The association of several comorbidities, including diabetes mellitus, hypertension, cardiovascular disease, heart failure and chronic kidney or liver disease, with acute kidney injury (AKI) is well established. Evidence on the effect of sex and socioeconomic factors are scarce. This study was designed to examine the association of sex and socioeconomic factors with AKI and AKI-related mortality and further to evaluate the additional relationship with other possible risk factors for AKI occurrence.We included 3534 patients  admitted to Queen Elizabeth or Heartlands Hospitals, Birmingham, between October 2013 and January 2016. Patients were prospectively followed-up for a median 47.70  months. Study-endpoints were incidence of AKI, based on KDIGO-AKI Guidelines, and all-cause mortality. Data acquisition was automated, and information on mortality was collected from the Hospital Episode Statistics and Office of National Statistics. Socioeconomic status was evaluated with the Index of Multiple Deprivation (IMD).P < 0.001). Model regression analysis revealed significant association of male sex with higher AKI risk ; this association remained significant after adjustment for age, eGFR, IMD, smoking, alcohol consumption, ethnicity, existing comorbidities and treatment . All-cause mortality was higher in patients with compared to those without AKI. Males with AKI had higher mortality rates in the first 6-month and 1-year periods after the index AKI event. The association of male sex with mortality was independent of socioeconomic factors but was not statistically significant after adjustment for existing comorbidities.Incidence of AKI was higher in men compared to women (11.3% vs 7.1%; Men are at higher risk of AKI and this association is independent from existing risk factors for AKI. The association between male sex and AKI-related mortality was not independent from existing comorbidities. A better understanding of factors associated with AKI may help accurately identify high-risk patients.The online version contains supplementary material available at 10.1186/s13293-021-00373-4. The reported incidence of acute kidney injury (AKI) in hospitalized patients is highly variable, depending on definitions and populations studied 5.4–18.3%), while incidence can increase to 40% in patients requiring admission to an intensive care unit 8.3%, whi. The mosSeveral risk factors for AKI have been consistently identified, including older age, comorbidities such as cardiovascular disease, heart failure, CKD and diabetes, as well as severe infections and the use of nephrotoxic drugs . DespiteIn order to develop effective AKI prevention and management policies, a better understanding of the nature of these relationships is needed. However, the impact of the above sociodemographic factors on the incidence of AKI and subsequent outcomes have been less well studied. In particular, female sex is listed among the “shared susceptibility factors” that confers a higher risk of AKI according to the Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury . FurtherThis is a secondary analysis of the ACQUATIK study, i.e., a prospective, multicentre, and observational study including patients admitted during the acute unselected medical takes at two large hospitals in Birmingham, i.e., the Queen Elizabeth Hospital and Birmingham Heartlands Hospital. The two hospitals treat over 2 million patients per year and perform over 2400 medical admissions on a monthly basis . We enroInformation on patient’s history and data from the index hospital admission and follow-up data were collected from the Hospital Episode Statistics (HES), which collates information on patients admitted to all NHS hospitals in England. Information for the haematology and biochemistry tests throughout the index admission were electronically collected from the individual hospital electronic health records (EHR). The HES also provides prognostic classification of existing comorbidities by evaluating the Charlson Comorbidity Index (CCI) . DiagnosP < 0.05 (two-tailed) were considered statistically significant in all comparisons. Continuous variables are expressed as mean ± standard deviation (SD) for normally distributed variables or median and interquartile range [IQR] for non-normally distributed variables and compared using the t-test or Mann-Whitney U test, accordingly. Categorical variables are expressed as absolute and relative frequencies and were compared using the Chi-squared test. All variables used in the analysis had < 5% of values missing and were therefore treated as missing completely at random with case-wise deletion. Proportional hazards assumption across groups was evaluated with log minus log survival curves. Kaplan-Meier survival curves were drawn to assess differences between male and female patients with and without AKI for time-to-event data and compared using the Log-rank test. The association of sex with AKI occurrence and mortality was evaluated with stepwise logistic or Cox regression modelled analysis (backwards method). Adjustments were performed for socioeconomic parameters, existing habits, comorbidities, laboratory results and medication intake that could possibly be associated with the outcome of interest and may confound its association with sex. Odds ratios (OR) and hazard ratios (HR) are presented with 95% confidence intervals (95% CI). A P value threshold of < 0.15 was selected in order to retain all potential risk factors and minimize the chance of type II errors. To address confounding by the between-group differences in baseline parameters, we estimated a propensity score for the diagnosis of admission, ethnicity, IMD, smoking habit, alcohol intake, baseline renal function, anaemia, BMI and existing comorbidities. Propensity score matching was implemented between male and female patients (1:1 ratio) using the nearest-neighbour strategy and a matching tolerance of 0.0001%.Analyses were performed using SPSS 22.0 . Values of P = 0.03]. Prevalence of diabetes, hypertension, coronary heart disease, peripheral vascular disease, heart failure and malignancy were higher in male patients, while pulmonary disease was higher in females and previous stroke, renal and liver disease was similar between the two study groups. Male patients had higher CCI compared to females . Male patients had higher proportions of active (27.7% vs 24.2%) or previous smoking (41.4% vs 30.7%) and alcohol consumption . The number of patients receiving antihypertensive treatment was higher for males compared with females . Estimated glomerular filtration rate  was similar between the two groups. Distribution across the diagnosis of admission was different between males and females  with the majority of patients within each group having stage 1 AKI . In the propensity-matched cohort, incidence of AKI was again significantly higher in male compared to female patients . In Table P < 0.001) in univariable analysis (model 1). The association between male sex and AKI persisted, with little modification, after adjustment for age, eGFR, IMD, smoking, alcohol consumption, ethnicity, existing comorbidities, treatment and laboratory variables . The comparisons in the propensity-matched groups were to the same direction indicating higher risk for AKI in male patients  patients had AKI during admission. The incidence of AKI was higher in men compared to women  and in female  patients. The increased mortality in patients with AKI persisted in both males and females at 6 months, 1 year and 48 months with no differences between the sexes . Male patients with AKI had the lowest 6-month cumulative survival, followed by the females with AKI and the patients without AKI (logrank-P < 0.001). Results during the 1-year follow-up were to the same direction (logrank-P < 0.001). During the 48-month follow-up period, females had lower cumulative survival compared to males with AKI, while cumulative survival was higher in patients without AKI (logrank-P = 0.001). Comparisons for all-cause mortality in the propensity-matched male and female patients with and without AKI yielded significant differences between groups during all follow-up periods . This association persisted after adjustment for age, eGFR, IMD, smoking status, alcohol consumption and ethnicity with little modification (models 2–4). However, the association between male sex and higher 6-month mortality after AKI was not significant after the inclusion of existing comorbidities in the model . During the 1-year follow-up period, male sex was associated with increased risk for all-cause mortality after AKI independently of age, eGFR, ethnicity, socioeconomic and lifestyle factors . In contrast, male patients presented increased risk for 48-month mortality after AKI only after fitting the model for age , but further adjustment rendered this association not statistically significant. The same analysis in propensity-matched males and females revealed similar risk for all-cause mortality after AKI in the two groups  in their meta-analysis [Importantly, the KDIGO guidelines list female sex as a susceptibility factor, while several clinical scoring systems associate female sex with higher risk of AKI , 16–18. analysis . Our stuanalysis .Evidence from the literature suggest that socioeconomic status is strongly associated with CKD, but the mechanism through which low-income associates with renal dysfunction is unclear. Preliminary data suggest that impaired access to health care may play a significant role . An obseP = 0.04) but was attenuated after additional adjustment for differences in insurance  or income  [Previous data on the association between smoking, alcohol consumption, ethnicity and sex with AKI occurrence are scarce. This mainly comes from the fact that discrimination among these factors is usually very difficult. Observational data suggest that smoking habit and increased alcohol consumption is more common in males or most deprived populations or specific ethnicities –49. In c = 0.40) . The resThis study has several strengths. We included a large, ethnically diverse population and patients were followed-up for a median of 4 years. We carefully chose to record data on specific factors related with social status and habits, which could possibly confound the observed differences between males and females. We followed a fully automated approach to acquire patients’ data and information on prespecified outcomes using the HES and ONS systems, which resulted in very complete data collection with very few missing values. We also used the IMD score to subjectively acquire information on the socioeconomic status of the patients included. Although propensity score methods may not fully eliminate confounding variables, repeated analysis in propensity-matched groups further support the association between male sex and increased risk for AKI. However, there are also limitations that need to be acknowledged. We used the admission SCr as the baseline SCr for both the diagnosis and the classification of severity of AKI. However, it is possible that the AKI was already established prior to admission and this would potentially reduce both the reported incidence and severity of AKI. The optimum way of diagnosing AKI is still unclear and other methods of establishing the baseline renal function are currently being investigated , 54. We To the best of knowledge, this is the first study evaluating the association of several sociodemographic factors on the association of sex with AKI and subsequent outcomes from longitudinal data. We found that men are at a higher risk for AKI occurrence and AKI-related mortal events. Although numbers of patients with severe AKI were very small, our data suggested that women may present with more severe AKI (Stage 3), but this did not appear to confer higher mortality rates. This needs to be further explored in future studies. Importantly, the association between sex and AKI occurrence or mortality after AKI was not affected by the social status, ethnicity, smoking habit and alcohol consumption of the patients. However, differences in mortality may be attributed, to an extent, to the higher prevalence of existing comorbidities in males. These findings provide a better understanding of risk factors for AKI leading to adverse outcomes and provide additional evidence on the factors that should be considered when it comes to planning future studies on interventions to prevent AKI.Additional file 1: Table S1. Baseline characteristics in patients by sex and in the propensity-matched population sample. Table S2. Stepwise logistic regression modeled analysis for the association of male sex with acute kidney injury in the propensity matched population. Table S3. Comparisons of 30-day, 6-month, 1-year and 48-month all-cause mortality in propensity matched male and female patients with and without AKI. Table S4. Stepwise Cox regression modeled analysis for the association of male sex with all-cause mortality after acute kidney injury occurrence during the 30-day and the 6-month follow-up periods in the the propensity-matched population sample. Figure S1. Kaplan Meier curves in propensity-matched male and female patients with and without AKI during the (A) 30-day, (b) 6-month, (C) 1-year and (D) 48-month follow-up periods.


