bluuebunny/crossref_metadata_2025 huggingface dataset:
The V118I Mutation as a Marker of Advanced HIV Infection and Disease Progression
Authors: Zaccarelli Mauro , Tozzi Valerio , Lorenzini Patrizia , Forbici Federica , Narciso Pasquale , Ceccherini-Silberstein Francesca , Trotta Maria Paola , Bertoli Ada , Liuzzi Giuseppina , Marconi Patrizia , Mosti Silvia , Perno Carlo Federico , Antinori Andrea
Published: April 2022

Background

The V118I mutation is included in the nucleoside analogue mutations (NAMs) set. It contributes to thymidine-analogue resistance and, consequently, to resistance to the whole nucleoside reverse transcriptase inhibitor (NRTI) class. We focused on the V118I mutation in order to evaluate factors associated with its detection and its relationship with HIV progression.

Methods

Clinical and laboratory data at genotypic resistance test (GRT) of highly active antiretroviral therapy-failing patients were collected and their association with the V118I mutation was analysed. Patients were also followed over time to determine factors related to progression to a new AIDS-related event or death.

Results

Of the 792 patients included, 114 (14.4%) carried the V118I mutation. In univariate analysis, the V118I mutation was significantly associated with a higher HIV RNA level, lower CD4+ T-cell count, Centers for Disease Control and Prevention (CDC) stage C, higher number of pre-GRT regimens and class-wide resistance (CWR) to NRTIs, protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Higher numbers of pre-GRT regimens and NRTI CWR were also associated in the multivariable analysis. Within the post-GRT observation period of up to 6 years (median: 72 months; interquartile range: 33–109) 107 events (58 new AIDS-related diseases and 49 deaths) were observed. Using the Cox proportional hazard model and the major clinical, behavioural and laboratory data, the V118I mutation was found to be associated with the endpoint (hazard ratio: 1.93, 95% confidence interval: 1.06–3.50; P=0.031). Other factors associated with disease progression were CDC stage C and lower CD4+ T-cell count at GRT.

Conclusions

The analysis of our observational database suggests that the onset of the V118I mutation after treatment failure is unfavourable for the patient and can be considered a strong marker of disease progression.
Long-Term Foscarnet Therapy Remodels Thymidine Analogue Mutations and Alters Resistance to Zidovudine and Lamivudine in HIV-1
Authors: Mathiesen Sofie , Dam Elisabeth , Roge Birgit , Joergensen Louise Bruun , Laursen Alex Lund , Gerstoft Jan , Clavel Francois
Published: April 2022

Objective

To study the evolution of multi-drug-resistant HIV-1 in treatment-experienced patients receiving foscarnet (PFA) as part of salvage therapy and to investigate the virological consequences of emerging mutations.

Methods

Genotypic and phenotypic resistance tests were performed on plasma viruses from seven patients at baseline and during treatment with PFA. The phenotypic effects of mutations suspected to be associated with PFA resistance were evaluated by site-directed mutagenesis of wild-type or thymidine analogue mutations (TAM)-carrying pNL4–3. Reversion of single mutations was performed in a patient-derived recombinant clone.

Results

Baseline multi-drug-resistant isolates exhibited hypersusceptibility to PFA. In two patients who received >12 months of PFA treatment, a novel mutation pattern including K70G, V75T, K219R and L228R emerged. These viruses had 3–6-fold resistance to PFA, a 2–20-fold decrease in resistance to zidovudine compared to baseline, and 14–39-fold resistance to lamivudine, in the absence of M184V. In wild-type clones mutations K70G and V75T induced moderate PFA resistance. In the case of TAMs, combinations of ≥3 mutations (K70G+K219R+L228R±V75T) induced PFA resistance and decreased zidovudine resistance 3–13-fold. These mutants exhibited high-level lamivudine resistance (>20-fold) without mutation M184V. Reversion of K70G→R and K219R→E in a patient-derived clone confirmed the contribution of individual mutations and the negative association between PFA resistance and zidovudine resistance.

Conclusions

In the context of multiple TAMs, hypersusceptibility to PFA was observed and a novel pattern of resistance, including alternative amino acid substitutions at TAM loci, emerged. This mutational pattern was associated with decreases in zidovudine resistance and surprisingly high-level lamivudine resistance.
The Magnitude of Week 4 HCV RNA Decay on Pegylated Interferon/Ribavirin Accurately Predicts Virological Failure in Patients with Genotype 1
Authors: Bárcena Rafael , Moreno Ana , Del Campo Santos , Muriel Alfonso , Mateos María L , Garrido Elena , García Miguel , Quereda Carmen , Moreno Santiago , Moreno Alberto
Published: April 2022

Background

Current stopping rules during pegylated interferon (peg-IFN)/ribavirin (RBV) treatment rely on week 12 HCV RNA response, but earlier identification of non-responders offers clinical and economic advantages. Aims and

Methods

To evaluate, among 129 HCV-genotype-1-infected, treatment-naive patients receiving peg-IFN/RBV, the feasibility of predicting treatment failure using receiver operating characteristics (ROC) curves after measuring week 4 HCV RNA decreases, and to assess baseline predictors of not achieving sustained virological response (SVR).

Results

Peg-IFN-α2b was used in 84.5% of patients. Fifty-three (41%) reached SVR. The best cutoff value of HCV RNA decrease at week 4 to predict non-SVR corresponded to 1 log10 IU/ml: sensitivity and negative predictive value: 100%; specificity: 64%; positive predictive value: 66%; ROC curve area: 0·91 (95% confidence interval [CI]: 0·86–0·96). By applying this threshold, treatment could have been discontinued at week 4 in 64% of virological non-responders (49/76). By univariate analysis, baseline HCV RNA >800,000 IU/ml ( P=0.029), older age ( P=0.011), and higher aspartate aminotransferase (AST) levels ( P=0.005) or AST/alanine aminotransferase ratio values ( P=0.04) were associated with failure. After multivariate analysis, only baseline HCV RNA >800,000 IU/ml (odds ratio [OR]: 2.12; 95% CI: 1.005–4.488; P=0.048) and higher AST levels (OR: 1.01; 95% CI: 1.003–1.024; P=0.011) remained statistically significant.

