bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amprenavir and Lopinavir Pharmacokinetics following Coadministration of Amprenavir or Fosamprenavir with Lopinavir/Ritonavir, with or without Efavirenz
Authors: Pham Paul A , Hendrix Craig W , Barditch-Crovo Patricia , Parsons Teresa , Khan Wasif , Parish Michelle , Radebaugh Christine , Carson Kathryn A , Pakes Gary E , Qaqish Roula , Flexner Charles 
Published: April 2022

Background Amprenavir (APV), fosamprenavir (FPV), lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) are to varying degrees substrates, inducers and inhibitors of CYP3A4. Coadministration of these drugs might result in complex pharmacokinetic drug-drug interactions. Methods Two prospective, open-label, non-randomized studies evaluated APV and LPV steady-state pharmacokinetics in HIV-infected patients on APV 750 mg twice daily + LPV/RTV 533/133 mg twice daily with EFV ( n=7) or without EFV ( n=12) + background nucleosides (Study 1) and after switching FPV 1,400 mg twice daily for APV ( n=10) (Study 2). Results In Study 1 EFV and non-EFV groups did not differ in APV minimum plasma concentration (Cmin; 1.10 versus 1.06μg/ml, P=0.89), area under the concentration-time curve (AUC; 17.46 versus 24.34μg•h/ml, P=0.22) or maximum concentration (Cmax; 2.61 versus 4.33 μg/ml, P=0.08); for LPV there was no difference in Cmin (median: 3.66 versus 6.18μg/ml, P=0.20), AUC (81.84 versus 93.75 μg•h/ml, P=0.37) or Cmax (10.36 versus 10.93 μg/ml, P=0.61). In Study 2, after switching from APV to FPV, APV Cmin increased by 58% (0.83 versus 1.30 μg/ml, P=0.0001), AUC by 76% (19.41 versus 34.24 μg•h/ml, P=0.0001), and Cmax by 75% (3.50 versus 6.14, P=0.001). Compared with historical controls, LPV and RTV pharmacokinetics were not changed. All treatment regimens were well tolerated. Seven of eight completers (88%) maintained HIV-1 RNA <400 copies/ml 12 weeks after the switch (1 lost to follow up). Conclusions EFV did not appear to significantly alter APV and LPV pharmacokinetic parameters in HIV-infected patients taking APV 750 mg twice daily + LPV 533/133 mg twice daily. Switching FPV 1,400 mg twice daily for APV 750 mg twice daily resulted in an increase in APV Cmin, AUC, and Cmax without changing LPV or RTV pharmacokinetics or overall tolerability.
Intracellular Nucleoside Triphosphate Concentrations in HIV-Infected Patients on Dual Nucleoside Reverse Transcriptase Inhibitor Therapy
Authors: Moore Jeff D , Acosta Edward P , Johnson Victoria A , Bassett Roland , Eron Joseph J , Fischl Margaret A , Long Mary C , Kuritzkes Daniel R , Sommadossi Jean-Pierre 
Published: April 2022

