bluuebunny/crossref_metadata_2025 huggingface dataset:
Construction, Training and Clinical Validation of An Interpretation System for Genotypic HIV-1 Drug Resistance Based on Fuzzy Rules Revised by Virological Outcomes
Authors: Luca Andrea De , Vendittelli Marilena , Baldini Francesco , Giambenedetto Simona Di , Trotta Maria Paola , Cingolani Antonella , Bacarelli Alessandra , Gori Caterina , Perno Carlo Federico , Antinori Andrea , Ulivi Giovanni
Published: April 2022

Objectives

To evaluate whether fuzzy operators can be usefully applied to the interpretation of genotypic HIV-1 drug resistance by experts, and to improve the prediction of salvage therapy outcome by adapting interpretation rules of genotypic resistance on the basis of their association with virological response data.

Methods

We used a clinical dataset of 231 patients failing highly active antiretroviral therapy (HAART) and starting salvage therapy with baseline resistance genotyping and virological outcomes after 3 and 6 months. A set of rules predicting genotypic resistance was initially derived from an expert (ADL). Rules were implemented using a fuzzy logic approach and the virological outcomes dataset used for the training phase. The resulting algorithm was validated using a separate set of 184 selected patients by correlating the resulting predicted activity with observed virological response at 3 months. For comparison, the expert systems from the drug resistance group of the Agence Nationale de Recherches sur le SIDA (ANRS-AC11) and the algorithm from the Stanford's HIV drug resistance database (Stanford HIVdb) were evaluated on the same set.

Results

The starting algorithm had a correlation with virological outcomes of R2=0.06 ( P=0.0001). After the training phase the correlation with virological outcomes increased to R2=0.19 ( P<0.000001). In the validation set of patients, the activity of the salvage regimen predicted by the fuzzy algorithm was the only variable independently predictive of the 3-month viral load change even after adjusting by the activity predicted by the two expert systems and baseline viral load (for each 10% salvage regimen's activity increase, mean HIV RNA change from baseline: -0.27 log10 copies/ml; 95% CI -0.39, -0.15).

Conclusion

Using fuzzy operators in a virological outcomes training database to implement a rules-based algorithm for genotypic resistance interpretation, significant improvements of outcomes prediction were obtained. The resulting algorithm showed an independent predictive capability of virological outcomes over that of two rules-based interpretation algorithms made by experts. Although the system was trained and validated on a limited number of cases, the approach deserves further evaluation. Presented in part at the XI International Drug Resistance Workshop, Seville, Spain 2002 [Abstract 85]. Antiviral Therapy 2002; 7:S71.
Prostratin Induces HIV Activation and Downregulates HIV Receptors in Peripheral Blood Lymphocytes
Authors: Rullas Joaquín , Bermejo Mercedes , García-Pérez Javier , Beltrán Manuela , González Nuria , Hezareh Marjan , Brown Stephen J , Alcamí José
Published: April 2022

Induction of HIV expression through lymphocyte activation has been proposed as a strategy to purge latent reservoirs. Prostratin is a non-tumourogenic phorbol ester that delays HIV replication in vitro, but paradoxically activates HIV expression in latently infected cells. To get a better insight into the mechanisms of action of prostratin, we have analysed the effect of prostratin on HIV activation and HIV receptor and coreceptors’ surface expression in human lymphocytes. Peripheral blood mononuclear cells (PBMCs) were transfected with luciferase expression constructs under the control of wild type HIV-long terminal repeat (LTR) and consensus sequences for transcription factors involved in HIV-LTR transactivation (NF-κB, SP1, NFAT). Prostratin stimulates transactivation of LTR vectors, κB- and SP-1-driven luciferase constructs. In another set of experiments, PBMCs were transfected with a full-length infectious viral clone. Prostratin induced HIV transcription and viral expression as detected by luciferase activity in cellular extracts and p24 levels in culture supernatants, respectively. Expression of the HIV coreceptors CCR5 and CXCR4 was decreased by prostratin and, concomitantly, prostratin inhibited the infection of PBMCs with R5 and X4 strains. However, prostratin did not inhibit infection with a pseudotyped viral clone that enters into the cells independently of HIV receptors. These results help to explain the paradoxical effects of prostratin. On one hand, prostratin induces HIV activation in latently infected cells through the induction of NF-κB and Sp1. On the other hand, strong and persistent downregulation of HIV receptors decreases infection of new targets and delays HIV propagation. These data support the potential use of prostratin to activate HIV from latency and purge viral reservoirs.
Gynaecomastia in HIV-Infected Men on Highly Active Antiretroviral Therapy: Association with Efavirenz and Didanosine Treatment
Authors:   for the Grupo Andaluz para el Estudio de las Enfermedades Infecciosas (GAEI), Mira José A , Lozano Fernando , Santos Jesús , Ramayo Emilia , Terrón Alberto , Palacios Rosario , León Eva M , Márquez Manuel , Macías Juan , Fernández-Palacín Ana , Gómez-Mateos Jesús , Pineda Juan A
Published: April 2022

Background

Gynaecomastia has been described in HIV-infected men undergoing highly active antiretroviral therapy (HAART). However, there are insufficient data on the relationship between gynaecomastia and any specific antiretroviral drug and hormone abnormality.

Objective

To assess the frequency of gynaecomastia in HIV-infected men receiving HAART and its association with antiretroviral drugs and hormone abnormalities.

Methods

We carried out a prospective study of 1304 HIV-infected men undergoing HAART. In addition, we included a case (with gynaecomastia)-control (without gynaecomastia) analysis in the second part of this study. Cases and controls were matched according to age, HIV infection CDC clinical category, HCV infection, the date of study and the physician responsible for the patient. Patients bearing known causes of gynaecomastia were excluded. We analysed epidemiological, clinical, haematological and immunological characteristics and the use and duration of the antiretroviral therapy. In 13 cases and 13 controls a sexual hormone profile was carried out.