Conclusions

The lack of ≥1 log10 IU/ml decrease in baseline HCV RNA at week 4 was 100% predictive of treatment failure, independently associated with HCV RNA >800,000 IU/ml and higher AST levels.
First-line Highly Active Antiretroviral Regimens in 2001–2002 in the French Hospital Database on HIV: Combination Prescribed and Biological Outcomes
Authors: Potard Valérie , Rey David , Mokhtari Saadia , Frixon-Marin Véronique , Pradier Christian , Rozenbaum Willy , Brun-Vezinet Françoise , Costagliola Dominique ,   the French Hospital Database on HIV, ANRS C04
Published: April 2022

Introduction

We compared biological outcomes in anti-retroviral-naive patients with viral load (VL) >5,000 copies/ml starting combivir-based, three-drug highly active antiretroviral therapy regimens in 2001–2002 according to the third component, namely abacavir (ABC), nelfinavir (NFV), indinavir/ritonavir (IDV/r), lopinavir/ritonavir (LPV/r), nevirapine (NVP) or efavirenz (EFV).

Methods

We evaluated virological response (HIV RNA <500 copies/ml) and immunological response (increase of ≥50 CD4+ T-cells/u, l) separately in patients with baseline VL <100,000 copies/ml ( n=992) and ≥100,000 copies/ml ( n=1,048). Hazard ratios (HR) were calculated with Cox models stratified for quintiles of propensity scores, estimated by multinomial regression from baseline characteristics.

Results

Median follow up was 19 months. EFV had better virological efficacy than NFV and IDV/r among patients with baseline VL <100,000 copies/ml, with respective HRs of 0.71 and 0.72, compared with 0.81 for NVP, 0.89 for ABC and 0.99 for LPV/r. The immunological efficacy of EFV was lower than that of LPV/r (1.37) and similar to that of NFV (0.96), IDV/r (0.81), NVP (1.08) and ABC (1.04). Among patients with baseline VL ≥100,000 copies/ml, the virological efficacy of EFV was similar to that of NVP (0.90) and LPV/r (0.97) and better than that of NFV (0.62), ABC (0.75) and IDV/r (0.78). The immunological results found in these patients were similar to those observed in patients with baseline VL <100,000 copies/ml.

Conclusions

For first-line therapy, in this observational setting, EFV, LPV/r and NVP, when added to the combivir backbone, were more likely to drive viral load <500 copies/ml. LPV/r showed the best immunological effectiveness.
Plasma Concentrations of the HIV-Protease Inhibitor Lopinavir are Suboptimal in Children Aged 2 Years and Below
Authors: Verweel Gwenda , Burger David M , Sheehan Nancy L , Bergshoeff Alina S , Warris Adilia , Van Der Knaap Linda C , Driessen Gertjan , de Groot Ronald , Hartwig Nico G
Published: April 2022

Background

Lopinavir/ritonavir (LPV/r) has been licensed for the treatment of HIV-infected children >6 months in the US and >2 years in the EU. Limited LPV paediatric pharmacokinetic data are available. We studied LPV pharmacokinetics to determine whether the recommended dose (230/57.5 mg/m2 twice daily) results in optimal LPV exposure in all age groups. Virological efficacy was a secondary objective.

Methods

HIV-1-infected children who started treatment with LPV/r and two nucleoside reverse transcriptase inhibitors underwent a 12-h pharmacokinetic curve. LPV plasma concentrations were determined with a validated HPLC method with UV detection. If Cmin was <1.0 mg/l LPV/r dose was increased by 33%. Plasma trough levels were drawn subsequently. HIV-1 RNA was followed-up until week 48.

Results

A total of 23 children were included (seven girls; 16 boys), with a median (range) age of 5.6 (0.4–13.2) years. Mean (±SD) AUC0–12h, Cmax and Cmin of LPV were 75.3 (±33.7) mg/l.h, 9.33 (±3.27) mg/l and 3.68 (±2.48) mg/l, respectively, which is similar to previously published data. Interindividual variability was large. Cmin was inadequate in 7/23 children. Significantly more children <2 years had inadequate Cmin compared with children >2 years. Dose increase to ±300/75 mg/m2 LPV/r led to Cmin >1.0 mg/l. The studied regimen provided excellent viral suppression for naive and pretreated patients.

Conclusions

Mean LPV pharmacokinetic parameters in these HIV-infected children are similar to published data, but exposure is significantly reduced in children <2 years. Prospective pharmacokinetic studies using 300/75 mg/m2 LPV/r in this age population are urgently warranted.
Some HIV Antiretrovirals Increase Oxidative Stress and Alter Chemokine, Cytokine or Adiponectin Production in Human Adipocytes and Macrophages
Authors: Lagathu Claire , Eustace Brenda , Prot Matthieu , Frantz Dan , Gu Yong , Bastard Jean-Philippe , Maachi Mustapha , Azoulay Stephane , Briggs Michael , Caron Martine , Capeau Jacqueline
Published: April 2022

Objectives

Adipose tissue from patients with HIV-related lipodystrophy presents a state of chronic inflammation. Altered expression of cytokines/adipokines and macrophage infiltration could be involved in patients’ insulin resistance and lipoatrophy. We tested whether antiretrovirals affected adipokine release by human subcutaneous adipocytes and cytokine/chemokine production by human macrophages and examined whether reactive oxygen species (ROS) hyperproduction was related to the effect of antiretrovirals.

