Content validation of a new measure of patient-reported barriers to antiretroviral therapy adherence, the I-Score: results from a Delphi study

Background Over a third of people living with HIV (PLHIV) have suboptimal adherence to antiretroviral therapy (ART). Measures of barriers to ART adherence often lack comprehensiveness. To help manage ART adherence barriers in HIV care, we are developing a new patient-reported outcome measure (PROM) of these barriers (the I-Score). Methods We assessed the content validity of 100 items (distinct barriers) to retain only those most relevant to both PLHIV and HIV health/social service providers. A web-based Delphi was conducted in Canada and France, collecting data from December 2018 to October 2019. Items were evaluated on relevance (the combined rated importance and actionability for HIV care of items among both PLHIV and providers); comprehensibility (rated item clarity); comprehensiveness (examined against our conceptual framework); cross-cultural equivalence (based on comparisons by questionnaire language (English, French) and country of residence). Pearson’s chi-square tests were used for comparisons by language, country, gender, and stakeholder group (PLHIV, providers). Results Panelists included 40 PLHIV and 57 providers (66% response rate). Thirty-one items were retained based on consensus thresholds for relevance (minimum: 50% for PLHIV, 60% for providers) and showed good comprehensibility and comprehensiveness, when compared to our conceptual framework (representation of: 6/6 domains, 15/20 subdomains). No significant difference in relevance based on language or country was found among retained items, suggestive of cross-cultural equivalence. Among all 100 items, only 6 significant differences on relevance were observed for gender. For 62 items, the relevance ratings of PLHIV and providers differed significantly, with providers showing greater endorsement of all items but one. Discussion The Delphi led to a much-needed item reduction. Remaining items highlight the panel’s multidimensional priorities for the PROM on ART adherence barriers, with few, if any, differences by language, country, and gender. While the analyses may lack generalizability and power, the sample size is considered adequate for a PROM validation study. Conclusion Retained items showed good content validity. The different patterns of item endorsement observed underscore the utility of engaging multiple stakeholder groups in PROM development for use in clinical practice. The greater endorsement of items by providers versus patients merits further investigation, including the implications of such differentials for measure development.KE is partially supported by a SPOR Mentorship Chair in Innovative Clinical Trials awarded by the CIHR to BL (Grant No. 383427). BL is supported by a career award, LE 250, from the Quebec Ministry of Health for researchers in Family Medicine. The Delphi benefited from methodological expertise and funding from the Quebec SPOR Support Unit -McGill Methodological Developments Platform (Grant No. M006). The Delphi is a subproject of the PROM development study, the I-Score Study, which is supported, in part, by the CIHR HIV Clinical Trials Network (CTN 283) and by a research Grant from the Investigator Initiated Studies Program of Merck Canada Inc. (Grant No. IISP-53538), neither of which had a hand in the design, conduct, or writing up of this work. The opinions expressed in this study are those of the authors and do not necessarily represent those of Merck Canada Inc or its affiliates or related companies

Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients.

BACKGROUND AND AIMS People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone

Prognostic value of non-invasive scores based on liver stiffness measurement, spleen diameter and platelets in HIV-infected patients

BACKGROUND AND AIMS: People living with HIV (PLWH) are at high risk for advanced chronic liver disease and related adverse outcomes. We aimed to validate the prognostic value of non-invasive scores based on liver stiffness measurement (LSM) and on markers of portal hypertension (PH), namely platelets and spleen diameter, in PLWH. METHODS: We combined data from eight international cohorts of PLWH with available non-invasive scores, including LSM and the composite biomarkers liver stiffness-spleen size-to-platelet ratio score (LSPS), LSM-to-Platelet ratio (LPR) and PH risk score. Incidence and predictors of all-cause mortality, any liver-related event and classical hepatic decompensation were determined by survival analysis, controlling for competing risks for the latter two. Non-invasive scores were assessed and compared using area under the receiver operating curve (AUROC). RESULTS: We included 1695 PLWH (66.8% coinfected with hepatitis C virus). During a median follow-up of 4.7 (interquartile range 2.8-7.7) years, the incidence rates of any liver-related event, all-cause mortality and hepatic decompensation were 13.7 per 1000 persons-year (PY) (95% confidence interval [CI], 11.4-16.3), 13.8 per 1000 PY (95% CI, 11.6-16.4) and 9.9 per 1000 PY (95% CI, 8.1-12.2), respectively. The AUROC of LSM was similar to that of the composite biomarkers, ranging between 0.83 and 0.86 for any liver-related event, 0.79-0.85 for all-cause mortality and 0.87-0.88 for classical hepatic decompensation. All individual non-invasive scores remained independent predictors of clinical outcomes in multivariable analysis. CONCLUSIONS: Non-invasive scores based on LSM, spleen diameter and platelets predict clinical outcomes in PLWH. Composite biomarkers do not achieve higher prognostic performance compared to LSM alone

Estimating Loss to Follow-Up in HIV-Infected Patients on Antiretroviral Therapy: The Effect of the Competing Risk of Death in Zambia and Switzerland

