bluuebunny/crossref_metadata_2025 huggingface dataset:
Threats to academic freedom: The French case
Authors: Wieviorka Michel
Published: April 2022

Academic freedom is currently threatened not only in dictatorial or authoritarian regimes but in democracies as well. Thus, this analysis of the contemporary French experience, in which we observe a destructive climate maintained by intellectuals and political actors on both the right and the left. The extremization, intolerance, and radicalization of debates have increased since the election of Emmanuel Macron in 2017. At the same time, university institutions often appear overwhelmed or powerless in the face of both internal and external dangers.
Minimum 2-Year Clinical Outcomes of Medial Meniscus Root Tears in Relation to Coronal Alignment
Authors: Ridley Taylor J. , Ruzbarsky Joseph J. , Dornan Grant J. , Woolson Thomas E. , Poulton Richard T. , LaPrade Robert F. , Provencher Matthew T. , Vidal Armando F.
Published: April 2022

Background:

The effect of coronal plane alignment on the outcomes of repairs of the medial meniscus root remains unclear.

Hypothesis:

Increased preoperative varus alignment is associated with higher failure rates and lower patient-reported outcomes (PROs) after isolated repair of the medial meniscus root.

Study Design:

Case series; Level of evidence, 4.

Methods:

Patients aged 18 years or older who underwent arthroscopy-assisted repair of the medial posterior meniscus root over a 7-year period were included. The mechanical axis of the knee was measured preoperatively. Osteoarthritis was assessed radiographically preoperatively and at the final follow-up according to the Kellgren-Lawrence grading scale. Failure was defined as any patient having to undergo revision root repair, partial meniscectomy of the previously repaired meniscus, debridement, lysis of adhesions, or conversion to arthroplasty.

Results:

A total of 53 patients (29 women, 24 men) with a mean age of 51.3 years were included in the follow-up analysis. The mean time of follow-up after surgery was 3.3 years (range, 22-77 months). Significant improvements were observed in all PROs analyzed. Decreased varus as measured by alignment percentage was correlated with baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain ( P = .023) and WOMAC Stiffness ( P = .022). Alignment percentage was also significantly negatively correlated with postoperative WOMAC Stiffness ( P = .005) and positively correlated with Lysholm ( P = .003) and International Knee Documentation Committee ( P = .009) scores. Higher baseline Kellgren-Lawrence grade was correlated with worse postoperative PROs ( P < .05), except 12-Item Short Form Health Survey Mental Component Summary and satisfaction. Eight patients who underwent a concomitant high tibial osteotomy (HTO) achieved lower PROs in all scales analyzed, regardless of their alignment. When excluding patients who underwent HTO, postoperative Lysholm score ( P = .004) and postoperative WOMAC Stiffness (p = 0.014) were inferior among the patients with >5° of varus.

Conclusion:

Lower extremity alignment closest to neutral correlated with improved PROs. Patients who underwent a concurrent HTO had worse PROs than those who did not undergo HTO.
Formative Evaluation of a Workforce Investment Organization to Provide Scaled Training for Home Health Aides Serving Managed Long-Term Care Plan Clients in New York State
Authors: Russell David , Fong Mei-Chia , Gao Oude , Lowenstein Dan , Haas Marian , Wiggins Faith , Brickner Carlin , Franzosa Emily
Published: April 2022

As part of its Medicaid program restructuring, New York State funded 11 Workforce Investment Organizations (WIO) to support training initiatives for the long-term care workforce. Focusing on one WIO, this formative evaluation examined quality improvement training programs delivered to 11,163 Home Health Aides employed by home care agencies serving clients of Managed Long-Term Care plans. Results are presented from a thematic analysis of qualitative interviews with organizational and program stakeholders examining contextual factors influencing program objectives, implementation, barriers and facilitators, and perceived outcomes. Findings suggested that WIO training programs were implemented during a period of shifting organizational strategies alongside value-based payment reforms and challenges to aide recruitment and retention. Stakeholders appraised WIO training programs positively and valued program flexibility and facilitation of communication and collaboration between agencies and plans. However, delivery and implementation challenges existed, and industry-wide structural fragmentation led stakeholders to question the WIO’s larger impact.
Using the Herd: How Firms Can Leverage Peer Effects to Increase Share Plan Participation
Authors: Stebe Markus , Muntermann Marc , Wolff Michael , Hullmann Rieke , Loth Natascha
Published: April 2022

Well implemented and communicated, employee share purchase plans (ESPPs) constitute an effective management instrument and positively affect firm performance. However, their success depends on the participation of employees. Current studies show that there is still potential to improve participation rates. Peer effects represent a lever to boost participation. The Share Matching Program at Siemens is a great example of successfully implementing and communicating an ESPP. Since this ESPP is globally implemented, it provides a unique opportunity to analyze and compare peer effects for different employee groups. Using ordinary least square regressions, we show that the individual participation decision is significantly associated with the average participation within the employee’s organizational unit and that this relationship varies across countries, age groups, and corporate functions. By indicating employee groups that are most prone to peer effects, the findings provide critical managerial implications for employee communication strategies at Siemens and other firms.
Cost-Effectiveness of Sacubitril–Valsartan Compared to Angiotensin-Converting Enzyme Inhibitors in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Febrinasari Ratih P. , Putra Stefanus E. , Hafizhan Muhammad , Probandari Ari N.
Published: April 2022

