bluuebunny/crossref_metadata_2025_split huggingface dataset:
Partial Immunological and Mitochondrial Recovery after Reducing Didanosine doses in Patients on Didanosine and Tenofovir-Based Regimens
Authors: Negredo Eugènia , Garrabou Glòria , Puig Jordi , Lòpez Sònia , Morén Constanza , Bellido Rocio , Ayen Rafaela , Cardellach Francesc , Miró Óscar , Clotet Bonaventura 
Published: April 2022

Background Tenofovir disoproxil fumarate (TDF) has a safe toxicity profile; however, administration together with didanosine (ddI) increases ddI levels causing mitochondrial damage and CD4+ T-cell decline. We assessed whether a simple reduction of the ddI dose in patients receiving ddI (400 mg/day) and TDF could revert this side effect. Methods Immunological and mitochondrial changes were analysed in 20 patients at baseline, after 14 months of receiving ddI (400 mg/day), TDF (300 mg/day) and nevirapine (NVP; 400 mg/day) and 14 months after a ddl dose reduction to 250 mg/day. Immunological analyses measured CD4+ and CD8+ T-cell counts and mitochondrial studies in peripheral blood mononuclear cells assessed mitochondrial DNA content by quantitative real-time PCR, cytochrome c oxidase (COX) activity by spectrophotometry and mitochondrial protein synthesis (COX-II versus β-actin or COX-IV expression) by western blot. Results Treatment with TDF, ddI (400 mg/day) and NVP for 14 months produced significant decreases in mitochondrial parameters and CD4+ T-cell counts. The reduction in ddI dose resulted in mitochondrial DNA recovery; however, the remaining mitochondrial parameters remained significantly decreased. Levels of CD4+ T-cells were partially restored in 35% of patients. Subjects presenting a significant reduction in CD4+ T-cells during the high ddI dose period showed greater mitochondrial impairment in this stage and better mitochondrial and immunological recovery after drug reduction. Conclusions Administration of high ddI doses together with TDF was associated with mitochondrial damage, which may explain the observed CD4+ T-cell decay. A reduction of the ddI dose led to mitochondrial DNA recovery, but was not sufficient to recover baseline CD4+ T-cell counts. Other mitochondrial toxicity in addition to DNA γ-polymerase inhibition could be responsible for CD4+ T-cell toxicity.
Distinct Hepatitis C virus Kinetics in HIV-Infected Patients Treated with Ribavirin plus Either Pegylated Interferon α2a or α2b
Authors: Vispo Eugenia , Barreiro Pablo , Rodríguez-Nóvoa Sonia , Morello Judit , Labarga Pablo , Martín-Carbonero Luz , Maida Ivana , García-Gascó Pilar , Soriano Vincent 
Published: April 2022

Background Pegylated interferon (PEG-IFN) α2a and α2b differ in their pharmacokinetic properties, which might have an effect on their antiviral effects against hepatitis C virus (HCV). Differences between PEG-IFN-α molecules could be more pronounced in HIV-coinfected individuals, in whom response to HCV treatment is impaired. Methods All HCV–HIV-coinfected patients included in PRESCO and EXTENT trials recruited at one referral centre were retrospectively analysed. In both trials, ribavirin (RBV) 1,000–1,200 mg/day was prescribed together with standard doses of PEG-IFN-α2a or -α2b. The attainment of serum HCV RNA <10 IU/ml at weeks 4, 12 and 24 was assessed. On-treatment analyses were made to estimate the intrinsic potency of PEG-IFN-α2a versus -α2b. Results A total of 218 patients were examined, 138 on PEG-IFN-α2a and 80 on PEG-IFN-α2b. Baseline characteristics were comparable in both groups. Undetectable serum HCV RNA at weeks 4, 12 and 24 was more frequently attained using PEG-IFN-α2a than -α2b (45% versus 27% [ P=0.02]; 65% versus 45% [ P=0.01]; and 75% versus 55% [ P=0.01], respectively), regardless of HCV genotype. Plasma RBV levels did not differ between groups. In multivariate analysis, HCV genotypes 2/3 (odds ratio [OR] 12.5; 95% confidence interval [95% CI] 3.45–33.33; P<0.001), use of zidovudine (OR 0.30; 95% CI 0.11–0.85; P=0.02) and treatment with PEG-IFN-α2a (OR 2.12; 95% CI 1.02–4.54; P=0.04) were independent predictors of undetectable HCV RNA at week 24. Conversely, the incidence of serious adverse events was more common with PEG-IFN-α2a than -α2b (13.2% versus 3.6%; P=0.018). Conclusions The antiviral effect against HCV seems to be greater for PEG-IFN-α2a than -α2b in the HIV setting. A shorter half-life of PEG-IFN-α2b could explain this finding.
Treatment of Patients with Chronic Hepatitis B who have Failed Previous Antiviral Treatment with Pegylated Interferon α2a (40 kDa; PEGASYS®)
Authors: Chan Henry L-Y , Wong Vincent W-S , Chim Angel M-L , Wong Grace L-H , Chan Hoi-Yun , Sung Joseph J-Y 
Published: April 2022