Results

A total of 30 (2.3%) HIV-infected men presented with gynaecomastia of unexplained cause. In 22 (73%) of these individuals, gynaecomastia completely resolved after a median time of 9 months (range: 5–22 months). The percentage of individuals who were receiving efavirenz and didanosine at the time of the study was higher among patients with gynaecomastia [57% vs 17% ( P=0.004) and 50% vs 13% ( P=0.003), respectively]. Plasma total testosterone, free testosterone index and bioavailable testosterone levels were lower in patients with gynaecomastia, whereas plasma free testosterone levels were not significantly different in either population.

Conclusions

Gynaecomastia is not uncommon in HIV-infected men undergoing HAART and it is usually transient. Efavirenz and didanosine treatment are associated with the emergence of gynaecomastia. An underlying hypoandrogenism seems to contribute to the emergence of this disorder in these patients.
Antivirogram or Phenosense: A Comparison of their Reproducibility and an Analysis of their Correlation
Authors: Wang Kai , Samudrala Ram , Mittler John E
Published: April 2022

The Antivirogram and PhenoSense assays are widely used phenotypic tests for HIV drug resistance. There are limited data on the reproducibility of each assay, and little is known about the correlation between the two. Using data from the Stanford HIV drug resistance database, we performed a comprehensive analysis of the reproducibility of each assay, and calculated the correlation and concordance of the two assays using both general IC50 fold change cutoff values and drug-specific cutoff values. Although the within-assay correlations were high (rank correlation coefficients r=0.94 and r=0.95 for the Antivirogram and PhenoSense assays, respectively), the between-assay correlation was considerably lower ( r=0.36). Using drug-specific cutoff values for viruses classified as resistant by the Antivirogram or PhenoSense assays, respectively, only 71.4% [95% confidence intervals (95% CI): 58.7–82.1%] and 57.0% (95% CI: 45.3–68.1%) of the samples were classified as resistant using the other assay. The poor agreement between the assays was primarily due to the extremely poor correlation between these assays for samples with low resistance values ( r=0.02 and r=0.61 for samples with the Antivirogram measurements lower or higher than 2.0, respectively). Since the cutoff values for both assays are relatively low, our analysis suggests that one should be very careful when interpreting measurements that are near the cutoff values for drug resistance.
Expression of Pregnane-X-Receptor Transcript in Peripheral Blood Mononuclear Cells and Correlation with Mdr1 Mrna
Authors: Owen Andrew , Chandler Becky , Back Dave J , Khoo Saye H
Published: April 2022

P-glycoprotein (P-gp) limits bioavailability and accumulation of HIV protease inhibitors (PIs). PIs are ligands for the pregnane-X-receptor (PXR), which regulates P-gp expression. This occurs when ligands activate the receptor, initiating binding to response elements in the MDR1 promoter. PXR also activates cytochrome P4503A4 (CYP3A4) and a correlation between hepatic PXR and CYP3A4 mRNA has been reported. We have examined the relationship between MDR1 and PXR mRNA in peripheral blood cells and demonstrate a significant correlation in 18 volunteers (R2=0.4; P<0.005). PXR was approximately 250-fold lower in peripheral blood mononuclear cells than in liver (1.6 ±1.2 vs 450 ±298; n=6; P<0.01).
The Plasma and Intracellular Steady-State Pharmacokinetics of Lopinavir/Ritonavir in HIV-1-Infected Patients
Authors: Crommentuyn Kristel ML , Mulder Jan W , Mairuhu Albert TA , van Gorp Eric CM , Meenhorst Pieter L , Huitema Alwin DR , Beijnen Jos H
Published: April 2022

Therapeutic drug monitoring of protease inhibitors (PIs) is usually performed on plasma samples although their antiretroviral effect takes place inside cells. Little is known, however, about the intracellular accumulation and related plasma pharmacokinetics of PIs such as lopinavir/ritonavir (LPV/RTV). Therefore, we studied the plasma and intracellular (cell-associated) steady-state pharmacokinetics of this PI combination in a dosage of 400/100 mg twice daily in a non-randomized cohort of HIV-1-infected individuals. Plasma (0–12 h) and peripheral blood mononuclear cell (PBMC; 0–8 h) samples were drawn during a 12-h dosing interval in 11 subjects.

The plasma concentrations versus time curves of LPV and RTV were characterized by an irregular absorption phase showing double-peaks (Cmax) in most subjects and single-peaks in the remaining patients between 1 and 3 h after drug intake. Pre-dose concentrations of both agents in plasma were significantly higher than the concentrations at the end of the dosing interval indicating the presence of a circadian rhythm in their pharmacokinetics. The course of the intracellular concentrations versus time curves appeared to be similar to the plasma concentration curves, with the highest intracellular concentration measured 3 h after drug intake. The intracellular RTV concentrations were higher than reported in vitro EC50 values and might therefore contribute to the antiretroviral effect of LPV/RTV. The median intracellular-to-plasma concentration ratios (interquartile range) were 1.18 (0.74–2.06) and 4.59 (3.20–7.70) for LPV and RTV, respectively.

