bluuebunny/crossref_metadata_2025 huggingface dataset:
High Doses of Stavudine Induce Fat Wasting and Mild Liver Damage without Impairing Mitochondrial Respiration in Mice
Authors: Igoudjil Anissa , Abbey-Toby Adjé , Begriche Karima , Grodet Alain , Chataigner Karine , Peytavin Gilles , Maachi Mustapha , Colin Marion , Robin Marie-Anne , Lettéron Philippe , Feldmann Gérard , Pessayre Dominique , Fromenty Bernard
Published: April 2022

Objective

Stavudine (d4T), a nucleoside reverse-transcriptase inhibitor (NRTI), can induce lipoatrophy, fatty liver, hyperlactataemia and abnormal liver tests. NRTI toxicity is usually ascribed to mitochondrial DNA (mtDNA) depletion and impaired mitochondrial respiration. However, NRTIs could have effects unrelated to mtDNA. Recently, we reported that 100 mg/kg/day of d4T stimulated fatty acid oxidation (FAO) in mouse liver, and reduced body fatness without depleting white adipose tissue (WAT) mtDNA. We hypothesized that higher d4T doses could further reduce adiposity, while inhibiting hepatic FAO.

Methods

Mice were treated for 2 weeks with d4T (500 mg/kg/day), L-carnitine (200 mg/kg/day) or both drugs concomitantly. Body fatness was assessed by dual energy X-ray absorptiometry, and investigations were performed in plasma, liver, muscle and WAT.

Results

D4T reduced the gain of body adiposity, WAT leptin, whole body FAO and plasma ketone bodies, and increased liver triglycerides and plasma aminotransferases with mild ultrastructural abnormalities in hepatocytes. Plasma lactate and respiratory chain activities in tissues were unchanged. Stearoyl-CoA desaturase (SCD-1), an enzyme negatively regulated by leptin, was overexpressed in liver. High doses of β-aminoisobutyric acid (BAIBA), a d4T catabolite, increased plasma ketone bodies. Although L-carnitine did not correct body adiposity, it prevented d4T-induced impairment of FAO and liver abnormalities.

Conclusions

D4T overdosage triggers fat wasting, leptin insufficiency and mild liver damage, without causing respiratory chain dysfunction. Overexpression of SCD-1 reduces fatty acid oxidation and overcomes the stimulating effect of BAIBA on hepatic FAO. L-carnitine does not correct leptin insufficiency but prevents d4T-induced impairment of FAO and liver damage.
Nevirapine-Based Antiretroviral Therapy Started Early in the Course of Tuberculosis Treatment in Adult Malawians
Authors: Van Oosterhout Joep JG , Kumwenda Johnstone J , Beadsworth Michael , Mateyu Gabriel , Longwe Temba , Burger David M , Zijlstra Eduard E
Published: April 2022

Background

The tuberculosis (TB) mortality rate of registered TB patients in Malawi is 23%, and 59% of the deaths occur in the first 2 months of treatment. HIV-related complications appear to be an important cause. Starting antiretroviral therapy early during tuberculosis treatment may improve outcome but problems often arise with drug interactions, adherence, toxicity and immune reconstitution disease (IRD).

Methods

We prospectively followed 27 HIV-infected adult Malawians after starting Triomune® (a generic fixed drug combination of stavudine, lamivudine and nevirapine) in the second week of tuberculosis treatment.

Results

At baseline, 88% had CD4+ T-cell counts <100 cells/ml, all were anaemic and 78% were malnourished. Five patients (19%) died, two withdrew consent and one stopped all drugs due to hepatitis. At 6 months, all but one of the 19 remaining patients had good virological results (16 patients: <400 copies/ml, two patients: <1,000 copies/ml) and the median CD4+ T cell increase was 170 cells/ml. Adverse events were numerous, particularly in the first 2 months. Suspected IRD episodes could be managed without treatment interruptions. During the lead-in phase, 59% of nevirapine plasma levels were sub-therapeutic despite good adherence, compared with only 14% during weeks 4 and 8.

Conclusion

It is feasible to start Triomune® early during TB treatment with good treatment outcome. The nevirapine lead-in phase should be avoided when rifampicin-based tuberculosis treatment is started >1 week beforehand.
Factors Associated with Early Hospital Discharge of Adult Influenza Patients
Authors: Lee Nelson , Chan Paul KS , Choi Kin Wing , Lui Grace , Wong Bonnie , Cockram Clive S , Hui David SC , Lai Raymond , Tang Julian W , Sung Joseph JY
Published: April 2022

Background

Understanding factors affecting length of hospital stay (LOS) in patients with severe influenza may improve their management.

Methods

A retrospective cohort study on laboratory-confirmed, adult influenza patients hospitalized in 2004 and 2005 was conducted. For all influenza cases during that period, immunofluorescence assay on nasopharyngeal aspirate was used for rapid diagnosis, and oseltamivir (75 mg twice daily for 5 days) prescribed if the patient presented within 2 days of symptom onset. Independent factors associated with time to discharge were identified using Cox proportional hazards models. An adjusted hazard ratio (aHR) >1 signifies a higher chance of early discharge. Viral shedding and influenza vaccination history were studied during one ‘flu’ season.

Results

A total of 356 patients (influenza A 93.5%) were studied. The majority of patients were old (70.2 ±8.4years), had ≥1 comorbid illness (69.1%) and developed respiratory or cardiovascular complications (69.4%). Oseltamivir initiated within 2 days of illness was associated with shorter total LOS (Kaplan-Meier estimated median 4 versus 6 days [-33%]; aHR for discharge 1.54, 95% confidence intervals [95% CI] 1.23–1.92, P<0.0001). Older age (≥70 years), comorbidities and complications were associated with prolonged LOS. Prolonged viral RNA detection >day 4 of illness (23 out of 99 consecutive patients) was also independently associated with longer LOS (aHR 0.36 [95% CI 0.19–0.71], P=0.003), whereas influenza vaccination within 6 months was associated with shorter LOS (aHR 2.14 [95% CI 1.18–3.85], P=0.012).

