Millions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.We analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries . Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor  plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir , or protease inhibitor monotherapy . Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events , or events that resulted in treatment modification.Between April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group , UK Medical Research Council, Instituto de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, Merck, ViiV Healthcare, WHO. Over 17 million people currently receive antiretroviral therapy (ART) for HIV infection worldwide, most of whom live in resource-limited settings. ART is usually delivered using the WHO-recommended public health approach, characterised by use of standardised sequential regimens and simplified monitoring and care.There are theoretical reasons why replacing the NRTIs with raltegravir in second-line therapy might be advantageous, primarily the absence of cross-resistance to first-line therapy. Three randomised controlled trialsEvidence before this studyWe searched PubMed using terms including “second-line therapy”, “protease inhibitors”, and the individual drug names, and reviewed relevant HIV conference abstracts to identify clinical trials done in patients who had failed on a first-line non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based combination, which compared the standard-of-care protease inhibitor plus NRTI combination for second-line therapy with either a protease inhibitor plus raltegravir combination or with protease inhibitor monotherapy. No language or date restrictions were used. No relevant studies were identified in our initial search on March 1, 2009. An updated search on June 1, 2017, using the same terms, identified three published randomised controlled trials reporting outcomes after 48 or 96 weeks' treatment with the protease inhibitor plus raltegravir combination  that concluded that this option was non-inferior, and two randomised controlled trials reporting outcomes after 48 or 96 weeks' treatment with protease inhibitor monotherapy , which concluded that this option was inferior to standard of care.Added value of this studyThis trial provides the first comparative, randomised data on long-term (144 weeks) outcomes with the protease inhibitor plus raltegravir regimen in second-line therapy. With this longer duration of follow-up, we found that non-inferiority was not consistently demonstrated across all analyses, and there was no evidence of a safety benefit with the protease inhibitor plus raltegravir regimen compared with the standard-of-care protease inhibitor plus NRTI combination. The trial also confirms that the initial response of the protease inhibitor plus NRTI regimen is durable with longer-term follow-up and that reintroduction of combination therapy restores virological suppression after prolonged protease inhibitor monotherapy, emphasising the contribution of NRTIs to second-line regimen activity.Implications of all the available evidenceTaking into account the higher cost of raltegravir, the absence of clear advantages of protease inhibitor plus raltegravir seen in any trial and the failure to show non-inferiority consistently across all analyses after 144 weeks of treatment in this trial suggest that there is no compelling reason for national programmes to adopt this combination as the standardised second-line therapy in the public health approach to antiretroviral therapy.Here, we report outcomes after 144 weeks of follow-up from the EARNEST trial, the largest of the trials assessing protease inhibitor plus raltegravir and the only trial with follow-up beyond 96 weeks, and examine its performance in subgroups relevant for resource-limited settings. We also report outcomes after reintroduction of NRTIs after an initial period of protease inhibitor monotherapy as second-line treatment.The EARNEST trial was a randomised controlled trial done in 14 sites in five sub-Saharan African countries . Eligible patients were HIV-infected adults or adolescents older than 12 years who were no longer responding to a first-line combination of NRTIs with a non-NRTI .The protocol was approved by ethics committees in all participating countries and the UK. All participants (and caregivers of adolescents younger than 18 years) provided written informed consent.vs ≥200 cells per μL). The computer-generated, sequentially numbered randomisation list (variable block sizes) was preprepared by the trial statistician and incorporated in the online secure database. Randomisation was done by the trial manager at each centre, who could access the next number, but not the whole list. Treatment was given open-label .Patients were randomly assigned (1:1:1) to one of three treatment groups. Randomisation was stratified by centre, and screening CD4 count  plus two NRTIs (protease inhibitor plus NRTI group), plus raltegravir 400mg twice per day , or alone as monotherapy  and were followed up for 144 weeks. In the protease inhibitor plus NRTI group, NRTIs were selected by the physician without resistance testing, following WHO algorithms  and taking into account side-effects on first-line, local standard-of-care, and local drug availability. The protocol initially allowed treatment with three NRTIs in Malawi . After a data monitoring committee (DMC) recommendation based on poorer viral-load suppression and more protease inhibitor resistance in the protease inhibitor monotherapy group than in the protease inhibitor plus NRTI group, patients in the protease inhibitor monotherapy group were switched to combination therapy  after May, 2013 .Patients were assessed every 4–8 weeks, with most visits done by nurses. Adherence was assessed at each visit through structured questions, with intensive adherence counselling when lapses were identified. Treatment was monitored clinically, with full blood count, alanine transaminase, serum creatinine, and urine dipstick tests for glucose, protein, and leucocytes done at weeks 12, 48, 96, and 144 after randomisation, and CD4 cell counts every 12–16 weeks in the local site's laboratory. Additional tests were permitted at the discretion of the treating clinician to evaluate and monitor incident adverse events. Within-class ART substitutions were allowed for toxicity or poor tolerability. There was no real-time viral-load monitoring, but if a patient developed clinical or immunological failure , and an alternative regimen was available locally, sites could do open local viral-load testing  after approval from a clinical expert review committee (CERC) and change treatment if needed. In the protease inhibitor monotherapy group, after the recommendation by the DMC to reintroduce combination treatment, all trial viral-load and resistance testing results were provided to the treating clinicians who were permitted to additionally test for viral load and resistance in these patients at their discretion. Women assigned protease inhibitor monotherapy who became pregnant added NRTIs while pregnant or breastfeeding. Tuberculosis was treated using rifabutin, with ART unchanged.Stanford algorithm (version 7). Subtype was determined using REGA (version 3.0). Viral loads and genotypes were reviewed by the DMC, but not provided to treating clinicians during the trial .During the trial, viral load was measured centrally  in batches of samples stored at weeks 48 and 96 using the Abbott RealTime HIV-1 assay ; individuals who did the assays were blinded to randomised allocation. After trial closure, viral-load testing was done on samples stored at weeks 4, 12, 24, 36, 64, 80, 110, 126, and 144 . Genotyping  was done blinded on all post-randomisation samples with viral load of more than 1000 copies per mL at Janssen Diagnostics . Genotyping (reverse transcriptase) of baseline samples from patients in the protease inhibitor plus NRTI group and protease inhibitor plus raltegravir group was done at the JCRC . Drug susceptibility prediction used the Neurocognitive function and peripheral neuropathy were assessed using standard methods.The primary endpoint for the 96-week analysis,For the sample size calculation, we assumed that 75% of patients in the protease inhibitor plus NRTI group would have good disease control at week 96 and 10% would be lost to follow-up. With a one-sided α of 0·025 for the non-inferiority comparison and two-sided α of 0·025 for the superiority comparison, we estimated that 400 patients per group provided 80% power to show non-inferiority of protease inhibitor monotherapy using a 10% non-inferiority margin, and 87% power to demonstrate superiority of protease inhibitor plus raltegravir assuming 10% greater response rate.2 tests, and continuous variables using mean change from baseline and t tests or ANOVA. Time-to-event endpoints were analysed using Cox proportional hazards regression and Kaplan-Meier. Generalised estimating equations  were used to test difference between groups across all visit weeks. Prevalence of intermediate-high level resistance at week 144 was adjusted for failed or missing genotypes using sampling weights.All comparisons were according to randomised arm (intention-to-treat) regardless of ART changes after randomisation. Statistical tests were two-sided and did not adjust for multiplicity. 95% CIs correspond to a two-sided test for superiority; for non-inferiority comparisons, the focus was on the lower confidence limit. The endpoint of good disease control used multiple imputations to account for missing CD4 cell count, viral loads, and genotypes (<5% of observations). Following the statistical analysis plan, the primary analysis of all other endpoints used complete-case analyses and excluded deaths, individuals lost to follow-up, and missed visits. Binary endpoints were compared using risk differences and χOf three protocol-specified viral-load thresholds , we selected 400 copies per mL as the main outcome because it is less affected by transient, low-level viral-load blips, is closest to failure thresholds used in most contemporary treatment guidelines ,Subgroup analyses comparing protease inhibitor plus NRTI versus protease inhibitor plus raltegravir groups at week 144 were done following the intention-to-treat principle, on the complete-case population using the same non-inferiority margin of 10% to compare the two treatment groups, although we recognise that the power to determine non-inferiority is lower within subgroups and the trial was not formally powered for this  of 367 participants in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL, 276 (75%) had viral loads of less than 50 copies per mL, and 321 (87%) had viral loads of less than 1000 copies per mL . At weekIn the protease inhibitor plus raltegravir group, 312 (81%) of 383 participants had viral loads of less than 400 copies per mL, 275 (72%) had viral loads of less than 50 copies per mL, and 321 (84%) had viral loads of less than 1000 copies per mL at week 144 . Viral-lvs protease inhibitor plus NRTI at week 144). Intermediate or high-level resistance to lopinavir was seen in 31 participants .In the protease inhibitor monotherapy group at week 144, 292 (78%) of 375 participants had viral loads of less than 400 copies per mL, 246 (66%) had viral