In conclusion, both LPV and RTV accumulate to potential therapeutic concentrations in PBMCs. Irregular absorption and circadian plasma clearance patterns were observed for the PI combination LPV/RTV.
Management of Antiviral Resistance in Patients with Chronic Hepatitis B
Authors: Locarnini Stephen , Hatzakis Angelos , Heathcote Jenny , Keeffe Emmet B , Liang T Jake , Mutimer David , Pawlotsky Jean-Michel , Zoulim Fabien
Published: April 2022

A meeting of physicians and scientists involved in the management of chronic hepatitis B (CHB) was held to review current scientific data regarding antiviral resistance in hepatitis B virus (HBV) infection. The goals of the meeting were to describe current treatments for CHB, discuss emerging issues in HBV drug resistance and to delineate patient monitoring, including markers for resistance, during administration of antiviral therapy. The aim of this review article is to provide treating physicians with a framework for the management of CHB in the context of antiviral resistance. Definitions of primary and secondary antiviral treatment failure can be used to aid monitoring and early diagnosis of drug resistance before disease progression occurs as a consequence of viral breakthrough. Primary antiviral treatment failure is defined as failure of a drug to reduce HBV DNA levels by ≥1xlog10 IU/ml within 3 months following initiation of therapy, and secondary antiviral treatment failure as a rebound of HBV replication of ≥1xlog10 IU/ml from nadir in patients with an initial antiviral treatment effect (≥1xlog10 IU/ml decrease in serum HBV DNA). Confirmation of antiviral drug failure can be established by sequencing the HBV DNA polymerase and identifying specific genetic markers of antiviral drug resistance. In addition to virological assays, HBV resistance can be assessed from a clinical perspective including increased serum alanine aminotransferase levels and the development of systemic symptoms or signs of liver failure. Potential strategies to prevent the emergence of resistance and how to manage drug-resistant HBV once it emerges are discussed.
Lack of Interferon Sensitivity-Determining Region in the Genome of Hepatitis B Virus Genotype Ba
Authors: Liu Chun-Jen , Chen Pei-Jer , Lai Ming-Yang , Chen Ting-Chih , Wang Hurng-Yi , Huang Wen-Ling , Kao Jia-Horng , Chen Ding-Shinn
Published: April 2022

Background/aims

In chronic hepatitis B, both host and viral factors may predict the response to interferon (IFN) treatment. Whether IFN sensitivity-determining regions exist within the hepatitis B virus (HBV) genomic background remains largely unknown. We therefore performed full-length viral genomic comparison between HBVs obtained from IFN responders and non-responders.

Methods

We enrolled 18 HBV genotype Ba patients who had received 24-week IFN 5 MU three times weekly and were followed monthly for 12 months post-treatment. There were 10 responders and eight non-responders. Pretreatment full-length viral nucleotide consensus sequence was obtained. In six non-responders and four responders, post-treatment viral nucleotide sequence was further compared with their corresponding pre-treatment specimens. In addition, the average number of nucleotide substitutions of the HBV quasispecies was compared between three responders and three non-responders.

Results

HBV nucleotide consensus sequence was identical between responders and non-responders. We found 0–15 (mean 7.7) nucleotide substitutions in the post-treatment HBV genome in the six non-responders and 0–14 (mean 3.8) nucleotide substitutions in the four responders, respectively. Genetic complexity of HBV quasispecies was comparable between responders and non-responders.

Conclusions

Our results suggest that an IFN sensitivity-determining region might not exist within the genome of HBV genotype Ba. Host factors and virus–host interactions may be more important in determining the response to IFN treatment.
Antiretroviral Drugs with Adverse Effects on Adipocyte Lipid Metabolism and Survival Alter the Expression and Secretion of Proinflammatory Cytokines and Adiponectin In Vitro
Authors: Lagathu Claire , Bastard Jean-Philippe , Auclair Martine , Maachi Mustapha , Kornprobst Michel , Capeau Jacqueline , Caron Martine
Published: April 2022

Objective

The lipodystrophy syndrome is a major adverse effect of highly active antiretroviral therapy (HAART), associated with altered circulating levels and adipose tissue mRNA expression of proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor (TNF)α, and adiponectin. Proinflammatory cytokines and adiponectin, which are secreted by adipose tissue, regulate fat metabolism, insulin sensitivity and adipose cell apoptosis. We examined the direct effects of individual antiretrovirals on lipid metabolism and cytokine and adiponectin production by cultured adipocytes.

Methods

Differentiating 3T3-F442A cells and differentiated 3T3-L1 adipocytes were treated for 12 or 4 days, respectively, with protease inhibitors (PIs) indinavir, nelfinavir, amprenavir, lopinavir and ritonavir, or nucleoside reverse transcriptase inhibitors (NRTIs) stavudine and zidovudine, at near-Cmax concentrations. Lipid metabolism was estimated by Oil Red O staining of intracellular lipids, mRNA expression of fatty acid synthase and adipocyte lipid binding protein 2, and insulin activation of lipogenesis. Apoptosis was estimated by flow cytometry. The expression and secretion of proinflammatory cytokines (IL-6, TNFα and IL-1β) and adiponectin were evaluated by real-time reverse transcription PCR and ELISA.

Results

Chronic treatment of 3T3-F442A differentiating adipocytes and differentiated 3T3-L1 adipocytes with PIs and NRTIs reduced lipid accumulation, mRNA expression of lipid markers and insulin-induced lipogenesis. IL-6, TNFα, IL-1β and adiponectin expression and secretion were markedly altered in differentiating 3T3-F442A adipocytes. PIs had either no effect on differentiated 3T3-L1 adipocytes (TNFα expression and secretion) or their effect was less marked than in 3T3-F442A cells. Indinavir and amprenavir did not alter cytokine secretion and expression by mature adipocytes. The effects of stavudine and zidovudine on differentiating and mature adipocytes were similar, despite the difference in treatment procedure. The drugs with the strongest effect on TNFα expression also increased adipocyte apoptosis, in contrast to the drugs that only moderately increased TNFα expression.

