Functional near-infrared spectroscopy (fNIRS) identifies neurophysiological differences between psychiatric disorders by assessing cortical hemodynamic function. Few trials have studied differences in brain functional activity between first-episode medication-naïve depression patients (FMD) and recurrent major depression (RMD). We aimed to determine the differences between FMD and RMD in oxygenated hemoglobin concentration ([oxy-Hb]), and to investigate the correlation between frontotemporal cortex activation and clinical symptoms.We recruited 40 patients with FMD, 53 with RMD, and 38 healthy controls (HCs) from May 2021 to April 2022. Symptom severity was assessed with the 24-item Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). A 52-channel fNIRS measured changes in [oxy-Hb] during VFT performance.p < 0.05), but there was no significant difference between the two patient groups. Analysis of variance showed that mean [oxy-Hb] activation was lower in both the frontal and temporal lobes in the MDD group compared with HCs (FDR p < 0.05). Additionally, patients with RMD had a significantly lower hemodynamic response in the right dorsolateral prefrontal cortex (DLPFC) and dorsal frontal pole cortex (DFPC) than patients with FMD (FDR p < 0.05). No significant correlation was found between changes in mean [oxy-Hb] and either medical history or clinical symptoms (FDR p < 0.05).Both patient groups performed poorly during the VFT task compared with HC (FDR The presence of different neurofunctional activity in some of the same brain regions in FMD and RMD patients implied a link between the level of complexity activation in frontal regions and the stage of MDD. Cognitive impairment may already be present at the beginning of an MDD episode.www.chictr.org.cn, identifier ChiCTR2100043432. Major depression disorder (MDD) is a common global psychiatric disorder marked by low mood, loss of interest or pleasure, anhedonia, and low self-worth . The curDifferences between first-episode medication-naive depressed patients (FMD) and RMD have been described. One study found that patients with RMD were more likely to experience anxiety, fatigue, and sleep problems that affected their quality of life and increased the risk of recurrent episodes compared with FMD patients . Sheets Previous studies have shown differences in brain function between FMD and RMD. A functional magnetic resonance imaging (fMRI) study identified different blood oxygenation-level dependent (BOLD) signals in frontoparietal region of patients with FMD and RMD, increased activation of the right inferior frontal gyrus and bilateral middle frontal gyrus and decreased activation of the right middle frontal gyrus in patients with RMD . A similFunctional near-infrared spectroscopy (fNIRS) is an emerging functional neuroimaging modality which may be particularly suited as a diagnostic and efficacy prediction tool for psychiatric disorders. The technology can continually monitor hemodynamic changes in the cerebral cortex using near-infrared light . WavelenWe hypothesized that hypoactivation of the frontotemporal cortex is typical of patients with MDD, and the degree of frontotemporal [Oxy-Hb] activation differs between FMD and RMD. The primary study aim was to use fNIRS to explore differences of changes in the features of specific cortical regions in HCs, and patients with FMD and RMD when performing the Chinese version of VFT. fNIRS may identify biomarkers that predict the recurrence of depression and add the pathogenesis of what is known of depressive episodes. The secondary aim was to investigate the relationship between cortical [oxy-Hb] and clinical factors, probing the brain areas associated with symptom severity.Outpatients and inpatients with MDD at the Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China, were recruited between May 2021 and April 2022. Experienced psychiatrists diagnosed 40 first-episode medication-naïve MDD and 53 recurrent MDD patients following the criteria of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fifth edition. For all patients, we used the 24-item Hamilton Depression Rating Scale (HAMD-24) to assess the severity of depression. We used the 14-item Hamilton Anxiety Rating Scale (HAMA-14) to measure anxiety levels. The inclusion criteria were (1) 18–60 years of age, (2) HAMD-24 score ≥ 20, (3) ≥9 years of education, and (4) right-handed. The exclusion criteria were (1) severe and unstable physical illness, (2) received electroconvulsive therapy within 1 year, (3) family history of mental disorders, (4) a history of drug/substance abuse or addiction, (5) pregnancy or breastfeeding, and (6) do not agree to participate in the fNIRS study.Thirty-eight HC participants were recruited from the local community. They were all right-handed, free of medication, between 18 and 60 years old, and had a senior middle school or higher education. An experienced psychiatrist evaluated each participant to exclude mental illness using the International Neuropsychiatric Interview. Those with long-term substance abuse, severe medical illness, or cognitive impairment were excluded. The Ethics Committee of the Second Affiliated Hospital of Xinxiang Medical University  approved the study (No. XYEFYLL2021-27), which was registered with the Chinese Clinical Trials Registry (ChiCTR2100043432). Each participant gave informed consent.Before the trial began, participants practiced the VFT with the Chinese character “大,” which means “big.” The exercise was necessary to ensure that participants understood the task and responded correctly to the prompts. The task paradigm included a 30 s pre-task baseline period, a 60 s task period, and a 70 s post-task baseline period. During the pre- and post-task periods, participants were asked to count from one to five repeatedly and aloud. The 60 s task period was divided into three sequential 20 s blocks. During each block, one of three Chinese syllables  was audibly presented to the participants, who were then asked to generate as many phrases or four-character idioms as possible, speaking softly . The phrBefore recording fNIRS measurements, participants were asked to sit straight on a comfortable chair in a quiet room. To avoid artifacts, participants focused on a red dot on the wall about 2 m in front of them, and were told to minimize blinking and head, body and mouth movements during the VFT. The VFT was performed using a 52-channel NIRS system  and two wavelengths of near-infrared light (695 nm and 830 nm) to measure relative changes in [oxy-Hb] based on a modified Beer–Lambert law. The probes, including 17 emissions and 16 detectors, forming a 52-channel configuration, were covered on the bilateral frontal and temporal cortices, and fixed with 3 × 11 thermoplastic shells. The distance between the emission and the detector probes was 3.0 cm, and the area measured between the probes was defined as a channel . The sam1 System noise and physiological changes were removed with the hemodynamic response function (HRF) and a wavelet-minimum description length (MDL)-based detrending method  was employed after adjusting for age and duration of illness. One-sample t-test were used to compare within-group task-related [oxy-Hb] vs. [oxy-Hb] = 0 (null hypothesis). The combined equivalent dose was calculated for patients who received more than one drug in each class  version 25.0 .Differences in demographic and clinical variables were compared with appropriate tests. Continuous variables were tested by one-way analysis of variance or Student’s ch class . The reft = −5.590, p < 0.001) and number of episodes  were significant.The clinical characteristics of the three groups are shown in F = 8.196, p = 0.001) by the FMD, RMD, and HC groups . Post hoc pairwise comparisons showed that performance was worse in the FMD (p = 0.000) and RMD (p = 0.002) groups than in the HCs. The difference in the performance of the FMD and RMD groups was not significant (p = 0.083).There were significant differences in the number of words generated during the VFT  in the FMD group. In the RMD group, there were 12 channels with significant increases of [oxy-Hb] . In the HCs, except for channel 6, all the others were significantly active (FDR p < 0.05), as shown in A significant increase in the [oxy-Hb] changes occurred during the task period in 43 channels,. The results of post hoc tests revealed that the FMD group had significantly lower activation of [oxy-Hb] than the HC group in six channels . Compared with the HC group, patients with RMD had lower [oxy-Hb] activation in 26 channels . When duration of illness was included as a covariate, the RMD group demonstrated significant hypoactivation relative to FMD at 2 channels during the VFT , as shown in We found prefrontal activation during VFT was significantly different among the three groups in 27 channels . In patients with RMD, VFT performance was positively correlated with mean [oxy-Hb] changes in six channels . Before the FDR correction, FMD group mean [oxy-Hb] changes and the duration of illness were negatively correlated in one channel , and age at onset were positively correlated in one channel . Age of onset, duration of illness, and number of depressive episodes were not significantly associated with mean [oxy-Hb] changes in the RMD group. However, none of correlations remained significant after FDR correction (FDR p < 0.05). In the FMD group, HAMA score and [oxy-Hb] activation were positively correlated in channel 23 , but not with the HAMD-24 scores. The mean [oxy-Hb] in the RMD group changes were positively correlated with HAMD-24 scores in channel 11  and the HAMA scores in channel 46 . We did not find significant correlations of mean [oxy-Hb] changes with antidepressant, anxiolytic, or antipsychotic drug dose. There were also no significant correlations with any of the 52-channels after FDR correction.In patients with FMD, mean [oxy-Hb] changes had a significant positive correlation with the VFT performance in five channels  and dorsal frontal pole cortex (DFPC) occurred in the RMD but not in the FMD group.Patients with MDD spoke significantly fewer words during the VFT compared with controls, which is consistent with evidence that patients with MDD have cognitive impairment , 34. PreWe observed significant increases of the mean [oxy-Hb] in 51 channels in HCs, in the bilateral frontotemporal lobes, which consistent with most previous fNIRS studies –40. ThosWe had a very encouraging discovery that patients with RMD had significantly lower mean [oxy-Hb] changes in channel 12  and channel 16  during the VFT compared with patients with FMD, and the channels located in RDLPFC and DFPC. The DLPFC is involved in executive function, including executive control of working memory, thinking activity, and executive control of behavior , 47. It The VFT was not associated with a significant correlation between mean [oxy-Hb] and depression severity in either the FMD or the RMD group. That was consistent with previous studies. Huang et al.  did not As the RMD patients were on medications, we evaluated correlation of the use of various classes of medications with changes in [oxy-Hb], but none were significant. In a cross-sectional study, stepwise regression to control for any confounding factors influencing frontal centroid value did not find significant associations of clinical variables with the frontal centroid value . Large sThe VFT revealed cognitive impairment in all patients with FMD and RMD. The study also confirmed the presence of asymmetry in brain activation in patients with MDD and significant differences in the signals of RDLPFC and DFPC brain regions under fNIRS measurements in FMD and patients with RMD. Our results confirmed the relationship between the [oxy-Hb] signal in the aforementioned brain regions and MDD. It also showed that MDD-specific pathology needed further study. The activation patterns measured by fNIRS were used to aid clinical diagnosis. The findings increase our understanding of the pathogenesis and clinical predictors of patients with MDD. RDLPFC and DFPC are expected to be important targets for interventions to prevent recurrent episodes of MDD.One of the study limitations was that all patients with RMD were taking medications and we could not exclude the influence of medication and anxiety disorders on the psychiatric disorders. However, for ethical and safety reasons, it was considered unacceptable to recruit patients with RMD and not allow them to receive medication. Regardless, we did not find any relationships between mean [oxy-Hb] changes and drug dose in the RMD group. Also, we included the first-episode in patients without medication, which might have an original pattern of cognitive impairment in patients with FMD. Secondly, unlike fMRI and PET, there is no standard analysis of NIRS data, and different research groups have performed analyses based on different complex analysis tools , 62. AddThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Second Affiliated Hospital of Xinxiang Medical University . The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.TY, JL, and ZZ designed the study. TY, HW, HD, and GC collected the data. TY, JH, and HW analyzed the experiment data. TY drafted the manuscript. TY, JM, JZ, JW, and ZZ approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.


