bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypogonadism in HIV-1-Infected Men is common and does not resolve during antiretroviral therapy
Authors: Wunder Dorothea M , Bersinger Nick A , Fux Christoph A , Mueller Nicolas J , Hirschel Bernard , Cavassini Matthias , Elzi Luigia , Schmid Patrick , Bernasconi Enos , Mueller Bruno , Furrer Hansjakob ,   the Swiss HIV Cohort Study
Published: April 2022

Objectives

To assess the prevalence of abnormal testosterone and gonadotropin values in HIV-infected men before and after 2 years of combination antiretroviral therapy (cART).

Design

Multicentre cohort of HIV-infected adults.

Methods

We identified 139 Caucasian antiretroviral-naive male patients who started zidovudine/ lamivudine-based cART that was virologically successful over a 2 year period. Ninety-seven were randomly chosen and plasma hormone determinations of free testosterone (fT) and luteinizing hormone (LH) at baseline and after 2 years of cART were evaluated.

Results

At baseline 68 patients (70%) had subnormal fT levels. In these, LH levels were low in 44%, normal in 47% and high in 9%. There was a trend for an association between lower CD4+ T-cell counts and hypogonadism. Most participants had normal FSH levels. No significant changes of fT, LH and FSH levels were observed after 2 years of cART.

Conclusions

Low fT levels, mainly with normal or low LH levels and thus indicating secondary hypogonadism, are found in the majority of HIV-infected men and do not resolve during 2 years of successful cART.
The Impact of Reducing Stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients
Authors: Milinkovic Ana , Martinez Esteban , López Sonia , De Lazzari Elisa , Miró Oscar , Vidal Sergi , Blanco José L , Garrabou Gloria , Laguno Montserrat , Arnaiz Joan A , Leon Agathe , Larrousse Maria , Lonca Montserrat , Mallolas Josep , Gatell José M
Published: April 2022

Background

Stavudine (d4T)-containing regimens are associated with a potential for lipoatrophy and dyslipidaemia. We assessed the safety and efficacy of reducing the dose of stavudine compared with switching to tenofovir or maintaining the standard dose of d4T.

Methods

Clinically stable HIV-infected patients receiving antiretroviral therapy containing stavudine 40 mg twice daily with a plasma HIV RNA <200 copies/ml for at least 6 months were randomized to maintain stavudine 40 mg twice daily (d4T40 arm), to reduce to 30 mg twice daily (d4T30 arm), or to switch from d4T to tenofovir (TDF arm).

Results

Fifty-eight (93% male) patients were included: 22 in the d4T40 arm, 19 in the d4T30 arm and 17 in TDF arm. At baseline, median time on d4T was 6 years (interquartile range [IQR] 2.6–7.1), median age 43 years (IQR 36–51) and median CD4+ T-cell count was 587/mm3 (IQR 329–892). At week 24, median limb fat changes (g) were as follows: d4T40=-182 (95% CI: -469—5); d4T30=527 (95% CI: -343–694); and TDF=402 (95% CI: 130–835; d4T40 versus TDF, P=0.0003). Significant differences between median values of laboratory parameters were detected: triglycerides (mg/dl): d4T40=19; d4T30=-23 and TDF=-79 (d4T40 versus TDF, P=0.03); and total cholesterol (mg/dl): d4t40=22, d4T30=-4, and TDF=-28 (d4T40 versus TDF, P=0.04). No significant difference was observed in mitochondrial function assessed in peripheral blood mononuclear cells.

Conclusions

Although both strategies were associated with a trend toward a decrease in plasma lipids and an increase in body fat, the only significant changes were observed among those who switched to tenofovir.
Fate and Function of Hepatitis-C-Virus-Specific T-Cells during Peginterferon-α2b therapy for Acute Hepatitis C
Authors: Wiegand Johannes , Cornberg Markus , Aslan Nuray , Schlaphoff Verena , Sarrazin Christoph , Kubitschke Anne , Buggisch Peter , Ciner Ayse , Jaeckel Elmar , Manns Michael P , Wedemeyer Heiner
Published: April 2022

Background

Strong hepatitis C virus (HCV)-specific T-cell responses are associated with spontaneous clearance of acute hepatitis C. However, recent studies described a decline in HCV-specific CD8+ T-cells during interferon treatment, suggesting that the success of acute HCV therapy might be independent of adaptive immunity.

Methods

T-cell responses of eight human leukocyte antigen (HLA)-A2-positive, acutely infected patients treated with peginterferon-α2b were studied by ELISPOT and proliferation assays and flow cytometry analysis using HCV-specific tetramers.

Results

HCV-specific T-cells predominately declined during therapy. However, diverse patterns of CD4+ and CD8+ T-cell kinetics were observed. In patients with sustained virological response chemokine receptor 3 (CXCR-3) expression of HCV-specific CD8+ T-cells was upregulated, indicating homing to the liver. Low levels of T-cells remained detectable throughout treatment and follow up. In contrast, T-cells of a relapse patient did not upregulate CXCR-3 but displayed a higher staining for annexin-V, followed by a complete loss of peripheral virus-specific CD8+ T-cells by week 12.

