Deferred Treatment Group Research Articles

Immediate Versus Deferred Systemic Therapy in Patients With Mesothelioma

BackgroundThe 2018 ASCO pleural mesothelioma (PM) treatment guideline states that “a trial of expectant observation may be offered” in patients with asymptomatic inoperable epithelioid mesothelioma with low disease burden. The aim of our analysis was to evaluate clinical characteristics and outcomes in PM-patients managed with initial observation and deferred treatment initiation. MethodsWe retrospectively collected clinicodemograhic and outcome data of patients with inoperable PM. Patients were assigned to 2 treatment decision groups: decision to start immediate systemic treatment (Immediate Treatment Group) versus observation and deferring treatment (Deferred Treatment group). ResultsOf 222 patients with advanced PM, systemic treatment was started immediately in the majority of patients (189, 85%; immediate group); treatment was deferred in 33 (15%) patients (deferred group); systemic therapy was chemotherapy-based in 91% and 79% respectively. Patients in the deferred group were older (70 vs 67 years, p = .05), less likely to have stage IV disease (28% vs. 51%, p = .08) and more often had epithelioid histology (90% vs. 70%, p = .03). Nineteen patients (58%) in the deferred group eventually received treatment.With a median follow-up time of 10.9 months median overall survival (OS) in the entire cohort was 12.4 months and was significantly longer in the deferred group (20.6 months vs. 11.5 months, p = .02). No difference in median progression-free survival (PFS) in first-line treatment between groups was seen (5.4 and 5.3 months). ConclusionThis real-world analysis suggests that deferral of systemic therapy and close observation may not impact OS or physician-assessed PFS in selected PM-patients.

Long-term physical and psychiatric morbidities and mortality of untreated, deferred, and immediately treated epilepsy.

In Australia, 30% of newly diagnosed epilepsy patients were not immediately treated at diagnosis. We explored health outcomes between patients receiving immediate, deferred, or no treatment, and compared them to the general population. Adults with newly diagnosed epilepsy in Western Australia between 1999 and 2016 were linked with statewide health care data collections. Health care utilization, comorbidity, and mortality at up to 10 years postdiagnosis were compared between patients receiving immediate, deferred, and no treatment, as well as with age- and sex-matched population controls. Of 603 epilepsy patients (61% male, median age = 40 years) were included, 422 (70%) were treated immediately at diagnosis, 110 (18%) received deferred treatment, and 71 (12%) were untreated at the end of follow-up (median = 6.8 years). Immediately treated patients had a higher 10-year rate of all-cause admissions or emergency department presentations than the untreated (incidence rate ratio [IRR] = 2.0, 95% confidence interval [CI] = 1.4-2.9) and deferred treatment groups (IRR = 1.7, 95% CI = 1.0-2.8). They had similar 10-year risks of mortality and developing new physical and psychiatric comorbidities compared with the deferred and untreated groups. Compared to population controls, epilepsy patients had higher 10-year mortality (hazard ratio = 2.6, 95% CI = 2.1-3.3), hospital admissions (IRR = 2.3, 95% CI = 1.6-3.3), and psychiatric outpatient visits (IRR = 3.2, 95% CI = 1.6-6.3). Patients with epilepsy were also 2.5 (95% CI = 2.1-3.1) and 3.9 (95% CI = 2.6-5.8) times more likely to develop a new physical and psychiatric comorbidity, respectively. Newly diagnosed epilepsy patients with deferred or no treatment did not have worse outcomes than those immediately treated. Instead, immediately treated patients had greater health care utilization, likely reflecting more severe underlying epilepsy etiology. Our findings emphasize the importance of individualizing epilepsy treatment and recognition and management of the significant comorbidities, particularly psychiatric, that ensue following a diagnosis of epilepsy.