Despite strong induction chemotherapy response rates, only 30%-40% of patients with adult B-cell acute lymphoblastic leukemia (ALL) attain long-term remission. This study analyzes ALL in Latin America (LA) and recommends diagnosis, treatment, and management protocols.The Americas Health Foundation organized a panel of hematologists from Argentina, Brazil, Chile, Colombia, and Mexico to examine ALL diagnosis and therapy and produce recommendations.Lack of regional data, unequal access to diagnosis and therapy, inadequate treatment response, and uneven health care distribution complicate adult ALL management. The panel recommended diagnosis, first-line and refractory treatment, and post-transplantation maintenance. Targeted treatments, including rituximab, blinatumomab, and inotuzumab ozogamicin, are becoming available in LA and must be equitably accessed.This review adapts global information on treating ALL to LA. Governments, the medical community, society, academia, industry, and patient advocates must work together to improve policies. Its epidemiology varies widely among populations, on the basis of ethnicity and other factors.Acute lymphoblastic leukemia (ALL) is a heterogeneous malignant disease with a notable proliferation of immature lymphoid cells that invade the bone marrow, blood, and extramedullary sites.Key ObjectiveThis review provides a state-of-the-art series of recommendations for treating adult B-cell acute lymphoblastic leukemia in Latin America.Knowledge GeneratedThis review, written by a panel of oncologists from Argentina, Brazil, Chile, Colombia, and Mexico, provides detailed first- and second-line treatment protocols for patients in the region.RelevanceTo advance targeted treatment and precision medicine, all stakeholders must collaborate to create and enforce policies that provide the best available care for patients.2 Although there have been improved outcomes for pediatric patients, adult prognosis remains poor. In addition, adult patients with precursor B-cell ALL present with high-risk (HR) genetic alterations four times more often than pediatric patients. Despite high response rates to induction chemotherapy, only 30%-40% of adult patients achieve long-term remission.3 This review examines the landscape and challenges of ALL in Latin America (LA) and provides recommendations for its diagnosis and treatment tailored to the region. The recommendations are based on an extensive literature review and expert opinion to contribute to uniform patient care and improved outcomes.Interestingly, Latin American populations have a lower incidence among all subtypes of leukemias except ALL, where Latin Americans have a higher incidence and a more dismal prognosis.The Americas Health Foundation (AHF) gathered nine ALL hematologists from Argentina, Brazil, Chile, Colombia, and Mexico. They held a 3-day conference on February 20-22, 2022, to generate recommendations for diagnosing, treating, and managing adult ALL in LA. The AHF researched ALL through PubMed, MEDLINE, and EMBASE. Treatment, diagnosis, management, and allogeneic hematopoietic stem-cell transplantation in combination with Latin America, Argentina, Brazil, Chile, Colombia, and Mexico were searched with dates ranging from January 1, 2016, until December 10, 2021. The articles identified were in English, Portuguese, and Spanish. The AHF supplemented this search by contacting thought leaders in the LA medical community to ensure that the list appropriately reflected the relevant areas. This manuscript's authors include all the specialists who attended the conference.The AHF prepared questions to address barriers restricting access to ALL diagnosis and treatment in LA and allocated one to each panel member (Data Supplement). Panel members submitted written responses to their question on the basis of the literature and their knowledge. The panel examined and modified each narration during the 3-day meeting via multiple debate rounds. An AHF staff member moderated the debate. The panel unanimously endorsed the recommendations on the basis of the facts obtained, professional opinion, and personal experience. The completed paper was sent to the panel for evaluation and approval after the conference.2 A global analysis found the highest incidence of leukemia in Hispanic people, with 35 cases per million.4 Data suggest that the rate has been increasing rapidly over time and a worse prognosis was observed when compared with other ethnic groups. The underlying cause for this is unknown although several hypotheses exist, including socioeconomic disparities, environmental risks, and genetic variants.8There are scarce epidemiologic data on ALL in LA. Still, retrospective studies indicate that ALL may be more prevalent in people of LA descent than in the United States and Europe. The US's SEER Program reported a frequency of 18 cases per million for all ages and races. However, in the Latin population in the United States, the proportion increased significantly to 26.6 cases per million.9 Transplant data may support the hypothesis that ALL is more prevalent in LA. For instance, a comparison of patients undergoing allogeneic hematopoietic stem-cell transplants  because of ALL in LA (27%) was higher than those in Europe (16%).11 More regional data are crucial to determine the actual prevalence of ALL, understand the disease behavior, and improve regional patient outcomes.The lack of regional data on ALL reflects the methodology used in the public health registries, where data are either lacking or only provided as a histopathologic diagnosis. A study of over 1,000 adults in LA with leukemia diagnosed by multiparametric flow cytometry (MFC) found that 519 patients were diagnosed with leukemia (51%). Of those, 486 patients (93.6%) had B-cell lineage.1 20%-66% of LA residents face health care barriers like long wait times, geographical distances, availability, accessibility, and convenience.12 In LA and the Caribbean, the percentage of the gross domestic product (GDP) invested in health care is less than half that of the US level.13Geography, natural resources, politics, development, racial and ethnic representation, education, wealth distribution, and health care are diverse in LA.14 Basic treatment is generally guaranteed. However, high-cost therapies and medications like monoclonal antibodies (MoAbs) and allo-HSCT8 are often inaccessible. In some cases, sponsored programs from the pharmaceutical industry fund these therapies, providing a short-term solution to access.14Access to adequate diagnosis and treatment of ALL is often challenging in LA. A survey conducted by the American Society for Hematology and LA Hematology societies showed that countries in LA have heterogeneous access, which varies according to whether the patient has public or private health insurance.15 Initial workup should include a thorough medical history, physical examination, laboratory assays, and imaging studies.16The diagnosis of ALL was based on 2016 WHO classification guidelines that integrate the characterization of cell morphology, immunophenotypes, genetics, and cytogenetics.17 Emerging data are appearing in LA in the pediatric population.18Patients with Philadelphia-like ALL are highly heterogeneous, with a broad spectrum of genetic alterations requiring different identification approaches.1 Although the suggested diagnostic workup permits the identification of some HR subsets, clinical risk groups are further determined by several disease- or host-related factors. Response dynamics refine prognoses. Patients presenting with no risk factors are defined as standard-risk (SR). Classic prognostic factors are shown in Table 19 However, some of these parameters have been identified, at least in part, as surrogate markers for other abnormalities, in particular, genetic alterations.Identifying risk factors and stratification are needed to select appropriate treatment regimens and assess allo-HSCT eligibility.20 Multiparameter flow cytometry has been widely used because it is faster, relatively inexpensive, and sensitive. However, it requires significant technical expertise and standardization. Recognizing the benefits of the MFC, low-income countries have increased efforts for widespread adoption to allow for broader data reproducibility.Treatment response is recognized as a prognostic factor in ALL. The measurable residual disease (MRD), which is the presence of disease in patients in complete remission (CR) by conventional analysis, has become the standard measure for evaluating the prognostic impact of treatment. Flow cytometry and molecular methods can be used to detect MRD:quantitative polymerase chain reaction (qPCR) for immunoglobulin variable region heavy-chain gene rearrangements, qPCR for gene fusions, and next-generation sequencing can measure MRD, with a high correlation in results between molecular and immunophenotype assays.21 A result of positive MRD indicates treatment resistance and, thus, the need for allo-HSCT or targeted therapy.18 Only one targeted therapy, blinatumomab, is approved to eradicate MRD.22Current recommendations are to incorporate MRD in making therapeutic decisions, considering MRD+ after induction and in early consolidation a powerful predictor of relapse and low overall survival (OS).23In general terms, adults' response to ALL treatment remains unsatisfactory. In pediatric patients, long-term remissions have reached 