The survival-incorporated median versus the median in the survivors or in the always-survivors: What are we measuring? And why?

Many clinical studies evaluate the benefit of treatment based on both survival and other ordinal/continuous clinical outcomes, such as neurocognitive scores or quality-of-life scores. In these studies, there are situations when the clinical outcomes are truncated by death, where subjects die before their clinical outcome is measured. Treating outcomes as "missing" or "censored" due to death can be misleading for treatment effect evaluation. We show that if we use the median in the survivors or in the always-survivors to summarize clinical outcomes, we may conclude a trade-off exists between the probability of survival and good clinical outcomes, even in settings where both the probability of survival and the probability of any good clinical outcome are better for one treatment. Therefore, we advocate not always treating death as a mechanism through which clinical outcomes are missing, but rather as part of the outcome measure. To account for the survival status, we describe the survival-incorporated median as an alternative summary measure for outcomes in the presence of death. The survival-incorporated median is the threshold such that 50\% of the population is alive with an outcome above that threshold. We use conceptual examples to show that the survival-incorporated median provides a simple and useful summary measure to inform clinical practice

Sensitivity Analysis for the Assessment of Causal Vaccine Effects on Viral Load in HIV Vaccine Trials

Vaccines with limited ability to prevent HIV infection may positively impact the HIV/AIDS pandemic by preventing secondary transmission and disease in vaccine recipients who become infected. To evaluate the impact of vaccination on secondary transmission and disease, efficacy trials assess vaccine effects on HIV viral load and other surrogate endpoints measured after infection. A standard test that compares the distribution of viral load between the infected subgroups of vaccine and placebo recipients does not assess a causal effect of vaccine, because the comparison groups are selected after randomization. To address this problem, we formulate clinically relevant causal estimands using the principal stratification framework developed by Frangakis and Rubin (2002), and propose a class of logistic selection bias models whose members identify the estimands. Given a selection model in the class, procedures are developed for testing and estimation of the causal effect of vaccination on viral load in the principal stratum of subjects who would be infected regardless of randomization assignment. We show how the procedures can be used for a sensitivity analysis that quantifies how the causal effect of vaccination varies with the presumed magnitude of selection bias

Vitamin D Status and TB Treatment Outcomes in Adult Patients in Tanzania: A Cohort Study.

Vitamin D is an immunomodulator and can alter response to tuberculosis (TB) treatment, though randomised trials have been inconclusive to date. We present one of the first comprehensive analysis of the associations between vitamin D status and TB treatment, T-cell counts and nutritional outcomes by HIV status. Cohort study. Outpatient clinics in Tanzania. 25-hydroxyvitamin D levels were assessed in a cohort of 677 patients with TB (344 HIV infected) initiating anti-TB treatment at enrolment in a multivitamin supplementation (excluding vitamin D) trial (Clinicaltrials.gov identifier: NCT00197704). Information on treatment outcomes such as failure and relapse, HIV disease progression, T-cell counts and anthropometry was collected routinely, with a median follow-up of 52 and 30 months for HIV-uninfected and HIV-infected patients, respectively. Cox and binomial regression, and generalised estimating equations were used to assess the association of vitamin D status with these outcomes. Mean 25-hydroxyvitamin D concentrations at enrolment were 69.8 (±21.5) nmol/L (27.9 (±8.6) ng/mL). Vitamin D insufficiency (<75 nmol/L) was associated with a 66% higher risk of relapse (95% CI 4% to 164%; 133% higher risk in HIV-uninfected patients). Each unit higher 25-hydroxyvitamin D levels at baseline were associated with a decrease of 3 (p=0.004) CD8 and 3 (p=0.01) CD3 T-cells/µL during follow-up in patients with HIV infection. Vitamin D insufficiency was also associated with a greater decrease of body mass index (BMI; -0.21 kg/m(2); 95% CI -0.39 to -0.02), during the first 8 months of follow-up. No association was observed for vitamin D status with mortality or HIV disease progression. Adequate vitamin D status is associated with a lower risk of relapse and with improved nutritional indicators such as BMI in patients with TB, with or without HIV infection. Further research is needed to determine the optimal dose of vitamin D and effectiveness of daily vitamin D supplementation among patients with TB

