bluuebunny/crossref_metadata_2025 huggingface dataset:
Missionary Self-Transformations in the Cross-Cultural Mission
Authors: Arnold Maik
Published: April 2022

This article analyses the implications of religious mission as a specific type of ‘human enhancement’ linked to the optimisation of human nature in light of missionaries’ beliefs. The study draws on the autobiographical narratives of German Protestants, which show that missionary intent is inseparably linked to the Christian imaginations of the ‘renewed person’. This can best be characterised by (a) cultural adjustment, (b) persuasive communication, and (c) self-alterations of others. Hence, missions represent a specific prototype of goal-directed, intentional, and strategic human action aiming for the self-transformation of others and missionaries themselves.
Church Talks on Peace Talks
Authors: Crisostomo-Pilario Junesse d.R.
Published: April 2022

This article studies the rhetoric of a traditional Protestant denomination, the United Church of Christ in the Philippines (UCCP), in advocating the resumption of peace talks during the Duterte administration. The church believes that the peace negotiations between the Philippine government and communist revolutionary groups will solve the fifty-year conflict that has claimed thousands of lives of combatants and civilians in the countryside.

At the beginning of Duterte’s term, the UCCP extended support for his administration. This was based on the alignment between the church and the President’s goals of purging of systemic sins in Philippine society through peacemaking. Using the theological rhetoric of the social gospel as framework, the UCCP first considered President Duterte as the ideal rhetorical audience who can address urgent needs through the resumption of peace talks. However, after two years of Duterte’s broken campaign promises, the church began to address its own constituents as the rhetorical audience they need to persuade in order to purge the systemic sins of Philippine society. Church members must be in solidarity with their leaders in opposing President Duterte’s policies. Through a shift from a rhetoric of transcendence to that of resistance, the church persuades its audiences of the sacredness of political support or opposition, giving religious justification to the mission of social reform.
Introductory Formulae and Jesus’s Teaching in James
Authors: Parker Thomas J.
Published: April 2022

While many scholars note the presence and influence of Jesus’s teaching in James, this study seeks to focus on whether there are any recurrent words or phrases that may introduce, indicate, or ‘demark’ the presence of Jesus’s teaching within James. This study analyses the presence of the words ‘hear’ and ‘listen’, ἀδελφός language, and the phrases ἄγε νῦν and ἀδελφοί μου ἀγαπητοί and their potential connection with Jesus’s teaching found within the epistle of James. As a result, this study notes the correlation between the use of these phrases and the subsequent presence of Jesus’s teaching, which suggests the potential for these phrases to ‘demark’ or introduce the presence of the words of Jesus in James’s epistle. Consequently, this study suggests that these key words and phrases function in the introduction to Jesus’s teaching within James, highlighting the upcoming presence of a Jesus saying to the audience.
Intraductal Papilloma on Breast Biopsy: Upstaging Rate and Implications for Practice Guidelines
Authors: Jee Yoonsun , Bakht Azad , Burner Jordan M. , Coldren Daniel L. , Howard-McNatt Marissa , Chiba Akiko
Published: April 2022

Background

The recommendation for management of intraductal papilloma has not been clearly established and its surgical excision criteria remain controversial. This study determines the institutional malignancy upstage rate of benign intraductal papillomas and identifies risk factors for upstage.

Methods

Retrospective review was conducted on female patients who were diagnosed with intraductal papillomas without atypia on core needle biopsy at Atrium Health Wake Forest Baptist Hospital between 1/2012 and 6/2021. Patients were excluded if there was a concomitant malignancy or atypia or deemed to be discordant with imaging. Features associated with upstage on imaging and histopathology were obtained from the electronic medical record.

Results

This study included 245 intraductal papillomas without atypia in 231 women (mean age, 59.1 ± 12.3 [SD] years). Approximately 31% (76/245) of the papillomas were excised, whereas 69% (169/245) of the papillomas underwent surveillance. Of the patients who underwent excisional biopsy, upstage rate for DCIS was 1.3% (1/76) and 5.3% (4/76) for atypia. All of the papillomas upstaged to DCIS or atypia had lesion size ≥10 mm on imaging. Out of the 139 intraductal papillomas that underwent radiologic surveillance, two (1.4%) developed malignancy and three (2.2%) developed atypia.

Discussion

The risk of upstaging of intraductal papilloma without atypia to malignancy remains extremely low. Therefore, routine surgical excision may not be necessary. While the papillomas upstaged to either malignancy or atypia have size abnormality ≥10 mm, other potential selective excision criteria should be explored to further decrease the risk of an upstage.
Undergraduate education in public administration and public service motivation: A quasi-experiment with the intervention of an introductory course
Authors: Kim Taehee , Kim Kiwhan , Kim Sangmook
Published: April 2022

This study aims to explore whether an introductory undergraduate course in Public Administration might be an appropriate educational tool for enhancing public service motivation (PSM) among undergraduate students. A quasi-experimental design involves surveying participants both before and after the intervention (taking an Introduction to Public Administration course) to examine whether their levels of PSM increase as a result of the intervention. The hypotheses were tested by comparing 96 students exposed to an intervention (experimental group) with 166 students who were not exposed (control group). There was no significant change in the total score of PSM and its individual dimensions before and after the intervention in both groups, and so the Introduction to Public Administration course was not effective in enhancing the level of PSM. The implications and limitations of this quasi-experiment are also discussed.
Establishment of prognostic nomogram for high-grade parotid gland mucoepidermoid carcinoma based on the SEER database
Authors: Wu Yubin , Wu Shihai , Li Xianming
Published: April 2022