90% in some series, depending on risk factors. By contrast, adults have a 5-year OS of <45%. Patients older than 60 years are a particularly vulnerable group, not only because of the disease but also the frailty and comorbidities this group generally presents, with only 20% attaining 5-year OS.1 With promising results, the transition toward personalized treatment appears to be underway. An intelligent combination of conventional chemotherapy with novel drugs has the potential to change the game in the treatment of ALL.However, novel drugs such as tyrosine kinase inhibitors (TKI), MoAbs-directed against CD19, CD20, and CD22 and drugs interfering with the overexpression of genes involved in tumor survival offer opportunities to personalize therapy on the basis of clinical characteristics and organ fitness of the patient.21 Several protocols are used in LA to treat adults with ALL.34 Results with first-line regimens used in LA for adult patients with B-cell precursor ALL are shown in Table The patient's age range  must be considered when determining the best ALL treatment, and treatment goals differ accordingly. The first-line treatment typically includes four phases over 2-3 years: induction, consolidation, intensification, and long-term maintenance. In addition, directed treatment is given to treat or prevent central nervous system (CNS) disease. The protocol includes serial intensive intrathecal chemotherapy with methotrexate alone or methotrexate, cytarabine, and corticosteroids in conjunction with high-dose intravenous methotrexate and cytarabine. In select patients, cranial radiotherapy may be needed in the case of CNS leukemia .1 The most frequently used protocols are given in Tables 36 may be used in young adults, according to each center's expertise.Different prospective trials have validated the role of first-line treatment with pediatric-inspired protocols in adolescents and young adults. The primary treatment is continuous exposure to intensive and cumulative doses of nonmyelotoxic drugs such as asparaginase and corticosteroids. These protocols have early patient stratification per response during and/or after induction and consolidation, increasing chemotherapy doses when the therapeutic response is unfavorable. Administered hematopoietic growth factors avoid delaying the number of cycles.37 The CR was 92%, and with a median follow-up of 63 months, OS and CR were 38% in 5 years.38 Hyper-CVAD is highly myelosuppressive and requires well-organized and funded departments. Early death rate and OS were worse compared with pediatric-inspired protocols in patients younger than 45 years in Mexican experience.34Hyper-CVAD Table  is an inP < .001).39In the CALGB-8811 Table , patient40 The aim is to reduce toxicity while striving for MRD− status.When treating elderly patients, hematologists must consider treatment morbidity and mortality and eligibility for highly intensive consolidation therapies such as allo-HSCT, in addition to performance status. Treatment recommendations range from low-intensive protocols such as a combination of vincristine and corticosteroids or 6-mercaptopurine + vincristine + methotrexate + prednisone, whose objective is solely disease control, to moderate-intensity protocols on the basis of multiple drugs. Specifically for patients older than 60 years, the protocols must be adjusted using lower doses such as mini-Hyper-CVAD or GRAALL SA1.42 Combining imatinib with corticosteroids is feasible and can induce CR in most patients with Ph+ ALL without the need for hospitalization. Moreover, results from the EWALL-Ph-01 trial showed a 96% CR rate with dasatinib and low-intensity chemotherapy combination in elderly patients with high comorbidity scores and a 5-year OS of 36%.43Introduction of TKI represents one of the significant advances in the treatment of Ph+ patients, inducing deeper responses in combination with conventional chemotherapy. Imatinib and dasatinib are indicated in the initial treatment phases, and ponatinib is used in subsequent lines, especially in the case of resistance. It is essential to highlight that not all TKIs have been evaluated and/or compared with specific protocols. The TKI must be introduced at the induction phase and sustained throughout treatment until and after allo-HSCT.44The CR from a recent phase 2 trial using dasatinib and blinatumomab, a chemotherapy-free protocol combination, as first-line treatment for Ph+ ALL was 98%. The median age was 54 years, and 38% of patients were referred to allo-HSCT.45Adult induction regimens effectively induce CR, but maintaining remission and curing patients with ALL remains difficult. Long-term survival after relapse is low, and graft versus leukemia (GVL) can occur. allo-HSCT relies on chemotherapy/radiotherapy cytotoxicity and donor T-cell GVL.46 after induction, allo-HSCT as upfront consolidation is recommended. Patients with MRD+ disease may proceed with allo-HSCT with curative intent, but their outcomes are likely inferior to those with MRD− disease.47 In the case of MRD+ disease in patients without comorbidities, myeloablative conditioning (MAC) regimens should be prioritized.45For SR patients in CR1 treated with pediatric-inspired regimens that achieve early MRD response, intensive chemotherapy consolidation and maintenance phases are recommended, with allo-HSCT reserved for CR2 patients. For HR patients and persistent MRD48 When imatinib was combined with Hyper-CVAD or a lower-intensity Hyper-CVAD in a randomized fashion, the benefit of allo-HSCT was restricted to patients who did not achieve MMR after two cycles.49 A retrospective analysis of patients with Ph+ ALL undergoing allo-HSCT in CR1 found that reduced-intensity conditioning (RIC) and MAC regimens were associated with similar overall outcomes for patients whose disease was MRD− before transplantation. By contrast, RIC was inferior in those whose disease was MRD+.50 Achieving BCR-ABL1–negative CR1 is likely favorable, but whether these patients can avoid allo-HSCT remains an area of active investigation. Therefore, allo-HSCT upfront for patients with Ph+ ALL is recommended.45In Ph+ ALL, the added benefit of allo-HSCT in achieving deep molecular remissions with more potent TKI is now being questioned. Among patients treated with Hyper-CVAD + a TKI without allo-HSCT, the 4-year OS rate was 66% in patients who achieved complete molecular response at 3 months. By contrast, patients who do not achieve at least a major molecular response (MMR) may benefit from allo-HSCT in CR1.51 A positive MRD is associated with relapse, so the disease should be well-controlled before transplantation. Outcomes in patients undergoing allo-HSCT in CR2 are inferior to those in CR1. Patients with active disease should only receive allo-HSCT in a clinical trial.In patients with relapsed or refractory (R/R) ALL who achieve CR2, allo-HSCT should be performed.53 However, no randomized data exist comparing RIC allo-HSCT with chemotherapy or MAC and RIC in patients with ALL undergoing allo-HSCT.55 A CIBMTR study of 1,521 patients with Ph− ALL receiving a MAC regimen  or a RIC regimen (n = 93) found similar transplant-related mortality in the two groups but a greater risk of relapse in the RIC group, resulting in similar age-adjusted survival despite a substantially older median age. Similarly, another study by the European Society for Blood and Marrow Transplantation (EBMT) of 576 patients with ALL found that the RIC versus MAC was not significantly associated with leukemia-free survival (LFS), concluding that RIC allo-HSCT is a potential therapeutic option for patients not eligible for MAC.55Randomized data supporting allo-HSCT for ALL come from older studies in younger patients treated with intensive MAC.54 The current recommendation is to use MAC in fit patients and reserve RIC for patients not eligible for MAC. However, we acknowledge that other disease- and transplantation-related factors, such as MRD status, may influence the choice of conditioning intensity.50Reduced-intensive regimens make transplantation accessible to older adults with ALL. They have been associated with promising outcomes  in patients older than 55 years .41 Thus, we recommend TBI-based conditioning for patients deemed fit for MAC (until 40-45 years). Older or less fit patients should be treated with RIC regimens.Chemotherapy-based regimens have been studied to avoid short- and long-term toxicities of ablative total body irradiation (TBI). An EBMT analysis of 2,780 patients with ALL found that TBI improves LFS and OS over chemotherapy-based MAC, regardless of pretransplantation MRD status.56 Currently, there are no published reports of maintenance therapy for Ph− disease.Whether post–allo-HSCT maintenance therapy (initiated while the patient remains in CR) or pre-emptive therapy (triggered by the detection of MRD) improves disease control or survival remains unknown.57For Ph+ ALL, increasing evidence suggests that post–allo-HSCT TKI therapies targeting BCR-ABL may be associated with improved outcomes compared with historical data, including small prospective clinical investigations using imatinib, dasatinib, or nilotinib, as well as institutional experiences with various TKIs.Therefore, our current recommendation for patients with Ph+ ALL is to consider post-transplantation TKI as either maintenance or pre-emptive MRD-guided therapy although there are limited controlled data to support