Conclusions

These results suggest that increased cytokine and decreased adiponectin secretion and expression induced by some PIs and NRTIs may contribute to the adipose tissue loss (via apoptosis and lipid leakage) and insulin resistance associated with the lipodystrophy syndrome.
Low-Dose Hepatitis B Immune Globulin and Higher-Dose Lamivudine Combination to Prevent Hepatitis B Virus Recurrence after Liver Transplantation
Authors: Karasu Zeki , Ozacar Tijen , Akyildiz Murat , Demirbas Tolga , Arikan Cigdem , Kobat Arzu , Akarca Ulus , Ersoz Galip , Gunsar Fulya , Batur Yucel , Kilic Murat , Tokat Yaman
Published: April 2022

Post-transplant prevention of hepatitis B virus (HBV) infection is based on treatment with lamivudine and/or hepatitis B immune globulin (HBIG). However, optimum doses and duration for these drugs are not yet clear. We tested high doses of lamivudine (300 mg/day) in combination with low doses of HBIG (200–400 IU/2–4 weeks). Eighty patients who had post-transplant prophylaxis of lamivudine and HBIG were included in the study. Of those, 20 had hepatitis D virus co-infection and eight were HBV DNA-positive at the time of transplantation. Ten HBV DNA-positive patients were treated with lamivudine (150 mg/day) before transplantation; all were HBV DNA-negative after lamivudine treatment.

All patients in the anhepatic phase were given 4000 IU of HBIG. Following this, 400 or 800 IU HBIG was administered intramuscularly daily for 5–10 days post-transplantation and 2–4 times weekly thereafter, according to serum titre of antibodies to hepatitis B surface antigen (anti-HBs). Lamivudine was maintained or initiated at the time of transplantation and was continued indefinitely.

Median follow-up was 21 months (range 3–73 months). Recurrence of hepatitis B surface antigen (HBsAg)-positivity occurred in only three out of 78 (4%) patients; two of these three were HBV DNA-positive. Median anti-HBs titre at the final follow-up was 68 IU. Patient and graft survival was 85% at 1 year.

In conclusion, a combination of lamivudine 300 mg/day and low-dose HBIG prevents post-transplantation recurrence of hepatitis B, even in the presence of viral replication in the pre-transplant period.
Complications Associated with Nrti Therapy: Update on Clinical Features and Possible Pathogenic Mechanisms
Authors: Nolan David , Mallal Simon
Published: April 2022

The availability of durable, effective antiretroviral therapy for HIV-infected patients has fundamentally altered the prognosis of this disease and has also increased awareness that long-term drug toxicities have the potential to cause significant morbidity and even mortality in this patient population. The long-term use of nucleoside analogue reverse transcriptase inhibitor (NRTI) drugs has been associated with a number of clinically relevant toxicities including hyperlactataemia and lactic acidosis, neuropathy, pancreatitis and, more recently, a syndrome of pathological loss of subcutaneous fat tissue (lipoatrophy). Importantly, the toxicity profile of each NRTI drug within this class is unique in terms of the overall risk of long-term complications, as well as the tissue specificity of its toxic effects. In this review, the clinical manifestations, risk factors and pathological basis for NRTI-associated toxicity syndromes are explored, with an emphasis on clinical assessment and management.
Clevudine Therapy with Vaccine Inhibits Progression of Chronic Hepatitis and Delays Onset of Hepatocellular Carcinoma in Chronic Woodchuck Hepatitis Virus Infection
Authors: Korba Brent E , Cote Paul J , Menne Stephan , Toshkov Ilia , Baldwin Betty H , Wells Frances V , Tennant Bud C , Gerin John L
Published: April 2022

We examined a rational approach to therapy of chronic hepatitis B virus (HBV) infection that utilized the reduction of viral load combined with appropriately timed immune modulation/stimulation. In a placebo-controlled study, chronic woodchuck hepatitis virus (WHV) carrier woodchucks received clevudine (l-FMAU), previously shown to have especially potent and sustained antiviral activity in woodchucks, for 32 weeks followed by WHV surface antigen (WHsAg) alum-adjuvanted vaccine at 32, 36, 40 and 48 weeks. Clevudine induced significant reductions in viraemia, surface antigenaemia, hepatic WHV nucleic acids, and hepatic core and surface antigens. Viral replication markers remained markedly suppressed in 75% of the clevudine-treated woodchucks following drug withdrawal, but remained at high levels in the vaccine monotherapy and placebo groups. Combination drug and vaccine therapy had benefits based on sustained reduction of viraemia, antigenaemia, and hepatic WHV DNA and RNA; inhibition of progression of chronic hepatitis; reduced frequency of chronic liver injury; and delayed onset of hepatocellular carcinoma (HCC). Combination therapy contributed to prevention of HCC in up to 38% of treated carriers, although the growth rate of established HCC was not affected. This study demonstrates enhanced benefits of combination chemo-immunotherapy against viral load and disease progression in chronic hepadnaviral infection, and provides a platform for further development of such treatment regimens.
Virological Effects of Isis 14803, An Antisense Oligonucleotide Inhibitor of Hepatitis C Virus (HCV) Internal Ribosome Entry Site (IRES), on HCV Ires in Chronic Hepatitis C Patients and Examination of the Potential Role of Primary and Secondary HCV Resistance in the Outcome of Treatment
Authors: Soler Muriel , McHutchison John G , Kwoh T Jesse , Dorr F Andrew , Pawlotsky Jean-Michel
Published: April 2022