Objectives: The goal of this study was to compare cost-effectiveness of sacubitril/valsartan with angiotensin-converting enzyme (ACE) inhibitors for treating chronic heart failure patients with reduced ejection fraction (HFrEF) from the published articles and explore the methodology applied in the studies. Methods: Systematic research was conducted in February 2021 using PubMed, Cochrane, and EBSCO. A combination of MeSH terms of “cost-effectiveness analysis,” “heart failure with reduced ejection fraction,” “sacubitril valsartan,” and “angiotensin converting enzyme inhibitor” was employed. The review selected for articles published in the last five years in English. Results: A total of 15 studies were included in this review. We found that these studies had been conducted in 12 different countries. The United States had the greatest number of publications (5), followed by the Netherlands (2). The study method most used was the Markov decision model (73%). Almost all studies produced ICERs and QALYs that were numerically high. Conclusions: The use of sacubitril/valsartan associates with longer life expectancy and incremental cost-effectiveness ratio than angiotensin-converting enzyme inhibitors.
Holding Back or Letting Go? The Effect of Emotion Suppression on Relationship Viability in New Venture Teams
Authors: Ivanova Stela , Treffers Theresa , Langerak Fred , Groth Markus
Published: April 2022

Drawing on emotion regulation theory, this study investigates if and how emotion suppression informs relationship viability within new venture teams (NVTs) when such teams face obstacles. In particular, we use a dyadic approach to examine the suppressor’s authenticity and team members’ perceptions of appropriateness as mediators in the link between emotion suppression and relationship viability. A round-robin study with 93 respondents nested in 37 NVTs, which generated 167 observations, provides empirical support for the theoretically derived model by showing that both authenticity and appropriateness fully mediate the relationship between emotion suppression and relationship viability. In particular, the findings show that the negative indirect effect of emotion suppression on relationship viability via authenticity is larger than the positive indirect effect via appropriateness. A follow-up study after two years indicates that relationship viability and emotion suppression significantly predict venture survival. Together, these findings make ample contributions to the literature and provide interesting opportunities for further research.
From Home Base to Swing States: The Evolution of Digital Advertising Strategies during the 2020 US Presidential Primary
Authors: Brodnax NaLette M , Sapiezynski Piotr
Published: April 2022

Political advertising on digital platforms has grown dramatically in recent years as campaigns embrace new ways of targeting supporters and potential voters. We examine how political campaign dynamics have evolved in response to the growth of digital media by analyzing the advertising strategies of US presidential election campaigns during the 2020 primary cycle. To identify geographic and temporal trends, we employ regression analyses of campaign spending across nearly 600,000 advertisements published on Facebook. We show that campaigns employed a new strategy of targeting voters in candidates’ home states during the “invisible primary.” In contrast to earlier studies, we find that home state targeting is a key strategy for all campaigns, rather than just for politicians with existing political and financial networks. While all candidates advertised to their home state, those who dropped out during the invisible primary tended to spend disproportionately more than the candidates who outlasted them. We also find that as the first wave of state caucuses and primary elections approach, campaigns shift digital ad expenditures to states with early primaries such as Iowa and New Hampshire and, to a lesser extent, swing states.
Survival Outcomes and Safety of Programmed Cell Death/Programmed Cell Death Ligand 1 Inhibitors for Unresectable Hepatocellular Carcinoma: Result From Phase III Trials
Authors: Zeng Linyan , Su Junwei , Qiu Wenqi , Jin Xuehang , Qiu Yunqing , Yu Wei
Published: April 2022

Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. The aim of this study was conducted a meta-analysis to assess the efficacy and safety of PD-1/PD-L1 inhibitors in patients with unresectable hepatocellular carcinoma (uHCC). A total of 1657 patients were included. The completed phase III trials with details data, such as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse effects (AEs) were included. The pooled hazard ratio (HR) of OS and PFS were .75 (95% CI: .61–.92) and .74 (95% CI: .56–.97) with heterogeneity between PD-1/PD-L1 inhibitors groups and control groups. Sensitivity analysis revealed IMbrave-150 could be the most important factor of heterogeneity for OS, while CheckMate-459 was the main fact of heterogeneity for PFS. In addition, the relative risk (RR) of ORR and DCR were 2.43 (95% CI: 1.80–3.26) and 1.26 (95% CI: 1.11–1.43) with low heterogeneity in PD-1/PD-L1 inhibitors groups. The therapeutic effect of PD-1/PD-L1 inhibitors was better in females, Asia without Japan, BCLC status C and infected hepatitis groups. The RR of AEs from any cause and serious adverse events (SAEs) for patients receiving PD-1/PD-L1 inhibitors were 1.03 (95% CI: .93–1.13) and 1.13 (95% CI: .89–1.44), respectively. Pruritus was the most common AEs reported in 10% of patients or more (RR = 1.69, 95% CI: 1.33–2.15). In conclusion, PD-L1 inhibitor combined with anti-VEGF antibody could improve the prognosis of patients with uHCC. However, caution should be taken for AEs during patients receiving PD-1/PD-L1 inhibitors.
Reliability and Factor Structure of the Sex Offender Treatment Intervention and Progress Scale
Authors: Miner Michael H. , Brouillette-Alarie Sébastien , Davies Simon T. , Newstrom Nicholas , Robinson Beatrice “Bean” E. , Thornton David , Hanson R Karl
Published: April 2022

