bluuebunny/crossref_metadata_2025 huggingface dataset:
The Early HCV RNA Dynamics in Patients with Acute Hepatitis C Treated with Pegylated Interferon-α2B
Authors: Rosa Francesco G De , Bargiacchi Olivia , Audagnotto Sabrina , Garazzino Silvia , Cariti Giuseppe , Veronese Lorenzo , Raiteri Riccardo , Calleri Guido , Perri Giovanni Di
Published: April 2022

Interferon and pegylated interferon (peg-IFN) are highly effective in patients with acute hepatitis caused by hepatitis C virus (acute hepatitis C, AHC), but the optimal timing of treatment is still under debate. In this open-labelled, uncontrolled trial, 19 patients with AHC, including 12 intravenous drug users (IVDUs), were treated early in the course of the infection with peg-IFN-α2b for 12 weeks. Diagnosis was made according to standardized criteria. The HCV RNA decay was analysed during the first 4 weeks of treatment by quantitative branched-DNA and by qualitative RT-PCR. Of the patients, 11 (58%) had genotype 1. Sustained virological response (SVR) was achieved in 14 out of 19 patients (74%) and the mean time to achieve a negative RT-PCR for HCV RNA was 2.5 weeks. The SVR was associated by univariate analysis with peg-IFN dosage ≥1.33 μg/kg/week ( P=0.026) and HCV RNA level at onset of therapy ( P=0.017). Using a logistic regression model, only peg-IFN dosage ≥1.33 μg/kg/weekly was significantly associated with SVR ( P=0.0379, OR: 14.7; 95% CI: 1.16–185.2). The SVR was 100% and 83.3%, respectively, in genotype 1 and non-1 infected patients treated with a dosage equal to or higher than 1.33 μg/kg, compared with 40% and 50%, respectively, in those who received a lower dosage. Efforts should be made to propose a 12-week treatment with peg-IFN-α2b for AHC, and to maximize peg-IFN dosage. Early treatment is associated with early disappearance of HCV RNA.
A Randomized, Placebo-Controlled Trial of Thymosin-α1 and Lymphoblastoid Interferon for Hbeag-Positive Chronic Hepatitis B
Authors: Lim Seng Gee , Wai Chun-Tao , Lee Yin Mei , Dan Yock Young , Sutedja Dede Selamat , Wee Aileen , Suresh Shirley , Wu Ying Juan , Machin David , Lim Chee Chian , Fock Kwong Ming , Koay Evelyn , Bowden Scott , Locarnini Steven , Ishaque Shamsuddin Mohammed
Published: April 2022

Combination therapy between two immunomodulators used for treatment of chronic hepatitis B was explored based on reported therapeutic efficacy of interferon-α, and thymosin-α1 as monotherapeutic agents to determine if combination therapy was superior to interferon alone. This double-blinded, randomized, placebo-controlled trial compares the addition of thymosin-α1, 1.6 μg taken three times per week (combination therapy) or thymosin placebo (monotherapy) to lymphoblastoid interferon (Wellferon®), 5 million international units (MIU) taken three times per week, for 24 weeks. Entry criteria included positive hepatitis B e antigen (HBeAg); alanine aminotransferease (ALT) ≥1.5x upper normal limit, but ≤10xupper normal limit; positive HBV DNA; absence of cirrhosis; treatment naivety and no co-morbid factors. A total of 98 HBeAg-positive patients were recruited, of which 48 were randomized to combination therapy and 50 to monotherapy. The primary endpoint was the loss of HBeAg at 72 weeks. The secondary endpoints were HBeAg seroconversion, normalization of ALT, loss of HBV DNA and improvement in histology. The HBeAg loss was 45.8% and 28.0% for combination therapy and monotherapy, respectively (difference, 17.8%; 95% CI -1.2%-35.3%, P=0.067). There was a trend towards HBeAg loss when using combination therapy. There were also no statistically significant differences between the different therapies with respect to the secondary endpoints of HBeAg seroconversion, changes in histology, normalization of ALT or loss of HBV DNA. In conclusion, this trial showed a 17.8% improvement in HBeAg loss rates using combination therapy over interferon monotherapy. This could clinically indicate a potential important difference that would need confirmation in subsequent trials.
Boosted versus Unboosted Indinavir with Zidovudine and Lamivudine in Nucleoside Pre-Treated Patients: A Randomized, Open-Label Trial with 112 Weeks of Follow-Up (HIV-Nat 005)
Authors: Boyd Mark A , Srasuebkul Preeyaporn , Khongphattanayothin Mana , Ruxrungtham Kiat , Hassink Elly AM , Duncombe Christopher J , Ubolyam Sasiwimol , Burger David M , Reiss Peter , Stek Michael , Lange Joep MA , Cooper David A , Phanuphak Praphan
Published: April 2022

Introduction

The use of HIV protease inhibitors (PIs) in a ritonavir (RTV)-boosted form is now common. However, randomized data comparing boosted with unboosted PI strategies are scarce.

Methods

This randomized, open-label trial compared indinavir (IDV) 800 mg three times daily with IDV/RTV 800/100 mg twice daily, both given with zidovudine (AZT)/lamivudine (3TC) twice daily in individuals with at least 3 months previous AZT experience. The primary endpoint was the time-weighted average change in HIV RNA from baseline. Designed as a 48-week study, follow-up continued until week 112. Primary analysis is by intention to treat.

