bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Randomized Trial of Nelfinavir and Abacavir in Combination with Efavirenz and Adefovir Dipivoxil in HIV-1-Infected Persons with Virological Failure Receiving Indinavir
Authors: Hammer Scott M , Bassett Roland , Squires Kathleen E , Fischl Margaret A , Demeter Lisa M , Currier Judith S , Mellors John W , Morse Gene D , Eron Joseph J , Santana Jorge L , DeGruttola Victor ,   for the ACTG 372B/D Study Team
Published: April 2022

Objectives (1) To determine the efficacy and safety of nelfinavir versus placebo and abacavir versus other approved nucleoside reverse transcriptase inhibitors (NRTIs), in combination with efavirenz and adefovir dipovoxil, in subjects experiencing virological failure on an indinavir-containing regimen. (2) To determine the relationship of baseline viral drug resistance genotype and phenotype to virological outcome. Design and methods A prospective, randomized, controlled, multicentre study in non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive subjects conducted by the Adult AIDS Clinical Trials Group (ACTG 372B) and an open-label, single-arm, multicentre study in NNRTI-experienced subjects (ACTG 372D). Ninety-four subjects were randomized in ACTG 372B, which used a factorial design. All subjects received efavirenz and adefovir dipivoxil, and were randomly assigned to nelfinavir versus nelfinavir placebo and abacavir versus previously FDA-approved NRTIs. Twenty subjects received abacavir, efavirenz, adefovir dipivoxil and nelfinavir in ACTG 372D. Primary analysis time-point was at 16 weeks with follow-up through 48 weeks. Measures of efficacy were plasma HIV-1 RNA levels and CD4 cell counts. Adverse events were recorded according to ACTG criteria. Baseline reverse transcriptase and protease genotype, and drug susceptibility phenotype were determined. Resistance analyses were combined for ACTG 372B and D. Results At 16 weeks in ACTG 372B, 67% of subjects reached a primary study treatment failure end-point. In factorial analyses, nelfinavir was superior to nelfinavir placebo in rate of this failure end-point (56 vs 78%, P=0.02), but abacavir was not different from other NRTIs. No differences by nelfinavir or abacavir factor were noted at week 48. The failure end-point rate was significantly lower in those with baseline RNA levels ≤15000 copies/ml versus those with >15000 copies/ml (42 vs 79%, P<0.001). Higher genotypic and phenotypic sensitivity scores were significantly correlated with better virological responses ( P=0.003 and 0.030, respectively). Conclusions: (1) Treatment responses were low in this trial of nelfinavir, abacavir, efavirenz and adefovir dipivoxil for subjects experiencing virological failure on an indinavir-containing regimen. (2) Subjects with plasma HIV-1 RNA levels ≤15000 copies/ml had a significantly better virological response than those with >15000 copies/ml at baseline. Switching at lower, rather than higher, viral load levels improved response rates in treatment-experienced subjects. (3) Summary measures of regimen sensitivity (such as, genotypic and phenotypic sensitivity scores) are useful in the evaluation of multidrug combination regimens.
Effect of Individual Cognitive Behaviour Intervention on Adherence to Antiretroviral Therapy: Prospective Randomized Trial
Authors:   the Swiss HIV Cohort Study, Weber Rainer , Christen Lisanne , Christen Stephan , Tschopp Simone , Znoj Hansjoerg , Schneider Christine , Schmitt Joachim , Opravil Milos , Günthard Huldrych F , Ledergerber Bruno , 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 , Opravil M , Paccaud F , Pantaleo G , Perrin L , Piffaretti J-C , Rickenbach M , Rudin C , Schupbach J , Speck R , Telenti A , Trkola A , Vernazza P , Wagels Th , Weber R , Yerly S 
Published: April 2022