either choice.58 In a phase III trial, patients included in the GRAAL 2005 protocol were randomly assigned to receive chemotherapy with or without 16-18 rituximab infusions. When rituximab was given during all treatment phases, the estimated 2-year event-free survival rates were 65% in the rituximab group and 52% in the control arm (P = .04). Rituximab should probably be administered throughout the therapy, as the GRAAL trial did, since a study from UKALL investigators did not find any improvement when rituximab was given only in induction.59 Standard-dose rituximab incorporated into the Hyper-CVAD regimen improved outcomes for young adults with CD20+ ALL, with older patients not benefiting.23 Therefore, an anti-CD20 MoAb might be included in first-line treatment for adult patients with CD20+ (>20%) ALL.The expression of CD20 in blasts of B-ALL has demonstrated an adverse prognosis and prompted the incorporation of rituximab, a chimeric MoAb targeting CD20, into intensive chemotherapy regimens.60 The treatment cycle consists of a 4-week continuous IV infusion, which is the main limitation of the drug's use. Neurologic side effects and cytokine release syndrome may deserve special attention when using the drug. In 2018, the FDA approved blinatumomab for patients in CR1 or CR2 with positive MRD disease.22Blinatumomab is a bispecific CD19-directed CD3 T-cell engager, fully approved by the US Food and Drug Administration (FDA) in 2017 for treating R/R ALL on the basis of two clinical trials.61Inotuzumab ozogamicin (InO) is a humanized anti-CD22 MoAb conjugated to calicheamicin, a cytotoxic antibiotic. Inotuzumab ozogamicin is given as an intravenous infusion over one hour, making it more feasible in outpatient settings. Special attention concerning hepatotoxicity is necessary since this drug raises the risk of hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS), mainly in older patients. Reducing the exposure to only two cycles can reduce the incidence of VOD/SOS.62 Further studies are needed to consolidate the use of this strategy for older patients.A phase 2 trial of mini-Hyper-CVAD in combination with InO as first-line treatment for older patients with ALL Ph− showed that 52 patients (median age of 68 years) had a 2-year progression-free survival of 59% and a mortality of 12%.63 In adults, 5%-10% of patients are refractory to initial therapy and 30%-60% relapse despite improved CR rates and OS with optimized chemotherapy regimens and improvements in supportive care. The response rate decreases with successive salvage chemotherapy regimens, 21% after a second salvage and 11% after the third or higher salvage. The 1- and 3-year OS rates also decrease considerably after first (26% and 11%), second (18% and 6%), and third or higher salvage (15% and 4%).64 Predictors for outcomes include age, site of relapse, duration of the first remission, response to initial salvage therapy, disease burden at the time of diagnosis (particularly for patients with hyperleukocytosis), previous allo-HSCT, and fitness.Treatment of R/R ALL represents an unmet medical need; new CR can be attained in 20%-40% of patients. The main reasons for treatment failure are refractory disease and relapse, and its prognosis remains poor.65Multiple regimens have been explored to treat patients with relapsed ALL, but none has emerged as a standard of care. A regimen of fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor, either alone or in combination with idarubicin (FLAG-IDA), yields response rates around 40% in the relapsed and refractory setting.66 Moreover, reduced toxicity allows patients to undergo allo-HSCT, serving as a bridge therapy to cure.Blinatumomab, InO, and chimeric antigen receptor (CAR) T-cell therapy for R/R B-ALL has achieved CR2 with significantly improved response rate, including a proportion of undetectable MRD, altering the treatment landscape for these patients.v 16%), 6-month event-free survival , and OS  in the blinatumomab arm, with 76% of MRD response for those in CR.67The phase III TOWER trial results, which compared salvage chemotherapy and blinatumomab in patients with Ph− ALL, had superior rates of CR .68 Responders had a higher rate of MRD negativity (78% v 28%), with more patients proceeding to allo-HSCT (41% v 11%).The phase III trial InO-VATE that compared InO with standard-of-care chemotherapy in patients with R/R ALL demonstrated an overall response rate (ORR) significantly higher than the chemotherapy arm  was 63%; 44% had CR with minimal residual disease negativity. Liver-related adverse events were comparable with the pivotal study,60In Ph+ ALL, the goal is to achieve negative molecular MRD. Patients with R/R Ph+ may be considered for second-line therapy with a TKI different from the one used as first-line. Mutation testing for the ABL/BCR is recommended, and the treatments are based on the mutation profile. Ponatinib has activity against T315I and effectively treats patients with R/R disease exposed to multiple TKIs. Combinations of TKI with multidrugs and/or MoAbs and/or corticosteroids should be an option for elderly patients who cannot tolerate intensive chemotherapy.71 Two CAR T cells are approved for clinical use in the B-ALL–relapsed and B-ALL–refractory setting: tisagenlecleucel (4-1BB-CART19 product) on the basis of Eliana trial (25 years and younger) and brexucabtagene autoleucel (CD28-CART19 product) on the basis of the Zuma-3 study (adults 18 years or older).72 However, they are not yet in clinical practice in LA, except in Brazil where tisagenlecleucel has been recently approved.73CAR-T-cell therapy relies on the genetic manipulation of a patient's T cells to generate a response against a leukemic cell-surface antigen, most commonly CD19. Clinical trials using CAR T cells for B-ALL in adults showed a CR of 70%-89%.74 The role of consolidative HSCT after CAR-T-cell therapy remains controversial.CAR-T-cell activation can cause severe cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), and infectious risks, but treatment-related mortality is low and the side effects are usually reversible. Most experts favor consolidative HSCT after CAR-T, especially in HSCT-naïve and fit patients.8 and CAR-T-cell therapy occurs in LA. These therapies also require specialized centers with trained personnel and regulatory approval.We must improve widespread and equal access to diagnosis, classification, and cutting-edge treatment for ALL. In this article, we have gathered the global information on adult ALL diagnosis and treatment and tried to adapt it to the realities of countries in LA. Different variables may affect the success of the ALL treatment. Figure 75 Medication prices vary widely because of local negotiating policies. Lack of transparency regarding the prices that countries pay for the same drug exists. In some countries, government-led national funds have been established, but they are insufficient to increase access to medication. For instance, a panel of chronic myelogenous leukemia (CML) experts stated that the price of drugs reflects their unsustainable costs.76 On the basis of this analysis, we recommend forming a LA council comprising representatives from the pricing authorities of all nations. One of its goals would be to improve affordability for regional health care systems and manufacturers of leukemia medication. New policies for pharmaceutical companies would require full transparency of R&D costs, including company, public, and philanthropic investments. These could assess the cancer medicine's cost-effectiveness at various prices and incremental cost-effectiveness ratios per quality-adjusted life-year. Another approach to improve access established in Chile and Brazil is the Farmacia Popular Program, which provides a specified list of essential medicines subsidized by the government and supplied by many public and private pharmacies. This program has reduced drug reference prices by approximately 30%.77Cost is the biggest limitation for implementing diagnostic tests and innovative treatments.Improved policies require a multistakeholder approach, including governments, the medical community and societies, academia, industry, payers, and patient advocates.78 Up to 17% of patients with adult ALL had poor adherence to treatment in a Mexican study, and electronic health support has a great potential to improve access to health systems in this setting.32 There is also a need for clinical trials in LA. A consortium of medical professionals, similar to that seen for CML, across LA is needed for professionals dealing with ALL.Each stakeholder has a different perspective regarding cancer care and provides unique viewpoints. By integrating data from these systems and industry sales, sophisticated data systems and metrics for measuring the quality of care and health outcomes could be used for concerted actions to establish priorities in cancer medication use and implement national interventions. Patient navigation, telemedicine, and artificial intelligence, which are increasingly used in high-income countries and show promising results, can partly alleviate health disparities.Finally, the publication of real-world data from cooperative groups working on ALL in LA helps us better understand the long-term benefit and cost-effectiveness of specific interventions. Every effort should be made to improve the outcomes in this patient population in all the countries of LA.