Novel Renal Autologous Cell Therapy for Type 2 Diabetes Mellitus Chronic Diabetic Kidney Disease: Clinical Trial Design

Background: Cell therapies explore unmet clinical needs of patients with chronic kidney disease with the potential to alter the pathway toward end-stage kidney disease. We describe the design and baseline patient characteristics of a phase II multicenter clinical trial utilizing the novel renal autologous cell therapy (REACT), by direct kidney parenchymal injection via the percutaneous approach in adults with type 2 diabetic kidney disease (T2DKD), to delay or potentially avoid renal replacement therapy. Design: The study conducted a prospective, multicenter, randomized control, open-label, phase II clinical trial between an active treatment group (ATG) receiving REACT from the beginning of the trial and a contemporaneous deferred treatment group (DTG) receiving standard of care for 12 months before crossing over to receive REACT. Objectives: The objective of this study was to establish the safety and efficacy of 2 REACT injections with computed tomography guidance, into the renal cortex of patients with T2DKD administered 6 months apart, and to compare the longitudinal change in renal function between the ATG and the DTG. Setting: This was a multicenter study conducted in major US hospitals. Patients: We enrolled eighty-three adult patients with T2DKD, who have estimated glomerular filtration rates (eGFRs) between 20 and 50 mL/min/1.73 m². Methods: All patients undergo an image-guided percutaneous kidney biopsy to obtain epithelial phenotype selective renal cells isolated from the kidney tissue that is then expanded ex vivo over 4–6 weeks, resulting in the REACT biologic product. Patients are randomized 1:1 into the ATG or the DTG. Primary efficacy endpoints for both study groups include eGFR measurements at baseline and at 3-month intervals, through 24 months after the last REACT injection. Safety analyses include biopsy-related complications, REACT injection, and cellular-related adverse events. The study utilizes Good Clinical and Manufacturing Practices and a Data and Safety Monitoring Board. The sample size confers a statistical power of 80% to detect an eGFR change in the ATG compared to the DTG at 24 months with an α = 0.05. Limitations: Blinding cannot occur due to the intent to treat procedure, biopsy in both groups, and open trial design. Conclusion: This multicenter phase II randomized clinical trial is designed to determine the efficacy and safety of REACT in improving or stabilizing renal function among patients with T2DKD stages 3a–4.

Elbasvir/Grazoprevir for HCV Infection in Russia: A Randomized Trial.

PurposeHepatitis C virus (HCV) infection is a major healthcare concern in Russia, where almost 5 million individuals are viremic. Elbasvir/grazoprevir is a fixed-dose combination therapy for the treatment of HCV genotype 1 and genotype 4 infection. The present analysis aimed to assess the safety and efficacy of elbasvir/grazoprevir in individuals with HCV infection enrolled at Russian study sites in the C-CORAL study.Patients and MethodsC-CORAL (Protocol PN-5172-067; NCT02251990) was a Phase 3, placebo-controlled, double-blind study conducted throughout Asia and Russia. Treatment-naive participants with chronic HCV infection were randomly assigned to receive immediate or deferred treatment with elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks. Participants in the immediate-treatment group received elbasvir/grazoprevir for 12 weeks, and those in the deferred-treatment group received placebo for 12 weeks, followed by open-label elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12).ResultsOne hundred and nineteen Russian participants were randomized (immediate-treatment group, n=88; deferred-treatment group, n=31). Most participants were white (99%) with HCV genotype 1b infection (97%) and mild-to-moderate (F0–F2) fibrosis (70%). SVR12 was achieved by 98.9% participants in the immediate-treatment group and by 100% of those receiving deferred elbasvir/grazoprevir in the deferred-treatment group. One participant relapsed with nonstructural protein 5A (NS5A) L28M and Y93H resistance-associated substitutions at baseline and at time of failure. Drug-related adverse events were reported by 19% of participants receiving elbasvir/grazoprevir in the immediate-treatment group and by 16% of those receiving placebo in the deferred-treatment group. No serious adverse event or deaths occurred, and no participant discontinued treatment owing to an adverse event.ConclusionElbasvir/grazoprevir for 12 weeks was highly effective in treatment-naive Russian individuals with HCV genotype 1b infection.