Conclusion

Our analyses suggest that timely oseltamivir treatment is independently associated with shorter LOS in patients hospitalized for severe influenza. Efforts to ensure early diagnosis and therapeutic intervention are warranted.
Three-Year Immune Reconstitution in PI-Sparing and PI-Containing Antiretroviral Regimens in Advanced HIV-1 Disease
Authors: Samri Assia , Goodall Ruth , Burton Catherine , Imami Nesrina , Pantaleo Giuseppe , Kelleher Anthony , Poli Guido , Gotch Frances , Autran Brigitte
Published: April 2022

Background

The long-term immunological benefit of protease inhibitor (PI)-sparing antiretroviral therapy (ART) using non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains poorly investigated.

Methods

A total of 120 ART-naive, HIV-1-infected participants were included in the immunology substudy of INITIO, an international randomized trial comparing two NRTIs (didanosine + stavudine) combined with either: one NNRTI (efavirenz; EFV), one non-boosted PI (nelfinavir; NFV), or one NNRTI + one PI (EFV/NFV). CD4+ T-cell counts, HIV-1 plasma RNA load (VL), T-cell pheno-type, T-cell proliferation and IFN-γ production against opportunistic/recall and HIV-1 antigens/peptides were compared at baseline and at week (W) 96 and W156.

Results

Participants (37 EFV, 44 NFV, 39 EFV/NFV) had similar baseline VL; median CD4+ T-cell counts/mm3 were: 144 (64–303) EFV, 212 (42–313) NFV and 257 (86–331) EFV/NFV. At W156, the proportion of patients with VL ≤50 copies/ml was not different between the arms ( P=0.3). From baseline to W156 there was a significant increase in CD4+ T-cell counts ( P<0.001) and in naive CD4+ T cells ( P<0.001), with no difference between arms and percentages of total and activated CD8+ T cells decreased significantly ( P<0.001) in all arms. The decrease in activated memory CD4+T-cells was significantly greater in the EFV arm at W96 ( P=0.03) and W156 ( P=0.01), but did not persist after adjusting for baseline CD4+ T-cell counts. During follow-up, responses to opportunistic pathogens increased in all patients while specific T-cell responses to HIV-1-p24 and gp160 recombinant proteins or to Gag and Nef peptides were not restored.

Conclusion

Regimens using/sparing PIs provide similar levels of long-term immune reconstitution even in patients with low CD4+ T-cell counts.
The Independent Effect of Highly Active Antiretroviral Therapy on Severe Opportunistic Disease Incidence and Mortality in HIV-Infected Adults in Côte D'Ivoire
Authors: Losina Elena , Yazdanpanah Yazdan , Deuffic-Burban Sylvie , Wang Bingxia , Wolf Lindsey L , Messou Eugène , Gabillard Delphine , Seyler Catherine , Freedberg Kenneth A , Anglaret Xavier
Published: April 2022

Background

Studies in developed countries have shown highly active antiretroviral therapy (HAART) decreases incidence of severe opportunistic diseases (ODs) in HIV-infected patients beyond that which is expected from changes in CD4+T-cell count.

Objective

To estimate the independent impact of HAART on reducing ODs and mortality in Côte d'Ivoire.

Methods

Within two longitudinal studies of HIV-infected adults (1996–2003), we identified time on ‘cotrimoxazole alone’ and ‘HAART plus cotrimoxazole’. WHO stage 3–4 defining events and severe malaria were divided into those preventable and not preventable with cotrimoxazole. Incidence of ODs by CD4 count stratum was estimated using incidence density analysis. CD4+ T-cell count at time of OD was estimated using linear interpolation. Using Poisson regression, we estimated the effect of HAART on OD incidence and mortality by CD4 count stratum.

Results

Totals of 446 and 135 adults were followed during 6,216 and 3,412 person-months in the cotrimoxazole alone and HAART plus cotrimoxazole periods, respectively. There was a CD4+ T-cell-independent risk reduction for ODs and mortality during the HAART plus cotrimoxazole period compared with cotrimoxazole alone, which varied by time on HAART, CD4 count stratum and OD type. It was mainly seen after 6 months on HAART and for ODs not preventable by cotrimoxazole. The HAART effect differed significantly by CD4 count stratum ( P=0.02), but was significant in all strata after 6 months on HAART.

Conclusions

In these sub-Saharan African adults, HAART initiation reduced ODs and mortality beyond that which was expected through the HAART-induced CD4+ T-cell increase. Further studies should examine practical implications of this independent ‘HAART effect’ on clinical outcomes in patients on HAART.
Safety, Pharmacokinetics and Immune Effects in Normal Volunteers of CPG 10101 (ACTILON™), an Investigational Synthetic Toll-like Receptor 9 Agonist
Authors: Vicari Alain P , Schmalbach Tess , Lekstrom-Himes Julie , Morris Mary Louise , Al-Adhami Mohammed J , Laframboise Chantal , Leese Philip , Krieg Arthur M , Efler Susan M , Davis Heather L
Published: April 2022

CPG 10101 (ACTILON™) is a novel potent and selective unmethylated cytidine-phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV.

Objectives and Methods

In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks.

Results

A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2’,5’-oligoadenylate synthetase were sustained for several days.