Conclusions

Kinetics of HCV-specific T-cell responses are heterogeneous in interferon-treated patients with acute hepatitis C. The decline of T-cells might be a consequence of both apoptosis and homing. The balance between cell death and regulation of chemokine receptors might lead to different long-term outcomes.
Premature Treatment Discontinuation in HIV/HCV-Coinfected Patients Receiving Pegylated Interferon plus Weight-Based Ribavirin
Authors: Soriano Vincent , Miralles Celia , Berdún Miguel Angel , Losada Elena , Aguirrebengoa Koldo , Ocampo Antonio , Arazo Piedad , Cervantes Manuel , De Los Santos Ignacio , Joaquín Isabel San , Echeverria Santiago , Galindo María J , Asensi Victor , Barreiro Pablo , Sola Julio , Hernandez-Burruezo Juan J , Guardiola Josep , Blanco Francisco , Martin-Carbonero Luz , García-Samaniego Javier , Nuñez Marina
Published: April 2022

Background

Chronic hepatitis C therapy in HIV patients is often penalized by more frequent premature treatment discontinuations. It is unclear what the relative contribution of more adverse events and/or early virological failures are.

Methods

PRESCO was a prospective, multicentre, comparative trial, in which 389 HIV/HCV-coinfected patients with CD4+ T-cell counts >300 cells/ml and elevated aminotransferases received pegylated interferon-α2a (peg IFN-α2a) 180 mg per week plus ribavirin (RBV) 1,000–1,200 mg daily. Patients with HCV genotypes 1 or 4 were treated for 48 or 72 weeks while HCV genotypes 2 or 3 carriers were treated for 24 or 48 weeks. Use of didanosine was not allowed.

Results

Sustained virological response (SVR) was achieved by 193 (49.6%), and was significantly greater in HCV-2/3 than in HCV-1/4 patients (72.4% versus 35%; P<0.0001). Premature treatment discontinuations occurred in 174 patients (44.7%). This was due to early virological failure in 66 (17%), serious adverse events in 32 (8.2%), loss-to-follow-up in 12 (3.1%) and voluntary withdrawal in 64 (16.4%). Only 10 patients (2.6%) stopped HCV therapy due to severe anaemia. Two patients stopped HCV medication due to symptomatic mitochondrial toxicity. There were no episodes of hepatic decompensation.

Conclusions

Treatment with RBV 1,000–1,200 mg/day plus peg IFN-α2a is relatively safe and provided SVR in nearly half of the HIV/HCV-coinfected patients, twice as many amongst the HCV-2/3 than HCV-1/4 carriers. Avoidance of didanosine, limited use of zidovudine and therapy restricted to patients with CD4+ T-cell counts >300 cells/ml most probably explains the lower and different spectrum of serious adverse events in PRESCO compared with prior trials conducted in coinfected patients.
Altered Expression of Nucleoside Transporter Genes (SLC28 and SLC29) in Adipose Tissue from HIV-1–Infected Patients
Authors: Guallar Jordi P , Cano-Soldado Pedro , Aymerich Ivette , Domingo Joan C , Alegre Marta , Domingo Pere , Villarroya Francesc , Casado F Javier , Giralt Marta , Pastor-Anglada Marçal
Published: April 2022

Background

Nucleoside transporter proteins (NTs) encoded by members of the SLC28 and SLC29 gene families contribute to nucleoside and nucleobase recycling but also modulate extracellular adenosine levels and thus adenosine-regulated metabolic targets.

Methods

We have examined the expression pattern of NT-encoding genes in human adipose tissue and we have further analysed whether the mRNA related to these genes show changes in their amounts associated with either HIV-1 infection, highly active antiretroviral therapy (HAART) or development of HIV-1-associated lipodystrophy syndrome (HALS).

Results

Human adipocytes express SLC28A1, SLC28A2 and SLC28A3 (encoding hCNT1, hCNT2 and hCNT3, respectively) and SLC29A1 and SLC29A2 (encoding hENT1 and hENT2, respectively). HIV-1 infection, prior to HAART and HALS development, is associated with the upregulation of the mRNA levels of the genes encoding hCNT1, hCNT3 and hENT2. The increase in the mRNA amounts for the former two genes may be due to the action of tumour necrosis factor-α (TNF-α), a cytokine with enhanced expression in adipose tissue following HIV-1 infection, as the effect is also observed in human adipocytes in culture after treatment with TNF-α. HAART and HALS development are associated with the upregulation of the mRNA levels encoding hCNT2 and hENT1, and further enhancement of hCNT1, hCNT3 and hENT2 gene expression.

Conclusions

These data suggest that selected genes of the SLC28 and SLC29 families are not only targets of HIV-1 infection, but might also contribute to the development of adipose tissue alterations leading to lipodystrophy.
Relationships between Drug Exposure, Changes in Metabolic Parameters and Body Fat in HIV-Infected Patients Switched to a Nucleoside Sparing Regimen
Authors: Autar Reshma S , Boyd Mark A , Wit Ferdinand WMN , Ruxrungtham Kiat , Sankote Jongkol , Lange Joep MA , Cooper David A , Phanuphak Praphan , Burger David M , Reiss Peter
Published: April 2022

Background

The pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood.

Methods

Relationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively.

Results

Ritonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks).

Conclusions

Reduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each - to varying degrees - associated with various metabolic disturbances.
Response to HAART in French patients with resistant HIV-1 treated at primary infection: ANRS Resistance Network
Authors: Chaix Marie-Laure , Desquilbet Loic , Descamps Diane , Costagliola Dominique , Deveau Christiane , Galimand Julie , Goujard Cécile , Signori-Schmuck Anne , Schneider Veronique , Tamalet Catherine , Pellegrin Isabelle , Wirden Marc , Masquelier Bernard , Brun-Vezinet Francoise , Rouzioux Christine , Meyer Laurence ,   for the French PRIMO Cohort Study Group (ANRS CO 06) and the French ANRS AC11 Resistance Study Group
Published: April 2022

Objective

The aim of the study was to analyse the response to highly active antiretroviral therapy (HAART) initiated at the time of primary HIV infection (PHI) in patients infected with a virus resistant to ≥1 drug of their treatment compared with patients infected with a wild-type virus.

