bluuebunny/crossref_metadata_2025 huggingface dataset:
Resistance Profiling of Hepatitis C Virus Protease Inhibitors using Full-Length NS3
Authors: Dahl Göran , Sandström Anja , Åkerblom Eva , Danielson U Helena
Published: April 2022

Background

The NS3 protease of hepatitis C virus (HCV) is a prime target for anti-HCV drugs but resistance towards inhibitors of the enzyme is likely to emerge because of mutations in the viral genome that modify the structure of the protein. Enzyme inhibition data supporting this is limited to studies with few compounds and analysis performed with truncated NS3.

Experimental

The potential of HCV acquiring resistance towards NS3 protease inhibitors and the structural features associated with resistance has been explored with a series of inhibitors and by using full-length NS3 protease/helicase variants with amino acid substitutions (A156T, D168V and R155Q) in the protease domain.

Results

The A156T and D168V substitutions did not influence the kinetic properties of the protease, whereas the R155Q substitution reduced the catalytic efficiency 20 times, as compared with the wild type. Inhibition studies revealed that these substitutions primarily affected the potency of compounds which effectively inhibit the wild-type enzyme, and had little effect on weak or moderate inhibitors. As a consequence, all compounds had similar inhibitory potencies to the substituted enzyme variants. An exception was VX-950, which inhibited the D168V enzyme more efficiently than the wild type. For this inhibitor, the present data correlated better with replicon data than data from assays with truncated enzyme.

Conclusions

These results have provided a structural basis for designing inhibitors that may be less susceptible to resistance by three known mutations, and suggest that the present variants of full-length NS3 constitute effective models for resistance profiling of NS3 protease inhibitors.
Serum α-Foetoprotein Level Predicts Treatment Outcome in Chronic Hepatitis C
Authors: Males Sylvia , Gad Rita Raafat , Esmat Gamal , Abobakr Hasan , Anwar Mohamed , Rekacewicz Claire , Hoseiny Mostafa El , Zalata Khaled , Abdel-Hamid Mohamed , Bedossa Pierre , Pol Stanislas , Mohamed Mostafa K , Fontanet Arnaud
Published: April 2022

Objectives

To analyse the association between serum α-foetoprotein (AFP) levels and sustained virological response (SVR) in treated patients.

Methods

One-hundred patients with chronic hepatitis C were treated with pegylated interferon α-2a plus ribavirin for 48 weeks. The primary endpoint was SVR. Linear regression analysis was performed to identify clinical, biological, and histological factors affecting baseline AFP levels. The association between pretreatment serum AFP and SVR was assessed by multivariate logistic regression analysis.

Results

Of 100 patients, 95 were infected with genotype 4, one with genotype 1, and four with undetermined genotype. The median serum AFP level was 4.5 ng/ml and AFP values ranged from 1.2 to 49.8 ng/ml. In multivariate analysis, higher fibrosis stage and higher steatosis score were independently associated with higher serum AFP levels. SVR rate was 61.0% (61/100), and was lower for patients with AFP levels above rather than below the median value (40.8% versus 80.4%, respectively, P<0.001). In multivariate analysis, including adjustment for age, gender, body mass index, steatosis score, fibrosis stage, ALT level, haemoglobin level, clotting time, HCV RNA viral load, and treatment dose received, a baseline serum AFP level above the median value was associated with a lower SVR rate (OR [95% CI]=0.10 [0.03–0.42], P<0.001). None of the seven patients with increased (above 15 ng/ml) pretreatment AFP achieved SVR.

Conclusions

In this study, higher baseline serum AFP levels independently predicted a lower SVR rate among patients with chronic hepatitis C. If confirmed with genotypes other than 4, these findings would suggest adding serum AFP to the list of factors predictive of treatment response.
Substitutions Due to Antiretroviral Toxicity or Contraindication in the First 3 years of Antiretroviral Therapy in a Large South African Cohort
Authors: Boulle Andrew , Orrell Catherine , Kaplan Richard , Van Cutsem Gilles , McNally Matthew , Hilderbrand Katherine , Myer Landon , Egger Matthias , Coetzee David , Maartens Gary , Wood Robin ,   Collaboration for the International Epidemiological Databases to Evaluate Aids in Southern Africa (IeDEASA)
Published: April 2022

Introduction

The patterns and reasons for antiretroviral therapy (ART) drug substitutions are poorly described in resource-limited settings.

Methods

Time to and reason for drug substitution were recorded in treatment-naive adults receiving ART in two primary care treatment programmes in Cape Town. The cumulative proportion of patients having therapy changed because of toxicity was described for each drug, and associations with these changes were explored in multivariate models.

Results

Analysis included 2,679 individuals followed for a median of 11 months. Median CD4+ T-cell count at baseline was 85 cells/μl. Mean weight was 59 kg, mean age was 32 years and 71% were women. All started non-nucleoside reverse transcriptase inhibitor-based ART (60% on efavrienz) and 75% started on stavudine (d4T). After 3 years, 75% remained in care on-site, of whom 72% remained on their initial regimen. Substitutions due to toxicity of nevirapine (8% by 3 years), efavirenz (2%) and zidovudine (8%) occurred early. Substitutions on d4T occurred in 21% of patients by 3 years, due to symptomatic hyper-lactataemia (5%), lipodystrophy (9%) or peripheral neuropathy (6%), and continued to accumulate over time. Those at greatest risk of hyperlactataemia or lipodystrophy were women on ART ≥6 months, weighing ≥75 kg at baseline.