Background Although nucleot(s)ide analogues can effectively suppress hepatitis B virus (HBV) replication, many patients experience relapse of hepatitis after cessation of treatment. We aimed to investigate the efficacy of pegylated interferon α2a (PEG-IFN-α2a) in these difficult-to-treat patients. Methods Chronic hepatitis B patients who have received antiviral drugs for ≥12 months and stopped for ≥6 months were treated by 48-week PEG-IFN-α2a. Virological response was defined as HBV DNA <10,000 copies/ml and hepatitis B e antigen (HBeAg) seroconversion (for HBeAg-positive patients). Results A total of 40 patients, 29 HBeAg-positive and 11 HBeAg-negative, with median log10 HBV DNA 7.3 copies/ml and alanine aminotransferase 110 IU/ml were studied. The last antiviral treatment was given for 92 +61 weeks and stopped for 176 +88 weeks. At the end of treatment, 22 (12 HBeAg-positive and 10 HBeAg-negative; 55%) patients had virological response and 16 (7 HBeAg-positive and 9 HBeAg-negative; 40%) patients had undetectable HBV DNA (<100 copies/ml). At 24 weeks post-treatment, 14 (8 HBeAg-positive and 6 HBeAg-negative; 35%) patients had virological response and 9 (5 HBeAg-positive and 4 HBeAg-negative; 23%) patients had undetectable HBV DNA. Two (5%) patients had lost hepatitis B surface antigen. HBV DNA levels at week 24 best predicted sustained virological response (area under curve 0.76, 95% confidence interval 0.60–0.92, P=0.007). At HBV DNA cutoffs of 3 logs and 5 logs at week 24, the sensitivity/specificity for sustained virological response were 50%/85% and 86%/62%, respectively. Conclusions PEG-IFN-α2a was effective in the treatment of chronic hepatitis B patients who have failed previous antiviral treatment.
HIV RNA viral Load and CD4+ T-cell Counts in HIV-Infected Pregnant Women with and without Treatment Discontinuation in Early Pregnancy
Authors:   the Italian Group on Surveillance on Antiretroviral Treatment in Pregnancy, Tamburrini Enrica , Ravizza Marina , Floridia Marco , Tibaldi Cecilia , Alberico Salvatore , Anzidei Gianfranco , Maccabruni Anna , Meloni Alessandra , Antoni Anna Degli , Mori Fernanda , Dalzero Serena , Conserva Valentina , Pinnetti Carmela , Ferrazzi Enrico 
Published: April 2022

Background In pregnant women taking antiretroviral treatment at conception treatment may be transiently stopped for safety concerns. Limited data are available on the consequences of such discontinuations. Methods We used data from a national study to compare different treatment pathways during pregnancy. Overall, 321 women were evaluated and classified into three groups: women not on treatment at conception and who started treatment during pregnancy (starters; n=91); women on treatment at conception who temporarily discontinued treatment during first trimester (discontin-uers; n=114); and women on treatment at conception who maintained treatment (continuers; n=116). Results At conception, the three groups had similar CD4+ T-cell counts (499, 495 and 470 cells/mm3, respectively; P>0.10); starters had significantly higher median HIV RNA levels at conception (5,690 copies/ml) compared with both continuers (58 copies/ml, P<0.001) and discontinuers (49 copies/ml, P<0.001). Continuers maintained undetectable HIV RNA at all pregnancy trimesters, while discontinuers showed at first and second trimester transient negative effects on HIV (4,776 and 386 copies/ml, respectively) and CD4+ T-cell levels (376 and 392 cells/mm3, respectively), which were reversed at last trimester (52 copies/ml and 432 cells/mm3, respectively). No significant differences were observed among the groups in HIV RNA and CD4+ T-cell counts at third trimester, preterm delivery, low birth weight or mode of delivery. The number of cases of HIV transmission and birth defects were too limited to allow comparisons. Conclusions Early discontinuation of antiretroviral treatment in pregnancy produces transient virological and immunological effects without precluding the achievement of a good viral suppression at the end of pregnancy; no clinical consequences were observed.
Pharmacokinetics and 48-Week Efficacy of Nevirapine: 400 mg Versus 600 mg per day in HIV–Tuberculosis Coinfection Receiving Rifampicin
Authors: Avihingsanon Anchalee , Manosuthi Weerawat , Kantipong Pacharee , Chuchotaworn Charoen , Moolphate Saiyud , Sakornjun Waraporn , Gorowara Meena , Yamada Norio , Yanai Hideki , Mitarai Satoshi , Ishikawa Nobukatsu , Cooper David A , Phanuphak Praphan , Burger David , Ruxrungtham Kiat 
Published: April 2022