loads of less than 50 copies per mL and 301 (80%) had viral load of less than 1000 copies per mL . In protThere was no difference between the three randomised groups at week 144 in the proportions of patients with good disease control (composite endpoint used for primary week 96 comparison), who were alive, were alive without new WHO stage 4 events, or who had CD4 counts of more than 250 cells per μL ; or in m2 , grade 3 or 4 adverse events , or events that resulted in treatment modification  approach or multiple secondary analyses, consistent with previously reported findings at 48–96 weeks from EARNEST and other trials.The explanation for these unexpected findings  is unclear, but pharmacokinetic factors might have an important role. Raltegravir has a low genetic barrier to resistance and relatively short half-life and might therefore be more susceptible to the development of resistance during episodes of non-adherence compared with tenofovir, which has a moderate genetic barrier and long intracellular half-life.The strengths of this trial are its size, follow-up duration, low withdrawal or loss to follow-up, and regular storage of samples for subsequent centralised viral-load and resistance testing. The broad eligibility criteria and pragmatic approach to delivering treatment  all enhance generalisability to programme settings in which most patients receive second-line ART, and viral-load testing remains challenging and resistance testing is rarely available.The main limitation of this study is that treatment was given open-label ; however, very few patients changed from their allocated treatment strategy and the main outcomes were laboratory parameters assayed blind to treatment received. Most patients were taking a zidovudine or stavudine-based NRTI regimen first-line, and switched to tenofovir at the start of second-line therapy. Current WHO guidelines indicate tenofovir is preferred in first-line, with switch to zidovudine for second-line. However, the virological efficacy of the second-line protease inhibitor plus NRTI regimen does not appear to depend on activity of particular NRTIs, so it is unlikely that this difference in the sequence of NRTIs used would have a substantial impact on our results.Our findings have important implications for the selection of regimens for second-line therapy in the public health approach. The good longer-term outcomes with the combination of a protease inhibitor (in this case lopinavir) with two NRTIs provides support for this regimen as the WHO-recommended preferred second-line combination.In settings where therapy can be individualised, a protease inhibitor plus raltegravir regimen could be of value in selected patients if used with regular virological monitoring and adjusted (with drug substitutions) as needed. In the public health approach, a decision to change the standardised sequence of regimens will affect millions of people, and the consequences of an underperforming regimen might not be easily detected and reversed at an individual level. This trial, with its unexpected outcomes, reinforces the need for robust randomised trials with substantial long-term follow-up to be done in resource-limited settings in the populations in whom the public health approach is used before recommendations are changed.


Two thirds of the world’s new HIV infections are in sub-Saharan Africa. Acute HIV infection (AHI) is the time of virus acquisition until the appearance of HIV antibodies. Early HIV infection, which includes AHI, is the interval between virus acquisition and establishment of viral load set-point. This study aimed to detect acute and early HIV infections in a hyper-endemic setting.This was a cross-sectional diagnostic study that enrolled individuals who had negative rapid HIV results in five clinics in South Africa. Pooled nucleic acid amplification testing (NAAT) was performed, followed by individual sample testing in positive pools. NAAT-positive participants were recalled to the clinics for confirmatory testing and appropriate management. HIV antibody, p24 antigen, Western Blot and avidity tests were performed for characterization of NAAT-positive samples.The study enrolled 6910 individuals with negative rapid HIV results. Median age was 27 years (interquartile range {IQR}: 23–31). NAAT was positive in 55 samples, resulting in 0.8% newly diagnosed HIV-infected individuals . The negative predictive value for rapid HIV testing was 99.2% (95% CI: 99.0–99.4). Characterization of NAAT-positive samples revealed that 0.04% (95% CI: 0.000–0.001) had AHI, 0.3% (95% CI: 0.1–0.4) had early HIV infection, and 0.5% (95% CI: 0.5–0.7) had chronic HIV infection. Forty-seven (86%) of NAAT-positive participants returned for follow-up at a median of 4 weeks (IQR: 2–8). Follow-up rapid tests were positive in 96% of these participants.NAAT demonstrated that a substantial number of HIV-infected individuals are misdiagnosed at South African points-of-care. Follow-up rapid tests done within a 4 week interval detected early and chronic HIV infections initially missed by rapid HIV testing. This may be a practical and affordable strategy for earlier detection of these infections in resource-constrained settings. Newer molecular tests that can be used at the points-of-care should be evaluated for routine diagnosis of HIV in hyper-endemic settings. Halting and reversing the spread of HIV was part of Millennium Development Goal (MDG) 6A . AlthougAcute HIV infection (AHI) refers to the time of virus acquisition until the appearance of HIV antibodies. Early or primary HIV infection, which includes AHI, is regarded as the interval between virus acquisition and the establishment of HIV viral load (VL) set-point . ChronicRapid HIV tests play a crucial role in detecting HIV infections, and thereby initiating a cascade of linking infected patients to care. These rapid tests are commonly used for diagnosis of HIV infection in low resource settings such as in sub-Saharan Africa, but have poor sensitivity for detection of early HIV infection ,9, whichManagement of early HIV infection has benefits for the infected individual, and prevents secondary spread of HIV in the population ,5. This This was a cross-sectional diagnostic study, conducted between March 2012 to June 2015, which enrolled individuals who had negative rapid HIV results and were 14 years or older. Participants were recruited and enrolled from 5 HIV counseling and testing (HCT) clinics in the Tshwane district of South Africa (SA). Four of these HCT clinics were antenatal clinics and one was a general HCT clinic. Rapid HIV testing was done according to the SA HIV testing guidelines, which recommend a serial HIV testing strategy at the points-of-care . TestingWritten consent was obtained from all participants before enrollment. The study was approved by the University of Pretoria’s Faculty of Health Sciences Ethics Committee (Protocol number– 295/2015) and by Tshwane Research Ethics Committee (TMREC 2010/26). The legal ages for consenting to HIV testing and medical treatment in South Africa are 12 and 14 years, respectively . Th. Th26]. This study showed that follow-up rapid tests done within a 4 week interval are able to detect individuals with early or chronic HIV infection previously misdiagnosed by rapid HIV tests. It is likely that other participants who came for follow-up later than the 4 week interval would have tested positive on rapid HIV tests if they had presented within this interval Tables  and 2. TParallel testing algorithm, where HIV testing at the points-of-care is done on two different rapid strips concurrently, could be considered for improving the sensitivity of rapid HIV testing at points-of-care. This strategy has been reported to have a higher sensitivity ,33. Howeth generation HIV ELISA. However, HIV ELISA is costly and laboratory-based, and thus may also lead to a high rate of loss to follow-up. Molecular tests are now available for use at the points-of-care. These are not readily available in the developing world owing to high costs [The other alternative strategy for detection of HIV-infected individuals misdiagnosed by rapid tests in resource limited countries would be to screen individuals testing negative on rapid HIV test with the 4gh costs ,39. If NAdvantages of making an accurate diagnosis of HIV infection include opportunities to preserve HIV-specific immune responses if treatment is made available early, and prevent secondary transmission in the population . There iPreventing the secondary spread of HIV during the window period is an important public health preventive measure because of extremely high viral loads during this period . IndividUndiagnosed or untreated HIV infection in pregnant women results in a high risk of vertical transmission of HIV, and this risk is much higher with early HIV infection ,43. AlthThe high frequency of new HIV infections undermines the global efforts of eliminating new HIV infections. The first 90 of 90-90-90 UNAIDS target might not be properly assessed if there are many HIV-infected individuals that are misdiagnosed by rapid tests at points-of-care in resource-constrained settings. A test and treat strategy might not have a desired impact in low resource setting if point-of-care testing for HIV is not strengthened. Misdiagnosis of HIV infection could lead to inadvertent use of pre-exposure prophylaxis in HIV-infected individuals, thus resulting in emergence and transmission of ARV drug-resistant strains.Detection of new HIV infections allows a close monitoring of the HIV epidemiology. This monitoring can be used to assess the effectiveness of the existing HIV diagnostic, treatment and prevention policies, and inform necessary changes to such policies.The finding that the majority of participants (95%) who were misdiagnosed at the points-of-care were positive on HIV ELISA is not surprising as the rapid tests have poorer sensitivity for the detection of HIV antibodies, especially during the early HIV phase . In thisOther researchers have previously showed inferior performance of some rapid HIV tests on finger-stick whole blood compared to testing done on serum in a setting where testing was done by skilled personnel . Black eThe limitations of this study are that follow-up visits for NAAT-positive participants were done at different intervals and there was no active tracing of their partners. However, all participants identified with HIV infection were encouraged to disclose to their partners, and return with them to the clinics. Repeat rapid testing from plasma samples was not done before NAAT and serology testing. If done earlier, this would have led to faster identification of HIV-infected individuals as most rapid tests were positive in plasma samples.These data show that it is feasible to detect acute, early and chronic HIV infections initially missed by rapid tests in an HIV hyper-endemic setting with limited resources. The routine implementation of a 4 week follow-up rapid test would reduce both HIV diagnostic and transmission window periods. Rapid HIV tests with higher performance in finger-stick whole blood should be used in resource poor settings with high HIV prevalence. The newer molecular tests that can be used at the points-of-care should be evaluated for routine diagnosis of HIV in HIV hyper-endemic settings.