Background Intracellular nucleoside reverse transcriptase inhibitor triphosphate (NRTI-TP) concentrations are crucial in suppressing HIV replication. Little is known about how commonly used dual-NRTI regimens affect the intracellular levels of NRTI-TPs, the active form of these drugs. This study investigates the effect of dual-NRTI therapy in intracellular NRTI-TP levels. Methods NRTI and NRTI-TP concentrations were evaluated in HIV-infected patients receiving either lamivudine (3TC) and stavudine (d4T) or lamivudine with zidovudine (ZDV); NRTI and NRTI-TP concentrations were determined using a validated HPLC/MS/MS method. Plasma HIV-1 RNA levels were determined at baseline and monthly to examine the relationship between NRTI-TP concentrations and plasma HIV-1 RNA. Results Forty-one subjects completed the study. 3TC-TP significantly increased between day 1 and week 28 from 1.48 to 5.00 pmol/106 peripheral blood mononuclear cells (PBMC; P<0.0001). NRTI-TP concentrations for d4T and ZDV did not significantly increase, with values at week 28 of 0.011 and 0.02 pmol/106 PBMC, respectively. Mean NRTI-TP/plasma ratios were 3%, 0.007% and 0.05% for 3TC, d4T and ZDV, respectively. Linear relationships were observed between ZDV- and 3TC-TP and changes in plasma HIV-1 RNA. Conclusion Of the three drugs studied, only 3TC-TP levels increased significantly between day 1 and week 28. ZDV-TP and 3TC-TP levels were unaffected by dual-NRTI therapy relative to monotherapy, regardless of the combination (3TC-ZDV or 3TC-d4T). Intracellular levels of d4T-TP were similar to previous reports for dual-NRTI therapy; however, in the case of d4T, these values appear lower than those achieved with d4T monotherapy.
The association of bone mineral density with HIV infection and antiretroviral treatment in women
Authors: Anastos Kathryn , Lu Dalian , Shi Qiuhu , Mulligan Kathleen , Tien Phyllis C , Freeman Ruth , Cohen Mardge H , Justman Jessica , Hessol Nancy A 
Published: April 2022

Background Low bone mineral density (BMD) has been reported in HIV-infected women and men. Methods We analysed cross-sectional BMD measured by regional dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN) in 152 HIV-negative and 274 HIV-positive (HIV+) women, adjusted for traditional low BMD risk factors. Results BMD was significantly lower in protease inhibitor (PI) users than in all other groups, and highest in HIV-negative women. In multivariate analyses the prevalence of T-score <-1.0 was significantly higher in the HIV+ women naive to antiretroviral therapy (ART; odds ratio [OR] 4.36, 95% confidence interval [CI] 1.61, 11.8) and the women receiving PI-containing HAART (OR 3.72, CI 1.43, 9.68), with a non-significant difference in non-PI HAART users (OR 2.43, CI 0.92, 6.45), compared with HIV-negative women. In pair-wise adjusted comparisons, BMD was lower in ART-naive than in HIV-negative women (1.22 versus 1.30 g/cm2 at LS; P=0.004), in PI compared with non-PI HAART users (1.00 versus 1.05 g/cm2 at FN; P=0.014) and with those ART-naive (1.00 versus 1.03 g/cm2 at FN; P=0.146). Potential confounders, including duration of ART, prior treatment regimens and traditional risk factors for low BMD did not explain these differences. Longer lopinavir use was significantly correlated with lower BMD (r2=-0.39, P=0.024 and r2=-0.46, P=0.006 at LS and FN, respectively) and longer efavirenz use with higher BMD (r2=+0.32, P=0.004 at FN). Conclusions HIV infection was associated with lower BMD in women, independent of the traditional risk factors for low BMD. PI-containing HAART compared with non-PI-containing HAART, and longer lopinavir use, were both associated with lower BMD, and efavirenz use was associated with higher BMD.
Risk Factors for Acute Liver Enzyme Abnormalities in HIV-Hepatitis B Virus-Coinfected Patients on Antiretroviral Therapy
Authors: Chauvel Olivia , Lacombe Karine , Bonnard Philippe , Lascoux-Combe Caroline , Molina Jean-Michel , Miailhes Patrick , Girard Pierre-Marie , Carrat Fabrice 
Published: April 2022