Methods

Differentiated human adipocytes and PMA-THP-1 macrophages were treated with protease inhibitors (PIs: indinavir, nelfinavir, amprenavir, lopinavir, ritonavir and atazanavir) or nucleoside reverse transcriptase inhibitors (NRTIs: stavudine, zidovudine and abacavir) for 24–48 h without or with diphenylene iodonium (DPI), an inhibitor of oxidative stress. Lipid content was assessed by Oil Red O staining and ROS production by nitroblue tetrazolium (NBT) reduction. Cytokine/chemokines, adiponectin and leptin release was evaluated by ELISA or multiplex assays.

Results

In human adipocytes, PIs and NRTIs (except amprenavir, atazanavir and abacavir) reduced lipid content, adiponectin and leptin release and increased in parallel ROS production and monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 release. The effects of PIs, but not of NRTIs, were prevented by the addition of DPI. In PMA-THP-1 macrophages, all PIs, but no NRTI, increased macrophage inflammatory protein-1α and MCP-1 release. Lopinavir, nelfinavir, zidovudine and stavudine markedly increased ROS production and release of IL-1β and tumour necrosis factor-α.

Conclusions

Some PIs altered adipokine secretion and lipid content through ROS production in human subcutaneous adipocytes. Thymidine analogues altered adipocyte functions but their effect on adipokine secretion was not reverted by ROS production inhibition. Increased chemokine/cytokine production by adipocytes and macrophages could be involved in macrophage recruitment and participate in lipoatrophy and insulin resistance.
Rapid virological response at week 4 predicts response to pegylated interferon plus ribavirin among HIV/HCV-coinfected patients
Authors: Mira José A , Valera-Bestard Bárbara , Arizcorreta-Yarza Ana , González-Serrano Mercedes , Torre-Cisneros Julián , Santos Ignacio , Vergara Salvador , Gutiérrez-Valencia Alicia , Girón-González José A , Macías Juan , López-Cortés Luis F , Pineda Juan A
Published: April 2022

Introduction

The clinical applicability of early viral kinetics at week 4 in predicting sustained virological response (SVR) of pegylated interferon (peg-IFN) plus ribavirin (RBV) in HIV/HCV-coinfected patients is unclear. Our objective was to determine if rapid virological response (RVR) at week 4 of therapy with peg-IFN and RBV could predict SVR among HIV/HCV-coinfected patients.

Methods

HIV/HCV-coinfected patients in whom an HCV viral load determination had been carried out at week 4 of therapy were included in the study. The positive predictive value (PPV) and the negative predictive value (NPV) of RVR (undetectable serum HCV RNA at 4 week) for SVR were calculated in the study population. Receiver operating characteristic curves were calculated to determine the best cutoff of HCV RNA decrease to predict treatment failure.

Results

A total of 101 HIV/HCV-coinfected patients were included. RVR and SVR were observed in 39 (39%) and in 49 (48%) individuals, respectively. Of patients with RVR, 37/39 patients achieved SVR (PPV: 95%), whereas 50/62 individuals without RVR did not show SVR (NPV: 81%). The highest NPV (96%) was reached by using a cutoff level of HCV RNA decrease of 0.6 log10. By applying this cutoff level, treatment could have been discontinued in 25 (25%) patients.

Conclusions

An undetectable serum HCV RNA determination at week 4 of treatment with peg-IFN plus RBV is a reliable predictor of SVR in HIV/HCV-coinfected patients. In addition, a decrease of HCV RNA less than 0.6 log10 at this point of treatment could identify an appreciable proportion of individuals who will fail to achieve SVR.
Key reports from the 9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 2007
Authors: Nestorowicz Ann , Cameron Stephen
Published: April 2022

The 9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV provided a forum for the presentation of basic and clinical research focused on the pathogenesis and management of lipodystrophy and other adverse events associated with antiretroviral therapy. New data were reported on the contribution of both antiretroviral therapy and HIV infection itself on the development of metabolic abnormalities in patients with lipodystrophy, including insulin resistance and dyslipidaemia, which are associated with an increased risk of diabetes and cardiovascular disease. In addition, an emerging role of HIV and antiretroviral therapy in bone, liver and kidney disease were highlighted. A major focus of the data presented in these areas concerned the identification and evaluation of risk factors and appropriate surrogate markers for defining cardiovascular disease risk as well as other outcomes of long-term treatment. The complexity of defining such risk factors was underscored by data describing the impact of race, age and gender in the progression of metabolic disease and related complications among different HIV-infected populations. Finally, advances in the development of pharmacovigilance reporting systems in resource-limited settings and their impact upon healthcare policies and the provision of patient care were also described.
High frequency of primary mutations associated with antiretroviral drug resistance in recently diagnosed HIV-infected children
Authors: Vignoles Moira , Barboni Graciela , Agosti María Rosa , Quarleri Jorge , García Mariel Karina , Giraudi Vera , Ayala Silvia González , Salomón Horacio
Published: April 2022

Introduction

The aim of our study was to analyse the frequency of primary mutations associated with HIV drug resistance in a population of children born to HIV-infected mothers.

Design

A prospective study included newly HIV-diagnosed children treated at two public paediatric hospitals.

Patients and methods

Clinical and antiretroviral therapy (ART) data were collected in mother-child pairs. HIV-1 subtyping and ART resistance mutations were assayed in children by sequencing a region of HIV pol gene.

Results: A total of 67 children were enrolled

22 less than 12 months of age, 20 between 1 and 5 years and 25 between 6 and 14 years. Six (9.0%) children had viral strains with at least one primary mutation associated with resistance to reverse transcriptase and protease inhibitors. A significantly ( P=0.019) higher frequency of resistance (22.7%, n=5/22) was found among children aged <12 months. Fourteen children (20.9%) had a subtype B HIV-1 strain and 53 (79.1%) had an inter-subtype B/F recombinant variant.