Purpose: We aim to investigate the clinical factors that affect the prognosis of overall survival (OS) for patients with high-grade parotid gland mucoepidermoid carcinoma (high-grade pMEC) and construct a nomogram for prognosis prediction. Subjects and method: Totally, 519 patients diagnosed as high-grade pMEC from the surveillance, epidemiology, and end results (SEER) database between 2004 and 2015 were reviewed. Independent prognostic factors for OS were identified by univariate and multivariate Cox regression analyses. Nomogram was generated to predict the individual’s 3- and 5- year OS rates by using R software. Prediction ability was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC) and model calibration was evaluated through calibration plots. Decision curve analysis (DCA) was used to assess the clinical usefulness and net benefit. Results: The results of univariate analysis demonstrated that age, AJCC stage, T stage, N stage, M stage, extraparenchymal lesions, regional lymph nodes status, lymph node dissection status, radiotherapy, chemotherapy, and surgery were significantly correlated with the OS (P < 0.05). Multivariate Cox regression analyses showed that older age at diagnosis, advanced AJCC stage, and positive regional lymph nodes were independent risk factors for OS. In addition, the present study revealed that radiotherapy and surgery were independent protective factors for OS (P < 0.05). The nomograms showed accurate prognostic ability that individually predict 3-years and 5-years overall survival (OS) rates based on age, AJCC stage, regional lymph nodes status, radiotherapy, and surgery. The area under the receiver operating characteristic (ROC) curve (AUC) of the nomogram used to predict the 3-year and 5-year overall survival rate were 0.779 and 0.793, indicating that the model had a good predictive power for the overall survival in high-grade pMEC patient. Conclusions: Using the SEER database, we performed univariate and multivariate analyses to determine independent prognostic factors in high-grade pMEC patients. Subsequently, we constructed and validated a prognostic nomogram to predict 3-and 5-year OS rates based on the SEER database and can assist clinicians to intuitively evaluate prognosis of high-grade pMEC patients.
A Comparison of Modern and Popular Approaches to Calculating Reliability for Dichotomously Scored Items
Authors: Béland Sébastien , Falk Carl F.
Published: April 2022

Recent work on reliability coefficients has largely focused on continuous items, including critiques of Cronbach’s alpha. Although two new model-based reliability coefficients have been proposed for dichotomous items (Dimitrov, 2003a,b; Green & Yang, 2009a), these approaches have yet to be compared to each other or other popular estimates of reliability such as omega, alpha, and the greatest lower bound. We seek computational improvements to one of these model-based reliability coefficients and, in addition, conduct initial Monte Carlo simulations to compare coefficients using dichotomous data. Our results suggest that such improvements to the model-based approach are warranted, while model-based approaches were generally superior.
“Can We Have Class Outside?”
Authors: Del Rosso Jared
Published: April 2022

Can we have class outside? This question raises issues about the conditions in which we teach and learn, as well as about the power relations of the classroom. This Final Thought makes a case for surrendering to the question. Can we learn to love it? Can we learn, even, to begin asking it to the people who learn with us in our courses?
Critical citizenship and democratic legitimacy
Authors: Reber Bernard
Published: April 2022

In political science, the theme of critical citizenship is often interpreted negatively and understood to express distrust. However, criticism can be motivated by positive aspirations towards democracy and how to improve it. In order to test this idea, we asked respondents to the Democracy and citizenship survey to rank how the features of different types of democratic legitimacy appealed to them. The module adopted an innovative methodology by bringing together philosophy (political theory) and political science. This approach led to a series of results that tempered and questioned the more prevalent pessimistic understandings of critical citizenship. Furthermore, this article looks closely at controversy surrounding the meaning ascribed to criticism and discusses the presuppositions made by many political sociology studies and their differing hypotheses on critical citizenship. It shows that the very definition of criticism remains unclear and proposes a ‘critical understanding of criticism’ adopting a meta-critical stance (as is often the case in philosophy) to better identify four possible types of criticism: reactive criticism (primary), evaluative, propositional (first or secondary order) and pluralist political criticism.
NSAIDs Reduce Therapeutic Efficacy of Mesenchymal Stromal Cell Therapy in a Rodent Model of Posttraumatic Osteoarthritis
Authors: Sok Daniel , Raval Sarvgna , McKinney Jay , Drissi Hicham , Mason Amadeus , Mautner Ken , Kaiser Jarred M. , Willett Nick J.
Published: April 2022

Background:

Intra-articular injections of human mesenchymal stromal cells (hMSCs) have shown promise in slowing cartilage degradation in posttraumatic osteoarthritis (PTOA). Clinical use of cell therapies for osteoarthritis has accelerated in recent years without sufficient scientific evidence defining best-use practices. Common recommendations advise patients to avoid nonsteroidal anti-inflammatory drug (NSAID) use before and after cell injection over concerns that NSAIDs may affect therapeutic efficacy. Recommendations to restrict NSAID use are challenging for patients, and it is unclear if patients are compliant.

Hypothesis:

NSAIDs will reduce the efficacy of hMSC therapy in treating a preclinical model of PTOA.

