Post-traumatic stress disorder as a risk factor for major adverse cardiovascular events: a cohort study of a South African medical insurance scheme.

AIMS: Prior research, largely focused on US male veterans, indicates an increased risk of cardiovascular disease among individuals with post-traumatic stress disorder (PTSD). Data from other settings and populations are scarce. The objective of this study is to examine PTSD as a risk factor for incident major adverse cardiovascular events (MACEs) in South Africa. METHODS: We analysed reimbursement claims (2011-2020) of a cohort of South African medical insurance scheme beneficiaries aged 18 years or older. We calculated adjusted hazard ratios (aHRs) for associations between PTSD and MACEs using Cox proportional hazard models and calculated the effect of PTSD on MACEs using longitudinal targeted maximum likelihood estimation. RESULTS: We followed 1,009,113 beneficiaries over a median of 3.0 years (IQR 1.1-6.0). During follow-up, 12,662 (1.3%) persons were diagnosed with PTSD and 39,255 (3.9%) had a MACE. After adjustment for sex, HIV status, age, population group, substance use disorders, psychotic disorders, major depressive disorder, sleep disorders and the use of antipsychotic medication, PTSD was associated with a 16% increase in the risk of MACEs (aHR 1.16, 95% confidence interval (CI) 1.05-1.28). The risk ratio for the effect of PTSD on MACEs decreased from 1.59 (95% CI 1.49-1.68) after 1 year of follow-up to 1.14 (95% CI 1.11-1.16) after 8 years of follow-up. CONCLUSION: Our study provides empirical support for an increased risk of MACEs in males and females with PTSD from a general population sample in South Africa. These findings highlight the importance of monitoring cardiovascular risk among individuals diagnosed with PTSD.

Implementation of a comprehensive clinical risk management system in a university hospital.

BACKGROUND: Adverse events during hospital treatment are common and can lead to serious harm. This study reports the implementation of a comprehensive clinical risk management system in a university hospital and assesses the impact of clinical risk management on patient harms. METHODS: The clinical risk management system was rolled out over a period of eight years and consisted of a training of interdisciplinary risk management teams, external and internal risk audits, and the implementation of a critical incident reporting system (CIRS). The risks identified during the audits were analyzed according to the type, severity, and implementation of preventive measures. Other key figures of the risk management system were obtained from the annual risk reports. The number of liability cases was used as primary outcome measurement. RESULTS: Of the 1,104 risks identified during the risk audits, 56.2% were related to organization, 21.3% to documentation, 15.3% to treatment, and 7.2% to patient information and consent. The highest proportion of serious risks was found in the category organization (22.7%), the lowest in the category documentation (13.6%). Critical incident reporting identified between 241 and 370 critical incidents per year, for which in 79.5% to 83% preventive measures were implemented within twelve months. The frequency of incident reports per department correlated with the number of active risk managers and risk team meetings. Compared with the years prior to the introduction of the clinical risk management system, an average annual reduction of harms by 60.1% (95% CI: 57.1; 63.1) was observed two years after the implementation was completed. On average, the rate of harms dropped by 5% per year for each 10% increase in roll-out of the clinical risk management system (incidence rate ratio: 0.95; 95% CI: 0.93; 0.97) . CONCLUSION: The results of this project demonstrate the effectiveness of clinical risk management in detecting treatment-related risks and in reducing harm to patients.

Sustained high fatality during TB therapy amid rapid decline in TB mortality at population level: A retrospective cohort and ecological analysis from Shiselweni, Eswatini.