Methods

We analysed data from 350 patients who were enrolled from 1996–2004 in the French ANRS PRIMO Cohort or in the ANRS Resistance Group and treated with HAART during PHI. During the study period, HAART was initiated before the result of the genotypic resistance test was available. We compared patients infected with a virus resistant to ≥1 drug of their regimen (GR group, n=46) with patients harbouring a wild-type virus (WT group, n=304). Virological and immunological response to treatment according to drug-resistance profile was analysed 3 months and 6 months after HAART initiation.

Results

In GR and WT groups, HIV RNA level was <400 copies/ml in 68% and 83% ( P=0.02) and <50 copies/ml in 23% and 40% ( P=0.08) 3 months after HAART initiation. In multivariable logistic regression taking into account gender, age, boosted PI regimen, plasma HIV RNA and CD4+ T-cell count at HAART initiation, patients with virus resistant to ≥1 drug of their regimen were significantly less likely to achieve undetectable viral load at month 3 (odds ratio 0.32, 95% confidence interval 0.15–0.72) than the others. This difference was sustained up to month 6.

Conclusion

In this large cohort of HAART-treated PHI-patients, the presence of drug resistance mutations led to suboptimal response to early therapy.
Health-Related Quality of Life and Tolerability in Treatment-Experienced HIV-1–Infected Patients on Tipranavir versus Comparator Regimens
Authors: Huang I-Chan , Wu Albert W , Finnern Henrik W , Thijs Herbert , Gathe Joseph C , Fairclough Diane L
Published: April 2022

Background

Antiretroviral therapy including tipranavir boosted with ritonavir (TPV/r) has shown superior viral suppression and immunological response compared with comparator ritonavir-boosted protease inhibitor (CPI/r) regimens in treatment-experienced HIV-1-infected patients. This study assesses the influence of adverse events (AEs) on health-related quality of life (HRQOL) and change in HRQOL in patients treated with TPV/r versus CPI/r regimens.

Methods

Changes in HRQOL over 48 weeks were assessed using Medical Outcomes Study HIV Health Survey (MOS-HIV) data combined from two randomized, open-label, Phase III studies (RESIST-1 and RESIST-2). Generalized estimating equations (GEE) were used to compare physical health and mental health summary scores and 10 subscale scores, and to compare scores of patients with and without AEs. To compare AE incidences in the two treatment groups, AEs were exposure-adjusted.

Results

There were 984 patients in the HRQOL analysis. AE occurrence and severity resulted in significantly lower MOS-HIV scores across both treatment arms ( P<0.05). Overall incidence of AEs was higher in the CPI/r versus TPV/r group (562.8 versus 514.4 per 100 patient-exposure years); treatment-related AEs were more frequent in the TPV/r group (75.0 versus 56.6 per 100 patient-exposure years). HRQOL was maintained in patients on TPV/r over 48 weeks of treatment across all summary and subscale scores. Compared with CPI/r, TPV/r was associated with a significant but small (sd<0.2) improvement in pain scores (+4.8 points; P<0.05).

Conclusions

HRQOL was maintained across both summary and all subscale scores from baseline to 48 weeks in the TPV/r and CPI/r treatment arms, despite the incidence of treatment-related AEs.
Suboptimal Response to Adefovir Dipivoxil Therapy for Chronic Hepatitis B in Nucleoside-Naive Patients is not due to Pre-Existing Drug-Resistant Mutants
Authors: Carrouée-Durantel Sandra , Durantel David , Werle-Lapostolle Bettina , Pichoud Christian , Naesens Lieve , Neyts Johan , Trépo Christian , Zoulim Fabien
Published: April 2022

Background

Adefovir dipivoxil (ADV) has demonstrated activity against wild-type and lamivudine-resistant hepatitis B virus (HBV). After 1 year of therapy, a median 3.5–4.0 log10 decrease in viral load is observed. Our aim was to characterize the different profiles of response to ADV in relation to the in vitro susceptibility of viral strains to ADV.

Methods

In an international Phase III randomized, placebo-controlled study of ADV in patients positive for hepatitis B virus e antigen (HBeAg), different profiles of virological response to ADV 10 mg/day were identified at week 48. The top 25% patients (quartile 1, Q1) showed >4.91 log10 reduction in serum HBV DNA at week 48, in Q2 patients demonstrated a 3.52 to 4.90 log10 reduction of viral load, whereas in Q3 a 2.22 to 3.51 log10 reduction in viral load was observed. The bottom 25% of patients (Q4) showed <2.22 log10 reduction in HBV DNA levels. The influence of baseline characteristics and drug compliance on response was investigated. The replication capacity and drug susceptibility of HBV genomes of selected clinical isolates that were considered representative of the treatment response quartiles were analysed using a phenotypic assay.

Results

The lowest quartile of response (Q4) appears to have worse compliance. Higher alanine aminotransferase levels at baseline are associated with improved response. Phenotypic analysis of viral strains in vitro in Huh7 and HepG2 cells showed that HBV genomes remained susceptible to ADV, regardless of treatment response observed in patients.