Overactive bladder (OAB) and urinary incontinence are common problems that have significant impact on quality of life (QOL). Less than half of sufferers seek help from their physicians; many who do are dissatisfied with treatment and their physicians’ understanding of their problems. Little is known about the sociolinguistic characteristics of physician-patient communication about OAB in community practice.An IRB-approved observational sociolinguistic study of dialogues between patients with OAB and treating physicians was conducted. Study design included semi-structured post-visit interviews, post-visit questionnaires, and follow-up phone calls. Conversations were analyzed using techniques from interactional sociolinguistics.Communication was physician- rather than patient-centered. Physicians spoke the majority of words and 83% of questions were closed-ended. The impact of OAB on QOL and concerns about and adherence to treatment were infrequently addressed by physicians, who were poorly aligned with patients in their understanding. These topics were addressed more frequently when open-ended questions successfully eliciting elaborated responses were used in ask-tell-ask or ask-tell sequences.Clinical dialogue around OAB is physician-centered; topics critical to managing OAB are infrequently and inadequately addressed. The use of patient-centered communication is correlated with more discussion of critical topics, and thus, more effective management of OAB. Overactive bladder (OAB) and urinary incontinence are common problems that affect quality of life (QOL). Urinary incontinence affects 45% of women between the ages of 30 and 90, ranging from 28% of women in their thirties to 55% of women aged 80 to 90 years. The prevThis was an observational study of naturally-occurring dialogues between patients with OAB and their physicians. It was conducted in April-May 2012, with the oversight of the Independent Investigational Review Board, Inc., and designed in compliance with the Health Insurance Portability and Accountability Act of 1996 (HIPAA). All recorded participants provided informed written consent.Potential physicians (n = 1000) in community-based practices with a substantial population of OAB patients (as determined by prescribing decile on a sponsor-provided list) were invited to participate in a physician-patient communication study of patients diagnosed with OAB. The sponsor was not identified to participants and participant identities were not revealed to the sponsor.Physicians were required to be board-certified, in practice 2–30 years, full-time, in an office-based practice, spend at least 80% of time in direct care, conduct at least 75% of patient discussions in English, not have participated in market research regarding management of OAB in the past three months, and not be employed or have an immediate family member employed by a pharmaceutical company, government regulatory agency, or as a consultant to any pharmaceutical or market research agency. During an average month, primary care physicians (PCPs) were required to see at least 400 patients, and urologists, gynecologists, and urogynecologists were required to see at least 300 patients. Additionally, during an average month, PCPs, gynecologists, and urogynecologists were required to see at least five patients to discuss OAB and write at least three OAB prescriptions, and urologists were required to see at least eight patients and write at least six prescriptions. Of the last 30 OAB prescriptions they wrote, at least 80% were required to be new or refills of prescriptions that they had initiated, rather than refills of prescriptions that had been initiated by others. Of the last 30 patients who presented with OAB symptoms that they treated with prescription medication, at least 5% were required to be treated with solifenacin succinate. A total of 21 (0.021%) physicians responded, of these 17 (0.017%) met the criteria and agreed to participate, which was a typical response rate for this methodology and fell within the goal range.–19 PCPs Patients were recruited on the day of fieldwork. One member of a team of ethnographic researchers conducted a day of research at each practice. Physicians and any other recorded participants provided informed written consent. A staff member at each office invited patients with a regularly scheduled appointment that day and met the criteria, to participate in a study regarding physician-patient communication. Patients were required to have a physician-identified pre-existing diagnosis of OAB, with a scheduled visit to discuss OAB treatment, be fluent in English, not be cognitively impaired as determined by their physician, and be either a newly diagnosed (within the last six months) female patient, or an established (six months or more) male or female patient. Patients who expressed interest met with the researcher to receive study information and sign consent.One visit per patient was video- and audio-recorded without the researcher present. Following the visit, patients participated in 20-minute semi-structured interviews and completed questionnaires. Physicians participated in interviews at the end of the day, in which they answered questions about their beliefs and practices (10–15 minutes) and about each participating patient (20 minutes each). Physicians were able to use medical records to aid recall, but these were not shared with researchers. Physicians also completed written questionnaires about each patient. Physicians and patients were asked similar questions in the interviews and questionnaires to assess alignment. Approximately one month after the visit, patients were interviewed again by telephone. All participants received a small compensation for participation in the research.Overall, 56 patients were approached, all were consented, and all had their visits recorded, but some of these visits did not meet the eligibility requirements resulting in 14 patients being excluded. Of these, three did not have a diagnosis of OAB, two had limited discussion of OAB treatment, and nine established patients were excluded to achieve an approximately even distribution of newly diagnosed and established patients. The remaining 42 visits contributed to the findings, which is a typical sample size for discourse analysis.–19 Each All visits and interviews were transcribed using audio recordings. Video recordings allowed for transcript quality control and assessment of non-verbal cues (e.g. nodding). Interactional sociolinguistic methods were used. These include categorizing discourse at the word and topic level, flow of information, and the roles of those speaking., 21 An aAnalyses followed and built upon previously established sociolinguistic techniques.–21 ThesePresence, robustness, and linguistic characteristics of discussions about QOL, treatment concerns, and adherence were also assessed. Treatment changes were captured, by evaluation of visit dialogue and physician post-visit interview. “Alignment” between physicians and patients about the impact of OAB symptoms on QOL was evaluated by comparing responses to similar questions in post-visit assessments. To insure consistency in scoring, all of the ask-tell-ask sequence analysis was conducted by one of the authors (KAH) and any instances of uncertainty regarding characterization of sequences was resolved by consensus with a second author (SRH). Descriptive statistics were applied to components of interest.A total of 17 physicians and 42 patients were enrolled in the study Tables Physicians had an average of 19 years in practice and were predominantly male , Physician-patient dialogue was predominantly physician-centered. Physicians spoke 62% of the words and 83% of physician’s questions were closed-ended. Physicians  asked at least one open-ended question in 67% (n = 28) of visits. Physicians  used successful ask sequences eliciting more than a yes/no or short response in 52% (n = 22) of visits, and these constituted an average of 16% of all ask sequences, Despite conversations that comprised predominantly closed-ended questions, patients often gave elaborated responses, i.e. they went beyond the asked for “yes” or “no” and responded as though they had been asked an open-ended question. On average, there were 5.5 patient-elaborated responses per encounter and at least one patient-elaborated response in 95% of encounters.Several key topics were rarely discussed during visits. Physicians  discussed the impact of OAB on QOL in 40% (n = 17) of visits and physicians  brought it up in 19% (n = 8) of visits. However, in response to open-ended and structured questions during post-visit interviews, most patients  said that their urinary problems had a significant impact on QOL, and most physician-patient pairs were not aligned on the impact their symptoms had on QOL . Physicians  changed OAB treatment in 33% (n = 14) of visits.P = 0.912). Physicians more often identified when patients stopped medication on their own; they classified 85% of the 35 patients who admitted to stopping as sometimes nonadherent but this association was not statistically significant .Physicians  attempted to allay patients’ concerns about OAB treatments in 24% (n = 10) of visits. Physicians  discussed adherence to OAB treatment in 17% (n = 7) of visits. However, during post-visit interviews, one-third of patients prescribed medication admitted to nonadherence . Physicians believed that 63% (24 of 38) of their patients on medications always followed recommendations and that 37% (14 of 38) sometimes did not. An equal proportion 63% (24 of 38) of patients described themselves as never skipping medications and 37% (14 of 38) acknowledged that sometimes they skip or forget. However, there was no association between the patients’ self-report and physicians’ perceptions of patients’ adherence behavior. Just over half (53% n = 19) of physician-patient pairs were aligned on skipping or forgetting medication  and more ask-tell sequences  and patients had more patient elaborated responses . Treatments were changed in three of three of the encounters that included two or three ask-tell-ask sequences compared to 18% (2/11) of those with only one and 32% (9/28) of those with no ask-tell-ask sequences (P = 0.028) Physicians were more likely to change treatment for patients who were dissatisfied with their treatment  compared to those who were satisfied  or extremely satisfied . Medications were changed in 60% (6 of 10) of visits where the patient expressed their dissatisfaction during the visit compared to 25% (8 of 32) of visits where dissatisfaction was not expressed (P = 0.040)In visits where physicians changed treatments, physicians used more ask-tell-ask sequences Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S3 Text(DOCX)Click here for additional data file.S4 Text(DOCX)Click here for additional data file.S5 Text(DOCX)Click here for additional data file.S1 Data(XLSX)Click here for additional data file.