Study Design:

Controlled laboratory study.

Methods:

Lewis rats underwent medial meniscal transection (MMT) surgery to induce PTOA or a sham (sham group) surgery that did not progress to PTOA. Rats received naproxen solution orally daily before (Pre-NSAID group) or after (Post-NSAID group) hMSC treatment, throughout the course of the experiment (Full-NSAID group), or received hMSCs without NSAIDs (No NSAID). Cartilage morphology and composition were quantified using contrast-enhanced micro–computed tomography and histology. Pain (secondary allodynia) was measured using a von Frey filament.

Results:

Injection of hMSCs attenuated cartilage degeneration associated with MMT. hMSCs prevented proteoglycan loss, maintained smooth cartilage surfaces, reduced cartilage lesions, reduced mineralized osteophyte formation, and reduced pain by week 7. The Pre-NSAID group had decreased proteoglycan levels compared with the hMSC group, although there were no other significant differences. Thus, pretreatment with NSAIDs had minimal effects on the therapeutic benefits of hMSC injections. The Post-NSAID and Full-NSAID groups, however, exhibited significantly worse osteoarthritis than the hMSC-only group, with greater proteoglycan loss, surface roughness, osteophyte volume, and pain.

Conclusion:

Use of NSAIDs before hMSC injection minimally reduced the therapeutic benefits for PTOA, which included preservation of cartilage surface integrity as well as a reduction in osteophytes. Use of NSAIDs after injections, however, substantially reduced the therapeutic efficacy of cellular treatment.

Clinical Relevance:

Our data support the clinical recommendation of avoiding NSAID use after hMSC injection but suggest that using NSAIDs before treatment may not substantially diminish the therapeutic efficacy of cell treatment.
The Effect of the Medicare Advantage Value-Based Insurance Design Model Test on Utilization in 2017
Authors: Eibner Christine , Buttorff Christine , Cefalu Matthew , Khodyakov Dmitry , Taylor Erin A.
Published: April 2022

In 2015, the Centers for Medicare and Medicaid Services announced the Medicare Advantage (MA) Value-Based Insurance Design (VBID) model test, which allows MA insurers to use flexible benefit design strategies, such as reduced cost-sharing, to encourage beneficiaries with chronic disease to use high-value care. During the first year of implementation (2017), nine MA insurers offered VBID in 45 health plans to a total of 96 053 eligible beneficiaries. We used MA encounter data to estimate the impact of VBID on health services utilization in 2017 using a difference-in-differences research design. We found that VBID increased use of 10 out of 18 targeted services, and led to general increases in primary care visits, specialty care visits, and drug fills across eligible beneficiaries. The model was also associated with increases in ambulatory care sensitive inpatient and emergency department visits, an unanticipated effect that may be temporary. Overall, our findings suggest that VBID successfully increased the use of high-value services among eligible MA beneficiaries, an important first step along the pathway to better chronic disease management, lower spending, and improved beneficiary health.
Stress is a Latent Construct: Exploring the Differential Experience of Stress and Discrimination on Depressive Symptoms Among Black Older Adults
Authors: Brown Lauren L. , García Catherine , Reeves Alexis N. , Pamplin John R. , Mitchell Uchechi A.
Published: April 2022

Objectives: While evidence highlights the detrimental mental health consequences of chronic stress exposure, the impact of this stress exposure on older Black Americans’ mental health varies by exposure to other types of stressors like discrimination as well as subjective evaluations of stress like chronic stress appraisal. Methods: Using data from the 2010/2012 Health and Retirement Study, we use latent profile analysis (LPA) to describe 2,415 Black older adults experience with chronic stress exposure, appraisal, and discrimination and examine which stress contexts are associated with depressive symptomology. Results: Analyses revealed five stress clusters—demonstrating the diversity in the stress experience for older Black adults. Black older adults with stress profiles that include lower stress appraisal report fewer depressive symptoms regardless of number of stress exposures. Discussion: LPA is as an alternative approach to examining the stress-mental health link that can define stress profiles by both exposure and appraisal-based measures.
Computer-aided diagnosis for breast cancer detection and classification using optimal region growing segmentation with MobileNet model
Authors: Dafni Rose J , VijayaKumar K , Singh Laxman , Sharma Sudhir Kumar
Published: April 2022

Globally, breast cancer is considered a major reason for women’s morality. Earlier and accurate identification of breast cancer is essential to increase survival rates. Therefore, computer-aided diagnosis (CAD) models are developed to help radiologists in the detection of mammographic lesions. Presently, machine-learning (ML) and deep-learning (DL) models are widely employed in the disease diagnostic process. In this view, this paper designs a novel CAD using optimal region growing segmentation with a MobileNet (CAD-ORGSMN) model for breast cancer identification and classification. The proposed CAD-ORGSMN model involves different stages of operations, namely, pre-processing, segmentation, feature extraction, and classification. Primarily, the proposed model uses a Weiner filtering (WF)–based pre-processing technique to remove the existence of noise in the mammogram images. The CAD-ORGSMN model involves a glowworm swarm optimization (GSO)–based region growing technique for image segmentation where the initial seed points and threshold values are optimally created by the GSO algorithm. Besides, a MobileNet-based feature extractor is used in which the hyperparameters of the MobileNet model are optimally selected using a swallow swarm optimization (SSO) algorithm. Lastly, variational autoencoder is applied as a classifier to determine the class labels for the input mammogram images. The utilization of the GSO algorithm for the region growing technique and the SSO algorithm for hyperparameter optimization helps to considerably improve the breast cancer detection performance of the CAD-ORGSMN model. The performance validation of the CAD-ORGSMN model takes place against the Mini-MIAS database, and the obtained results highlighted the promising performance of the CAD-ORGSMN model over the recent state-of-the-art methods in terms of different measures.
Increased Incidence of Indinavir Nephrolithiasis in Patients with Hepatitis B or C Virus Infection
Authors: Malavaud Bernard , Dinh Barbara , Bonnet Eric , Izopet Jacques , Payen Jean-Louis , Marchou Bruno
Published: April 2022