OBJECTIVES: Despite declining TB notifications in Southern Africa, TB-related deaths remain high. We describe patient- and population-level trends in TB-related deaths in Eswatini over a period of 11 years. METHODS: Patient-level (retrospective cohort, from 2009 to 2019) and population-level (ecological analysis, 2009-2017) predictors and rates of TB-related deaths were analysed in HIV-negative and HIV-coinfected first-line TB treatment cases and the population of the Shiselweni region. Patient-level TB treatment data, and population and HIV prevalence estimates were combined to obtain stratified annual mortality rates. Multivariable Poisson regressions models were fitted to identify patient-level and population-level predictors of deaths. RESULTS: Of 11,883 TB treatment cases, 1302 (11.0%) patients died during treatment: 210/2798 (7.5%) HIV-negative patients, 984/8443 (11.7%) people living with HIV (PLHIV), and 108/642 (16.8%) patients with unknown HIV-status. The treatment case fatality ratio remained above 10% in most years. At patient-level, fatality risk was higher in PLHIV (aRR 1.74, 1.51-2.02), and for older age and extra-pulmonary TB irrespective of HIV-status. For PLHIV, fatality risk was higher for TB retreatment cases (aRR 1.38, 1.18-1.61) and patients without antiretroviral therapy (aRR 1.70, 1.47-1.97). It decreases with increasing higher CD4 strata and the programmatic availability of TB-LAM testing (aRR 0.65, 0.35-0.90). At population-level, mortality rates decreased 6.4-fold (-147/100,000 population) between 2009 (174/100,000) and 2017 (27/100,000), coinciding with a decline in TB treatment cases (2785 in 2009 to 497 in 2017). Although the absolute decline in mortality rates was most pronounced in PLHIV (-826/100,000 vs. HIV-negative: -23/100,000), the relative population-level mortality risk remained higher in PLHIV (aRR 4.68, 3.25-6.72) compared to the HIV-negative population. CONCLUSIONS: TB-related mortality rapidly decreased at population-level and most pronounced in PLHIV. However, case fatality among TB treatment cases remained high. Further strategies to reduce active TB disease and introduce improved TB therapies are warranted.

Life years lost associated with mental illness: A cohort study of beneficiaries of a South African medical insurance scheme.

BACKGROUND: People with mental illness have a reduced life expectancy, but the extent of the mortality gap and the contribution of natural and unnatural causes to excess mortality among people with mental illness in South Africa are unknown. METHODS: We analysed reimbursement claims from South African medical insurance scheme beneficiaries aged 15-85 years. We estimated excess life years lost (LYL) associated with organic, substance use, psychotic, mood, anxiety, eating, personality, developmental or any mental disorders. RESULTS: We followed 1,070,183 beneficiaries for a median of three years, of whom 282,926 (26.4 %) received mental health diagnoses. Men with a mental health diagnosis lost 3.83 life years (95 % CI 3.58-4.10) compared to men without. Women with a mental health diagnosis lost 2.19 life years (1.97-2.41) compared to women without. Excess mortality varied by sex and diagnosis, from 11.50 LYL (95 % CI 9.79-13.07) among men with alcohol use disorder to 0.87 LYL (0.40-1.43) among women with generalised anxiety disorder. Most LYL were attributable to natural causes (men: 3.42, women: 1.94). A considerable number of LYL were attributable to unnatural causes among men with bipolar (1.52) or substance use (2.45) disorder. LIMITATIONS: Mental diagnoses are based on reimbursement claims. CONCLUSIONS: Premature mortality among South African individuals with mental disorders is high. Our findings support interventions for the prevention, early detection, and treatment of physical comorbidities in this population. Targeted programs for suicide prevention and substance use treatment, particularly among men, can help reduce excess mortality from unnatural causes.

Determinants of low health-related quality of life in patients with myelodysplastic syndromes: EUMDS Registry study.

