Urine Lipoarabinomannan Testing in Adults With Advanced Human Immunodeficiency Virus in a Trial of Empiric Tuberculosis Therapy.

BACKGROUND: The urine lipoarabinomannan (LAM) antigen test is a tuberculosis (TB) diagnostic test with highest sensitivity in individuals with advanced human immunodeficiency virus (HIV). Its role in TB diagnostic algorithms for HIV-positive outpatients remains unclear. METHODS: The AIDS Clinical Trials Group (ACTG) A5274 trial demonstrated that empiric TB therapy did not improve 24-week survival compared to isoniazid preventive therapy (IPT) in TB screen-negative HIV-positive adults initiating antiretroviral therapy with CD4 counts <50 cells/µL. Retrospective LAM testing was performed on stored urine obtained at baseline. We determined the proportion of LAM-positive participants and conducted modified intent-to-treat analysis excluding LAM-positive participants to determine the effect on 24-week survival, TB incidence, and time to TB using Kaplan-Meier method. RESULTS: A5274 enrolled 850 participants; 53% were male and the median CD4 count was 18 (interquartile range, 9-32) cells/µL. Of the 850, 566 (67%) had LAM testing (283 per arm); 28 (5%) were positive (21 [7%] and 7 [2%] in the empiric and IPT arms, respectively). Of those LAM-positive, 1 participant in each arm died and 5 of 21 and 0 of 7 in empiric and IPT arms, respectively, developed TB. After excluding these 28 cases, there were 19 and 21 deaths in the empiric and IPT arms, respectively (P = .88). TB incidence remained higher (4.6% vs 2%, P = .04) and time to TB remained faster in the empiric arm (P = .04). CONCLUSIONS: Among outpatients with advanced HIV who screened negative for TB by clinical symptoms, microscopy, and Xpert testing, LAM testing identified an additional 5% of individuals with TB. Positive LAM results did not change mortality or TB incidence.

A framework for considering the risk-benefit trade-off in designing noninferiority trials using composite outcome approaches.

When a new treatment regimen is expected to have comparable or slightly worse efficacy to that of the control regimen but has benefits in other domains such as safety and tolerability, a noninferiority (NI) trial may be appropriate but is fraught with difficulty in justifying an acceptable NI margin that is based on both clinical and statistical input. To overcome this, we propose to utilize composite risk-benefit outcomes that combine elements from domains of importance (eg, efficacy, safety, and tolerability). The composite outcome itself may be analyzed using a superiority framework, or it can be used as a tool at the design stage of a NI trial for selecting an NI margin for efficacy that balances changes in risks and benefits. In the latter case, the choice of NI margin may be based on a novel quantity called the maximum allowable decrease in efficacy (MADE), defined as the marginal difference in efficacy between arms that would yield a null treatment effect for the composite outcome given an assumed distribution for the composite outcome. We observe that MADE: (1) is larger when the safety improvement for the experimental arm is larger, (2) depends on the association between the efficacy and safety outcomes, and (3) depends on the control arm efficacy rate. We use a numerical example for power comparisons between a superiority test for the composite outcome vs a noninferiority test for efficacy using the MADE as the NI margin, and apply the methods to a TB treatment trial.

Early Bactericidal Activity of Different Isoniazid Doses for Drug-Resistant Tuberculosis (INHindsight): A Randomized, Open-Label Clinical Trial.

Rationale: High-dose isoniazid is recommended in short-course regimens for multidrug-resistant tuberculosis (TB). The optimal dose of isoniazid and its individual contribution to efficacy against TB strains with inhA or katG mutations are unknown.Objectives: To define the optimal dose of isoniazid for patients with isoniazid-resistant TB mediated by inhA mutations.Methods: AIDS Clinical Trials Group A5312 is a phase 2A, open-label trial in which individuals with smear-positive pulmonary TB with isoniazid resistance mediated by an inhA mutation were randomized to receive isoniazid 5, 10, or 15 mg/kg daily for 7 days (inhA group), and control subjects with drug-sensitive TB received the standard dose (5 mg/kg/d). Overnight sputum cultures were collected daily. The 7-day early bactericidal activity (EBA) of isoniazid was estimated as the average daily change in log10 cfu on solid media (EBAcfu0-7) or as time to positivity (TTP) in liquid media in hours (EBATTP0-7) using nonlinear mixed-effects models.Measurements and Main Results: Fifty-nine participants (88% with cavitary disease, 20% HIV-positive, 16 with isoniazid-sensitive TB, and 43 with isoniazid-monoresistant or multidrug-resistant TB) were enrolled at one site in South Africa. The mean EBAcfu0-7 at doses of 5, 10, and 15 mg/kg in the inhA group was 0.07, 0.17, and 0.22 log10 cfu/ml/d, respectively, and 0.16 log10 cfu/ml/d in control subjects. EBATTP0-7 patterns were similar. There were no drug-related grade ≥3 adverse events.Conclusions: Isoniazid 10-15 mg/kg daily had activity against TB strains with inhA mutations similar to that of 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with katG mutations will be explored next.Clinical trial registered with www.clinicaltrials.gov (NCT01936831).