Background Little is known about the prognostic factors of acute liver enzyme variations in HIV-hepatitis B virus (HBV)-coinfected patients. Objectives To identify prognostic factors of acute liver enzyme abnormalities in HIV-HBV-coinfected patients with a focus on the putative role of antiretroviral drugs. Design Data from a 3-year, prospective, multicentre cohort study involving HIV-HBV patients were used. Methods A Markov model was used to identify prognostic factors of acute episodes of cytolysis and cholestasis in 300 HIV-HBV-coinfected patients. The effect of antiretroviral therapy was analysed according to the classes of drugs, duration of treatment and treatment modifications. Results The incidence rates of acute episodes of cytolysis and cholestasis were 13.4 per 100 patient-years (95% confidence interval [CI] 9.5–17.3) and 7.1 per 100 patient-years (95% CI 4.2–10.0), respectively (median follow up 34.1 months). Independent risk factors for cytolysis were a high level of HBV or HIV replication, as well as a low of CD4+ T-cell count. No antiretroviral drug was associated with cytolysis, whereas protease inhibitors seemed to be independently associated with cholestasis, along with treatment modifications and the duration of HIV infection. Conclusion Acute and reversible episodes of cytolysis or cholestasis were common and associated with virus- and host-related determinants. The choice of the optimal antiretroviral combination in HIV-HBV-coinfected patients must take into account the necessity of exerting an efficient control of HIV and HBV replication (associated with transient cytolysis) and the risk of inducing cholestasis (associated with the use of protease inhibitors and treatment modifications).
Lack of Rapid Virological Response Predicts Interferon-α2b/Ribavirin Therapy failure in HCV Genotype 2 Patients: A Single-Centre Study
Authors: Rumi Maria Grazia , Aghemo Alessio , D'Ambrosio Roberta , Ronchi Guido , Ninno Ersilio Del , Gallus Silvano , Colombo Massimo 
Published: April 2022

Background A minority of patients with HCV-2 chronic hepatitis does not attain a sustained virological response to interferon-based therapies. Registration trials have failed to identify the real proportion of HCV-2 non-responders, and predictors of non-response. The analysis of ‘real-life’ HCV-2 patients might help define the effectiveness of anti-HCV therapy and the role of response moderators. Methods A re-analysis of all treatment-naive HCV-2 patients who consecutively received weight-dosed ribavirin with either 3 MU three times a week standard interferon-α2b or 1.5 μg/kg/week pegylated interferon-α2b. Results The 94 interferon-treated patients and the 136 pegylated-interferon-treated patients were comparable for demography, prevalence of cirrhosis (25%) and adherence to therapy (74%). By intention-to-treat analysis, the overall sustained virological response rate was 80% (82% interferon versus 78% pegylated interferon). Overall, sustained virological rates were 83% for the 182 patients who cleared HCV RNA at week 4 (rapid virological response) and 52% for the 48 who did not ( P<0.001). The corresponding week 12 figures of HCV RNA clearance were 90% and 32%, respectively ( P<0.001). Sustained response was independent of gender, age, body mass index, modality of infection, duration and severity of liver disease, adherence to therapy and interferon type. After stratification for interferon type, the only treatment failure predictor was persistence of HCV RNA at week 4 and 12. Conclusions Despite the prevalence of moderators of treatment outcome, HCV-2 patients showed as high sustained virological response rates as those reported in registration trials for HCV-2 and HCV-3 pooled patients; pegylated interferon therapy failure was predicted by lack of rapid virological response.
External Quality Assessment of HLA-B*5701 Reporting: An International Multicentre Survey
Authors: Hammond Emma , Almeida Coral-Ann , Mamotte Cyril , Nolan David , Phillips Elizabeth , Schollaardt Tineke Asma , Gill M John , Angel Jonathan B , Neurath Doris , Li Jianping , Giulivi Tony , McIntyre Cathy , Koultchitski Galina , Wong Betty , Reis Marciano , Rachlis Anita , Cole David E , Chew Choo Beng , Neifer Stefan , Lalonde Richard , Roger Michel , Jeanneau Annie , Mallal Simon 
Published: April 2022