Patients with myelodysplastic syndromes (MDS) frequently experience a significant symptom burden, which reduces health-related quality of life (HRQoL). We aimed to identify determinants of low HRQoL in patients recently diagnosed with MDS, for guiding early intervention strategies. We evaluated longitudinal data in 2205 patients with MDS during their first year after diagnosis. Median values of EQ-5D 3-level (EQ-5D-3L) index (0.78) and visual analog scale (VAS) score (0.70) were used as thresholds for low HRQoL. In addition, the 5 dimensions of EQ-5D-3L were analyzed for impairments (any level vs "no problem" category). After multiple imputation of missing values, we used generalized estimating equations (GEE) to estimate odds ratios (OR) for univariable determinant screening (P < .15), and to subsequently derive multivariable models for low HRQoL with 95% confidence intervals (CI). Multivariable GEE analysis showed the following independent determinants (OR, 95% CI) for low EQ-5D index: increased age (60-75 years: 1.33, 1.01-1.75; >75: 1.84, 1.39-2.45), female sex (1.70, 1.43-2.03), high serum ferritin level (≥1000 vs ≤300 µg/L: 1.41, 1.06-1.87), comorbidity burden (per unit: 1.11, 1.02-1.20), and reduced Karnofsky performance status (KPS, per 10 units: 0.62, 0.58-0.67). For low VAS score, additional determinants were transfusion dependence (1.53, 1.03-2.29), low hemoglobin <10 g/dL (1.34, 1.12-1.61), and high body mass index (≥30 vs 23-29.9 kg/m2: 1.26, 1.02-1.57). Sex, KPS, comorbidity burden, hemoglobin count, and transfusion burden were determinants for all EQ-5D dimensions. Low HRQoL is determined by multiple factors, which should be considered in the management and shared decision making of patients with MDS. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

Life-years lost associated with mental illness: a cohort study of beneficiaries of a South African medical insurance scheme.

Importance: People with mental illness have a reduced life expectancy, but the extent of the mortality gap and the contribution of natural and unnatural causes to excess mortality among people with mental illness in South Africa are unknown. Objective: To quantify excess mortality due to natural and unnatural causes associated with mental illness. Design setting and participants: Cohort study using reimbursement claims and vital registration of beneficiaries of a South African medical insurance scheme, aged 15-84 years and covered by medical insurance at any point between January 1, 2011, and June 30, 2020. Exposures: ICD-10 diagnoses of mental disorders including organic, substance use, psychotic, mood, anxiety, eating, personality, and developmental disorders. Outcomes: Mortality from natural, unnatural, unknown and all causes, as measured by the life-years lost (LYL) metric. Results: We followed 1 070 183 beneficiaries (51.7% female, median age 36.1 years for a median duration of 3.0 years, of whom 282 926 (26.4%) received mental health diagnoses and 27 640 (2.6%) died. Life expectancy of people with mental health diagnoses was 3.83 years (95% CI 3.58-4.10) shorter for men and 2.19 years (1.97-2.41) shorter for women. Excess mortality varied by sex and diagnosis, ranging from 11.50 LYL (95% CI 9.79-13.07) among men with alcohol use disorder to 0.87 LYL (0.40-1.43) among women with generalised anxiety disorder. Most LYL were attributable to natural causes (3.42 among men and 1.94 among women). A considerable number of LYL were attributable to unnatural causes among men with bipolar (1.52) or substance use (2.45) disorder. Conclusions and Relevance: The burden of premature mortality among persons with mental disorders in South Africa is high. Our findings support implementing interventions for prevention, early detection, and treatment of physical comorbidities among people with mental disorders. Suicide prevention and substance use treatment programmes are needed to reduce excess mortality from unnatural causes, especially among men. Key points: Question: How much shorter is the life expectancy of people with mental illness compared to the general population and how many life years are lost due to natural and unnatural causes of death?Findings: The life expectancy of people with mental health diagnoses was 3.83 years shorter for men and 2.19 years shorter for women. Most excess life years lost were attributable to natural causes (3.42 among men and 1.94 among women). However, bipolar and substance use disorders were associated with considerable premature mortality from unnatural causes.Meaning: Our findings support the implementation of interventions for improving the physical health of people with mental illness and targeted suicide prevention and substance use treatment programmes.

High Unreported Mortality in Children and Youth (<25 Years) Living With HIV Who Were Lost to Care From Antiretroviral Therapy Programs in Southern Africa: Results From a Multicountry Tracing Study.

BACKGROUND: Antiretroviral therapy program mortality maybe underestimated if deceased patients are misclassified as lost. METHODS: We used two-stage inverse probability weighting to account for probability of being: sampled for tracing and found by the tracer. RESULTS: Among 680 children and youth aged <25 years on antiretroviral therapy who were lost and traced in Southern Africa between October 2017 and November 2019, estimated mortality was high at 9.1% (62/680). After adjusting for measured covariates and within-site clustering, mortality remained lower for young adults aged 20-24 years compared with infants aged <2 years [adjusted hazard ratio: 0.40 (95% confidence interval: 0.31 to 0.51)]. CONCLUSIONS: Our study confirms high unreported mortality in children and youth who are lost and the need for tracing to assess vital status among those who are lost to accurately report on program mortality.