Materials and Methods

A HIV-1 patient database was scanned in March 1998, and 750 patients were identified who had received HAART including indinavir. Of these, 28 cases had nephrolithiasis; and 85 asymptomatic indinavir-treated patients were randomly selected as controls. The characteristics of cases and controls were compared by analysis of variance for quantitative parameters and by Fisher's exact test for classes.

Results

We observed a significant increase in the incidence of nephrolithiasis in patients co-infected with HIV-1 and either hepatitis C virus (HCV) (HCV RNA-positive) or hepatitis B virus (HBV) (HBs antigen-positive) (odds ratio and 95% confidence intervals: 2.8 and 1.1–7.7), whereas no significant differences were demonstrated between cases and controls with regard to age (42.4±8.0 versus 39.8±9.8 years), sex (male patients 70.4 versus 74.1%), duration of HIV-1 infection (8.6±3.1 versus 7.7±4.0 years), duration of indinavir treatment (16.1±5.8 versus 14.1±5.4 months), AST increase ≥1.25 of normal (29.6 versus 25.9%), or ALT increase ≥1.25 of normal (33.3 versus 22.4%). In co-infected patients, ALT increase (≥1.25 of normal), but not AST increase, at the time of indinavir initiation was statistically related to the occurrence of nephrolithiasis.

Conclusions

We found a significant increase of nephrolithiasis incidence in patients co-infected with HIV-1 and HCV or HBV, which suggests that underlying multifactorial hepatic damage may limit liver catabolism of indinavir, and consequently increase its renal excretion and the risk of nephrolithiasis. Caution is therefore advised when initiating indinavir treatment in HIV patients with evidence of HBV or HCV infection.
Persisting HIV-1 Replication Triggered by Acute Hepatitis a Virus Infection
Authors: Ridolfo Anna Lisa , Rusconi Stefano , Antinori Spinello , Balotta Claudia , Galli Massimo
Published: April 2022

We report the case of two patients in whom acute hepatitis A was associated with a marked and prolonged increase in human immunodeficiency virus type 1 (HIV-1) viral load. Although in one patient the rise in HIV-1 RNA might also have been related to the interruption of antiretroviral therapy, we also observed a similar pattern in the other patient who had a stable undetectable plasma viraemia prior to acute hepatitis and never received treatment with antiretrovirals. Our observation supports the hypothesis that immune activation that is induced by acute hepatitis A virus (HAV) infection may trigger HIV-1 replication. This highlights the importance of maintaining antiretroviral therapy throughout the acute phase of hepatitis A and of preventing HAV infection through active immunization.
Principles of HIV Resistance Testing and Overview of Assay Performance Characteristics
Authors: Richman Douglas D
Published: April 2022

HIV drug resistance testing is becoming an integral part of antiretroviral drug development and of patient management. The parameters that characterize the performance of both phenotypic and genotypic assays and the validation of this performance are essential to their proper use for these applications. Several principles and biological factors impacting drug resistance testing are summarized. Considerations regarding quality control and validation of the performance of genotypic and phenotypic assays are also addressed.
Transmission and Prevalence of HIV Resistance among Treatment-Naive Subjects
Authors: Little Susan J
Published: April 2022

Recent reports demonstrate the transmission of drug-resistant HIV-1 variants to newly infected individuals, although estimates of the prevalence of drug resistance among populations from different geographic regions are highly varied. The interpretation and comparison of available study results are confounded by the lack of consensus regarding the nomenclature and reporting of antiviral resistance. This report re-evaluates previously presented and published data using uniform criteria for genotypic and phenotypic drug resistance. Treatment-inexperienced and recently or chronically infected populations are reviewed. The prevalence of transmitted drug resistance ranges from 1% to 11% among recently infected persons using these criteria. Programmes to monitor and characterize drug resistance among newly infected persons and their source partners are essential to evaluate the selection processes that influence the transmission of certain genetic variants of HIV. Temporal trends in the prevalence of transmitted drug resistance among diverse populations are necessary to evaluate the potential need for selective and generalized drug resistance screening programmes among newly infected, treatment-naive patients.
Intensification of Background Antiretroviral Therapy with Abacavir during Low-Level Failure May Restore Optimal Suppression
Authors: Degen Olaf , Van Lunzen Jan , Stellbrink Hans-Jürgen
Published: April 2022

Objective

To investigate the antiviral activity of abacavir added to stable background therapy. Design: Retrospective analysis.