Direct-acting antivirals (DAAs) have been a breakthrough therapeutic innovation in the treatment of chronic hepatitis C virus (HCV) with significantly improved efficacy, safety, and tolerability.To evaluate the cost-effectiveness of treating patients with HCV with DAAs compared with pre-DAAs or no treatment over a lifetime horizon from the perspective of the US Veterans Affairs (VA) health care system.A hybrid decision-tree and Markov model simulated the health outcomes of a cohort of 142,147 patients with HCV with an average age of 63 years. Demographic data, treatment rates and distribution, treatment efficacy by subpopulation, and health state costs were sourced from VA data. Treatment costs and utility values were sourced from publicly available databases and prior publications for older regimens.Over a lifetime horizon, the use of DAAs results in a significant reduction in advanced liver disease events compared with pre-DAA and no treatment. Total cost savings of $7 and $9 billion over a lifetime horizon (50 years) were predicted for patients who received DAA treatments compared with patients treated with pre-DAA treatments and those who were untreated, respectively. Cost savings were achieved quickly after treatment, with DAAs being inexpensive when compared with both the pre-DAA and untreated scenarios within 5 years. The DAA intervention dominated  for both the pre-DAA and untreated strategies on both a per-patient and cohort basis.The use of DAA-based treatments in patients with HCV in the VA system significantly reduced long-term HCV-related morbidity and mortality, while providing cost savings within only 5 years of treatment. This study compared the costs and clinical benefits of direct-acting antivirals (DAAs) vs pre-DAAs or no treatment for hepatitis C virus (HCV) among veterans. DAAs reduce the risk of liver disease. DAAs are also safe for patients with HCV infection. The effect of DAAs on health care costs in the United States is less well characterized. Study findings suggest that DAAs provide cost savings within 5 years of treatment. DAAs are more effective and less costly than pre-DAAs or no treatment. Implications for managed care pharmacyThe use of DAAs in patients with HCV in the US Veterans Affairs (VA) health care system was projected to substantially reduce advanced liver disease and mortality vs pre-DAA treatments. Over a lifetime horizon, cost savings of approximately $7 and $9 billion were predicted for DAA vs pre-DAA and no treatment strategies across all patients with HCV in the VA health care system. The evaluation of DAAs from the VA health care system perspective is important given that VA developed a national strategy to eradicate HCV infection.1 HCV infection causes progressive hepatic inflammation frequently leading to cirrhosis, end-stage liver disease, hepatocellular carcinoma (HCC), and liver-related death.5Hepatitis C virus (HCV) is the most common blood-borne infection in the United States, with an estimated prevalence of 6.4 million.6 These drugs were associated with low rates of treatment uptake owing to low efficacy, unfavorable safety profiles, and multiple contraindications.7 The HCV treatment landscape has dramatically evolved since 2013 with the introduction of DAAs,8 which have high efficacy rates, excellent tolerability, and ability to be safely prescribed to nearly all patients regardless of HCV genotype, cirrhosis status, treatment experience, and hepatic decompensation status in contrast to treatments available prior to 2014 .13 DAAs have demonstrated initial sustained virologic response (SVR) rates of greater than 95%,11 whereas PEG-IFN-based and RBV-based treatments have low SVR rates (40%-50% for genotype 1 and 55%-65% for genotype 4 patients).14 Further, DAAs have a shorter treatment duration (8-12 weeks) than PEG-IFN-based and RBV-based treatments (24-48 weeks)14; hence, DAA treatments require less monitoring and positively impact adherence.15 Achievement of SVR reduces liver disease progression, thereby decreasing hepatic decompensation, hepatocellular carcinoma, and overall mortality.17Pegylated-interferon (PEG-IFN) and ribavirin (RBV) were used to treat patients with HCV prior to the approval of direct-acting antivirals (DAAs) and were also used in combination with HCV NS3/4A protease inhibitors, telaprevir, and boceprevir.18 In 2014, bolstered by a congressional allocation to treat HCV in all veterans, 5.4% of whom were infected with HCV,19 the US Veterans Affairs (VA) health care system developed a national strategy to eradicate HCV infection.20 The presence of a national electronic medical record, high patient retention, and comprehensive cost accounting information make the VA the optimal clinical setting to evaluate the value of these medications from the perspective of a VA health care system. The objective of this study was to evaluate the cost-effectiveness of treating patients with HCV with DAAs compared with pre-DAAs or no treatment over a lifetime horizon from the perspective of the VA system.Although improvement of clinical outcomes from the application of DAA therapy has been well established, the impact of DAA on health care costs in the United States is less well characterized. HCV elimination, a goal set by the World Health Organization by 2030, requires significant resource allocation but could result in long-term savings to health systems.21 A time horizon of 50 years was modeled assuming patients who enter the model will reach death based on the life tables of the US population.22 Health and economic outcomes were discounted at an annual rate of 3%.23A previously developed lifetime Markov cohort model was adapted to project the impact of treatment with DAA or pre-DAA regimens (or no treatment) on health and economic outcomes from the perspective of the VA health care system.21 was used for this study , laboratory tests required to calculate noninvasive fibrosis 4 score (FIB-4), MELDNa, and electronic Child-Turcotte-Pugh score indicating liver disease severity were obtained as previously described.25 Cirrhosis was defined as the presence of ICD-9/10 codes for cirrhosis and FIB-4 greater than or equal to 1.45 or, in absence of ICD-9/10 code, a FIB-4 greater than or equal to 3.25. Decompensation was identified by a previously validated algorithm.26Data regarding patient characteristics were sourced from the VA data . All VA patients  with a positive HCV RNA by a qualitative or quantitative polymerase chain reaction (PCR) test were included. Age at diagnosis and treatment, race/ethnicity, alcohol use by the validated alcohol use disorder questionnaire (AUDIT-C),The modeled cohort comprised a total of 142,147 patients with a mean age of 63 years. This cohort reflected the patients with HCV eligible for treatment in the VA system in 2014. The demographic characteristics of the cohort were based on the VA data to reflect the target population. The baseline distribution of fibrosis stages was genotype 1 (83.8%), 2 (9.2%), 3 (6.1%), 4 (0.8%), and 5/6 (0%). At baseline, the proportion of patients previously treated for HCV was 15% and the distribution of liver disease stage was assumed to be 73%, 20%, and 7% across NC, CC, and DCC, respectively. The proportion of patients treated in the DAA scenario comprised 85%  and the pre-DAA scenario comprised 12%  of the model cohort and was reflective of the number of patients treated in the VA system between 2014-2019 and 2008-2013, respectively. The untreated scenario included 100% of the population; no patients were assumed to be treated in the no-treatment scenario.Data regarding antiviral medication use were sourced from the VA data (data on file). All released prescription fills for HCV antiviral therapy including various interferon-α preparations, RBV, sofosbuvir (SOF) mono- and combination therapies , simeprevir (SIM), telaprevir (TPV), boceprevir (BOC), daclatasvir (DAC), grazoprevir (GRZ)/elbasvir (ELB), glecaprevir (GLE)/pibrentasvir (PIB), ombitasvir (OBV)/paritaprevir (PTV)/ritonavir (RTV) + dasabuvir (DSV), and OBV/PTV/RTV were chronologically arranged for each patient to determine the specific combination of concomitant medications and treatment start date. Treatment completion was assigned as 28 days after the final release for a specific regimen, and the first date for possible assessment of SVR12 was assigned to 84 days after treatment completion. Each course of therapy was based on post-SVR12 date HCV PCR results and characterized as cured, relapsed, or untested if no PCR test was available.The model evaluated 3 scenarios. First, treatment with DAAs was assumed to be reflective of regimens available from 2014 onward and used in the VA. The regimens for DAAs included in the analysis were SOF/PR, SOF/RBV, SOF/SIM, SOF/DAC, SOF/VEL, OBV, DSV and RTV-boosted PTV, GLE/PIB, ELB/GRZ, SOF/VEL/VOX, and LDV/SOF. Second, treatment with pre-DAA regimens was assumed to include PR, PR/BOC, and PR/TPV. Third, a scenario for no treatment was included in the model. The US Food and Drug Administration prescribing information was used for each treatment to determine dosing and duration of therapy.Supplementary Table 1 (available in online article) summarizes annual transition probabilities between health states, which were derived from data specific to the VA (data on file) as well as from the literature.33 It was assumed that patients will not experience disease progression during the initial first year of treatment. Achieving SVR was assumed to reduce disease progression in patients with NC, CC, and DCC.34 In addition, patients with stage 3 (F3) and stage 4 (F4) fibrosis achieving SVR were assumed to experience fibrosis regression.3536The model accounted for direct costs such as treatment-related costs and health state costs (data on file). Given the limited availability of net prices for all products in this analysis, wholesale acquisition costs were used and sourced from IBM Micromedex RED BOOK.38 For untreated patients, costs were calculated for each year of follow-up until death or lost to follow-up. For treated patients, costs were categorized temporally relative to treatment initiation as follows: Year −2 included days −730 to −366; Year −1 included days −365 to −1; Antiviral period day s0 to 90 days after treatment completion; Year +1 from day 90 to 455 after treatment completion; Year +2 from day 456 to 820 after treatment completion; and Year +3 from day 821 to 1,185 after treatment completion. For analysis related to liver cancer and LT costs, the initial treatment period, year +1 and year +2 were based on 365-day periods from the date of diagnosis or transplant, respectively. These estimates were then used to derive health state costs used in the model. All costs were adjusted to 2021 US dollars, inflated using the Consumer Price Index,39 where required. Cost inputs are provided in Supplementary Table 1.Health state costs and treatment monitoring costs for pre-DAA treatments were derived from the VA (data on file). For these cost estimates, Health Economics Research Center (HERC) average cost estimates and Fee-Basis costs were used for outpatient and inpatient care within the VA and external costs, respectively. For