Virologic non-suppression and early loss to follow up among pregnant and non-pregnant adolescents aged 15-19 years initiating antiretroviral therapy in South Africa: a retrospective cohort study.

INTRODUCTION: Older adolescents aged 15-19 years continue to have high rates of loss to follow up (LTFU), and high rates of virologic non-suppression (VNS) compared to younger adolescents and adults. Adolescent females are at risk of pregnancy, which puts those living with HIV at a dual vulnerability. Our study assessed the factors associated with VNS and LTFU in older adolescents (including pregnant females) who initiated antiretroviral therapy (ART) in South Africa. METHODS: We included adolescents aged 15-19 years initiating ART between 2004 and 2019, with ≥ one viral load (VL) measurement between 4 and 24.5 months, and ≥ 6 months follow-up, from six South African cohorts of the International epidemiology Databases to Evaluate AIDS-Southern Africa (IeDEA-SA). We defined VNS as VL ≥400 copies/ml and LTFU as not being in care for ≥180 days from ART start and not known as transferred out of the clinic or dead in the first 24 months on ART. We examined factors associated with VNS and LTFU using Fine&Gray competing risk models. RESULTS: We included a total of 2733 adolescents, 415 (15.2%) males, median (IQR) age at ART start of 18.6 (17.3, 19.4) years. Among females, 585/2318 (25.2%) were pregnant. Over the 24-month follow-up, 424 (15.5%) of all adolescents experienced VNS: range (11.1% pregnant females and 20.5% males). Over half of all adolescents were LTFU before any other event could occur. The hazard of VNS reduced with increasing age and CD4 count above 200 cells/µl at ART initiation among all adolescents having adjusted for all measured patient characteristics [adjusted sub-distribution hazard ratio (aSHR) 19 vs. 15 years: 0.50 (95% CI: 0.36, 0.68), aSHR: >500 vs. ≤200 cells/µl: 0.22 (95% CI: 0.16, 0.31)]. The effect of CD4 count persisted in pregnant females. Increasing age and CD4 count >200 cells/µl were risk factors for LTFU among all adolescents. CONCLUSIONS: Older adolescents had a high risk of LTFU shortly after ART start and a low risk of VNS, especially those initiating treatment during pregnancy. Interventions addressing adherence and retention should be incorporated into adolescent-friendly services to prevent VNS and LTFU and endeavour to trace lost adolescents as soon as they are identified.

Causal evidence in health decision making: methodological approaches of causal inference and health decision science.