Background We aim here to determine the appropriate dose of nevirapine (NVP) in Thai HIV–tuberculosis (TB)-coinfected patients receiving rifampicin. Methods Thirty-two HIV-infected adults with CD4+ T-cell counts <200 cells/mm3 and active TB, receiving rifampicin for 2–6 weeks were randomized to receive either NVP 400 mg (NVP400) or 600 mg (NVP600) per day plus two nucleoside reverse transcriptase inhibitors; a 2-week NVP lead-in was performed at 200 mg once daily (OD) and 200 mg twice daily, respectively. Plasma NVP levels were determined at weeks 2, 4 and 12. Twelve-hour pharmacokinetics (PK) were obtained ( n=20) at week 4. Results Baseline body weight was comparable. There were more patients with NVP plasma concentration at 12 h (C12) <3.1 mg/l at week 2 in NVP400 than in NVP600 (79% versus 19%, respectively; P=0.002). However, the proportions were comparable at weeks 4 and 12. From week 4, 12 h PK studies showed that NVP400 had lower median NVP area under the plasma concentration-0–12 h (AUC0–12 h), maximum concentration in plasma (Cmax) and C12 than NVP600 ( P<0.05). Four patients in NVP600 developed NVP hypersensitivity. At week 48, the median CD4+ T-cell count rise and proportion with viral load <50 copies/ml (intention-to-treat analysis 56% versus 50% and as-treated analysis 75% versus 89%) were comparable. Conclusions In rifampicin-treated patients, 200 mg NVP OD lead-in led to a significant short-term suboptimal NVP C12 level, while NVP 400 mg lead-in then 600 mg/day was associated with a high rate of NVP hypersensitivity. Forty-eight week efficacy was comparable. Thus, NVP 600 mg/day in rifampicin-treated patients is not recommended.
Single- and multiple-dose pharmacokinetics of etravirine administered as two different formulations in HIV-1-infected patients
Authors: Kakuda Thomas N , Schöller-Gyμre Monika , Workman Cassy , Arasteh Keikawus , Pozniak Anton L , Smedt Goedele De , Beets Greet , Peeters Monika , Vandermeulen Kati , Woodfall Brian J , Hoetelmans Richard MW 
Published: April 2022

Background An open-label, randomized, crossover study to evaluate the pharmacokinetics of two different formulations of etravirine after single and multiple dosing. Methods Treatment-experienced HIV-1-infected patients with viral load <50 copies/ml continued their current antiretroviral regimen and added etravirine twice daily for 7 days with a morning intake on day 8. Etravirine was administered following food as either 800 mg twice daily of the Phase II formulation or 100 mg or 200 mg twice daily of the Phase III formulation. A 12 h pharmacokinetic assessment was performed on days 1 and 8. Results After single- and multiple-dose administration, the exposure to etravirine was lower with 100 mg twice daily and higher with 200 mg twice daily compared with 800 mg twice daily. On day 8, the mean (±sd) area under the plasma concentration-time curve over 12 h (AUC0–12 h) was 1,284 (±958) ng•h/ml when etravirine was administered as 100 mg twice daily ( n=33), 3,713 (±2,069) ng•h/ml when administered as 200 mg twice daily ( n=27) and 2,607 (±2,135) ng•h/ml when administered as 800 mg twice daily ( n=32). Both formulations and all doses of etravirine tested were generally safe and well tolerated. Conclusions The range of exposure to etravirine was comparable between 200 mg twice daily dose and 800 mg twice daily. The Phase III formulation of etravirine significantly improves the bioavailability of etravirine over the Phase II formulation with reduced interpatient variability in etravirine pharmacokinetics.
Adherence to antiretroviral therapy in patients enrolled in a comprehensive care program in Cambodia: A 24-month follow-up assessment
Authors: Spire Bruno , Carrieri Patrizia , Sopha Pal , Protopopescu Camelia , Prak Narom , Quillet Catherine , Ngeth Chanchhaya , Ferradini Laurent , Delfraissy Jean-François , Laureillard Didier 
Published: April 2022