Conclusion

Suboptimal response to ADV might result from a host pharmacological effect or from patient compliance issues rather than from a reduced susceptibility of HBV to ADV.
Hepatitis B virus Quantification and Detection of YMDD Mutants in a Single Reaction by Real-Time PCR and Annealing Curve Analysis
Authors: Shih Yi-Hsien , Yeh Shiou-Hwei , Chen Pei-Jer , Chou Wen-Pin , Wang Hurng-Yi , Liu Chun-Jen , Lu Su-Feng , Chen Ding-Shinn
Published: April 2022

Background

Long-term antiviral therapy, although effective for treatment of hepatitis B, might select the emergence of drug-resistant hepatitis B virus (HBV) mutants. Detection of HBV mutants and determination of viral titre are two crucial parameters for monitoring treatment response and occurrence of mutants. In this study, we take lamivudine resistance as an example to develop a method that can determine both parameters in a single-tube PCR reaction.

Methods

The method contained two consecutive steps: in the first step, real-time PCR was used for quantification; in the second step, a novel annealing curve analysis was used for detecting YMDD mutants. For accurate quantification, PCR primers and hybridization probes were chosen from highly conserved regions to ensure the equivalent amplification of all HBV genotypes. Within the sensor probe, there were signature nucleotide polymorphisms that could effectively differentiate YMDD mutants from wild type by distinct melting temperatures (Tm) values. The clinical applicability of the assay was tested in serial samples from 90 patients receiving lamivudine treatment.

Results

This assay could readily differentiate YMDD, YIDD and YVDD mutants by their distinct Tm values. The quantification results showed great consistency in a linear range from 103 to 1011 copies/ml. Moreover, this assay could detect YMDD mutants accounting for ≤10% of the total viral population. Its clinical feasibility has been verified in primary specimens.

Conclusions

The newly designed YMDD detection method is simple, sensitive, cost-effective, time-saving and provides a useful tool for follow-up of patients treated with lamivudine or other antiviral drugs.
Pharmacokinetics of Elvitegravir and Etravirine following Coadministration of Ritonavir-Boosted Elvitegravir and Etravirine
Authors: Ramanathan Srinivasan , Kakuda Thomas N , Mack Rebecca , West Steve , Kearney Brian P
Published: April 2022

Background

This crossover, open-label clinical study evaluated the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (elvitegravir/r), an HIV integrase inhibitor, and etravirine, a non-nucleoside reverse transcriptase inhibitor.

Methods

Healthy volunteers were randomized into one of two groups, each with two arms. Group 1 ( n=20) followed a sequence of 10-day dosing of elvitegravir/r (150/100 mg once daily) and elvitegravir/r plus etravirine (200 mg twice daily) or the reverse ( n=10 per sequence). Group 2 ( n=14) followed a sequence of 10-day dosing of etravirine and etravirine plus elvitegravir/r or the reverse ( n=7 per sequence), all under fed conditions. Elvitegravir, ritonavir and etravirine pharmacokinetics were determined on days 10 and 20 using non-compartmental analyses. Lack of pharmacokinetic alteration bounds for 90% confidence intervals (CI) about the geometric mean ratio (GMR; coadministration versus alone) were 70–143% for elvitegravir and ritonavir pharmacokinetics (maximum concentration [Cmax], concentration at the end of the dosing interval [Ctau] and area under the plasma concentration–time curve [AUCtau; 0–24 h] and 80–125% for etravirine pharmacokinetics (AUCtau 0–12 h).

Results

Of the 34 enrolled participants, 31 completed the study. There were three discontinuations, but none were caused by adverse events (AEs). The most common treatment-emergent AE was headache. Elvitegravir pharmacokinetic GMR was 6–7% higher following elvitegravir/r plus etravirine dosing versus elvitegravir/r. The GMR for etravirine and ritonavir AUCtau were 2.4% and 12.3% lower, respectively. Importantly, the 90% CI for elvitegravir and etravirine pharmacokinetics and AUCtau and Cmax for ritonavir were within the lack of alteration bounds.

Conclusions

Elvitegravir/r and etravirine do not undergo clinically relevant drug interactions and can be coadministered without dose adjustment.
Optimizing outcomes in patients with hepatitis C virus genotype 2 or 3
Authors: Berg Thomas , Carosi Giampiero
Published: April 2022

On-treatment predictors of response could be useful in optimizing treatment for patients with hepatitis C virus (HCV) genotype 2 or 3. Early virological response (EVR) has limited value as a predictor of response in genotype 2 or 3 patients, as it is achieved by 97% of this population. However, rapid virological response (RVR) measured at week 4 is a strong predictor of sustained virological response (SVR) in this group, and patients achieving an RVR may be suitable candidates for shorter treatment durations. Several small studies investigating the efficacy of shortened treatment durations in this population have been published; however, differences in study design have made their collective interpretation difficult. We discuss these studies, followed by a comparison of the data from ACCELERATE, the largest, randomized trial carried out to investigate abbreviated therapy in genotype 2 and 3 patients. The data confirm that RVR, and its use alongside significant baseline predictors, can assist in optimizing therapy. Patients achieving an RVR have high SVR rates and might be candidates for shorter treatment duration, particularly those displaying a low viral load at baseline; however, the need to consider the increased rate of relapse versus the benefits of abbreviated therapy must also be considered. Conversely, in patients who do not achieve an RVR there is evidence to suggest they may benefit from intensified therapy (longer therapy and/or increased doses). As in genotype 1 and 4 patients, response-guided therapy aims to optimize treatment outcomes for individuals, without compromising SVR rates.
Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment
Authors: Erhardt Andreas , Deterding Katja , Benhamou Yves , Reiser Markus , Forns Xavier , Pol Stanislas , Calleja José Luis , Ross Susanne , Spangenberg Hans Christian , Garcia-Samaniego Javier , Fuchs Michael , Enríquez Jaime , Wiegand Johannes , Stern Jerry , Wu Kate , Kukolj George , Marquis Martin , Beaulieu Pierre , Nehmiz Gerhard , Steffgen Jürgen
Published: April 2022

Background

BILB 1941 is a potent and specific non-nucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase in vitro.