Objectives: Public health decision making is a complex process based on thorough and comprehensive health technology assessments involving the comparison of different strategies, values and tradeoffs under uncertainty. This process must be based on best available evidence and plausible assumptions. Causal inference and health decision science are two methodological approaches providing information to help guide decision making in health care. Both approaches are quantitative methods that use statistical and modeling techniques and simplifying assumptions to mimic the complexity of the real world. We intend to review and lay out both disciplines with their aims, strengths and limitations based on a combination of textbook knowledge and expert experience. Methods: To help understanding and differentiating the methodological approaches of causal inference and health decision science, we reviewed both methods with the focus on aims, research questions, methods, assumptions, limitations and challenges, and software. For each methodological approach, we established a group of four experts from our own working group to carefully review and summarize each method, followed by structured discussion rounds and written reviews, in which the experts from all disciplines including HTA and medicine were involved. The entire expert group discussed objectives, strengths and limitations of both methodological areas, and potential synergies. Finally, we derived recommendations for further research and provide a brief outlook on future trends. Results: Causal inference methods aim for drawing causal conclusions from empirical data on the relationship of pre-specified interventions on a specific target outcome and apply a counterfactual framework and statistical techniques to derive causal effects of exposures or interventions from these data. Causal inference is based on a causal diagram, more specifically, a directed acyclic graph (DAG), which encodes the assumptions regarding the causal relations between variables. Depending on the type of confounding and selection bias, traditional statistical methods or more complex g-methods are needed to derive valid causal effects. Besides the correct specification of the DAG and the statistical model, assumptions such as consistency, positivity, and exchangeability must be checked when aiming at causal inference. Health decision science aims for guiding policy decision making regarding health interventions considering and balancing multiple competing objectives of a decision based on data from multiple sources and studies, for example prevalence studies, clinical trials and long-term observational routine effectiveness studies, and studies on preferences and costs. It involves decision analysis, a systematic, explicit and quantitative framework to guide decisions under uncertainty. Decision analyses are based on decision-analytic models to mimic the course of disease as well as aspects and consequences of the intervention in order to quantitatively optimize the decision. Depending on the type of decision problem, decision trees, state-transition models, discrete event simulation models, dynamic transmission models, or other model types are applied. Models must be validated against observed data, and comprehensive sensitivity analyses must be performed to assess uncertainty. Besides the appropriate choice of the model type and the valid specification of the model structure, it must be checked if input parameters of effects can be interpreted as causal parameters in the model. Otherwise results will be biased. Conclusions: Both causal inference and health decision science aim for providing best causal evidence for informed health decision making. The strengths and limitations of both methods differ and a good understanding of both methods is essential for correct application but also for correct interpretation of findings from the described methods. Importantly, decision-analytic modeling should be combined with causal inference when developing guidance and recommendations regarding decisions on health care interventions.

Predicting, Diagnosing, and Treating Acute and Early HIV Infection in a Public Sector Facility in Eswatini.

BACKGROUND: The lack of acute and early HIV infection (AEHI) diagnosis and care contributes to high HIV incidence in resource-limited settings. We aimed to assess the yield of AEHI, predict and diagnose AEHI, and describe AEHI care outcomes in a public sector setting in Eswatini. SETTING: This study was conducted in Nhlangano outpatient department from March 2019 to March 2020. METHODS: Adults at risk of AEHI underwent diagnostic testing for AEHI with the quantitative Xpert HIV-1 viral load (VL) assay. AEHI was defined as the detection of HIV-1 VL on Xpert and either an HIV-seronegative or HIV-serodiscordant third-generation antibody-based rapid diagnostic test (RDT) result. First, the cross-sectional analysis obtained the yield of AEHI and established a predictor risk score for the prediction of AEHI using Lasso logistic regression. Second, diagnostic accuracy statistics described the ability of the fourth-generation antibody/p24 antigen-based Alere HIV-Combo RDT to diagnose AEHI (vs Xpert VL testing). Third, we described acute HIV infection care outcomes of AEHI-positive patients using survival analysis. RESULTS: Of 795 HIV-seronegative/HIV-serodiscordant outpatients recruited, 30 (3.8%, 95% confidence interval: 2.6% to 5.3%) had AEHI. The predictor risk score contained several factors (HIV-serodiscordant RDT, women, feeling at risk of HIV, swollen glands, and fatigue) and had sensitivity and specificity of 83.3% and 65.8%, respectively, to predict AEHI. The HIV-Combo RDT had sensitivity and specificity of 86.2% and 99.9%, respectively, to diagnose AEHI. Of 30 AEHI-positive patients, the 1-month cumulative treatment initiation was 74% (95% confidence interval: 57% to 88%), and the 3-month viral suppression (<1000 copies/mL) was 87% (67% to 98%). CONCLUSION: AEHI diagnosis and care seem possible in resource-limited settings.

New Perspective for Soft Tissue Closure in Medication-Related Osteonecrosis of the Jaw (MRONJ) Using Barbed Sutures.