Limited correlation between systemic biomarkers and neurocognitive performance before and during HIV treatment.

The AIDS Clinical Trials Group (ACTG) study A5303 investigated the associations between neuropsychological performance (NP) and inflammatory biomarkers in HIV-infected participants. Fifteen NP tests were administered at baseline and week 48 to 233 ART naïve participants randomized to maraviroc- or tenofovir-containing ART. Neurocognition correlated modestly with markers of lymphocyte activation and inflammation pre-ART (percent CD38+/HLA-DR+(CD4+) (r = - 0.22, p = 0.02) and percent CD38+/HLA-DR+(CD8+) (r = - 0.25, p = 0.02)), and with some monocyte subsets during ART (r = 0.25, p = 0.02). Higher interleukin-6 and percent CD38+/HLA-DR+(CD8+) were independently associated with worse severity of HIV-associated neurocognitive disorders (HAND) (p = 0.04 and 0.01, respectively). More studies to identify HAND biomarkers are needed.

Applying a Risk-benefit Analysis to Outcomes in Tuberculosis Clinical Trials.

Although it is common to analyze efficacy and safety separately in clinical trials, this could yield a misleading study conclusion if an increase in efficacy is accompanied by a decrease in safety. A risk-benefit analysis is a systematic approach to examine safety and efficacy jointly. Both the "rank-based" and "partial-credit" methods described in this paper allow researchers to create a single, composite outcome incorporating efficacy, safety, and other factors. The first approach compares the distribution of rankings between arms. In the second approach, a score can be assigned to each outcome category, considering its severity and comparing the mean or median scores of arms. The methods were applied to the A5279/Brief Rifapentine-Isoniazid Efficacy for TB Prevention study, and design considerations for future clinical trials are discussed, including the challenge of arriving at a consensus on rankings/scorings. If well designed, a risk-benefit analysis may allow for a superiority comparison and, therefore, avoid setting a noninferiority margin. Clinical Trials Registration. NCT01404312 (A5279).

Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial.

BACKGROUND: Clinical studies suggest that isoniazid contributes rapid bacterial killing during the initial two days of tuberculosis treatment but that isoniazid's activity declines significantly after day three. We conducted a 14-day phase IIa open label, randomized trial to assess the essentiality of isoniazid in standard tuberculosis therapy. METHODS: A total of 69 adults with newly diagnosed sputum-positive tuberculosis from the South African Western Cape region were enrolled and randomized to a four-arm parallel assignment model. Participants were followed for 14 days as inpatients at either the University of Cape Town Lung Institute or at the TASK Applied Science clinical research organization. All arms received standard daily rifampicin, ethambutol, and pyrazinamide but differed as follows: isoniazid only on days one and two (n=17), isoniazid on days one and two then moxifloxacin on days three through 14 (n=16), no isoniazid (n=18), and a control group that received isoniazid for all 14 days (standard therapy, n=18). The primary endpoint was the rate of colony forming unit (CFU) decline during the first 14 days of treatment. RESULTS: For 62 participants analyzed, the initial 14-day mean daily fall in log10 CFU (95% CI) was 0·14 (0·11, 0·18) for participants receiving isoniazid for two days only; 0·13 (0·09, 0·17) for participants receiving isoniazid for two days followed by moxifloxacin; 0·12 (0·08, 0·15) for those not receiving isoniazid; and 0·13 (0·09, 0·16) for the standard therapy group. CONCLUSIONS: The 14 day EBA for the combination rifampicin, ethambutol, and pyrazinamide was not significantly changed by the addition of isoniazid for the first two days or for the first 14 days of treatment. In a post hoc analysis, significantly higher day-two EBAs were observed for all groups among participants with higher baseline sputum CFUs. Our finding that INH does not contribute to EBA suggests that INH could be replaced with another drug during standard treatment to improve efficacy and decrease rates of resistance to first-line drugs. (Funded by the NIH AIDS Clinical Trial Groups and NIH; A5307 ClinicalTrials.gov number, NCT01589497).