Deferred treatment with sofosbuvir–velpatasvir–voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1

Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir-velpatasvir-voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment. This open-label, deferred treatment substudy was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. Patients who received placebo in the primary study and who did not have a new clinically significant illness at the post-treatment week 4 assessment were eligible to enter this substudy. Participants received a combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) once daily for 12 weeks. The primary efficacy outcome was achievement of sustained virological response (defined as HCV RNA concentration below the lower limit of quantification) 12 weeks after the end of treatment (SVR12). The primary safety outcome was the proportion of patients who discontinued treatment due to adverse events. This study is registered with ClinicalTrials.gov, number NCT02607735, and the EU Clinical Trials Register, number 2015-003455-21. 152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, of whom 147 were enrolled from March 30, 2016, to Oct 12, 2016. All 147 patients completed treatment, and 143 (97%; 95% CI 93-99) achieved SVR12. Four (3%) patients had virological relapse; all had HCV genotype 1a infection and one also had compensated cirrhosis. The most common adverse events were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]). No deaths, treatment discontinuations, or treatment-related serious adverse events occurred. Supporting the results from the blinded portion of the phase 3 primary study, the single-tablet regimen of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was safe, well tolerated, and highly effective in patients with chronic HCV infection who had previous treatment failure with NS5A inhibitor-containing regimens. A salvage regimen for this population represents an important advance for patients with limited retreatment options. Gilead Sciences.

Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4–5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomised, double-blind, placebo-controlled trial

In the C-SURFER study, therapy with the all-oral elbasvir plus grazoprevir regimen for 12 weeks in patients with chronic hepatitis C virus (HCV) infection and stage 4-5 chronic kidney disease resulted in a high rate of virological cure compared with placebo. Here, we report sustained virological response (SVR), safety data, health-related quality-of-life (HRQOL), and virological resistance analyses in patients in C-SURFER who received immediate antiviral therapy or who received placebo before therapy. In this phase 3, multicentre, randomised, placebo-controlled study, we randomly assigned adults with HCV genotype 1 infection and stage 4-5 chronic kidney disease enrolled at 68 centres worldwide to either elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks beginning at week 16 (deferred treatment group). The primary safety and efficacy endpoints for the immediate treatment group and placebo phase of the deferred treatment group have been reported previously. Here, we report safety and efficacy data for the treatment phase of the deferred treatment group, as well as HRQOL assessed using the 36-Item Short Form Health Survey for all groups, and baseline and treatment-emergent resistance-associated substitutions (RASs). SVR at 12 weeks (SVR12) was assessed in the modified full analysis set (FAS), defined as all patients excluding those who did not receive at least one dose of study drug, who died, or who discontinued the study before the end of treatment for reasons determined to be unrelated to HCV treatment. This trial is registered with ClinicalTrials.gov, Number NCT02092350. Between March 30 and Nov 28, 2014, 235 patients were enrolled and received at least one dose of study drug. The modified FAS included 116 patients assigned to immediate treatment and 99 assigned to deferred treatment. 115 (99·1%; 95% CI 95·3-100·0) of 116 assigned to immediate treatment achieved SVR12 compared with 97 (98·0%; 92·9-99·7) of 99 assigned to deferred treatment. In patients with genotype 1a infections, SVR12 was achieved by 11 (84·6%) of 13 patients with detectable baseline NS5A RASs and in 98 (100%) of 98 without. HRQOL did not differ at week 12 between immediate treatment and the placebo phase of deferred treatment. Safety was generally similar between patients receiving immediate treatment and those receiving placebo in the deferred treatment group. One serious adverse event during deferred treatment (interstitial nephritis) and one during the placebo phase of deferred treatment (raised lipase concentration) were deemed related to study drug. Four patients died, one who received immediate treatment (cardiac arrest) and three who received deferred treatment (aortic aneurysm, pneumonia, and unknown cause); all four deaths were considered unrelated to study drugs. Of the three deaths in the deferred treatment group, one occurred during placebo treatment and two occurred before starting active treatment. There were no notable differences in aminotransferase elevations in the deferred treatment group compared with the immediate treatment group, and no patients in the deferred treatment group had total bilirubin elevations. These data add to the growing body of clinical evidence for the fixed-dose combination regimen of elbasvir plus grazoprevir for 12 weeks and support use of this therapy in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. Merck Sharp & Dohme.