Assessment of risk of sexual recidivism has progressed from tools containing only static factors to tools including dynamic (i.e., changeable) risk factors. The psychometric properties and factor structure of one such scale, the Sex Offender Treatment Intervention and Progress Scale (SOTIPS) were explored. Seven hundred and thirty-one men assigned probation for sexual crimes in New York City and Maricopa County, Arizona were administered SOTIPS three times: intake into probation, six months later, and six months after that. SOTIPS showed good internal consistency (Time 1 ω = .87, Time 2 ω = .89, and Time 3 ω = .91), and acceptable inter-rater reliability (for the 26 cases rated in the same month, ICC =.821). An exploratory factor analysis did not result in the original factor structure proposed by the developers; instead, SOTIPS showed two factors: sexual risk and antisocial opposition. This factor structure required the averaging of two items to avoid collinearity. SOTIPS showed temporal invariance indicating that its factor structure and its association to underlying latent variables are consistent over time.
The democratic embargo: regime type and proxy war
Authors: Grauer Ryan , Tierney Dominic
Published: April 2022

Democracies rarely fight interstate wars against one another, but democratic dyads frequently engage in hostile acts short of war, such as militarized interstate disputes and the backing of coups. Do democracies wage proxy war against other elected regimes by aiding rebels with weapons and other assistance? Scholars have found that democracies generally avoid doing so—a phenomenon we term the “democratic embargo.” However, the democratic embargo remains under-theorized. Using both datasets and close examination of purported instances of democratic aid to rebels fighting other democracies, we show that the democratic embargo is stronger than first thought. In addition, we explain the democratic embargo by arguing that strong democratic institutions prevent elected leaders from engaging in proxy war against sister regimes, and embargo violations tend to occur when democratic institutions are weak. We test our theory in two ways. First, using large-N qualitative analysis (LNQA), we examine all potential exceptions to the democratic embargo between 1945 and 2011 to establish the external validity of our claim. Second, we use case studies of the Irish decision not to aid rebels fighting the United Kingdom in Northern Ireland and Pakistan’s decision to support rebels fighting India in Kashmir to assess the internal validity of our theoretical logic. The results provide clear support for our institutional explanation of the democratic embargo. Our argument has significant implications for the democratic peace theory, the study of proxy wars, and the capacity of democracies to fight rebellions.
Who votes for virtue? Religion and party choice in Thailand’s 2019 election
Authors: Larsson Tomas , Thananithichot Stithorn
Published: April 2022

Does religion shape political competition in Thailand? Despite the prominence of religiously inflected rhetoric of good and evil in contemporary political contestation, existing research suggests that it does not. This article challenges this conventional wisdom. Survey data collected in connection with Thailand’s 2019 general election, which marked a transition from direct military rule to a hybrid regime, allow us to examine the political relevance of religious belonging, belief, and behaviour. Our analysis finds evidence for the political salience of a secular/religious cleavage: voters who self-identified as more religious were more inclined to support the main pro-military party Palang Pracharath and its closest allies, whilst more secularised voters tended to support anti-military parties in general and the Future Forward Party in particular. We also find that Thailand’s religious minorities were politically divided: Muslims and Protestants backed the pro-military parties whilst Catholics opposed them. Our analysis underscores the need for more attention to the role of religious cleavages in Thai political contention.
Limits of Resistance Testing
Authors: D'Aquila Richard T
Published: April 2022

Interpretation of antiretroviral testing is complicated by many factors, including those related to HIV biology and genetics, as well as the intricacies of drug selection pressure in vivo. These complex factors can limit the usefulness of resistance testing. However, knowledge about these issues can help to avoid misinterpreting resistance test results and thereby help clinicians to use resistance testing to individualize antiretroviral drug choices.
The Role of Resistance Testing in Clinical Trial Design and Product Labelling: A Regulatory Perspective
Authors: Laessig Katherine A , Murray Jeffrey S , Chikami Gary
Published: April 2022

Assays that attempt to characterize HIV susceptibility or resistance are among the latest technologies that are likely to impact HIV clinical trial design, antiretroviral drug development and patient management. However, at present the Food and Drug Administration (FDA) have yet to approve any phenotypic or genotypic HIV resistance assay and the role of resistance testing in clinical management of patients and in drug development is ill defined. In November 1999, the Division of Antiviral Drug Products at the FDA convened a meeting of its advisory committee to consider the available information about HIV resistance testing, and to generate some recommendations about how these assays could be utilized in anti-retroviral drug development. In addition, the committee was presented with several hypothetical regulatory scenarios in order to illustrate how HIV resistance testing might be incorporated in antiretroviral drug development and drug labelling. In this article, we discuss the regulatory history of resistance testing in antimicrobial drug development, the current use of resistance testing for antiretrovirals, as well as a summary of the hypothetical scenarios that were presented to the committee and the discussion of the committee members regarding those scenarios.
Prevalence of Transmitted Nucleoside Analogue-Resistant HIV-1 Strains and Pre-Existing Mutations in Pol Reverse Transcriptase and Protease Region: Outcome after Treatment in Recently Infected Individuals
Authors: Balotta Claudia , Berlusconi Alberto , Pan Angelo , Violin Michela , Riva Chiara , Colombo M Chiara , Gori Andrea , Papagno Laura , Corvasce Stefano , Mazzucchelli Renata , Facchi Guido , Velleca Rossella , Saporetti Giorgia , Galli Massimo , Rusconi Stefano , Moroni Mauro
Published: April 2022