outpatient care, HERC uses relative values from Medicare’s Resource-Based Relative Value System to assign costs to 12 different categories of outpatient care. HERC estimates the cost of inpatient stays based on a regression model that uses Diagnosis Related Groups weight, intensive care unit days, length of stay, and patient characteristics to estimate cost-adjusted charges using Medicare Relative Value Units. Cost of outpatient pharmacy was obtained from Managerial Cost Accounting  data.44 A utility value was assigned to each health state modeled ranging between 1  and 0 (death) representing the quality of life for patients in that health state (Supplementary Table 1). It was assumed that there are no utility differences between treatment-naive and treatment-experienced patients.Utility values were sourced from the literature.Model outcomes included the number of advanced liver disease events over a lifetime horizon for each scenario , total costs on both a patient and population level, and cost-effectiveness outcomes including total life-years (LYs) and quality-adjusted life-years (QALYs).One-way sensitivity analysis was conducted to examine the robustness of model results by varying one parameter at a time to examine changes in the net monetary benefit (NMB). NMB is a summary statistic that represents the value of an intervention in monetary terms when a willingness to pay threshold for a unit of benefit . Parameters were varied by ±10% of their base-case values. The probabilistic sensitivity analysis randomly sampled parameters from within chosen distributions over 5,000 iterations.In the DAA scenario, 85%  of patients were treated and 15%  were not treated in the analysis period. In contrast, in the pre-DAA period, only 12%  patients were estimated to be treated and 88%  with pre-DAA regimens. In the untreated scenario, 100% of patients were not treated.Over a lifetime horizon, the use of DAAs resulted in a significant reduction in advanced liver disease events. More advanced liver disease cases occurred in the pre-DAA vs DAA cohort . CompareSimilarly, more advanced liver disease cases occurred in the no-treatment cohort than in the DAA cohort . CompareThe DAA treatment strategy incurred higher initial costs owing to higher drug costs. However, this strategy resulted in cost savings on a per-patient basis due to a reduction in advanced liver disease events and corresponding costs. Total predicted cost savings were $49,969 and $62,576 for patients who received DAA treatments compared with pre-DAA treatments and untreated, respectively .Further, the DAA treatment strategy also resulted in cost savings over a lifetime horizon. Total discounted cost savings of $7 and $9 billion over a lifetime (50 years) horizon were predicted for patients who received DAA treatments compared with patients treated with pre-DAA treatments and those who were untreated, respectively . FurtherOn a per-patient level, the DAA scenario conferred more LYs and QALYs than the pre-DAA scenario: 0.61 and 1.01 per patient with HCV, respectively . In addiAt a cohort level, the DAA scenario conferred more LYs and QALYs than the pre-DAA scenario: 86,863 and 142,864 per patient, respectively . In addiSupplementary Figure 1A). This could be due to a majority of patients being in these subgroups: HCV genotype 1 (83.8%), NC (73%), and treatment-naive patients (94%). In the DAA vs untreated analysis, parameters that influenced NMB the most were the proportion of patients with genotype 1 in the DAA cohort, cost of treatment-naive patients with NC, and proportion of patients treated in the DAA era .Sensitivity analyses were robust when model parameters were varied. In the DAA vs pre-DAA scenario, the NMB was most sensitive to the proportion of treatment-naive patients in the pre-DAA cohort, the proportion of patients with NC in the pre-DAA cohort, and the proportion of patients with genotype 1 HCV in the DAA cohort .The probabilistic sensitivity analysis findings were consistent with the base-case analysis. In the current model scenario using discounted costs and QALYs, the DAA scenario dominated both the pre-DAA and untreated scenarios  after 9 years of follow-up whereas a net cost increase was predicted among non-cirrhotic individuals.49 Chidi et al evaluated the cost-effectiveness of the first-generation DAA therapy with various strategies related to treatment prioritization, finding that OBV-based regimens conferred long-term cost savings to the VA system ($67.6M) relative to no treatment.50 Our study found even greater cost savings for patients treated with DAA over a lifetime horizon—$7 and $9 billion compared with patients treated with pre-DAA treatments and those who were untreated. Cost savings were evident at year 5 after treatment, similar to findings suggested in a study modeling the Australian “treat-all” approach adopted in 2016.51 DAA treatment strategies were dominant in the incremental cost-effectiveness analysis, with greater LYs and QALYs and lower cost. An observational study estimated the annual and cumulative impact of DAAs on national Medicaid costs from 2013 through 2022; the magnitude of per-person and overall cost saving estimated appears quite similar to those from the US Medicaid population , projected $12 billion system savings from 2013 to 2022.52 Thus, our data further demonstrate the clinical and cost savings of expanded DAA access in the United States. Despite scientific information and guideline recommendations for DAAs, the high price of these drugs has been the major obstacle, preventing access to HCV treatment for those in need. This has led to affordability- and access-related issues resulting from payer-driven rationing of care in the United States.53 However, some health systems such as VA had developed a national strategy to eradicate HCV infection.20 The current assessment of cost-effectiveness using the data from VA showed that DAA strategy substantially reduces liver disease burden on health care, by reducing liver-related morbidity and mortality and long-term health care costs. Therefore, the findings suggest that the payer systems that had taken an initiative to expand access to DAAs have achieved benefit with substantial cost savings. This has implications for the use of DAAs for the treatment of HCV in other payer settings for both patients and health care systems.To the best of our knowledge, this is the first study that assessed the cost-effectiveness of all oral HCV DAA regimens compared with pre-DAA regimens or no treatment from the VA payer perspective. The VA has treated more than 100,000 HCV-infected veterans since January 2014, with cure rates exceeding 90%.5455 supporting the health outcomes observed with our analysis. Further, real-world studies looking at the efficacy of DAAs have shown similar efficacy as observed in clinical trials,58 substantially higher than pre-DAAs,60 similar to our analysis.Limited data are available examining post-DAA costs in patients with HCV, and similarly for comparisons of post-DAA vs pre-DAA health care expenditures to validate our findings; however, prior real-world studies have shown increases in treated patients and higher SVR rates after introduction of DAAs vs pre-DAAs,62 In a modeling study performed for the French national health care system, Leleu et al demonstrated that DAAs result in a total cost saving of €1.1 billion vs pre-DAAs, with an average cost saving of €15,000 per DAA-treated patient.61 In a modeling study performed for the Spanish health care system, Turnes et al demonstrated that a total cost saving of €468,149,590 was achieved over a lifetime horizon (50 years) with post-DAA strategy compared with pre-DAA.62Our data confirm and validate similar analyses from integrated health systems in Europe. In these analyses, a marked increase in the absolute number of patients treated with DAA relative to pre-DAA regimens has been observed owing to higher efficacy, better safety profiles, and increased tolerability, which in turn has been demonstrated to reduce population-level HCV-related morbidity and mortality.34; however, results were robust across different values of disease progression in the model. Further, our analysis did not consider fibrosis restrictions to treatment, which may overestimate cost savings; of note, DAAs were cost saving in the Spanish analysis that did consider fibrosis restriction to treatment.62 Therefore, the exclusion of this consideration may not impact our findings to a greater extent. Second, drug costs were calculated based on published wholesale acquisition costs,36 which may not reflect the actual cost of drugs paid by the VA. We note that the wholesale acquisition cost prices are certainly higher than the net prices paid by the VA, which would be conservative against DAAs, as they would be more greatly discounted, particularly in recent years with the introduction of generic SOF/VEL and GLE/PIB. Incorporation of net pricing would likely reduce the upfront financial impact of DAAs, reducing the time to “breakeven” of investment. Further, we assumed that all 120,825 patients are treated in the first year of the model. Although this is not reflective of actual treatment patterns, we note that this would maximize the impact of acquisition costs for DAAs as compared with a scenario in which treatment occurs over the course of several years. Third, DAA treatment was only considered for patients with NC, CC, and DCC; however, newer DAAs can treat patients with HCC, LT, and post-LT, and thus, additional gains in HCV-related morbidity and mortality were not captured in this analysis for these subpopulations. Fourth, the societal perspective to examine the impact of the treatment regimens on wider social opportunity costs  was not considered by the analysis. Incorporating such a perspective would lead to greater gains for DAA regimens given the reduction in advanced liver disease events, which are known to impact work productivity and participation in the workforce. Finally, the impact of a higher proportion of patients achieving cure was not reflected in terms of possible downstream impacts on HCV incidence and prevalence. We would expect greater gains in HCV-related morbidity and mortality, as well as in terms of the economic impact if the curative impact of DAA therapy on disease transmission was also accounted for in the model. Costs of care expended in the VA are generally lower than those in other US health care systems63; therefore, the magnitude of these findings may not directly translate to the US Medicare-insured or commercially insured populations. However, we expect the direction of cost savings to be similar.Strengths of this analysis include the detailed clinical, demographic, and cost data in a large, national, diverse cohort. However, our findings should be interpreted in light of their limitations. First, data on reduction in disease progression among patients who have achieved SVR were derived from published literature and not the VAThe use of DAA-based treatments in patients with HCV in the VA significantly reduced long-term HCV-related morbidity and mortality, resulting in lifetime cost savings and cost savings within 5 years of treatment.