Burkitt's lymphoma (BL) is an aggressive B-cell non-Hodgkin's lymphoma and one of the fastest growing tumors in humans. It is an acquired immunodeficiency syndrome- (AIDS-) defining disease and occurs with relatively preserved CD4 cell counts. It rarely affects the orbital region in the setting of AIDS. We report unusual presentation of a fatal case of AIDS-associated BL in a 42-year-old female patient with severe CD4 cell depletion who presented with dramatic fast growing (within days) bilateral orbital masses leading to striking facial deformities. To the best of our knowledge, this is the first report of bilateral orbital involvement in AIDS-associated BL. Non-Hodgkin's lymphomas (NHLs) are the second most common malignancy in patients with the acquired immunodeficiency syndrome (AIDS). Burkitt's lymphoma (BL) is a highly aggressive NHL and is one of the fastest growing tumors in humans , 2. It wEndemic BL is usually multifocal and presents mainly as extranodal jaw or orbital masses. Unlike endemic BL, sporadic BL occurs throughout the world, very rarely involves the jaw or orbits, and commonly presents with abdominal and nodal involvement , 2. LikeWe wish to report unusual presentation of AIDS-associated BL in a 42-year-old female patient with severe CD4 cell count depletion and dramatic fast growing (within days) orbital, eyelid, and frontal masses. To the best of our knowledge, this is the first report of bilateral orbital involvement in AIDS-associated BL.3 to 48/mm3 and all 6 plasma viral load measurements yielded very high values (range: 5.4 to 6.7 log), which is suggestive of nonadherence. On examination, the patient appeared to be chronically ill and was oriented and with conjunctival pallor. Vital signs were normal.  c-myc translocation was not performed. Chemotherapy with EPOCH  and filgrastim was started. Her clinical condition, however, worsened. The total white blood cell count dropped to 50/mm3 and the patient eventually died of respiratory failure five days later.A 42-year-old HIV-infected female patient, born in and resident of Rio de Janeiro State, Brazil, was admitted to our hospital in August 2015 because of a rapidly growing painful mass in her left shoulder, first noted 4 weeks previously. She also complained of two additional smaller masses over the left eyebrow and right orbits, first noted 3 weeks earlier. The patient was first seen at our outpatient unit in May 2006 due to a diagnosis of HIV infection made in 2003. She had a history of illicit drug use (cocaine). Between 2006 and 2015, she was offered several highly active antiretroviral therapy (HAART) regimens but proved to have poor adherence to treatment. Her current prescribed regimen was lamivudine, tenofovir, atazanavir, and ritonavir. Between 2006 and 2015, the CD4 cell count dropped from 144/mm c-myc immunoglobulin (Ig) translocation. The most common translocation is t involving c-myc and IgH loci [ c-myc protein gene, resulting in rapid cell proliferation.AIDS-related lymphomas are comprised almost exclusively of high-grade tumors of B-cells. Among these, BL is the second most common histological subtype. The advent of HAART has not reduced the risk of BL in these patients, despite a decreased risk for other NHLs , 6. BL iIgH loci . BL pathHIV-associated BL most often presents with gastrointestinal and lymph node involvement, in a manner similar to sporadic BL. Orbital, ocular, and eyelid compromises are exceedingly rare. To the best of our knowledge, only four cases of orbital involvement in adult, AIDS-associated BL have been previously described –11. An a3. It is not known whether a different pathogenic trigger exists for the development of BL in patients with advanced HIV infection. No CD4 cell count data is available from previous reports of orbital BL in HIV-infected patients [It has been shown that the risk of AIDS-associated BL declines steeply at very low CD4 cell counts, suggesting that its expression may require functional CD4 lymphocytes . Therefopatients –12.BL can be successfully treated with aggressive chemotherapy. Early recognition and treatment of orbital BL can prevent permanent visual loss and disability. Patients such as ours, with severely depressed CD4 cell count, will pose treatment challenges. The administration of rituximab, for example, was avoided in the present case due to the risk of opportunistic complications.In summary, physicians who care for HIV-infected patients should be aware that AIDS-associated BL may unusually present as rapidly growing bilateral orbital masses in adult patients with very low CD4 cell counts.


This study aimed to explore the functional connectivity of the default modenetwork (DMN) in crack-cocaine users, in comparison with that observed inage-matched non-drug-using controls.Inpatient crack-cocaine users who had been abstinent for at least four weeksand age-matched non-drug-using controls underwent resting state functionalmagnetic resonance imaging. Images were acquired while the subjects restedwith their eyes closed. After data preprocessing, DMNs were defined byspatial independent component analysis and seed-based correlation analysis,by chosen regions of interest centered in the ventral anterior cingulatecortex and in the posterior cingulate cortex.The functional connectivity of the DMN determined by independent componentanalysis did not differ between the crack-cocaine users and the controls.However, the seed-based correlation analysis seeking a single metric offunctional connectivity between specific brain regions showed that thenegative connectivity between the ventral anterior cingulate cortex and theleft superior parietal lobule was significantly greater in the crack-cocaineusers than in the controls.The results suggest that selective extrinsic network connectivity of the DMNrelated to motor and executive function is impaired during crack-cocaineaddiction. How it affects the nervous system remains unknown.However, certain neural circuits are supposedly involved in the establishment andmaintenance of drug addiction(3). According to Volkow et al.(4), there are fourinterrelated circuits that are involved in or affected by drug addiction: the rewardcircuit-involving several nuclei in the basal ganglia, notably the nucleus accumbensof the ventral striatum, and relaying information to the ventral pallidum; themotivation/drive circuit-involving the orbitofrontal and subcallosal cortices,dorsal striatum, and motor cortex; the learning/memory circuit-involving theamygdala and the hippocampus; and the control circuit-which controls cognitiveflexibility and planning, involving the dorsolateral prefrontal cortex, anteriorcingulate cortex, and inferior frontal cortex. Many of these brain structures areassociated with the default mode network (DMN)(7), one of the brain networks seen in resting statefunctional magnetic resonance imaging (rs-fMRI) studies(8). The DMN is composed ofbrain regions that are typically deactivated during task demands but exhibitsynchronous low frequency oscillation in the resting state(9). It is believed that theDMN is related to attention and self-monitoring(10), or, more precisely,the general monitoring of sensory information associated with the posteriorcingulate and adjacent precuneus, as well as the evaluation of the salience of thisinformation together with the medial and orbitofrontalcortices(9). This provides a new perspective on brain functionby addressing the importance of ongoing or intrinsic activity(7).Crack-cocaine has emerged as a substance that readily supplies the active principle(cocaine) through the inhalation of smoke from burning rocks of the substance,typically by means of a pipePrevious rs-fMRI studies have identified changes in functional connectivity inindividuals who abuse or are addicted to drugs such as cocaine, heroin, morphine,nicotine, alcohol, and caffeine. However, to our knowledge, there have been no suchstudies involving individuals addicted to crack-cocaine. We hypothesized that theDMN would be affected in crack-cocaine users. Therefore, this study aimed to explorethe functional connectivity of the DMN by using independent component analysis (ICA)and seed-based correlation analysis of rs-fMRI data collected from crack-cocaineusers and age-matched non-drug-using controls.For this study, we interviewed 38 individuals with crack-cocaine addiction, asdefined in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition(DSM-IV), recruited from among those under treatment at a mental health clinic fordrug dependence treatment in the state of Espírito Santo, Brazil. Of those 38individuals, 10 met the inclusion criteria. At the mental health clinic, thesubjects were evaluated in a highly restricted and controlled environment. Urinesamples were collected for drug testing, and all of the subjects tested negative. Weacquired rs-fMRI scans in a 1.5 T scanner at the Cassiano Antônio de MoraesUniversity Hospital, operated by the Federal University of Espírito Santo.Because of technical problems during the acquisition of the images, data for two ofthe subjects were excluded from the analysis. Therefore, data for eightcrack-cocaine users were included in all analyses.As a control group, healthy, non-drug-using, aged-matched male subjects wererecruited from among the employees of the University Hospital and of the privateclinic, as well as from among students at the Federal University of EspíritoSanto. The rs-fMRI scans of the control group subjects were acquired in the samescanner as were those of the study group.The inclusion criteria for the crack-cocaine user group were as follows: being male;being over 18 years of age; meeting the criteria for a clinical diagnosis ofcrack-cocaine dependence, as defined in the symptom checklist for mental disordersof the International Classification of Diseases, 10th revision, and in the DSM-IV;being in stable clinical condition ; being able toread, write, and speak Portuguese; and presenting with no signs or symptoms ofsevere withdrawal at baseline.Subjects who were intoxicated with or