We studied the psychometric properties of the 12-item short version of the Berger HIV stigma scale and assessed the correlates of HIV-related stigma among adults living with HIV on the Kenyan coast.Cross-sectional study.Comprehensive Care and Research Centre in the Kilifi County Hospital.Adults living with HIV on combination antiretroviral therapy were recruited and interviewed between February and April 2018 (n=450).HIV-related stigma.450 participants with a median age of 43 years (IQR=36–50) took part in the study. Of these, 356 (79.1%) were female. Scale reliability and validity were high . Using confirmatory factor analysis, we observed that the 12-item short version of the HIV stigma scale had a good fit for its hypothesised model . Multigroup confirmatory factor analysis indicated measurement invariance across gender and age groups as ΔCFI was ≤0.01. Multivariate linear regression established that being female , HIV status non-disclosure  and co-occurrence of depressive and anxiety symptoms  were significant predictors of perceived HIV-related stigma and that these variables accounted for 10.2% of the explained variability in HIV-related stigma among adults living with HIV from Kilifi.Our results indicate that the 12-item short version of the HIV stigma scale is a valid and reliable measure of HIV stigma in Kenya. Furthermore, our study indicates that interventions aimed at reducing stigma need to take into account gender to address the specific needs of women, people who have not disclosed their HIV status, and those exhibiting symptoms of depression and anxiety, thereby improving their quality of life. This is the first study to report the 12-item HIV stigma scale’s measurement characteristics in the sub-Saharan African context.We report on the correlates of HIV stigma based on a culturally adapted measurement tool with good psychometric properties.We cannot generalise our findings to all adults living with HIV in Kenya as data were collected from one geographical setting and excluded adults older than 60 years.We cannot conclude how individuals experience stigma over time because of the study design limitation.HIV/AIDS remains a considerable public health concern globally, with sub-Saharan Africa (SSA) bearing the most HIV-related disease burden.2Erving Goffman7Although efforts have been scaled up to raise awareness and increase public knowledge about HIV since the epidemic started decades ago, social stigma is still associated with the disease.10From previous research, HIV stigma experienced by PLWHA can either be enacted, anticipated or internalised.12A variety of instruments designed to measure HIV-related stigma have been published.Empirical evidence indicates that sociodemographic characteristics such as age,34Despite the abundance of published reports on HIV-related stigma and its predictors among specific subgroups of the adult population, there is a paucity of research findings focusing on predictors of HIV-related stigma across the entire adult population. Further, no study in the SSA context has tested for the validity and reliability of the HSS-12. This study aims to determine the correlates of HIV-related stigma among adults living with HIV from Kilifi, Coastal Kenya. Specifically, the study aims to: (1) examine the psychometric properties of the 12-item Berger Stigma Scale and (2) establish the correlates of stigma among adults living with HIV in Kilifi.This cross-sectional study was conducted at the Kenya Medical Research Institute-Wellcome Trust Research Programme (KEMRI), Centre for Geographic Medicine Research(Coast), Kilifi, Kenya. It was based at the Comprehensive Care and Research Centre (CCRC) in the Kilifi County Hospital (KCH). The majority of Kilifi County residents are poor (71.4% live below the poverty line), lack formal education, and earn a living mainly through subsistence farming or fishing.This data are part of a larger project focusing on diverse outcomes in adults living with HIV, including mental health and health-related quality of life. A cross-sectional survey of 450 study participants among patients attending an HIV care and treatment clinic at the KCH was conducted between February and April 2018 . The parStudy data were collected and managed using Research Electronic Data Capture (REDCap) tools hosted at KEMRI Wellcome Trust Programme.The short version HSS-12) of the Berger HSS of the BPatient Health Questionnaire version 9 (PHQ-9)42Generalised Anxiety Disorder version 7 (GAD-7)A sociodemographic questionnaire was used to collect information on the participants’ age, gender, relationship status, educational level, employment status and whom they currently shared a residence. Furthermore, an asset index previously used in this setting46Participants’ data were extracted from the clinic’s medical record database and filled into a clinical record form. This information included participants’ dates of HIV-diagnosis, cART initiation, most current cART regimen, cluster of differentiation 4 (CD4) cell count, viral load (within the last 1 year), recent height and weight (for body mass index (BMI) calculation) and data on WHO clinical staging. Participants’ clinical information was retrieved from their clinical records after consent was granted. Patient-unique clinic numbers were used to access participants’ medical records. We report substantial missing participant data on viral load from the database (n=145) with no follow-up record of CD4 cell count for all study participants.The English version of the HSS-12 was forward translated by two independent bilingual translators to Kiswahili and back-translated into English by two independent back translators . A group of Kenyan HIV researchers bilingual and fluent in both Kiswahili and English and the translators had a harmonisation meeting to review the content, conceptual, semantic and idiomatic equivalence of the questionnaires to ensure the cultural relevance of the HSS-12. Before conducting the formal phase of the study, 15 pretest interviews were conducted to assess instrumentation rigour and develop measures to address any limitations or threats to bias and management procedures. The final version of the questionnaire was obtained after the incorporation of changes emerging from pretesting. Pretesting procedures have been elaborated further elsewhere.47Patients were not involved in the design and conduct of this study.2 test, Comparative Fit Index (CFI), Tucker Lewis Index (TLI) and root mean square error of approximation (RMSEA). The data were expected to have a good fit to the model if the χ2 test was non-significant, CFI and TLI values were greater than 0.90, and RMSEA score was lower than 0.05.50First, confirmatory factor analysis (CFA) was used to examine the HSS’s factor structure. A CFA model representing the Swahili version of the HSS-12 was set up and analysed with weighted least square mean and variance adjusted using the lavaanSecond, after defining the model, Multi-Group CFA52Means and SD were used to evaluate the distribution of scores within the subscale and among the items. Itemised means and SD were expected to be almost the same within the subscale, justifying item scores’ aggregation into subscale scores.54Cronbach’s alpha and ordinal alpha were used to examine each subscale’s internal consistency and overall scores of the Swahili version of the HSS-12. Cronbach’s alpha was considered acceptable if greater than (>0.7).57Frequencies and means (with percentages and SD) were used to describe sample characteristics. Univariate and multivariable linear regression were used to assess factors associated with both stigma subscales and the overall stigma scale. In the regression model, stigma scores were expressed as a continuous measure. Independent variables included age, gender, marital status, education level, employment status, SES, BMI, viral load, WHO clinical stages, months since HIV diagnosis, months since cART initiation, HIV status disclosure, self-reported opportunistic infections, and the co-occurrence of depressive and anxiety symptoms. Our review of the literature informed factors included in the model. All variables with p<0.20 were included in the multivariable regression model apart from viral load because participants had missing values (n=145). The final multivariable models were generated using a backward stepwise approach by eliminating all variables independently with p>0.05. Assumptions of linear regression testing were visually inspected through histograms (linearity), normal probability plots  and plots of residual vs predicted values (homoscedasticity). Multicollinearity was assessed using the variance inflation factor. There were no multicollinearity problems. Modelling was undertaken five times in total: once to predict overall stigma and once to predict each of the four subscales. R (V.4.0.2) statistical software package58The 450 participants had a median age of 43 years (IQR=36–50), ranging from 18 to 60 years. The vast majority of the sample were female (79.1%), had attained basic primary level education (53.1%), lived with a family member (82.4%) and were unemployed (59.8%). Less than half of the study participants (43.8%) were separated, divorced or widowed. The mean BMI was within the normal range (mean (SD)=22.4 (4.8)). Most study participants had disclosed their HIV status to others (94.0%). The median time since HIV diagnosis was 8.8 years (IQR=4.67–11.50), ranging from 0 to 18 years. A total of 417 (93.7%) were in stage 1 of the WHO clinical staging, and 425 (95.3%) were on the first-line cART regimen . The medPerceived overall stigma scores ranged from 12 to 48, with a median score of 28 (IQR=23–33). Using PHQ-9 and GAD-7 cut-off score of ≥10, which has been shown to maximise specificity and sensitivity for depression2 test was statistically significant  but alternate fit measures indicated acceptable fit; RMSEA: 0.044; CFI:0.966 and TLI: 0.955. These results generally indicate that the data had a good fit to the model and that we can confidently use both total and subscale scores in this population. Measurement invariance across age groups and gender was supported because ΔCFIs are lower than 0.01 in all models suggesting that measurement invariance can be assumed.10.1136/bmjopen-2021-050709.supp1Supplementary dataThe factor loading of all items on the hypothesised scale was good except for item 6 (0.21) under the disclosure concern subscale. Convergent validity of the HSS-12 was demonstrated by the small to moderate correlations between HSS-12 and the correlation with the following relevant measures: GAD-7  and PHQ-9  Cronbach’s alpha (α) for the subscales and overall scale were all >0.7 see  except fPersonalised stigma was significantly associated with being female, being single, separated, divorced or widowed, self-employed or unemployed, having a low asset index score, having a viral load of >1000 copies/mL, having any current opportunistic infection, and the co-occurrence of depressive and anxiety symptoms. Disclosure concern was significantly associated with being separated, divorced or widowed, having no level of education, having a low asset index score, less time elapsed since HIV diagnosis, less time elapsed since cART initiation, and HIV status non-disclosure. Concern with public attitudes was significantly associated with being female, having primary or no level of education, decreased duration since cART initiation, and the co-occurrence of depressive and anxiety symptoms. Negative self-image was significantly associated with being separated, widowed or divorced, having no level of education, being self-employed or unemployed, having a viral load of >1000 copies/mL, decreased duration since HIV diagnosis, decreased duration since cART initiation, having any current opportunistic infection and the co-occurrence of depressive and anxiety symptoms.When a multiple linear regression model was run, it was found that being female , HIV status disclosure  and co-occurrence of depressive and anxiety symptoms  were significant predictors of perceived HIV stigma. Having no education was associated with increasing stigma levels at p=0.051 . Regression results indicated that the model explained 10.2% of the variance and that the model was a significant predictor of perceived HIV stigma F =7.46, p<0.001).Concerning the four subscales, we found that personalised stigma was positively correlated with being female and the co-occurrence of depressive and anxiety symptoms. Disclosure concern was inversely correlated with duration since HIV diagnosis and positively correlated