Discussion

A high proportion of adult patients are able to tolerate their initial ART regimen for up to 3 years. In most instances treatment-limiting toxicities occur early, but continue to accumulate over time in patients on d4T. Whilst awaiting other treatment options, the risks of known toxicities could be minimized through early identification of patients at the highest risk.
Abacavir Plasma Pharmacokinetics in the Absence and Presence of Atazanavir/Ritonavir or Lopinavir/Ritonavir and Vice Versa in HIV-Infected Patients
Authors: Waters Laura J , Moyle Graeme , Bonora Stefano , D'Avolio Antonio , Else Laura , Mandalia Sundhiya , Pozniak Anton , Nelson Mark , Gazzard Brian , Back David , Boffito Marta
Published: April 2022

Background

Significant interactions between abacavir and other antiretrovirals have not been reported. This study investigated the steady-state plasma pharmacokinetics of abacavir when co-administered with atazanavir/ritonavir or lopinavir/ritonavir in HIV-infected individuals.

Methods

HIV-infected subjects on abacavir (600 mg once daily) plus two nucleoside reverse transcriptase inhibitors (NRTIs) (excluding tenofovir) underwent a 24 h pharmacokinetic assessment for plasma abacavir concentrations. Atazanavir/ritonavir (300/100 mg once daily; arm 1) or lopinavir/ritonavir (400/100 mg twice daily; arm 2) were then added and the 24 h pharmacokinetic assessment repeated. Arm 3 included subjects stable on atazanavir/ritonavir or lopinavir/ritonavir and two NRTIs (excluding tenofovir or abacavir). These patients underwent a pharmacokinetic assessment for atazanavir/ritonavir or lopinavir/ritonavir concentrations on day 1, abacavir (600 mg once daily) was then added to the regimen and the pharmacokinetic assessment repeated. Within-subject changes in drug exposure were evaluated by geometric mean (GM) ratios and 95% confidence intervals (CI).

Results

Twenty-four patients completed the study. GM (95% CI) abacavir area under the curve (AUC) was 18,621 (15,900–21,807) and 15,136 (13,339–17,174) ng.h/ml without and with atazanavir/ritonavir and 15,136 (12,298–18,628) and 10,471 (9,270–11,828) ng.h/ml without and with lopinavir/ritonavir. GM (95% CI) atazanavir AUC without and with abacavir was 26,915 (13,252–54,666) and 28,840 (19,213–43,291) ng.h/ml; lopinavir AUC without and with abacavir was 60,253 (48,084–75,509) and 63,096 (48,128–82,718) ng.h/ml.

Conclusions

No changes in atazanavir or lopinavir exposures were observed following the addition of abacavir; however, decreases in abacavir plasma exposure of 17% and 32% were observed following the addition of atazanavir/ritonavir or lopinavir/ritonavir, respectively.
Pharmacokinetics of Darunavir/Ritonavir and TMC125 alone and Coadministered in HIV-Negative Volunteers
Authors: Schöller-Gyüre Monika , Kakuda Thomas N , Sekar Vanitha , Woodfall Brian , De Smedt Goedele , Lefebvre Eric , Peeters Monika , Hoetelmans Richard M
Published: April 2022

Objective

To evaluate the pharmacokinetics of TMC125 (etravirine) and darunavir (DRV) with low-dose ritonavir (DRV/r).

Design

Open-label, randomized, two-way crossover Phase I trial.

Methods

Thirty-two HIV-negative volunteers were randomized 1:1 to two panels. All received TMC125 100 mg twice daily for 8 days and, after 14 days washout, DRV/r 600/100 mg twice daily for 16 days. During days 9–16, TMC125 100 or 200 mg twice daily was coadministered (Panel I or II, respectively).

Results

Twenty-three volunteers completed the trial. With DRV/r coadministration, mean exposure (area under the plasma concentration-time curve from 0 to 12 h [AUC12h]) to TMC125 given as 100 mg twice daily was decreased by 37%; maximum and minimum plasma concentrations (Cmax and Cmin) were decreased by 32% and 49%, respectively. For TMC125 200 mg twice daily coadministered with DRV/r, AUC12h, Cmax and Cmin of TMC125 were 80%, 81% and 67% greater, respectively, versus TMC125 100mg twice daily alone. DRV pharmacokinetics were unchanged except a 15% increase in AUC12h when given with TMC125 200 mg twice daily.

Conclusions

No clinically relevant changes in DRV pharmacokinetics were observed when combined with TMC125; therefore DRV dose adjustment is not required. Coadministration of TMC125 100 mg twice daily with DRV/r decreased TMC125 exposure by 37%. The increase of TMC125 exposure by 80% when given as 200 mg twice daily reflects the higher dose and the interaction with DRV/r. The magnitude of this interaction is comparable to TMC125 interactions with other boosted PIs observed in Phase IIb trials in HIV-1-infected patients. As these trials demonstrated TMC125 efficacy, no dose adjustment of TMC125 is needed when combined with DRV/r.
Treatment and Prognosis of AIDS-Related Lymphoma in the Era of Highly Active Antiretroviral Therapy: Findings from the Swiss HIV Cohort Study
Authors: Simcock Mathew , Blasko Monika , Karrer Urs , Bertisch Barbara , Pless Miklos , Blumer Liisa , Vora Samir , Robinson James Owen , Bernasconi Enos , Terziroli Benedetta , Moirandat-Rytz Sophie , Furrer Hansjakob , Hirschel Bernard , Vernazza Pietro , Sendi Pedram , Rickenbach Martin , Bucher Heiner C , Battegay Manuel , Koller Michael T ,   the Swiss HIV Cohort Study, Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Gorgievski M , Günthard H , Hirsch H , Hirschel B , Hösli I H , Kahlert Ch , Kaiser L , Karrer U , Kind C , Klimkait Th , Ledergerber B , Martinetti G , Martinez B , uUller N M , Nadal D , Opravil M , Paccaud F , Pantaleo G , Rickenbach M , Rudin C , Schmid P , Schultze D , Schüpbach J , Speck R , Taffé P , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S
Published: April 2022

Objective

To assess the characteristics of combination antiretroviral therapy (cART) administered concomitantly with chemotherapy and to establish prognostic determinants of patients with AIDS-related non-Hodgkin's lymphoma.