in withdrawal from a substance other thancrack-cocaine were excluded, as were those who had been diagnosed with a psychiatricor physical disorder, including substance abuse disorder and addiction to anysubstance other than crack-cocaine, nicotine, or caffeine. We also excluded subjectswho had been diagnosed with epilepsy or convulsive disorder; those who hadexperienced delirium tremens during abstinence from crack-cocaine use; those with ahistory of drug hypersensitivity or adverse reactions to diazepam, otherbenzodiazepines, or haloperidol; those presenting with any contraindication for MRI,such as electronic implants, metal implants, and claustrophobia, as well aspermanent makeup or tattoo received within the last three months; and those withvascular, traumatic, inflammatory, or neoplastic processes detectable by MRI. Itshould be stated that medications were given to the crack-cocaine users to relievethe symptoms of anxiety and depression that can arise during abstinence.The study was approved by the Institutional Review Board of the Federal University ofEspírito Santo (CAAE Protocol Nos. 19403713.6.0000.5060 and13528213.2.0000.5060). The study procedures were in strict adherence to theDeclaration of Helsinki and in accordance with the ethical standards established bythe Committee on Human Experimentation of the Federal University of EspíritoSanto, where the study was conducted. All participating subjects gave writteninformed consent.We assessed ten inpatients diagnosed with crack-cocaine dependence and eightnon-drug-using controls. To do so, we used a brief structured interview designed toobtain sociodemographic data and information regarding the characteristics of druguse.The rs-fMRI scans were obtained while subjects rested quietly, with their eyesclosed but awake. The images were acquired in 1.5 T MRI scanners , with a specific 8-channelsensitivity encoding head coil , at theradiology center of the Cassiano Antônio de Moraes UniversityHospital.Functional images were acquired using a gradient echo echo-planar imagingsequence-repetition time/echo time (TR/TE): 3000/50 ms; flip angle = 90º; 35axial slices; matrix: 64 × 64; field of view = 230 mm; and voxel size:3.59 × 3.59 × 4.0 mm-with an echo planar imaging factor of 39 andan acquisition time of 10 min 9 s per subject. For registration purposes, aT1-weighted anatomical image was also acquired: TR/TE: 8.8/4.05 ms; flip angle =80º; matrix: 240 × 240; voxel size: 1 × 1 × 1 mm; 180 axialslices; field of view = 240 mm; and acquisition time = 1 min 28 s.Functional images were pre- and post-processed with the Functional MagneticResonance Imaging of the Brain software library . In brief, traditional pre-processingsteps were performed: head motion, by realigning each volume to the middlevolume; slice-timing correction; non-brain material extraction; spatialsmoothing, using a 6 mm  kernel; high-pass temporalfiltering (0.01 Hz); and normalization to the Montreal Neurological Institutestandard-space template (2-mm resolution). In addition, to reduce physiologicalnoise, tissues were segmented by using the structural T1-weighted images fromeach subject. The average white matter and cerebrospinal fluid signals werefiltered using linear regression, the residuals of that analysis being used inthe subsequent steps .(12). We performed two separate group ICAruns concatenating the time series of the individuals in each group.Images were spatially and temporally decomposed in a four-dimensional (time× voxels) data matrix into a set of time courses and associatedspatial maps with the multivariate exploratory linear decomposition intoindependent components interface of the FSL . This in(13), to generate subject-specific versionsof the spatial maps, and associated time series(14) were used inorder to test for voxel-wise group differences. We adopted a nonparametrictest, using the "randomize" permutation-testing tool of the FSL andcalculating the maximum of 5,000 permutations, with a threshold ofp = 0.05 corrected for multiple comparisons throughoutthe brain.For dual regression analysis ,the setSeed-based correlation analysis(15). The difference was that the seed-basedcorrelation analysis was based on regions of interest (ROIs), as shown in(5) defined as the main regions constituting theDMN. Thus, two ROIs (each 8 mm in diameter) were chosen, one centered in theposterior cingulate cortex and the other centered in the ventral anterior cingulate cortex . For each participant, the signalextracted from those seed regions were input into two separate whole-brainanalyses (one for each seed), allowing the positive and negativecorrelations to be evaluated. Correlation scores were converted toz-scores using Fisher'sz-transformation. We performed group-level analyses usingthe mixed-effects model implemented in the fMRI Expert Analysis Tool of theFSL, adopting a voxel threshold of z > 2.3 andcorrecting for multiple comparisons at the cluster level using Gaussianrandom field theory with a cluster significance threshold ofp = 0.05.The seed-based correlation analysis employed the same input data employed inthe ICABaseline sociodemographic characteristics and patterns of drug use are presented inThe ICA applied to the rs-fMRI data satisfactorily determined the componentrepresenting the DMN individually for subjects in the control andcrack-cocaine user groups, accurately providing the mean for each group.Neither the dual regression analyses considering the control group as thetemplate nor the randomized permutation analyses identified any differencesbetween the two groups.p <0.0322).Activities in the ventral anterior cingulate cortex  and in the posterior cingulate cortex , as depicted in In this study, we used ICA and seed-based correlation analysis to evaluate thefunctional connectivity of the DMN in crack-cocaine addicts. The seed-basedcorrelation analysis showed that the negative or antiphasic relationship between themedial frontal site of the DMN and the superior parietal lobule was stronger incrack-cocaine addicts who had abstinent for at least four weeks than it was inage-matched non-drug-using control subjects.(16). Studies employingrs-fMRI to investigate the effects or consequences of cocaine dependence haveproduced mixed results, from hyperconnectivity of the anterior cingulatecortex(17) to decreases in connectivity between the DMN andother networks(21).Exploring the DMN and its connectivity in drug addiction has been of great interestto help improve the understanding of this complex disease(6), the DMN supports processes related to emotionalprocessing , self-referential mentalactivity , and the recollection ofprior experiences (involving posterior elements of the DMN). The DMN is afunctioning network that is never inactive; its level of activity seems to vary onlyaccording to the level of consciousness(23). It remains active during mildsedation(24), anesthesia(25), and even during a vegetativestate(26), although with some variations of itsconnectivity(23), and is completely silent only in braindeath(26). Therefore, it seems reasonable to consider thatthe DMN would be affected only under extremely life-threatening conditions, whichfortunately might not be the case for crack users. In that sense, it is hearteningto have found that the overall DMN connectivity in crack users is not yet affectedin comparison with that observed in age-matched non-drug-using controls.Consequently, although the use of crack is highly detrimental to our young patientsin many ways, there is hope that there will be a good recovery, given that intrinsicbrain functioning is preserved or re-established after abstinence.The precise brain function supported by the DMN remains unknown. According toRaichle(27). In the present study,the seed-based correlation analysis showed that negative connectivity between theventral anterior cingulate cortex and the left superior parietal lobule was greaterin crack-cocaine users. This brain area, corresponding to Brodmann's area 5, issituated immediately posterior to the primary somatosensory areas , anterior and to the right of Brodmann's area 7. The superior parietal lobulehas been proven to be necessary for the executive rearrangement of information inworking memory(28), impairment of the connectivity between the medialfrontal region and the superior parietal lobule observed here in crack-cocaineusers, thus potentially being strictly related to the severe executive dysfunctiontypically seen in crack-cocaine dependent subjects(29), a condition thataggravates and maintains the drug addiction(30). Albeit intriguing, this result needs to beinterpreted with great caution and confirmed in a larger sample, especiallyconsidering that the veracity of the "negativity" between network relationships ishighly uncertain and is still a matter of debate(31).Compulsive cocaine use has been associated with a balance between increasedstriatal-anterior prefrontal/orbitofrontal connectivity and decreasedstriatal-dorsal anterior cingulate connectivityThis study has certain limitations. We included data from a small number of subjects.Although data from a larger sample were collected, many of the subjects had to beexcluded because of technical issues such as artifacts and large head movements.This study was focused only on the analysis of the DMN as the principal restingstate network of interest. Therefore, in this exploratory study, the total DMNfunctional connectivity determined by ICA was found to be preserved in crack-cocainedependent subjects who had been abstinent for at least four weeks in comparison withthat observed for age-matched non-drug-using controls. However, the negativeconnectivity between the superior parietal lobule and the ventral anterior cingulatecortex in crack-cocaine users was greatest when we performed seed-based correlationanalysis with a single metric of functional connectivity. Our results suggest that,in crack-cocaine addiction, the DMN is intrinsically unaffected, although theremight be restricted functional connectivity with a region extrinsically related tothe DMN.