Antisense oligonucleotides represent a promising class of antiviral agents. ISIS 14803 is a 20-unit phosphorothioate oligodeoxynucleotide that inhibited hepatitis C virus (HCV) replication and protein expression in cell culture and mouse models. A Phase I dose-escalation clinical study of ISIS 14803 was performed in 24 patients with HCV genotype 1 chronic hepatitis C. The patients received 0.5, 1.0, 2.0 or 3.0 mg/kg of ISIS 14803 for 4 weeks. Two of them receiving 2.0 mg/kg, experienced a significant (>1.0 log10) viral load reduction and nine other patients experienced minor (<1.0 log10) viral load reductions that were difficult to definitively distinguish from assay or patient variations. The aims of this study were to examine the effect of ISIS 14803 on its target site and neighbouring region quasispecies evolution, and to determine whether primary and secondary HCV resistance contributed to the observed virological response rate. The HCV internal ribosome entry site (IRES), including the ISIS 14803 target site in virus specimens collected from patients at baseline and end-of-treatment, was sequenced. An extensive IRES quasispecies analysis was performed in 10 of the patients at various time points before, during and after ISIS 14803 treatment. A significant IRES genetic evolution was found in three out of 10 patients through quasispecies analysis suggesting that treatment with ISIS 14803, a drug designed to bind to HCV RNA, exerted a selective pressure on HCV IRES. However, no mutations in the ISIS 14803 target site, which would inhibit binding of the oligonucleotide to HCV RNA, were detected before (primary resistance) or after treatment (secondary resistance) with the oligonucleotide. Furthermore, no obvious nucleotide changes in the surrounding IRES region that might possibly affect oligonucleotide binding were detected.
Mitochondrial Effects of a 24-Week Course of Pegylated-Interferon plus Ribavirin in Asymptomatic HCV/HIV Co-Infected Patients on Long-Term Treatment with Didanosine, Stavudine or Both
Authors: Ballesteros Àngel Luis , Miró Òscar , López Sònia , Fuster Daniel , Videla Sebastiá , Martínez Eva , Garrabou Glòria , Salas Anna , Côté Hélène , Tor Jordi , Rey-Joly Celestino , Planas Ramon , Clotet Bonaventura , Tural Cristina
Published: April 2022

Background

It has been suggested that the addition of ribavirin (RBV) as a part of the treatment for chronic hepatitis C virus (HCV) in HIV co-infected patients on didanosine (ddI) or stavudine (d4T) might increase the nucleoside-induced impairment of mitochondrial function. Design: Comparative study to investigate the impact on mitochondrial function of adding RBV to a long-term treatment with ddI, d4T or both in HCV/HIV non-cirrhotic, asymptomatic patients. We included 26 patients: 16 continued with their current antiretroviral therapy (control group) and 10 patients received a concomitant 24-week course of RBV plus pegylated interferon (PEG-IFN) α-2b therapy (HCV-treated group).

Methods

We assessed peripheral blood mononuclear cells mitochondrial DNA (mtDNA) content and mitochondrial respiratory chain (MRC) function at baseline and at 24 weeks of follow-up. In the HCV-treated group we performed additional determinations at 12 weeks during anti-HCV therapy and 24 weeks after finishing anti-HCV therapy.

Results

Times on ddI or d4T exposure were 194 ±54.9 and 131 ±66.5 weeks in the HCV-treated and control groups, respectively. There were no differences either in mtDNA content, the enzyme activity of MRC complexes or clinical parameters at baseline. Throughout the study, mitochondrial measurements remained stable within groups and without differences when we compared HCV-treated and control groups.

Conclusions

In our study, the addition of RBV and PEG-IFN during a 24-week period in HCV/HIV non-cirrhotic, asymptomatic patients on long-term ddI, d4T or both had no impact on mitochondrial function. These findings could suggest that additional triggers are required to achieve a critical threshold in the degree of mitochondrial damage needed for symptoms to develop.
The Problems Faced When Assessing the Prevalence and Incidence of Antiretroviral-Related Toxicities
Authors: Smith Colette J , Sabin Caroline A
Published: April 2022

Although the dramatic effect of highly active antiretroviral therapy (HAART) in reducing morbidity and mortality must not be underestimated, it is also important to consider the incidence and prevalence of HAART-related toxicities. Although several studies have investigated HAART-related toxicities, there has been great variety between them in the reported incidence and prevalence rates of these toxicities. Various factors, including whether the study type was a clinical trial or an observational study, the definition of the toxicity endpoints, the demographic characteristics of the study populations and the effect of calendar year on analyses, may all influence the rates observed. We investigated the possible explanations for the differences in the incidence and prevalence rates of HAART-related toxicities between studies, focussing on metabolic and hepatotoxic disorders.
Health-Related Quality of Life in HIV Patients Switching to Twice-Daily Indinavir/Ritonavir Regimen or Continuing with Three-Times-Daily Indinavir-Based Therapy
Authors:   the BestQol study group, Badía Xavier , Podzamczer Daniel , Moral Irene , Roset Montse , Arnaiz Joan A , Loncà Montse , Casiró Arnaldo , Rosón Beatriz , Gatell Jose M , Grinberg N , Puentes T , Furst MJ López , Julio Méndez Sanatorio , Lupo S , Suárez C , Agostini M , Cassetti I , Bologna R , Salud Helios , Cahn P , Patterson P , Krolewiecki A , David DO , Luna N , Cruceta A , Pich J , Varea S , Carné X , Mallolas J , Clotet B , Romeu J , Cruz L , Arrizabalaga J , Iribarren JA , Rodríguez F , Von Wichmann MA , Jimeno B , Pulido F , Rubio R , Flores J , González-Lahoz J , Rodríguez-Rosado R , Núñez M
Published: April 2022

Objective

To evaluate health-related quality of life (HRQoL) changes in patients treated with indinavir three-times daily after switching to a twice-daily indinavir/ritonavir regimen or continuing with the same regimen.