Methods

In a double-blind sequential group comparison, 96 male HCV genotype 1 patients with minimal to mild liver fibrosis (Ishak or Metavir score 0–2) were randomized (8 to active treatment and 2 to placebo per dose group) and treated with 10–450 mg BILB 1941 every 8 h over 5 days. Viral load (VL) was measured using Roche Cobas TaqMan® assays.

Results

VL decreased by ≥1 log10 IU/ml in 2/8, 2/8, 1/8, 2/7, 0/8, 2/8 and 4/5 patients on 60, 80, 100, 150, 200, 300 and 450 mg, respectively. No response was seen with placebo. HCV subtype 1b showed better response than 1a, the effect of other covariables including prior interferon treatment was not significant. NS5B population sequencing and phenotyping identified baseline samples with reduced BILB 1941 susceptibility, but did not detect an on-treatment emergence of resistant mutants. Plasma drug levels were linear until 300 mg. No serious adverse events (AEs) were reported. AEs were mainly gastrointestinal-related (most frequent diarrhoea) and frequency increased with dose. On 450 mg, all five active-treated patients discontinued (four for gastrointestinal intolerance and one for increased aspartate aminotransferase and alanine aminotransferase levels) and the trial was discontinued.

Conclusions

BILB 1941 monotherapy demonstrated antiviral activity against HCV genotype 1, but gastrointestinal intolerance precluded testing of higher doses.
Modelling Hepatitis C virus Kinetics: The Relationship between the Infected Cell Loss rate and the Final Slope of Viral Decay
Authors: Dahari Harel , Shudo Emi , Cotler Scott J , Layden Thomas J , Perelson Alan S
Published: April 2022

Background

Patients infected with hepatitis C virus (HCV) who respond to treatment with interferon-α plus ribavirin exhibit biphasic or triphasic viral load decreases. While the rapid first phase is indicative of the effectiveness of therapy in blocking viral production (e), the slope of the final phase ( X), that is, the second phase in biphasic decreases and the third phase in triphasic decreases, depends on the infected cell loss rate (δ). In standard models, X is approximately εδ when the viral clearance rate c>>δ, as has been previously estimated.

Methods

The relationship among e, S, X and the baseline fraction of HCV-infected hepatocytes (π) was investigated in a model that included proliferation of hepatocytes.

Results

We found that X was not proportional to e, but rather obeyed a complex relationship that could lead to dramatic increases in estimates of 8 as e increased. In particular, when ε<99%, X moderately underestimated 8 in patients with a small π, whereas δ might be up to 10-fold larger than λ in patients with a large π. Interestingly, when ε>99%, δ∼λ regardless of π.

Conclusions

Our results indicated that in patients undergoing therapy who achieved a 2 log10 reduction in viral load (ε<99%), previously estimated δ values might represent only a minimal estimate of the infected cell loss rate. Moreover, combining interferon-α with new antiviral agents to achieve ε>99% should allow for a more accurate estimate of 8 in HCV RNA kinetic studies. This might be important when using viral kinetics to estimate the effect of the immune response on viral elimination and the attainment of sustained virological response.
Plasma efavirenz concentrations and the association with CYP2B6-516 G >T polymorphism in HIV-infected Thai children
Authors: Puthanakit Thanyawee , Tanpaiboon Pranoot , Aurpibul Linda , Cressey Tim R , Sirisanthana Virat
Published: April 2022

Background

Concerns have been raised about the possibility of subtherapeutic efavirenz (EFV) plasma levels in children with the current dosing guideline. Single nucleotide polymorphisms of the hepatic cytochrome P450 isoenzyme 2B6 (CYP2B6) gene have been associated with high inter-individual variations in EFV plasma concentrations. Our objective was to determine the adequacy of EFV dosing and explore the influence of CYP2B6-516G>T polymorphisms on EFV plasma concentrations in Thai HIV-infected children.

Methods

A total of 63 HIV-infected children receiving EFV for ≥4 weeks were assessed. Children received EFV daily doses on the basis of body weight bands. Between 12 to 16 h after EFV intake, a blood sample was drawn to measure the EFV plasma concentration and to determine the CYP2B6-516G>T polymorphism using HPLC and direct gene sequencing, respectively.

Results

The median age (range) was 12.3 years (3.1- 18.7). The mean (±SD) EFV plasma concentration was 3,138 ng/ml (3,313). Eight (13%), 45 (71%) and 10 (16%) children had an EFV concentration <1,000 ng/ ml, 1,000-4,000 ng/ml and >4,000 ng/ml, respectively. CYP2B6-516 G/G, G/T and T/T genotypes were found in 48%, 41% and 11% children, respectively. The CYP2B6-516G>T allele frequency was 31.75%. The mean (±SD) EFV concentration for children with G/G, G/T and T/T genotypes were 1,604 ng/ml (729), 2,635 ng/ml (1,199) and 11,582 ng/ml (2,972), respectively ( P<0.001). A correlation between EFV concentrations >4,000 ng/ml and psychiatric side effects was observed ( P=0.02), but there was no association with rash, hepatotoxicity or central nervous system disturbances.