The aim of this study was to compare the effectiveness of barbed versus smooth sutures for soft tissue closure of exposed jawbone sites in medication-related osteonecrosis of the jaw (MRONJ) patients. Exposed necrotic jawbone sites surgically managed by intraoral soft tissue closure were evaluated. Either barbed sutures (Stratafix™ or V-Loc™) together with Prolene® or Vicryl® sutures were used. We estimated the effect of barbed sutures (BS) with Prolene® compared to smooth sutures (Vicryl®) on the hazard rate of intraoral soft tissue dehiscence using a multivariate Cox regression model within a target trial framework, adjusting for relevant confounders. In total, 306 operations were performed in 188 sites. In the primary analysis 182 sites without prior surgery were included. Of these, 113 sites developed a dehiscence during follow-up. 84 sites were operated using BS and Prolene®. A total of 222 sites were operated with Vicryl® (control group). In the BS group, the median time to event (i.e., dehiscence) was 148 days (interquartile range (IQR), 42-449 days) compared to 15 days (IQR, 12-52 days) in the control group. The hazard rate of developing intraoral dehiscence was 0.03 times (95%-confidence interval (CI): 0.01; 0.14, p < 0.001) lower for BS patients compared to the control group. Within the limits of a retrospective study, BS showed a high success rate and are therefore recommended for soft tissue closure of exposed jawbone sites in MRONJ patients. Additional studies are warranted to further evaluate this novel application of BS.

Targeted COVID-19 Vaccination (TAV-COVID) Considering Limited Vaccination Capacities-An Agent-Based Modeling Evaluation.

(1) Background: The Austrian supply of COVID-19 vaccine is limited for now. We aim to provide evidence-based guidance to the authorities in order to minimize COVID-19-related hospitalizations and deaths in Austria. (2) Methods: We used a dynamic agent-based population model to compare different vaccination strategies targeted to the elderly (65 ≥ years), middle aged (45-64 years), younger (15-44 years), vulnerable (risk of severe disease due to comorbidities), and healthcare workers (HCW). First, outcomes were optimized for an initially available vaccine batch for 200,000 individuals. Second, stepwise optimization was performed deriving a prioritization sequence for 2.45 million individuals, maximizing the reduction in total hospitalizations and deaths compared to no vaccination. We considered sterilizing and non-sterilizing immunity, assuming a 70% effectiveness. (3) Results: Maximum reduction of hospitalizations and deaths was achieved by starting vaccination with the elderly and vulnerable followed by middle-aged, HCW, and younger individuals. Optimizations for vaccinating 2.45 million individuals yielded the same prioritization and avoided approximately one third of deaths and hospitalizations. Starting vaccination with HCW leads to slightly smaller reductions but maximizes occupational safety. (4) Conclusion: To minimize COVID-19-related hospitalizations and deaths, our study shows that elderly and vulnerable persons should be prioritized for vaccination until further vaccines are available.

Dental pathologies in tumor patients with bone metastases or multiple myeloma scheduled for antiresorptive therapy.

Background: Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe complication of mainly antiresorptive drugs. We evaluated the frequency of dentoalveolar pathologies in patients scheduled for antiresorptive therapy in a 'real-world' setting, also including patients with poor oral health potentially requiring tooth extractions and/or other dentoalveolar surgery. This approach is in contrast to the setting of recent randomized trials with restrictive exclusion criteria. Patients & methods: We prospectively included patients suffering from solid tumors with osseous metastases or multiple myeloma. Screening for dentoalveolar pathologies was done prior to initiation of antiresorptive therapy at the specialized MRONJ clinic of the University Hospital for Cranio-Maxillofacial and Oral Surgery, Innsbruck, Austria. Results: 119 subjects could be included. In 76 patients (63.9%), a dental focus was revealed including deep caries (24.4% of patients), chronic apical periodontitis (26.9%), periodontal disease (45.8%), root remnants (16%), jaw cysts (2.5%), partially impacted teeth (5.0%) and peri-implantitis (5.0%). Conclusion: Considering the high number of dentoalveolar pathologies (63.9%), systematic dental focus screening prior to initiation of antiresorptive therapy is of utmost importance to lower the risk for MRONJ.

The Impact of Same-Day Antiretroviral Therapy Initiation Under the World Health Organization Treat-All Policy.