Methods

The study included 91 patients with AIDS-related non-Hodgkin's lymphoma from the Swiss HIV Cohort Study enrolled between January 1997 and October 2003, excluding lymphomas of the brain. We extracted AIDS-related non-Hodgkin's lymphoma- and HIV-specific variables at the time of lymphoma diagnosis as well as treatment changes over time from charts and from the Swiss HIV Cohort Study database. Cox regression analyses were performed to study predictors of overall and progression-free survival.

Results

During a median follow up of 1.6 years, 57 patients died or progressed. Thirty-five patients stopped chemotherapy prematurely (before the sixth cycle) usually due to disease progression; these patients had a shorter median survival than those who completed six or more cycles (14 versus 28 months). Interruptions of cART decreased from 35% before chemotherapy to 5% during chemotherapy. Factors associated with overall survival were CD4+ T-cell count (<100 cells/μl) (hazard ratio [HR] 2.95 [95% confidence interval (CI) 1.53–5.67], hepatitis C seropositivity (HR 2.39 [95% CI 1.01–5.67]), the international prognostic index score (HR 1.98–3.62 across categories) and Burkitt histological subtypes (HR 2.56 [95% CI 1.13–5.78]).

Conclusions

Interruptions of cART were usually not induced by chemotherapy. The effect of cART interruptions on AIDS-related non-Hodgkin's lymphoma prognosis remains unclear, however, hepatitis C seropositivity emerged as a predictor of death beyond the well-known international prognostic index score and CD4+ T-cell count.
HIV-1 Viral Replication below 50 Copies/ml in Patients on Antiretroviral Therapy is not associated with CD8+ T-cell Activation
Authors: Steel Alan , Cox Alison E , Shamji Mohamed H , John Laurence , Nelson Mark , Henderson Don C , Gotch Frances M , Gazzard Brian G , Kelleher Peter
Published: April 2022

Objectives

To determine if the expression of CD38 on CD8+ T-cells could be used as a marker of viral replication <50 copies/ml in peripheral blood.

Methods

In a cross-sectional study of patients attending a single HIV clinic in London, an ultra-sensitive HIV RNA viral load assay, with a limit of detection of 3 copies/ml, was used to determine HIV-1 replication in plasma in 70 patients who had sustained viral suppression <50 copies/ml by bDNA assays. Immune activation using the expression of CD38 on CD8+ T-cells was also assessed in patients on antiretroviral therapy (ART) with sustained viral suppression, individuals with persistent low-level viraemia <400 copies/ml and subjects failing ART (viral load >400 copies/ml).

Results

There was no significant difference in the percentage of CD8+CD38++ T-cells between patients with <50 copies or <3 copies/ml. Immune activation was significantly increased in patients with persistent low-level viraemia and in subjects failing ART. CD4+ T-cell counts in patients on long-term successful ART are inversely associated with CD8+ T-cell activation.

Conclusions

T-cell activation in patients on long-term successful ART is not due to residual low-level viral replication in the blood compartment of HIV-1. CD8+ T-cell activation in this patient group appears to be associated with poor CD4+ T-cell recovery.
Potent Inhibition of Genital Herpesvirus Infection in Goats by Cidofovir
Authors: Tempesta Maria , Camero Michele , Bellacicco Anna Lucia , Tarsitano Elvira , Crescenzo Giuseppe , Thiry Julien , Martella Vito , Decaro Nicola , Elia Gabriella , Neyts Johan , Thiry Etienne , Buonavoglia Canio
Published: April 2022

Background

Like human herpesvirus 2 (HHV-2) in humans, infection by caprine herpesvirus 1 in goats is associated with genital lesions, and this provides a unique model to study the efficacy and effects of anti-herpetic drugs.

Methods

The antiviral activity of cidofovir was assessed in goats infected experimentally, using various therapeutic protocols.

Results

Topic administration of cidofovir 1% cream prevented the onset of virus-induced genital lesions and drastically reduced virus shedding.

Conclusion

Cidofovir appears to be a very efficient drug for the prevention of genital lesions caused by an alphaherpesvirus.
The effect of Depressive Symptoms at ART Initiation on HIV Clinical Progression and Mortality: Implications in Clinical Practice
Authors: Villes Virginie , Spire Bruno , Lewden Charlotte , Perronne Christian , Besnier Jean-Marc , Garré Michel , Chêne Geneviève , Leport Catherine , Carrieri Maria Patrizia , Le Moing Vincent ,   ANRS CO-8 APROCO-COPILOTE Study Group
Published: April 2022

Background

Depression is common in HIV-infected patients receiving antiretroviral therapy. However, longitudinal studies addressing the role that depression might play in HIV clinical progression and mortality remain rare. This is especially true for those studies that also consider the possible confounding influence of patient's adherence to treatment.

Methods

The ANRS CO-8 APROCO-COPILOTE cohort study enrolled 1,281 individuals at the initiation of a protease-inhibitor-containing regimen between 1997 and 1999. Adherence, depressive symptoms and other psychosocial factors were measured using self-administered questionnaires. Predictors of progression to AIDS or death were studied using Cox models.

