investigated the safety and immunogenicity of two doses of a recombinant zoster vaccine (RZV) in lung transplant recipients (≥50 years). We enrolled 50 patients of which 49 received at least one vaccine dose. Anti-glycoprotein E (gE) antibody levels (n = 43) increased significantly compared to baseline (median optical density [OD] 1.96; interquartile range [IQR]: 1.17–2.89) after the first (median OD 3.41, IQR 2.54–3.81, p < .0001) and second vaccine dose (median OD 3.63, IQR 3.39–3.86, p < .0001). gE-specific polyfunctional CD4+ T cell frequencies (n = 38) also increased from baseline (median 85 per 10⁶ CD4+ T cells; IQR: 46–180) to the first (median 128 per 10⁶ CD4+ T cells; IQR: 82–353; p = .023) and after the second dose (median 361 per 10⁶ CD4+ T cells; IQR: 146–848; p < .0001). Tenderness (83.0%; 95%CI: 69.2–92.4%) and redness (31.9%; 95%CI: 19.1–47.1%) at injection site were common. One rejection episode within 3 weeks of vaccination was observed. This is the first study demonstrating that RZV was safe and elicited significant humoral and cell-mediated immunity in lung transplant recipients. RZV is a new option for the prevention of shingles in this population.     

Alcohol use,suicidality and virologic non-suppression among young adults with perinatally acquired HIV in Thailand: a cross-sectional study

Introduction

Young adults with perinatally acquired HIV (YA-PHIV) are facing transitions to adult life. This study assessed health risk behaviours (including substance use), mental health, quality of life (QOL) and HIV treatment outcomes of Thai YA-PHIV.

Methods

A cross-sectional study was conducted in Thai YA-PHIV aged 18–25 years who were enrolled in a prospective cohort study at five tertiary paediatric HIV care centres in Thailand. Study data were obtained through face-to-face interviews from November 2020 to July 2021. Assessments were performed for alcohol use (Alcohol Use Disorders Identification Test; AUDIT), smoking (Fagerstrom Test for Nicotine Dependence), drug/substance use (Drug Abuse Screening Test; DAST-10), depression (Patient Health Questionnaire for Adolescents; PHQ-A), anxiety (Generalized Anxiety Disorder; GAD-7) and QOL (World Health Organization QOL Brief-Thai). HIV treatment outcomes were extracted from the National AIDS Program database.

Results

Of 355 YA-PHIV, 163 (46%) were males: their median age was 21.7 (interquartile range, IQR 20.2–23.5) years. There were 203 YA-PHIV (58%) who reported ever having sex; 141 (40%) were sexually active in the past 6 months, of whom 86 (61%) reported 100% condom use. Overall, 49 (14%) met the criteria for harmful alcohol use; 28 (7.9%) were alcohol dependent. Sixty (17%) were current smokers and 37 (11%) used drugs/substances. The frequency of moderate up to severe symptoms for depression was 18% and for anxiety was 9.7%. Their overall QOL was good in 180 (51%), moderate in 168 (47%) and poor in five (1.4%). There were 49 YA-PHIV (14%) with CD4 <200 cells/mm³ and 85 (24%) with virologic non-suppression (HIV-RNA >200 copies/ml). On multivariate analyses, the highest education at the primary to high school or vocational school levels (adjusted odds ratio [aOR] 2.02, 95% CI 1.40–3.95, p 0.04), harmful alcohol use (aOR 2.48, 95% CI 1.24–4.99, p 0.01), alcohol dependence (aOR 3.54, 95% CI 1.51–8.31, p <0.01) and lifetime suicidal attempt (aOR 2.66, 95% CI 1.11–6.35, p 0.03) were associated with non-suppression.

Conclusions

Regular screening for alcohol use and mental health, including suicidality, would be useful to identify YA-PHIV who need more intensive psychosocial support or referral services to ensure they can achieve and maintain a high QOL into adult life.     

Dolutegravir–lamivudine as initial therapy in HIV‐1 infected,ARV‐naive patients, 48‐week results of the PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) study

Introduction : A proof‐of‐concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two‐drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)‐naive patients. Methods : PADDLE is a pilot study including 20 treatment‐naive adults. To be selected, participants had no IAS‐USA‐defined resistance, HIV‐1 RNA ≤100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV‐1 RNA <50 copies/mL in an intention to treat (ITT)‐exposed analysis at 48 weeks (the FDA snapshot algorithm). Results : Median HIV‐1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686–36,794). Albeit as per protocol, all patients had pVL ≤100,000 copies/mL at screening as required by inclusion criteria, four patients had ≥100,000 copies/mL at baseline. Median baseline CD4+ T‐cell count was 507 per cubic millimetre (IQR: 296–517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm³ (IQR: 180–462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low‐level protocol‐defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end‐of‐study visit without having changed the two‐drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in ARV‐naive patients. Conclusions : This novel dual regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV‐therapy‐naive patients. ClinicalTrials.gov Identifier : NCT02211482.     