Conclusions

Current EFV dosing guidelines provide adequate plasma drug concentrations in Thai HIV-infected children. CYP2B6-516G>T polymorphisms significantly affect the drug metabolism of EFV in children.
Avanti 1: Randomized, Double-Blind Trial to Evaluate the Efficacy and Safety of Zidovudine plus Lamivudine versus Zidovudine plus Lamivudine plus Loviride in HIV-Infected Antiretroviral-Naive Patients
Authors: Gatell J , Lange J , Gartland M ,   The AVANTI study group
Published: April 2022

The objective of this randomized double-blind, placebo-controlled trial was to investigate the effect of combination antiretroviral therapy on plasma HIV-1 RNA as measured by HIV RNA PCR and to assess the safety and tolerability of such regimens. The trial was carried out in seven European countries, Australia and Canada and involved antiretroviral-naive patients ( n=106) with CD4 counts between 150–300 cells/mm3 (CDC group A) and 150–500 cells/mm3 (CDC group B/C). Patients were randomly assigned to zidovudine (200 mg three times daily) plus lamivudine (300 mg twice daily) or to zidovudine plus lamivudine plus loviride (100 mg three times daily) for 52 weeks. The main outcome measures were degree and duration of reduction of plasma HIV-1 RNA as measured by RNA PCR and the development of drug-related toxicities sufficiently severe to warrant dose modification, interruption or permanent discontinuation. A mild, though statistically significant difference in favour of zidovudine plus lamivudine plus loviride for log10 plasma HIV-1 RNA ( P=0.022), as compared to zidovudine plus lamivudine, was observed using area-under-the-curve minus baseline (AUCMB). An increase in CD4 cell count in the zidovudine plus lamivudine plus loviride group was observed with a median improvement of 124 cells/mm3 at week 52 compared with 70 cells/mm3 in the zidovudine plus lamivudine group ( P=0.06). Both treatment regimens were well tolerated.
Qualitative Research Studies Online: Using Prompted Weekly Journal Entries During the COVID-19 Pandemic
Authors: Rudrum Sarah , Casey Rebecca , Frank Lesley , Brickner Rachel K. , MacKenzie Sami , Carlson Jesse , Rondinelli Elisabeth
Published: April 2022

Solicited journal entries are a qualitative research method with a fairly strong tradition in sociological research and particularly in qualitative health research. However, the practices and strengths associated with solicited journal entries have not been explored as frequently or comprehensively as more conventional qualitative research methods, such as interviews. During the COVID-19 pandemic we carried out two online studies employing solicited written journal entries and photos. One study focused on pregnancy and health care experiences during the pandemic and the other on everyday life while working from home due to public health restrictions. Here, we discuss solicited online journal entries as a qualitative method and reflect on the strengths and challenges we encountered, including those related to using the online survey tool LimeSurvey for a qualitative diary-based study. The richness of data and the ability to solicit participants’ contemporaneous reflections over the course of a set length of time, the ability to reach people across time zones and in multiple places, and the ability to adapt prompts in a quickly changing research context are major strengths of online journaling. The level of commitment required by participants, the potential for attrition, the need for literacy and technology access, and the large amount of data from each participant are potential limitations for researchers to consider.
Geriatric assessment for older adults receiving less-intensive therapy for acute myeloid leukemia: report of CALGB 361101
Authors: Ritchie Ellen K. , Klepin Heidi D. , Storrick Elizabeth , Major Brittny , Le-Rademacher Jennifer , Wadleigh Martha , Walker Alison , Larson Richard A. , Roboz Gail J.
Published: April 2022

Geriatric assessment (GA) predicts survival among older adults with acute myeloid leukemia (AML) treated intensively. We evaluated the predictive utility of GA among older adults treated with low-intensity therapy on a multisite trial. We conducted a companion study (CALGB 361101) to a randomized phase 2 trial (CALGB 11002) of adults ≥60 years and considered “unfit” for intensive therapy, testing the efficacy of adding bortezomib to decitabine therapy. On 361101, GA and quality of life (QOL) assessment was administered prior to treatment and every other subsequent cycle. Relationships between baseline GA and QOL measures with survival were evaluated using Kaplan-Meier estimation and Cox proportional hazards models. One-hundred sixty-five patients enrolled in CALGB 11002, and 96 (52%) of them also enrolled in 361101 (median age, 73.9 years). Among participants, 85.4% completed ≥1 baseline assessment. In multivariate analyses, greater comorbidity (hematopoietic cell transplantation-specific comorbidity index >3), worse cognition (Blessed Orientation-Memory-Concentration score >4), and lower European Organization for Research and Treatment of Cancer global QOL scores at baseline were significantly associated with shorter overall survival (P < .05 each) after adjustment for Karnofsky Performance Status, age, and treatment arm. Dependence in instrumental activities of daily living and cognitive impairment were associated with 6-month mortality (hazard ratio [HR], 3.5; confidence interval [CI], 1.2-10.4; and HR, 3.1; CI, 1.1-8.6, respectively). GA measures evaluating comorbidity, cognition, and self-reported function were associated with survival and represent candidate measures for screening older adults planned to receive lower-intensity AML therapies. This trial was registered at www.clinicaltrials.gov as #NCT01420926 (CALGB 11002).
Proteomics analysis: inhibiting the expression of P62 protein by chloroquine combined with dacarbazine can reduce the malignant progression of uveal melanoma
Authors: Fei Xifeng , Xie Xiangtong , Qin Ruwei , Wang Anqi , Meng Xuan , Sun Fei , Zhao Yifan , Jiang Dongyi , Chen Hanchun , Huang Qiang , Ji Xiaoyan , Wang Zhimin
Published: April 2022

Background

Although uveal melanoma (UM) at the early stage is controllable to some extent, it inevitably ultimately leads to death due to its metastasis. At present, the difficulty is that there is no way to effectively tackle the metastasis. It is hypothesized that these will be treated by target molecules, but the recognized target molecule has not yet been found. In this study, the target molecule was explored through proteomics.