Rapid initiation of antiretroviral therapy (ART) is recommended for people living with human immunodeficiency virus (HIV), with the option to start treatment on the day of diagnosis (same-day ART). However, the effect of same-day ART remains unknown in realistic public sector settings. We established a cohort of ≥16-year-old patients who initiated first-line ART under a treat-all policy in Nhlangano (Eswatini) during 2014-2016, either on the day of HIV care enrollment (same-day ART) or 1-14 days thereafter (early ART). Directed acyclic graphs, flexible parametric survival analysis, and targeted maximum likelihood estimation (TMLE) were used to estimate the effect of same-day-ART initiation on a composite unfavorable treatment outcome (loss to follow-up, death, viral failure, treatment switch). Of 1,328 patients, 839 (63.2%) initiated same-day ART. The adjusted hazard ratio of the unfavorable outcome was higher, 1.48 (95% confidence interval: 1.16, 1.89), for same-day ART compared with early ART. TMLE suggested that after 1 year, 28.9% of patients would experience the unfavorable outcome under same-day ART compared with 21.2% under early ART (difference: 7.7%; 1.3%-14.1%). This estimate was driven by loss to follow-up and varied over time, with a higher hazard during the first year after HIV care enrollment and a similar hazard thereafter. We found an increased risk with same-day ART. A limitation was that possible silent transfers that were not captured.

Virologic response of adolescents living with perinatally acquired HIV receiving antiretroviral therapy in the period of early adolescence (10-14 years) in South Africa.

BACKGROUND AND OBJECTIVES: Adolescents living with perinatally acquired HIV (ALPHIV) on antiretroviral therapy (ART) have been noted to have poorer adherence, retention and virologic control compared to adolescents with non-perinatally acquired HIV, children or adults. We aimed to describe and examine factors associated with longitudinal virologic response during early adolescence. DESIGN: A retrospective cohort study. METHODS: We included ALPHIV who initiated ART before age 9.5 years in South African cohorts of the International epidemiology Database to Evaluate AIDS-Southern Africa (IeDEA-SA) collaboration (2004-2016); with viral load (VL) values <400 copies/ml at age 10 years and at least one VL measurement after age 10 years. We used a log-linear quantile mixed model to assess factors associated with elevated (75th quantile) VLs. RESULTS: We included 4396 ALPHIV, 50.7% were male, with median (interquartile range) age at ART start of 6.5 (4.5, 8.1) years. Of these, 74.9% were on a non-nucleoside reverse transcriptase inhibitor (NNRTI) at age 10 years. After adjusting for other patient characteristics, the 75th quantile VLs increased with increasing age being 3.13-fold (95% CI 2.66, 3.68) higher at age 14 versus age 10, were 3.25-fold (95% CI 2.81, 3.75) higher for patients on second-line protease-inhibitor and 1.81-fold for second-line NNRTI-based regimens (versus first-line NNRTI-based regimens). There was no difference by sex. CONCLUSIONS: As adolescents age between 10 and 14 years, they are increasingly likely to experience higher VL values, particularly if receiving second-line protease inhibitor or NNRTI-based regimens, which warrant adherence support interventions.

HIV-1 Subtype C Tier 3 Viruses Have Increased Infectivity Compared to Tier 2 Viruses.

A primary concern of an antibody-based HIV-1 therapy is the virus' ability to rapidly escape antibody responses. Therefore, we investigated the relationships between antibody neutralization sensitivity, viral phenotype, and infectivity in 13 subtype C viruses using a HeLa transfectant-based assay. We observed that the seven tier 3 viruses exhibited higher infectivity than the tier 2 viruses, suggesting that higher neutralization resistance did not have a substantial entry cost. There was no relationship between neutralization resistance and susceptibility to entry inhibitors Maraviroc, PSC RANTES, or the fusion inhibitor T20, indicating that neutralization resistance may not alter these inhibitor target sites. By analyzing glycosylation patterns in 82 subtype C viruses, we found that the presence of an N-linked glycan motif at position N413 and its absence at N332 were the most important predictors of neutralization resistance. In a set of 200 subtype C viruses, tier 3 strains were more resistant than tier 2 or 1B viruses to several broadly neutralizing monoclonal antibodies targeting three different epitopes. This suggests that it is unlikely that resistance to antibodies targeting a single epitope drives overall resistance. In the context of an antibody-based intervention, highly resistant viruses with increased infectivity, circulating in the population, could hinder HIV-1 control since entry of tier 3 viruses is not always selected against. Therefore, for any long-term antibody-based intervention to be globally relevant, it must elicit responses that limit the occurrence of resistance.