HIV viral load as an independent risk factor for tuberculosis in South Africa: collaborative analysis of cohort studies

Introduction : Chronic immune activation due to ongoing HIV replication may lead to impaired immune responses against opportunistic infections such as tuberculosis (TB). We studied the role of HIV replication as a risk factor for incident TB after starting antiretroviral therapy (ART). Methods : We included all HIV‐positive adult patients (≥16 years) in care between 2000 and 2014 at three ART programmes in South Africa. Patients with previous TB were excluded. Missing CD4 cell counts and HIV‐RNA viral loads at ART start (baseline) and during follow‐up were imputed. We used parametric survival models to assess TB incidence (pulmonary and extrapulmonary) by CD4 cell and HIV‐RNA levels, and estimated the rate ratios for TB by including age, sex, baseline viral loads, CD4 cell counts, and WHO clinical stage in the model. We also used Poisson general additive regression models with time‐updated CD4 and HIV‐RNA values, adjusting for age and sex. Results : We included 44,260 patients with a median follow‐up time of 2.7 years (interquartile range [IQR] 1.0–5.0); 3,819 incident TB cases were recorded (8.6%). At baseline, the median age was 34 years (IQR 28–41); 30,675 patients (69.3%) were female. The median CD4 cell count was 156 cells/µL (IQR 79–229) and the median HIV‐RNA viral load 58,000 copies/mL (IQR 6,000–240,000). Overall TB incidence was 26.2/1,000 person‐years (95% confidence interval [CI] 25.3–27.0). Compared to the lowest viral load category (0–999 copies/mL), the adjusted rate ratio for TB was 1.41 (95% CI 1.15–1.75, p < 0.001) in the highest group (>10,000 copies/mL). Time‐updated analyses for CD4/HIV‐RNA confirmed the association of viral load with the risk for TB. Conclusions : Our results indicate that ongoing HIV replication is an important risk factor for TB, regardless of CD4 cell counts, and underline the importance of early ART start and retention on ART.     

Absolute quantification of donor‐derived cell‐free DNA as a marker of rejection and graft injury in kidney transplantation: Results from a prospective observational study

Donor‐derived cell‐free DNA (dd‐cfDNA) is a noninvasive biomarker for comprehensive monitoring of allograft injury and rejection in kidney transplantation (KTx). dd‐cfDNA quantification of copies/mL plasma (dd‐cfDNA[cp/mL]) was compared to dd‐cfDNA fraction (dd‐cfDNA[%]) at prespecified visits in 189 patients over 1 year post KTx. In patients (N = 15, n = 22 samples) with biopsy‐proven rejection (BPR), median dd‐cfDNA(cp/mL) was 3.3‐fold and median dd‐cfDNA(%) 2.0‐fold higher (82 cp/mL; 0.57%, respectively) than medians in Stable Phase patients (N = 83, n = 408) without rejection (25 cp/mL; 0.29%). Results for acute tubular necrosis (ATN) were not significantly different from those with biopsy‐proven rejection (BPR). dd‐cfDNA identified unnecessary biopsies triggered by a rise in plasma creatinine. Receiver operating characteristic (ROC) analysis showed superior performance (P = .02) of measuring dd‐cfDNA(cp/mL) (AUC = 0.83) compared to dd‐cfDNA(%) (area under the curve [AUC] = 0.73). Diagnostic odds ratios were 7.31 for dd‐cfDNA(cp/mL), and 6.02 for dd‐cfDNA(%) at thresholds of 52 cp/mL and 0.43%, respectively. Plasma creatinine showed a low correlation (r = 0.37) with dd‐cfDNA(cp/mL). In a patient subset (N = 24) there was a significantly higher rate of patients with elevated dd‐cfDNA(cp/mL) with lower tacrolimus levels (<8 μg/L) compared to the group with higher tacrolimus concentrations (P = .0036) suggesting that dd‐cfDNA may detect inadequate immunosuppression resulting in subclinical graft damage. Absolute dd‐cfDNA(cp/mL) allowed for better discrimination than dd‐cfDNA(%) of KTx patients with BPR and is useful to avoid unnecessary biopsies.     