Conclusion

This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV.
Dynamics of Apoptotic Activity during Antiviral Treatment of Patients with Chronic Hepatitis C
Authors: Kronenberger Bernd , Zeuzem Stefan , Sarrazin Christoph , Mihm Ulrike , Von Wagner Michael , Hofmann W Peter , Piiper Albrecht , Herrmann Eva
Published: April 2022

Introduction

Cell death during antiviral therapy of patients with chronic hepatitis C is not well understood.

Methods

In the present study, apoptotic activity was monitored by quantification of apoptotic cytokeratin-18 neoepitopes in serum from patients with chronic hepatitis C before and 4, 12, 24 and 48 weeks after initiation of antiviral therapy with pegylated interferon-α2a and ribavirin and was compared with viral kinetic parameters.

Results

After 4 weeks of treatment apoptotic activity decreased significantly compared with baseline. Later during treatment, however, apoptotic activity increased again to levels similar to baseline. Alanine aminotransferase (ALT) activity also showed a significant decrease at week 4 compared with baseline but, in contrast to apoptotic activity, ALT remained at a reduced level during the treatment period. Baseline apoptotic activity was inversely correlated with the infected cell loss while an increase of apoptotic activity within the first 4 treatment weeks compared with baseline was positively correlated with the infected cell loss.

Conclusions

Apoptosis appears to be an important form of cell death during interferon-α-based treatment and is associated with infected cell loss and underestimated by ALT activity.
Effect of Ribavirin on the Hepatitis C Virus (JFH-1) and its Correlation with Interferon Sensitivity
Authors: Brochot Etienne , Duverlie Gilles , Castelain Sandrine , Morel Virginie , Wychowski Czeslaw , Dubuisson Jean , François Catherine
Published: April 2022

Background

The consensus therapy for chronic hepatitis C infection is based on a synergistic combination of pegylated interferon and ribavirin. The therapy leads to a sustained virological response in around 60% of infected patients. The mechanism by which this synergy occurs has not yet been elucidated. Several mechanisms of action have been proposed; one suggests that ribavirin, which is a nucleoside analogue, is incorporated into the RNA strand and generates an increase in the error rate. Such an accumulation of mutations would threaten the integrity of the virus's genetic information.

Methods

The effects of ribavirin on the new infectious hepatitis C virus cell culture (HCVcc) system were investigated using Huh-7 cells. Cells were cultured for 1 month in either 0 μM, 20 μM or 50 μM ribavirin. The HCV interferon sensitivity and the NS5A quasispecies were analysed.

Results

An increase in the mutation rate in the HCV NS5A gene was observed when the infected cells were treated with 50 μM ribavirin for 1 month. Amino acid sequence analysis revealed that ribavirin exerts an increase in G to A transition events as predicted by its mutagenic effect and a selective pressure on the HCV NS5A sequence. Furthermore, ribavirin treatment modified the efficacy of interferon (IFN) treatment. The IFN half-inhibition concentration (IC50) was significantly lower for viruses obtained after 1 month's exposure to 50 μM ribavirin than for viruses cultured in the absence of ribavirin.

Conclusions

ribavirin's mutagenic effect could explain in part its synergistic action with interferon.
Transient Viral Load Increases in HIV-Infected Children in the UK and Ireland: What do They Mean?
Authors: Lee Katherine J , Shingadia Delane , Pillay Deenan , Walker A Sarah , Riordan Andrew , Menson Esse , Duong Trinh , Tudor-Williams Gareth , Gibb Diana M
Published: April 2022

Objectives

To investigate transient increases in viral load during sustained suppression in children in the UK and Ireland Collaborative HIV Paediatric Study (CHIPS).

Design

Cohort of HIV-infected children from 39 centres.

Methods

Transient viraemia was defined as ≥1 detectable viral loads (≥50 copies/ml) between two undetectable values (<50 copies/ml) <280 days apart, during a period of sustained viral suppression (from a confirmed level of <50 copies/ml until the last undetectectable measurement before antiretroviral therapy change or until a confirmed level of >50 copies/ml).

Results

Of 595 children initiating HAART without previous treatment, 347 (58%) achieved sustained suppression. Of these, 78 (23%) experienced 109 episodes of transient viraemia (median 134 copies/ml); 92 (84%) had levels of <1,000 copies/ml (maximum 39,839). Transient viraemia was more common during second-line therapy (25/100 child-years [CY]) and following a previous episode (19/100 CY) compared with first-line therapy without a previous episode (11/100 CY). Rates decreased with age at HAART initiation (incidence rate ratio [IRR] 0.95 per year older; P=0.05), but were higher in those suppressed for longer (IRR 1.63 in those suppressed for ≥1 year versus <1 year; P=0.03). CD4+ and CD8+ T-cell counts were similar before and after transient viraemia. Of detectable viral loads during periods of suppression 44% were transient increases rather than virological failure: experiencing transient viraemia did not increase subsequent virological failure ( P=0.20).

Conclusions

Transient viraemia is relatively common among children on HAART, occurring more frequently in those starting HAART at younger ages, on second-line therapy and after longer suppression. It does not appear to affect CD4+ or CD8+ T-cell counts or the risk of subsequent virological failure. Natural variation, assay effects and adherence might all have a role.
HIV Genotypic Resistance Testing to Optimize Antiretroviral Prescribing: Is There Room for Improvement?
Authors: Uy Jonathan , Brooks John T , Baker Rose , Hoffman Mark , Moorman Anne , Novak Richard ,   the HOPS investigators
Published: April 2022

Background

Clinical utilization of genotype resistance testing is evolving. We examined the extent to which HIV care providers requesting genotype resistance tests used the information appropriately and the impact of inappropriate utilization.

Methods

Data from a prospective cohort of HIV-infected patients (the HIV Outpatient Study) were used in the analysis. We analysed the frequency with which patients were prescribed any non-nucleoside reverse transcriptase inhibitor after identification of the K103N mutation in reverse transcriptase and the frequency of prescription of nelfinavir after identification of the D30N mutation in HIV protease; the short-term impact of this action on HIV viral load and CD4+ T-cell count was assessed.