Methods

Transgenic enhanced green fluorescent protein (EGFP) inbred nude mice, which spontaneously display a tumor microenvironment (TME), were used as model animal carriers. The UM cell line 92.1 was inoculated into the brain ventricle stimulating metastatic growth of UM, and a graft re-cultured Next, the UM cell line 92.1-A was obtained through monoclonal amplification, and a differential proteomics database, between 92.1 and ectopic 92.1-A, was established. Finally, bioinformatics methodologies were adopted to optimize key regulatory proteins, and in vivo and in vitro functional verification and targeted drug screening were performed.

Results

Cells and tissues displaying green fluorescence in animal models were determined as TME characteristics provided by hosts. The data of various biological phenotypes detected proved that 92.1-A were more malignant than 92.1. Besides this malignancy, the key protein p62 (SQSTM1), selected from 5267 quantifiable differential proteomics databases, was a multifunctional autophagy linker protein, and its expression could be suppressed by chloroquine and dacarbazine. Inhibition of p62 could reduce the malignancy degree of 92.1-A.

Conclusions

As the carriers of human UM orthotopic and ectopic xenotransplantation, transgenic EGFP inbred nude mice clearly display the characteristics of TME. In addition, the p62 protein optimized by the proteomics is the key protein that increases the malignancy of 92.1 cells, which therefore provides a basis for further exploration of target molecule therapy for refractory metastatic UM.
Dissociated optic nerve fiber layer-like appearance indicating an internal limiting membrane defect associated with an epiretinal membrane: two case reports
Authors: Ishida Yuichiro , Ota Naomichi , Tsuboi Kotaro , Kamei Motohiro
Published: April 2022

Background

We report for the first time a way to predict the 2-dimensional extension of an internal limiting membrane (ILM) defect by detecting the area with dissociated optic nerve fiber layer (DONFL)-like spots in the preoperative optical coherence tomography (OCT) en-face images.

Case presentations

Case 1 was a 67-year-old man with metamorphopsia and decreased vision in his right eye. His best-corrected visual acuity (BCVA) was 20/100, with a pterygium, a moderate nuclear cataract, and an epiretinal membrane (ERM). Case 2 was a 73-year-old man with metamorphopsia and decreased vision in his left eye. His BCVA was 20/25, with a moderate nuclear cataract and an ERM. Both patients underwent simultaneous cataract surgery and pars plana vitrectomy with ERM and ILM peeling. Brilliant Blue G staining, performed before ERM and ILM peeling, revealed an unstained area. A careful evaluation of the area showed that it was not covered by either the ERM or ILM. A postoperative evaluation of the preoperative OCT images obtained from these cases showed DONFL-like low-brightness spots in the ILM defect area on the OCT en-face images.

Conclusions

OCT en-face images may indicate the area of the ILM defect. To avoid iatrogenic damage to the retinal nerve fiber layer by touching/pinching it with forceps, detecting areas with DONFL-like spots in the preoperative OCT en-face images may be useful to predict an ILM defect.
Cumulative lifetime violence severity, social determinants and anxiety in a national sample of Canadian men
Authors: Scott-Storey Kelly , O’Donnell Sue , Busolo David , DiTommaso Enrico , Malcolm Jeannie , Taylor Petrea , Vincent Charlene D. , Wuest Judith
Published: April 2022

Background

Despite anxiety disorders being the ninth leading cause of disability and associated with social inequities, little attention has been given to how intersections among social determinants of health and chronic stressors such as cumulative lifetime violence affect the likelihood of experiencing anxiety disorders. Our purpose was to explore the relationships among cumulative lifetime violence severity as target and perpetrator, social determinants of health and generalized anxiety disorder in Canadian men.

Methods

Using a community sample of 592 Canadian men who self-identified as having experienced violence, we developed and tested an evidence-based model of generalized anxiety disorder including indicators of cumulative lifetime violence, gender, social location, socio-economic disparity, personal resources and other chronic stressors using logistic regression.

Results

Most men (76.4%, n = 452) reported experiences as both target and perpetrator. The model accounted for 50.8% of the variance in anxiety severity χ2 (8) = 264.43, p = .000). The prevalence of probable generalized anxiety disorder was 30.9%, a rate higher than that found among Canadian men in general in the same period. Remarkably, the likelihood of generalized anxiety disorder increased by a factor of 5.30 for each increase of 1 in cumulative lifetime violence severity, and six-fold for feeling overwhelmed by demands of everyday life (aOR = 6.26). Masculine discrepancy stress, having been born in Canada, unemployment, and food insecurity also contributed significantly to increasing the likelihood of generalized anxiety disorder. Both social support and mastery had significant aORs < 1, suggesting possible protective effects. Together these findings delineate characteristics and social determinants that may heighten vulnerability to generalized anxiety disorder and influence its progression among men who have experienced lifetime violence.