Methods

Patients on HAART including indinavir three-times-daily with undetectable viral load were randomly assigned to continue with this therapy or to change to a twice-daily indinavir/ritonavir (800/100 mg) regimen. The Medical Outcomes Study HIV Health Survey (MOS-HIV) questionnaire was used as the HRQoL measure.

Results

A total of 118 patients participated in the study, of which 59 (50%) were randomly assigned to continue with the three-times-daily regimen. Patients had a mean age of 39 years and 80% of them were male. At baseline, subjects included in the three-times-daily group presented a significantly greater number of symptoms than subjects in the twice-daily group, but no statistically significant differences were observed in MOS-HIV scores between the groups. In the intention-to-treat (ITT) analysis, a reduction in HRQoL scores was observed in both groups, which was greater in the twice-daily group. In the per protocol analysis, reduction of HRQoL was minimal.

Conclusions

A HRQoL deterioration, greater in the twice-daily group, was observed in this study in the ITT analysis, while HRQoL remained stable in both groups in patients who continued with and tolerated the allocated regimen.
Interaction of Nucleoside Inhibitors of HIV-1 Reverse Transcriptase with the Concentrative Nucleoside Transporter-1 (Slc28A1)
Authors: Cano-Soldado Pedro , Larráyoz Ignacio M , Molina-Arcas Míriam , Casado F Javier , Martinez-Picado Javier , Lostao M Pilar , Pastor-Anglada Marçal
Published: April 2022

Human concentrative nucleoside transporter-1 (hCNT1) (SLC28A1) is a widely expressed, high-affinity, pyrimi-dine-preferring, nucleoside transporter implicated in the uptake of naturally occurring pyrimidine nucleosides as well as a variety of derivatives used in anticancer treatment. Its putative role in the uptake of other pyrimidine nucleoside analogues with antiviral properties has not been studied in detail to date. Here, using a hCNT1 stably transfected cell line and the two-electrode voltage-clamp technique, we have assessed the interaction of selected pyrimidine-based antiviral drugs, inhibitors of HIV-1 reverse transcriptase such as zidovudine (AZT), stavudine (d4T), lamivudine (3TC) and zalcitabine (ddC), with hCNT1. hCNT1 transports AZT and d4T with low affinity, whereas 3TC and ddC are not translocated, the latter being able to bind the transporter protein. Selectivity appears to rely mostly upon the presence of a hydroxyl group in the 3′-position of the ribose ring. Thus, hCNT1 cannot be considered a broad-selectivity pyrimidine nucleoside carrier; in fact, very slight changes in substrate structure provoke a dramatic shift in selectivity.
Increased Sensitivity of Sars-Coronavirus to a Combination of Human Type I and Type II Interferons
Authors: Scagnolari Carolina , Vicenzi Elisa , Bellomi Francesca , Stillitano Maria Giuseppina , Pinna Debora , Poli Guido , Clementi Massimo , Dianzani Ferdinando , Antonelli Guido
Published: April 2022

There is currently an urgent need to identify effective antiviral agents that will prevent and treat severe acute respiratory syndrome coronavirus (SARS-CoV) infection. In this study, we have investigated and compared the antiviral effect of different interferons (IFNs) on SARS-CoV replication in the epithelial kidney monkey Vero cell line. The results showed that SARS-CoV grown in Vero cells is moderately sensitive to IFN-β and only weakly sensitive to IFN-α and IFN-γ, in comparison to other IFN-sensitive viruses, such as those for encephalomyocarditis, vesicular stomatitis and Newcastle disease. Simultaneous incubation of Vero cells with IFN-β and IFN-γ indicated that they may act synergistically against SARS-CoV replication. The IFN-induced MxA protein was detected in the IFN-treated Vero cells. The data, however, suggest that the antiviral activity of IFN against SARS-CoV virus is independent of MxA expression.
Management of Hepatitis B Patients with Antiviral Resistance
Authors: Fung Scott K , Lok Anna SF
Published: April 2022

Drug resistance is an expected consequence of antiviral therapy for chronic hepatitis B because of the high rate of hepatitis B virus (HBV) replication, the lack of proofreading during reverse transcription of the pregenomic RNA and the low efficacy of available therapies in eliminating covalently closed circular HBV DNA. Mutations involving the YMDD motif of the catalytic domain of HBV reverse transcriptase have been reported in patients who have received lamivudine, emtricitabine and telbivudine. Drug-resistant mutations affecting other regions of HBV polymerase have also been reported, but at much lower rates in patients who have received adefovir dipivoxil or entecavir. Antiviral resistance is initially manifested as virological breakthrough infection. In most patients, this is followed by biochemical breakthrough and, in some patients, hepatitis flares and hepatic decompensation. Monitoring drug resistance may improve the management of patients with antiviral-resistant HBV and can guide the selection of salvage therapy. The optimal management of patients with antiviral-resistant HBV continues to evolve. The ideal approach is to prevent antiviral resistance through judicious use of antiviral therapy and the use of more potent antiviral agents, possibly in combination.
Body Fat Changes among Antiretroviral-Naive Patients on Pi- and Nnrti-Based Haart in the Swiss HIV Cohort Study
Authors:   the Swiss HIV Cohort Study, Young Jim , Rickenbach Martin , Weber Rainer , Furrer Hansjakob , Bernasconi Enos , Hirschel Bernard , Tarr Philip E , Vernazza Pietro , Battegay Manuel , Bucher Heiner C , Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Dubs R , Egger M , Elzi L , Erb P , Fantelli K , Fischer M , Flepp M , Fontana A , Furrer H , Gorgievski M , Günthard H , Hirschel B , Kaiser L , Kind C , Klimkait Th , Ledergerber B , Lauper U , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rickenbach M , Rudin C , Schmid P , Schüpbach J , Speck R , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S
Published: April 2022

Background

Body fat changes are common in patients with HIV. For patients on protease inhibitor (PI)-based highly active antiretroviral therapy (HAART), these changes have been associated with increasing exposure to therapy in general and to stavudine in particular. Our objective is to show whether such associations are more or less likely for patients on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART.