Materials and Methods

In 27 subjects with detectable plasma viraemia during stable treatment abacavir was added as the only agent. Patients were pre-treated for 180 weeks (mean) with regimens containing zidovudine (102 weeks) and lamivudine (88 weeks). Results were analysed in two groups: group 1, >400 HIV RNA copies/ml; group 2, 25–399 copies/ml. In 7/13 group 1 patients genotypic resistance analysis was performed prior to abacavir.

Results

Median follow-up was 28 weeks, median HIV RNA load at baseline 2.48 log10 copies/ml (3.52 and 1.66 log10 copies/ml in groups 1 and 2, respectively). Plasma viraemia was reduced to less than 400 HIV RNA copies/ml in 2/13 subjects in group 1 and 11/11 in group 2 (week 24). Only one patient in group 1 responded transiently to less than 25 HIV RNA copies/ml. In contrast, 10/14 and 11/11 in group 2 reached values below this threshold at weeks 12 and 24, respectively. Overall, 7/13 group 1 patients were found with ≥2 zidovudine resistance-associated mutations. The lamivudine resistance-associated mutation M184V was present in four of seven cases. All of these patients showed only a moderate and transient reduction of plasma viraemia (medium peak reduction of 0.73 log10 after 20 weeks).

Conclusions

The addition of abacavir during low-level treatment failure may restore or achieve suppression to levels below the cut-off of the ultrasensitive PCR.
Searching for Antiviral Drugs for Human Papillomaviruses
Authors: Underwood Mark R , Shewchuk Lisa M , Hassell Anne M , Phelps William C
Published: April 2022

The human papillomaviruses (HPVs) are ubiquitous human pathogens that cause a wide variety of benign and pre-malignant epithelial tumours. Of the almost 100 different types of HPV that have been characterized to date, approximately two dozen specifically infect genital and oral mucosa. Mucosal HPVs are most frequently sexually transmitted and, with an incidence roughly twice that of herpes simplex virus infection, are considered one of the most common sexually transmitted diseases throughout the world. A subset of genital HPVs, termed ‘high-risk’ HPVs, is highly associated with the development of genital cancers including cervical carcinoma. The absence of a simple monolayer cell culture system for analysis and propagation of the virus has substantially retarded progress in the development of diagnostic and therapeutic strategies for HPV infection. In spite of these difficulties, great progress has been made in the elucidation of the molecular controls of virus gene expression, replication and pathogenesis. With this knowledge and some important new tools, there is great potential for the development of improved diagnostic and prognostic tests, prophylactic and therapeutic vaccines, and traditional antiviral medicines.
Antiretroviral Therapy and the Lipodystrophy Syndrome
Authors: John Mina , Nolan David , Mallal Simon
Published: April 2022

‘Lipodystrophy syndrome’ in the setting of HIV infection has come to encompass a collection of morphological and metabolic abnormalities linked with the use of antiretroviral therapy and other risk factors. We review the clinical literature on this subject as it has evolved historically, taking pertinent methodological issues into account.
Prevalence of Genotypic Resistance among Antiretroviral Drug-Naive HIV-1-Infected Patients in Belgium
Authors: Van Vaerenbergh K , Debaisieux L , De Cabooter N , Declercq C , Desmet K , Fransen K , Maes B , Marissens D , Miller K , Muyldermans G , Sprecher S , Stuyver L , Vaira D , Verhofstede C , Zissis G , Van Ranst M , De Clercq E , Desmyter J , Vandamme A-M
Published: April 2022

Objectives

To estimate the prevalence and the evolution over time (1995–1998) of genotypic resistance to antiviral drugs in antiretroviral drug-naive HIV-1-infected patients in Belgium.

Design

Belgian Aids Reference Laboratories provided retrospective samples and clinical data from antiretroviral drug-naive HIV-1-infected patients who visited the hospital for the first time in 1995 ( n=45), 1997 ( n=75) and 1998 ( n=111). Genotypic resistance to the three available classes of drugs was monitored using the Line Probe Assay (Innogenetics, Gent, Belgium). Additionally, ARMS-151 was performed for scoring multinucleoside resistance.

Results

The prevalence of genotypic resistance at baseline to nucleoside analogue reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were each between 10% and 20% for 1995, 1997 and 1998 without an increasing trend over time. For NRTIs, resistance mutations were mainly related to zidovudine in 1995, whereas in 1997 and 1998 baseline resistance was scored for zidovudine, lamivudine or for both drugs simultaneously. No patients displayed the multi-nucleoside resistance Q151M mutation. Baseline resistance mutations to protease inhibitors (PIs) did not rise significantly: 4.4% in 1995, 8% in 1997 and 9.9% in 1998. When scoring any resistance-related mutation, 26.6% displayed genotypic baseline resistance in 1995, 26.6% in 1997 and 31.5% in 1998.