We retrospectively studied 38 Italian recently HIV-1-infected subjects who seroconverted from 1994 to 1997 to investigate: (i) the prevalence of nucleoside reverse transcriptase inhibitors (NRTI)-related mutations at primary infection; (ii) the proportion of naturally occurring mutations in reverse transcriptase (RT) and protease regions of patients naive for non-nucleoside RT inhibitors (NNRTIs) and protease inhibitors (PIs); (iii) the drug-susceptibility to NRTIs and PIs in subjects with NRTI-and/or PI-related mutations; and (iv) the outcome of seroconverters treated with various NRTIs or NRTI/PI regimens. Baseline HIV-1 plasma viraemia and absolute CD4 count at baseline could not be used to distinguish patients with NRTI- and/or PI-related pre-existing mutations from those with wild-type virus ( P=0.693 and P=0.542, respectively). The frequency of zidovudine-related mutations was 21% in the study period. The response to treatment was not significantly different in subjects with or without genotypic zidovudine-related mutations at primary infection ( P=0.744 for HIV-1 RNA and P=0.102 for CD4 cells). Some natural variation (2.6%) was present within regions 98–108 and 179–190 of RT involved in NNRTI resistance. The high natural polymorphism in the protease region present in our patients was similar to that reported by others. In our study some PI-associated substitutions, thought to be compensatory in protease enzymatic function, could confer intermediate to high PI-resistance. As discrepancies between genotypic and phenotypic results may exist in recent seroconverters, our data suggest that the role of transmitted NRTI- and PI-resistant variants remain to be fully elucidated in vivo.
HIV Drug Susceptibility and Treatment Response to Mega-Haart Regimen in Patients from the Frankfurt HIV Cohort
Authors: Miller Veronica , Cozzi-Lepri Alessandro , Hertogs Kurt , Gute Peter , Larder Brendan , Bloor Stuart , Klauke Stefan , Rabenau Holger , Phillips Andrew , Staszewski Schlomo
Published: April 2022

Objective

To assess the relationship between viral susceptibility at baseline and virological response in human immunodeficiency virus (HIV)–infected patients treated with multi-drug salvage regimens after multiple previous treatment failures.

Design

Retrospective analysis of 50 patients from the Frankfurt HIV cohort who had received treatment with a minimum of six drugs, and for whom a sample for baseline viral phenotyping was available. Methods: Viral drug susceptibility was measured retrospectively from stored samples using the Antivirogram, a recombinant virus assay based method. Virological response was defined as a viral load of <400 copies/ml at week 24. For analysis of treatment response, drop-outs were dealt with in two ways, either as failures (DAF) or censored (DAC). Several logistical regression models were applied to identify predictors of response, including baseline virus load, number of new drugs and phenotypic sensitivity scores.

Results

At baseline, drug resistance was extensive: 96% of patients had viruses resistant to at least one drug class and 32% had viruses resistant to all three drug classes. In the DAF analysis, 39 patients experienced virological failure. In the DAC analysis, eight were censored and 31 patients experienced virological failure. In multivariate models that adjust for baseline viral load, the number of new drugs and total phenotypic sensitivity scores, the baseline viral load and phenotypic sensitivity score remained significantly associated with virological outcome, whereas in those adjusted for baseline viral load, the number of new drugs, NRTI phenotypic sensitivity score and PI phenotypic sensitivity score, only the latter remained significantly associated with virological outcome. Both the DAF and DAC analyses produced similar results. In all models used, virological failure was shown to be significantly associated with baseline viral load and phenotypic sensitivity score.

Conclusions

In this retrospective analysis based on a small number of patients, viral drug susceptibility at baseline was strongly associated with virological outcome at 24 weeks, independent of covariates such as baseline viral load and treatment history. Baseline viral load also maintained a significant, independent association with virological outcome in most models.
Genotypic and Phenotypic Nevirapine Resistance Correlates with Virological Failure during Salvage Therapy Including Abacavir and Nevirapine
Authors: Jørgensen Louise Bruun , Katzenstein Terese L , Gerstoft Jan , Mathiesen Lars R , Pedersen Court , Nielsen Claus
Published: April 2022

Objective

To study the development of resistance during 8 weeks of salvage therapy with abacavir and nevirapine in combination with other reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs).

Methods

Samples obtained at baseline and after 8 weeks of therapy from 16 heavily pretreated patients were analysed for genotypic and phenotypic resistance. Genotypic resistance was analysed in cell-associated DNA and plasma HIV-RNA using direct sequencing. Phenotypic resistance was analysed in a PBMC-based assay and in a recombinant virus assay. Plasma viral load was measured at baseline and after 2, 4 and 8 weeks of therapy.