Clostridioides difficile infection (HO-CDI) standardized infection ratios (SIRs).To evaluate the impact of a standardized, process-validated intervention utilizing daily hospital-wide patient-zone sporicidal disinfectant cleaning on incidence density of healthcare-onset Multi-site, quasi-experimental study, with control hospitals and a nonequivalent dependent variable.The study was conducted across 8 acute-care hospitals in 6 states with stable endemic HO-CDI SIRs.Following an 18-month preintervention control period, each site implemented a program of daily hospital-wide sporicidal disinfectant patient zone cleaning. After a wash-in period, thoroughness of disinfection cleaning (TDC) was monitored prospectively and optimized with performance feedback utilizing a previously validated process improvement program. Mean HO-CDI SIRs were calculated by quarter for the pre- and postintervention periods for both the intervention and control hospitals. We used a difference-in-differences analysis to estimate the change in the average HO-CDI SIR and HO-CAUTI SIR for the pre- and postintervention periods.Following the wash-in period, the TDC improved steadily for all sites and by 18 months was 93.6% for the group. The mean HO-CDI SIRs decreased from 1.03 to 0.6 . In the adjusted difference-in-differences analysis in comparison to controls, there was a 0.55 reduction  in HO-CDI (P < .001) or a 50% relative decrease from baseline.This study represents the first multiple-site, quasi-experimental study with control hospitals and a nonequivalent dependent variable to evaluate a 4-component intervention on HO-CDI. Following ongoing improvement in cleaning thoroughness, there was a sustained 50% decrease in HO-CDI SIRs compared to controls. Clostridioides difficile accounts for between 400,000 and 500,000 infections in the United States each year and is the leading cause of healthcare associated infections. The average prevalence of C. difficile infection (CDI) is estimated to be 13.1 per 1,000 hospitalized patients, with ∼75% being healthcare associated, making in-hospital prevention critical to decreasing the overall impact on healthcare. identified C. difficile as the cause of antibiotic associated diarrhea in 1978, Fekety et al documented widespread healthcare environmental contamination of surfaces, both near and more distant to patients with CDI. In 1988, Katz et al described the favorable impact of a bleach-based disinfectant in decreasing environmental contamination and an associated outbreak of C. difficile. Subsequently, numerous quasi-experimental studies incorporating dilute bleach substitution for nonsporicidal disinfectants have reported a reduction in healthcare facility-onset CDI (HO-CDI) during outbreaks. As a result of these reports, use of a sporicidal disinfectant for daily and discharge cleaning of CDI isolation rooms has become a standard practice in acute-care hospitals during outbreaks and for endemic cases.Three years after Bartlett et al However, in 2015 Kundrapu et al reported that spore shedding and near patient environmental contamination with CD spores was substantially influenced when asymptomatic C. difficile–colonized patients were administered antibiotics, the clinical relevance of this phenomenon has only recently been clarified. In 2016, Freedburg et al analyzed a cohort of >100,000 patients who sequentially occupied a given hospital bed. Independent of the prior room-occupant’s CDI status, administration of antibiotics to the prior bed occupant was the most significant factor associated with an increased risk of the next bed-occupant developing CDI. The same phenomenon was also reported by Dowling Root in 2021. In this study of 17,285 patient room occupancies, the risk of HO-CDI was significantly associated with prior room-occupant antibiotic usage . The results of these 2 large studies, which can only be explained by recipient acquisition of residual CD spores asymptomatically shed onto surfaces in the patient zone by the preceding room occupant, further support the hypothesis that daily hospital-wide sporicidal cleaning could mitigate HO-CDI.As noted in Figure  which is nondamaging to surfaces became available did it become feasible to develop an assessment of such a cleaning intervention for all patient zone surfaces on the occurrence of HO-CDI. Because no study has evaluated hospital-wide sporicidal cleaning, this study was developed to analyze the impact of the concomitant implementation of daily and discharge cleaning of all inpatient rooms using a sporicidal disinfectant combined with a program to optimize thoroughness of cleaning on the HO-CDI standardized infection ratio (SIR) in an opportunity sample of 8 acute-care hospitals in the United States.Only when a highly effective, environmentally safe, sporicidal disinfecting chemistry All 8 acute-care hospitals included in the intervention group were members of Trinity Health, a national multi-institutional 92-facility healthcare system. The intervention hospitals ranged in size from a 532-bed tertiary-care hospital to a 44-bed regional critical-access hospital  located in 6 geographically diverse states. Furthermore, 9 randomly selected Trinity Health hospitals that had not enrolled in the standardized system environmental services (EVS) program (intervention) served as controls. The control hospitals ranged from 552 to 44 beds . Prior to the intervention period, all hospitals were using a dilute bleach-based protocol for daily and discharge room cleaning of rooms occupied by patients with CDI, and none had implemented disinfection cleaning thoroughness monitoring and optimization per CDC level II recommendations. Thoroughness of disinfection cleaning (TDC) is defined as the proportion of actually cleaned objects in a room compared to the number of objects recommended to be cleaned by policy, and expressed as a percentage. TDC was monitored in an identical fashion by all study sites, as previously described, using a standardized fluorescent marking system  specifically developed not to be easily visible to the EVS staff. Outcome data were collated centrally but were not shared between the sites and were not used for educational purposes during the study.We performed a quasi-experimental study with a control group and a nonequivalent dependent variable to evaluate the impact of objectively optimized, daily, hospital-wide, sporicidal disinfection cleaning on CDC NHSN Lab-ID reported HO-CDI standardized infection ratio (SIR).C. difficile spores and a 3-minute contact time for most other bacteria and viruses. Concomitantly, a structured performance monitoring and feedback program using the fluorescent marker system, compliant with CDC guidance level II recommendations, was used to optimize cleaning practice.Following a 30- to 60-day period of covert evaluation of cleaning thoroughness, all EVS technicians and managers participated in a structured and standardized educational program consisting of both classroom and hands-on training as part of Trinity Health’s C.L.E.A.N. Suite EVS Program, which that was operated from the system’s headquarters. Prior to and during the training they continued to perform traditional disinfection cleaning: general patient zone daily and discharge cleaning of surfaces with a quarternary ammonium disinfectant substituting dilute bleach for cleaning rooms use to isolate patients with CDI. Each site independently implemented the intervention protocol at various time points during 2017 and was evaluated over 18 months. During the intervention, daily hospital-wide, patient-zone, surface-disinfection cleaning was implemented using a 1-step sporicidal disinfectant cleaner. This hydrogen peroxide-peroxyacetic acid-based, disinfectant  has a 5-minute contact time for efficacy against  During the 39 months of the intervention all cleaning evaluations were done by infection preventionists and/or trained individuals not directly involved in environmental cleaning activities.The primary outcome, NSHN Lab-ID–reported HO-CDI (SIR) results were collected monthly and were collated centrally by quarter for 18 months prior to beginning the program and for 18 months following the wash-in period. Following the 3-month wash-in period, disinfection cleaning monitoring results were collected on an ongoing basis to provide objective analysis cleaning practice to optimize process improvement through direct feedback and education. for each hospital to assess trends that might impact HO-CDI for both intervention and control sites. NHSN reported HO–catheter-associated urinary tract infections (HO-CAUTI) SIRs were evaluated as a nonequivalent dependent variable (or “removed treatment design”) that should be affected by similar hospital-level factors as HO CDI but not by the intervention studied. We also evaluated 6 other variables that could have impacted HO-CDI SIRs using a standardized questionnaire including changes in transmission-based precautions, specimen collection stewardship, the C. difficile laboratory testing method used, new antimicrobial stewardship initiatives and proton-pump inhibitor use.Because the HO-CDI SIR may be affected by the severity of hospitalized patient illness and the duration of hospitalization, we explored the average length of stay and Medicare case-mix index We fit linear mixed-effects regression models for each outcome as a function of intervention or control group status, the pre- or postintervention period, and their interaction. The model also included a hospital indicator as a random intercept and a time trend indicator. The interaction term is the difference-in-differences estimate of the association between the intervention and