Results

One hundred and three patients commenced therapy and are included in the analysis. Patients had a median of 29 months past nucleoside reverse transcriptase inhibitor (NRTI) exposure. Baseline median (interquartile range) log10 HIV RNA was 4.0 (3.3–4.5) and CD4+T-cell count 166 (40–323) cells/μl. After 112-weeks of study there was no significant difference observed between arms in the mean (sd) change in time-weighted average HIV RNA from baseline (-1.6 [1.1] HIV RNA copies/week/ml three times daily arm; -1.4 [1.1] HIV RNA copies/week/ml twice daily arm; P=0.3). Both arms were associated with substantial toxicity expressed as serious adverse events and study drug interruptions. The twice daily arm experienced greater dyslipidaemia. Mean (sd) changes in time-weighted CD4+ T-cell count from baseline were similar [88 (84) cells/week/μl three times daily arm; 70 [109] cells/week/μl twice daily arm; P=0.3).

Conclusions

RTV-boosted IDV 800/100 mg twice daily demonstrated comparable efficacy to unboosted IDV 800mg three times daily dosing. Both regimens were associated with substantial toxicity. Use of lower doses of RTV-boosted IDV may result in better tolerability without loss of efficacy and warrant further research.
Neuropsychiatric Adverse Events after Switching from An Antiretroviral Regimen Containing Efavirenz without Tenofovir to An Efavirenz Regimen Containing Tenofovir: A Report of Nine Cases
Authors: Allavena Clotilde , Le Moal Gwenael , Michau Christophe , Chiffoleau Anne , Raffi François
Published: April 2022

The combination of tenofovir (TDF) and efavirenz (EFV) has not been associated with any pharmakokinetic interaction or with enhancement of neuropsychiatric disturbances. We report nine cases of neuropsychiatric intolerance occurring early after a switch from an antiretroviral regimen without TDF to an EFV and TDF-containing regimen. Nine HIV-1-infected patients were treated with an EFV-containing regimen for a median duration of 31 months without any EFV-related central nervous system (CNS) effects. They were switched to an EFV-TDF-containing regimen because of lipodystrophy (n=2) and/or the wish to simplify to a once-daily regimen ( n=9). Moderate to severe neuropsychiatric events occurred immediately (<48 hours) after TDF initiation in five patients and 2 weeks to 24 months after the switch in the remaining four patients. Treatment modifications occurred in six patients (switch to EFV-nevirapine [ n=3], TDF-zidovudine [ n=2] or treatment discontinuation [ n=1]), leading to a marked improvement of CNS intolerance. Treatment remained unchanged in three patients; two patients experienced chronic persistent sleeping disorders and one patient underwent a spontaneous improvement of symptoms within 2 weeks. EFV plasma concentrations, which were available in two patients before the switch and in four patients after the switch, remained in the therapeutic range. Although the exact mechanism of these symptoms remains hypothetical, neuropsychiatric disorders could be either a consequence of an unexplained interaction between EFV and TDF or an infrequent TDF-related side effect. The incidence of these side effects needs to be evaluated in large databases or pharmacokinetic studies.
In Vitro Evaluation of the Anti-HIV Activity and Metabolic Interactions of Tenofovir and Emtricitabine
Authors: Borroto-Esoda Katyna , Vela Jennifer E , Myrick Florence , Ray Adrian S , Miller Michael D
Published: April 2022

Background

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are nucleoside reverse transcriptase inhibitors (NRTIs) with once-daily dosing approved for use in HIV-1 infection. We evaluated this combination for anti-HIV activity and intracellular metabolic interactions in vitro.

Methods

Intracellular anabolism of combinations of FTC and tenofovir (TFV) were studied in the human T leukaemic cell line CEM and human peripheral blood mononuclear cells (PBMCs). The anti-HIV activity of the combination was studied in the human T leukaemic MT-2 cell line against wild-type or mutant virus (K65R and M184V) and in PBMCs against wild-type virus. Antiviral synergy was quantitated by isobologram and MacSynergy methods.

Results

Both TFV and FTC were efficiently converted to their active metabolites in PBMCs and CEM cells. In CEM cells, there was a statistically significant increase in the levels of TFV diphosphate ( P=0.047) and FTC triphosphate ( P=0.0069) following a 24 h incubation with the combination compared with the levels seen with the individual drugs. In PBMCs, similar levels of active metabolites were observed for each drug when they were incubated individually or in combination. The combination of TFV and FTC displayed additive to synergistic activity against HIV replication in PBMCs and resulted in strongly synergistic anti-HIV activity in MT-2 cells against both wild-type and mutant virus.

Conclusions

The combination of TFV and FTC showed additive to synergistic anti-HIV activity in vitro, which correlated with the levels of intracellular phosphorylation observed. These results support the use of these drugs as a dual NRTI backbone in combination therapy for the treatment of HIV-1.
Viral Kinetics in Patients with Chronic Hepatitis C Treated with the Serine Protease Inhibitor Biln 2061
Authors: Herrmann Eva , Zeuzem Stefan , Sarrazin Christoph , Hinrichsen Holger , Benhamou Yves , Manns Michael P , Reiser Markus , Reesink Henk , Calleja José L , Forns Xavier , Steinmann Gerhard G , Nehmiz Gerhard
Published: April 2022

We analysed viral kinetics from a 2-day treatment with BILN 2061, a serine protease inhibitor of hepatitis C virus, in patients chronically infected with genotype 1 hepatitis C virus. The efficiency (ε), describing inhibition of viral production, was above 99.45% in all patients with minor or moderate fibrosis receiving doses of 200 mg and 500 mg twice daily and larger than in previous studies for interferon-based treatments. However, ε was slightly smaller in patients with cirrhosis given 200 mg and markedly smaller in patients given 25 mg. Estimates of viral clearance and infected-cell loss support conclusions on these rates and on treatment mechanisms from previous studies on interferon-α-based treatments.
A Longitudinal Analysis of Healthcare Costs after Treatment Optimization following Genotypic Antiretroviral Resistance Testing: Does Resistance Testing pay off?
Authors: Simcock Mathew , Sendi Pedram , Ledergerber Bruno , Keller Tamara , Schüpbach Jörg , Battegay Manuel , Günthard Huldrych F ,   Swiss HIV Cohort Study, Backmann S , Battegay M , Bernasconi E , Bucher H , Bürgisser Ph , Egger M , Erb P , Fierz W , Fischer M , Flepp M , Francioli P , Furrer HJ , Gorgievski M , Günthard H , Grob P , Hirschel B , Kaiser L , Kind C , Klimkait Th , Ledergerber B , Lauper U , Nadal D , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rickenbach M , Rudin C , Schüpbach J , Speck R , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S
Published: April 2022

Objective

To assess the impact of antiretroviral therapy optimized by genotypic antiretroviral resistance testing (GRT) on healthcare costs over a 2-year period in patients after antiretroviral treatment failure.