Methods

We included all antiretroviral-naive patients in the Swiss HIV Cohort Study starting HAART after April 2000 who had had body weight, CD4 cell count and plasma HIV RNA measured between 6 months before and 3 months after starting HAART, and at least one assessment of body fat changes after starting HAART. At visits scheduled every 6 months, fat loss or fat gain is reported by agreement between patient and physician. We estimate the association between reported body fat changes and both time on therapy and time on stavudine, using conditional logistical regression.

Results

Body fat changes were reported for 85 (9%) out of 925 patients at their first assessment; a further 165 had only one assessment. Of the remaining 675 patients, body fat changes were reported for 156 patients at a rate of 13.2 changes per 100 patient-years. Body fat changes are more likely with increasing age [odds ratio (OR) 1.18 (1.00–1.38) per 10 years], with increasing BMI [OR 1.06 (1.01–1.11)] and in those with a lower baseline CD4 cell count [OR 0.91 (0.83–1.01) per 100 cells/μl]. There is only weak evidence that body fat changes are more likely with increasing time on HAART [OR 1.16 (0.93–1.46)]. After adjusting for time on HAART, fat loss is more likely with increasing stavudine use [OR 1.70 (1.34–2.15)]. There is no evidence of an association between reported fat changes and time on NNRTI therapy relative to PI therapy in those patients who used either one therapy or the other [OR 0.98 (0.56–1.63)].

Conclusion

Fat loss is more likely to be reported with increasing exposure to stavudine. We find no evidence of major differences between PI and NNRTI therapy in the risk of reported body fat changes.
Viral Interaction and Responses in Chronic Hepatitis C and B Coinfected Patients with Interferon-Alpha plus Ribavirin Combination Therapy
Authors: Chuang Wan-Long , Dai Chia-Yen , Chang Wen-Yu , Lee Li-Po , Lin Zu-Yau , Chen Shinn-Cherng , Hsieh Ming-Yuh , Wang Liang-Yen , Yu Ming-Lung
Published: April 2022

Background/aims

We conducted a case-control study to investigate the efficacy of interferon-alpha (IFN-α) and ribavirin combination therapy for patients with chronic hepatitis C and B virus (HCV/HBV) coinfection and to elucidate the interaction of these two viruses.

Methods

Forty-two chronic HCV/HBV-coinfected patients (29 IFN-naive, 13 IFN-relapsed) and 84 HCV-monoinfected controls, matched for age, sex and previous history of IFN-α therapy, were enrolled. All patients were treated with IFN-α-2b 6 MU three-times weekly plus ribavirin 1000–1200 mg daily for 24 weeks. Serum HCV RNA and HBV DNA were determined every 24 weeks for 72 weeks.

Results

The rate of HCV sustained virological response (SVR) was comparable among IFN-naive and IFN-relapsed HCV/HBV-coinfected patients and IFN-naive and IFN-relapsed HCV-monoinfected patients (69.0%, 69.2%, 67.2% and 57.7%, respectively; intention-to-treat analysis). HCV genotype 1b, high pretreatment HCV RNA levels and liver fibrosis were significantly associated with a lower HCV SVR. Of 16 baseline HBV viraemic patients, five (31.3%) achieved HBV SVR, which correlated negatively to HCV genotype non-1b and HCV SVR. Only one (6.3%) had simultaneous seroclearance of HCV and HBV. Antibodies to HBV surface antigen seroconversion developed in five (11.9%) patients during long-term follow-up. HCV responders had significantly higher rates of HBV DNA resurgence than HCV non-responders during and after treatment. Reciprocal viral interference was noted between HCV and HBV after IFN-α/ribavirin therapy.

Conclusions

IFN-α/ribavirin combination therapy is effective for HCV/HBV-coinfected patients in eradicating HCV infection and might promote HBV seroclearance, and there is a mutual viral response and reciprocal viral interaction between HBV and HCV.
Changes in Mitochondrial Rna Production in Cells Treated with Nucleoside Analogues
Authors: Galluzzi Lorenzo , Pinti Marcello , Troiano Leonarda , Prada Nicole , Nasi Milena , Ferraresi Roberta , Salomoni Paolo , Mussini Cristina , Cossarizza Andrea
Published: April 2022

Background

To investigate mitochondrial (mt) toxicity of antiretroviral drugs further, we developed a novel realtime PCR-based assay for the quantification of mtRNA. We analysed the effects of stavudine (d4T), didanosine (ddI) and zidovudine (AZT) on the production of mtRNAs in different human cell lines and compared the production with the amount of mtDNA present in the same cells. Materials and methods: HUT78, CEM and U937 cells were exposed to different nucleoside reverse transcriptase inhibitors (NRTIs) for 7 days. Thereafter, nucleic acids were isolated and Taqman-based real-time PCR was used to quantify mtDNA and three different mtRNAs (ND1, CYTB and ND6 gene products).