HO-CDI or HO-CAUTI.The mean and interquartile range of TDC scores were calculated by quarter for the pre- and postintervention periods for the 8 intervention hospitals. Similarly, mean and interquartile range of HO-CDI standardized infection ratios were calculated by quarter for the pre- and postintervention periods for both the intervention and the control hospitals. We used a difference-in-differences analysis to estimate the change in the average HO-CDI SIR and HO-CAUTI SIR for the pre- and postintervention periods.P = .0007) .Each hospital evaluated their preintervention disinfection cleaning over 1–2 months between the last quarter of 2016 (one site) and quarter 3 of 2017. Prior to implementation of the intervention, covert evaluation of cleaning thoroughness showed that 59% of policy defined patient zone surfaces were being disinfection cleaned by environmental services personnel  Fig. . SubsequP = .009). Over the next 5 quarters, the HO-CDI SIR continued to decrease and stabilized during the last three quarters evaluated to a mean SIR of 0.6 . In the adjusted difference-in-differences analysis .As noted in Figure P = .60).With respect to the nonequivalent dependent variable analysis and as noted in Figure With the exception of 1 site that restructured transmission-based precautions for known CDI patients in quarter 3 of the preintervention year, no other site modified isolation policies or procedures related to CDI Fig. . None ofP = .0009)  Concomitantly, NHSN reported HO-CDI decreased 52% in quarter 1 in the intervention hospitals (P = .0009) , by 18 months after the intervention. Although sites B and A, with the highest SIRs prior to implementing the program, showed large decreases in HO-CDI (93% and 84%) could have biased the overall results of this relatively small study, the 3 sites with preintervention SIRs <1.0 improved by 40%, 40%, and 44%, along with the sustained responses noted by all sites. This finding suggests that even sites with low endemic rates of HO-CDI could benefit from a program that includes hospital-wide daily sporicidal disinfection cleaning, education, monitoring, and feedback to mitigate endemic HO-CDI.This study represents the first multisite, quasi-experimental study with control hospitals and a nonequivalent dependent variable to evaluate a 4-component intervention on HO-CDI. After an 18-month preintervention period and immediately following a 3-month wash-in period, there was a 46% improvement in cleaning from 59% to 86% immediately following the wash-in period with 5 sites at ≥88% (09) Fig.  Over the09) Fig. . Over th and showed that the nonequivalent dependent variable of CAUTI SIR did not change during the intervention period in intervention hospitals. Lastly the other hospital-level factors that could have driven lower C. difficile rates showed no identifiable changes between the preintervention and postintervention periods.Our findings suggest that the intervention program was associated with the observed decrease in HO-CDI for the intervention sites. This conclusion is supported by the following findings: The intervention site patient acuity was stable over 39 months. The endemic HO-CDI SIRs before the intervention were stable. There was an abrupt, concomitant increase in cleaning thoroughness and decrease in CDI in the first quarter of the intervention, which was sustained over 2 years. We also utilized a “removed treatment design” in the previously noted report. In reviewing their finding that antibiotic administration to prior room occupant was the most important risk factor for CDI development in the subsequent room occupants, it was suggested that there could be a benefit from “focusing cleaning protocols on the rooms of patients who have a risk factor for CDI ” Although such a program could be implemented, the fact that most hospitalized patients receive antibiotics along with the frequent occurrence of patients occupying more than a single room during their hospitalization would make such a program logistically challenging.The potential value of broadly implemented sporicidal cleaning to mitigate HO-CDI was discussed by Freedberg et al 24% to >90% in 12 hospitals (2010), 61% to 89% in 22 hospitals (2017), and 63% to 82% in 9 hospitals (2017). Limitations of the study design precluded evaluation of the relative impact of each of the individual components of the program. However, previous studies have reported the following findings: (1) that environmental spore contamination decreased only after disinfection cleaning had been optimized in 9 intervention hospitals compared to controls; (2) that a good level of cleaning thoroughness was ineffective in decreasing environmental spore contamination until daily cleaning had been implemented; (3) that a high level of disinfection cleaning had no impact on HO-CDI until hospital wide sporicidal cleaning was implemented in a single site study; and (4) that daily sporicidal cleaning failed to impact HO-CDI over 2 years until a program to optimize TCD was implemented. These findings suggest that each of the components of our intervention are critical to achieving the impact on HO-CDI presented in this report.This study has several limitations. Unmeasured factors might have limited the generalizability of our findings. However, the fact that there was a wide range in the location of the intervention sites, their size and patient acuity, as well as the fact that the preintervention SIR for the group was at the national norm  for NHSN-reported HO-CDI SIRs in 2017 supports the plausible generalization of our findings. Some hospitals might not be able to achieve high levels of disinfection cleaning, thereby limiting the impact of hospital-wide sporicidal cleaning. However, 77 hospitals that implementing CDC guidance level II disinfection cleaning monitoring identical to that described in this report all documented sustained improvement in TDC (baseline vs improved) from 48% to 73% in 36 hospitals (2008), Since it compares outcomes between the intervention group and the control group without the exposure (preimplementation) and the intervention group to itself with the exposure (postimplementation), the investigator is able to subtract the background changes in outcomes. Given the challenges of a randomized trial to answer our question of interest, we note an agent-based modeling study by Barker et al (2020) that evaluated the impact of multiple single and bundled interventions on HO-CDI prevention and found that the single most clinically effective as well as cost-effective intervention was daily sporicidal disinfection cleaning of all patient zone surfaces. Furthermore, quantative input analysis of the model found that “enhanced level” (80% TDC) provided benefits (as seen in this study), but that there was only a limited additional incremental benefit from increasing modeling parameters of thoroughness of cleaning from an “enhanced level” (80% TDC) to an “ideal level” (94% TDC). Thus, daily patient zone sporicidal cleaning could realize a substantial impact on C. difficile transmission at TDC levels lower than those achieved by this group of hospitals.A randomized controlled trial could, in theory, further clarify and quantify the results of this intervention, but such an undertaking would require some sites to defer implementing potentially effective design elements of the intervention. The difference-in-differences analysis used in this study is arguably the “next best” approach when randomization is not appropriate or feasible. The strength of the difference-in-differences approach stems from the fact that it uses a comparison group that is experiencing the same trends but is not exposed to the intervention.Core Components of Environmental Cleaning and Disinfection, including the following: ongoing integration of environmental services and infection prevention activities (component 1); use of standardized cleaning and disinfection chemistry products tailored to the setting (component 3); optimized, setting-specific cleaning and disinfection protocols (component 4); and the use of objective ongoing programmatic performance monitoring to optimize disinfection cleaning .Notably, the design of our intervention program also is in line with several elements of the CDC October 2020 guidance  found relatively little cost-benefit of such measures once a hospital implemented daily sporicidal cleaning and achieved a TDC of 80 to 94%.This study provides support for the clinical benefit of an integrated 4-component, intervention, not bundled with other transmission mitigating activities, focusing solely on environmental hygiene practice that includes daily, hospital-wide sporicidal disinfectant cleaning with objectively optimized thoroughness of cleaning to reduce endemic HO-CDI. Although optimizing other bundled interventions might lead to additional mitigation of HO-CDI beyond the impact of the intervention described in this report, Baker et al MRSA, MDROs, CRE capable of plasmid-mediated carbenapenemase gene transfer and organisms such as norovirus and Candida auris. Along with facilitating environmental control of C. difficile transmission such a broadly horizontal approach to healthcare-associated pathogen transmission supports the guidance provided in the Commentary, “Approaches for preventing healthcare-associated infections: Go Long or Go Wide?” by Septimus et al as well as the recent CDC guidance, Core Elements of Hospital Environmental Hygiene.Notably, multiple recent studies provide strong support for the likely benefit of the intervention described in this report in mitigating transmission of a wide range of healthcare-associated pathogens, including VRE,