Study design

Non-randomized, prospective, tertiary care, clinic-based study.

Patients

One-hundred and forty-two HIV patients enrolled in the ‘ZIEL’ study and the Swiss HIV Cohort Study who experienced virological treatment failure.

Methods

For all patients GRT was used to optimize the antiretroviral treatment regimen. All healthcare costs during 2 years following GRT were assessed using micro-costing. Costs were separated into ART medication costs and healthcare costs other than ART medication (that is, non-ART medication costs, in-patient costs and ambulatory [out-patient] costs). These cost estimates were then split into four consecutive 6-month periods (period 1–4) and the accumulated cost for each period was calculated. Univariate and multivariate regression modelling techniques for repeated measurements were applied to assess the changes of healthcare costs over time and factors associated with healthcare costs following GRT.

Results

Overall healthcare costs after GRT decreased over time and were significantly higher in period 1 (32%; 95% confidence interval [CI]: 18–47) compared with period 4. ART medication costs significantly increased by 1,017 (95% CI: 22–2,014) Swiss francs (CHF) from period 1–4, whereas healthcare costs other than ART medication costs decreased substantially by a factor of 3.1 (95% CI: 2.6–3.7) from period 1 to period 4. Factors mostly influencing healthcare costs following GRT were AIDS status, costs being 15% (95% CI: 6–24) higher in patients with AIDS compared with patients without AIDS, and baseline viral load, costs being 12% (95% CI: 6–17) higher in patients with each log increase in plasma RNA.

Conclusions

Optimized antiretroviral treatment regimens following GRT lead to a reduction of healthcare costs in patients with treatment failure over 2 years. Patients in a worse health state (that is, a positive AIDS status and high baseline viral load) will experience higher overall costs.
Naive HIV/HCV-Coinfected Patients Have Higher Intrahepatic Pro-Inflammatory Cytokines than Coinfected Patients Treated with Antiretroviral Therapy
Authors: Sitia Giovanni , Bona Anna De , Bagaglio Sabrina , Galli Laura , Paties Carlo T , Uberti-Foppa Caterina , Guidotti Luca G , Lazzarin Adriano , Morsica Giulia
Published: April 2022

In the era of antiretroviral therapy, liver disease has emerged as an important cause of morbidity and mortality in HIV/hepatitis C virus (HCV) coinfected patients. It is believed that HCV is a non-cytopathic virus and that T-cell-mediated events (including the production of pro-inflammatory cytokines) have an important role in promoting both liver damage and viral clearance. Whether HIV coinfection or antiretroviral therapies influence such events is still unclear. In the current study, we compared the expression of NKp46 (a natural killer cell marker), CD3 (a T-cell marker), interferon-γ (IFN-γ), tumour-necrosis factor-α (TNF-α; pro-inflammatory cytokines) and interleukin-10 (IL-10; an anti-inflammatory cytokine) mRNA in the liver of naive HIV/HCV-coinfected patients (group one, n=14), coinfected patients treated with antiretroviral therapy (group two, n=23) and naive HCV mono-infected patients (group three, n=24). All three groups had comparable HCV viremia, with coinfected patients showing similar and relatively high CD4+ T-cell counts and significantly different HIV vireamia. Interestingly, when compared to groups two and three, group one showed significantly higher intrahepatic mRNA levels for CD3, IFN-γ and TNF-α, whereas the expression of NKp46 and IL-10 were comparable in all three groups. Further, higher histopathological grading scores within each group were independently associated with higher mRNA contents for CD3 and IFN-γ and higher serum alanine aminotransferase levels at the time of liver biopsy. Together, these results suggest that HIV infection may exacerbate the immune-mediated inflammatory response in the liver of patients chronically infected with HCV and antiretroviral therapy may prevent this effect.
Three-Year Clinical Outcomes of Resistance Genotyping and Expert Advice: Extended follow-up of the Argenta Trial
Authors: Luca Andrea De , Giambenedetto Simona Di , Cingolani Antonella , Bacarelli Alessandra , Ammassari Adriana , Cauda Roberto
Published: April 2022

Objective

To investigate the influence of genotypic resistance-guided HIV-treatment decisions on long-term clinical and virological outcomes in patients failing anti-retroviral therapy by a prospective 30-month observation following a 6-month randomized study (Argenta trial).

Methods

Patients ( n=174) with virological failure on highly active antiretroviral therapy (HAART) were initially randomized (1:1) to receive empirical therapy or guidance by genotypic resistance results. After month 6, all patients with HIV RNA >1,000 copies/ml received genotypic resistance tests and expert advice. Predictors of virological and clinical outcomes were analysed by logistic regression and Cox's regression models.