Similar changes in neuropsychological functioning in english and spanish speaking HIV patients.

OBJECTIVE: Primary language has been reported to influence the results of neuropsychological (NP) testing. We sought to determine whether being a primary Spanish versus English speaker affects changes in neuropsychological evaluations in persons living with HIV. METHOD: Data from 209 (188 English speakers and 21 Spanish speakers) ART-naïve HIV-infected adults were extracted from ACTG A5303, a 48-week randomized clinical trial of two HIV treatment regimens. Participants' mean (standard deviation) age and years of education were 35.1 (10.7) and 14.3 (2.7) years respectively. Changes from baseline to week 48 of antiretroviral therapy (ART) in individual, total, and domain z-scores for NP tests and Global Deficit Scores (GDS) were compared between the primary languages using linear regression models, adjusted for baseline scores and years of education. RESULTS: Baseline demographic characteristics were comparable except Spanish speakers had less years of education than the English speakers (p < 0.001). Although differences in some NP measures and domains were detected at baseline, the adjusted changes in individual, total and domain NPz-scores from baseline to 48 weeks of ART were not significantly different between the two primary language groups. The 48-week changes in GDS were also similar. CONCLUSION: Changes in NP during ART were similar between English and Spanish speaking HIV-infected individuals for all NP measures. This suggests that studies of longitudinal changes in NP can pool participants across these languages.

Hepatotoxicity During Isoniazid Preventive Therapy and Antiretroviral Therapy in People Living With HIV With Severe Immunosuppression: A Secondary Analysis of a Multi-Country Open-Label Randomized Controlled Clinical Trial.

BACKGROUND: Hepatotoxicity associated with isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) has not been well studied in severely immunosuppressed people with HIV. Our objective was to determine risk factors for hepatotoxicity in severely immunosuppressed individuals taking IPT and ART. SETTING: Multicenter study in resource-limited settings with high burden of tuberculosis. METHODS: We conducted a secondary analysis of data from 1 randomized arm of the REMEMBER trial. The analysis includes participants with pre-ART CD4 cell counts of <50 cells/µL receiving IPT and ART for 24 weeks. Hepatotoxicity was defined as elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 × upper limit of normal or symptomatic hepatitis during IPT and ART. Logistic regression was used to identify baseline risk factors for hepatotoxicity. Time to occurrence of hepatotoxicity was estimated by the Kaplan-Meier method. RESULTS: Among 426 participants (53% male, median age 35 years, median CD4 count 19 cells/µL), 31 developed hepatotoxicity (7.3%). Raised pretreatment AST/ALT (odds ratio [OR] 3.6, 95% confidence interval [CI]: 1.7 to 7.7) and hepatitis B surface antigen (HBsAg) seropositivity at baseline (OR 4.7, 95% CI: 1.7 to 12.9) were significantly associated with an increased risk of developing hepatotoxicity. Participants with both raised AST/ALT and positive HBsAg had a higher risk (OR 19.9, 95% CI: 5.3 to 74.3) and earlier onset of hepatotoxicity than participants who did not have these conditions at baseline. CONCLUSIONS: The incidence of hepatotoxicity during IPT and ART was high. Severely immunosuppressed individuals with raised pretreatment AST/ALT or HBsAg seropositivity need closer monitoring for hepatotoxicity.

Risk factors for early mortality on antiretroviral therapy in advanced HIV-infected adults.

BACKGROUND: Many HIV-infected individuals present with advanced HIV disease. These patients are at high risk of death after antiretroviral therapy (ART) initiation, but risk factors for death in these patients are unclear. METHODS: We used data from a multisite randomized trial comparing empiric vs. preventive tuberculosis therapy in HIV-infected adults initiating ART with CD4 T-cell counts less than 50 cells/µl to evaluate risk factors for death within 48 weeks after ART initiation. Cox proportional hazards models were fit to evaluate characteristics present at baseline and at 4 weeks after ART initiation, including the week 4 CD4 T-cell response and new opportunistic infections. RESULTS: Of 850 enrolled, the median pre-ART CD4 T-cell count was 18 cells/µl and 67 (7.9%) died. Baseline risk factors for death included lymphadenopathy, lower CD4 T-cell count, lower serum albumin, high white blood cell count, elevated neutrophil percentage, and lower hemoglobin. Among 746 participants with data at week 4, the median changes in CD4 T-cell count and viral load for those who died (n = 43) vs. survived were 26 vs. 56 cells/µl and -2.7 vs. -2.7 log10 copies/ml, respectively. Each 20 cell/µl lower change in week 4 CD4 T-cell count was associated with a 20% increased risk of post week-4 mortality (adjusted hazard ratio 1.20, 1.01-1.42, P = .038). CONCLUSION: Evidence of active infection and suboptimal immunologic response during the first month of ART are associated with death in the first year after ART initiation in those with advanced HIV disease taking tuberculosis preventive therapy. Strategies to reduce early mortality in this population warrant further investigation.