All-oral regimens are associated with higher effectiveness and shorter treatment duration for chronic hepatitis C. Given its superior effect and enormous patients in China, clinicians or patients may be compelled to consider delaying treatment for all-oral regimen.To estimate cost-effectiveness of delaying treatment for all-oral regimen in the subsequent years under different assumptions about their price and efficacy compared with standard of care in China.A state-transition Markov model was developed to estimate lifetime costs and quality-adjusted life years (QALYs). Incremental cost-effectiveness ratio (ICER) and net monetary benefit (NB) were calculated. And sensitivity analyses were also performed to assess the impact of uncertainty.st year were associated with increase in QALYs of 0.62 and increase in cost of $10114 compared with initiating PegIFN regimen at present, which resulted in a positive NB of $3115.For treatment naive patients with Genotype 1, immediate treatment with all-oral regimen under assumed cost and efficacy at present was cost-effective compared with peginterferon α-2a (PegIFN) regimen at present with an ICER of $12536 per QALY gained and a positive NB of $6832 at a willingness-to-pay threshold of $21209. And it was more than 95% likely to be cost-effective if weekly drug cost was less than $1000. Moreover, patients delaying treatment for all-oral regimen in the 1From a payer perspective, all-oral regimen is associated with good long-term health and economic benefit for treatment-naive patients infected with HCV genotype 1. Particularly, if all-oral regimen would become available at lower price in the future, delaying treatment for all-oral regimen may be a good choice for patients in China. Hepatitis C virus (HCV) infection is a growing public health problem in both developing and developed countries . Recent Until then, the standard of care in China for treatment naïve patients infected with genotype 1 is peginterferon α-2a (PegIFN) or interferon α (IFN) plus ribavirin (RBV) for 48 weeks . These rAll-oral regimens may represent important improvements over current options. Ledipasvir/sofosbuvir , ombitasvir/paritaprevir/ritonavir/dasabuvir  and elbasvir/grazoprevir  could achieve SVR rate >90% and had acceptable safety profile with shorter treatment duration . In ChinLittle is known about the relative economic and health benefit of all-oral regimens for hepatitis C compared with current options in China. Therefore, the aim of our analysis was, first, to explore the balance between health benefit and expenditures under different assumptions about the price and efficacy, and second, to estimate cost-effectiveness of delaying treatment for all-oral regimens in the subsequent years given that these regimens will soon be available in China.Because CHC is a chronic disease characterized by the ongoing risk of fibrosis progression and developing advanced liver-related complications over time, a Markov modeling technique is appropriate . In thisApproximately 56.8% of HCV-positive patients were infected with HCV genotype 1b in China . Most ofAccording to Chinese guideline , all-oraRR = 0.0857 and 0.2400 for decompensated cirrhosis and hepatocellular carcinoma, respectively) [According to the natural history of CHC, patients without cirrhosis could transition to a more advanced stage of fibrosis . Becausectively) . Moreovectively) . Annual Only direct medical cost was included from the payer perspective. And there were three types of cost: drug costs, monitoring costs and health state costs. For each health state, in-patient, out-patient, emergency department, ambulatory and pharmacy costs were accounted for. All costs were converted to USD using official exchange rates as of 2016 (1 USD = 6.6594 CNY) and were inflated to 2016 prices using China Consumer Price Index (CPI) . Since aThe average costs applied to each health state were derived from published literature. A cross sectional survey had reported that more advanced the disease progress, higher costs to the condition . For patAn alternative approach to health-related quality of life (HRQOL) involves the measurement of utilities, to indicate preferences for particular health outcomes . Health-Assessing the consistency of the model was classified into three categories: internal consistency, external consistency, and between-model consistency . To inveR2 statistics of 0.979, 0.997, respectively .What’s more, between-model consistency was also assessed by comparing some features of our model with those of existing models and by comparing results simulated from our model with those of Ferrante et al . After tectively . And comWhen considering options, several factors might affect the decision to adopt appropriate treatment regimen. Most of patients may suffer from side effects because of IFN-based regimen (PegIFN). Balancing the risk of side effects and treatment effectiveness, delaying treatment for upcoming all-oral regimen would be a considerable approach for them. Therefore, scenario analysis was conducted to evaluate potential cost-effectiveness under assumed price and efficacy for different scenarios including (a) Immediate treatment with PegIFN regimen (b) delaying treatment for upcoming all-oral regimen when it was available in the next five years . IncremeC1 is the total cost of comparative regimen (higher), C2 is the total cost of reference treatment regimen, E1 is the total effectiveness of comparative regimen (higher), E2 is the total effectiveness of reference regimen and λ is the cost-effective threshold (willingness-to-pay). Lifetime costs and quality-adjusted life years (QALYs) associated with different treatment regimens were estimated from markov model. According to suggestions from World Health Organization (WHO), three times of GDP per capita worked as the cost-effective threshold. Gross domestic product (GDP) per capita of 2014 was $7070 (1 USD = 6.6594 CNY) based on the national data from National Bureau of Statistics of China [of China . TherefoMoreover, baseline characteristic (mean age or fibrosis stage) also has an impact on cost-effectiveness in the next five years. Patients should understand their fibrosis stage to help guide their own treatment decisions at different ages. And to accommodate uncertainty of cost-effectiveness results, one-way sensitivity analysis was conducted with fixed weekly drug cost of $2000 and SVR rate of 90%. Key inputs including transition probabilities (95% CI), utility estimates (±20%), discounting rate (±3%), SVR rates (±20% to a maximum of 100%) and weekly drug cost (±20%) were varied in the way that was similar to the recent study . ParticuMoreover, probabilistic sensitivity analysis was conducted and all the inputs of model were varied simultaneously. Ranges of different inputs were used to calculate the standard error for each input, which was then utilized to determine the key parameters of each specific distribution. Beta distribution was assigned to transition probabilities, utility estimates and SVR rates; Gamma distribution was assigned to each cost. 1000 independent sets of inputs were sampled from the probability distributions and a cohort of 1000 hypothetical patients per treatment regimen was modeled for each set. The results were reported using cost-effectiveness acceptability curves.st  year, this option would result in a 54%  reduction of NB compared with those treated immediately at present. Patients initiating all-oral regimen in the 1st year were associated with overall increase in QALYs of 0.62 and increase in cost of $10114 compared with PegIFN regimen, which resulted in a positive NB of $3115 and those in the next years led to negative NBs. In conclusion, patients could wait for up to one year until all-oral regimen became available. Otherwise, patients should be treated with PegIFN regimen at present. The earlier patients initiating all-oral regimen, the more economic benefits will be gained.Lifetime cumulative costs and QALYs of each regimen were estimated in According to baseline characteristic, estimates of cost-effectiveness were stratified by a series of 20 cohorts which represent possible combinations of age and fibrosis stage (4 × 5 = 20) in The result of base-case was sensitive to variations in utility estimates, weekly drug cost and SVR rates. One-way sensitivity analysis was presented using tornado diagrams in Moreover, patients could wait until all-oral regimen was available in China if it had relatively lower weekly drug cost. Under the assumed SVR rate, delaying treatment for all-oral regimen in the next two years from now on appeared to be cost-effective when weekly drug cost was less than $1500 . But if Furthermore, results of probabilistic sensitivity analysis were presented in The revolution of novel regimens is being realized at a rapid pace in western counties, yet they have not been listed in China at present. Considering the large population of patients infected with HCV in China, the demand for these new drugs is exponentially increasing over time. Particularly, all-oral regimens are associated with excellent efficacy and safety protocols. In this study, the cost-effectiveness of initiating all-oral regimen at present or delaying treatment for all-oral regimen in the next five years for Chinese patients was assessed.The results indicate that an all-oral regimen greatly improved clinical and economic effectiveness, which is also supported by previous cost-effectiveness analyses of all-oral regimens , 46. FroDue to the potential side effects and redundant treatment duration, several patients may not accept treatment at present. In this case, patients may delay treatment and wait until the all-oral regimen is listed in China with a lower price. Therefore, another important, though controversial, issue is whether delaying treatment for an all-oral regimen in the next five years is cost-effective. In our analysis, this strategy consistently appeared to be cost-effective for patients diagnosed with F1 or F2 fibrosis in all age groups. But for patients diagnosed with F0 fibrosis, they were expected to experience less advanced disease progression than those diagnosed with F1-F4 fibrosis. Therefore, treatment with PegIFN regimen for them also gained higher QALYs, resulting in a reduction in the incremental effect compared with an all-oral regimen, almost always leading to a negative