Objectives HLA-B*5701 strongly predicts abacavir hypersensitivity (HSR), but implementation of effective routine screening into clinical practice requires testing be practical and accurate. We tested the proficiency of HLA-B*5701 typing among laboratories using sequence-specific primer PCR. Design and methods DNA panels (1 and 2) were distributed to seven laboratories (A to G) for blinded typing of the HLA-B*5701 allele. Panel 1 ( n=10 samples; n=7 laboratories) included 3 positives and other closely related B17 subtypes (B*5702, B*5703, B*5704 and B*5801). Panel 2 ( n=96 samples; n=4 laboratories) included 36 positives among a broad spectrum of other B alleles. Two laboratories (A and B) also submitted 96 routine samples, typed by the same methodology, to the reference centre for additional analysis by sequence-based typing. Results All laboratories correctly typed panel 1 for HLA-B*5701 carriage. Laboratories A, B and C identified HLA-B*5701 alleles in panel 2 with 100% sensitivity and 100% specificity. Laboratory D reported one false negative, reportedly due to a sampling error. The results obtained for routine samples typed by laboratories A and B and those generated by the reference laboratory using sequencing were fully concordant. Conclusions Detection of HLA-B*5701 alleles among laboratories was 100% specific and 99.4% sensitive, indicating that participating HIV testing laboratories were currently offering effective primary screening to identify individuals at high risk of abacavir HSR. Accurate reporting of HLA-B*5701 status is critical for the safe administration of this drug and participation in quality assurance programmes by all sites who report HLA-B*5701 status should be promoted.
Predicting HIV Coreceptor Usage on the Basis of Genetic and Clinical Covariates
Authors: Sing Tobias , Low Andrew J , Beerenwinkel Niko , Sander Oliver , Cheung Peter K , Domingues Francisco S , Büch Joachim , Däumer Martin , Kaiser Rolf , Lengauer Thomas , Harrigan P Richard 
Published: April 2022

Background We compared several statistical learning methods for the prediction of HIV coreceptor use from clonal HIV third hypervariable (V3) loop sequences, and evaluated and improved their effectiveness on clinical samples. Methods Support vector machines (SVM), artificial neural networks, position-specific scoring matrices (PSSM) and mixtures of localized rules were estimated and tested using 10x ten-fold cross-validation on a clonal dataset consisting of 1,100 matched clonal genotype-phenotype pairs from 332 patients. Different SVMs were also trained and tested on a clinically derived dataset, representing 920 patient samples from British Columbia, Canada. Methods were evaluated using receiver operating characteristic (ROC) curves. Results In the clonal analysis, the sensitivity of the 11/25 rule at 92.5% specificity was 59.5%. PSSMs and SVMs increased sensitivity to 71.9% and 76.4%, respectively, at the same specificity ( P<<0.05). In clinical samples, the sensitivity of the 11/25 rule and SVM decreased to 25.9% (specificity 93.9%) and 39.8% (specificity 93.5%), respectively. However, the integration of clinical data resulted in a further 2.4-fold increase in sensitivity over the 11/25 rule (63%). Univariate analyses identified 41 V3 mutations significantly associated with coreceptor usage. Conclusion For all methods tested, a substantial sensitivity decrease is observed on clinical data, probably owing to the heterogeneity of the viral population in vivo. In response to these complications, we present an SVM-based approach that integrates sequence information with clinical and host data, resulting in improved performance and sensitivity compared with purely sequence-based approaches.
Viral and Clinical Factors associated with Surface Gene Variants among Hepatitis B Virus Carriers
Authors: Roque-Afonso Anne Marie , Férey Marie-Pierre , Ly Thoai Duong , Graube Arielle , Costa-Faria Luciana , Samuel Didier , Dussaix Elisabeth 
Published: April 2022