BACKGROUND: Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland. METHODS AND FINDINGS: HIV-infected patients aged ≥18 years who started ART 2004-2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells <100 cells/µl and 15.4% among patients starting with ≥350 cells/µL. The estimates from CR cumulative incidence were 22.9% and 13.6%, respectively. Little difference was found between naïve and CR analyses in Switzerland since only few patients died. The results from Cox and Fine and Gray models were similar: in Zambia the risk of loss to follow-up and death increased with decreasing CD4 counts at the start of ART, whereas in Switzerland there was a trend in the opposite direction, with patients with higher CD4 cell counts more likely to be lost to follow-up. CONCLUSIONS: In ART programmes in low-income settings the competing risk of death can substantially bias standard analyses of LTFU. The CD4 cell count and other prognostic factors may be differentially associated with LTFU in low-income and high-income settings

Screening for nonalcoholic steatohepatitis by using cytokeratin 18 and transient elastography in HIV mono-infection.

HIV-infected individuals are at high risk of developing nonalcoholic steatohepatitis (NASH), a leading cause of end-stage liver disease in Western countries. Nonetheless, due to the invasiveness of liver biopsy, NASH remains poorly understood in HIV mono-infection. We aimed to characterize the prevalence and predictors of NASH in unselected HIV mono-infected patients by means of non-invasive diagnostic tools.HIV-infected adults without significant alcohol intake or co-infection with hepatitis B or C underwent a routine screening program employing transient elastography (TE) with controlled attenuation parameter (CAP) and the serum biomarker cytokeratin-18 (CK-18). NASH was diagnosed non-invasively as the coexistence of fatty liver (CAP ≥248 dB/m) and CK-18 >246 U/L. Identified cases of NASH were offered a diagnostic liver biopsy. Predictors of NASH were determined by multivariate logistic regression analysis.202 consecutive HIV mono-infected patients were included. NASH was non-invasively diagnosed in 23 cases (11.4%). Among them, 17 underwent a liver biopsy, and histology confirmed NASH in all cases. The prevalence of NASH was higher in patients with hypertriglyceridemia (17.1%), insulin resistance defined by homeostasis model for assessment of insulin resistance (HOMA-IR) (25%), those with detectable HIV viral load (42.9%) and those with elevated ALT (53.6%). After adjustment, higher HOMA-IR (adjusted odds ratio [aOR] = 1.20, 95% CI 1.01-1.43; p = 0.03) and ALT (aOR = 2.39, 95% CI 1.50-3.79; p<0.001) were independent predictors of NASH.NASH, diagnosed by a non-invasive diagnostic approach employing CK-18 and TE with CAP, is common in unselected HIV mono-infected individuals, particularly in the presence of insulin resistance and elevated ALT

Prevalence, predictors, and severity of lean nonalcoholic fatty liver disease in patients living with human immunodeficiency virus

Background. The burden of nonalcoholic fatty liver disease (NAFLD) is growing in people living with human immunodeficiency virus (HIV). NAFLD is associated with obesity; however, it can occur in normoweight (lean) patients. We aimed to investigate lean NAFLD in patients living with HIV. Methods. We included patients living with HIV mono-infection from 3 prospective cohorts. NAFLD was diagnosed by transient elastography (TE) and defined as controlled attenuation parameter ≥248 dB/m, in absence of alcohol abuse. Lean NAFLD was defined when a body mass index was &lt;25 kg/m2. Significant liver fibrosis was defined as TE ≥7.1 kPa. The presence of diabetes, hypertension, or hyperlipidemia defined metabolically abnormal patients. Results. We included 1511 patients, of whom 57.4% were lean. The prevalence of lean NAFLD patients in the whole cohort was 13.9%. NAFLD affected 24.2% of lean patients. The proportions of lean NAFLD patients who were metabolically abnormal or had elevated alanine aminotransferase (ALT) were higher than among those who were lean patients without NAFLD (61.9% vs 48.9% and 36.7% vs 24.2%, respectively). Lean NAFLD patients had a higher prevalence of significant liver fibrosis than lean patients without NAFLD (15.7% vs 7.6%, respectively). After adjusting for sex, ethnicity, hypertension, CD4 cell count, nadir CD4 &lt;200µ/L, and time since HIV diagnosis, predictors of NAFLD in lean patients were age (adjusted OR [aOR], 1.29; 95% confidence interval [CI], 1.04–1.59), high triglycerides (aOR, 1.34; 95% CI, 1.11–1.63), and high ALT (aOR, 1.15; 95% CI, 1.05–1.26), while a high level of high-density lipoprotein cholesterol was protective (aOR, 0.45; 95% CI, .26–.77). Conclusions. NAFLD affects 1 in 4 lean patients living with HIV mono-infection. Investigations for NAFLD should be proposed in older patients with dyslipidemia and elevated ALT, even if normoweight

Non-alcoholic fatty liver disease predicts development of metabolic comorbidities in HIV-infected patients

Cardiovascular and liver disease are main contributors to mortality in people with HIV (PWH). In HIV-uninfected patients, non-alcoholic fatty liver disease (NAFLD) is associated with incident metabolic complications. We investigated the effect of NAFLD on development of metabolic comorbidities in PWH