Background The long-term maintenance of antiretroviral therapy (ART) remains an important issue, especially in limited-resource settings where additional barriers exist. A cross-sectional study was performed 24 months after ART initiation for patients treated in Cambodia in order to estimate the prevalence and identify determinants of non-adherence. Methods Adults receiving ART for 24 ±2 months were considered eligible for the study. Self-reported non-adherence was defined according to an algorithm based on six items. The questionnaire also assessed ART-related side effects and HIV disclosure. HIV-1 RNA plasma viral load was measured using real-time PCR. Multivariate rare events logistic regression analysis was used to identify independent factors associated with non-adherence. Results A total of 346 patients participated in the study. At 24 months, 95% of patients were adherent, 80% had HIV RNA <40 copies/ml and 75% had CD4+ T-cell counts >200 cells/mm3. Virological success was significantly higher in adherent patients than in non-adherent patients (81% versus 56%, P=0.021). Living in a rural area, limited HIV disclosure and perceived lipodystrophy were independently associated with non-adherence. Conclusions At 24 months, adherence to ART was high and explained positive virological outcomes. In order to maintain adherence and long-term virological benefits, special attention should be given to patients living in rural areas, those with lipodystrophy-related symptoms and others who express difficulties disclosing their condition to close family members.
The Oncogenic Potential of Hepatitis B virus rtA181T/ Surface Truncation Mutant
Authors: Lai Ming-Wei , Yeh Chau-Ting 
Published: April 2022

Background Previously, a less prevalent lamivudine-resistant mutant (rtA181T) was discovered in Taiwanese patients, in which a stop codon in the surface gene concomitantly occurred, leading to impaired secretion of hepatitis B virus (HBV) surface antigen. The rtA181T mutant also conferred drug resistance to adefovir. We discovered a 39-year-old patient with advanced hepatocellular carcionoma, who was seropositive for HBV e antigen but seronegative for HBV surface antigen. Nucleotide sequence analysis revealed the presence of polymerase rtA181T/surface truncation mutant in both the serum and hepatoma samples. Surprisingly, this patient has never received lamivudine or adefovir antiviral therapy. Here, we aimed to evaluate the oncogenic potential of HBV rtA181T/surface truncation mutant. Methods Site-directed mutagenesis experiments followed by transactivation assays were performed in HepG2 cells to evaluate the transactivation activities of the corresponding pre-S/S truncation mutant for c-Myc, c-Fos and Simian virus 40 promoters. NIH3T3 cells stably expressing the mutant were used to assess the tumourigenicity in nude mice. Results Transactivation experiments revealed that the corresponding pre-S/S truncation mutant was capable of transactivating the Simian virus 40 and human c-Myc promoters but not the c-Fos promoter. NIH3T3 cells stably expressing this mutant were tumourigenic in four of the five nude mice tested. Conclusion Our data indicate that an HBV polymerase rtA181T/surface truncation mutant could emerge spontaneously without previous antiviral treatment. The presence of this mutant in a patient with advanced hepatocellular carcinoma as well as its oncogenic potential warrants careful re-evaluation of the current strategy of prolonged antiviral therapy.
Using Biomarkers to Stage Disease Progression in a Lethal Mousepox Model Treated with CMX001
Authors: Parker Scott , Schriewer Jill , Oberle Christina , Robertson Alice , Lanier Randall , Painter George , Buller R Mark 
Published: April 2022