Background Understanding the prevalence of potential antigenic variation of the hepatitis B virus (HBV) surface antigen (HBsAg) is fundamental for assay design and to future changes in vaccine formulation. In this study, the nature and frequency of HBsAg polymorphisms occurring in France in chronic carriers and in newly diagnosed patients were determined. We focused on variations in the major hydrophilic region (MHR), the central core of HBsAg known to be exposed on the surface and involved in antibody binding. Methods Two patient groups were identified: 51 chronic HBV carriers followed at our institution for >1 year; and 129 newly diagnosed patients (63 of whom had a first HBsAg-positive result at our hospital laboratory and 66 a first positive result in a private laboratory). DNA sequences of HBsAg were obtained from these 180 patients and compared with consensus sequences built with 168 full-length HBV sequences imported from GenBank. Polymorphisms of the MHR of HBsAg were analysed with the Mutation Master Software. Literature review and BLOSUM scores were used to define potentially altered antigenicity. Results The global frequency of MHR variants was 27.8%. Occurrence of MHR variants was independent of viral load, HBeAg status and sex, but was associated with the chronic carriers’ group, advancing age, the presence of antibodies to HBsAg, immunoprophylaxis administration, antiviral treatment and genotypic resistance to antivirals. In multivariate analysis, the independent variables associated with MHR variants were advancing age and the presence of genotypic resistance to nucleoside or nucleotide analogues. Conclusion Most MHR variants emerge with longer disease duration and upon indirect selective pressure. Variation of the MHR may serve to restore virus replication of resistant strains. Combined envelope and polymerase variants could impair diagnostic assays and limit treatment alternatives.
Activity of the Anti-Orthopoxvirus Compound ST-246 against Vaccinia, Cowpox and Camelpox Viruses in Cell Monolayers and Organotypic Raft Cultures
Authors: Duraffour Sophie , Snoeck Robert , De Vos Rita , Van Den Oord Joost J , Crance Jean-Marc , Garin Daniel , Hruby Dennis E , Jordan Robert , De Clercq Erik , Andrei Graciela 
Published: April 2022

Background The potential use of variola virus as a biological weapon has renewed efforts in the development of antiviral agents against orthopoxviruses. ST-246 [4-trifluoromethyl-W-(3,3a,4,4a,5,5a,6,6a-octahydro-1,3-dioxo-4,6-ethenocycloprop [f]isoindol-2(1H)-yl)-benza-mide] is an anti-orthopoxvirus compound active against several orthopoxviruses including vaccinia virus (VV), cowpox virus (CPV), camelpox virus (CMLV), ectromelia virus (ECTV) and variola virus in cell culture. The compound has been shown to inhibit the release of extracellular virus by targeting the F13L VV protein and to protect mice from VV, CPV and ECTV orthopoxvirus-induced disease. Methods The antiviral activity of ST-246 was assessed against extracellular and intracellular VV, CPV and CMLV production in human embryonic lung (HEL) fibroblasts and primary human keratinocyte (PHK) cell monolayers, as well as in three-dimensional raft cultures. Results ST-246 inhibited preferentially the production of extracellular virus compared with intracellular virus production in HEL and PHK cells (for VV) and in PHK cells (for CMLV). In organotypic epithelial raft cultures, ST-246 at 20 μg/ml inhibited extracellular VV and CMLV production by 6 logs, whereas intracellular virus yield was reduced by 2 logs. In the case of CPV, both extracellular and intracellular virus production were completely inhibited by ST-246 at 20 μg/ml. Histological sections of the infected rafts, treated with increasing amounts of drug, confirmed the antiviral activity of ST-246: the epithelium was protected and there was no evidence of viral infection. Electron microscopic examination confirmed the absence of intracellular enveloped virus forms in VV-, CPV- and CMLV-infected cells treated with 10 μg/ml of ST-246. Conclusions These data indicate that ST-246 is a potent anti-orthopoxvirus compound; the mode of inhibition is dependent on the virus and cell type.
Predictive Factors for Response to a Boosted Dual HIV-Protease Inhibitor Therapy with Saquinavir and Lopinavir in Extensively Pre-Treated Patients
Authors: Von Hentig Nils , Babacan Errol , Staszewski Schlomo , Stürmer Martin , Doerr Hans W , Lötsch Jörn 
Published: April 2022