Results

The majority of patients was genotypically and phenotypically resistant to lamivudine, abacavir, zidovudine and PIs, whereas 50% of the patients showed resistance to nevirapine at baseline in at least one of the methods used. After 8 weeks of salvage therapy, no additional development of resistance against nucleoside reverse transcriptase inhibitors and PIs could be detected. However, the amount of patients resistant to nevirapine increased to 83%. When the patients were divided into two groups according to baseline resistance against nevirapine, a significantly higher transient reduction in viral load was observed in patients with nevirapine-sensitive HIV at baseline compared to patients with resistant HIV at baseline.

Conclusions

The transient effect of salvage therapy including abacavir and nevirapine was due to the effect of nevirapine. The lack of effect of abacavir was most likely due to cross-resistance between abacavir and lamivudine/zidovudine used in previous treatment.
Haart Tolerability: Post-Exposure Prophylaxis in Healthcare Workers versus Treatment in HIV-Infected Patients
Authors: Quirino Tiziana , Niero Fosca , Ricci Elena , Pusterla Luigi , Carradori Silvia , Gabbuti Andrea , Iemoli Enrico , Landonio Simona , Faggion Ivano , Bonfanti Paolo ,   for the CISAI study group
Published: April 2022

The aim of our study is to compare the tolerability of zidovudine/lamivudine/indinavir when used in post-exposure prophylaxis (PEP) subjects and in HIV-infected patients. HIV-negative patients were enrolled as part of the surveillance protocol for professional exposure at the Luigi Sacco Hospital in Milan. HIV-positive patients were selected among all subjects undergoing treatment with zidovudine/lamivudine/indinavir from the CISAI cohort, an Italian cohort for the evaluation of adverse reactions to HAART. In both studies patients were followed prospectively and the severity of the reactions was evaluated using the AIDS Clinical Trial Group adverse experience grading scales. Up to September 1999, 37 HIV-seronegative subjects had undergone treatment with zidovudine/lamivudine/indinavir. From a total of 1207 patients belonging to the CISAI cohort, 199 were identified as being treated with the same regimen. The frequency of adverse events in the PEP subjects was 70.3% compared to 11.1% for HIV-infected patients. In the first group, adverse events caused treatment interruption in 21 subjects (56.7%) versus 14 patients (7%) among the HIV-infected group. Only one case of a severe event (grade 3–4) was observed in the prophylaxis group against 12 in the treatment group. Our study shows that treatment interruption is eight times higher in HIV-negative subjects compared to HIV-seropositive patients, and that the incidence of adverse events is approximately six times higher, though such events, are for the most part, not severe.
In Vitro Inhibition of HIV-1 by Met-Sdf-1β Alone or in Combination with Antiretroviral Drugs
Authors: Rusconi Stefano , Merrill Debra P , La Seta Catamancio Simona , Citterio Paola , Bulgheroni Elisabetta , Croce Francesco , Chou Ting-Chao , Yang Otto O , Herrmann Steven H , Galli Massimo , Hirsch Martin S
Published: April 2022

Compounds that can block the CXCR4 chemokine receptor are a promising new class of antiretroviral agents. In these experiments we studied the effect of a modified form of the native stromal cell-derived factor-1 (SDF-1), Met-SDF-1β. The in vitro susceptibility of two different CXCR4-tropic HIV-1 strains was determined. Antiviral effect was assessed by the reduction of p24 antigen production in PHA-stimulated peripheral blood mononuclear cells with exposure to the modified SDF-1 molecule. The 50% inhibitory concentrations (IC50) were derived from six separate experiments. The IC50 against the two HIV-1 isolates was in 1.0–2.8 μg/ml range for Met-SDF-1β. Met-SDF-1β showed synergy to additivity with either zidovudine or nelfinavir at IC75, IC90 and IC95. Additivity was seen when Met-SDF-1β was combined with efavirenz. No cellular toxicity was observed at the highest concentrations when these agents were used either singly or in combination. This compound is a promising new candidate in a receptor-based approach to HIV-1 infection in conjunction with currently available combination antiretroviral drug therapies.
Phenotypic HIV-1 Resistance Correlates with Treatment Outcome of Nelfinavir Salvage Therapy
Authors: Walter Hauke , Schmidt Barbara , Rascu Astrid , Helm Martin , Moschik Brigitte , Paatz Christiane , Kurowski Michael , Korn Klaus , Überla Klaus , Harrer Thomas
Published: April 2022

In order to analyse whether drug sensitivity testing would be beneficial for clinical decision-making in heavily pretreated patients, we retrospectively studied viral genotype and phenotypic drug resistance in 12 HIV-1-infected patients, each of them with a history of failing at least one therapeutic regimen including one or two protease inhibitors (PIs). The salvage therapy included nelfinavir as new PI in all cases. Four patients showed a sustained and five patients a transient viral load decrease. Three patients failed to show a significant decline of plasma HIV-1 RNA. In the baseline samples of these cases, resistance against all components of their combination therapy could be detected, whereas at least one antiretroviral drug was still active in the cases with transient treatment response. All patients with sustained therapy response harboured viruses that were either fully sensitive or resistant to only one of the drugs administered. In our study, phenotypic drug resistance was predictive for the success of antiretroviral salvage regimens.
Experience with Nevirapine in Previously Treated HIV-1-Infected Individuals
Authors: Wit Ferdinand WNM ,   for the Dutch HIV-treating physicians
Published: April 2022

Objective

To assess the tolerability, virological, immunological and clinical effects of nevirapine in the setting of a compassionate use programme in pretreated HIV-infected individuals.