Results

Out of 1,028 individuals eligible for the present analysis, 92 individuals either died or had an AIDS-defining event during a median follow up of 54 months. At baseline, 377 individuals (41%) reported depressive symptoms and 124 (12%) reported non-adherence at month 4. Depressive symptoms at baseline were associated with progression (hazard ratio [HR] 2.1; P=0.001). Despite the association between depressive symptoms and non-adherence, depressive symptoms remained a predictor of clinical progression (adjusted HR [aHR] [95% confidence interval (CI)] 1.6 [1.0–2.5]) after adjustment for several factors: initial non-adherence (aHR [95% CI] 2.0 [1.1–3.6]), having a steady partner (aHR [95% CI] 0.5 [0.3–0.7]), older age (aHR [95% CI] 1.40 [1.12–1.74] per 10-year increment), HIV clinical stage C (aHR [95% CI] 2.5 [1.6–4.0]), plasma HIV RNA ≥100,000 copies/ml (aHR [95% CI] 1.7 [1.1–2.87]) and more than 8 years since HIV diagnosis (aHR [95% CI] 1.8 [1.1–2.8]).

Conclusion

Depressive symptoms and non-adherence are independent predictors of HIV clinical progression and mortality. Screening and appropriate treatment of depressive symptoms at antiretroviral treatment initiation should be included in the standard care of HIV-infected patients.
Modelling of Early Viral Kinetics and Pegylated Interferon-α2b Pharmacokinetics in Patients with HBeAg-Positive Chronic Hepatitis B
Authors: Ter Borg Martijn J , Hansen Bettina E , Herrmann Eva , Zeuzem Stefan , Cakaloglu Yilmaz , Karayalcin Selim , Flisiak Robert , Van ‘t Veen Annemarie , De Man Robert A , Schalm Solko W , Janssen Harry LA , Haagmans Bart L ,   for the HBV 99–01 Study Group
Published: April 2022

Background

Pegylated interferon α2b (PEG-IFN-α2b) is effective for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, although its mechanism of action remains unclear. HBeAg loss is achieved in 36% of patients after one year of PEG-IFN-α2b treatment and combination therapy with lamivudine is not superior to PEG-IFN-α2b monotherapy.

Methods

Early pharmacokinetics and viral kinetics were analysed in patients treated for 52 weeks with PEG-IFN-α2b with or without lamivudine.

Results

After 4 weeks of treatment, there was a median viral decline of 2.94 log10 copies/ml in those treated with PEG-IFN-α2b and lamivudine and only 0.45 log10 copies/ml in the PEG-IFN-α2b monotherapy group. Peak PEG-IFN-α2b levels were reached approximately one day after administration and subsequently declined exponentially, consistent with a viral load rebound near to baseline levels at the end of the dosing period in most patients receiving PEG-IFN-α2b monotherapy. Modelling of pharmacokinetics and viral kinetics data in this group revealed that viral load was minimal 3.6 days after PEG-IFN-α2b administration, the mean maximal and mean antiviral effectiveness was 70% and 48% with a mean infected cell loss rate of 0.07 per day, while no significant biphasic decline was observed.

Conclusions

PEG-IFN-α2b induces a sustained response in a considerable number of patients despite limited direct antiviral activity during the first weeks of antiviral therapy.
Virological response to Salvage Therapy in HIV-Infected Persons Carrying the Reverse Transcriptase K65R Mutation
Authors: Antinori Andrea , Trotta Maria Paola , Lorenzini Patrizia , Torti Carlo , Gianotti Nicola , Maggiolo Franco , Ceccherini-Silberstein Francesca , Nasta Paola , Castagna Antonella , Luca Andrea De , Mussini Cristina , Andreoni Massimo , Perno Carlo Federico ,   for the GNOMO Study Group
Published: April 2022

Background

The effect of the HIV reverse transcriptase K65R mutation on virological response to salvage therapy has not been clearly defined.

Methods

From six Italian clinical centres, all consecutive patients starting salvage antiretroviral therapy after virological failure in the presence of the K65R mutation identified by a genotypic resistance test were selected.

Results

Among 145 subjects included over a 197 person-year follow-up, the estimated probability of virological response (VR, defined as reaching HIV RNA <50 copies/ml after salvage therapy) at 24 and 48 weeks was 36% and 60%, respectively. The strongest independent predictor of VR was the inclusion of a thymidine analogue (TA) in the salvage regimen. The presence of M184V and the introduction of lopinavir/ritonavir as new drug were both marginally associated with better outcome. After 24 weeks of salvage therapy, the median reduction in HIV-1 RNA was -1.36 log10 copies/ml (interquartile range [IQR] 0.10–2.46): at multivariable regression analysis, salvage regimens containing a TA (β=+0.80; P=0.02) and lamivudine (β=+1.21; P=0.02) as new drug had a positive effect on the reduction of HIV-1 RNA.

Conclusions

Development of the K65R mutation does not preclude a high rate of virological response to rescue therapy. Inclusion of a TA in the salvage regimen and the presence of a M184V mutation could have a favourable effect on virological outcome.
The 3-O-(3’,3’-dimethylsuccinyl) derivative of betulinic acid (DSB) inhibits the assembly of virus-like particles in HIV-1 Gag precursor-expressing cells
Authors: DaFonseca Sandrina , Blommaert Armand , Coric Pascale , Hong Saw See , Bouaziz Serge , Boulanger Pierre
Published: April 2022

Background

The 3- O-(3’,3’-dimethylsuccinyl) derivative of betulinic acid (DSB) blocks HIV-1 maturation by interfering with viral protease (PR) at the capsid (CA)-SP1 cleavage site, a crucial region in HIV-1 morphogenesis.