Continuing or adding IL-2 in patients treated with antiretroviral therapy (ACTG Protocol A5051, a rollover trial of ACTG Protocol A328)

<p>Abstract</p> <p>Background</p> <p>Effective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic infections and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks.</p> <p>Results</p> <p>The patients previously receiving IL-2 continued to have elevated CD4 levels with extended use of IL-2. The prior ART-alone recipients had increases in CD4 levels to comparable levels as the prior IL-2 recipients (median 804 versus 847 cells/mm³at week 72; 60% versus 9% had >50% increase in A5051 to week 72, p < 0.001). Those who had previously received IL-2 required fewer IL-2 cycles to maintain their CD4 T-cell counts compared to those newly initiating IL-2. The treatments were well tolerated with no significant differences in toxicity or discontinuations between those newly versus previously receiving IL-2. There were few clinical events observed.</p> <p>Conclusions</p> <p>Although sustained CD4 T-cell count increases were seen with IL-2 administration as in other studies, the absence of clinical benefit in two recent randomized trials has demonstrated no apparent role for IL-2 as a therapy in HIV disease.</p> <p>Trial Registration</p> <p>A5051 ClinicalTrials.gov Identifier: NCT00000923.</p

A Trial of the Effect of Micronutrient Supplementation on Treatment Outcome, T Cell Counts, Morbidity, and Mortality in Adults with Pulmonary Tuberculosis.

Tuberculosis (TB) often coincides with nutritional deficiencies. The effects of micronutrient supplementation on TB treatment outcomes, clinical complications, and mortality are uncertain. We conducted a randomized, double-blind, placebo-controlled trial of micronutrients (vitamins A, B complex, C, and E, as well as selenium) in Dar es Salaam, Tanzania. We enrolled 471 human immunodeficiency virus (HIV)-infected and 416 HIV-negative adults with pulmonary TB at the time of initiating chemotherapy and monitored them for a median of 43 months. Micronutrients decreased the risk ofTB recurrence by 45% overall (95% confidence interval [CI], 7% to 67%; P = .02) and by 63% in HIV-infected patients (95% CI, 8% to 85%; P = .02). There were no significant effects on mortality overall; however, we noted a marginally significant 64% reduction of deaths in HIV-negative subjects (95% CI, -14% to 88%; P = .08). Supplementation increased CD3+ and CD4+ cell counts and decreased the incidence of extrapulmonary TB and genital ulcers in HIV-negative patients. Micronutrients reduced the incidence of peripheral neuropathy by 57% (95% CI, 41% to 69%; P < .001), irrespective of HIV status. There were no significant effects on weight gain, body composition, anemia, or HIV load. Micronutrient supplementation could improve the outcome in patients undergoing TB chemotherapy in Tanzania

Predictors and Consequences of Anaemia Among Antiretroviral-Naïve HIV-Infected and HIV-Uninfected Children in Tanzania.

Predictors and consequences of childhood anaemia in settings with high HIV prevalence are not well known. The aims of the present study were to identify maternal and child predictors of anaemia among children born to HIV-infected women and to study the association between childhood anaemia and mortality. Prospective cohort study. Maternal characteristics during pregnancy and Hb measurements at 3-month intervals from birth were available for children. Information was also collected on malaria and HIV infection in the children, who were followed up for survival status until 24 months after birth. Dar es Salaam, Tanzania. The study sample consisted of 829 children born to HIV-positive women. Advanced maternal clinical HIV disease (relative risk (RR) for stage > or =2 v. stage 1: 1.31, 95 % CI 1.14, 1.51) and low CD4 cell counts during pregnancy (RR for <350 cells/mm3 v. > or =350 cells/mm3: 1.58, 95 % CI 1.05, 2.37) were associated with increased risk of anaemia among children. Birth weight <2500 g, preterm birth (<34 weeks), malaria parasitaemia and HIV infection in the children also increased the risk of anaemia. Fe-deficiency anaemia in children was an independent predictor of mortality in the first two years of life (hazard ratio 1.99, 95 % CI 1.06, 3.72). Comprehensive care including highly active antiretroviral therapy to eligible HIV-infected women during pregnancy could reduce the burden of anaemia in children. Programmes for the prevention of mother-to-child transmission of HIV and antimalarial treatment to children could improve child survival in settings with high HIV prevalence

Sex Differences in The effects of Maternal Vitamin Supplements on Mortality and Morbidity among Children Born to HIV-Infected women in Tanzania.