Results

Among 441 patients demonstrating either mutation, 18% who were taking the resistant antiretroviral at the time of the test were continued on the medication for >6 months after this finding. In 33% of these instances, prescribers reported these actions were erroneous oversights. For persons taking the resistant antiretroviral at the time of the genotype test, stopping this medication within 6 months of the test produced greater decreases in viral load (-1.35 versus -0.43 log copies/ml, P=0.025) and a greater likelihood of achieving an undetectable viral load (25.3% versus 7.3%, P=0.012) at 9 months. Changes in CD4+ T-cell count differed (+22.8 versus -23.0 cells/mm3), but not significantly ( P=0.167).

Conclusions

Following evidence of definitive resistance by genotype testing, a substantial fraction of antiretroviral prescriptions were continued in error leading to an attenuated therapeutic response. These data highlight the need to consider better systems to manage genotype resistance testing data in the clinical setting.
Natural History of Compensated and Decompensated HCV-Related Cirrhosis in HIV-Infected Patients: A Prospective Multicentre Study
Authors: Girón-González José A , Brun Francisco , Terrón Alberto , Vergara Antonio , Arizcorreta Ana
Published: April 2022

Objective

To define the course of HIV-HCV-coinfected patients with compensated and decompensated liver cirrhosis and to investigate the survival and the risk factors for death.

Patients and methods

Ninety-two HIV-infected patients with HCV-related cirrhosis (50 of them without and 42 with previous decompensations) were prospectively followed up during a median period of 20 months. Clinical, biochemical, virological and immunological factors were analysed. Multivariate analyses were performed of those factors associated with decompensations and mortality.

Results

There were 168 readmissions due to liver-disease-related causes. A Child-Pugh index ≥6 in those without previous decompensations (hazard ratio [HR] 7.94, 95% confidence interval [CI] 1.59–39.58; P=0.014), and Child-Pugh index ≥9 (HR 2.68, 95% CI 1.13–6.33; P=0.003) and absence of HAART (HR 0.44, 95% CI 0.19–0.98; P=0.048) in those with previous decompensations were independently associated with decompensation during the follow up. There were 27 deaths, 22 of them attributable to liver disease. Independent factors associated with liver-related mortality were a Child-Pugh index ≥9 (HR 6.24, 95% CI 2.31–16.85; P<0.001), progression of Child-Pugh index during the follow up (HR 4.27, 95% CI 1.54–11.80; P=0.008), more than one decompensation (HR 24.25, 95% CI 7.27–40.45; P<0.001) and absence of HAART (HR 0.35, 95% CI 0.12–0.98; P=0.002).

Conclusions

Evolution from compensated to decompensated cirrhosis and death is influenced by markers of liver function and the absence of HAART. The importance of this last element must be adequately stressed.
Different Mutations in the HHV-6 DNA Polymerase Gene Accounting for Resistance to Foscarnet
Authors: Bonnafous Pascale , Naesens Lieve , Petrella Stéphanie , Gautheret-Dejean Agnès , Boutolleau David , Sougakoff Wladimir , Agut Henri
Published: April 2022

Background

Human herpesvirus 6 (HHV-6), which is closely related to human cytomegalovirus, is sensitive to foscarnet (PFA). Up to now, the resistance of HHV-6 to PFA has not been investigated.

Objectives

The goal of the study was to isolate and characterize PFA-resistant HHV-6 mutants in order to determine the mechanisms of resistance to the drug.

Methods

PFA-resistant viruses, isolated in MT4 cell culture under increasing concentrations of PFA, were characterized phenotypically and genotypically. The mutations identified in the HHV-6 DNA polymerase gene were evaluated in a functional assay using recombinant mutated forms of the enzyme, and their effect on protein structure was analysed in a three-dimensional model derived from available structures of DNA polymerases.

Results

Two mutants were selected and were 8- and 15-fold more resistant to PFA than the wild-type strain. Four amino acid changes were detected in the HHV-6 DNA polymerase in association with PFA resistance: T435R, H507Y, C525S, located in the δC conserved domain, and F292S. Either alone or in combination, these substitutions significantly decreased the inhibitory effect of PFA at the level of the polymerase, as measured by the incorporation of radiolabeled nucleotides in a DNA elongation assay. In the three-dimensional model of HHV-6 DNA polymerase structure the four changes were not located within the putative catalytic site, but they might induce either a disturbance of local conformation or a restricted access of PFA to its target site.

Conclusion

This first characterization of HHV-6 resistance to PFA highlights the role of distinct DNA polymerase gene mutations.
Predictors of Clinical Progression among HIV-1–Positive Patients starting HAART with CD4+ T-cell Counts ≥200 cells/mm3
Authors: Lapadula Giuseppe , Torti Carlo , Maggiolo Franco , Casari Salvatore , Suter Fredy , Minoli Lorenzo , Pezzoli Chiara , Pietro Massimo Di , Migliorino Guglielmo , Quiros-Roldan Eugenia , Ladisa Nicoletta , Sighinolfi Laura , Costarelli Silvia , Carosi Giampiero ,   for the Italian MASTER Cohort, Carosi G , Puoti M , Torti C , Roldan E Quiros , Paraninfo G , Casari S , Antinori A , Antonucci G , Ammassari A , Angarano A , Saracino A , Cauda R , De Luca A , Monforte A D'Arminio , Cicconi P , Mazzotta F , Caputo S Lo , Marino N , Minoli L , Maserati R , Novati S , Tinelli C , Ghinelli F , Sighinolfi L , Pastore G , Ladisa N , Quirino T , Migliorino M , Suter F , Maggiolo F , Suligoi Barbara , Zeni Cristina , Brognoli Francesca , Bando Ruth
Published: April 2022

Background

Baseline and follow-up predictors of new AIDS-defining events (ADE) or death among patients who started HAART with CD4+ T-cell counts ≥200 cells/mm3 have rarely been assessed simultaneously.