Discussion

The prevalence of genotypic baseline resistance to any drug, as scored with LiPA, in naive HIV-1 patients in Belgium is 29%, with baseline resistance mutations to one or several drugs from all available classes of antiviral drugs. The ability of LiPA to pick up minor variants could be an explanation for the higher overall prevalence we observe, when compared to recent estimates in other countries of 16.3% and 22%, which were based on sequencing methods. According to the European guidelines for resistance testing, resistance testing in Belgium before starting antiviral therapy should be considered.
Avanti 3: A Randomized, Double-Blind Trial to Compare the Efficacy and Safety of Lamivudine plus Zidovudine versus Lamivudine plus Zidovudine plus Nelfinavir in HIV-1-Infected Antiretroviral-Naive Patients
Authors: Gartland Martin ,   Steering Committee, Clumeck N , Cooper DA , Gatell J , Gazzard B , Gerstoft J , Goebel F , Lange J , Montaner J , Reiss P , Rozenbaum W , Vella S ,   Centres and Investigators, Cooper DA , Haberl M , Clumeck N , Luyts D , Montaner J. , Rachlis A , Marina R , Gerstoft J , Mathiesen L , Soelberg U , Molina J-M , Pialloux G , Rozenbaum W , Cosby C , Goebel FD , Staszewski S , Hug M , Milazzo F , Moroni M , Panebianco R , Clotet B , Artigas JM Gatell , GonzalezLahoz J , Leal M , Gandarias B , Gazzard B , Johnson M , Watkins K , Page V , Sandstrom E , Darbyshire J ,   Agouron Pharmaceuticals:, Petersen A , Athisegaran R , Coughlan M , Fiddian P , Gartland M , Harrigan R , Henry T , Larder B , Maguire M , Millard J , Moore S , Patel K , Shortino D , Tisdale M , Vafidis I , Yeo J
Published: April 2022

The objective of our randomized, multicentre, double-blind, placebo-controlled study was to investigate the safety, tolerability, and antiretroviral and immunological effect of double and triple combination therapy regimens. A total of 105 antiretroviral therapy-naive patients were randomized to receive either zidovudine (300 mg twice per day) plus lamivudine (150 mg twice per day) plus nelfinavir placebo (three times per day) ( n=52), or zidovudine/lamivudine (dose as before) plus nelfinavir (750 mg three times per day) ( n=53) for 28 weeks. After this time, patients were allowed to switch to open-label zidovudine/lamivudine/nelfinavir. The overall log10 reduction from baseline in plasma HIV-1 RNA was significantly greater in the zidovudine/lamivudine/nelfinavir group than the zidovudine/lamivudine group ( P=0.001; median treatment difference, –1.01 log10 copies/ml; 95% confidence interval –1.23 to –0.79), as measured by the average area under the curve minus baseline over 28weeks. Increases from baseline in CD4 cell counts were statistically significantly greater in the zidovudine/lamivudine/nelfinavir group (101.5 cells/ml) than the zidovudine/lamivudine group (47.0 cells/ml; P=0.027) at week 28.

Of note, the addition of nelfinavir from weeks 28–52 led to an increase in the proportion of subjects with plasma HIV-1 RNA <400 copies/ml from 17% (9/52 patients on zidovudine/lamivudine) to 50% (13/26 patients who switched to zidovudine/lamivudine/nelfinavir). Incidence of drug-related adverse events was similar in the two groups, except for nausea (more common in zidovudine/lamivudine group; 40 versus 17%) and diarrhoea (more common in zidovudine/lamivudine/nelfinavir group; 45 versus 14%). In conclusion, our study confirms the efficacy of triple combination therapy with two nucleoside analogues and a protease inhibitor compared with double-nucleoside therapy. Interestingly, the addition of nelfinavir to zidovudine/lamivudine, even after 6 months of double nucleoside therapy, led to a substantial virological benefit that was sustained over 24weeks in a subset of patients.
Treatment Intensification with Abacavir in HIV-Infected Patients with at Least 12 Weeks Previous Lamivudine/Zidovudine Treatment
Authors: Rozenbaum Willy , Katlama Christine , Massip Patrice , Bentata Michelle , Zucman David , Delfraissy Jean-Francois , Trepo Christian , David Frederique , Lanier E Randall , Vavro Cindy , Mamet Jean-Philippe
Published: April 2022

Objectives

To demonstrate that lamivudine and zidovudine, given separately (lamivudine/zidovudine) or as a single combination tablet (Combivir™), had equivalent efficacy. To evaluate the safety and antiretroviral activity of intensification with abacavir in patients treated with lamivudine/zidovudine for ≥12 weeks.

Design

A 12-week, equivalence study of lamivudine/ zidovudine versus Combivir. Patients who completed this study could enter a 48-week, intensification study of Combivir plus abacavir.

Methods

In the equivalence study, treatment-naive patients were assessed for HIV-1 RNA, CD4 cell count and genotype. The same assessments plus phenotype were made in the intensification study. Serious adverse events were recorded in the equivalence study and all adverse events in the intensification study.

Results

Lamivudine/zidovudine ( n=40) and Combivir ( n=35) gave equivalent reductions in plasma HIV-1 RNA levels at week 12. An identical proportion of patients (74%) in each treatment group harboured virus with the M184V mutation after 12 weeks. Fifty-two patients entered the intensification study and 44 completed 48 weeks of treatment. At the time of intensification with abacavir, all 35 patients with evaluable isolates harboured HIV-1 containing M184V. Addition of abacavir to Combivir led to further decreases in plasma HIV-1 RNA and increases in CD4 cell counts compared with the start of intensification ( P<0.001 at week 48). After 48 weeks of triple therapy, multi-nucleoside resistance mutations at codons 69 and 151 were not detected in any patients. All treatment regimens were generally well tolerated. Conclusion: Lamivudine/zidovudine and Combivir have equivalent antiretroviral activity over 12 weeks. Adding abacavir to Combivir can be a safe and effective therapeutic option for patients, including those harbouring virus with the M184V mutation.
Drug Resistance Mutations in HIV-1-Infected Subjects during Protease Inhibitor-Containing Highly Active Antiretroviral Therapy with Nelfinavir or Indinavir
Authors: Yerly Sabine , Rickenbach Martin , Popescu Matei , Taffe Patrick , Craig Charles , Perrin Luc ,   the Swiss HIV Cohort Study, Battegay M , Bernard M-C , Bernasconi E , Bucher H , Bürgisser Ph , Egger M , Erb P , Fierz W , Flepp M , Francioli P , Furrer HJ , Gorgievski M , Günthard H , Grob P , Hirschel B , Kind C , Klimkait T , Ledergerber B , Lauper U , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rickenbach M , Rudin C , Schupbach J , Telenti A , Vernazza P , Wagels T , Weber R
Published: April 2022