Methods

We analysed the effect of DSB on the assembly of HIV-1 Gag precursor (Pr55GagHIV) into membrane-enveloped virus-like particles (VLP) in baculovirus-infected cells expressing Pr55GagHIV, in a cellular context devoid of viral PR.

Results

DSB showed a dose-dependent negative effect on VLP assembly, with an IC50∼10 μM. The DSB inhibitory effect was p6-independent and was also observed for intracellular assembly of non-N-myristoylated Gag core-like particles. HIV-1 VLP assembled in the presence of DSB exhibited a lower stability of their inner cores upon membrane delipidation compared with control VLP, suggesting weaker Gag-Gag interactions. DSB also inhibited the assembly of simian immunodeficiency virus SIVmac251 VLP, although with a twofold lower efficacy (IC50∼20 μM). No detectable inhibitory activity was observed for murine leukaemia virus (MLV) VLP; however, fusion of the SP1-NC-p6 domains from HIV-1 to the matrix (MA)-CA domains from MLV conferred DSB sensitivity to the chimaeric Gag precursor Pr72GagMLV–HIV (IC50=30 μM). This observation suggested that the main DSB target on Pr55Gag was the SP1 domain, but the higher degree of DSB resistance for Pr72GagMLV–HIV compared with Pr55GagHIV implied that other upstream Gag region(s) might contribute to DSB reactivity.

Conclusions

Sequence alignment and three-dimensional modelling by homology of the CA-SP1-NC junction in HIV-1, SIVmac251 and Pr72GagMLV–HIV suggested that a higher hydrophilic character of the CA region immediately upstream to the HIV-1 CA-SP1 junction, as occurred in Pr72GagMLV–HIV, correlated with a lower DSB sensitivity.
A 6-Month Interruption of Antiretroviral Therapy Improves Adipose Tissue Function in HIV-Infected Patients: The ANRS EP29 Lipostop Study
Authors: Kim Min Ji , Leclercq Pascale , Lanoy Emilie , Cervera Pascale , Antuna-Puente Barbara , Maachi Mustapha , Dorofeev Elena , Slama Laurence , Valantin Marc Antoine , Costagliola Dominique , Lombes Anne , Bastard Jean-Philippe , Capeau Jacqueline
Published: April 2022

Objective

To examine the reversibility of adipose tissue alterations in HIV-infected patients after a 6-month interruption of antiretroviral therapy (ART).

Methods

Forty HIV-infected patients on stable effective ART were enrolled, 33 of them completed the study. Patients underwent a physical examination, laboratory tests and needle biopsy of subcutaneous abdominal adipose tissue both at inclusion and at month 6. Changes in fat morphology, mitochondrial DNA (mtDNA) content and gene expression were examined in 29, 23 and 20 patients, respectively.

Results

Body fat distribution was not clearly modified at month 6. Adipose tissue inflammation improved markedly, with fewer infiltrating macrophages and fewer tumour necrosis factor a (TNFα)- and interleukin 6 (IL6)-expressing cells. Expression of peroxisome proliferator-activated receptor γ (PPAR-γ) and of markers of mitochondrial function and biogenesis (cytochrome oxidase 2 and PPAR-γ coreceptor 1α) improved after protease inhibitor (PI) withdrawal. In patients who stopped taking stavudine or zidovudine, the number of TNFα- and IL6-expressing cells was lower at month 6 than at month 0, and so was CD68 expression, a macrophage marker. Adipocyte mitochondrial status also improved, with lower mitochondrial density and cytochrome oxidase 4 mRNA levels, and higher mtDNA content. Sterol regulatory element binding protein 1 mRNA levels increased, reflecting better adipocyte differentiation.

Conclusions

A 6-month ART interruption markedly improved adipose tissue functions, although fat distribution did not visibly change. Stavudine and zidovudine were associated with marked inflammation, which improved when these drugs were withdrawn; they also had a negative effect on differentiation and mitochondrial status. PIs were also associated with altered adipocyte differentiation and mitochondrial status. These data clearly show the detrimental effect of antiretroviral drugs, in particular thymidine analogues, on adipose tissue and argue for switch strategies sparing these drugs.
Tenofovir Use is associated with a Reduction in Calculated Glomerular Filtration Rates in the Swiss HIV Cohort Study
Authors: Fux Christoph A , Simcock Mathew , Wolbers Marcel , Bucher Heiner C , Hirschel Bernard , Opravil Milos , Vernazza Pietro , Cavassini Matthias , Bernasconi Enos , Elzi Luigia , Furrer Hansjakob ,   Swiss HIV Cohort Study, Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Fux C , Gorgievski M , Günthard H , Hirschel B , Hösli I , Kahlert Ch , Kaiser L , Karrer U , Keiser O , Kind C , Klimkait Th , Ledergerber B , Martinez B , Müller N , Nadal D , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rauch A , Rickenbach M , Rudin C , Schmid P , Schultze D , Schüpbach J , Speck R , Taffé P , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S
Published: April 2022

Background

A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort.

Methods

We compared treatment-naive patients or patients with treatment interruptions ≥12 months starting either a TDF-based combination antiretroviral therapy (cART) ( n=363) or a TDF-sparing regime ( n=715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model.

Results

Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58–0.72) and 0.80 (95% CI 0.76–0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR]=2.34 [95% CI 1.24–4.42]), higher baseline cGFR (HR=1.03 [95% CI 1.02–1.04] by 10 ml/min), TDF use (HR=1.84 [95% CI 1.35–2.51]) and boosted protease inhibitor use (HR=1.71 [95% CI 1.30–2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency.