Neutralizing antibodies against Rift Valley fever virus in wild antelope in far northern KwaZulu‐Natal,South Africa,indicate recent virus circulation

Rift Valley fever (RVF) is a zoonotic viral disease of domestic ruminants in Africa and the Arabian Peninsula caused by a mosquito‐borne Phlebovirus. Outbreaks in livestock and humans occur after heavy rains favour breeding of vectors, and the virus is thought to survive dry seasons in the eggs of floodwater‐breeding aedine mosquitoes. We recently found high seroconversion rates to RVF virus (RVFV) in cattle and goats, in the absence of outbreaks, in far northern KwaZulu‐Natal (KZN), South Africa. Here, we report the prevalence of, and factors associated with, neutralizing antibodies to RVFV in 326 sera collected opportunistically from nyala (Tragelaphus angasii) and impala (Aepyceros melampus) culled during 2016–2018 in two nature reserves in the same area. The overall seroprevalence of RVFV, determined using the serum neutralization test, was 35.0% (114/326; 95%CI: 29.8%–40.4%) and tended to be higher in Ndumo Game Reserve (11/20; 55.0%; 95%CI: 31.5%–76.9%) than in Tembe Elephant Park (103/306; 33.6%; 95%CI: 28.4%–39.3%) (p = .087). The presence of antibodies in juveniles (6/21; 28.6%; 95%CI: 11.3%–52.2%) and sub‐adults (13/65; 20.0%; 95%CI: 11.1%–37.8%) confirmed that infections had occurred at least until 2016, well after the 2008–2011 RVF outbreaks in South Africa. Odds of seropositivity was higher in adults than in sub‐adults (OR = 3.98; 95%CI: 1.83–8.67; p = .001), in males than in females (OR = 2.66; 95%CI: 1.51–4.68; p = .001) and in animals collected ≤2 km from a swamp or floodplain compared with those collected further away (OR = 3.30; 95%CI: 1.70–6.38; p < .001). Under similar ecological conditions, domestic and wild ruminants may play a similar role in maintenance of RVFV circulation and either or both may serve as the mammalian host in a vector–host reservoir system. The study confirms the recent circulation of RVFV in the tropical coastal plain of northern KZN, providing the basis for investigation of factors affecting virus circulation and the role of wildlife in RVF epidemiology.     

The association between personal habits and bladder cancer in Turkey

Aims  In this study, we analyzed the effect of Turkish coffee and black tea consumption, alcohol intake and smoking on bladder cancer. Methods  A total of 164 patients with bladder tumors and 324 individuals without primary tumors were included in the study. The habits of coffee and tea consumption, alcohol intake and smoking were queried. Results  No association was found between bladder cancer and drinking coffee (p = 0.89) and tea (p = 0.37), but alcohol intake was found to be associated, with an odds ratio (OR) of 1.85 (95% CI 1.15–2.96; p = 0.009). While there was a relationship between bladder cancer and smoking and quitting smoking (OR: 4.84 [95% CI 2.93–8.00; p < 0.001] and OR: 4.10 [95% CI 2.41–6.97; p < 0.001] respectively), the associations between bladder cancer and smoking and quitting smoking were similar (OR: 1.18, 95% CI 0.74–1.86; p = 0.477). Smoking <10 cigarettes a day created an OR of 2.14 (95% CI 1.11–4.12; p < 0.001); 10–20 cigarettes an OR of 4.50 (95% CI 2.74–7.37; p < 0.001); >20 cigarettes an OR of 14.85 (95% CI 6.83–32.27; p < 0.001); smoking by inhaling the smoke an OR of 4.72 (95% CI 2.94–7.59; p < 0.001), and smoking by not inhaling the smoke an OR of 3.34 (95% CI 1.75–6.38; p < 0.001). The associations between bladder cancer and inhaling smoke and not inhaling smoke were similar (OR: 1.41, 95% CI 0.85–2.48; p = 0.228). Conclusion  We found that smoking and alcohol consumption are closely connected with bladder cancer. Our data showed that not inhaling the smoke was as much associated with bladder cancer as inhaling the smoke. The association between smoking and bladder cancer lasts after quitting smoking.     