Methods

A prospective observational cohort study (1996–2002) is reported. HIV-infected patients initiating HAART with a CD4+ T-cell count ≥200 cells/mm3 were studied. Baseline and time-varying factors were tested for the prediction of new ADE/death using Cox regression models.

Results

A total of 896 subjects were studied over a median of 5.1 years. The incidence of a new ADE was 1.6 (95% confidence interval 1.3–2.1) per 100 person-years. Among baseline factors, higher CD4+ T-cell counts before HAART were associated with lower risk of ADE/death, but not after adjustment for time-varying factors. On a multivariable analysis including both baseline and time-varying covariates, longer delay from HIV diagnosis to HAART was an independent predictor of ADE/death (per year, hazard ratio [HR] 1.06; P=0.025) and was independent of CD4+ T-cell count before treatment. Longer time spent with HIV RNA <400 copies/ml (per month, HR 0.96; P=0.003) and higher latest CD4+ T-cell count (per log2 cells/mm3, HR 0.65; P<0.001) were found to be protective.

Conclusions

Patients with higher CD4+ T-cell counts before HAART initiation had a better prognosis. However, except for the delay in starting HAART, viro-immunological evolution outweighed the effect of baseline factors. Moreover, suppressing HIV replication for as long as possible could improve the clinical outcome. Prospective randomized clinical trials to assess the optimal timing of HAART initiation are both feasible and urgently needed.
Sexual Dysfunction in HIV-Infected Men: Role of Antiretroviral Therapy, Hypogonadism and Lipodystrophy
Authors: Guaraldi Giovanni , Luzi Kety , Murri Rita , Granata Antonio , Paola Maria De , Orlando Gabriella , Squillace Nicola , Malmusi Davide , Carani Cesare , Comelli Dante , Esposito Roberto , Martinez Esteban
Published: April 2022

Background

Both psychological and organic factors have been recognized to be associated with sexual dysfunction in HIV-infected individuals.

Methods

In this cross-sectional study we evaluated the prevalence and factors associated with sexual dysfunction in a cohort of HIV-infected adult men. Evaluation tools included: the International Index of Erectile Function (erectile dysfunction [ED], desire, orgasm, intercourse satisfaction, overall satisfaction), the Assessment of Body Change and Distress (body image satisfaction), the Medical Outcomes Study HIV Health Survey (mental and physical health-related quality of life), and plasma free and total testosterone level (hypogonadism).

Results

Three-hundred and fifty-seven men were enrolled. Among 336 patients reporting sexual activities in the 4 weeks before, 94 (29.6%) had mild, 30 (9.4%) moderate and 34 (10.1%) severe dysfunction. The Mental Health Summary score was 2.28 units (95% confidence interval [CI] 1.51, 3.06) lower for each unit higher of body image dissatisfaction and 0.31 units (95% CI 0.27, 0.36) higher for each unit higher of the score for body change interference with habits. At regression analysis, ED was independently related to the body mass index (B=0.31, 95% CI 0.08, 0.62). Desire, orgasm and overall satisfaction domains were associated with mental health score (B=0.87, 95% CI 0.47, 1.27; B=0.75, 95% CI 0.23, 1.26; B=0.86, 95% CI 0.45, 1.28, respectively). An improved intercourse satisfaction domain was associated with a lower interference of body changes with habits and social life (B=0.39, 95% CI 0.05, 0.73). Testosterone, metabolic alterations and HAART were not associated with sexual function domains.

Conclusions

Body image and mental health but not HAART or hypogonadism were associated with sexual function domains.
Toxicogenetics of Antiretroviral Therapy: Genetic Factors that Contribute to Metabolic Complications
Authors: Tarr Philip E , Telenti Amalio
Published: April 2022

Metabolic complications of antiretroviral therapy (ART) have emerged as a major concern for long-term, successful management of HIV infection. Variability in the response to ART between individuals has been increasingly linked to the genetic background of patients, as regards efficacy and susceptibility to adverse reactions (toxicogenetics). This review summarizes the biological and methodological background for the genetic prediction of metabolic toxicity of ART. Recent studies are discussed which suggest that single-nucleotide polymorphisms (SNPs) in several genes involved in lipid metabolism and lipid transport in the general population (ABCA1, APOA5, APOC3, APOE, CETP) might modulate plasma triglyceride and high-density lipoprotein cholesterol levels in HIV-infected patients. At present, genetic prediction of lipodystrophy is not possible. Lipodystrophy has been linked to an accumulation of mtDNA mutations, a finding causally associated with ageing phenotypes in animal models. No mutations in LMNA, a gene linked to rare, inherited forms of lipodystrophy, have been identified in small studies of patients with lipodystrophy, and a possible link to a TNF promoter SNP remains to be confirmed. With the rapidly decreasing cost of genetic testing, the main issues that need to be addressed prior to introduction of toxicogenetic prediction in HIV clinical practice include reproducibly high predictive values of SNP associations with clinically relevant and well defined metabolic outcomes, studies that evaluate the contribution of SNPs in the context of multi-SNP and haplotype analysis, and the validation of genetic markers in independent, large patient cohorts. Comprehensive, whole genome approaches are increasingly being used.
Future Treatment of Chronic Hepatitis C
Authors: Keeffe Emmet B
Published: April 2022