Objective To evaluate predictive factors for therapy outcome of a boosted double-protease inhibitor (PI) regimen in 58 extensively pre-treated patients with HIV. Methods Patients received lopinavir/ritonavir 400/100 mg and saquinavir 1,000 mg twice daily without reverse transcriptase inhibitors (RTI). The primary outcome parameter was HIV RNA <400 copies/ml at week 48, secondary parameters were HIV-1 RNA and CD4+ T-cell count changes from baseline to week 48. Pharmacokinetics, genotypic resistance and clinical and individual parameters were correlated with the clinical outcome in regression analyses. Covariates for the analyses were minimum plasma concentration (Cmin), maximum plasma concentration, area under the concentration versus time curve, half-life and clearance of lopinavir and saquinavir, the genotypic inhibitory quotients (GIQ) of archived (GIQarch) and baseline PI resistance mutations, previously taken antiretrovirals, archived and baseline viral resistance mutations, baseline HIV-1 RNA and CD4+ T-cell count. Results The analyses detected correlations between the primary outcome parameter and several factors: baseline CD4+ T-cell count ( P=0.001); absence of mutations at V82T/A/F/I/S plus I54M/V/L ( P=0.002) or K20M/R ( P=0.010); and lopinavir CminGIQarch ( P=0.046). This regression model had a predictability of 97.0% for response to therapy. Covariates for the decrease of HIV-1 RNA from baseline to week 48 were baseline HIV-1 RNA ( P<0.001), lopinavir CminGIQarch ( P=0.013), presence/absence of mutations at V82T/A/F/I/S or I84A/V plus L10I/R/V/F, I54M/V/L or L63P ( P=0.018), and previously taken antiretrovirals ( P=0.034). Conclusions Baseline HIV-1 RNA <5.0 log10 and CD4+ T-cell count >200 cells/μl, lopinavir CminGIQarch >2,000 ng/ml and the absence of viral resistance mutations at V82T/A/F/I/S and I54M/V/L are highly predictive for therapeutic success of a regimen of saquinavir/lopinavir/ ritonavir without RTI in a heterogenic cohort of patients with an extensive pre-treatment history and highly variable pharmacokinetics.
Adverse Events to Antiretrovirals in the Swiss HIV Cohort Study: Effect on Mortality and Treatment Modification
Authors: Keiser Olivia , Fellay Jacques , Opravil Milos , Hirsch Hans H , Hirschel Bernard , Bernasconi Enos , Vernazza Pietro L , Rickenbach Martin , Telenti Amalio , Furrer Hansjakob ,   Swiss HIV Cohort Study, Battegay M , Bernasconi E , Böni J , Bucher H , Bürgisser Ph , Cattacin S , Cavassini M , Dubs R , Egger M , Elzi L , Erb P , Fischer M , Flepp M , Fontana A , Francioli P , Furrer H , Gorgievski M , Günthard H , Hirschel B , Hösli I , Kahlert Ch , Kaiser L , Karrer U , Keiser O , Kind C , Klimkait Th , Ledergerber B , Martinez B , Müller N , Nadal D , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rickenbach M , Rudin C , Schmid P , Schultze D , Schüpbach J , Speck R , Taffé P , Tarr P , Telenti A , Trkola A , Vernazza P , Weber R , Yerly S 
Published: April 2022

Background Antiretroviral therapy (ART) decreases morbidity and mortality in HIV-infected patients but is associated with considerable adverse events (AEs). Methods We examined the effect of AEs to ART on mortality, treatment modifications and drop-out in the Swiss HIV Cohort Study. A cross-sectional evaluation of prevalence of 13 clinical and 11 laboratory parameters was performed in 1999 in 1,078 patients on ART. AEs were defined as abnormalities probably or certainly related to ART. A score including the number and severity of AEs was defined. The subsequent progression to death, drop-out and treatment modification due to intolerance were evaluated according to the baseline AE score and characteristics of individual AEs. Results Of the 1,078 patients, laboratory AEs were reported in 23% and clinical AEs in 45%. During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality with an adjusted hazard ratio (HR) of 1.3 (95% confidence interval [CI] 1.2–1.5; P<0.001) per score point. For clinical AEs no significant association with increased mortality was found. In contrast, an increasing score for clinical AEs (HR 1.11, 95% CI 1.04–1.18; P=0.002), but not for laboratory AEs (HR 1.07, 95% CI 0.97–1.17; P=0.17), was associated with antiretroviral treatment modification. AEs were not associated with a higher drop-out rate. Conclusions The burden of laboratory AEs to antiretroviral drugs is associated with a higher mortality. Physicians seem to change treatments to relieve clinical symptoms, while accepting laboratory AEs. Minimizing laboratory drug toxicity seems warranted and its influence on survival should be further evaluated.