Objective A high level of adherence to antiretroviral therapy is required for complete suppression of HIV replication, immunological and clinical effectiveness. We investigated whether cognitive behaviour therapy can improve medication adherence. Design Prospective randomized 1-year trial. Setting Collaboration of HIV university outpatient clinic and psychotherapists in private practice. Participants 60 HIV-infected persons on stable anti-retroviral combination therapy and viral load below 50 copies/ml. Intervention Cognitive behaviour intervention in individual patients, in addition to standard of care. Main outcome measures Feasibility and acceptance of intervention; adherence to therapy assessed using medication event monitoring system (MEMS) and self-report questionnaire; virological failure; psychosocial measures. Results The median number of sessions for cognitive behaviour intervention per patient during the 1-year trial was 11 (range 2–25). At months 10–12, mean adherence to therapy as assessed using MEMS was 92.8% in the intervention and 88.9% in the control group ( P=0.2); the proportion of patients with adherence ≥95% was 70 and 50.0% ( P=0.014), respectively. While there was no significant deterioration of adherence during the study in the intervention arm, adherence decreased by 8.7% per year ( P=0.006) in the control arm. No differences between the intervention group and standard of care group were found regarding virological outcome. Compared with the control group, participants in the intervention group perceived a significant improvement of their mental health during the study period. Conclusions Cognitive behavioural support in addition to standard of care of HIV-infected persons is feasible in routine practice, and can improve medication adherence and mental health.
No Benefit to Continue Lamivudine Therapy after Emergence of Ymdd Mutations
Authors: Liaw Yun-Fan , Chien Rong-Nan , Yeh Chau-Ting 
Published: April 2022

Background Mutations in the sequence of the conserved tyrosine-methionine-aspartate-aspartate (YMDD) locus of the HBV RNA-dependent DNA polymerase (rt M 204 I/V) may develop after 6–9 months of lamivudine therapy. The current practice of continuing lamivudine therapy has been associated with hepatitis flares or even hepatic decompensation. In addition, experiments have shown that the defective replication competency of rt M 204 I/V restores upon addition of lamivudine. Aim To evaluate whether continuing lamivudine therapy after emergence of rt M 204 I/V is appropriate. Patients and methods The clinical courses of 66 patients with continuing lamivudine therapy (continued group) and 68 patients who discontinued lamivudine therapy (discontinued group) were monitored monthly or more frequently if condition required. Hepatitis flare, jaundice, hepatic decompensation and hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive patients were documented as events. Results In a 12-month period, hepatitis flares and decompensations occurred in 67 and 11%, respectively, in patients who continued lamivudine therapy, as compared with 54 and 7%, respectively ( P>0.05), in those who stopped therapy. HBeAg seroconversion rate was 19% in continued group and 35% in discontinued group ( P=0.08). Serum HBV DNA increased in 48 (73%) of the continued group, and the median level increased from 46 pg/ml upon first detection of mutation to 330 pg/ml ( P<0.001) at the end of 12 months continuing therapy. In contrast, serum HBV DNA level in the discontinued group increased in 22 (33%) patients but decreased in 39 patients, and median level decreased from 172 to 55 pg/ml at the end of 12 months after stopping lamivudine. Conclusion These results suggest that there is no benefit to continued lamivudine therapy after emergence of rt M 204 I/V. Presented in part at the Digestive Disease Week, San Francisco, Calif., USA, May 2002.
Interferon–Lamivudine Combination is No Better than Lamivudine Alone in Anti-Hbe-Positive Chronic Hepatitis B
Authors: Akarca Ulus Salih , Ersoz Galip , Gunsar Fulya , Karasu Zeki , Saritas Elif , Yuce Gul , Batur Yucel 
Published: April 2022

Background and aims Results of studies using lamivudine and interferon combination in the treatment of chronic hepatitis B are not consistent or conclusive. This study aimed to evaluate the efficacy of interferon plus lamivudine use versus single lamivudine in anti-HBe-positive chronic hepatitis B. Methods Eighty patients were treated with either lamivudine or lamivudine plus simultaneously started interferon. Patients were assigned in groups according to random allocation rule. Lamivudine was given 150 mg/day for 96 weeks in each group; interferon was administered 10 MU three times a week for 24 weeks in the combination therapy group. Results Alanine aminotransferase (ALT) normalization was achieved earlier in patients treated with lamivudine alone. At the end of treatment, there was no difference between the groups with respect to HBV DNA negativity, ALT normalization and breakthrough rate. Histological improvement was remarkable in each group, but fibrosis score and necro-inflammatory activity were much lower in lamivudine-treated patients. Conclusions Addition of interferon to the lamivudine regimen does not increase the effectiveness of the treatment. Considering the side effects of interferon treatment, this combination seems not to be convenient for anti-HBe-positive chronic hepatitis B.
Prophylactic and Therapeutic Effects of Small Interfering Rna Targeting Sars-Coronavirus
Authors: Zheng Bo-jian , Guan Yi , Tang Qingquan , Cheng Du , Xie Frank Y , He Ming-Liang , Chan Kwok-Wah , Wong Kin-Ling , Lader Eric , Woodle Martin C , Lu Patrick Y , Li Baojian , Zhong Nanshan 
Published: April 2022