Conclusion

There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.
Human Coronaviruses: What Do They Cause?
Authors: Van Der Hoek Lia
Published: April 2022

SARS-CoV, human coronavirus NL63 (HCoV-NL63) and HCoV-HKU1 were first described in 2003, 2004 and 2005 respectively. Nevertheless, discovery of three new human coronaviruses does not necessary represent a sudden increase in emerging infections by new coronaviruses. Only SARS-CoV has recently been introduced to the human population; the other two have been circulating in humans for a long time. HCoV-HKU1 and HCoV-NL63 are respiratory coronaviruses, are frequently found during lower and upper respiratory tract infections, have spread worldwide, and prefer the winter season. These characteristics do not differ greatly from the symptoms described for the ‘old’ viruses HCoV-229E and HCoV-OC43. This report presents an overview of the current knowledge of the four human coronavirus that are now circulating in the human population.
Discovery and Characterization of the 1918 Pandemic Influenza Virus in Historical Context
Authors: Taubenberger Jeffery K , Hultin Johan V , Morens David M
Published: April 2022

The 2005 completion of the entire genome sequence of the 1918 H1N1 pandemic influenza virus represents both a beginning and an end. Investigators have already begun to study the virus in vitro and in vivo to better understand its properties, pathogenicity, transmissibility and elicitation of host responses. Although this is an exciting new beginning, characterization of the 1918 virus also represents the culmination of over a century of scientific research aiming to understand the causes of pandemic influenza. In this brief review we attempt to place in historical context the identification and sequencing of the 1918 virus, including the alleged discovery of a bacterial cause of influenza during the 1889–1893 pandemic, the controversial detection of ‘filter-passing agents’ during the 1918–1919 pandemic, and subsequent breakthroughs in the 1930s that led to isolation of human and swine influenza viruses, greatly influencing the development of modern virology.
The Epidemiology, Natural History and Prevention of Hepatitis B: Implications of HIV Coinfection
Authors: McGovern Barbara H
Published: April 2022

Approximately 350 million people have chronic hepatitis B infection, a leading cause of cirrhosis and hepatocellular carcinoma (HCC). Patients who are infected through parenteral or sexual transmission are also at risk for acquisition of HIV. Concomitant HIV infection can lead to an increased risk of morbidity and mortality from hepatitis B virus (HBV)-related cirrhosis, end-stage liver disease and HCC. This review will focus on the epidemiology, natural history and prevention of HBV infection and the modulating effect of HIV on the clinical expression of HBV disease.
Diagnosis, Diagnostic Tests and Monitoring of Hepatitis B Virus in Monoinfected and HIV-Coinfected Patients
Authors: Thio Chloe L
Published: April 2022

With the recent approval of several drugs for the management of chronic hepatitis B, the proper diagnosis and classification of this disease is necessary to determine if therapy is needed and what the best treatment options are. The diagnosis of chronic hepatitis B relies on serological testing, and disease stage is further characterized with HBV DNA levels and an assessment of liver disease through biopsy or non-invasive methods. A regular screening protocol is necessary for patients with chronic hepatitis B to monitor the development of cirrhosis and hepatocellular carcinoma. Patients receiving treatment also need regular monitoring for response to determine if a different therapeutic regimen is needed or if drug-resistant variants are being selected. This review discusses the various tests for hepatitis B diagnosis and for monitoring disease progression and treatment response. In addition, noninvasive methods for classifying liver disease stage are discussed, as are special considerations that are needed for individuals coinfected with HIV.
Contribution of Mitochondrial Dysfunction and Oxidative Stress to Cellular Premature Senescence Induced by Antiretroviral Thymidine Analogues
Authors: Caron Martine , Auclair Martine , Vissian Anais , Vigouroux Corinne , Capeau Jacqueline
Published: April 2022

Objectives

Treatment of HIV-infected patients is associated with early onset of aging-related comorbidities. Some of the adverse effects of antiretroviral therapy have been attributed to the mitochondrial toxicity of nucleoside reverse transcriptase inhibitors (NRTI), and it is of note that mitochondrial dysfunction and oxidative stress are involved in the aging processes. In this regard, we examined whether NRTIs could accelerate the senescence of cultured cells.

Methods

Human fibroblasts were exposed to NRTIs from culture passage 1 to 14. Cytochrome c-oxidase (COX) subunits 2 and 4, mitochondrial potential and mass, and reactive oxygen species (ROS) were quantified at each passage. Proliferation, cell-cycle arrest, senescence-associated β-galactosidase activity, and morphology were assessed in parallel. Mitochondrial and senescence markers were assessed in cultured murine preadipocytes and in fat samples from lipodystrophic HIV-infected patients.

Results

Stavudine and zidovudine induced mitochondrial dysfunction and increased ROS levels in fibroblasts at early culture passages, while cell division gradually slowed. At passages 8–12, fibroblasts exposed to stavudine or zidovudine but not abacavir, didanosine, lamivudine and tenofovir were senescent, on the basis of p16INK4 and p21WAF-1 protein expression, cell morphology and senescence-associated-β-galactosidase activity. Senescence markers and COX2 underexpression were also found in 3T3-F442A preadipocytes exposed for 7 weeks to stavudine or zidovudine, but not lamivudine, and in adipose tissue samples from lipodystrophic HIV-infected patients on antiretroviral regimens containing stavudine or zidovudine.