The current standard therapy for chronic hepatitis C is peginterferon plus ribavirin and yields a sustained virological response rate of approximately 50% overall. Over the past 2–3 years, many new therapeutic agents directed at a number of different viral targets have entered into development for the treatment of patients with chronic hepatitis C. Many of these agents exhibit high levels of potency against the hepatitis C virus and have a rapid onset of activity. Some agents have been abandoned because of lack of efficacy or toxicity, but many others have shown promise and are undergoing further testing. Although debated, new therapies in the immediate future will most likely be used in combination with peginterferon, either alone or with ribavirin. This concise review is focused on new drugs undergoing development for the treatment of patients with chronic hepatitis C, and on drugs that have shown efficacy in preliminary investigations and progressed to Phase II or III trials. This information should allow physicians involved in the care of patients with chronic hepatitis C to provide realistic expectations of what types of drugs are progressing in clinical development, the likelihood that new treatment will include peginterferon with or without ribavirin, and when these novel therapies might become available.
Predictors of Severe Haematological Toxicity Secondary to Pegylated Interferon plus Ribavirin Treatment in HIV-HCV-Coinfected Patients
Authors: Mira José A , López-Cortés Luis F , Merino Dolores , Arizcorreta-Yarza Ana , Rivero Antonio , Collado Antonio , Ríos-Villegas María J , González-Serrano Mercedes , Torres-Tortosa Manuel , Macías Juan , Valera-Bestard Bárbara , Fernández-Fuertes Elisa , Girón-González José A , Lozano Fernando , Pineda Juan A ,   for the Grupo para el Estudio de las Hepatitis Víricas de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI)
Published: April 2022

Background

Haematological adverse events related to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy could affect the patients’ quality of life; however, the risk factors for severe haematological toxicity associated with this therapy in patients coinfected with hepatitis C virus (HCV) and HIV are unclear. The objective of this study was to identify predictors of severe haematological toxicity among HIV-HCV-coinfected patients treated with PEG-IFN plus RBV.

Methods

This retrospective multicentric study included 237 HIV-HCV-coinfected patients on PEG-IFN plus RBV. Predictors of severe anaemia, neutropenia, thrombocytopenia and overall haematological toxicity were analyzed.

Results

Eighty (34%) individuals showed an episode of severe haematological toxicity. Severe anaemia, neutropenia and thrombocytopenia occurred in 32 (13%), 42 (18%) and 26 (11%) patients, respectively. In the multivariate analysis, zidovudine use (adjusted odds ratio [AOR] 3.3; 95% confidence interval [CI] 1.6–10; P=0.001), baseline body weight <65 kg (AOR 2.5; 95% CI 1.1–5; P=0.024), cirrhosis (AOR 5; 95% CI 1.6–16.6; P=0.006), PEG-IFN-α2a (AOR 2.7; 95% CI 1.1–6.6; P=0.029) and pretreatment haemoglobin level <14 g/dl (AOR 2.7; 95% CI 1.3–5.5; P=0.005) were associated with any kind of severe haematological toxicity. Likewise, haemoglobin level <13 g/dl, neutrophil counts <2,500 cells/mm3 and platelet counts <175,000 cells/mm3 were independent predictors of severe anaemia, neutropenia and thrombocytopenia, respectively.

Conclusions

Zidovudine treatment, cirrhosis, baseline low body weight, use of PEG-IFN-α2a, and baseline haemoglobin level <14 g/dl are predictors of overall severe haematological toxicity secondary to PEG-IFN plus RBV in HIV-infected individuals. Low pretreatment levels of each haematological series predict a significant decrease of their values during therapy.
Early Monitoring of Ribavirin Serum Concentration is not Useful to Optimize Hepatitis C Virus treatment in HIV-Coinfected Patients
Authors: Crespo Manuel , Pou Leonor , Esteban Juan I , Falcó Vicenç , Ribera Esteban , Lopez Rosa , Sauleda Silvia , Curran Adriá , Del Saz Sara Villar , Feijoo María , Ocaña Inma , Pahissa Albert
Published: April 2022

Background

Emerging data suggest that higher ribavirin (RBV) exposure could improve early hepatitis C virus (HCV) response. Furthermore, interindividual RBV bioavailability shows high variation, and dose-limiting haemolytic anaemia is a common adverse event. Therefore, it has been suggested that monitoring RBV serum levels could be used to drive dose modification and to optimize management of HCV-infected patients receiving combination treatment.

Methods

To assess the effect of RBV serum levels on HCV RNA clearance at week 4 and 12 of treatment, and to determine the correlation between RBV serum concentration and haemoglobin decrease, RBV trough levels were measured by HPLC in stored serum samples obtained from 94 HCV-HIV-coinfected patients at week 4 and 12 of treatment with peginterferon-α2b (1.5 μg/kg/weekly) plus ribavirin (800–1,200 mg/day).

Results

The median RBV levels increased from 1.70 μg/ml at week 4 to 1.97 μg/ml at week 12 of treatment ( P=0.001) and were independently predicted by weight-adjusted dose of RBV and co-administration of tenofovir. Haemoglobin drop was higher among patients who received zidovudine and weakly correlated with RBV level. Although RBV concentration was lower in genotype 1 or 4 HCV-infected patients who cleared the virus at treatment week 4, the ability of this parameter to discriminate between responders and non-responders at treatment week 4 and 12 was poor.