Discussion

A high percentage of recently diagnosed infants were found to carry primary ART resistance mutations. Limited options for ART of HIV-infected children might lead to increased HIV-associated morbidity and mortality. Thus, consideration should be given to mandatory screening for primary ART resistance before initiating therapy for infants aged <12 months in countries where HIV mother-to-child transmission is still present, such as in Argentina. This will allow for the rationalized and individualized use of drugs and will contribute to the increased cost-effectiveness of local health systems.
Amphipathic DNA Polymers are Candidate Vaginal Microbicides and Block Herpes Simplex Virus Binding, Entry and Viral Gene Expression
Authors: Guzman Esmeralda M , Cheshenko Natalia , Shende Vikas , Keller Marla J , Goyette Nathalie , Juteau Jean-Marc , Boivin Guy , Vaillant Andrew , Herold Betsy C
Published: April 2022

Background

Amphipathic DNA polymers are promising therapies for the prevention of HIV and genital herpes infections. Recent studies on a panel of such compounds indicated potent activity against HIV binding and entry. This current study was conducted to explore the anti-herpes simplex virus (HSV) activity of the same panel of compounds and to determine their mechanism of activity.

Methods

The anti-HSV activity of a 40-nucleotide degenerate polymer (REP 9), a 40-nucleotide polycytidine amphipathic DNA polymer (REP 9C) and an analogue lacking amphipathic activity (Randomer 3) were compared in plaque reduction assays in the absence or presence of human genital tract secretions; the mechanisms of anti-HSV activity were explored.

Results

REP 9 inhibited HSV infection 10,000-fold, whereas Randomer 3 displayed no anti-HSV activity. The antiviral activity was independent of sequence but was dependent on size: the most potent activity was observed for analogues of 40 nucleotides in length. Mechanistic studies indicated that REP 9 and REP 9C blocked HSV-2 binding and entry, were active when added post-entry, inhibited viral gene expression and blocked HSV-induced apoptosis. Confocal microscopy studies showed rapid delivery of fluorescently tagged REP 9 and REP 9C into human epithelial cells, and delivery was significantly greater in infected cells as compared with uninfected cells. REP 9 exhibited no cytotoxicity and retained anti-HSV activity in the presence of cervicovaginal secretions and when virus was introduced in seminal plasma.

Conclusions

REP 9 and REP 9C represent a novel class of antiviral agents that act by multiple mechanisms. These compounds warrant further development for systemic or topical delivery for the prevention and treatment of HIV and HSV.
Lipodystrophy and metabolic changes in HIV-infected children on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy
Authors: Aurpibul Linda , Puthanakit Thanyawee , Lee Benjamin , Mangklabruks Ampica , Sirisanthana Thira , Sirisanthana Virat
Published: April 2022

Background

Highly active antiretroviral therapy (HAART) has recently been implemented in Thailand. Its long-term effects have not been clearly evaluated. The objective of this study was to estimate the prevalence of lipodystrophy (LD) and other metabolic changes in HIV-infected children receiving HAART.

Methods

Ninety children who began HAART (either nevirapine or efavirenz, together with lamivudine and stavudine) were prospectively followed. LD was assessed by waist-to-hip ratio and LD checklist. Hypercholesterolemia was defined as total cholesterol >200 mg/dl and low-density lipoprotein cholesterol >130 mg/dl. Low levels of high-density lipoprotein cholesterol (HDL-c), hypertriglyc-eridaemia and hyperglycaemia were defined as HDL-c <40 mg/dl, triglyceride >200 mg/dl and plasma glucose >110 mg/dl, respectively.

Results

The mean age at entry was 7.6 (sd 2.9) years. Fifty-three children received nevirapine- and 37 received efavirenz-based HAART. The prevalence of LD was 9%, 47% and 65% at 48, 96 and 144 weeks after HAART initiation, respectively. Patterns of LD at week 144 were central lipohypertrophy (46%), peripheral lipoatrophy (20%), and combined type (34%). A higher prevalence of LD was found among females (61% versus 39%; P=0.04) and those with more advanced disease (CDC category B or C) at baseline (73% versus 51%; P=0.04). There was no difference in prevalence of LD between the two regimens. At 144 weeks, fasting hypertriglyceridaemia was detected in 12%, hypercholesterolaemia in 11%, and increased plasma glucose in 4% of children. Low HDL-cholesterolaemia decreased from 94% at baseline to 12% at week 144 ( P<0.01).

Conclusions

More than half of the children developed LD at 144 weeks after HAART. Dyslipidaemia occurred in 11–12% of children.
The Prophylactic Administration of a Monoclonal Antibody against Human Metapneumovirus Attenuates viral Disease and Airways Hyperresponsiveness in Mice
Authors: Hamelin Marie-Eve , Couture Christian , Sackett Melanie , Kiener Peter , Suzich JoAnn , Ulbrandt Nancy , Boivin Guy
Published: April 2022

Background

Human metapneumovirus (hMPV) is one of the most frequent causes of respiratory tract infections in children. Our objective was to assess the prophylactic benefit of a monoclonal antibody (mAb) against the hMPV fusion protein in a murine model.

Methods

BALB/c mice received one intramuscular injection of either 5 or 10 mg/kg of mAb 338 (MedImmune, Inc.) and were infected intranasally 24 h later with 1x108 TCID50 (50% tissue culture infectious dose) of hMPV. On days 5 and 42 post-infection, lung samples were collected for determination of viral titres and for histopathological studies. Pulmonary function was characterized by plethysmography.

Results

Mean lung viral titres were significantly lower in mice treated with 5 or 10 mg/kg of mAb 338 compared with infected controls on day 5 (283, 45.6 and 1.49x105 TCID50/g, respectively; P<0.05). Similarly, lung viral RNA copies were significantly reduced in treated mice on day 42 (292, 101 and 607 copies per 0.01 g of lungs for mice that received 5 mg/kg, 10 mg/kg or no mAb, respectively; P<0.05). Histopathological changes characterized by important alveolar and interstitial inflammation were less severe in treated mice on days 5 and 42 compared with control. Airways obstruction was also significantly reduced in both treated groups on days 5 and 42, but development of hyperresponsiveness following the acute phase of infection was only significantly reduced in 10 mg/kg treated mice.