Results

There was a gradual increase in the proportion of patients with HIV RNA <400 copies/ml with 29.3% at 36 months (intent-to-treat) without differences between initial randomization arms. Independent predictors of 36-month virological response were the use of a salvage therapy with less daily doses and a more pronounced 3-month viral load drop. At 36 months, 84% survived without new AIDS events/death. Independent predictors of new AIDS events/death were previous AIDS events, higher baseline viral load, less pronounced 3-month viral load drop and, in a separate model, baseline protease substitutions K20M/R and I84V

Conclusions

The virological benefit of genotype-guided treatment decisions was continuously appreciable over time. Short-term virological response and viral cross-resistance were independent predictors of long-term outcomes.
Prevalence and Impact of HIV-1 Protease Codon 33 Mutations and Polymorphisms in Treatment-Naive and Treatment-Experienced Patients
Authors:   Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), Kozal Michael J , Hullsiek Katherine Huppler , Leduc Robert , Novak Richard M , MacArthur Rodger D , Lawrence Jody , Baxter John D
Published: April 2022

Background

HIV-1 protease gene mutations at codon 33 have been associated with resistance to some but not all protease inhibitors (PIs). Little is known about the difference in prevalence of codon 33 mutations and polymorphisms between treatment-naive and treatment-experienced patients, and the effect of codon 33F on PI phenotypic resistance patterns.

Methods

Baseline genotypes (TRUGENE) from 772 patients participating in two different randomized clinical trials [504 antiretroviral treatment-naive patients and 268 antiretroviral treatment-experienced patients] were evaluated for the presence of protease codon 33 mutations and polymorphisms. Baseline phenotypes (Antivirogram), including fold-change in resistance for 16 antiretroviral drugs, were available for the 268 treatment-experienced patients. Multivariate linear regression models were used to determine factors associated with phenotypic fold-change for PIs.

Results

The prevalence of codon 33 mutations and polymorphisms was 5.2% in the naive cohort (0.2% 33F, 2.5% 33V, 2.5% 33I) and 34.7% in the experienced cohort (30.2% 33F, 1.5% 33V, 3.0% 33I). In the antiretroviral-experienced cohort (mean = 4.2 prior PIs, 10.6 prior antiretroviral drugs overall), a model adjusting for the presence of specific major protease and multi-PI resistance conferring mutations, the number of other minor PI mutations, prior PI drug exposure (current, prior only, never), and HIV transmission risk factor was used to estimate the phenotypic fold-change in resistance for those with and without mutation 33F. Those with 33F had a significantly higher fold-change for amprenavir (33 vs 19, P<0.0001), ritonavir (162 vs 82, P<0.0001), lopinavir (49 vs 38, P=0.04), and saquinavir (47 vs 41, P=0.02). The presence of the 33F was not a significant predictor of fold change in susceptibility for indinavir or nelfinavir.

Conclusions

At protease codon 33, the prevalences of polymorphisms 33V and 33I were similar for PI-naive and PI-experienced patients (<3.0%), but the prevalence of 33F was significantly different (0.2% versus 30.2%). In the treatment-experienced cohort, the differences in phenotypic fold-change for amprenavir, lopinavir, saquinavir, and ritonavir between those with and without 33F persist after adjustment for the presence of other major PI mutations and PI drug exposure history. Given the availability of newer PIs that may select for 33F, monitoring for the presence of this mutation should be ongoing for both treatment-naive and treatment-experienced patients.
Incidence of and Risk Factors for Insulin Resistance in Treatment-Naive HIV-Infected Patients 48 Weeks after Starting Highly Active Antiretroviral Therapy
Authors: Palacios Rosario , Merchante Nicolás , Macías Juan , González Mercedes , Castillo Jesús , Ruiz Josefa , Márquez Manuel , Gómez-Mateos Jesús , Pineda Juan A , Santos Jesús
Published: April 2022

Objectives

to assess the incidence and risk factors for insulin resistance (IR) in a cohort of naive HIV-infected patients 48 weeks after satarting highly active antiretroviral therapy (HAART).

Design

prospective, two centre, observational, cohort study.

Methods

One-hundred and thirty-seven patients who started HAART and maintained the same regimen for 48 weeks were included. IR was determined by the homeostasis model assessment (HOMA-IR) method. Individuals with a HOMA-IR value >3.8 were defined as insulin resistant. Independent associations with the development of IR at 48 weeks were evaluated.

Results

Seventeen (12.4%) individuals showed a HOMA-IR value >3.8 at baseline and were excluded for incidence analyses. Fifteen patients developed IR at 48 weeks of HAART, giving an incidence of 13%. Independent predictors of the development or IR were indinavir exposure (β-coefficient 5.45, 95% confidence interval [CI] 1.30–22.8; P=0.02), and hepatitis C virus (HCV) antibody positivity (β-coefficient 5.22, 95% CI 1.34–20.33; P=0.01). The appearance of IR was associated with a higher BMI (β-coefficient 1.72 for each 2 kg/m2 increase, 95% CI 1.54–1.94; P=0.02) and with the presence of lipodystrophy at 48 weeks (β-coefficient 5.59, 95% CI 1.45-21.5; P=0.01).

Conclusions

HAART induces the development of IR in previously naive non-insulin-resistant HIV-infected individuals, with an incidence of 13% in the first year of therapy. Indinavir exposure, and HCV coinfection are associated with an increased risk of developing IR.
Impact of Lamivudine on the Risk of Liver-Related Death in 2,041 Hbsag- and HIV-Positive Individuals: Results from An Inter-Cohort Analysis
Authors: Puoti Massimo , Cozzi-Lepri Alessandro , Arici Claudio , Moller Nina Friis , Lundgren Jens D , Ledergerber Bruno , Rickenbach Martin , Suarez–Lozano Ignacio , Garrido Myriam , Dabis Francois , Winnock Maria , Milazzo Laura , Gervais Anne , Raffi Francois , Gill John , Rockstroh Juergen , Qurishi Nazifa , Mussini Cristina , Castagna Antonella , Luca Andrea De , Monforte Antonella d'Arminio
Published: April 2022

Background

The impact of lamivudine (3TC) as part of combination antiretroviral therapy (cART) on the risk of liver-related death (LRD) in HIV/hepatitis B virus (HBV)-coinfected patients has not been extensively studied.