Conclusion

Intracellular RBV accumulation early in treatment might improve the kinetics of HCV response in difficult to treat patients. Although this hypothesis and the potential interaction between RBV and tenofovir warrant further research, our data do not support RBV serum monitoring as a tool to optimize treatment in HCV-HIV-coinfected patients.
Long-Term Lamivudine Therapy Reduces the Risk of Long-Term Complications of Chronic Hepatitis B Infection even in Patients without Advanced Disease
Authors: Yuen Man-Fung , Seto Wai-Kay , Chow Danny Hoi-Fan , Tsui Kit , Wong Danny Ka-Ho , Ngai Vincent Wing-Shun , Wong Benjamin Chun-Yu , Fung James , Yuen John Chi-Hang , Lai Ching-Lung
Published: April 2022

Background

Long-term effects of lamivudine treatment on chronic hepatitis B patients without advanced disease remain unknown. Our aim was to investigate the effects of long-term lamivudine treatment and lamivudine-resistant virus (YMDD) on the development of cirrhosis and hepatocellular carcinoma (HCC) in asymptomatic patients without advanced disease.

Methods

One hundred and forty-two hepatitis B e antigen (HBeAg)-positive patients (median age: 33.9 years) on long-term lamivudine (median treatment duration: 89.9 months) and 124 HBeAg-positive controls (median age: 33.4 years) were prospectively followed up. Patients were monitored for the development of cirrhosis and HCC, liver biochemistry, hepatitis B virus (HBV) DNA levels, HBeAg seroconversion and hepatitis flares. YMDD mutations (YMDD-MT) were determined annually.

Results

Lamivudine-treated patients had a significantly lower cumulative rate of development of cirrhosis and/or HCC compared with controls ( P=0.005). YMDD-MT occurred in 76.3% of patients after 8 years of lamivudine treatment. When compared with controls and patients with YMDD-MT, patients without YMDD-MT had the greatest reduction of HBV DNA and bilirubin levels, slowest decline of albumin level, highest rate of HBeAg seroconversion and lowest risk of hepatitis flare. Patients with YMDD-MT still had a lower risk for developing cirrhosis and/or HCC ( P=0.024) and a greater HBV DNA reduction ( P=0.001) in comparison with controls. Patients with YMDD-MT and controls had a similar chance of hepatitis flares and hepatic decompensation.

Conclusions

Long-term lamivudine treatment was associated with a reduced chance of developing cirrhosis and HCC in patients without advanced disease. Although YMDD-MT reduced the benefits from lamivudine therapy, the outcome of these patients was still better than untreated patients.
Treatment of Chronic Hepatitis B
Authors: Loomba Rohit , Liang T Jake
Published: April 2022

Hepatitis B virus (HBV) infection is the leading cause of chronic liver disease and hepatocellular carcinoma worldwide. Approximately 350 million individuals are infected with HBV and >500,000 deaths per year can be attributed to HBV. Although universal vaccination has reduced HBV incidence in many countries, it still remains a major public health problem, especially in parts of Asia and Africa. Improved understanding of HBV virology and virus-host interactions has revolutionized chronic hepatitis B therapy in the past two decades. Development of oral nucleoside/nucleotide analogues heralds a new era of safe and effective treatment of this disease. On the basis of these advances, new guidelines for the treatment of chronic hepatitis B have been issued. Successful long-term treatment of chronic hepatitis B may rest on combination therapy that is based on molecular approaches targeting various stages of the HBV life-cycle. In this review, we summarize the current modalities and highlight important issues in the treatment of chronic hepatitis B monoinfection.
Special Considerations and Treatment of Patients with HBV-HIV Coinfection
Authors: Dieterich Douglas T
Published: April 2022

Coinfection with HIV and hepatitis B virus (HBV) substantially alters the natural course of HBV infection as well as its management. Therapy for HBV infection in HIV-coinfected patients requires several factors to be taken into consideration, such as whether the antiviral activity of a particular agent is specific for HBV (that is, adefovir, entecavir, telbivudine and pegylated interferon) or for both viruses (that is, lamivudine, emtricitabine and tenofovir), whether the chosen drug has the potential for inducing drug resistance and cross-resistance, and whether use of the agent is associated with hepatotoxicity. For coinfected patients who do not require therapy for their HIV infection, clinicians should avoid prescribing monotherapy with agents that have activity against HIV (that is, tenofovir, entecavir, emtricitabine or lamivudine) so as not to compromise future HIV care. This review discusses the current status of treatment of hepatitis B in the setting of HIV infection. It describes emerging therapeutic strategies and addresses challenges in the treatment of coinfection.
In vitro and in vivo Protection against the Highly Pathogenic H5N1 Influenza virus by an Antisense Phosphorothioate Oligonucleotide
Authors: Duan Ming , Zhou Zhe , Lin Ru-Xian , Yang Jing , Xia Xian-Zhu , Wang Sheng-Qi
Published: April 2022

Background

Current vaccination strategies and antiviral drugs only provide limited protection against influenza virus infection. In this study, we investigated the use of a novel antisense oligonucleotide (named IV-AS), which is specific for the 5’-terminal conserved sequence found in all eight viral RNA segments of influenza A virus.

Methods

The activity of IV-AS was monitored both in vitro, in Madin-Darby canine kidney (MDCK) cells, and in vivo using a mouse model. IV-AS was given intranasally to H5N1-infected mice once daily for 6 days starting 6 h after infection. A three-base mismatch of IV-AS was used as a control.

Results

IV-AS inhibited influenza virus A induced cytopathic effects in MDCK cells with the 50% effective concentration (EC50) ranging from 2.2 to 4.4 μM. IV-AS was effective against H5N1 virus in preventing death, lessening weight reduction, inhibiting lung consolidation and reducing lung virus titres. Dosages of 40 and 60 mg/kg/day provided 40% and 60% survival rates and prolonged mean survival days in comparison with the infected control group ( P<0.05). The lung index in mice treated with IV-AS, at a dose of 20, 40 or 60 mg/kg/day, had been inhibited on day 4 or 6 ( P<0.05 or P<0.01); virus titres in lung had declined to 2.42, 1.51 and 1.54 log10 TCID50/g of lung, respectively, whereas the yields in the infected control mice were 6.00 log10 TCID50/g of lung.