Objectives

The aim of this retrospective study was to evaluate treatment outcome and characterize the pattern of genotype mutations in subjects with treatment failure on highly active antiretroviral therapy (HAART) containing nelfinavir or indinavir.

Study design and methods

The database of the Swiss HIV Cohort Study was screened for all subjects naive to protease inhibitor (PI) treatment who started HAART with nelfinavir or indinavir, responded initially (HIV-RNA <400 copies/ml) and received >24 weeks of treatment. Responders with subsequent treatment failure (HIV-RNA >1000 copies/ml, bordered by HIV-RNA >400 copies/ml) were selected for genotypic analysis.

Results

Initial treatment response, maintenance of response and subsequent virological failure were observed at a comparable frequency in 1143 nelfinavir and 1555 indinavir subjects. Of the treatment-naive patients, 13% who took nelfinavir and 16% who took indinavir had HIV-RNA >1000 copies/ml at least once. These values increased to 24 and 27%, respectively, for reverse transcriptase inhibitor-experienced subjects. Genotypic analysis in a subset of subjects with virological failure identified 30N as the only primary mutation in the nelfinavir subjects (8 out of 21, 38%) whereas isolated or combined 82A/T and 46I/L mutations were detected in the indinavir subjects (9 out of 20, 45%).

Conclusions

In this population of previously PI-naive subjects, the rate of virological failure and the frequency of resistance mutations at the time of virological failure were comparable in subjects receiving nelfinavir- or indinavir-containing HAART. In nelfinavir subjects, 30N was the only primary mutation whereas isolated or combined 82A/T and 46I/L mutations were detected in indinavir subjects.
Pseudo-Primary Infection Syndrome following Discontinuation of Antiretroviral Therapy
Authors: Zeller Valérie , Charlois Cécile , Duvivier Claudine , Bricaire François , Katlama Christine
Published: April 2022

We report the case of a retroviral rebound syndrome associated with parotid gland enlargement in a chronically HIV-infected man.
Ritonavir/Saquinavir plus One Nucleoside Reverse Transcriptase Inhibitor (NRTI) versus Indinavir plus Two Nrtis in Protease Inhibitor-Naive HIV-1-Infected Adults (Iris Study)
Authors: Florence Eric , Dreezen Christa , Desmet Patrick , Smets Eric , Fransen Katrien , Vandercam Bernard , Pelgrom Jolanda , Clumeck Nathan , Colebunders Robert
Published: April 2022

Objectives

To compare the efficacy, tolerability and safety of a ritonavir 400 mg/saquinavir hard gel fomulation 400 mg twice daily versus an indinavir 800 mg once every 8 h containing first-line protease inhibitor (PI) treatment regimen.

Methods

Open, randomized, multicentre clinical trial. PI-naive patients received either ritonavir/saquinavir and one nucleoside reverse transcriptase inhibitor (NRTI) or indinavir and two NRTIs. Intention-to-treat (ITT) and on-treatment (OT) analyses were performed.

Results

The baseline characteristics of the study participants were similar in both arms, 67 patients (37%) were naive to antiretroviral treatment. The proportion of patients who achieved a plasma viral load below the level of detection of 400 copies/ml at week 48 was 43% (39/90) in the ritonavir/saquinavir arm and 63% (57/90) in the indinavir arm ( P=0.005, ITT analysis). Using an OT analysis, these percentages were 84% and 88%, respectively ( P=0.6). There were more drop-outs in the ritonavir/saquinavir arm than in the indinavir arm (35.6% (32/90) versus 15.6% (14/90), P=0.002), mainly due to gastro-intestinal side-effects. Abnormal liver tests and increased lipids levels were more frequently reported in the ritonavir/saquinavir arm than in the indinavir arm.

Conclusion

In PI-naive patients, indinavir in combination with two NRTIs was more effective and better tolerated than ritonavir/saquinavir plus one NRTI. Both treatments were very effective for patients who were able to tolerate them.
A Genotypic Drug Resistance Interpretation Algorithm that Significantly Predicts Therapy Response in HIV-1-Infected Patients
Authors: Van Laethem Kristel , De Luca Andrea , Antinori Andrea , Cingolani Antonella , Perno Carlo Federico , Vandamme Anne-Mieke
Published: April 2022

Objectives

The development of a genotypic drug resistance interpretation algorithm, and the evaluation of its power to predict therapy outcome.