Efficacy and Safety of Elbasvir/Grazoprevir in Patients with Chronic Hepatitis C Virus Infection and Inherited Blood Disorders: Final Data from the C-Edge Ibld Study

Efficacy and Safety of Elbasvir/Grazoprevir in Patients with Chronic Hepatitis C Virus Infection and Inherited Blood Disorders: Final Data from the C-Edge Ibld Study

Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial.

Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID). To evaluate elbasvir-grazoprevir in treating HCV infection in PWID. Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688). Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States. 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT). The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks. The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events. The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event. These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID. Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT. Merck & Co.

Deferred Treatment Is Associated with Improved Overall Survival in Patients with Newly Diagnosed Mantle Cell Lymphoma

Background: Although mantle cell lymphoma (MCL) has traditionally been considered an aggressive lymphoma with shortened survival, the long-term outcomes and initial presentation can be heterogeneous. Martin et al (JCO 2009) reported that 32% of patients with MCL at an academic referral center deferred therapy for at least 3 months, with a median overall survival (OS) of 64 months for patients treated within 90 days of diagnosis and median OS not reached for those who deferred therapy. We used the National Cancer Database (NCDB) to perform a national cohort analysis of the impact of deferred therapy in MCL.Methods: The NCDB is a nationwide oncology outcomes database sponsored by the Commission on Cancer of the American College of Surgeons and the American Cancer Society, capturing nearly 70% of all newly diagnosed cases of cancer in the United States. We included all patients ≥18 years old who received initial treatment for newly diagnosed MCL in 2004-2011. MCL patients were identified by the International Classification of Diseases for Oncology code 9673 and variables of interest were captured using the Facility Oncology Registry Data Standards. Patients were determined to have received deferred therapy if their time to initial treatment was > 90 days. Chi-square tests were used as appropriate to compare baseline characteristics between immediate and deferred treatment groups, and OS was estimated using the Kaplan-Meier method. Log-binomial regression models were developed to identify characteristics associated with deferred treatment and multivariable Cox proportional hazard models were fit to evaluate the relationship between deferred treatment and OS.Results: Of 8209 patients with MCL, 492 (6.1%) received therapy > 90 days from diagnosis with a median time to treatment for this group of 121 days (range 91-1152). Among all patients, 64% were > 60 years of age, 73% were male, 85% were stage III/IV, and 83% had primarily nodal disease. Additional comorbidities were identified in 22% of patients, and 28% of patients presented with B-symptoms at diagnosis. Approximately 1/3 of patients received therapy in a high volume teaching/research institution. Compared to patients treated within 90 days of diagnosis, patients receiving deferred therapy were more likely to have early stage disease (22% vs 15% p<0.0001), extranodal presentation (24% vs 17%, p<0.0001), to be located in the Northeast region (26% vs 20%, p<0.0001), and to be treated at a high volume teaching/research institution (41% vs 33%, p=0.005). Patients treated within 90 days of diagnosis more commonly had B-symptoms (29% vs 16%, p<0.0001). There were no significant differences between the two groups with regard to gender, age, year of diagnosis, socioeconomic status (based on location of residence), or primary payer. When analyzed in a multivariable model, lack of B-symptoms (RR 1.67, 95% CI 1.38-2.03, p < 0.0001) and extra-nodal status (RR 1.24, 95% CI 1.00-1.53, p = 0.0468) were two strong clinical predictors of deferred therapy. Multivariable analysis demonstrated improved OS for patients who received deferred therapy (HR 0.79: 95% CI 0.67-0.93, p = 0.005; See Figure 1). Additional significant predictors of improved OS included age ≤ 60 years (HR 0.60: 95% CI 0.54-0.66, p < 0.0001), early stage disease (HR 0.66: 95% CI 0.59-0.74, p < 0.0001), lack of B-symptoms (HR 0.75: 95% CI 0.70-0.81, p < 0.0001), and lack of comorbidities (HR 0.63: 95% CI 0.58-0.68, p < 0.0001). Non-Hispanic black patients had inferior OS compared to the other racial/ethnic groups. Among patients who deferred therapy, male gender (p=0.046), age ≤ 60 years (p=0.0002) and lack of comorbidities (p<0.0001) were associated with improved OS, while remaining variables including region, stage, race, B-symptoms, and extranodal presentation were not.Discussion: This national cohort analysis supports prior reports that deferred therapy in MCL is safe for a subgroup of patients with MCL. We found that deferred therapy > 90 days was associated with improved OS and that lack of B-symptoms was a strong predictor for deferred therapy. Predictors of improved survival for patients deferring therapy included young age and lack of comorbidities. These data support use of watchful waiting approach for well-selected newly diagnosed MCL patients. [Display omitted] DisclosuresCohen:BMS: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Millennium: Consultancy; Celgene: Consultancy; Janssen: Research Funding. Flowers:Infinity Pharmaceuticals: Research Funding; Acerta: Research Funding; Millennium/Takeda: Research Funding; AbbVie: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Onyx Pharmaceuticals: Research Funding; Janssen: Research Funding; OptumRx: Consultancy; Spectrum: Research Funding; Seattle Genetics: Consultancy; Infinity Pharmaceuticals: Research Funding; Genentech: Research Funding; Millennium/Takeda: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Pharmacyclics: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Celegene: Other: Unpaid consultant, Research Funding; OptumRx: Consultancy.