Background The emergence of human monkeypox and the potential use of recombinant variola and monkey-pox viruses as biological terrorist agents have necessitated the development of therapeutic and prophylactic therapies. The primary, or index, cases of smallpox and/ or human monkeypox will likely be identified by a characteristic rash. Effective biomarkers will be required to monitor disease progression, guide the choice of therapeutic intervention strategies and evaluate their efficacies. To address this we have evaluated several biomarkers of disease in a lethal mousepox model. Methods The efficacy of a single dose of a hexadecyloxypropyl ester of cidofovir (CMX001) at 20, 25 and 30 mg/ kg doses administered on days 4, 5, 6 and 7 post-infection was evaluated in A/Ncr mice intranasally infected with low doses of ectromelia virus (<20 plaque-forming units). Mice were monitored for weight loss, blood interferon-γlevels, alanine aminotransferase (ALT), aspartate amino-transferase, viral DNA copies and neutrophilia levels to stage disease progression. Results We have used these biomarkers to establish the optimal dosing regimen for treatment and reveal that a single dose of 25 mg/kg of CMX001 can be efficacious at treating lethal mousepox when administered on days 4 or 5 post-infection. This dose significantly reduces ALT, interferon-γand DNA copies found in the blood of infected animals. Conclusions A single dose regimen of CMX001 is efficacious at treating mousepox. Disease progression and antiviral efficacy can be monitored using several biomarkers that could readily be used in the case of a human monkeypox or smallpox outbreak.
Antiviral Activity of Lauryl Gallate against Animal Viruses
Authors: Hurtado Carolina , Bustos Maria Jose , Sabina Prado , Nogal Maria Luisa , Granja Aitor G , González Maria Eugenia , Gónzalez-Porqué Pedro , Revilla Yolanda , Carrascosa Angel L 
Published: April 2022

Background Antiviral compounds are needed in the control of many animal and human diseases. Methods We analysed the effect of the antitumoural drug lauryl gallate on the infectivity of the African swine fever virus among other DNA (herpes simplex and vaccinia) and RNA (influenza, porcine transmissible gastroenteritis and Sindbis) viruses, paying attention to its effect on the viability of the corresponding host cells. Results Viral production was strongly inhibited in different cell lines at non-toxic concentrations of the drug (1–10 μM), reducing the titres 3–>5 log units depending on the multiplicity of infection. In our model system (African swine fever virus in Vero cells), the addition of the drug 1 h before virus adsorption completely abolished virus productivity in a one-step growth virus cycle. Interestingly, no inhibitory effect was observed when lauryl gallate was added after 5–8 h post-infection. Both cellular and viral DNA synthesis and late viral transcription were inhibited by the drug; however, the early viral protein synthesis and the virus-mediated increase of p53 remained unaffected. Activation of the apoptotic effector caspase-3 was not detected after lauryl gallate treatment of Vero cells. Furthermore, the presence of the drug abrogated the activation of this protease induced by the virus infection. Conclusions Lauryl gallate is a powerful antiviral agent against several pathogens of clinical and veterinary importance. The overall results indicate that a cellular factor or function might be the target of the antiviral action of alkyl gallates.
NICE Guidelines and a Treatment Algorithm for the Management of Chronic Hepatitis B: A Review of 12 Years Experience in West London
Authors: Kennedy Patrick TF , Lee Heather C , Jeyalingam Lukshmy , Malik Raza , Karayiannis Peter , Muir David , Main Janice , Thursz Mark , Goldin Robert , Smith Belinda , Brown Ashley , Thomas Howard C 
Published: April 2022

Background Treatment strategies in chronic hepatitis B (CHB) are evolving as more potent oral antivirals become available. However, drug resistance remains a major challenge and policy guidelines on management are limited by the evidence base. This study aims to review the implications of the National Institute for Health and Clinical Excellence (NICE) guidelines in a cohort of unselected CHB patients in the United Kingdom and to evolve a management algorithm for their treatment. Methods In total, 783 unselected hepatitis B surface antigen-positive patients, were assessed of whom 212 (27%) underwent liver biopsy. Age, alanine aminotransferase, hepatitis B virus DNA and necroinflammatory score were analysed to determine their value as predictors of fibrosis. Patients with biopsy evidence of fibrosis were offered treatment and followed longitudinally. Six-month on-treatment virologic response was evaluated to determine the validity of this strategy in predicting the early emergence of resistance. Results Age, gender and necroinflammatory score were predictors of fibrosis in CHB patients, whereas age >40 years was a predictor of cirrhosis in both hepatitis B e antigen (HBeAg)-positive ( P<0.03) and HBeAg-negative patients ( P<0.003). A total of 81% of HBeAg-positive and 65% of HBeAg-negative CHB patients who required adefovir add-on therapy were identifiable after 6 months of lamivudine monotherapy, by continuing HBV DNA positivity ( P<0.002 and P<0.0001, respectively). Conclusions Advanced liver disease was present in patients falling outside current treatment guidelines, highlighting the importance of liver histology in identifying fibrosis and the need for antiviral therapy. While 6 month on-treatment virologic response as a trigger for instituting add-on therapy may be an improvement on the current recommendations, such a strategy should be integrated into any new treatment algorithm, likely to consist of entecavir and tenofovir.