Conclusions

Our results suggest that the 5’-terminal conserved region of influenza A virus RNA segments can be targeted using antisense technology; therefore, IV-AS is a potential drug for prophylaxis and control of influenza virus infections.
Antiviral Activity and Safety of Aplaviroc with Lamivudine/Zidovudine in HIV-Infected, Therapy-Naive Patients: The ASCENT (CCR102881) Study
Authors:   the ASCENT study team, Currier Judith , Lazzarin Adriano , Sloan Louis , Clumeck Nathan , Slim Jihad , McCarty Deb , Steel Helen , Kleim Jörg-Peter , Bonny Tab , Millard Judith
Published: April 2022

Background

This Phase IIb study explored the antiviral activity and safety of the investigational CCR5 antagonist aplaviroc (APL) in antiretroviral-naive patients harbouring R5-tropic virus.

Methods

One hundred and forty-seven patients were randomized 2:2:1 to one of two APL dosing regimens or efavirenz (EFV). All dosage arms were administered twice daily and in combination with lamivudine/zidovudine (3TC/ZDV; Combivir, COM). Efficacy, safety, and pharmacokinetic parameters were assessed.

Results

This study was prematurely terminated due to APL-associated idiosyncratic hepatotoxicity. The primary endpoint of the study was the proportion of patients with plasma HIV-1 RNA <400 copies/ml who remained on randomized treatment through week 12. Of the 147 patients enrolled, 145 patients received one dose of treatment and were included in the intention-to-treat population. The proportion of patients with HIV-1 RNA <400 copies/ml at week 12 was 53%, 50% and 66% in the APL 600 mg twice daily, APL 800 mg twice daily, and EFV arms, respectively. Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated non-linear pharmacokinetics with high interpatient variability. In addition to the hepatic findings, there was an apparent dose–response relationship in the incidence of diarrhoea.

Conclusions

Whereas target plasma concentrations of APL were achieved, the antiviral activity of APL as the third agent in a triple drug regimen did not appear to be comparable to EFV in this treatment-naive patient population.
Should Treatment of Hepatitis B Depend on Hepatitis B virus Genotypes? A Hypothesis Generated from an Explorative Analysis of Published Evidence
Authors: Wiegand Johannes , Hasenclever Dirk , Tillmann Hans L
Published: April 2022

Objective

Standard treatment for hepatitis B is either based on interferon or on nucleos(t)ide analogues. Available evidence on treatment outcome by hepatitis B virus genotype was summarized and analysed to determine whether the genotype has a substantial role in selecting treatment.

Methods

Abstracts from PubMed, the European Association for the Study of the Liver and the American Association for the Study of the Liver Diseases were screened for publications with at least 30 patients and reporting hepatitis B treatment results (hepatitis B e antigen [HBeAg] seroconversion, loss of HBeAg or loss of HBV DNA) broken down by hepatitis B genotypes. Twenty reports were identified and included. Forest-plot techniques were applied to visualize the association of HBV genotypes (A versus D and B versus C) with treatment outcome given by type of treatment and HBeAg status. The potential size of a treatment by genotype interaction was estimated.

Results

Treatment response to nucleos(t)ide analogues is not significantly influenced by HBV genotype in HBeAg-positive or HBeAg-negative individuals. In contrast, HBV genotypes are informative concerning responses to interferon treatment in all patients with genotype A versus D and in HBeAg-positive patients with genotype B versus C.

Conclusion

If no contraindications are present, interferon may be considered as first-line therapy in all genotype A patients and in individuals with genotype B who are HBeAg positive. However, confirmation of this observation in a prospective clinical trial is warranted, because this analysis is explorative and hypothesis generating only.
HIV-1-Resistant Strains during 8-Week on 8-Week off Intermittent Therapy and their Effect on CD4+ T-cell Counts and Antiviral Response
Authors: Izopet Jacques , Marchou Bruno , Charreau Isabelle , Sauné Karine , Tangre Philippe , Molina Jean-Michel , Jean-Pierre Aboulker ,   for the Window (ANRS 106) Study Team
Published: April 2022

Background

We aimed here to study drug-associated HIV resistance mutations in peripheral blood mononuclear cells (PBMC) and plasma during intermittent therapy.

Methods

A substudy of 86 patients randomized to the intermittent treatment arm (8-week on/8-week off) of the ANRS 106 Window trial. HIV reverse transcriptase and protease genes were sequenced and resistance mutations identified according to the International AIDS Society list.

Results

Resistance mutations were detected in PBMC of 27/86 (31%) patients at baseline and 25/72 (35%) patients at week 96. Resistance mutations were detected in plasma of 28/86 (33%), 24/83 (29%) and 33/80 (41%) patients at weeks 8, 40 and 88, respectively. The detection of nucleoside reverse transcriptase inhibitor and protease inhibitor associated resistance mutations in plasma remained stable over time, but there was an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations in patients on an NNRTI-based regimen: 1/33 (3%) versus 7/26 patients (27%) at weeks 8 and 88, respectively ( P=0.02). The proportions of patients with plasma HIV RNA levels ≤400 copies/ml after 8 weeks of treatment at weeks 16, 48 and 96 in patients with drug-resistant and wild-type viruses were 93% versus 74% ( P=0.04), 96% versus 88% ( P=0.43) and 70% versus 84% ( P=0.13), respectively. Patients with drug-resistant virus had a lower CD4+ T-cell decrease from baseline at weeks 40 and 88 as compared to patients with wild-type virus ( P=0.05 and 0.002, respectively).

Conclusions

NNRTI-associated resistance mutations increased over time in plasma of patients who were given NNRTIs. Drug-associated HIV resistance mutations did not seem to impair short-term antiviral response and might be associated with reduced CD4+ T-cell loss during interruptions.