Design

Retrospective observational cohort-study in 13 HIV-outpatient clinics in The Netherlands.

Methods

Main outcome measures: plasma HIV-1 RNA levels; CD4 cell counts; incidence of new AIDS-defining diseases; multivariate analysis of predictors for virological success; incidence of skin rashes.

Results

187 HIV-infected individuals treated with nevirapine in the Nevirapine Named Patient Programme in The Netherlands were included. After 48 weeks, 38% of patients had an HIV-1 RNA level below 1000 copies/ml. In multivariate regression analysis, prior treatment with three or less nucleoside analogue reverse transcriptase inhibitors, and a higher baseline CD4 cell count was predictive of virological success. The median CD4 cell count remained stable over the 48 weeks. Eleven patients experienced a new AIDS-defining event. The total incidence of rash (including rash not leading to discontinuation of nevirapine) was 13.9 and 6.4% of the patients discontinued nevirapine because of rash. None of the 28 patients with undetectable HIV-1 RNA levels at baseline developed a rash.

Conclusions

We conclude that nevirapine when used as part of salvage therapy, is safe and most likely to give sustained suppression of HIV-1 in patients that have been less extensively pretreated. CD4 cell counts remained stable despite the low rate of virological success, this also occurred in patients not concurrently using protease inhibitors (PIs). The incidence of nevirapine-related rash in PI-pretreated patients and especially in patients with undetectable HIV-1 RNA levels at the start of nevirapine treatment, is considerably lower than previously reported for antiretroviral-naive patients.
The Virgo Study: Nevirapine, Didanosine and Stavudine Combination Therapy in Antiretroviral-Naive HIV-1-Infected Adults
Authors: Raffi François , Reliquet Véronique , Ferré Virginie , Arvieux Cédric , Hascoet Claudine , Bellein Véronique , Besnier Jean-Marc , Breux Jean-Philippe , Garré Michel , May Thierry , Molina Jean-Michel , Perré Philippe , Raguin Gilles , Rozenbaum Willy , Zucman David ,   the VIRGO Study team
Published: April 2022

The virological and immunological efficacy of the triple regimen containing nevirapine (once or twice daily), didanosine (once daily) and stavudine, in antiretroviral-naive patients infected with HIV-1, was evaluated in an open-label, prospective, non-randomized, multi-centre, 52-week study. The first 60 patients (VIRGO I) received nevirapine as the standard dose, 200 mg twice daily; the subsequent 40 patients (VIRGO II) received nevirapine at a dose of 400 mg once daily. All patients received 400 mg of didanosine once daily and 40 mg of stavudine twice daily, adjusted for body weight. At baseline, the median CD4 cell count and plasma viral load (pVL) were 414 cells/mm3 and 4.59 log10 copies/ml in VIRGO I, and 412 cells/mm3 and 4.87 log10 copies/ml in VIRGO II. Using an intent-to-treat, ‘non-completer equals failure’, analysis, 78% (95% CI, 68–88%) of patients in VIRGO I and 68% (95% CI, 53–83%) of those in VIRGO II had a pVL <500 copies/ml at 24 weeks; the proportions achieving a pVL of <50 copies/ml were 62% (95% CI, 50–74%) and 50% (95% CI, 35–65%), respectively. The week 24 median CD4 cell count increase was 168 cells/mm3 (VIRGO I) and 139 cells/mm3 (VIRGO II). At week 52, 39/45 (87%) of VIRGO I patients had pVL <500 copies/ml and 30/45 (67%) <50 copies/ml. Of the 100 patients, 44 experienced grade 2 to 4 adverse events; 20 permanently discontinued study medication because of an adverse event. Combination therapy with the three reverse transcriptase (RT) inhibitors stavudine, once-daily didanosine and either once- or twice-daily nevirapine could be considered as an alternative option for first-line antiretroviral therapy.
Measuring the Effectiveness of Antiretroviral Agents
Authors: Buss Neil , Cammack Nick
Published: April 2022

Considerable progress has been made recently in developing effective antiretroviral combination therapy that can suppress viral replication and delay disease progression in individuals infected with HIV. A range of up to 15 approved antiretroviral agents is now available, which target two different viral enzymes, while several agents are in clinical development. The rapid development and approval of antiretroviral agents, driven by the urgency of clinical need as well as the complexity of possible combinations, has precluded the extensive comparative clinical testing of regimens, which is necessary to establish the relative efficacy of various different agents. The lack of an appropriate animal model for HIV disease also increases reliance on in vitro measures. Several different in vitro and in vivo parameters have been defined in an attempt to quantify the effectiveness of antiretroviral agents, most importantly the 50% inhibitory and effective concentrations (IC50 and EC50). However, the clinical relevance of these measures is uncertain. Additionally, considerable variation exists in the usage of the terms ‘IC50’ and ‘EC50’ in recent publications in the literature. These issues pose interpretation problems to clinicians seeking information on the relative clinical efficacy of the agents. In this brief review, we attempt to clarify the different measures available and their potential utility for clinical decision-making, focusing particularly on the example of HIV protease inhibitors. There are many different quantifiable parameters that give information regarding the effectiveness of an antiviral drug. These include: inhibition of the viral target enzyme (inhibition constant, Ki); selectivity for viral versus host enzymes; inhibition of viral replication in cell culture (IC50); ratio of efficacy to cytotoxicity in vitro (therapeutic index); inhibition of viral replication or symptoms in an appropriate animal model of the disease (EC50); and the effect on surrogate markers, such as viral load or CD4 cell count, after administration to humans ( in vivo EC50). Each of these different parameters gives valid information about the properties of an antiretroviral agent, which can help to build up a picture of its potential clinical utility relative to other drugs. However, to gain meaningful results, it is important to apply this information intelligently, understanding the limitations of each parameter.
Laboratory Guidelines for the Practical Use of HIV Drug Resistance Tests in Patient Follow-Up
Authors: Vandamme A-M , Houyez F , Bànhegyi D , Clotet B , De Schrijver G , De Smet KAL , Hall WW , Harrigan R , Hellmann N , Hertogs K , Holtzer C , Larder B , Pillay D , Race E , Schmit J-C , Schuurman R , Shulse E , Sönnerborg A , Miller V
Published: April 2022