NB. Accordingly, immediate treatment with PegIFN regimen may be optimal even if we expect that an all-oral regimen will soon become available in China. Because of the great impact of fibrosis stages on cost-effectiveness, HCV screening and fibrosis assessment need to be promoted for individual patients at varying ages. In the future, individualized medical treatment and economic evaluation may become increasingly common. Moreover, the price and SVR rate of an all-oral regimen is not yet known in China, and even more novel regimens are likely to enter the market along with great competition of drug price. For that reason, weekly drug cost and SVR rates were varied in the sensitivity analysis.Since there is no comprehensive cost-effectiveness analysis of novel regimen for HCV in China, our study worked as a reference for economic evaluation for the near future of China. The ideas and findings from our study are supported by those from previous cost-effectiveness analyses that also investigated the decision of delaying treatment. Leidner A.J. et al  investigThere are several limitations and concerns for our study. First, the analysis only included treatment-naive patients with genotype 1. For future research, an analysis involving a more specific patient population would be necessary for China. Because of the limited data, adherence was not considered within the simulation. Second, the symptoms of patients infected with HCV may alter over time. More recent and comprehensive cross-sectional studies need to be conducted to collect more accurate information about these changing characteristics. In particular, METAVIR fibrosis scores should be promoted in China to obtain an accurate assessment of fibrosis stages. Owing to the lack of relevant studies done in China, the annual transition probabilities in the simulation were mainly based on the results from a US setting. Furthermore, effectiveness measurements were mainly described as QALYs that were based on the utilities. Utilities of several disease states in our study were derived from the studies on Hepatitis B in the Chinese population with the assumption that the quality of life was similar between these two diseases. All of these assumptions may lead to imprecision and bias. On account of that, more specific cohort studies need to be conducted to obtain more accurate data of utilities and annual costs for Chinese patients. In addition, the costs associated with the management of adverse events were not included from a conservative point of view, resulting in an under-estimation of cost-effectiveness even though a minimal impact was made. In future studies, real-world and clinical data for Chinese patients should be of particular importance.In summary, an all-oral regimen is associated with acceptable long-term health and economic benefits in treatment-naive patients infected with HCV genotype 1. In particular, delaying treatment for the all-oral regimen may be a suitable choice if this regimen would become available at lower prices in the future. Moreover, patients with varying ages or fibrosis stages may also lead to mixed results. For those diagnosed with F1 or F2 fibrosis, delaying treatment for an all-oral regimen was recommended in the next five years under the base-case assumption. In general, an appropriate strategy needs to be chosen based on an assortment of factors to maximize both health and economic benefits.S1 TableF0–F4, Metavir fibrosis score; DC, decompensated cirrhosis; HCC, hepatocellular carcinoma; LT, liver transplant; PLT, post-liver transplant; LD, liver-related death; SVR, sustained virologic response; F4 SVR, patients diagnosed at F4 fibrosis stage achieved SVR.(DOCX)Click here for additional data file.S2 TableF0–F4, METAVIR liver fibrosis scores. DC, decompensated cirrhosis; HCC, hepatocellular carcinoma; LT, liver transplant; PLT, post-liver transplant. All costs were converted to USD using official exchange rates as of 2016 (1 USD = 6.6594 CNY) and were inflated to 2016 prices using China Consumer Price Index (CPI).(DOCX)Click here for additional data file.S3 TableF0–F4, METAVIR liver fibrosis scores. DC, decompensated cirrhosis; HCC, hepatocellular carcinoma; LT, liver transplant; PLT, post-liver transplant; SVR, sustained virologic response.(DOCX)Click here for additional data file.S1 FigR2 = 0.997 for QALYs; R2 = 0.979 for costs). The comparison of regression coefficients of these two lines illustrated that the simulated data from the model was consistent with that from the published literature .The dotted line was fitted according to the exact data from the literature; The solid line was fitted according to the simulated data from the model ((TIF)Click here for additional data file.S2 FigThis analysis was conducted with fixed weekly drug cost of $2000 and SVR rate of 90% for all-oral regimen. Only top fifteen sensitive parameters were included in the diagram and incremental cost-effectiveness ratio was calculated. SVR, sustained virologic response; PegIFN, peginterferon α-2a; F0-F4, Metavir fibrosis scores; ICER, incremental cost-effectiveness ratio.(TIF)Click here for additional data file.


Antimicrobial stewardship in allogeneic hematopoietic stem cell transplantation  recipients remains underutilized in North America. European guidelines advise de-escalation of broad-spectrum therapy after 72 hours in select patients with neutropenic fever of unknown origin. This is not commonplace in the United States, as current guidelines recommend broad-spectrum therapy until neutrophil engraftment. If de-escalating after at least 5 days of broad-spectrum therapy and defervescence in neutropenic allo-HSCT recipients does not predispose them to recurrent fever or infection, the practice could afford several benefits.Clostridium difficile–associated infections, length of stay, intensive care unit (ICU) admission incidence, in-hospital mortality rate, need for re-escalation of therapy, rate of positive blood cultures for patients who had recurrent fevers, overall antimicrobial utilization from neutropenic fever onset, and pharmacoeconomic impact.The primary end point was rate of recurrent fever. Secondary outcomes included P = .026). Patients in cohort 1 received significantly less gram-positive broad-spectrum antimicrobials, with trends toward lower use of broad-spectrum gram-negative agents and lower associated costs and no differences in length of stay, ICU admission incidence, need for re-escalation of therapy, rate of culture-positive bacteremia after de-escalation or discontinuation of broad-spectrum therapy, or in-hospital mortality rate.A total of 120 patients were assessed in 2 groups as cohort 1 (n = 46), which received early de-escalation, and cohort 2 (n = 74), which did not. The primary end point met criteria for noninferiority, as 7 patients (15%) in cohort 1 had recurrent fever within the specified time frame compared with 14 (19%) in cohort 2 (90% CI, –0.0878 to 0.1629, De-escalating after at least 5 days of broad-spectrum therapy and defervescence did not appear to affect the rate of recurrent fever. This allowed for significant reductions in gram-positive broad-spectrum antimicrobial utilization, with trends toward lower use of broad-spectrum gram-negative agents and associated costs and no difference in clinical outcomes compared with those continuing such therapy until neutrophil engraftment. Antimicrobial stewardship is a vital component of health care at numerous institutions worldwide and affords several well-documented benefits . It is w3 is observed at least once and no fever is present for more than 48 hours, regardless of the patient’s clinical status or true validity of an infectious etiology  or 38°C [100.4°F] sustained over 1 hour [Staphylococcus aureus [MRSA], vancomycin-resistant Enterococcus [VRE], or penicillin-resistant Streptococcus pneumoniae), those with hemodynamic instability, clinically suspected serious catheter-related infection, skin or soft tissue infection at any site, radiographically documented pneumonia in a setting of MRSA colonization and severe mucositis if fluoroquinolone prophylaxis has been given and ceftazidime is employed as empirical therapy. Furthermore, empiric addition of tobramycin is reserved for patients with history of infection or colonization with an MDR gram-negative pathogen, those who exhibit signs of septic shock, or patients who are otherwise clinically unstable. In the absence of a proven infection, empiric gram-positive agents and tobramycin should be discontinued after 48 hours.Patients’ clinical data were retrieved from the institution’s electronic medical record system. Patients ≥18 years of age who received an allo-HSCT and developed neutropenic fever (ANC < 500 cells/mm3 for 3 consecutive days [Staphylococcus aureus and vancomycin-resistant Enterococcus polymerase chain reaction (PCR) screening was implemented on the day of admission for every patient, with VRE screening conducted on a once weekly basis thereafter. Antimicrobial order and utilization data were captured via bar code administration of medications and the associated documentation of time, route, drug, dose, and dosing frequency in the electronic medical record.Cohort 1 represents patients who were de-escalated early, defined as switching from broad-spectrum antimicrobial therapy to their original prophylactic antimicrobial agent while still neutropenic. Switches between broad-spectrum agents  were not included in this cohort. Cohort 2 represents patients who continued such therapy until neutrophil engraftment (ANC ≥ 500 cells/mmive days ). All paive days , 14. A 5Clostridium difficile–associated infections, length of stay , ICU admission incidence, in-hospital mortality rate, need for re-escalation of therapy , rate of culture-positive bacteremia after de-escalation or discontinuation of broad-spectrum therapy, overall antimicrobial utilization from neutropenic fever onset, and pharmacoeconomic impact.The primary end point was rate of recurrent fever within 72 hours of antimicrobial de-escalation. A 72-hour time frame was chosen as it has been previously utilized in an effort to minimize inclusion of any fever or antimicrobial re-escalation secondary to new infectious and/or noninfectious causes . This peDemographic information included gender, age, height, weight, and body surface area. Pretransplant information collected included MRSA or VRE