Conclusions

Mitochondrial changes and oxidative damage could partly explain the premature senescence of fibroblasts and adipose cells induced by stavudine and zidovudine. This suggests that thymidine analogues might be involved in the early aging-related diseases observed in some HIV-infected patients taking antiretroviral drugs.
Does Treatment of Hepatitis B virus (HBV) Infection Reduce Hepatitis Delta virus (HDV) Replication in HIV-HBV-HDV-Coinfected Patients?
Authors: Sheldon Julie , Ramos Belén , Toro Carlos , Ríos Pilar , Martínez-Alarcón José , Bottecchia Marcelle , Romero Miriam , Garcia-Samaniego Javier , Soriano Vincent
Published: April 2022

Background

Hepatitis delta virus (HDV) has a unique replication process that requires coinfection with hepatitis B virus (HBV). Treatment is currently limited to interferon therapy. The role of potent nucleos(t)ide analogues active against HBV has not been well examined in chronic delta hepatitis (CDH).

Methods

HIV-positive patients with CDH attending our hospital were identified and longitudinally studied. Serum HBV DNA, HDV RNA and HIV RNA, treatment regimens, and biochemical and serological markers were assessed at yearly intervals. Liver fibrosis was measured by transient elastography during the last 2 years.

Results

Sixteen patients were identified and treated with anti-HBV therapy (median time 6.1 years). The majority were male and previous intravenous drug users. Median baselines were: HDV RNA 7 log10 copies/ml, HIV RNA 1.7 log10 copies/ml, HBV DNA 1.1 log10 IU/ml and alanine aminotransferase (ALT) 98 IU/ml. A significant correlation was found between HDV RNA and HBV DNA (r=0.226, P=0.015), aspartate aminotransferase (r=0.430, P<0.0001), ALT (r=0.441, P<0.0001) and hepatitis B surface antigen (HBsAg) (r=0.557, P<0.0001). Overall, 13 patients showed a reduction in HDV viraemia and ALT levels, and three of them achieved undetectable HDV RNA and normal ALT levels.

Conclusion

Patients undergoing successful anti-HBV therapy with potent nucleos(t)ide analogues seem to indirectly benefit from suppression of HDV replication, albeit not very efficiently. Hypothetically, a significant and sustained reduction in serum HDV RNA might only be seen when a reduction in HBV covalently closed circular DNA or HBV surface antigen is achieved, which may require long periods of successful anti-HBV therapy. To our knowledge, this is the first evidence of the benefit of potent anti-HBV nucleos(t)ide analogue therapy in CDH.
Antiretroviral-Associated Portal Hypertension: A New Clinical Condition? Prevalence, Predictors and Outcome
Authors: Maida Ivana , Garcia-Gasco Pilar , Sotgiu Giovanni , Rios María José , Vispo María Eugenia , Martin-Carbonero Luz , Barreiro Pablo , Mura María Stella , Babudieri Sergio , Albertos Sonia , Garcia-Samaniego Javier , Soriano Vincent
Published: April 2022

Background

Cases of severe unexplained liver disease in HIV-infected individuals have recently been reported and are often associated with exposure to didanosine (ddI) and nodular regenerative hyperplasia. Herein, we examine the clinical outcome following ddI removal.

Methods

From 3,300 HIV-infected patients attending three clinics since 2004, all who exhibited persistently elevated aminotransferases and/or significant liver fibrosis in the absence of any known cause of liver damage were identified.

Results

Thirty-two individuals (prevalence ∼1%) met the inclusion criteria - all were on antiretroviral therapy. Of these, 84% were male and 68% had acquired HIV through homosexual contact. Liver biopsy was performed in 12, of whom three showed nonspecific advanced liver fibrosis, two nodular regenerative hyperplasia and three showed only periportal fibrosis. On follow up, nine patients developed episodes of hepatic decompensation, mainly as a consequence of portal hypertension; in eight cases (25%) portal thrombosis was diagnosed. No association was found with plasma HIV RNA or CD4+ T-cell count. All patients but three had been exposed to ddI for a median of 44 months; removal of ddI in 27 was followed 12 months later by improvement in clinical and laboratory parameters in 13 (48%) patients. Finally, a trend towards liver fibrosis improvement was recognised using FibroScan®.

Conclusions

Idiopathic persistent liver enzyme elevations in HIV-infected individuals are often associated with cirrhotic and non-cirrhotic portal hypertension. Although this is a relatively rare condition, prolonged exposure to ddI seems to play a pathogenic role and removal of the drug is associated with clinical and laboratory improvements.
Gln151 of HIV-1 Reverse Transcriptase Acts as a Steric Gate Towards Clinically Relevant Acyclic Phosphonate Nucleotide Analogues
Authors: Frangeul Antoine , Bussetta Cécile , Deval Jérôme , Barral Karine , Alvarez Karine , Canard Bruno
Published: April 2022

Background

In the treatment of HIV, the loose active site of the HIV-1 reverse transcriptase (RT) allows numerous nucleotide analogues to act as proviral DNA ‘chain-terminators’. Acyclic nucleotide phosphonate analogues (ANPs) represent a particular class of nucleotide analogue that does not possess a ribose moiety. The structural basis for their substrate efficiency regarding viral DNA polymerases is poorly understood.

Methods

Pre-steady-state kinetics on HIV-1 RT together with molecular modelling, were used to evaluate the relative characteristics of both the initial binding and incorporation into DNA of three different ANP diphosphates with progressively increasing steric demands on the acyclic linker: adefovir-diphosphate (DP), tenofovir-DP, and cidofovir-DP.