Conclusions

Prophylactic administration of mAb 338 attenuates acute and late consequences of hMPV disease in this mouse model.
Early Therapy in HIV-1-Infected Children: Effect on HIV-1 Dynamics and HIV-1-Specific Immune Response
Authors: Zanchetta Marisa , Anselmi Alessia , Vendrame Daniela , Rampon Osvalda , Giaquinto Carlo , Mazza Antonio , Accapezzato Daniele , Barnaba Vincenzo , Rossi Anita De
Published: April 2022

Background

Perinatal HIV-1 infection is acquired in the milieu of a developing immune system, leading to high levels of uncontrolled viral replication. Few data have been reported that address the viral dynamics and immunological response in infants who initiated aggressive antiretroviral therapy (ART) shortly after birth.

Methods

Six HIV-1-infected infants who started ART within 3 months of age were studied. The median follow-up was 61 months. Plasma HIV-1 RNA, cell-associated HIV-1 DNA, unspliced and multiply spliced HIV-1 mRNAs, HIV-1 antibodies, and CD4+ and CD8+ T-cell subsets were assessed in sequential peripheral blood samples. HIV-1 cellular immune response was measured by EliSpot assay.

Results

All children showed a decline in plasma viraemia to undetectable levels. HIV-1 DNA persisted in four children, but only two of these had detectable HIV-1 mRNA. All viral parameters remained persistently negative in two children. Only two children produced HIV-1 antibodies, while the others, after having lost maternal antibodies, remained seronegative. No HIV-1 cellular immune response was observed in any child. Therapy interruption was performed in two children: one HIV-1-seropositive and one HIV-1-seronegative with persistently undetectable levels of all viral parameters. Rebound of HIV-1 plasma viraemia in the seronegative child was more rapid and higher than that observed in the seropositive child.

Conclusions

Early ART treatment in infants modifies the natural course of infection by controlling HIV-1 replication and reducing viral load to below the threshold levels required for onset of HIV-1 immune response, but does not prevent the establishment of a reservoir of latently infected cells that precludes virus eradication.
Sequential Combination Therapy Leads to Biochemical and Histological Improvement Despite Low Ongoing Intrahepatic Hepatitis B virus Replication
Authors: Lutgehetmann Marc , Volz Tassilo , Quaas Alexander , Zankel Myrga , Fischer Conrad , Dandri Maura , Petersen Joerg
Published: April 2022

Background

We previously reported that 48 weeks of combination therapy with pegylated interferon-α2b (PEG-IFN-α2b) and adefovir dipivoxil (ADV) in patients with chronic hepatitis B led to marked decreases of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) (-2.4 log10 copies/ml). Combination therapy was followed by 96 weeks of ADV monotherapy.

Methods

Here, we report on the final outcome after 144 weeks of sequential antiviral treatment. Twenty-four patients were analysed, triplet liver biopsies (taken at baseline, week 48 and week 144) were available from 16 patients.

Results

At week 144, 12/15 patients positive for hepatitis B virus e antigen (HBeAg) had lost HBeAg, alanine transaminase (ALT) levels were normal in 23 patients (96%), median serum HBV DNA had decreased by -4.9 log10 copies/ml and was undetectable (<100 copies/ml) in 11/24 individuals (46%). Median total intrahepatic HBV DNA had decreased by -2.2 log. Although no further significant cccDNA changes occurred between week 48 and week 144, two years of ADV monotherapy proved capable of controlling cccDNA levels in most patients. Analysis of intrahepatic HBV DNA species demonstrated that combination therapy with PEG-IFN-α2b and ADV inhibited viral productivity by 99% and subsequent ADV monotherapy by 76%, respectively. Virus suppression to undetectability within the first 12 weeks of treatment was strongly associated with long-term virological response and HBeAg and hepatitis B virus surface antigen HBsAg seroconversion. Histological improvement was determined in 11/16 patients at week 144. Two patients developed ADV resistance during the third year of treatment.

Conclusions

Reduction of intrahepatic viral load achieved after 48 weeks of combination therapy with PEG-IFN-α2b and ADV was maintained in the following 96 weeks of ADV monotherapy and translated into long-term clinical benefit for most of the treated patients.
Effect of Pioglitazone on HIV-1-Related Lipodystrophy: A Randomized Double-Blind Placebo-Controlled Trial (ANRS 113)
Authors: Slama Laurence , Lanoy Emilie , Valantin Marc-Antoine , Bastard Jean-Philippe , Chermak Aziza , Boutekatjirt Amal , William-Faltaos Demiana , Billaud Eric , Molina Jean-Michel , Capeau Jacqueline , Costagliola Dominique , Rozenbaum Willy
Published: April 2022

Background

Although thiazolidinediones have been shown to increase subcutaneous fat in congenital lipodystrophy, rosiglitazone did not show convincing results in HIV lipoatrophy. We assess a potential specific effect of pioglitazone in this setting.

Methods

One-hundred and thirty HIV-1-infected adults with self-reported lipoatrophy confirmed by physical examination were randomized to receive pioglitazone 30 mg once daily ( n=64) or placebo ( n=66) for 48 weeks. Changes in limb fat between weeks 0 and 48 were measured using dual-energy X-ray absorptiometry. Subcutaneous and visceral fat was measured by single-slice computed tomography; fasting plasma measurements of glucose, insulin and lipids levels were recorded.