with having no level of education and HIV status non-disclosure. Concerns with public attitudes were positively correlated with being female. Negative self-image was positively correlated with having no level of education and the co-occurrence of depressive and anxiety symptoms.This cross-sectional analysis of data from adults living with HIV observed that the HSS-12 presents excellent psychometric properties. Additionally, we observed that stigma was associated with both physical and mental well-being. According to our study, correlates of HIV-related stigma include being female, HIV status non-disclosure, and the co-occurrence of depressive and anxiety symptoms.The study examined the stigma scale’s psychometric properties to assess its usefulness and describe the correlates of HIV-related stigma among adults living with HIV in Kilifi. Reliability and validity were acceptable, and CFA supported the four-factor solution measuring the four dimensions of HIV stigma. Cronbach’s alpha for the HSS-12 among the Kenyan population is similar to the Swedish population in which the scale was developed.60 61Measurement invariance of the Swahili HSS-12 was evaluated and confirmed across main interest groups: gender and age. Our results indicated that the measurement model of the Swahili HSS-12 as a patient-reported outcome to measure perceived HIV stigma among adults is comparable across age groups and gender .Test–retest reliability, an indicator of scale stability over time, was of acceptable levels. The original HSS-40 has been used in diverse settingsWe examined the construct validity of the scale using CFA since its hypothesised structure has been published.The HSS-12 was reliable and valid for detecting stigma among adults living with HIV at the Kenyan Coast. Consequently, HSS-12 can be practically used as a brief screening tool for stigma-related problems both for research and clinical purposes. Future research could examine its predictive validity and evaluate its sensitivity to changes. This information would be crucial in determining its usefulness as an evaluation tool for programmes and interventions.Being female was positively associated with increased perceived HIV-related stigma scores, personalised stigma, and concern with public attitudes. This finding agrees with previous studies from SSAet al found that PLWHA with higher levels of perceived HIV-related stigma reported greater levels of HIV disclosure concerns; therefore, they are less likely to disclose their status.HIV status disclosure was positively associated with overall HIV-related stigma scores and disclosure concerns, with persons who had not disclosed their HIV status reporting greater levels of concern about HIV disclosure concerns. Anakwa et alThe co-occurrence of depressive and anxiety symptoms was positively correlated with overall HIV-related stigma scores, personalised stigma and negative self-image. This finding corroborates previous studies among PLWHA carried out within SSAOther factors influencing the four subscales were also established. Having no level of education was positively associated with higher reported disclosure concerns and negative self-image, corroborating findings of studies carried out in Nigeria79disclosure concerns, with persons with a more recent diagnosis reporting greater levels of concern about HIV status disclosure. This is consistent with a study of PLWHA in ChinaMonths since HIV diagnosis was inversely associated with A potential strength is that this is the first study to report the measurement characteristics of the HSS-12 in the SSA context. We recognise several potential limitations in this study. First, the study was in a clinical setting where our study sample consisted of adults living with HIV on cART. Compared with untreated individuals living with HIV, it is likely that levels of HIV stigma would be lower in our sample because it has been shown that access to ART lowers stigma.From the study, the 12-item short version of the Berger HSS


The treatment paradigm for multiple myeloma (MM) continues to evolve with the development of novel therapies and the earlier adoption of continuous treatments into the treatment pathway. Lenalidomide-refractory patients now represent a challenge with inferior progression free survival (PFS) reported to subsequent treatments. We therefore sought to describe the natural history of MM patients following lenalidomide in the real world.This was a retrospective cohort review of patients with relapsed MM who received lenalidomide-based treatments in the U.K. Data were collected for demographics, subsequent therapies, treatment responses, survival outcomes and clinical trial enrollment.198 patients received lenalidomide-based treatments at a median of 2 prior lines of therapy at a median of 41 months (range 0.5-210) from diagnosis. 114 patients  became refractory to lenalidomide. The overall survival (OS) after lenalidomide failure was 14.7 months having received between 0-6 subsequent lines of therapy. Few deep responses were observed with subsequent treatments and the PFS to each further line was < 7 months. There was a steep reduction in numbers of patients able to receive further treatment, with an associated increase in number of deaths. The OS of patients progressing on lenalidomide who did not enter a clinical trial incorporating novel agents was very poor , although the trials group were a biologically fitter group.These data demonstrate the poor outcomes of patients failing lenalidomide-based treatments in the real world, the highlight need for more effective treatments. The duration of treatment response typically reduces with each line of therapy, as does the depth of response. A large retrospective study of European real-world data demonstrated that the proportion of patients able to receive treatment reduces with each subsequent line of treatment, with only 15% of patients reaching 4Lenalidomide, an immunomodulatory drug (IMiD), is a key backbone agent in the treatment of MM and commonly used as frontline treatment for both transplant eligible and ineligible patients either in combination with proteasome inhibitors (PI), alkylators and/or CD38 monoclonal antibodies or as a doublet with corticosteroids according to performance status , 3. AddiAs lenalidomide is typically continued until disease progression or intolerance, most patients become lenalidomide-refractory. Emerging data from sub-group analysis of clinical trials suggest that the treatment response and progression free survival (PFS) of lenalidomide-refractory patients are inferior to those that are sensitive –20. RealHowever, there may be discrepancies between clinical trial and real-world outcomes due to multiple patient-related, disease-related and treatment-related factors present between the two groups . The obsWe therefore sought to understand the long-term outcomes of patients with relapsed or refractory MM (RRMM) following lenalidomide failure in the real-world setting by characterizing the response and PFS to each subsequent treatment and investigating the impact of access to novel agents through clinical trials.This was a retrospective, observational chart review study involving two large U.K. myeloma specialist centers  and Leeds Teaching Hospitals NHS Trust). RRMM patients who had previously received lenalidomide between August 2006 and September 2017 were identified using the hospitals’ electronic health record systems. Patients were required to have at least one response assessment with a lenalidomide-based regimen in order to be included in the study. Baseline demographic details, disease characteristics and relevant laboratory blood results were recorded. International Staging System (ISS) at diagnosis and Eastern Cooperative Oncology Group (ECOG) performance status at the time of lenalidomide use were noted. Lenalidomide-based treatment was defined as T0 and subsequent treatments were labelled as T1, T2, T3 etc. Treatment details were extracted, including clinical trial participation and treatment response based on the International Myeloma Working Group (IMWG) uniform response criteria .The National Health Service Health Research Authority deemed that specific research ethical approval was not required due to the anonymous nature of the data collection (REF 704/60/88/81), and this study complied with information governance regulations at both hospitals.The primary objective was to estimate the duration of PFS at each subsequent line of therapy after lenalidomide-based treatment. Secondary objectives included describing overall response rate  and response categories, overall survival (OS), and outcomes according to participation in clinical trials.st November 2017. OS and PFS were calculated and presented as Kaplan-Meier curves. Differences in OS curves between groups were evaluated with the log-rank test. Cox regression analysis was used to examine the impact of different variables (univariate and multivariate) on OS post-lenalidomide. A p-value less than 0.05 was considered statistically significant. SPSS Statistics and GraphPad Prism were used to generate figures.Qualitative variables were presented as absolute percentage for each modality and quantitative variables were described in terms of mean, median, range and standard deviation. OS was measured from treatment start until death from any cause. PFS was measured from treatment start until whichever came first of disease progression or death from any cause. Patients with no events were censored at the data-cut off of 1198 RRMM patients were identified to have commenced lenalidomide-based treatment between August 2006 and September 2017 and had at least one evaluable response assessment. Of these, 159 were treated in UCLH and 39 in Leeds Teaching Hospitals NHS Trust. Patient demographics are shown in The median age at the start of lenalidomide based therapy (T0) was 66 years (range 35-88). Patients received a median of 2 prior treatment lines before T0 . The majority of patients  received both a PI and thalidomide prior to lenalidomide therapy. Patients commenced lenalidomide at a median of 41 months from diagnosis (range 0.5-210), predominantly as doublet lenalidomide-dexamethasone regimen . Other regimens used include bortezomib-lenalidomide-dexamethasone , ixazomib-lenalidomide-dexamethasone , lenalidomide-dexamethasone-elotuzumab , daratumumab-lenalidomide-dexamethasone , cyclophosphamide-lenalidomide-dexamethasone , and lenalidomide-conditioned reduced intensity allogeneic stem cell transplant . Lenalidomide doses at disease progression were available in 98 patients    patients. The majority of patients  became refractory to lenalidomide after an initial response. Despite this, 81 (51%) continued on lenalidomide for a median of 4.14 months (range 0.1-31.5) after evidence of progressive disease (PD). Out of these 81 patients, 24 continued on lenalidomide for more than 6 months. Overall, 31  patients progressed on lenalidomide and died without receiving any further treatment.The absolute numbers of patients that were able to receive treatment diminished at each subsequent line after lenalidomide  of patients were refractory to lenalidomide at the beginning of the next treatment (T1), PFS2 [from commencing lenalidomide to progression on next line of therapy (T1)] was assessed to review if there was an optimal salvage treatment for such patients, taking into consideration the duration of response to lenalidomide. The median PFS2 was similar irrespective of treatment choice : 23 months, bortezomib and Panobinostat (n=12): 24 months, bendamustine (n=16): 25 months, with clinical trials (n=9): 19 months, other therapies (n=48): 25 months (p=0.89 (log rank)) Figure 4Overall, 37 patients (33%) enrolled in a clinical trial at any time after lenalidomide-based treatment. These patients had a superior median OS from T1 to those that did not  observed. Additionally, the median PFS for each subsequent line was less than 7 months and more patients died at each subsequent line. These observations suggest that patients should be treated with optimal treatment as early as possible, rather than reserving treatments for later lines, as not all patients will live to reach this point. As treatment advances continue, new and effective treatments are under evaluation. The advent of B-cell maturation antigen (BCMA) targeted treatments such as Belantamab Mafodotin, chimeric antigen reception T-cells (CAR-T) and T-cell engagers as well as the incorporation of antibodies with standard to care regimens will lead to more effective salvage regimens for relapsed