Design

A rule-based algorithm was established by an individual expert and was based on published and inhouse results, independently from the data of the patients used in this evaluation. The predictive value of the algorithm for virological outcomes was retrospectively evaluated using the baseline genotype observed in patients on highly active antiretroviral therapy, failing virologically and subsequently starting a salvage regimen.

Methods

The independent association between the susceptibility score (calculated according to the algorithm) and the virological response at 3 months, was analysed using multivariable logistic regression and multiple linear regression models.

Results

In two clinical centres 240 patients were studied. At 3 months 35% had a viral load of <500 RNA copies/ml. Using multivariable logistic regression, the odds ratio of achieving a viral load <500 RNA copies/ml at month 3 per unit increase of susceptibility score was 2.0 (95% CI 1.3–3.1; P=0.002) after adjusting for baseline viral load, genotype-driven salvage therapy, number of new drugs in the regimen, use of a new drug class in the regimen, nelfinavir-containing salvage therapy and history of prior viral load <500 RNA copies/ml. Using multiple linear regression, the susceptibility score showed a significant linear correlation with the log viral load change (slope=–0.27 log10 RNA copies/ml; 95% CI –0.11 to –0.43; P=0.001) after adjusting for history of prior viral load <500 RNA copies/ml, number of new drugs in the salvage therapy, use of a new drug class in the salvage therapy and baseline viral load.

Conclusions

This algorithm proved to be a significant independent predictor of therapy response at 3 months in this cohort of HIV-1-infected patients on salvage therapy. However, it should be subject to regular updates as is needed in this fast developing field.
Impact of Stavudine Phenotype and Thymidine Analogues Mutations on Viral Response to Stavudine plus Lamivudine in Altis 2 Anrs Trial
Authors: Calvez Vincent , Costagliola Dominique , Descamps Diane , Yvon Anne , Collin Gilles , Cécile Agnès , Delaugerre Constance , Damond Florence , Marcelin Anne-Geneviève , Matheron Sophie , Simon Anne , Valantin Marc-Antoine , Katlama Christine , Brun-Vézinet Françoise
Published: April 2022

Objective

Stavudine-based antiretroviral combinations are less effective in zidovudine-experienced patients than in naive subjects and recently, mutations have been described to be associated to the use of both stavudine and zidovudine. In the ALTIS 2 trial, it was shown that a combination of stavudine and lamivudine is less effective in zidovudine-experienced patients than in naive patients. We conducted a retrospective genotypic and phenotypic resistance study (expressed as stavudine phenotypic index, calculated by dividing the inhibitory concentrations 50% [IC50] by the mean value of the sensitive viruses) to evaluate the factors associated with decrease in plasma HIV-1 RNA.

Design

Associations with continuous variables were studied using non-parametric Spearman correlation coefficients. Associations with categorical variables were studied using non-parametric Mann–Whitney tests. Multivariate stepwise regression analyses were used to determine independent prognostic factors of the virological response.

Results

At baseline, most of the subjects harboured zidovudine-associated mutations in plasma and peripheral blood mononuclear cells. Zidovudine and stavudine IC50 and IC90 were strongly associated with response. It appears that a cut-off of stavudine phenotypic index of 1.8-fold of IC50, much lower than the usually used value, could be clinically significant for response to stavudine. In the multivariate analysis, the stepwise model with the higher multiple correlation coefficient ( R2=0.742) included the presence of a 215 Y/F mutation, the number of previously used nucleoside analogues and a resistant stavudine phenotype.

Conclusion

These results argue for a phenotypic and genotypic cross resistance between stavudine and zidovudine. Modest increases of IC50 and IC90 for stavudine had an important impact on the virological response during the trial and plead for a new definition of the threshold value for stavudine phenotypic index.
Transient Rebounds of Low-Level Viraemia among HIV-Infected Patients under Haart are Not Associated with Virological or Immunological Failure
Authors: Mira José A , Macías Juan , Nogales Carmen , Fernández-Rivera Javier , García-García José A , Ramos Antonio , Pineda Juan A
Published: April 2022

Objective

To analyse whether blips are associated with a higher risk of virological or immunological failure than persistent undetectable viraemia (UND) among HIV-infected patients receiving HAART.

Design

Retrospective cohort study.

Subjects

Patients with blips or UND were selected from a prospective cohort of 330 patients under HAART for over 48 weeks. Blips were defined as detectable viraemia up to a maximum of 1000 copies/ml preceded by two consecutive visits and followed by one visit showing undetectable viraemia. Patients were included according to the following criteria: i) Blip group: patients that showed transient relapses of viraemia; ii) UND group: patients who had achieved UND on HAART before 24 weeks of therapy and that sustained viral suppression for four consecutive visits. Main outcome measures: Virological and immunological failure.

Results

Thirty seven (11%) and 65 (20%) patients showed blips and persistent UND, respectively. Virological failure was observed in three (8.1%) patients in the blip group and 11 (16.9%) patients in the UND group ( P=0.25). The time to virological failure was shorter in the UND group ( P=0.12). The rates of virological failure and the time to virological failure were similar between both groups after excluding patients with compliance <95%. The time to immunological failure was also similar in both groups ( P=0.5). In a Cox model, only the use of saquinavir hard gel-based regimens was independently associated with the time to virological and immunological failure.

Conclusion

Patients under HAART with transient low-level viraemia are not at an increased risk of developing virological or immunological failure.