Conclusions

These findings are the first evidence that Canadian men with lifetime violence histories are a sub-group disproportionately affected by chronic stressors and socio-economic disparities and that together the presence and/or severity of these factors increases their vulnerability to generalized anxiety disorder. Our results highlight the importance of strengths-based trauma- and violence-informed approaches to care, including practical resources to reduce the stress of everyday life, improve social support, and reinforce personal control and choice.
Validity and reliability of the Neilands sexual stigma scale among Kenyan gay, bisexual, and other men who have sex with men
Authors: Korhonen Christine J. , Flaherty Brian P. , Wahome Elizabeth , Macharia Pascal , Musyoki Helgar , Battacharjee Parinita , Kimani Joshua , Doshi Monika , Mathenge John , Lorway Robert R. , Sanders Eduard J. , Graham Susan M.
Published: April 2022

Background

We evaluated the validity and reliability of the Neilands sexual stigma scale administered to 871 gay, bisexual, and other men who have sex with men (GBMSM) at two research locations in Kenya.

Methods

Using cross-validation, exploratory factor analysis (EFA) was performed on a randomly selected subset of participants and validated using confirmatory factor analysis (CFA) on the remaining participants. Associations of the initial and final stigma scale factors with depressive symptoms, alcohol use, and other substance use were examined for the entire dataset.

Results

EFA produced a two-factor scale of perceived and enacted stigma. The CFA model fit to the two-factor scale was improved after removing three cross-loaded items and adding correlated errors (chi-squared = 26.5, df 17, p = 0.07). Perceived stigma was associated with depressive symptoms (beta = 0.34, 95% CI 0.24, 0.45), alcohol use (beta = 0.14, 95% CI 0.03, 0.25) and other substance use (beta = 0.19, 95% CI 0.07, 0.31), while enacted stigma was associated with alcohol use (beta = 0.17, 95% CI 0.06, 0.27).

Conclusions

Our findings suggest enacted and perceived sexual stigma are distinct yet closely related constructs among GBMSM in Kenya and are associated with poor mental health and substance use.
Strengthening the service experiences of women impacted by gambling-related intimate partner violence
Authors: O’Mullan Cathy , Hing Nerilee , Nuske Elaine , Breen Helen , Mainey Lydia
Published: April 2022

Background

While problem gambling does not directly cause intimate partner violence (IPV), it exacerbates that violence significantly. Women experiencing both gambling harm and IPV often find themselves in challenging situations; furthermore, stigma and shame frequently act as barriers to seeking help from health and social service agencies. Despite the links between problem gambling and IPV, little is known about women’s experiences of using support services for both IPV and gambling related issues. This paper explores positive experiences of help-seeking for gambling-related IPV in Australia by adopting a strengths-based research approach.

Methods

Qualitative, unstructured interviews were conducted for a larger study exploring the nature of the relationship between problem gambling and IPV. To gain new insights into the service experiences of women impacted by gambling related IPV, interviews with 48 women with lived experience of IPV relating to a male partner’s gambling, and 24 women with lived experience of IPV relating to their own gambling were reanalysed using thematic analysis.

Results

Three themes emerged from the data signifying or demonstrating strength-based responses: ‘Commitment to Integrated and Collaborative Responses’; ‘Therapeutic Support’; and ‘Instrumental Support’. The themes highlight the importance of recognising the intersectionality of gambling related IPV and supporting the person ‘at the centre of the service’. Tangible and instrumental supports, such as emergency accommodation and financial assistance, were also central to the recovery process.

Conclusion

Effective service responses are dependent on understanding how problem gambling and IPV intersect. Importantly, service providers must recognise and address the many facets of each woman’s situation and the shame associated with resolving interdependent and complex issues. Responding to the needs of women impacted by gambling related IPV requires both individual-level awareness and organisational support; recommendations to strengthen service provision are provided.
An implementation framework and a feasibility evaluation of a clinical decision support system for diabetes management in secondary mental healthcare using CogStack
Authors: Patel Dipen , Msosa Yamiko J , Wang Tao , Mustafa Omar G , Gee Siobhan , Williams Julie , Roberts Angus , Dobson Richard JB , Gaughran Fiona
Published: April 2022

Background

Improvements to the primary prevention of physical health illnesses like diabetes in the general population have not been mirrored to the same extent in people with serious mental illness (SMI). This work evaluates the technical feasibility of implementing an electronic clinical decision support system (eCDSS) for supporting the management of dysglycaemia and diabetes in patients with serious mental illness in a secondary mental healthcare setting.

Methods

A stepwise approach was taken as an overarching and guiding framework for this work. Participatory methods were employed to design and deploy a monitoring and alerting eCDSS. The eCDSS was evaluated for its technical feasibility. The initial part of the feasibility evaluation was conducted in an outpatient community mental health team. Thereafter, the evaluation of the eCDSS progressed to a more in-depth in silico validation.

Results

A digital health intervention that enables monitoring and alerting of at-risk patients based on an approved diabetes management guideline was developed. The eCDSS generated alerts according to expected standards and in line with clinical guideline recommendations.

Conclusions

It is feasible to design and deploy a functional monitoring and alerting eCDSS in secondary mental healthcare. Further work is required in order to fully evaluate the integration of the eCDSS into routine clinical workflows. By describing and sharing the steps that were and will be taken from concept to clinical testing, useful insights could be provided to teams that are interested in building similar digital health interventions.