Neurocognition with maraviroc compared with tenofovir in HIV.

OBJECTIVE: The objective was to determine whether maraviroc (MVC) has unique neurocognitive benefits in the context of initial antiretroviral therapy (ART). DESIGN: Randomized, double-blind, placebo-controlled, 48-week trial. SETTING: Participants were enrolled in US AIDS Clinical Trials Group clinical trial sites. PARTICIPANTS: Total 262 ART-naive, chemokine coreceptor 5 tropic HIV, and HIV RNA greater than 1000 copies/ml participants were randomized, 230 participants completed the study. INTERVENTION: Participants received MVC 150 mg or tenofovir disoproxil fumarate (TDF) 300 mg on a background of ritonavir-boosted darunavir and emtricitabine. MAIN OUTCOME MEASURE(S): The neuropsychological battery of 15 tests done at baseline, week 24 and week 48 assessed seven domains, and were standardized into z-scores then converted into deficit scores and a global deficit score. The 48-week changes from baseline in the neuropsychological scores and the global deficit score were compared by Wilcoxon or Kruskal-Wallis test between arms, and among baseline impairment groups [classified as normal, mild (2 deficit scores ≥1) and moderate (2 deficit scores ≥2)]. It was hypothesized that the MVC arm would have improved neuropsychological performance over TDF. RESULTS: In this double-blind, randomized, placebo-controlled trial, there were no differences in neuropsychological performance between MVC and TDF. Those with moderate neuropsychological impairment at baseline experienced greater ART-mediated neuropsychological improvement than those with mild or no neuropsychological impairment. CONCLUSION: Improvement in neurocognitive functioning was greater with more baseline impairment but was comparable with MVC or TDF.

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial.

BACKGROUND: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings. METHODS: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per µL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080. FINDINGS: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per µL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5-7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4-7·8); absolute risk difference of -0·06% (95% CI -3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group. INTERPRETATION: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease. FUNDING: National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.

Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV-seropositive individuals with cognitive impairment.

Elevated cerebrospinal fluid (CSF) levels of markers of oxidative stress, neuronal injury, and inflammation and decreased neurotransmitter levels have been reported in HIV-associated neurocognitive disorders (HAND). Minocycline may have a neuroprotective effect by inhibiting inducible nitric oxide synthase, which produces nitric oxide, a compound that induces oxygen free radical production. In A5235, "Phase II, Randomized, Placebo-Controlled, Double-Blind Study of Minocycline in the Treatment of HIV-Associated Cognitive Impairment," minocycline was not associated with cognitive improvement, but the effect on the above CSF measures was not examined previously. The objective of this study was to examine the effect of minocycline on markers of oxidative stress, neuronal injury, neurotransmitter levels, and inflammation from CSF in participants in A5235. One hundred seven HIV+ individuals received either minocycline 100 mg or placebo orally every 12 h for 24 weeks. Twenty-one HIV+ individuals received the optional lumbar punctures. Lipid and protein markers of oxidative stress (e.g., ceramides and protein carbonyls), glutamate, neurotransmitter precursors, kynurenine metabolites, neurofilament heavy chain, and inflammatory cytokines were measured in the CSF before and after treatment. The 24-week change in ceramides was larger in a beneficial direction in the minocycline group compared to the placebo group. The two groups did not differ in the 24-week changes for other markers.These results suggest that minocycline may decrease lipid markers of oxidative stress (ceramides) in individuals with HAND; however, an effect of minocycline on other CSF markers was not observed. A larger sample size is needed to further validate these results.

Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies.