patients. Indeed, the ORR and durations of response to these treatments are already demonstrating improvements over historical data (This study demonstrated that the survival after failing lenalidomide at 3cal data . HoweverIt is of interest that some patients continued on treatment with lenalidomide for over 6 months after IMWG defined disease progression due to lack of clinical relapse. This is relevant for treatment funders that may assume that treatments are stopped at the time of IMWG defined progression. Indeed, the clonal heterogeneity and patient variability observed in MM requires personalized decisions to be made based on the clinical phenotype of disease, genetic risk and patient preference, and as such some patients with indolent relapses continued on treatment for longer. There was no difference in PFS2 according to immediate next treatment, and so this dataset was unable to recommend an optimal treatment for lenalidomide-refractory patients, although those that had a PFS < 6 months had a shorter PFS with pomalidomide and should be considered for a class switch to a proteasome inhibitor-based combination. Ongoing clinical trials will be critical to guide this.This study is limited by its retrospective nature, the heterogeneity of the lenalidomide-refractory cohort who received lenalidomide in line 1 to 3, and that newer agents and combination regimens have been approved or made available since the beginning of data collection in 2006. In addition, this data focuses on the use of lenalidomide in the relapsed setting whereas today it can be used at first line. However, this historical data allows longer follow-up and the ability to describe longitudinal outcomes according to each subsequent line. It also provides interesting data describing that natural plight of MM patients that switch from treatment to treatment across multiple lines at relapse.Of note, one large U.S. real-world multi-sites myeloma dataset where 23.8% of patients were treated with lenalidomide upfront demonstrated a median PFS of 11.5 months , similarIn conclusion, these data provide valuable insights into the real-world outcomes of patients with relapsed refractory MM that have failed lenalidomide and highlights an unmet need for the development of more effective treatment strategies.The raw data supporting the conclusions of this article will be made available by the corresponding author upon reasonable request, without undue reservation.CL and JT are joint first authors. CL, JT, KY, GC, and RP designed the study. CP, GW, CK, LL, SM, XP, NR, JS, AW, KY, GC, and RP provided data. CL, JT, and JC collected the data. CL, JT, and WW analyzed the data. CL, JT, and RP wrote the paper. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Actual long-term survival rates for advanced epithelial ovarian cancer (EOC) are rarely reported.This study aimed to assess the role of histological subtypes in predicting the prognosis among long-term survivors (≥5 years) of advanced EOC.We performed a retrospective analysis of data among patients with stage III-IV EOC diagnosed from 2000 to 2014 using the Surveillance, Epidemiology, and End Results cancer data of the United States. We used the chi-square test, Kaplan–Meier analysis, and multivariate Cox proportional hazards model for the analyses.P<.001), mucinous , and clear cell  subtypes showed better ovarian cancer-specific survival than those with the serous subtype. Similar results were found regarding overall survival. However, ovarian cancer–specific survival and overall survival were comparable among those with endometrioid, clear cell, and mucinous tumors.We included 8050 patients in this study, including 6929 (86.1%), 743 (9.2%), 237 (2.9%), and 141 (1.8%) patients with serous, endometrioid, clear cell, and mucinous tumors, respectively. With a median follow-up of 91 months, the most common cause of death was primary ovarian cancer (80.3%), followed by other cancers (8.1%), other causes of death (7.3%), cardiac-related death (3.2%), and nonmalignant pulmonary disease (3.2%). Patients with the serous subtype were more likely to die from primary ovarian cancer, and patients with the mucinous subtype were more likely to die from other cancers and cardiac-related disease. Multivariate Cox analysis showed that patients with endometrioid (hazard ratio [HR] 0.534, Ovarian cancer remains the primary cause of death in long-term ovarian cancer survivors. Moreover, the probability of death was significantly different among those with different histological subtypes. It is important for clinicians to individualize the surveillance program for long-term ovarian cancer survivors. Advanced stage (stage III-IV) epithelial ovarian cancer (EOC) is usually incurable. However, approximately 25% and 15% of patients with EOC survive for >5 years and >10 years, respectively . AlthougBased on the World Health Organization classification of tumors of female reproductive organs, which was published in 2014, EOC can be classified into five histological subtypes: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous . A previThe endometrioid and mucinous subtypes are typically low-grade and early-stage, and patients with these subtypes show a better outcome than those with the high-grade serous subtype -10. MoreWe extracted EOC data from the Surveillance, Epidemiology, and End Results (SEER) database of the United States, which is a publicly available database and contains deidentified information on cancer incidence, demographic and clinicopathological variables, patterns of the first course of treatment, and survival data . We seleA total of 29,176 patients with stage III-IV EOC were identified. Of these patients, 5857 did not receive chemotherapy, 251 patients had a follow-up time of <60 months, 14,866 patients died within 60 months, and 152 patients did not receive surgery. A total of 8050 EOC patients with ≥5 years’ survival were included in this study.This study could be used to assist physicians in prognostic assessment at the time of diagnosis of EOC and help physicians better understand EOC from the long-term survivors to prolong the survival time of short-term survivors. The SEER program collects long-term follow-up cancer data, thus allowing us to assess the long-term survivors of EOC. We included the following demographic, clinicopathological, and treatment variables: age at diagnosis, race, stage, histological subtype, and nodal status. The definition of the staging system was based on the American Joint Committee on Cancer (AJCC) sixth edition staging system. The primary endpoints of this study were ovarian cancer–specific survival (OCSS) and overall survival (OS). OCSS was defined as the time from diagnosis to death due to ovarian cancer, censoring at the date of last contact, or nonovarian cancer related–death. OS was defined as the time from diagnosis of ovarian cancer to the death from any cause.P<.05 indicated statistical significance.The association among demographic, clinicopathological, and treatment variables for the histological subtypes was compared using the chi-square test and the Fisher exact test. Survival comparisons were made using Kaplan–Meier analysis and compared using the log-rank test. Multivariate Cox proportional hazards model was used to determine the prognostic factors associated with OCSS and OS. Prognostic factors with statistical significance on univariate analyses were entered into multivariate analyses. The proportional hazard assumption was tested both graphically and using the Schoenfield residual test to address whether our data met the proportional odds assumption, allowing for the use of the Cox proportional hazards model. Sensitivity analyses were performed on the basis of the age at diagnosis, race, AJCC staging, and nodal status to investigate the effect of the histological subtype on survival outcomes. SPSS  and Stata/SE  were used for analyses, and P<.001) and diagnosed with stage IV disease (P<.001) than those with the other 3 histological subtypes. In addition, patients with the serous subtype had a higher risk of regional lymph node metastasis than those with the endometrioid and mucinous subtypes (35.7% vs 26.2%-31.5%), while those with the clear cell subtype had a higher risk of regional lymph node metastasis than those with the other 3 histological subtypes (42.6% vs 26.2%-35.7%) (P<.001).Patient characteristics and causes of death data are listed in This cohort included 5967 patients surviving for ≥5 years and <10 years (60-119 months) and 2353 patients surviving ≥10 years (≥120 months). With a median follow-up of 91 (range 60-227) months, a total of 3874 deaths were recorded. The most common cause of death was primary ovarian cancer , followed by other cancers , other causes of death , cardiac-related death , and nonmalignant pulmonary disease (3.2%). Patients with the serous subtype were more likely to die from primary ovarian cancer, and those with the mucinous subtype were more likely to die from other cancers and cardiac-related disease . Among tThe causes of death after stratification by years of survival after diagnosis of EOC for long-term survivors are detailed in P<.001) and OS (P<.001) compared to those with the other 3 histological subtypes, while comparable OCSS (P=.55) (P=.91)  A and OS  (P=.91) B were obP<.001), mucinous , and clear cell  subtypes showed better OCSS than those with the serous subtype. Similar results were obtained regarding OS. Using clear cell tumor as a reference, similar OCSS and OS were observed in endometrioid  and mucinous cancers  compared to those with clear cell tumor. The effect of the histological subtype on OCSS  (P<.001)  A and OS (P<.001) B than thSensitivity analyses were focused on age at diagnosis, race, AJCC staging, and nodal status to investigate the effect of histology on survival outcomes . The obtHerein we used the SEER database to assess the role of histological subtypes in predicting the survival outcome among long-term survivors (≥5 years) of advanced EOC. Our results indicate that ovarian cancer remains the primary cause of death among long-term ovarian cancer survivors. Moreover, patients with endometrioid, clear cell, and mucinous tumors showed a significant improvement in OCSS and OS compared to those with serous tumors. This study provides a unique opportunity to determine the characteristics of long-term survivors of advanced EOC.There exist limited studies that have explored factors associated with long-term survival in EOC . Such stIn our previous studies, we have found a markedly increased mortality rate among patients with stage III-IV mucinous and clear cell cancers, but better survival among those with serous and endometrioid cancers ,22. ThesThe prognostic role of histological subtypes on the survival outcome among long-term survivors of advanced EOC has been explored by limited studies. A previous study by Son et al  reportedSeveral studies, including ours, have indicated that the survival outcome of clear cell and mucinous cancers were significantly inferior to that of serous cancers in advanced-stage disease -16. HoweThere were several limitations to our study. First, this is a retrospective study; hence, we could not exclude all potential selection biases. Second, information on chemotherapy regimens, administered dose, number of chemotherapy cycles, and completeness of chemotherapy were unavailable in the SEER database. Third, the size of residual tumors (before 2010), patterns of disease recurrence, and strategy of treatment after disease progression were also not recorded in the SEER database. Moreover, this database lacks a central review for histological subtype. On the other hand, the strengths of this study include its population-based design. This study involved a relatively large cohort of patients with EOC, with the data representing a real-world scenario. Furthermore, our results are expected to expand the current knowledge on the biological behavior of EOC by various histological subtypes after extensive follow-up. Further studies focusing on the prognostic factors regarding long-term survivors of EOC are needed.In conclusion, our study suggests that ovarian cancer remains the primary cause of death among long-term ovarian cancer survivors. Moreover, the probability of death is significantly different among those with different histological subtypes of EOC. It is important for clinicians to individualize the surveillance program for long-term ovarian cancer survivors. Further studies using diverse cohorts are warranted to confirm our findings and expand our understanding.