colonization, viral serologies , Karnofsky Performance Status (KPS) score, Sorror Comorbidity score, and ANC at admission. Primary malignancy, human leukocyte antigen match, graft-vs-host disease (GVHD) prophylaxis regimen, conditioning regimen (myeloablative vs reduced-intensity), and transplant days (any day from day of transplant to discharge or death) were also reported. Other variables assessed included ANC at neutropenic fever onset, quick Sepsis-related Organ Failure Assessment (qSOFA) score at administration of broad-spectrum therapy for neutropenic fever, time to and duration of neutropenic fever, antimicrobial utilization prior to de-escalation, noninfectious causes of fever or prolonged neutropenia post-transplant, and time to neutrophil engraftment. Days of therapy were assessed as any day a patient received broad-spectrum antimicrobials for the management of the first episode of neutropenic fever. To account for patients potentially receiving more antimicrobials secondary to prolonged hospitalizations, utilization data were standardized per 1000 transplant days, which were defined as the number of days from day of transplant to hospital discharge. The WHO Defined Daily Dose (DDD) Index was employed as a measuring unit for each agent as recommended for drug utilization studies . A slight tests or Mann-Whitney U tests were conducted for continuous variables, while χ2 tests or the Fisher’s exact test were employed for categorical variables. A P value of less than .05 was considered statistically significant. The primary end point was calculated with SAS software, while secondary outcome data and patient characteristics were analyzed using IBM SPSS Statistics version 21.To calculate the sample size necessary to meet power, an expected success proportion of 6% was utilized based on the rate of recurrent fever described in previous literature . AssuminAntimicrobial utilization data were derived based on the entire treatment course of the first episode of neutropenic fever and the first subsequent course of re-escalation therapy if initiated within 72 hours. The rationale was selected with a similar manner of thought—to eliminate antimicrobial re-escalation secondary to new infectious or noninfectious causes. Using the average wholesale price (AWP) at the time of data analysis, every individual dose administered over the study period was assigned a price and summed together to provide the cost of broad-spectrum antimicrobial therapy.P = .025). Patients in cohort 1 took an average of 18 days to reach neutrophil engraftment , compared with 15 days  in cohort 2 (P < .001).One-hundred twenty allo-HSCT recipients met assessment criteria during the study period, with 46 in cohort 1 and 74 in cohort 2. Baseline patient characteristics were similar between the 2 groups, as were transplant demographics . The majP = .026). Re-escalation or re-initiation of broad-spectrum therapy, as previously defined, occurred in 19 of the 21 patients with recurrent fever within 72 hours. Analysis of individual group rates revealed 7 patients in cohort 1 (15%) compared with 12 (16%) in cohort 2 (P = .884). In this patient subset, there was no difference in average time to re-escalation , nor was there a difference in mean days of gram-positive , gram-negative , or overall  agent utilization between cohorts 1 and 2, respectively.For the primary end point, a total of 21 patients in the overall study population (18%) had recurrent fever within the 72-hour time frame. Cohort 1 had 7 such incidences (cohort rate = 15%), while cohort 2 had 14 (cohort rate = 19%), which met criteria for noninferiority  and per 1000 transplant days (P = .012) (P = .668) or among survivors only , incidence of ICU admission , occurrence of Clostridium difficile–associated infections , or in-hospital mortality rate , there were no significant differences between cohort 1 and cohort 2 in any secondary clinical outcomes for the hospitalization course  . Whethern course . No patiTo our knowledge, this is the first published study to date evaluating de-escalation of broad-spectrum therapy for neutropenic fever of unidentified origin in adult allo-HSCT recipients who are still neutropenic. While the concept is not entirely new, limited literature exists on early de-escalation in HSCT recipients and the oncology population overall, especially this early in the course of therapy. Our study found that the rate of recurrent fever in the early de-escalation group (cohort 1) was comparable with the rate in those patients who continued on broad-spectrum therapy until neutrophil engraftment (cohort 2). Furthermore, none of the patients in either cohort with recurrent fevers had a subsequent culture-proven bacteremia. The similar baseline and transplant characteristics of the 2 groups  serve toWhile the primary end point demonstrated that there was no disadvantage to stopping broad-spectrum therapy early, others helped illustrate several potential benefits of utilizing this approach. As expected, cohort 1 had fewer days of broad-spectrum antimicrobial use per patient of both gram-negative and gram-positive broad-spectrum agents, with a significant reduction in the latter . UtilizaSome of the difference in antimicrobial utilization between the groups may be attributable to the higher initial use of gram-positive agents at the onset of neutropenic fever in cohort 2. The reason for this difference could not be identified. For patients presenting with neutropenic fever, the NCCN and IDSA guidelines recommend that vancomycin (or an agent with similar gram-positive activity) should be included in the initial regimen if a specific indication like a catheter-related infection, skin or soft-tissue infection, MRSA colonization, pneumonia, or hemodynamic instability exists , 9. In aAlthough one concern with stopping broad-spectrum therapy early may be the possibility of recurrent infection and subsequent need for re-escalation, this was not the case in our study. Whether de-escalating to a prophylactic agent in cohort 1 while the patient was still neutropenic or stopping antibacterial coverage altogether in cohort 2 after the patient had reached neutrophil engraftment, there was no difference in the proportion of patients requiring re-escalation within 72 hours of stopping broad-spectrum therapy. Additionally, examining those who required re-escalation revealed no difference between the groups in time to re-escalation of therapy or subsequent days of broad-spectrum agent utilization. Further, none of the patients with recurrent fevers in either cohort developed a bacteremia or suffered mortality. These low rates of adverse outcomes after early de-escalation are in alignment with the results of several similarly designed studies featured in a recent article by Orasch et al. that argued in support of such practices and the ECIL-4 recommendations . While sLimitations of this study include its retrospective study design, thus the inability to control for all variables that may influence the primary end point in addition to selection bias. This potential selection bias for de-escalation resulted from the Infectious Diseases service’s role as a consult service, which can only make recommendations for early de-escalation. The final decision at our institution rests with the primary transplant team. It is important to note that this study does not demonstrate superiority of early de-escalation of broad-spectrum therapy in allo-HSCT recipients with neutropenic fever of unknown origin, only illustrating that its outcomes appear to be no worse than continuing broad-spectrum therapy until neutrophil engraftment. In our study, patients who were de-escalated from broad-spectrum therapy early did not experience an increased incidence of bacteremias, ICU stay, or mortality. Future prospective studies with larger sample sizes and more robust study design  are needed to make any definitive conclusions regarding the superiority of this practice. In addition, any pharmacoeconomic assessments made in this study represent a rough estimate of the potential cost savings as we utilized the overall antimicrobial use data for the analysis. Such assessments were not designed to be the main focus of the article or to draw significant conclusions from, but only to promote the general idea that the implementation of early de-escalation practices could have a positive financial impact at an institution.Clostridium difficile, all of which become bigger issues as patients remain on broad-spectrum therapy for prolonged periods of time.Despite its limitations, this study has already impacted current practice at our institution in several ways. Utilization of these data has been implemented into our transplant department’s standard operating procedures. Both autologous HSCT (auto-HSCT) and allo-HSCT patients with neutropenic fever of unknown origin who have received 5 days of broad-spectrum therapy and been afebrile for ≥48 hours are routinely de-escalated back to their original prophylactic agent. Implementation of this protocol has increased the general awareness of the importance of antimicrobial stewardship, not just in the instance of neutropenic fever but for all infections. It has also encouraged the development of a similar study for hematology patients receiving induction therapy, in addition to an even more aggressive approach for HSCT patients in the future—one similar to that recommended by the ECIL guidelines . General principles from this study could have a great impact on outside practice as well. Early de-escalation of broad-spectrum therapy may promote cost savings on drug purchases and potentially facilitate earlier discharges with patients coming off broad-spectrum intravenous antimicrobials earlier in their stay. More importantly, it can help slow the development of resistant pathogens and infections from fungi and In summary, this study demonstrates many advantages of promoting antimicrobial stewardship in allo-HSCT recipients with neutropenic fever. De-escalating to a prophylactic agent after at least 5 days of broad-spectrum therapy and defervescence did not appear to adversely affect the rate of recurrent fever. This practice allowed for a reduction in broad-spectrum antimicrobial utilization, duration, and cost with no difference in key clinical outcomes in comparison with those who continued on such therapy until neutrophil engraftment.