Methods

We performed an analysis involving HIV/HBV-coinfected patients in 13 cohorts who initiated cART. The end–point was LRD – that is, death with concomitant decompensated liver disease (DLD) or hepatocellular carcinoma – as the main cause. Incidence rates of LRD after initiation of cART were expressed as number of events per 100 person–years of follow–up (PYFU). A Poisson regression model adjusted for cohort, gender, mode of HIV transmission, CD4+ T-cell count at cART initiation, liver disease pre–cART, duration of 3TC before cART, and hepatitis C virus was used to assess the association between use of 3TC and risk of LRD.

Results

We analysed 2,041 patients. Follow–up after starting cART was 7,648 PYFU (5,569 spent on 3TC-containing regimens) with a median per person of 48 months (range: 2–91). Of the total, 217 subjects died; 57 deaths were liver-related resulting in a rate of 7.5 per 1,000 PYFU [95% confidence intervals (CI): 5.6–9.7]. The relative risk of LRD per extra year of 3TC use was 0.73 (95% CI: 0.59–0.90, P=0.004).

Conclusion

The use of 3TC was associated with a reduced risk of LRD over 4 years of follow–up. This study supports the current view that the use of 3TC as part of cART should be considered in patients who are tested positive for HBsAg.
Defective Synthesis of Granulocyte-Colony Stimulating Factor in Pegylated Interferon-α Treated Chronic Hepatitis C Patients with Declining Leukocyte Counts
Authors: Durante-Mangoni Emanuele , Iardino Patrizia , Utili Riccardo , Adinolfi Luigi E , Ruggiero Giuseppe
Published: April 2022

Background

Pegylated-interferon-α (peg-IFN-α) is the mainstay of treatment for chronic hepatitis C (CHC). Treatment is often complicated by neutropaenia due to inhibition of haematopoiesis. However, there are no data on the kinetics of granulocyte-colony stimulating factor (G-CSF), a major neutrophil growth factor, in this setting. We therefore evaluated G-CSF synthesis in CHC patients on peg-IFN-α treatment.

Methods

A total of 40 CHC patients were studied. None had pre-existing haematological disorders, or hepatitis B virus or HIV coinfection. For controls, 30 healthy subjects were used. Laboratory examinations, including liver function tests, were performed at baseline and monthly over treatment and follow-up. Serum G-CSF was measured in all patients and controls at baseline and in a subgroup of 20 CHC patients also at weeks 2, 4, 24, 48 and 72 after treatment start.

Results

CHC patients had a significantly lower pre-treatment neutrophil count (3,256 ±1,197 versus 3,804 ±859; P=0.03). Notwithstanding, they showed lower baseline G-CSF serum levels than healthy controls (16.1 ±6.2 versus 19.4 ±7.5; P=0.048). Consistently, baseline G-CSF levels were poorly correlated with the neutrophil count in CHC patients (r=-0.2; P=0.2). Moreover, serum G-CSF levels did not increase in any of the 20 CHC patients during peg-IFN-α treatment, despite declining neutrophil counts.

Conclusions

The lower neutrophil counts observed in CHC might be related to an absolute deficiency in G-CSF production. In the human model of neutropaenia induced by peg-IFN-α, we show that endogenous G-CSF levels are not physiologically up-regulated to overcome the decline in neutrophil counts. Our study provides a rationale for the evaluation of recombinant human G-CSF treatment in peg-IFN-α-induced neutropaenia.
Impaired Response to Interferon-α2B plus Ribavirin in Cirrhotic Patients with Genotype 3A Hepatitis C Virus Infection
Authors: Aghemo Alessio , Rumi Maria Grazia , Soffredini Roberta , D'Ambrosio Roberta , Ronchi Guido , Del Ninno Ersilio , Gallus Silvano , Colombo Massimo
Published: April 2022

Patients with chronic infection with the 3a genotype of hepatitis C virus (HCV) are considered as ‘easy-to-treat’ with interferon/ribavirin (IFN/RBV), independent of liver disease severity. However, patients with extensive fibrosis or cirrhosis were under-represented in all the registration Phase III trials performed so far. To assess the influence of liver fibrosis on the outcome of anti-HCV therapy, all patients with genotype 3a hepatitis C who were naive to IFN-based therapies, and received RBV combined with standard IFN or pegylated IFN-α2b (peg-IFN-α2b) as standard of care for their disease, were investigated at our centre. A sustained virological response (SVR) was achieved in 68 of 91 patients (75%) independent of IFN type, pretreatment viraemia, clearance of HCV RNA at week 4 and relevant co-morbidities. A SVR was less common in cirrhotics (6 of 17) than in non-cirrhotics (62 of 74; 35% vs 84%; P<0.0005). Compared to non-cirrhotics, the age and sex adjusted odds ratio (OR) of treatment failure for cirrhotics was 10.1 (95% confidence interval: 2.4–41.7). By multivariate analysis, cirrhosis was the only predictor of non-SVR. In conclusion, cirrhosis is an independent predictor of IFN/RBV treatment failure in patients chronically infected with HCV 3a and is associated with an increased risk of post-treatment hepatitis relapse. Evaluation of liver fibrosis is important in the management of patients with genotype 3a hepatitis C, since it helps to predict response to IFN/RBV therapy.
A Randomized Trial to Evaluate Continuation versus Discontinuation of Lamivudine in Individuals Failing A Lamivudine-Containing Regimen: The Colate Trial
Authors: Fox Zoe , Dragsted Ulrik B , Gerstoft Jan , Phillips Andrew N , Kjaer Jesper , Mathiesen Lars , Youle Mike , Katlama Christine , Hill Andrew , Bruun Johan N , Clumeck Nathan , Dellamonica Pierre , Lundgren Jens D
Published: April 2022

Background

Lamivudine (3TC) therapy can cause the emergence of M184I/V. Previous studies suggest a higher fidelity of the mutant reverse transcriptase and lower replication capacity of the mutant virus. No data exist from clinical comparative studies evaluating the benefit of M184I/V in patients receiving combination antiretroviral therapy (cART).