OBJECTIVE: There is limited evidence for efficacy of analgesics as monotherapy for neuropathic pain associated with HIV-associated polyneuropathies, in spite of demonstrated efficacy in other neuropathic pain conditions. We evaluated the tolerability and analgesic efficacy of duloxetine, methadone, and the combination of duloxetine-methadone compared with placebo. DESIGN: This study was a phase II, randomized, double-blind, placebo-controlled, four-period crossover multicenter study of analgesic therapy for patients with at least moderate neuropathic pain due to HIV-associated polyneuropathy. Duloxetine, methadone, combination duloxetine-methadone, and placebo were administered in four different possible sequences. The primary outcome measure was mean pain intensity (MPI) measured daily in a study-supplied pain diary. RESULTS: A total of 15 patients were enrolled from eight study sites and eight patients completed the entire trial. Study treatments failed to show statistically significant change in MPI compared with placebo. Adverse events were frequent and associated with high rates of drug discontinuation and study dropout. CONCLUSIONS: Challenges with participant recruitment and poor retention precluded trial completion to its planned targets, limiting our evaluation of the analgesic efficacy of the study treatments. Challenges to successful completion of this study and lessons learned are discussed.

Randomized trial of minocycline in the treatment of HIV-associated cognitive impairment.

OBJECTIVE: To evaluate the efficacy and safety of minocycline in the management of HIV-associated cognitive impairment. METHODS: We enrolled HIV-positive participants with a CD4 count of 250 to 500 cells/µL in a randomized, double-blind, placebo-controlled study. They received 100 mg of minocycline or matching placebo orally every 12 hours for 24 weeks. Cognitive function was measured using the Uganda neuropsychological test battery summary measure (U NP Sum) and the Memorial Sloan-Kettering (MSK) scale. The primary efficacy measure was the 24-week change in an average of 9 standardized U NP Sum z scores. RESULTS: Seventy-three participants were enrolled. Of these, 90% were female, 49% were between the ages 30 and 39 years, and 74% had 6 or more years of education. One participant had MSK score of stage 1 (i.e., mild HIV dementia), and 72 participants had MSK stage 0.5 (i.e., equivocal or subclinical dementia) at the baseline evaluation. The minocycline effect on the 24-week change of the U NP Sum compared with placebo was 0.03 (95% confidence interval -0.51, 0.46; p = 0.37). CONCLUSION: Minocycline was safe and well tolerated in HIV-positive individuals. However, it did not improve HIV-associated cognitive impairment. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that 100 mg of minocycline given orally every 12 hours for 24 weeks had no significant effect compared with placebo in the improvement of cognitive function in antiretroviral therapy-naive, HIV-positive patients.

What are the clinical implications of new onset or worsening anxiety during the first two weeks of SSRI treatment for depression?

OBJECTIVE: To evaluate the prevalence of new onset or worsening of anxiety symptoms, as well as their clinical implications, during the first 2 weeks of Selective Serotonin Reuptake Inhibitor (SSRI) pharmacotherapy for depression. METHOD: Adult outpatients with nonpsychotic major depressive disorder were enrolled in an 8-week acute phase SSRI treatment trial at 15 clinical sites across the United States. Worsening anxiety was defined as a greater than 2-point increase on the Beck Anxiety Inventory (BAI) between baseline and Week 2. New onset of anxiety symptoms was ascribed when the BAI baseline rating was 0 and the Week 2 value was greater or equal to 2 points on the BAI. RESULTS: Overall, after 2 weeks of treatment, 48.8% (98 of 201 participants) reported improvement in anxiety symptoms, 36.3% (73 of 201) reported minimal symptom change, and 14.9% (30 of 201) reported worsening of anxiety symptoms. No association was found between change in anxiety symptoms within the first 2 weeks and change in depressive symptoms or remission at the end of 8 weeks of treatment. For participants with clinically meaningful anxiety symptoms at baseline, however, worsening of anxiety during the first 2 weeks of treatment was associated with worsening depressive symptoms by 8 weeks (P = .054). CONCLUSIONS: The trajectory of anxiety symptom change early in SSRI treatment is an important indicator of eventual outcome for outpatients with major depression and baseline anxiety symptoms.

Weighted Kaplan-Meier estimators for two-stage treatment regimes.