HIV drug resistance is one of the major limitations in the successful treatment of HIV-infected patients using currently available antiretroviral combination therapies. When appropriate, drug susceptibility profiles should be taken into consideration in the choice of a specific combination therapy. Guidelines recommending resistance testing in certain circumstances have been issued. Many clinicians have access to resistance testing and will increasingly use these results in their treatment decisions. In this document, we comment on the different methods available, and the relevant issues relating to the clinical application of these tests. Specifically, the following recommendations can be made: (i) genotypic and phenotypic HIV-1 drug resistance analyses can yield complementary information for the clinician. However, insufficient information currently exists as to which approach is preferable in any particular clinical setting; (ii) when HIV-1 drug resistance testing is required, it is recommended that testing be performed on plasma samples obtained before starting, stopping or changing therapy, on samples that have a viral load above the detection limit of the resistance test; (iii) the panel recommends that genotypic and phenotypic HIV-1 drug resistance testing for clinical purposes be performed in a certified laboratory under strict quality control and quality assurance standards; and (iv) the panel recommends that resistance testing laboratories provide clinicians with resistance reports that include a list of drug-related resistance mutations (genotype) and/or a list of drug-related fold resistance values (phenotype), with interpretations of each by an experienced virologist. The interpretation of genotypic and phenotypic analysis is a complex and developing science, and in order to understand HIV-1 drug resistance reports, communication between the requesting clinician and the expert that interpreted the resistance report is recommended.
A Dose-Ranging Study to Evaluate the Antiretroviral Activity and Safety of Amprenavir Alone and in Combination with Abacavir in HIV-Infected Adults with Limited Antiretroviral Experience
Authors: Schooley Robert T , Clumeck Nathan , Haubrich Richard , Thompson Melanie , Danner Sven A , van Der Ende Marchina E , Sereni Daniel , Antunes Francisco , Blake Denise , Myers Richard E , Tisdale Margaret , Millard Judith , Mustafa Norman , Nacci Pantaleo
Published: April 2022

Objective

To evaluate the antiretroviral activity and safety of multiple escalating doses of amprenavir administered alone, and in combination with abacavir in HIV-1-infected adults.

Design

Sixty-two HIV-1-infected subjects were enrolled in a multicentre, open-label, non-randomized, dose-escalating trial.

Methods

Subjects were assigned to one of six dose groups and received amprenavir 300 mg twice daily, 300mg three times daily, 900, 1050, or 1200 mg twice daily for 4 weeks. One dose group received amprenavir 900 mg twice daily in combination with abacavir 300 mg twice daily for 4 weeks. Antiretroviral activity was assessed by measuring changes from baseline in plasma HIV-1 RNA levels and CD4 cell counts. Safety was evaluated by monitoring clinical adverse events and changes in laboratory values. Genotypic and phenotypic analyses were performed using ABI sequencing and the recombinant virus assay, respectively.

Results

At week 4, amprenavir monotherapy (900, 1050, or 1200 mg twice daily) resulted in marked decreases in plasma HIV-1 RNA levels (1.3–1.6 log10 copies/ml), and substantial increases in CD4 cell counts in the two dose groups who received 1050 mg twice daily (118x106 cells/mm3) or 1200 mg twice daily (114x106 cells/mm3). Amprenavir/abacavir resulted in median plasma HIV-1 RNA reductions of 1.8 log10 copies/ml, and median CD4 cell count increases of 138x106 cells/mm3. Amprenavir was reasonably well tolerated with few treatment-limiting adverse events. No known active site mutations associated with amprenavir resistance were selected in any of the dose groups, and no significant phenotypic resistance to amprenavir developed during 4 weeks of therapy.

Conclusions

The antiviral effect of amprenavir monotherapy increased with escalating doses, and all amprenavir doses were reasonably well tolerated over 4 weeks of therapy. Amprenavir/abacavir combination therapy elicited a potent antiviral effect. The three highest doses of amprenavir (900, 1050 and 1200 mg twice daily) were selected to design subsequent Phase II and III studies that confirmed the safety profile and efficacy of amprenavir in combination regimens and led to the approval of amprenavir in the USA in 1999.
Antiretroviral Activity and Safety of Abacavir in Combination with Selected HIV-1 Protease Inhibitors in Therapy-Naive HIV-1-Infected Adults
Authors: McMahon Deborah , Lederman Michael , Haas David W , Haubrich Richard , Stanford James , Cooney Elizabeth , Horton James , Kelleher Dennis , Ross Lisa , Cutrell Amy , Lee Diana , Spreen William , Mellors John W
Published: April 2022

Objective

To assess antiretroviral efficacy and safety of abacavir in combination with selected HIV-1 protease inhibitors.