Results

Different amounts of mtRNAs exist in different cell lines. When mtRNA was measured in cells exposed to an NRTI, a marked decrease was observed in cells treated with d4T, but not with ddI or AZT. Changes in mtRNA production did not always correspond to modifications in mtDNA content: 1 μM d4T significantly changed mtRNA but not mtDNA content.

Conclusions

d4T, but not ddI or AZT, significantly alters mtRNA quantity and quality. The method we have developed can reveal changes that are not observed by measuring mtDNA content only, and can be used for ex vivo studies on drug toxicity.
Early Virological Failure with a Combination of Tenofovir, Didanosine and Efavirenz
Authors: Podzamczer Daniel , Ferrer Elena , Gatell Josep Maria , Niubo Jordi , Dalmau David , Leon Agathe , Knobel Hernando , Polo Carolina , Iniguez Daniel , Ruiz Isaac
Published: April 2022

Objective

To describe the occurrence of a high early virological failure (VF) rate and development of resistance mutations in antiretroviral-naive patients receiving tenofovir, didanosine and efavirenz.

Methods

HIV-infected antiretroviral-naive patients with viral load ≥30 000 copies/ml were enrolled in a pilot randomized trial of tenofovir/didanosine (250 mg)/ efavirenz with (arm A) or without (arm B) lopinavir/r for the first 12 weeks. As six cases of early VF (a drop of <2 log at month 3, or a rebound of >1 log from the nadir) were detected (five in arm B and one in arm A who had previously stopped lopinavir/r) an unplanned interim analysis was performed.

Results

A total of 29 out of 36 enrolled patients completed at least 3 months of follow-up and were included in the interim analysis. An intent-to-treat analysis showed treatment failure in 7/15 (46.7%) patients in arm B (five VF, one lost, one switched) versus 2/14 (14.3%) in arm A (one lost, one switched) ( P=0.109). The patient in arm A who interrupted lopinavir/r at day 3 and continued with tenofovir/didanosine/efavirenz later developed VF. At baseline, 6/6 VF patients had VL >100 000 copies/ml and an advanced stage of disease (CD4 <200 plus CDC stage C or B3) versus 0/8 non-VF patients taking the triple drug regimen ( P<0.001). At failure, G190S/E alone or associated with K103N and K101R mutations was detected in five patients, and K103N/L100I/V108I in the sixth patient. Additionally, L74V/I and K65R were detected in four and two patients, respectively.

Conclusions

A high early virological failure rate and the occurrence of resistance mutations were detected in a group of antiretroviral-naive patients treated with tenofovir/didanosine/efavirenz. Presented in part at the 13th International HIV Drug Resistance Workshop. 8–12 June 2004, Tenerife. Abstract 156.
Chronic Hepatitis C and Genotyping: The Clinical Significance of Determining HCV Genotypes
Authors: Hnatyszyn H James
Published: April 2022

Chronic hepatitis C, attributed to infection with hepatitis C virus (HCV), is a global health problem. The overall prevalence of viral hepatitis worldwide is estimated to be 3–5% with over 175 million people infected with HCV. Clinically, HCV can establish a persistent, chronic infection contributing to progressive liver disease, including cirrhosis and hepatocellular carcinoma (HCC), requiring intensive treatment regimens, possible liver transplantation and long-term care. Due to the chronic nature of HCV infection and the tremendous burden on healthcare resources, clinicians and laboratorians have looked for key epidemiological, pathological and viral characteristics that may provide insight into disease progression, severity and response to therapy to permit the administration of effective therapeutic regimens as well as long-term management of infected individuals. Determination of viral genotype has been identified as one parameter that could provide direction in the clinical management of patients with chronic HCV infections. The following review provides background on determination of HCV genotypes and the relevance of viral genome characterization in the current clinical setting.
Nucleoside Analogue-Sparing Strategy for the Treatment of Chronic HIV Infection: Potential Interest and Clinical Experience
Authors: Joly Véronique , Yeni Patrick
Published: April 2022

Nucleoside analogue-sparing antiretroviral combinations may be interesting as first-line therapies as they spare a complete class of drugs that will remain fully active for later use and prevent the risk of mitochondrial toxicity related to exposure to nucleoside reverse transcriptase inhibitors (NRTIs). This strategy is also used in patients failing NRTIs with cross-resistance to compounds in this class. Different combinations of antiretroviral drugs are theoretically available. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) associated with protease inhibitor (PI) and boosted double-PI combinations have been studied through small, non-comparative clinical studies and preliminary results suggest that they are efficient and often well-tolerated. However, NNRTIs and PIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions; a good knowledge of the interactions between NNRTIs and PIs, or between PIs, is helpful in assisting physicians in clinical practice in choosing drugs and doses. Access to a therapeutic drug monitoring service to confirm that appropriate drug exposures are achieved is useful when using such regimens. Some negative kinetic interactions may lead to complicated combinations with a high pill burden that reduces their applicability. Gastrointestinal toxicity often remains a limiting factor in the use of boosted double-PI combinations. Non-comparative studies have allowed selection of NRTI-sparing options that now need to be compared with the current standard of care in comparative clinical trials before being considered as valuable options. Other NRTI-sparing therapeutic strategies are emerging: PI monotherapy with lopinavir/ritonavir has been evaluated in a small group of naive patients and appears promising. Drugs belonging to new classes currently under investigation, such as entry inhibitors, might be included early in the antiretroviral treatment of patients as soon as compounds with a convenient route of administration are available, increasing the number of therapeutic combinations without NRTIs.
News in Hepatitis C: Report from the 39th Annual Meeting of the European Association for the Study of the Liver
Authors: Zeuzem Stefan
Published: April 2022

Report from the 39th Annual Meeting of the European Association for the Study of the Liver, 14–18 April 2004, Berlin, Germany.