Results

Limb fat increased by 0.38 kg in the pioglitazone group and 0.05 kg in the placebo group at week 48 (mean difference 0.33 kg, 95% confidence interval [CI] 0.10–0.56; P=0.051) by intention-to-treat analysis. In patients not receiving stavudine, an increase of 0.45 kg versus 0.04 kg was observed (mean difference, 0.40 kg, 95% CI 0.12–0.69; P=0.013), but this was not seen in patients on stavudine ( n=36; P=0.404). Overall, there was no significant difference in subcutaneous abdominal fat or in visceral fat areas on computed tomography at L4 vertebra. The lipid profile was not significantly different at week 48 except for levels of high-density lipoprotein cholesterol, which was improved in the pioglitazone group (+0.08 mmol/l versus -0.08; P=0.005).

Conclusions

Pioglitazone 30 mg once daily for 48 weeks improved limb fat atrophy in antiretroviral-treated HIV-1-infected patients, although clinical benefits were not perceived by the patients. Treatment did lead to a favourable lipid profile, however, suggesting that this thiazolidinedione should be considered in the context of HIV-related lipoatrophy.
Failure of Lamivudine to Reverse Hepatitis B Virus-Associated Changes in ERK, Akt and Cell Cycle Regulatory Proteins
Authors: Chin Ruth , Earnest-Silveira Linda , Koeberlein Bernd , Franz Susanne , Zentgraf Hanswalter , Bowden Scott , Bock C-Thomas , Torresi Joseph
Published: April 2022

Background

Chronic infection with hepatitis B virus (HBV) is a major factor associated with the development of hepatocellular carcinoma, but the mechanism by which this occurs is unknown. Treatment of chronic hepatitis B with lamivudine results in virological suppression and histological improvement; however, the role of lamivudine in preventing the development of hepatocellular carcinoma is less well defined. We recently reported that replication of HBV in a cell-culture system was associated with the upregulation of pERK, pAkt, pc-Myc, nuclear cyclin B1, p21cip1 and p53 together with G2 cell cycle arrest.

Methods

In order to determine whether lamivudine is able to reverse the HBV-induced changes on signal transduction and cell cycle, we infected Huh7 cells with a recombinant adeno-HBV virus in the presence of 0–50 μM of lamivudine. Signal transduction and cell cycle regulatory proteins were analysed by western immunoblot.

Results

Although lamivudine was able to inhibit HBV replication, it failed to reverse the changes on ERK and Akt phosphorylation. Correspondingly, levels of phospho-GSK3β and p21cip1/waf1 were increased, as were cyclin D1, cyclin B1, p53 and pc-Myc.

Conclusions

Lamivudine was ineffective in reversing the HBV-induced changes in signal transduction pathways and cell cycle regulatory proteins, indicating that the HBV-infected cells remained primed for oncogenic transformation despite viral suppression.
Retinoic Acid Analogues Inhibit Human Herpesvirus 8 Replication
Authors: Caselli Elisabetta , Galvan Monica , Santoni Fabio , Alvarez Susana , de Lera Angel R , Ivanova Diana , Gronemeyer Hinrich , Caruso Arnaldo , Guidoboni Massimo , Cassai Enzo , Dolcetti Riccardo , Di Luca Dario
Published: April 2022

Background

Retinoids have a pronounced antiviral effect against several viruses. In this study we aimed to investigate the effect of retinoids on human herpesvirus 8 (HHV-8).

Methods

A panel of retinoic acid compounds were tested for their antiviral activity against HHV-8 in human umbilical vascular endothelial cells (HUVECs) and in a human epithelial cell line. The presence, transcription and antigen expression of HHV-8 in infected cells – in the presence or absence of retinoic acid compounds – were evaluated by PCR, reverse transcriptase PCR and immunofluorescence assays; HHV-8 viral load was determined by real-time quantitative PCR. Angiogenesis induced by HHV-8 was also assessed using Cultrex® basement membrane extract.

Results

The compounds tested specifically inhibited viral promoters, during the early and late phases of infection in both cell systems tested, and resulted in up to 100fold reduction of viral titre and release of progeny virus. The inhibition of viral replication induced by retinoids in endothelial cells, the primary target of HHV-8-driven transformation in Kaposi's Sarcoma, prevented endothelial cells from developing spindle morphology and in vitro tube formation, characteristic changes associated with HHV-8 infection and transformation.

Conclusions

We show that retinoids inhibit HHV-8 replication and identify new retinoid compounds with a strong antiviral effect. Selective retinoids, particularly those with retinoic acid receptor agonist activity, may be good candidates for the development of antiviral drugs.
Prevalence, Genotypic Associations and Phenotypic Characterization of K65R, L74V and other HIV-1 RT Resistance Mutations in a Commercial Database
Authors: McColl Damian J , Chappey Colombe , Parkin Neil T , Miller Michael D
Published: April 2022

Background

Nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations (NAMs) can affect response to treatment with NRTIs and might also result in HIV-1 with reduced replication capacity.

Methods

A large commercial HIV-1 database ( n=60,487) was analysed for the prevalence of NAMs, antiviral drug susceptibilities and viral replication capacity.

Results

Thymidine analogue mutations (TAMs) and M184V were the most commonly observed NAMs (>25%). L74V/I was detected in 11% of isolates. K65R was detected in 3.3% of isolates and its frequency remained stable from 2003 to 2006, similar to trends observed for other NAMs. TAMs were rarely observed in combination with K65R, but frequently associated with L74V/I. HIV-1 with K65R or L74V/I alone were fully susceptible to zidovudine and stavudine. K65R was associated with reduced susceptibility to tenofovir, didanosine, abacavir and lamivudine; L74V/I was associated with reduced susceptibility to abacavir and didanosine. The addition of M184V to either K65R or L74V/I improved susceptibility to tenofovir, zidovudine and stavudine, but reduced susceptibility to abacavir, didanosine and lamivudine. Other NAMs commonly associated with K65R were A62V, S68G and Y115F; their NRTI susceptibilities were similar to those of viruses containing K65R alone. The replication capacity for HIV-1 with M184V/I or K65R was significantly reduced compared with wild-type (median 68% and 72%, respectively; P<0.0001), whereas replication capacity for HIV-1 with L74V or TAMs was not significantly reduced (88% and 97%, respectively).