Design

A 48-week, open-label study.

Materials and Methods

Eighty-two antiretroviral naive HIV-1-infected adults (CD4 cell count ≥100 cells/mm3, plasma HIV-1 RNA ≥5000 copies/ml) were randomly assigned to receive abacavir (300 mg twice daily) in combination with standard doses of one of five protease inhibitors: indinavir, saquinavir soft-gel, ritonavir, nelfinavir or amprenavir. Adults who met protocol-defined switch criteria at or after week 8 could modify their randomized therapy. Antiretroviral activity was assessed by the proportion of subjects with plasma HIV-1 RNA ≤400 and ≤50 copies/ml, and by changes in plasma HIV-1 RNA levels and CD4 cell counts. Safety was assessed by monitoring clinical adverse events and laboratory abnormalities.

Results

At week 48, the proportion of subjects in the indinavir, saquinavir, ritonavir, nelfinavir and amprenavir groups with plasma HIV-1 RNA ≤400 copies/ml was 53, 50, 50, 41 and 56%, respectively, and the proportion with HIV-1 RNA ≤50 copies/ml was 47, 56, 50, 47, and 44%, respectively (by intent-to-treat analysis). Median reductions from baseline in plasma HIV-1 RNA for each group ranged from 1.7 to 2.4 log10 copies/ml. The median CD4 cell count increase from baseline was 195, 131, 116, 136 and 259 cells/mm3 in the indinavir, saquinavir, ritonavir, nelfinavir, and amprenavir groups, respectively. Overall, the most common adverse events attributed to study drugs were diarrhoea, nausea, malaise/fatigue, headache and perioral paresthesia. The frequency of treatment-limiting adverse events did not differ between groups. Conclusions: Abacavir is safe and effective when used in combination with a protease inhibitor.
Antiretoviral Therapy and the Lipodystrophy Syndrome, Part 2: Concepts in Aetiopathogenesis
Authors: Nolan David , John Mina , Mallal Simon
Published: April 2022

Clinical research has indicated that the use of nucleoside reverse transcriptase inhibitor (NRTI) and HIV protease inhibitor (PI) therapy is associated with a risk of long-term toxicity syndromes, and that the aetiopathogenesis of these adverse effects is independent of the antiretroviral effects of these drugs. In relation to the lipodystrophy syndrome, it appears that the most powerful determinant of subcutaneous fat wasting is an interaction between these two drug classes. In this review, possible mechanisms underlying the contributions of both PI and NRTI drugs are reviewed, with an emphasis on their effects on adipose tissue. On this basis, an ‘adipocentric’, or minimal model of the syndrome is developed, in which divergent effects at the adipocyte of NRTIs (mitochondrial toxicity) and PIs (insulin resistance and impaired adipocyte maturation) interact to produce a phenotype that is consistent with clinical observations.
Low-Rate Emergence of Thymidine Analogue Mutations and Multi-Drug Resistance Mutations in the HIV-1 Reverse Transcriptase Gene in Therapy-Naive Patients Receiving Stavudine plus Lamivudine Combination Therapy
Authors: Mouroux Mireille , Descamps Diane , Izopet Jacques , Yvon Anne , Delaugerre Constance , Matheron Sophie , Coutellier Anne , Valantin Marc-Antoine , Bonmarchand Manuella , Agut Henri , Massip Patrice , Costagliola Dominique , Katlama Christine , Brun-Vezinet Françoise , Calvez Vincent
Published: April 2022

Objectives

Mutations usually associated with zidovudine exposure have been observed in zidovudine-naive patients treated by stavudine in combination. These mutations were named thymidine analogue mutations (TAMs). This fact, combined with phenotypical and biochemical findings provided additional evidence for cross-resistance between zidovudine and stavudine. A recent genotypic study in naive patients receiving stavudine/didanosine combination showed emergence of TAMs and a multidrug-resistance mutation (MDR), Q151M, in 36 and 10% of cases, respectively. Stavudine plus lamivudine is one of the most used binucleoside associations in the antiretroviral combinations. The objective of this study was to assess the genotypic changes in the HIV-1 reverse transcriptase (RT) gene in antiretroviral-naive patients treated by stavudine plus lamivudine.

Methods

We analysed the RT gene of 44 HIV-1 patients, naive of antiretroviral therapy, who were treated for 24 or 48 weeks with stavudine/lamivudine. Results: At the end of the follow-up, all patients acquired the lamivudine-associated mutation M184V. Only two subjects (4.5%) developed a TAM (T215Y; M41L), one subject developed a V75T/A mutation and one subject developed the particular MDR pattern F116Y, Q151M.

Conclusions

Our study clearly demonstrated that naive subjects treated with stavudine/lamivudine for 24–48 weeks selected a low rate of TAMs and MDR Q151M. One hypothesis explaining these results could be the development of the M184V mutation.