Methods

HIV-1-infected adults failing a 3TC-containing regimen were randomized to continue (On-3TC) or discontinue 3TC (Off-3TC) whilst receiving cART. The primary efficacy measure was the log10 average-area-under-the-curve-minus-baseline reduction in HIV RNA over 48 weeks. Cryopreserved plasma samples from patients with baseline and ≥1 follow-up sample with HIV RNA >500 copies/ml were sequenced for a nucleotide distances substudy. Evolutionary distances were compared between treatment arms and between viruses with and without M184I/V

Results

The overall 48-week log10 HIV RNA change was -1.4 (95% CI: -1.6, -1.1) for On-3TC ( n=65) and -1.5 (95% CI: -1.7, -1.2) for Off-3TC ( n=66; P=0.51). No difference was seen in the magnitude of the CD4+ T-cell count increases (median increase: 87 vs 76 cells/ml for 3TC vs Off-3TC, respectively). Thirty-seven patients had baseline and follow-up sequencing. Overall, there were 1.2 (95% CI: -2.2, 4.6) more nucleotide substitutions from baseline for Off-3TC patients ( P=0.50), and 10.7 (95% CI: 7.5, 14.0) fewer nucleotide changes in viruses containing M184I/V ( P<0.0001).

Conclusion

This study found no added virological or immunological benefit of continuing 3TC in patients on cART harbouring M184I/V Evolutionary distances from baseline were larger in viruses that did not contain M184I/V. More discernable benefits may be seen in patients with fewer drug options as potent cART may eclipse a benefit of M184I/V in COLATE.
HIV-1 Infection Alters Gene Expression in Adipose Tissue, Which Contributes to HIV-1/Haart-Associated Lipodystrophy
Authors: Giralt Marta , Domingo Pere , Guallar Jordi P , de la Concepción M Luísa Rodríguez , Alegre Marta , Domingo Joan C , Villarroya Francesc
Published: April 2022

Background

The aetiopathogenic bases of HIV-1-/highly active antiretroviral treatment (HAART)-associated lipodystrophy (HALS) are poorly known, but this syndrome indicates that adipose tissue is highly sensitive to either HIV-1 infection, antiretroviral drugs or their combination.

Methods

To assess the relative contribution of infection and drugs, we compared the expression of marker genes corresponding to mitochondrial function, adipocyte differentiation and metabolism, and adipokines in subcutaneous adipose tissue from healthy controls, untreated HIV-1-infected patients, and HIV-1-infected patients treated with HAART with or without HALS.

Results

Subcutaneous adipose tissue from HIV-1-infected patients contained lower concentrations of the mRNA of the mitochondrial DNA-encoded cytochrome c oxidase subunit II than that of controls. These concentrations decreased further in association with HAART. The expression of nuclear genes coding for mitochondrial proteins, peroxisome proliferator-activated receptor-γ, and adipocyte-specific markers was reduced in HIV-1-infected patients, treated or not, with respect to the controls. In contrast, the mRNA concentrations of uncoupling protein-3 and preadipocyte factor-1 increased in lipodystrophic HAART-treated patients. The genes coding for adipokines were strongly affected: tumour necrosis factor-α was upregulated, whereas adiponectin and leptin were downregulated in HIV-1-infected patients, treated or not. Thus, substantial alterations of gene expression were already present when naive patients were compared with controls. Further changes were associated with HAART and with the diagnosis of HALS.

Conclusions

Disturbances in adipose tissue gene expression are already present in untreated HIV-1-infected patients, thus indicating a role of HIV-1 infection itself in eliciting adipose tissue alterations that are worsened by HAART, which ultimately leads to HALS.
Resistance of Hepatitis C Virus to Ns3–4A Protease Inhibitors: Mechanisms of Drug Resistance Induced by R155Q, A156T, D168A and D168V Mutations
Authors: Courcambeck Jérôme , Bouzidi Mourad , Perbost Régis , Jouirou Besma , Amrani Nolwenn , Cacoub Patrice , Pèpe Gérard , Sabatier Jean-Marc , Halfon Philippe
Published: April 2022

Background/aims

One of the main issues in the development of antiviral therapy is the emergence of drug-resistant viruses. In the case of hepatitis C virus (HCV), selection of drug-resistant mutants was evidenced by in vitro studies on protease inhibitors (PIs); for example, BILN-2061, VX-950 and SCH-6. Four mutations in the HCV protease (R155Q, A156T, D168A and D168V) have been identified in vitro in the HCV replicon system that confer resistance to BILN-2061 (a reference inhibitor). However, the molecular mechanism of drug resistance is still unknown. The aim of this study is to unravel, using an molecular modelling strategy, the structural basis of such molecular mechanism of HCV resistance to PIs. We focused on protease mutations conferring HCV resistance to BILN-2061 and described for the first time such mechanism at a molecular level.

Methods

The structures of drug-resistant NS3 proteases were obtained by mutation of selected residues (R155Q, A156T, D168A and D168V) and the ternary complexes formed between NS3–4A and BILN-2061 were optimized using GenMol software ( www.3dgenoscience.com ; Genoscience, Marseille, France).

Results

Two mechanisms were evidenced for viral resistance to BILN-2061. A ‘direct’ resistance mechanism is based on contacts between the mutated R155Q and A156T protease residues and its inhibitor. In the ‘indirect’ resistance mechanism, the mutated D168A/V residue is not in close contact with the drug itself but interacts with other residues connected to the drug.