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. Merck Sharp & Dohme Corp.

CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5-year data from CIPRA HT-001.

Port-au-Prince, Haiti. To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals. Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was <200 cells/mm(3). The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up. A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm(3), 95% confidence interval [CI] 477-515 vs. 373 cells/mm(3), 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis. Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm(3) can result in long-term immune dysfunction and persistent increased risk for TB.

Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3–pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7.0 years (IQR 5.2-8.7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0.78, 95% CI 0.56-1.08; p=0.13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0.54, 95% CI 0.4-0.73, p<0.0001), with 5-year progression-free survival of 47.6% (95% CI 38.8-55.9) in the immediate treatment group and 31.8% (24.2-39.6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. Lilly, Canadian Cancer Society Research.

Optimisation of antiretroviral therapy in HIV-infected children under 3 years of age.

Optimisation of antiretroviral therapy in HIV-infected children under 3 years of age.

Outcome of early vs. deferred antiviral treatment for recurrent hepatitis C in liver transplant recipients

The optimal timing to treat recurrent hepatitis-C virus (HCV) after liver transplantation (LT) remains uncertain. We compared the outcome of early (acute phase) and deferred (chronic phase) antiviral treatment for recurrent HCV infection in this population. Consecutive HCV genotype-1 infected LT patients receiving antiviral therapy between 2001-2010 were retrospectively classified according to histology at treatment start into the early or deferred treatment group. Measured endpoints included sustained virological response (SVR) rates and long-term survival. The study cohort comprised 105 patients: 60 (57%) received early treatment (ET) and 45 (43%) deferred treatment (DT). The median interval from LT to antiviral start was 3 (1-9) and 18 months (11-74) in ET and DT respectively. The SVR rate was similar in both treatment groups (23% ET and 36% DT; p = 0.27). After a median follow-up of 5.8 years, all-cause and liver-related mortality were similar in both groups. Variables independently associated with mortality included pre-treatment bilirubin > 2 mg/dL (HR 6.1, 95%CI: 2.8-13.7; p < 0.001), donor age > 60 (HR 3.1, 95%CI: 1.4-6.7; p = 0.01), and failure to achieve SVR (HR 10.3, 95%CI: 1.3-18.3; p = 0.03). In conclusion, early treatment of recurrent HCV is safe, but does not lead to higher SVR rates. In HCV-infected LT recipients, elevated bilirubin, older donor age, and failure to achieve SVR are independently associated with increased mortality.

Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): a multicentre, randomised, open-label trial

The optimum time to start antiretroviral therapy for children diagnosed with HIV infection after 1 year of age is unknown. We assessed whether antiretroviral therapy could be deferred until CD4 percentages declined to less than 15% without affecting AIDS-free survival. In our multicentre, randomised, open-label trial at nine research sites in Thailand and Cambodia, we enrolled children aged 1-12 years who were infected with HIV and had CD4 percentages of 15-24%. Participants were randomly assigned (1:1) by a minimisation scheme to start antiretroviral therapy at study entry (early treatment group) or antiretroviral therapy to start when CD4 percentages declined to less than 15% (deferred treatment group). The primary endpoint was AIDS-free survival (based on US Centers for Disease Control and Prevention category C events) at week 144, assessed with the Kaplan-Meier analysis and the log-rank approach. This study is registered with ClinicalTrials.gov, number NCT00234091. Between March 28, 2006, and Sept 10, 2008, we enrolled 300 Thai and Cambodian children infected with HIV, with a median age of 6·4 years (IQR 3·9-8·4). 150 children were randomly allocated early antiretroviral therapy (one participant was excluded from analyses after withdrawing before week 0) and 150 children were randomly allocated deferred antiretroviral therapy. Median baseline CD4 percentage was 19% (16-22%). 69 children (46%) in the deferred treatment group started antiretroviral therapy during the study. AIDS-free survival at week 144 in the deferred treatment group was 98·7% (95% CI 94·7-99·7; 148 of 150 patients) compared with 97·9% (93·7-99·3; 146 of 149 patients) in the early treatment group (p=0·6). AIDS-free survival in both treatment groups was high. This low event rate meant that our study was underpowered to detect differences between treatment start times and thus additional follow-up of study participants or future studies are needed to answer this clinical question.

AIDS Drug Programs Tighten Belts Even as Medications Are Shown to Curb Contagion

THE TROUBLED ECONOMY IS CREATing funding shortfalls for AIDS Drug Assistance Programs (ADAPs), even as financial difficulties increase the need for help among some of the low-income HIV/AIDS patients who rely on these programs to supply their medication. Meanwhile, the need for such programs continues to intensify in the wake of a recent large-scale international study that demonstrated the effectiveness of oral antiretroviral drugs in safeguarding the uninfected sexual partners of individuals with HIV infection. The trial showed protective benefits when these drugs were taken by HIV-positive persons with an immune system that was still relatively uncompromised (the immediate-treatment group). Data from this randomized controlled trial from the HIV Prevention Trials Network (HPTN) were released in May, earlier than the scheduled 2015 completion date for the study, because of the markedly positive results. The ongoing trial (HPTN 052) is now being modified to offer antiretroviral therapy to all HIV-infected study participants in the deferred-treatment group, according to Myron S. Cohen, MD, chair of the study and director of the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill.

Unruptured Intracranial Aneurysms

The preventive treatment of unruptured aneurysms has been performed for decades despite the lack of evidence of a clinical benefit. Reports of observational studies such as the International Study of Unruptured Intracranial Aneurysms (ISUIA) suggest that preventive treatments are rarely justified. Are these reports compelling enough to guide clinical practice? The ISUIA methods and data are reviewed and analysed in a more conventional manner. The design of the appropriate clinical research program is approached by steps, reviewing potential problems, from the formulation of the precise research question to the interpretation of subgroup analyses, including sample size, representativity, duration of observation period, blinding, definition of outcome events, analysis of cross-overs, losses to follow-up, and data reporting. Unruptured intracranial aneurysms observed in ISUIA ruptured at a minimal annual rate of 0.8% (0.5-1%), despite multiple methodological difficulties biased in favour of a benign natural history. Available registries do not have the power or the design capable of providing normative guidelines for clinical decisions. The appropriate method to solve the clinical dilemma is a multicentric trial comparing the incidence of a hard clinical outcome events in approximately 2000 patients randomly allocated to a treatment group and a deferred treatment group, all followed for ten years or more. Observational studies have failed to provide reliable evidence in favour or against the preventive treatment of unruptured aneurysms. A randomized trial is in order to clarify what is the role of prevention in this common clinical problem.