PS-SiZer map to investigate significant features of body-weight profile changes in HIV infected patients in the IeDEA Collaboration.

OBJECTIVES: We extend the method of Significant Zero Crossings of Derivatives (SiZer) to address within-subject correlations of repeatedly collected longitudinal biomarker data and the computational aspects of the methodology when analyzing massive biomarker databases. SiZer is a powerful visualization tool for exploring structures in curves by mapping areas where the first derivative is increasing, decreasing or does not change (plateau) thus exploring changes and normalization of biomarkers in the presence of therapy. METHODS: We propose a penalized spline SiZer (PS-SiZer) which can be expressed as a linear mixed model of the longitudinal biomarker process to account for irregularly collected data and within-subject correlations. Through simulations we show how sensitive PS-SiZer is in detecting existing features in longitudinal data versus existing versions of SiZer. In a real-world data analysis PS-SiZer maps are used to map areas where the first derivative of weight change after antiretroviral therapy (ART) start is significantly increasing, decreasing or does not change, thus exploring the durability of weight increase after the start of therapy. We use weight data repeatedly collected from persons living with HIV initiating ART in five regions in the International Epidemiologic Databases to Evaluate AIDS (IeDEA) worldwide collaboration and compare the durability of weight gain between ART regimens containing and not containing the drug stavudine (d4T), which has been associated with shorter durability of weight gain. RESULTS: Through simulations we show that the PS-SiZer is more accurate in detecting relevant features in longitudinal data than existing SiZer variants such as the local linear smoother (LL) SiZer and the SiZer with smoothing splines (SS-SiZer). In the illustration we include data from 185,010 persons living with HIV who started ART with a d4T (53.1%) versus non-d4T (46.9%) containing regimen. The largest difference in durability of weight gain identified by the SiZer maps was observed in Southern Africa where weight gain in patients treated with d4T-containing regimens lasted 59.9 weeks compared to 133.8 weeks for those with non-d4T-containing regimens. In the other regions, persons receiving d4T-containing regimens experienced weight gains lasting 38-62 weeks versus 55-93 weeks in those receiving non-d4T-based regimens. DISCUSSION: PS-SiZer, a SiZer variant, can handle irregularly collected longitudinal data and within-subject correlations and is sensitive in detecting even subtle features in biomarker curves.

The Impact of Delayed Switch to Second-Line Antiretroviral Therapy on Mortality, Depending on Definition of Failure Time and CD4 Count at Failure.

Little is known about the functional relationship of delaying second-line treatment initiation for human immunodeficiency virus-positive patients and mortality, given a patient's immune status. We included 7,255 patients starting antiretroviral therapy during 2004-2017, from 9 South African cohorts, with virological failure and complete baseline data. We estimated the impact of switch time on the hazard of death using inverse probability of treatment weighting of marginal structural models. The nonlinear relationship between month of switch and the 5-year survival probability, stratified by CD4 count at failure, was estimated with targeted maximum likelihood estimation. We adjusted for measured time-varying confounding by CD4 count, viral load, and visit frequency. Five-year mortality was estimated to be 10.5% (95% CI: 2.2, 18.8) for immediate switch and to be 26.6% (95% CI: 20.9, 32.3) for no switch (51.1% if CD4 count was <100 cells/mm3). The hazard of death was estimated to be 0.37 (95% CI: 0.30, 0.46) times lower if everyone had been switched immediately compared with never. The shorter the delay in switching, the lower the hazard of death-delaying 30-59 days reduced the hazard by 0.53 (95% CI: 0.43, 0.65) times and 60-119 days by 0.58 (95% CI: 0.49, 0.69) times, compared with no switch. Early treatment switch is particularly important for patients with low CD4 counts at failure.