Conclusions

These data provide new insights in the understanding of the mechanisms of HCV drug escape, and may allow predicting potential cross-resistance phenomenon with other PIs. This approach can be used as a basis for future rational PI drug design candidates.
The Effect of HIV-1 Resistance Mutations after First-Line Virological Failure on the Possibility to Sequence Antiretroviral Drugs in Second-Line Regimens
Authors: Maggiolo Franco , Ripamonti Diego , Torti Carlo , Arici Claudio , Antinori Andrea , Quiros-Roldan Eugenia , Minoli Lorenzo , Sighinolfi Laura , Nasta Paola , Suter Fredy
Published: April 2022

Background

One of the more vigorous debates in the field of highly active antiretroviral therapy (HAART) is how to start it and what the optimal drug sequence is.

Methods

A retrospective cohort analysis was performed. The aim was to evaluate which variables could influence the virological response to second-line genotypic-based HAART in patients with virological documented first-line HAART failure. A positive response was defined as a confirmed HIV RNA level <50 copies/ml.

Results

Two hundred and eight patients were included. Demographic characteristics, risk factors for HIV acquisition, and drugs included in the initial treatment did not significantly influence the considered outcome. According to a multiple logistic model, the presence of thymidine analogue mutations (TAMs) had a negative association with the virological outcome ( P=0.006), whereas the use of a boosted protease inhibitor (PI) in second-line HAART was positively associated with the endpoint ( P=0.001). Patients receiving a genotypic-based second-line HAART containing a boosted PI achieved a viral load <50 copies/ml in a 74.2% of cases compared with 52.2% of those whose therapy did not contain a boosted PI. This difference was statistically significant ( P=0.002) with an odds ratio (OR) of 2.63 and a 95% confidence interval (CI) ranging from 1.46 to 4.76. This last variable positively influenced the outcome even when the analysis was restricted to patients harbouring a virus presenting TAMs. In this case, second-line HAART was successful in 66.7% of cases with an OR of 3.25 and a 95% CI ranging from 1.28 to 8.25 ( P=0.014).

Conclusions

the wider range of available therapeutic options has made resistance and drug-sequencing considerations a crucial point in selecting first-line HAART. Our data indicate that, by limiting the risk of selecting or accumulating TAMs, it could be possible to save further therapeutic options. In second-line regimens, the higher antiviral effect and genetic barrier of boosted PIs may overcome the limits of the use of NRTI backbones, which retain only a partial effectiveness.
Antiviral Activity of Proteasome Inhibitors in Herpes Simplex Virus-1 Infection: Role of Nuclear Factor-κB
Authors: Frazia Simone La , Amici Carla , Santoro M Gabriella
Published: April 2022

Background

Herpes simplex virus type 1 (HSV-1) is a potent inducer of nuclear factor-κB (NF-κB), a cellular transcription factor with a crucial role in promoting inflammation and controlling cell proliferation and survival.

Objectives

On the basis of the recent demonstration that HSV-1-induced NF-κB is actively recruited to κB-binding sites in the HSV-1 infected-cell protein 0 (ICP0) promoter enhancing viral transcription and replication, we investigated the effect of proteasome inhibitors MG132, MG115 and epoxomicin, which block NF-κB function by preventing the degradation of the inhibitory proteins IκBα, on HSV-1-induced NF-κB activation and viral replication.

Methods

Antiviral activity of proteasome inhibitors was analysed in HSV-1-infected HEp2 cells by determining infective virus titres by CPE50%, viral RNA synthesis by RT-PCR, and viral protein synthesis by immunoblot analysis or immunofluorescence. ICP0 transcription was studied in transient transfection experiments using the ICP0 promoter-luciferase IE1-Luc construct. IκBα degradation and NF-κB activity were determined by immunoblot analysis and EMSA, respectively.

Results

Proteasome inhibitors were found to prevent HSV-1-induced NF-κB activation in the early phase of infection. Block of virus-induced NF-κB activation resulted in inhibiting HSV-1 ICP0 gene expression, in decreasing the level of immediate-early and late viral proteins, and ultimately in greatly suppressing viral replication. The antiviral effect was lost if treatment was started after NF-κB activation, and appeared to be independent of the HSV-1-induced activation of the JNK pathway.

Conclusions

Proteasome inhibitors possess NF-κB-dependent antiherpetic activity. The results described further identify the IKK/NF-κB pathway as a suitable target for novel antiherpetic drugs.
Limited Impact of Immunosuppression and Haart on the Incidence of Cervical Squamous Intraepithelial Lesions in HIV-Positive Women
Authors: Heard Isabelle , Potard Valérie , Costagliola Dominique
Published: April 2022

Background

Although highly active antiretroviral therapy (HAART) has lowered the incidence of various opportunistic diseases, its impact on cervical squamous intraepithelial lesions (SILs) is unclear. Our objective was to compare the incidence of SILs in HIV-infected women receiving HAART versus those not receiving HAART and to determine the role of risk factors including immunosuppression in the pathogenesis of SIL.

Methods

A total of 298 HIV-infected women with normal Papanicolaou (Pap) smear and normal colposcopic findings at enrollment were followed-up until incident SIL or last follow-up visit. Cox regression modelling was used to assess risks factors for incident SIL.

Results

Eighty-eight women developed SILs, including 75 low-grade lesions, during a median follow-up of 28 months (16–52; incidence of 8.7 cases per 100 person-years). No invasive cervical cancers were identified. Incidence decreased from 10.7 to 6.5 per 100 person-years in non-receiving versus receiving HAART women (relative risk [RR]: 0.7; 95% confidence interval [CI]: 0.4–1.2, P=0.15, from the adjusted Cox model). Incident SIL was not associated to low CD4+ T-cell count ( P=0.54). In multivariate analysis, the only significant risk factor for incident lesion was the age between 30–39 compared with over 40 (RR: 3.5; 95% CI: 1.4–8.9; P=0.02).