HIV testing and the care continuum among transgender women: population estimates from Rio de Janeiro,Brazil

Introduction : Evidence suggests that, of all affected populations, transgender women (transwomen) may have the heaviest HIV burden worldwide. Little is known about HIV linkage and care outcomes for transwomen. We aimed to estimate population‐level indicators of the HIV cascade of care continuum, and to evaluate factors associated with viral suppression among transwomen in Rio de Janeiro, Brazil. Methods : We conducted a respondent‐driven sampling (RDS) study of transwomen from August 2015 to January 2016 in Rio de Janeiro, Brazil and collected data on linkage and access to care, antiretroviral treatment and performed HIV viral load testing. We derived population‐based estimates of cascade indicators using sampling weights and conducted RDS‐weighted logistic regression analyses to evaluate correlates of viral suppression (viral load ≤50 copies/mL). Results : Of the 345 transwomen included in the study, 89.2% (95% CI 55–100%) had been previously tested for HIV, 77.5% (95% CI 48.7–100%) had been previously diagnosed with HIV, 67.2% (95% CI 39.2–95.2) reported linkage to care, 62.2% (95% CI 35.4–88.9) were currently on ART and 35.4% (95% CI 9.5–61.4%) had an undetectable viral load. The final adjusted RDS‐weighted logistic regression model for viral suppression indicated that those who self‐identified as black (adjusted odds ratio [aOR] 0.06, 95% CI 0.01–0.53, p < 0.01), reported earning ≤U$160/month (aOR 0.11, 95% CI 0.16–0.87, p = 0.04) or reported unstable housing (aOR 0.08, 95% CI 0.01–0.43, p < 0.01) had significantly lower odds of viral suppression. Conclusions : Our cascade indicators for transwomen showed modest ART use and low viral suppression rates. Multi‐level efforts including gender affirming care provision are urgently needed to decrease disparities in HIV clinical outcomes among transwomen and reduce secondary HIV transmission to their partners.     

The risk of cytomegalovirus infection after treatment of acute rejection in renal transplant recipients

The risk of cytomegalovirus infection (CMV) after rejection treatment is poorly understood. To investigate this, we conducted a case/control (1:2) analysis of adult renal transplant recipients between January 1, 2005 and December 31, 2015, via incidence density sampling and survival analysis. Our objective was to evaluate the association of prior acute rejection with subsequent CMV, including epidemiology and outcomes. There were 2481 eligible renal transplants within the study period and 251 distinct CMV infections. Despite the use of antiviral prophylaxis rejection was a significant risk factor for CMV on unadjusted (HR 1.73 [1.34, 2.24] P < 0.05) and adjusted analysis (HR 1.46 [1.06, 2.04] P < 0.05). When matching cases to controls patients with CMV had significantly more rejection prior to CMV diagnosis (26.7% vs 14.2%, P < 0.01). CMV was associated with a twofold increased risk of prior rejection on unadjusted (OR 1.94, 95%CI: 1.28‐2.96, P < 0.01) and adjusted analysis (OR 2.16, 95% CI: 1.31‐3.58, P < 0.01). Patients with rejection preceding CMV had significantly increased graft loss (HR 2.89, 95% CI: 1.65‐5.09, P < 0.01) and mortality (HR 1.82, 95% CI: 1.12‐4.24, P = 0.03) as compared to those CMV cases without rejection. In conclusion, rejection is a risk factor for CMV infection that appears to persist for 1 year. Preceding rejection events increased risk of graft loss and mortality in CMV patients. Given this, prolonged surveillance monitoring for CMV after rejection may be warranted. Studies are needed investigating optimal monitoring strategies.     

The impact of surveillance and rapid reduction in immunosuppression to control BK virus‐related graft injury in kidney transplantation

We prospectively screened 609 consecutive kidney (538) and kidney‐pancreas (71) transplant recipients for BK viremia over a 4‐year interval using polymerase chain reaction viral load detection and protocol kidney biopsies. We found that BK viremia is common at our center: total cases 26.7%, cases during first year 21.3% (mean 4 months), and recipients with ≥10 000 copies/ml 12.3%. We found few predictive clinical or demographic risk factors for any BK viremia or viral loads ≥10,000 copies/ml, other than prior treatment of biopsy confirmed acute rejection and/or higher immunosuppressive blood levels of tacrolimus (P = 0.001) or mycophenolate mofetil (P = 0.007). Viral loads at diagnosis (<10 000 copies/ml) demonstrated little impact on graft function or survival. However, rising copy numbers demand early reductions in immunosuppressive drug doses of at least 30–50%. Viral loads >185 000 copies/ml at diagnosis were predictive of BK virus‐associated nephropathy (BKVAN; OR: 113.25, 95% CI: 17.22–744.6, P < 0.001). Surveillance for BK viremia and rapid reduction of immunosuppression limited the incidence of BKVAN to 1.3%. The addition of leflunomide or ciprofloxacin to immunosuppressive dose reduction did not result in greater rates of viral clearance. These data support the role of early surveillance for BK viremia to limit the impact on transplant outcome, although the most effective schedule for screening awaits further investigation.