Conclusions

These results demonstrate a relative stability in the prevalence of HIV-1 clinical isolates with NAMs from 2003 to 2006. Differences between the genotypic patterns, phenotype and replication capacity associated with common NAMs are described.
Partial Immunological and Mitochondrial Recovery after Reducing Didanosine doses in Patients on Didanosine and Tenofovir-Based Regimens
Authors: Negredo Eugènia , Garrabou Glòria , Puig Jordi , Lòpez Sònia , Morén Constanza , Bellido Rocio , Ayen Rafaela , Cardellach Francesc , Miró Óscar , Clotet Bonaventura
Published: April 2022

Background

Tenofovir disoproxil fumarate (TDF) has a safe toxicity profile; however, administration together with didanosine (ddI) increases ddI levels causing mitochondrial damage and CD4+ T-cell decline. We assessed whether a simple reduction of the ddI dose in patients receiving ddI (400 mg/day) and TDF could revert this side effect.

Methods

Immunological and mitochondrial changes were analysed in 20 patients at baseline, after 14 months of receiving ddI (400 mg/day), TDF (300 mg/day) and nevirapine (NVP; 400 mg/day) and 14 months after a ddl dose reduction to 250 mg/day. Immunological analyses measured CD4+ and CD8+ T-cell counts and mitochondrial studies in peripheral blood mononuclear cells assessed mitochondrial DNA content by quantitative real-time PCR, cytochrome c oxidase (COX) activity by spectrophotometry and mitochondrial protein synthesis (COX-II versus β-actin or COX-IV expression) by western blot.

Results

Treatment with TDF, ddI (400 mg/day) and NVP for 14 months produced significant decreases in mitochondrial parameters and CD4+ T-cell counts. The reduction in ddI dose resulted in mitochondrial DNA recovery; however, the remaining mitochondrial parameters remained significantly decreased. Levels of CD4+ T-cells were partially restored in 35% of patients. Subjects presenting a significant reduction in CD4+ T-cells during the high ddI dose period showed greater mitochondrial impairment in this stage and better mitochondrial and immunological recovery after drug reduction.

Conclusions

Administration of high ddI doses together with TDF was associated with mitochondrial damage, which may explain the observed CD4+ T-cell decay. A reduction of the ddI dose led to mitochondrial DNA recovery, but was not sufficient to recover baseline CD4+ T-cell counts. Other mitochondrial toxicity in addition to DNA γ-polymerase inhibition could be responsible for CD4+ T-cell toxicity.
Distinct Hepatitis C virus Kinetics in HIV-Infected Patients Treated with Ribavirin plus Either Pegylated Interferon α2a or α2b
Authors: Vispo Eugenia , Barreiro Pablo , Rodríguez-Nóvoa Sonia , Morello Judit , Labarga Pablo , Martín-Carbonero Luz , Maida Ivana , García-Gascó Pilar , Soriano Vincent
Published: April 2022

Background

Pegylated interferon (PEG-IFN) α2a and α2b differ in their pharmacokinetic properties, which might have an effect on their antiviral effects against hepatitis C virus (HCV). Differences between PEG-IFN-α molecules could be more pronounced in HIV-coinfected individuals, in whom response to HCV treatment is impaired.

Methods

All HCV–HIV-coinfected patients included in PRESCO and EXTENT trials recruited at one referral centre were retrospectively analysed. In both trials, ribavirin (RBV) 1,000–1,200 mg/day was prescribed together with standard doses of PEG-IFN-α2a or -α2b. The attainment of serum HCV RNA <10 IU/ml at weeks 4, 12 and 24 was assessed. On-treatment analyses were made to estimate the intrinsic potency of PEG-IFN-α2a versus -α2b.

Results

A total of 218 patients were examined, 138 on PEG-IFN-α2a and 80 on PEG-IFN-α2b. Baseline characteristics were comparable in both groups. Undetectable serum HCV RNA at weeks 4, 12 and 24 was more frequently attained using PEG-IFN-α2a than -α2b (45% versus 27% [ P=0.02]; 65% versus 45% [ P=0.01]; and 75% versus 55% [ P=0.01], respectively), regardless of HCV genotype. Plasma RBV levels did not differ between groups. In multivariate analysis, HCV genotypes 2/3 (odds ratio [OR] 12.5; 95% confidence interval [95% CI] 3.45–33.33; P<0.001), use of zidovudine (OR 0.30; 95% CI 0.11–0.85; P=0.02) and treatment with PEG-IFN-α2a (OR 2.12; 95% CI 1.02–4.54; P=0.04) were independent predictors of undetectable HCV RNA at week 24. Conversely, the incidence of serious adverse events was more common with PEG-IFN-α2a than -α2b (13.2% versus 3.6%; P=0.018).

Conclusions

The antiviral effect against HCV seems to be greater for PEG-IFN-α2a than -α2b in the HIV setting. A shorter half-life of PEG-IFN-α2b could explain this finding.
Treatment of Patients with Chronic Hepatitis B who have Failed Previous Antiviral Treatment with Pegylated Interferon α2a (40 kDa; PEGASYS®)
Authors: Chan Henry L-Y , Wong Vincent W-S , Chim Angel M-L , Wong Grace L-H , Chan Hoi-Yun , Sung Joseph J-Y
Published: April 2022

Background

Although nucleot(s)ide analogues can effectively suppress hepatitis B virus (HBV) replication, many patients experience relapse of hepatitis after cessation of treatment. We aimed to investigate the efficacy of pegylated interferon α2a (PEG-IFN-α2a) in these difficult-to-treat patients.

Methods

Chronic hepatitis B patients who have received antiviral drugs for ≥12 months and stopped for ≥6 months were treated by 48-week PEG-IFN-α2a. Virological response was defined as HBV DNA <10,000 copies/ml and hepatitis B e antigen (HBeAg) seroconversion (for HBeAg-positive patients).