Cardiac amyloidosis (CA) is a restrictive cardiomyopathy with a traditionally poor prognosis. Until recently, CA treatment options were limited and consisted predominantly of managing symptoms and disease-related complications. However, the last decade has seen significant advances in disease-modifying therapies, increased awareness of CA, and improved diagnostic methods resulting in earlier diagnoses. In this review, we provide an overview of current and experimental treatments for the predominant types of CA: transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain (AL)-mediated CA (AL-CA).TTR) silencing agents to prevent TTR formation, TTR tetramer stabilization and inhibition of oligomer aggregation to prevent fibril formation, anti-TTR fiber antibodies, and amyloid degradation. For end-stage CA, advanced interventions may need to be considered, including heart, heart-kidney, and, for hereditary ATTR-CA, heart-liver transplantation. Despite the evolution of treatment options, CA management remains complex due to patient frailty and therapeutic side effects or intolerance with advanced cardiac disease. This is particularly relevant for those with AL-CA, when active teamwork between the hematologist-oncologist and the cardiologist is critical for treatment success. Often, referral to an expert center is necessary for timely diagnosis, initiation of treatment, and participation in clinical trials.The mainstay of AL-CA treatment is proteasome inhibitor-based chemotherapy with daratumumab and, when feasible, autologous stem cell transplantation. For ATTR-CA, the stabilizer tafamidis is the only US Food and Drug Administration (FDA)-approved treatment. However, promising novel therapies on the horizon target various points in the ATTR-CA amyloidogenic cascade. These include transthyretin gene ( Table 1).2Cardiac amyloidosis (CA) is a rare and progressive disease resulting from protein buildup in cardiac muscle. Treatment options for CA were previously limited to symptom management. Over the last decade, however, there have been significant advances in disease-modifying therapies that provide hope for slowing disease progression to optimize quality of life and improve survival. Here we provide an overview of novel and experimental treatment strategies for the predominant types of CA, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain (AL)-mediated CA, or AL-CA  have been adapted from treatment of multiple myeloma, a related plasma cell dyscrasia. While treatment is directed by the hematologist-oncologist, many regimens have significant toxicities that are poorly tolerated in patients with cardiac involvement, so it is critical to have a close alignment with the cardiologist on the treatment team.4 Even in advanced cardiac disease (Mayo cardiac stage IIIb), early response at 1 month has been associated with improved overall survival.5 Success is determined by hematologic response (suppression of serum free light chains) and organ-specific response . A recently validated composite hematologic/organ response model6 classifies patients into two treatment response groups to determine early clinical benefit, and it has shown a higher prognostic power than assessment of isolated hematologic or organ response. Rapid improvement in left ventricular (LV) thickness and function is uncommon after treatment regardless of improvement in cardiac biomarkers. Global longitudinal strain and cardiac magnetic resonance imaging with T1 mapping and extracellular volume measurements provide more subtle evidence of structural treatment response.8The goal of treatment is to administer the strongest chemotherapy regimen that the patient can safely tolerate with the intent of improving organ function and survival.9 Bortezomib-based therapies are also used after ASCT for consolidation treatment if there is less than a very good partial response.Risk stratification dictates initial treatment strategy for AL-CA patients. High-dose melphalan with ASCT provides the greatest opportunity for long-term remission. However, to qualify for ASCT as initial therapy, patients must be low risk, defined as age < 70 years old with good functional status (Eastern Cooperative Oncology Group performance status [ECOG PS] < 2) and without significant organ dysfunction, including New York Heart Association (NYHA) class < III and biomarker levels below validated thresholds. Due to disease severity and comorbidities at the time of diagnosis, less than one in five patients are eligible for up-front ASCT. If there is high bone marrow plasma cell infiltration (> 10%) and/or any anticipated delay in initiation of ASCT, patients may require induction therapy with the proteosome inhibitor bortezomib, with dexamethasone and an alkylating agent. Bortezomib-based induction therapy has been shown to improve progression-free survival with an 84% hematologic response (39% complete response) and an 84% overall 5-year survival.10 patients who initially do not qualify for ASCT, chemotherapy is initiated, and ASCT can be reconsidered if reversible contraindications improve. For many years, the standard chemotherapy regimen was high-dose melphalan with dexamethasone, but the addition of bortezomib in recent years has become the standard of care, with significantly improved hematologic response and overall survival in a phase 3 randomized open-label trial.11 The two most common regimens are cyclophosphamide-bortezomib-dexamethasone (CyBorD) and bortezomib-melphalan-dexamethasone. Recently, the anti-CD38 human IgG-κ monoclonal antibody, daratumumab, previously used for relapsed or refractory AL, has also become part of the standard up-front regimen. The ANDROMEDA phase 3 trial showed that subcutaneously administered daratumumab plus CyBorD compared with CyBorD alone had more rapid and significant hematologic response (53% vs 18%) and improved survival from major organ deterioration or hematologic progression  for newly diagnosed AL.12 Although there was an overall increase in lymphopenia and severe infections, the incidence of overall severe adverse events was lower in the daratumumab group when adjusted for exposure to trial treatment. Of note, most of the trial population had NYHA class II (40%) and NYHA Class IIIa (34%) symptoms. In a prespecified subgroup analysis, daratumumab demonstrated an escalating hematologic response with higher NYHA class, suggesting particular efficacy and safety for those with higher-grade cardiac involvement. After the ANDROMEDA trial, daratumumab with hyaluronidase-fihj became the first FDA-approved treatment for AL amyloidosis.13For intermediate risk (cardiac stage I-IIIa)14High-risk patients with poor functional capacity (ECOG PS 4) and advanced cardiac involvement (NYHA class IIIb or IV) often do not tolerate standard chemotherapy and may require reduced doses or a sequential introduction of chemotherapy agents with frequent reassessment for potential aggressive escalation. Given the increasing evidence for daratumumab in this population, monotherapy daratumumab is being investigated for newly diagnosed stage IIIb AL in a phase 2 open-label trial.15 Additional consideration for regimen selection is the presence of genetic abnormalities. The chromosomal translocation 11; 14 is present in up to 60% of AL cases and is associated with poorer outcomes with bortezomib and immunomodulatory therapy (IMiD), whereas the gain of function 1(q21) has been associated with poorer response to melphalan. Alternative therapies for patients with contraindications to bortezomib are under investigation, including the oral selective B-cell lymphoma 2 inhibitor, venetoclax, for patients with t, although limited data are available.16Contraindications to bortezomib include pulmonary fibrosis and peripheral neuropathy. Carfilzomib is another second-generation proteasome inhibitor that is beneficial in place of bortezomib for those with significant neuropathy; however, it is associated with a rise in NT-proBNP and cardiotoxicity and therefore not used for those with AL-CA.18 Otherwise, IMiD and low-dose dexamethasone with or without cyclophosphamide are used. The IMiDs lenalidomide, pomalidomide, and thalidomide have shown efficacy in retrospective and phase 2 clinical trials but have not been compared to other regimens.19 Lenalidomide and thalidomide treatment have been associated with thrombotic complications requiring thromboprophylaxis. IMiDs have been associated with a discordant rise in NT-proBNP levels despite improvement in free light chains, which poses challenges for cardiac response assessment.20 An all-oral regimen for relapsed or refractory AL with the proteasome inhibitor ixazomib plus dexamethasone was studied in the TOURMALINE-AL1 phase 3 study; while not associated with improved overall hematologic response, it demonstrated a higher complete response rate (26% vs 18%) and longer progression-free survival compared with physicians’ choice .21 A non-IMiD–based rescue regimen with the alkylating agent bendamustine and dexamethasone has also been investigated in a phase 2 study and demonstrated a 57% hematologic response rate.Patients who relapse or are refractory to up-front therapy are usually treated with daratumumab, if not already initiated, based on many promising retrospective and phase 2 trials.22 Another chimeric monoclonal antibody, CAEL-101, which targets AL amyloid deposits, was found to be well tolerated in a phase 2 study23 and is now under investigation in two phase 3 trials in Mayo Stage IIIa24 and Stage IIIb25 disease.Immunotherapy with monoclonal antibody NEOD001 has also been investigated. However, the PRONTO phase 2b trial for AL-CA with refractory cardiac dysfunction failed to meet primary and secondary end points, and the VITAL phase 3 trial for treatment-naive AL-CA was discontinued based on futility analysis.26 EGCG has been investigated in three phase 2 trials for treatment of AL-CA. Two of these trials have completed enrollment—EpiCardiAL27 and TAME-AL—but results had not been published at time of publication.28 A small single-center Japanese study of 57 patients did not report a significant benefit for use of EGCG but also did not report any significant toxicity.29 Because EGCG is well tolerated, it is often added as an adjunct to AL-CA treatment regimens.Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, is a major antioxidant that has been shown to stabilize misfolded amyloid fibrils into a less toxic form and prevent formation of insoluble amyloid fibrils.31 It showed promise in retrospective studies to improve hematologic response and overall survival.33 However, a recent prospective trial of 140 patients randomized to CyBorD with doxycycline showed no benefit for hematologic or cardiac progression-free survival, so the role of doxycycline has become less clear.34 We await results of an ongoing randomized control trial investigating the addition of doxycycline to bortezomib-based therapy.35The antibiotic doxycycline has been shown to disrupt AL amyloid fibril formation in transgenic mice and to counteract AL amyloid toxicity in C elegans.Until recently, treatment of ATTR-CA was aimed at management of symptoms and disease-related complications. However, novel and experimental therapies for treatment of ATTR-CA wild-type (ATTRwt-CA) and hereditary/variant (ATTRv-CA) are emerging. Strategies for disease-modifying therapies target various steps along the ATTR-CA amyloid production process, including gene silencing to prevent hepatocyte TTR production, TTR stabilization to prevent TTR tetramer dissociation, anti-TTR antibodies, inhibition of TTR oligomer aggregation, and degradation of deposited ATTR fibrils with the goal to reverse the disease process, restore cardiac function, and consequently improve morbidity and mortality.Two gene silencer therapies, patisiran and inotersen, are FDA approved for ATTRv polyneuropathy based on multicenter, international, randomized controlled phase 3 trials. Findings from cardiac subgroup analyses have prompted investigation for utility in ATTRv-CA and ATTRwt-CA.36 In addition to demonstrating slower progression of polyneuropathy at 18-months, a prespecified ATTRv-CA subgroup demonstrated improvement in NT-proBNP levels as well as echocardiographic parameters, including cardiac output, LV wall thickness, end-diastolic volume, and global longitudinal strain.37 The sub-study also demonstrated improved functional capacity  as well as decreased hospitalization and mortality with patisiran compared to placebo at 18-months. These results prompted the APOLLO-B phase 3 randomized controlled trial,38 which has completed enrollment with results pending, to evaluate patisiran for ATTRv-CA and ATTRwt-CA with the primary end point of 6-minute walk test (6MWT) performance and secondary end points of death and hospitalization at 12 months.Patisiran is a small interfering RNA that binds to the RNA-induced silencing complex and mediates cleavage of the transthyretin mRNA to prevent formation of TTR. It is administered intravenously every 3 weeks. The APOLLO randomized controlled trial evaluated the effect of patisiran for treatment of 225 patients with ATTRv polyneuropathy, 126 (56%) of whom had concomitant cardiac involvement.39 evaluated inotersen for 172 ATTRv polyneuropathy patients, 105 (61%) with cardiac involvement. Like APOLLO, NEURO-TTR demonstrated slower progression of polyneuropathy and improved quality of life; unlike APOLLO, there was no significant improvement in echocardiographic parameters within the prespecified cardiac subgroup. However, in an interim analysis of inotersen in a single-center open-label study,40 33 patients with biopsy proven ATTR-CA without polyneuropathy (10 ATTRv-CA and 23 ATTRwt-CA) but with NYHA class I-III symptoms demonstrated a decrease in LV mass and improved exercise tolerance in 6MWT by 2 and 3 years of follow-up. A separate 24-month, single-center, open-label study of 50 patients with ATTRwt-CA or ATTRv-CA is ongoing.41Inotersen is an antisense oligonucleotide inhibitor of transthyretin mRNA produced by the liver that is administered weekly by subcutaneous injection. The NEURO-TTR randomized controlled trialAlthough the subcutaneous use of inotersen may be preferable to the intravenously administered patisiran, post-hoc comparison of the APOLLO and NEURO-TTR trials demonstrates more improved neuropathy symptoms and a lower risk of adverse effects for patisiran compared with inotersen. NEURO-TTR demonstrated a higher frequency of serious adverse events with inotersen compared to placebo , including thrombocytopenia and glomerulonephritis. In contrast, patisiran compared favorably with placebo in the APOLLO study. Patients in the patisiran group were premedicated with dexamethasone, acetaminophen, an H2-blocker, and an H1-blocker, which may have decreased adverse reactions.42 which was prematurely terminated at 6 months due to increased mortality compared with placebo (14% vs 3%). Most deaths were determined to be due to heart failure, and a post-hoc safety investigation failed to reveal a causative mechanism.From an historical perspective, it is important to note that a different RNA interference agent, revusiran, was evaluated for ATTRv-CA in the ENDEAVOUR phase 3 trial,43 is evaluating vutrisiran, another RNA interference therapy, with a primary composite end point of all-cause mortality and recurrent hospitalizations at 30 months. Like inotersen, vutrisiran is administered subcutaneously but with the advantage of dosing every 3 months rather than weekly. The CARDIO-TTRansform study44 is evaluating eplontersen, a ligand conjugated antisense oligonucleotide, for a primary end point of cardiovascular mortality and clinical events at 120 weeks. Eplontersen is administered every 4 weeks with an improved formulation targeting fewer side effects than inotersen.Other ongoing randomized controlled trials include two novel silencer treatments for ATTR-CA (ATTRv-CA and ATTRwt-CA): vutrisiran and eplontersen. The HELIOS-B study45 It is hoped that this one-time therapy provides durable knockdown of TTR with subsequent improvement in clinical outcomes. The initial pilot study in a small cohort suggests that treatment is safe and well tolerated with no signal for off-target gene editing. This is one of the first clinical applications for this gene editing technology, which appears particularly suited for ATTR because the protein is predominantly synthesized in the liver, and the CRISPR-Cas9 system can target the liver by encapsulation in a lipid nanoparticle with avidity for the low-density lipoprotein (LDL) receptor.Another exciting novel method for reduction of hepatocyte TTR production is the CRISPR-Cas9 system  gene editing treatment, which knocks out the TTR gene. In an open-label, multicenter study, intravenous injection of NTLA-2001 by the CRISPR-Cas9 method in six patients with ATTRv polyneuropathy was demonstrated to reduce serum concentrations of TTR by up to 87% by 4 weeks, with only mild adverse events in 3 patients.46 but has only been studied in small, nonrandomized, mostly noncomparative single-arm prospective cohort trials of predominantly ATTRv-CA.50 Although these studies suggest stabilization of cardiac biomarkers and echocardiographic parameters, formal randomized controlled trials are needed to confirm these findings and determine an impact on morbidity and mortality. While diflunisal is generally considered safe and well tolerated, as an NSAID it is contraindicated in patients with significant thrombocytopenia and or renal dysfunction (glomerular filtration rate < 40 mL/min/1.73m2) and can cause gastrointestinal intolerance, bleeding, and heart failure exacerbation.Diflunisal is a nonsteroidal anti-inflammatory (NSAID) medication that has demonstrated TTR stabilization in vitro51 This study evaluated 441 ATTR-CA patients (106 ATTRv-CA and 335 ATTRwt-CA) for treatment with oral tafamidis 80 mg vs tafamidis 20 mg vs placebo. In a pooled analysis, both doses of tafamidis were associated with a reduction in all-cause mortality  and cardiovascular hospitalizations  at 30 months . Secondary end points were notable for a lower rate of functional capacity decline by 6MWT distance and of quality-of-life decline by Kansas City Cardiomyopathy Questionnaire–Overall Summary score. There was a smaller increase in NT-proBNP levels and less worsening of circumferential and radial global strain without effect on other echocardiographic parameters, with no significant safety problems reported. However, there was a higher rate of cardiovascular-related hospitalizations in the patients with NYHA class III symptoms on treatment, which has been postulated to be due to longer survival in a more critical stage of disease. Nevertheless, poorer outcomes in more advanced disease states suggest the importance of early administration to prevent TTR fibril formation and concern for ineffectiveness for disease reversal with this strategy.An analog of diflunisal, tafamadis has TTR stabilization characteristics but is not an NSAID. It is the only FDA-approved medication for both types of ATTR-CA since May 2019 after showing positive results in the ATTR-ACT study .52With FDA approval and a reassuring safety profile, tafamidis has become a mainstay of treatment for ATTR-CA. Although tafamidis has demonstrated significant efficacy in staving off disease progression, patients require life-long therapy, and the cost for many is prohibitive despite insurance, charity, and drug maker assistance programs. A cost-effectiveness model has indicated that the cost of tafamidis would need to be reduced by > 90% to be cost effective.53 Acoramidis is currently being investigated in the phase 3 randomized controlled trial, ATTRIBUTE-CM, for treatment of ATTR-CA NYHA Class I-III symptoms.54Acoramidis, formerly known as AG-10, is a novel oral TTR stabilizer that mimics a protective TTR mutation (T119M). In ex vivo studies, acoramidis binds more strongly to TTR than tafamidis.56 although there have been only three small noncomparative prospective single-arm studies with follow-up for only 7 to 25 patients with ATTRwt-CA and ATTRv-CA.59 One 14-patient study demonstrated significant reduction in interventricular septal thickness in 12 patients, but it was not reproduced in the other studies.59 All cohorts demonstrated a very small reduction in LV mass by cardiac magnetic resonance imaging, and one study had a signal for mildly reduced T1 time without reduction in extracellular volume. Nevertheless, as with AL-CA, EGCG is often prescribed due to its benign safety profile.Epigallocatechin-3-gallate has been shown to inhibit TTR amyloid fibril formation in vitro and in vivo in mice,60 Only three noncomparative prospective single-arm studies have investigated this combination therapy, and they demonstrated modest results with a high attrition rate (~10%) due to esophageal and dermatologic intolerance from doxycycline.63 However, given the high cost of other disease-modifying therapies, doxycycline