Study design, recruitment, and baseline characteristics: the Department of Veterans Affairs Dental Diabetes Study

We are conducting a clinical trial of the efficacy of periodontal therapy in the improvement of glycaemic control in veterans with poorly controlled diabetes. This report describes study design, recruitment and randomization and compares baseline characteristics of the sample frame with those randomized into study groups. Veterans with poorly controlled diabetes were randomized in two groups: immediate periodontal therapy ("early treatment") or usual care followed by periodontal therapy ("deferred treatment"). Half of each group continued care for 12 months; the other half returned to their usual care. We studied baseline patient characteristics, self-reported health measures, and clinical examination data. We examined means for continuous variables, frequencies for categorical variables and compared groups using t-tests and chi(2) tests (alpha=0.05 for both). The 193 randomized participants were younger (58 years) and had slightly higher HbA1c (10.2%) than the 2534 non-randomized participants (64 years, HbA1c =9.8%). The deferred treatment group was more likely than the early treatment group to have a history of stroke, transient ischaemic attacks, and less likely to be current or former smokers. The mechanism for randomization was largely successful in this study.

Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial

The relative risks and benefits of starting or withholding antiepileptic drug treatment in patients with few or infrequent seizures are unclear. We sought to compare policies of immediate versus deferred treatment in such patients and to assess the effects of these policies on short-term recurrence and long-term outcomes. We undertook an unmasked, multicentre, randomised study of immediate and deferred antiepileptic drug treatment in 1847 patients with single seizures and early epilepsy. Outcomes comprised time to first, second, and fifth seizures; time to 2-year remission; no seizures between years 1 and 3 and between years 3 and 5 after randomisation; and quality of life. Analysis was by intention to treat. 404 patients invited to join the trial did not consent to randomisation; 722 were subsequently assigned immediate treatment with antiepileptic drugs and 721 were assigned deferred treatment. Immediate treatment increased time to first seizure (hazard ratio 1.4 [95% CI 1.2 to 1.7]), second seizure (1.3 [1.1 to 1.6]), and first tonic-clonic seizure (1.5 [1.2 to 1.8]). It also reduced the time to achieve 2-year remission of seizures (p=0.023). At 5-years follow-up, 76% of patients in the immediate treatment group and 77% of those in the deferred treatment group were seizure free between 3 and 5 years after randomisation (difference -0.2% [95% CI -5.8% to 5.5%]). The two policies did not differ with respect to quality of life outcomes or serious complications. Immediate antiepileptic drug treatment reduces the occurrence of seizures in the next 1-2 years, but does not affect long-term remission in individuals with single or infrequent seizures.

A Cognitive Behavioral Group Approach to Enhance Adherence to Hemodialysis Fluid Restrictions: A Randomized Controlled Trial

Adhering to fluid restrictions represents one of the most difficult aspects of the hemodialysis treatment regimen. This report describes a randomized controlled trial of a group-based cognitive behavioral intervention aimed at improving fluid-restriction adherence in patients receiving hemodialysis. It was hypothesized that the intervention would improve adherence, measured by means of interdialytic weight gain (IWG), without impacting negatively on psychosocial functioning. Fifty-six participants receiving hemodialysis from 4 renal outpatient settings were randomly assigned to an immediate-treatment group (ITG; n = 29) or deferred-treatment group (DTG; n = 27). Participants were assessed at baseline, posttreatment, and follow-up stages. Treatment consisted of a 4-week intervention using educational, cognitive, and behavioral strategies to enhance effective self-management of fluid consumption. No significant difference in mean IWGs was found between the ITG and DTG during the acute-phase analysis (F(1,54) = 0.03; P > 0.05). However, in longitudinal analysis, there was a significant main effect for mean IWG (F(1.76,96.80) = 9.10; P < 0.001) and a significant difference between baseline and follow-up IWG values (t55 = 3.85; P < 0.001), reflecting improved adherence over time. No adverse effects of treatment were indicated through measures of psychosocial functioning. Some significant changes were evidenced in cognitions thought to be important in mediating behavioral change. The current study provides evidence for the feasibility and effectiveness of applying group-based cognitive behavior therapy to enhance adherence to hemodialysis fluid restrictions. Results are discussed in the context of the study's methodological limitations.