In two-stage randomization designs, patients are randomized to one of the initial treatments, and at the end of the first stage, they are randomized to one of the second stage treatments depending on the outcome of the initial treatment. Statistical inference for survival data from these trials uses methods such as marginal mean models and weighted risk set estimates. In this article, we propose two forms of weighted Kaplan-Meier (WKM) estimators based on inverse-probability weighting-one with fixed weights and the other with time-dependent weights. We compare their properties with that of the standard Kaplan-Meier (SKM) estimator, marginal mean model-based (MM) estimator and weighted risk set (WRS) estimator. Simulation study reveals that both forms of weighted Kaplan-Meier estimators are asymptotically unbiased, and provide coverage rates similar to that of MM and WRS estimators. The SKM estimator, however, is biased when the second randomization rates are not the same for the responders and non-responders to initial treatment. The methods described are demonstrated by applying to a leukemia data set.

Insomnia in patients with depression: a STAR*D report.

INTRODUCTION: Insomnia symptoms, which are common in depression, have a significant impact on function and quality of life. However, little is known about the prevalence and associated features of insomnia symptoms in representative treatment-seeking patients with depression. METHODS: Data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were analyzed. STAR*D recruited 3,743 adult outpatients diagnosed with nonpsychotic major depressive disorder (MDD) from primary (n=18) and psychiatric care (n=23) clinics across the United States. Baseline sociodemographic and clinical features were compared between those with insomnia symptoms (84.7%) and those without (15.3%). RESULTS: The most common presentation was the simultaneous presence of sleep onset, mid-nocturnal, and early morning insomnia symptoms (27.1%). Of these three types of insomnia symptoms, mid-nocturnal insomnia symptoms were the most commonly found alone (13.5%) and in combination with one or more other types (82.3%). Insomnia symptoms were associated with several indicators of a more severe depressive illness. Only a small proportion of participants with insomnia symptoms were receiving treatment for sleep disturbances at study initiation, and the vast majority of those receiving treatment still reported having insomnia symptoms. CONCLUSION: In outpatients who seek treatment for nonpsychotic MDD in typical clinical settings, insomnia symptoms are very common, undertreated, and indicative of a more severe depression.

Early adverse events and attrition in selective serotonin reuptake inhibitor treatment: a suicide assessment methodology study report.

Adverse events during selective serotonin reuptake inhibitor (SSRI) treatment are frequent and may lead to premature treatment discontinuation. If attrition is associated with early worsening of adverse effects or the frequency, intensity, or burden of adverse effects, interventions to maximize retention could be focused on patients with these events. Outpatient participants (n = 265) with nonpsychotic major depressive disorder entered an 8-week trial with an SSRI. At baseline and week 2, specific adverse effects were evaluated with the Systematic Assessment for Treatment Emergent Events--Systematic Inquiry, and at week 2, the Frequency, Intensity, and Burden of Side Effects Rating globally assessed adverse effects. Attrition was defined by those participants who left treatment after week 2 but before week 8. No specific week 2 adverse effect, either treatment-emergent or with worsening intensity, was independently associated with attrition. Global ratings of adverse effect frequency, intensity, or burden at week 2 were also not associated with subsequent attrition. Neither global ratings nor specific adverse effects at week 2 were related to patient attrition during SSRI treatment. Other factors seem to contribute to patient decisions about continuing with treatment.

The functional impact of subsyndromal depressive symptoms in bipolar disorder: data from STEP-BD.

BACKGROUND: This report describes baseline characteristics and functional outcomes of subjects who have prospectively observed subsyndromal symptoms after a major depressive episode (MDE). METHODS: All subjects were participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). We identified subjects with at least 2 years of observation whose prior or current episode was a MDE, and who were in a stable clinical state of either recovered (no more than 2 moderate symptoms for at least 8 weeks), a MDE by DSM-IV criteria, or with continued subsyndromal symptoms. The subsyndromal group was defined a priori as 3 or more moderate affective symptoms but without meeting diagnostic criteria for major depression. RESULTS: The final cohort included 1094 recovered, 112 subsyndromal, and 310 individuals in a MDE. The average time spent in each clinical status ranged from 120 to 132 days. The subsyndromal group was most similar to those in a MDE, differing only on the intensity of depressive symptoms and the number of work days missed due to ongoing symptoms. Reported sadness, inability to feel and lassitude were each associated with multiple measures of impairment. LIMITATIONS: This study is limited by the cross-sectional approach to defining outcomes. CONCLUSIONS: These findings are consistent with studies in unipolar major depression that indicate that functional impairment observed in the context of subsyndromal depressive symptoms is comparable to that of a full episode. This work underscores the need to include subsyndromal symptoms in study outcomes and to target full remission in clinical practice.