with TUDCA/UDCA is a desirable, cheaper option if it is determined to be effective in a phase 3 randomized controlled trial that has completed recruitment, with results pending.64While many of the other ATTR-CA treatments target interference of amyloid formation and deposition, an amyloid degradation strategy targets already deposited amyloid fibrils and promotes breakdown and clearance. Doxycycline and tauroursodeoxycholic acid (TUDCA) or ursodeoxycholic acid (UDCA) have been shown to remove amyloid deposits in preclinical studies.65 Another anti-TTR recombinant human monoclonal antibody, NI006, has also shown high affinity for binding to ATTRv and ATTRwt ex vivo and in vivo.66 It is currently under investigation for ATTR-CA in a phase 1, randomized, placebo-controlled double-blind trial67 with plans for a subsequent open-label extension to investigate safety and efficacy. From an historical perspective, it is important to note that the anti-serum amyloid P (SAP) component antibody, GSK2315698, initially garnered excitement for amyloid fibril clearance in a phase 1 trial (excluding those with cardiac involvement).68 However, due to an adverse risk/benefit profile in a phase 2 trial of ATTR-CA, its development was terminated.69Immunotherapy is also being investigated for treatment of ATTR-CA. PRX004 (Prothena) is an intravenously administered anti-TTR humanized monoclonal antibody. In preclinical studies, it was shown to promote clearance of insoluble amyloid fibrils through antibody-mediated phagocytosis and inhibition of amyloid fibril formation. A recent phase I open-label multicenter study was terminated early due to the COVID-19 pandemic; however, analysis of 7 patients with ATTRv-CA (NYHA Class I and II) demonstrated safety, improvement in neuropathic symptoms, and a modest improvement in global longitudinal strain (-1.21%) after 9 months of treatment.In addition to specific disease-modifying therapies, general management of CA focuses on treatment of heart failure symptoms and arrhythmias with the goal of optimizing quality of life. Since CA has traditionally been considered a rare and lethal condition, CA patients have been excluded from heart failure randomized controlled trials, so treatment recommendations have been limited to expert consensus and small cohort studies.The cornerstone of treatment for CA is loop diuretic therapy. As CA patients have a very narrow window of volume optimization due to small, stiff ventricles with limited stroke volume, they can easily become volume overloaded with resultant pulmonary, hepatic, and renal congestion. Conversely, with slight overdiuresis, an already decreased stroke volume is further reduced, resulting in kidney, brain, and muscle hypoperfusion contributing to renal insufficiency and profound fatigue. Due to frequent gut edema, the more bioavailable loop diuretics, bumetanide and torsemide, are commonly used over furosemide and are sometimes paired with a mineralocorticoid receptor antagonist (MRA) with close monitoring of potassium and renal function. Compression stockings are also used to mobilize edema and to assist with frequent co-occurrence of autonomic dysfunction, particularly with AL-CA and ATTRv-CA. Patients are instructed to limit sodium intake and to closely monitor daily weights and blood pressure since subtle volume changes can have large hemodynamic effects.71 Since orthostatic hypotension can be challenging to treat, droxidopa may be used as an adjunct to midodrine and compression stockings and was recently approved specifically for management of symptomatic neurogenic orthostatic hypotension.72 Pyridostigmine, the acetylcholinesterase inhibitor, can also be used but has not been specifically studied in CA.73 Fludrocortisone should be avoided due to risk of volume retention.There is no established guideline-directed medical therapy for heart failure with preserved ejection fraction or reduced ejection fraction in patients with CA. Angiotensin receptor-neprilysin inhibitors, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, MRAs, and sodium-glucose cotransporter-2 inhibitors have not been studied in this population but may be poorly tolerated or even contraindicated due to autonomic dysfunction, oscillating fluid balance, and renal dysfunction. Vasoconstrictors such as midodrine may be needed to manage hypotension, particularly in patients with AL-CA and ATTRv-CA, where autonomic dysfunction can be debilitating.74Since CA patients have small stroke volumes, they are dependent on increases in heart rate to augment cardiac output. However, because of extensive fibrosis, CA patients are particularly prone to conduction system disease, syncope, and death. Thus, treatment with atrioventricular nodal blocking agents must be used cautiously since they can contribute to bradyarrhythmias and worsening low-output heart failure. Nondihydropyridine calcium channel blockers are typically contraindicated in CA patients because they bind avidly to amyloid fibrils, have profound negative inotropic effects, and exacerbate bradyarrhythmias.75 Since high pacing burden has been associated with deleterious remodeling and progressive heart failure symptoms in ATTR-CA, biventricular pacemaker upgrade may be necessary and has been shown to provide functional improvement.76 The role of implantable cardioverter defibrillators (ICD) is less clear and has been predominantly studied in AL-CA. While appropriate ICD therapies for ventricular arrhythmias are common, particularly in those with less-advanced CA, ICD implantation has not been shown to improve survival.77 Nevertheless, if a patient with CA has a sudden cardiac arrest with a reasonable survival of greater than 1 year, ICD implantation carries a class I-C recommendation.75With development of high-degree heart block with or without symptoms, pacemaker implantation is a Class 1-B recommendation.78 While there is no clear evidence to support a rate or rhythm control strategy in CA, rhythm control with amiodarone, and less commonly dofetilide or sotalol, is a class IIb-C recommendation due to frequent beta blocker intolerance. Digoxin sensitivity and toxicity was reported over 40 years ago and attributed to potentiated effects from myocardial binding79 and decreased renal clearance from concomitant renal dysfunction. However, a recent retrospective study of digoxin use in AL-CA suggests possible utility at lower doses and with close serologic monitoring.80 Cardioversion and ablation can also be considered in select cases and may be most beneficial in earlier disease states, although there is limited data in this population (Class IIb-C recommendation). Since left atrial appendage thrombosis occurs in up to one-third of patients, even in sinus rhythm without a diagnosis of atrial fibrillation, anticoagulation is prescribed for a diagnosis of atrial fibrillation regardless of the CHA2DS2-VASc score and should even be considered in select patients without atrial arrhythmias.82 Either warfarin or a direct oral anticoagulant may be safely prescribed. The benefit of atrial appendage occluder device placement in this population has also not been evaluated but can be considered for appropriate patients.Due to atrial enlargement from diastolic dysfunction and atrial fibrosis, atrial fibrillation is common and occurs in up to 44% of patients.83 Two recent studies demonstrate safety and similar outcomes for TAVR for ATTRwt-CA with aortic stenosis compared to those with lone aortic stenosis.85ATTRwt-CA has been reported in up to 16% of patients undergoing transcatheter aortic valve replacement (TAVR).86 Total artificial heart overcomes these barriers to LVAD and was shown to serve as a successful bridge to cardiac transplantation in a small retrospective study.87Due to the characteristically small and hypertrophied LV with frequent right ventricular involvement, LV assist devices (LVAD) are often not feasible for CA and have been associated with poor outcomes in small studies.91 Cardiac transplantation provides clinical improvement to facilitate subsequent chemotherapy and autologous stem cell transplantation for those with AL-CA.92 For patients with ATTRv-CA with neuropathy, heart-liver transplant has historically been performed to prevent progression of debilitating neuropathy but is now superseded by the availability of gene-silencing therapies.Increasingly, select patients with advanced cardiac disease, with or without renal disease, are considered for heart or combined heart-kidney transplantation, with improving survival rates.While the prognosis of CA is still poor relative to other forms of cardiomyopathies, the stars have started to align for improvement in CA prognosis with significant advances in diagnostic methods as well as novel and specific disease-modifying therapies. We eagerly await the results of ongoing randomized controlled trials as well as inclusion of this population in future studies to enhance our approach to this disease.While autologous stem cell transplantation was previously favored for up-front treatment of patients with light chain amyloidosis (AL) with acceptable risk, daratumumab in combination with a bortezomib-based chemotherapy regimen recently became the first treatment approved by the US Food and Drug Administration (FDA) for AL amyloidosis as it has demonstrated excellent hematologic and organ response in newly diagnosed AL.There is hope that daratumumab monotherapy may serve as a safe, tolerable, and efficacious treatment for those with advanced AL cardiac amyloidosis and is currently under investigation.The transthyretin (TTR) tetramer stabilizer, tafamidis, is the only FDA-approved treatment for transthyretin cardiac amyloidosis (ATTR-CA). However, there are promising novel therapies on the horizon that target pathogenic TTR fibril formation including TTR gene silencers, TTR tetramer stabilizers, oligomer aggregation inhibitors, anti-TTR fiber antibodies, and TTR amyloid degraders .For end-stage CA, advanced interventions including heart or heart-kidney transplantation may need to be considered. For patients with hereditary ATTR-CA with neuropathy, heart-liver transplant has been historically performed to prevent progression of debilitating neuropathy but is now superseded by the availability of gene-silencing therapies such as patisiran or inotersen.Despite the evolution of treatment options, CA management remains complex due to patient frailty and therapeutic side effects in advanced cardiac disease states.