We examined whether there are sex differences in the effect of vitamin supplements on birth outcomes, mortality and morbidity by 2 years of age among children born to HIV-infected women in Tanzania. A randomised placebo-controlled trial was conducted among 959 mother-infant pairs. HIV-infected pregnant women were randomly assigned to receive a daily oral dose of one of four regimens: multivitamins (vitamins B-complex, C and E), vitamin A plus beta-carotene, multivitamins including vitamin A plus beta-carotene or placebo. Supplements were administered during pregnancy and continued after delivery. The beneficial effect of multivitamins on decreasing the risk of low birth weight was stronger among girls (relative risks (RR) = 0.39, 95 % CI 0.22, 0.67) than among boys (RR = 0.81, 95 % CI 0.44, 1.49; P for interaction = 0.08). Maternal multivitamin supplements resulted in 32 % reduction in mortality among girls (RR = 0.68, 95 % CI 0.47, 0.97), whereas no effect was found among boys (RR = 1.20, 95 % CI 0.80, 1.78; P for interaction = 0.04). Multivitamins had beneficial effects on the overall risks of diarrhoea that did not differ by sex. Vitamin A plus beta-carotene alone increased the risk of HIV transmission, but had no effects on mortality, and we found no sex differences in these effects. Sex differential effects of multivitamins on mortality may be due to sex-related differences in the immunological or genetic factors. More research is warranted to examine the effect of vitamins by sex and better understand biological mechanisms mediating such effects

CD4 trajectory adjusting for dropout among HIV-positive patients receiving combination antiretroviral therapy in an East African HIV care centre

Objective: Estimates of CD4 response to antiretroviral therapy (ART) obtained by averaging data from patients in care, overestimate population CD4 response and treatment program effectiveness because they do not consider data from patients who are deceased or not in care. We use mathematical methods to assess and adjust for this bias based on patient characteristics. Design: We examined data from 25,261 HIV-positive patients from the East Africa IeDEA Consortium. Methods: We used inverse probability of censoring weighting (IPCW) to represent patients not in care by patients in care with similar characteristics. We address two questions: What would the median CD4 be “had everyone starting ART remained on observation?” and “were everyone starting ART maintained on treatment?” Results: Routine CD4 count estimates were higher than adjusted estimates even under the best-case scenario of maintaining all patients on treatment. Two years after starting ART, differences between estimates diverged from 30 cells/µL, assuming similar mortality and treatment access among dropouts as patients in care, to over 100 cells/µL assuming 20% lower survival and 50% lower treatment access among dropouts. When considering only patients in care, the proportion of patients with CD4 above 350 cells/µL was 50% adjusted to below 30% when accounting for patients not in care. One-year mortality diverged 6–14% from the naïve estimates depending on assumptions about access to care among lost patients. Conclusions: Ignoring mortality and loss to care results in over-estimation of ART response for patients starting treatment and exaggerates the efficacy of treatment programs administering it

Deflection of carbon dioxide laser and helium‐neon laser beams in a long‐pulse relativistic electron beam diode

Deflection of carbon dioxide and helium‐neon laser beams has been used to measure plasma and neutral density gradients during the operating mode and after the shorting time of a long‐pulse field‐emission electron beam diode. Plasma density gradients of (1014–1015) cm−4 were observed throughout the diode during the final microsecond of the 2–3 μs electron beam pulse. The neutral density gradient was less than 1×1018 cm−4 during the electron beam pulse. Upon diode shorting, neutral density gradients increased to (1018–1019) cm−4 over ∼1 μs, and decayed over many microseconds. Plasma density gradients of ∼1015 cm−4 were also observed after shorting. These experiments demonstrate the value of carbon‐dioxide laser and helium‐neon laser deflection for diagnosing plasma and neutral particles in long‐pulse electron beam diodes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70220/2/RSINAK-62-7-1776-1.pd