Results

A total of 40 patients, 29 HBeAg-positive and 11 HBeAg-negative, with median log10 HBV DNA 7.3 copies/ml and alanine aminotransferase 110 IU/ml were studied. The last antiviral treatment was given for 92 +61 weeks and stopped for 176 +88 weeks. At the end of treatment, 22 (12 HBeAg-positive and 10 HBeAg-negative; 55%) patients had virological response and 16 (7 HBeAg-positive and 9 HBeAg-negative; 40%) patients had undetectable HBV DNA (<100 copies/ml). At 24 weeks post-treatment, 14 (8 HBeAg-positive and 6 HBeAg-negative; 35%) patients had virological response and 9 (5 HBeAg-positive and 4 HBeAg-negative; 23%) patients had undetectable HBV DNA. Two (5%) patients had lost hepatitis B surface antigen. HBV DNA levels at week 24 best predicted sustained virological response (area under curve 0.76, 95% confidence interval 0.60–0.92, P=0.007). At HBV DNA cutoffs of 3 logs and 5 logs at week 24, the sensitivity/specificity for sustained virological response were 50%/85% and 86%/62%, respectively.

Conclusions

PEG-IFN-α2a was effective in the treatment of chronic hepatitis B patients who have failed previous antiviral treatment.
HIV RNA viral Load and CD4+ T-cell Counts in HIV-Infected Pregnant Women with and without Treatment Discontinuation in Early Pregnancy
Authors:   the Italian Group on Surveillance on Antiretroviral Treatment in Pregnancy, Tamburrini Enrica , Ravizza Marina , Floridia Marco , Tibaldi Cecilia , Alberico Salvatore , Anzidei Gianfranco , Maccabruni Anna , Meloni Alessandra , Antoni Anna Degli , Mori Fernanda , Dalzero Serena , Conserva Valentina , Pinnetti Carmela , Ferrazzi Enrico
Published: April 2022

Background

In pregnant women taking antiretroviral treatment at conception treatment may be transiently stopped for safety concerns. Limited data are available on the consequences of such discontinuations.

Methods

We used data from a national study to compare different treatment pathways during pregnancy. Overall, 321 women were evaluated and classified into three groups: women not on treatment at conception and who started treatment during pregnancy (starters; n=91); women on treatment at conception who temporarily discontinued treatment during first trimester (discontin-uers; n=114); and women on treatment at conception who maintained treatment (continuers; n=116).

Results

At conception, the three groups had similar CD4+ T-cell counts (499, 495 and 470 cells/mm3, respectively; P>0.10); starters had significantly higher median HIV RNA levels at conception (5,690 copies/ml) compared with both continuers (58 copies/ml, P<0.001) and discontinuers (49 copies/ml, P<0.001). Continuers maintained undetectable HIV RNA at all pregnancy trimesters, while discontinuers showed at first and second trimester transient negative effects on HIV (4,776 and 386 copies/ml, respectively) and CD4+ T-cell levels (376 and 392 cells/mm3, respectively), which were reversed at last trimester (52 copies/ml and 432 cells/mm3, respectively). No significant differences were observed among the groups in HIV RNA and CD4+ T-cell counts at third trimester, preterm delivery, low birth weight or mode of delivery. The number of cases of HIV transmission and birth defects were too limited to allow comparisons.

Conclusions

Early discontinuation of antiretroviral treatment in pregnancy produces transient virological and immunological effects without precluding the achievement of a good viral suppression at the end of pregnancy; no clinical consequences were observed.
Pharmacokinetics and 48-Week Efficacy of Nevirapine: 400 mg Versus 600 mg per day in HIV–Tuberculosis Coinfection Receiving Rifampicin
Authors: Avihingsanon Anchalee , Manosuthi Weerawat , Kantipong Pacharee , Chuchotaworn Charoen , Moolphate Saiyud , Sakornjun Waraporn , Gorowara Meena , Yamada Norio , Yanai Hideki , Mitarai Satoshi , Ishikawa Nobukatsu , Cooper David A , Phanuphak Praphan , Burger David , Ruxrungtham Kiat
Published: April 2022

Background

We aim here to determine the appropriate dose of nevirapine (NVP) in Thai HIV–tuberculosis (TB)-coinfected patients receiving rifampicin.

Methods

Thirty-two HIV-infected adults with CD4+ T-cell counts <200 cells/mm3 and active TB, receiving rifampicin for 2–6 weeks were randomized to receive either NVP 400 mg (NVP400) or 600 mg (NVP600) per day plus two nucleoside reverse transcriptase inhibitors; a 2-week NVP lead-in was performed at 200 mg once daily (OD) and 200 mg twice daily, respectively. Plasma NVP levels were determined at weeks 2, 4 and 12. Twelve-hour pharmacokinetics (PK) were obtained ( n=20) at week 4.

Results

Baseline body weight was comparable. There were more patients with NVP plasma concentration at 12 h (C12) <3.1 mg/l at week 2 in NVP400 than in NVP600 (79% versus 19%, respectively; P=0.002). However, the proportions were comparable at weeks 4 and 12. From week 4, 12 h PK studies showed that NVP400 had lower median NVP area under the plasma concentration-0–12 h (AUC0–12 h), maximum concentration in plasma (Cmax) and C12 than NVP600 ( P<0.05). Four patients in NVP600 developed NVP hypersensitivity. At week 48, the median CD4+ T-cell count rise and proportion with viral load <50 copies/ml (intention-to-treat analysis 56% versus 50% and as-treated analysis 75% versus 89%) were comparable.

Conclusions

In rifampicin-treated patients, 200 mg NVP OD lead-in led to a significant short-term suboptimal NVP C12 level, while NVP 400 mg lead-in then 600 mg/day was associated with a high rate of NVP hypersensitivity. Forty-eight week efficacy was comparable. Thus, NVP 600 mg/day in rifampicin-treated patients is not recommended.