Results

The increase of steric demand in ANPs induced a proportional loss of the binding affinity to wild-type HIV-1 RT ( K d cidofovir-D P>> K d tenofovir-D P> K d adefovir-DP∼ K d dNTPs), consistent with the lack of HIV-1 inhibitory activity for cidofovir. We show that, starting from adefovir-DP, the steric constraints mainly map to Gln151, as its mutation to alanine provides cidofovir-DP sensitivity. Interactions between the Gln151 residue and the methyl group of tenofovir-DP further increase with the mutation Gln151Met, resulting in a specific discrimination and low-level resistance to tenofovir-DP. This alteration is the result of a dual decrease in the binding affinity ( K d) and the catalytic rate ( k pol) of incorporation of tenofovir-DP. By contrast, the tenofovir resistance mutation K65R induces a broad ‘ k pol-dependent’ nonspecific discrimination towards the three ANPs.

Conclusions

Overall, our results show that the efficiency of ANPs to compete against natural nucleotides as substrates for RT is determined by their close interaction with specific amino acids such as Gln151 within the RT active site. These results should help us to map and predict ANP sensitivity determinants in cellular and viral DNA polymerase active sites for which the understanding of different ANP sensitivity patterns are of medical importance.
When to Initiate Highly Active Antiretroviral Therapy in Low-Resource Settings: The Moroccan Experience
Authors: Loubiere Sandrine , el Filal Kamal Marhoum , Sodqi Mustapha , Loundou Anderson , Luchini Stéphane , Cleary Susan , Moatti Jean-Paul , Himmich Hakima
Published: April 2022

Background

The aim of this study was to assess the cost-effectiveness of HIV treatment alternatives – with and without highly active antiretroviral therapy (HAART) – within alternative strata based on the CD4+ T-cell count at the initiation of treatment in a low-resource setting.

Methods

A retrospective observational study was conducted following 286 HIV-positive individuals admitted to the principal teaching hospital in Casablanca, Morocco, between 1995 and 2002. Patients were stratified by CD4+ T-cell count and regression models were fitted to determine risk of opportunistic infection. Data on healthcare resource use were derived from patient records and were evaluated from the hospital perspective.

Results

HAART led to a significant reduction in the number of HIV-related opportunistic infections ( P<0.0001), extended survival (61.3 versus 55.2 months; P<0.0001) and reduced hospital stays ( P<0.0001) in comparison with care in the absence of HAART. When medical care and drug costs were considered together, HAART was more costly than providing treatment for opportunistic infections. The incremental cost-effectiveness ratio was lower than gross domestic product (GDP) per capita for patients starting HAART with a CD4+ T-cell count <200 cells/mm3, but this increased to nearly three times GDP per capita when HAART was initiated at CD4+ T-cell counts above this threshold.

Conclusions

HAART is more cost-effective than treating HIV-related opportunistic infections and, contrary to conclusions drawn in developed countries, HAART is more cost-effective when the CD4+ T-cell count drops to <200 cells/mm3.
Clinical Implications of Resistance to Antiretrovirals: New Resistance Technologies and Interpretations
Authors: Mascolini Mark , Richman Douglas , Larder Brendan , Mellors John , Boucher Charles AB
Published: April 2022

Understanding resistance to antiretroviral therapy plays an ever more crucial role in managing HIV infection as new agents – including several in new antiretroviral classes – promise better control of multidrug-resistant virus in the developed world. Yet these new drugs have different, and often complex, resistance profiles. At the same time, resistance has assumed a key role in developing countries as access to additional antiretrovirals expands in the face of first-line regimen failures. Every year the International HIV Drug Resistance Workshop gathers leading investigators and resistance-savvy clinicians to share unpublished, peer-reviewed research on the mechanisms, pathogenesis, epidemiology, and clinical implications of resistance to licensed and experimental antivirals. The 2007 workshop, held on 12–16 June, proved particularly notable for its exploration of resistance to two new antiretroviral classes, integrase inhibitors and CCR5 antagonists, as well as to agents that control hepatitis C virus (HCV) infection. This report summarizes most oral presentations from the workshop and many posters.
Interruption of Antiretroviral Therapy and Risk of Cardiovascular Disease in Persons with HIV-1 Infection: Exploratory Analyses from the SMART Trial
Authors: Phillips Andrew N , Carr Andrew , Neuhaus Jacquie , Visnegarwala Fehmida , Prineas Ronald , Burman William J , Williams Ian , Drummond Fraser , Duprez Daniel , Belloso Waldo H , Goebel Frank-Detlef , Grund Birgit , Hatzakis Angelos , Vera Jose , Lundgren Jens D
Published: April 2022

Background

The SMART trial found a raised risk of cardiovascular disease (CVD) events in patients undergoing CD4+ T cell-count guided intermittent antiretroviral therapy (ART) compared with patients on continuous ART. Exploratory analyses were performed to better understand the reasons for this observation.

Methods

A total of 5,472 patients with CD4+ T-cell counts >350 cells/mm3 were recruited and randomized to either continuous ART (the viral suppression arm; VS) or CD4+ T-cell count-guided use of ART (the drug conservation arm; DC).

Results

Major CVD events developed in 79 patients. The hazard ratio (HR) for risk of CVD events for DC versus VS was 1.57 (95% confidence interval 1.00–2.46; P=0.05). There was no evidence that being off ART or a higher current HIV viral load were associated with increased CVD risk. Total cholesterol and low-density lipoprotein cholesterol were reduced as a result of ART interruption in DC patients but so was high-density lipoprotein (HDL) cholesterol, leading to a net unfavourable change in the total/HDL cholesterol ratio.

Conclusions

Reasons for the higher risk of CVD for DC compared with VS patients remain unclear. There was no clear evidence to suggest that ART interruption per se or a higher HIV viral load were associated with an increased CVD risk in the DC group. Lipid changes were less favourable among DC compared with VS patients, which could offer a partial explanation.