Background: The UNAIDS 90-90-90 Fast-Track targets provide a framework for assessing coverage of HIV testing services (HTS) and awareness of HIV status – the “first 90.” In Kenya, the bulk of HIV testing targets are aligned to the five highest HIV-burden counties. However, we do not know if most of the new HIV diagnoses are in these five highest-burden counties or elsewhere.Methods: We analyzed facility-level HTS data in Kenya from 1 October 2015 to 30 September 2016 to assess the spatial distribution of newly diagnosed HIV-positives. We used the Moran's Index (Moran's I) to assess global and local spatial auto-correlation of newly diagnosed HIV-positive tests and Kulldorff spatial scan statistics to detect hotspots of newly diagnosed HIV-positive tests. For aggregated data, we used Kruskal-Wallis equality-of-populations non-parametric rank test to compare absolute numbers across classes.Results: Out of 4,021 HTS sites, 3,969 (98.7%) had geocodes available. Most facilities , were not spatially autocorrelated for the number of newly diagnosed HIV-positives. For the rest, clustering occurred as follows; 438 (11.0%) were HH, 66 (1.7%) HL, 275 (6.9%) LH, and 156 (3.9%) LL. Of the HH sites, 301 (68.7%) were in high HIV-burden counties. Over half of 123 clusters with a significantly high number of newly diagnosed HIV-infected persons, 73(59.3%) were not in the five highest HIV-burden counties. Clusters with a high number of newly diagnosed persons had twice the number of positives per 1,000,000 tests than clusters with lower numbers .Conclusions: Although high HIV-burden counties contain clusters of sites with a high number of newly diagnosed HIV-infected persons, we detected many such clusters in low-burden counties as well. To expand HTS where most needed and reach the “first 90” targets, geospatial analyses and mapping make it easier to identify and describe localized epidemic patterns in a spatially dispersed epidemic like Kenya's, and consequently, reorient and prioritize HTS strategies. During 2016, it was estimated that between 1.6 million and 2.1 million people were tested positive for HIV and learned their status worldwide . This trThe focus on HIV programming to the “right places” and reprogramming of HIV diagnoses, care, and treatment activities to the highest-burden areas has been the cornerstone of targeting and resource allocation in recent years . It is eKenya has a generalized HIV epidemic with a prevalence among 15–49-year-olds estimated to be 5.9% in 2015 . In 2017Previous analysis of population-based household survey data in Kenya has shown that clusters of high rates of HIV infections may exist even in low burden counties . ExaminiKenya is a geographically diverse country in East Africa with a population density of 85.1 people per sq. km in 2016 . It has https://hiskenya.org/>. Data were aggregated at the facility-level and counties for analyses. Our hypothesis was that HIV-infected persons were distributed randomly within geolocations. In addition to the COP classification, we created county categories by standardizing the burden of HIV as the percentile distribution of the number of PLHIV per 100,000 population within a county.All HTS facilities report the number tested and the number newly diagnosed with HIV to the Ministry of Health through the District Health Information System version 2 (DHIS2) platform <http://www.epsg.org/> and other GIS data from <http://192.156.137.110/gis/search.asp>, <https://www.wri.org/resources/data-sets/kenya-gis-data> – all these data are freely available and their access and use are covered under the creative commons license CC BY 4.0. For all the projections, we used the world geodetic system (WGS) 1984 coordinate reference system. For point-pattern data, we obtained the master facility list that contains latitude and longitude coordinates of all public health facilities in the country from the Kenya Ministry of Health as a comma separated values (CSV) file format and imported this into the GIS software as a delimited text layer for analysis and mapping.Shape polygons were sourced from various public repositories: projections from <Our primary outcome of interest was the count of new HIV diagnoses from 1 October 2015 to 30 September 2016 by each health facility and further aggregated at the county level. These data are routinely collected and submitted centrally as part of HIV program monitoring in Kenya. HIV infections were diagnosed using the national HIV testing algorithm . The denn = 3,933). In the second approach, we used Kulldorff spatial-scan Poisson model implemented in the software SATScan™ ver. 9.6 to detect whether counts of newly diagnosed HIV-infected persons were randomly distributed over space or clustered in the detectable pattern(s). We considered the number tested for HIV as the population denominator in all the geocoded facilities. We set a circular scan window of 50 kilometers radius scan window that looped over geocoded locations collectively containing HIV-infected persons out of the tested population, assuming the population's proportion at risk to be the default ≤ 50%. We restricted cluster detection to those with at least 10 infected persons and high-rate clusters as those with a relative risk ≥ 1.0. We reported significant Standard Monte Carlo p-values for all identified clusters after looping through a maximum of 999 iterations. A cluster was considered statistically significant when its log-likelihood ratio was greater than the critical value. Finally, we compared the hotspots spatial scan output map to local Moran's I autocorrelation maps. For all analyses, statistical significance was considered at p-values < 0.05.In the first approach, we used local Moran's I in ArcGIS™ version 10.4 to analyze hotspots of the number of newly diagnosed HIV-infected persons at site level hence classifying sites as having no-clustering (random distribution) or autocorrelated neighbors using the four categories: HH, HL, LH, and LL. In these categories, hotspots are represented by an H, while an L denotes low spots. In this analysis, we used all the geocoded facilities  clusters had a significantly high number of newly diagnosed HIV-infected persons. Less than half of those, 53/123 (43.1%) were in the first and second percentile of HIV burden in Kenya (Median HIV case identification per facility was 22 new diagnoses in a year [interquartile range (IQR) 22–574]. The number of newly diagnosed HIV-infected persons varied by county classification in Kenya's country operational plan . Facilitin Kenya . Similarp < 0.001. Most facilities showed no clustering ; others were grouped as follows: HH , HL , LH , and LL . Of the HH sites, 301 (68.7%) were in high HIV-burden counties distributed within each: Homabay with 78/184 (42.4%), Kisumu 57/137 (41.6%), Siaya 50/145 (34.5%), Migori 43/139 (30.9%), and Nairobi 73/239 (30.5%). HH facilities in high burden counties were near water bodies  or within the urban core of a large city (Nairobi), and low HIV-burden areas were near major roads  had geocodes available. Using facility-level data, global Moran's I was 0.023, while the expected index was −0.00025, Z-score 33.9, and or roads .In Catha edulis commonly referred to as “Khat.” Khat is a plant whose leaves are chewed by people for its stimulant action and is a highly-valued export crop. Other clusters were near or within Isiolo town in eastern Kenya and around Nanyuki town in Laikipia county – both towns situated along a major transport corridor to northern Kenya  contributed to new diagnoses in clusters with many new HIV diagnoses . ClusterWhere are the newly diagnosed HIV positives in Kenya? About 3 out of 5 of clusters with a high number of newly diagnosed HIV-infected persons were not in the five highest HIV burden counties of Kenya, with a substantial proportion of sites contributing to an increased number of newly diagnosed HIV-infected persons in low HIV burden counties. We found sites with many newly diagnosed HIV-infected persons found in low-burden counties typically situated near transport corridors. Major transport corridors play a role in HIV transmission to relatively rural areas has been described by others . AdditioWe interpret our findings in two ways: firstly, we answer the question of whether higher numbers of newly diagnosed HIV-infected persons are found in the highest-burden counties, and secondly, we qualitatively examine the role of transport infrastructure in the geographic distributions of the newly diagnosed.Does the number of newly diagnosed HIV-infected persons follow the HIV burden? The common belief in HIV programming is that many newly diagnosed HIV-infected persons would be within high HIV-burden counties instead of low-burden counties. Our analyses demonstrate that while often true, there is a need to look more deeply into HTS data to identify finer geographic areas where there could be higher numbers of HIV-infected persons than expected. Facility-level data are aggregated at an areal geographic unit for analyses. There is a lack of congruence in high targets based on the need to identify as many newly diagnosed HIV-infected persons in HIV high-burden areas as to the actual presence of potentially newly-infected persons. Thus, there is a need to rethink the target-setting approaches in clusters with the highest potential and refine geographical planning units to smaller units for better outcomes. Under targeting could have caused the lack of congruence between HTS targets and testing achievements where a higher number of HIV-infected persons were identified than was expected.The role of transport infrastructure, including proximity and connectedness of road networks in HIV spread, has been described in sub-Saharan countries , and mayAlthough access to HTS is needed everywhere in Kenya, intensive testing efforts can be complicated in low prevalence areas without identifying localized epidemics within larger geographical areas. A-priori facility-level targeting for the identification of HIV-infected persons is problematic for various reasons. Firstly, many individual client level and HTS access factors are difficult to consider in the targeting process. Secondly, previously undiscovered epidemic and new HIV diagnoses may occur in traditionally non-endemic regions. Such outbreaks may be driven by infrastructural developments such as road construction or high-volume economic activities. Distinct environments or geospatial features need to be considered for focusing HTS programs, including workplace HTS, HIV awareness, and prevention programs. Targeting requires that we take into account, not just the HIV burden but also spatial scale to increase precision. Geographically-oriented targeting and programming have been suggested by others , 19. HowWith constrained funding for home-based counseling and testing and other community-based testing approaches, it is imperative to focus HTS efforts geographically. Newer HTS approaches may improve the identification of newly diagnosed HIV-infected persons . UnderstOur analyses had a few limitations. Firstly, we did not explore the spatial-temporal trend of HIV testing services or changing epidemiology of HIV, including transmission patterns over time due to the availability of data. Thus, our interpretation is limited to cross-sectional analyses and may not reflect the HIV program's historical investments in Kenya. Accounting for double reporting is difficult in Kenya because there are no unique healthcare identifiers to allow for an accurate account of duplicated results for both the number tested and the number diagnosed as HIV infected. Although our data were aggregated and did not explore individual characteristics of newly diagnosed HIV-infected persons, we could still get useful information for HIV program planning.Using geospatial analyses and mapping, we have established and demonstrated that clusters with a high number of HIV-infected persons are in both high and low-burden counties. For Kenya to control the HIV epidemic, it is crucial to interrupt the spread of HIV from regions with an increased number of newly diagnosed HIV-infected persons that neighbor those with low numbers of HIV-infected persons. Having identified clusters where the number of newly diagnosed HIV-infected persons is higher, even within counties, these analyses demonstrate the need for micro-spatial analysis for efficient planning. Achieving the “first 90” will become a reality if HTS resources are redirected to areas with the highest potential for identifying HIV-infected persons who were not previously diagnosed. Cluster detection analysis can be useful in directing public health response by identifying areas that may have budding HIV infections, initiating rapid HTS, thereby contributing to accelerated testing and achievement of the “first 90.”The raw data supporting this manuscript's conclusions will be made available by the authors, without undue reservation, to any qualified researcher.AW conceived the idea for this manuscript, prepared the concept, data analyses, and wrote the first and subsequent drafts of the manuscript. JW, JM, EZ-G, LN, FM, PWY, KD, and TT helped with results interpretation provided insights on HIV programmatic implications and recommendations. TA and JT helped with analytic methods and data interpretation. PY helped with data cleaning. All authors read the manuscript, provided feedback, and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.