Conclusion

No impact in the development of SIL was evidenced for CD4+ T-cell counts, but we cannot exclude a modest impact of HAART. All HIV-positive women should be offered to participate in cervical cancer screening programmes whether or not they receive effective antiretroviral therapy.
Inhibition of Simian Virus 40 Large T Antigen Helicase Activity by Fluoroquinolones
Authors: Ali Syed Hamid , Chandraker Anil , DeCaprio James A
Published: April 2022

Background

Fluoroquinolones represent a potent group of antibiotics that inhibit bacterial DNA replication by targeting the essential bacterial enzymes gyrase and topoisomerase IV. Inhibition of gyrase activity by quinolones involves the interaction of these drugs with the helicase component of bacterial gyrase. DNA tumour viruses also encode helicases that are essential for their DNA replication in the host.

Methods

In this study we have evaluated the effect of fluoroquinolones on viral DNA replication using the DNA tumour virus Simian virus 40 (SV40) as our model. Four different fluoroquinolones, namely, levofloxacin, trovafloxacin, ciprofloxacin and ofloxacin, were tested for their ability to inhibit viral DNA replication.

Results

We show here that all four quinolones tested were effective in the inhibition of SV40 plaque formation and DNA replication in CV1-P cells. In addition, we found that each of these quinolones was inhibitory to the helicase activity of SV40 large tumour antigen.

Conclusions

Fluoroquinolones and their derivates may therefore be useful in the treatment and/or prevention of infection by SV40-homologous human DNA viruses that encode helicase activity for their survival.
Liver Triglyceride Content in HIV-1-Infected Patients on Combination Antiretroviral Therapy Studied with 1H-MR Spectroscopy
Authors: Moreno-Torres Angel , Domingo Pere , Pujol Jesus , Blanco-Vaca Francisco , Arroyo Juan Antonio , Sambeat M Antonia
Published: April 2022

Objective

To carry out an exploratory evaluation of liver triglyceride content in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) using proton magnetic resonance spectroscopy and to study how both the treatment itself and the biochemical and physiological variables in which the treatment causes alterations are related to liver fat content.

Methods

Intracellular hepatic triglyceride content was determined in 29 HIV-1-infected patients on their first HAART regime by means of localized water-unsuppressed single voxel proton spectra. Other measurements were body mass index, waist-to-hip ratio, lipodystrophy assessment and a detailed blood biochemical analysis. The relationship between intracellular hepatic triglycerides and relevant descriptive, treatment and biochemical variables was studied by correlation and regression analysis.

Results

Intrahepatic triglycerides were detected in 58.6% of the patients and 13.8% showed a triglyceride content compatible with liver steatosis. Many variables (body mass index, waist-to-hip ratio, cumulative exposure to PIs, lactate, insulin, insulin resistance measured by the homeostasis model assessment method [HOMA-R index], pH, total triglycerides, high density lipoprotein cholesterol and very low density lipoprotein [VLDL] cholesterol) correlated individually with the amount of triglycerides. Stepwise multiple regression analysis showed that the combination of insulin or HOMA-R index and VLDL cholesterol accounted for up to 50.2% of the triglyceride liver variance. A positive relationship was found between the concomitant presence of the metabolic syndrome components (insulin resistance, dyslipidaemia and central obesity) and intrahepatic triglyceride content.

Conclusions

The study showed that intrahepatic triglyceride deposit appears to be a frequent feature of HIV-1-infected patients receiving HAART. A coherent multifactorial combination of biochemical and physiological factors associated with the deposit suggested that cumulative exposure to PIs might be a possible trigger event.
Altered Heterochromatin Organization after Perinatal Exposure to Zidovudine
Authors: Senda Sho , Blanche Stéphane , Costagliola Dominique , Cibert Christian , Nigon Fabienne , Firtion Ghilaine , Floch Corinne , Parat Sophie , Viegas-Péquignot Evani
Published: April 2022

Background

Zidovudine (3’-azido-3’-deoxythymidine, AZT), administered to pregnant women alone or in combination with other antiretroviral drugs, greatly reduces the mother-to-child transmission of HIV-1. The potential genotoxicity of these molecules is underestimated and wide-ranging evaluation of its biological and clinical consequences is required.

Methods

We investigated the nuclear organization of constitutive heterochromatin, a major domain participating in epigenetic regulation, in uninfected infants born to HIV-1-infected mothers treated with zidovudine and/or other nucleoside reverse transcriptase inhibitors (NRTIs) during pregnancy. We studied the organization of chromosome 1 heterochromatin (1q12) in peripheral leukocytes of 25 HIV-1-uninfected children (newborn to 9 years old): children born to HIV-1-infected mothers exposed to zidovudine and/or other NRTIs ( n=15), children born to HIV-1-infected mothers not exposed to any NRTIs ( n=6) and children born to HIV-1-uninfected mothers ( n=4).

Results

Results differed significantly between NRTI-exposed and -unexposed children. By contrast, there was no difference between NRTI-unexposed children born to HIV-1-infected mothers and children born to HIV-uninfected mothers. The anomaly persisted in lymphocytes cultured for 48 h. There was no evidence of abnormal DNA methylation, a major feature of constitutive heterochromatin and associated with the loss of its structure. In a complementary sample of children, analysis of chromosome 11 and 16 heterochromatin suggests that the defect affects most of the other heterochromatic sites of the human genome. The heterochromatin defect persists long after the end of the exposure and appears in leukocytes of both myeloid and lymphoid lineages, suggesting that haematopoietic stem cells are affected.