Objectives To identify and characterize the siRNA duplexes that are effective for inhibition of SARS-CoV infection and replication in the non-human primate cells. This in vitro study will serve as the foundation for development of novel anti-SARS therapeutics. Methods 48 siRNA sequences were designed for targeting regions throughout entire SARS-CoV genome RNA including open-reading frames for several key proteins. Chemically synthesized siRNA duplexes were transfected into foetal rhesus kidney (FRhK-4) cells prior to or after SARS-CoV infection. The inhibitory effects of the siRNAs were evaluated for reductions of intracellular viral genome copy number and viral titres in the cell culture medium measured by Q-RT-PCR and CPE-based titration, respectively. Four siRNA duplexes were found to achieve potent inhibition of SARS-CoV infection and replication. A prolonged prophylactic effect of siRNA duplexes with up to 90% inhibition that lasted for at least 72 h was observed. Combination of active siRNA duplexes targeting different regions of the viral genome resulted in therapeutic activity of up to 80% inhibition. Conclusion Chemically synthesized siRNA duplexes targeting SARS-CoV genomic RNA are potent agents for inhibition of the viral infection and replication. The location effects of siRNAs were revealed at both genome sequence and open-reading frame levels. The rapid development of siRNA-based SARS-CoV inhibitors marked a novel approach for combating newly emergent infectious diseases.
Peginterferon Alpha-2B plus Ribavirin with or without Amantidine for the Treatment of Non-Responders to Standard Interferon and Ribavirin
Authors: Hasan Fuad , Al-Khaldi Jameela , Asker Haifa , Al-Ajmi Misfer , Owayed Salem , Varghese Rosh , Siddique Iqbal , Al-Nakib Basil 
Published: April 2022

Background A significant proportion of hepatitis C patients treated with unmodified interferon plus ribavirin fail to respond. The optimal therapy for these patients has not been established yet. The objective of this study was to assess the efficacy and safety of peginterferon plus ribavirin with or without amantidine in such patients. Methods In this open-label, prospective controlled trial, a total of 63 patients were randomly divided into groups A and B with a ratio of 1:2. Group A (21 patients) received weekly peginterferon alpha-2b, 1.5 μg/kg concomitantly with ribavirin 1000–1200 mg per day. Group B (42 patients) received peginterferon and ribavirin as in group A, plus amantidine 200 mg per day. Results At the completion of treatment, serum levels of hepatitis C virus RNA were undetectable in 14% and 12% of patients in groups A and B, respectively ( P=NS). Hepatitis C virus RNA remained undetectable 24 weeks after the end of treatment in one patient (5%) in group A and three patients (7%) in group B ( P=NS). Sustained viral clearance was associated with sustained normalization of serum alanine aminotransferase level. Both drug regimens had similar side effect profiles. Conclusion Peginterferon plus ribavirin therapy with or without amantidine is associated with a low sustained virological response in patients who failed interferon and ribavirin combination therapy.
Effect of Long-Term Lamivudine in Chronic Hepatitis B Virus-Infected Children
Authors: Ozgenç Funda , Arikan Cigdem , Sertoz Ruchan Yazan , Nart Deniz , Aydogdu Sema , Yagci Rasit Vural 
Published: April 2022

Objective To evaluate, retrospectively, biochemical, serological and histological responses in chronic hepatitis B (CHB)-infected children who received combination therapy and continued with prolonged treatment with lamivudine (3TC). Patients and methods CHB infection was defined as the presence of hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg) and hepatitis B virus (HBV) DNA in serum screened at 3-month intervals for at least 1 year, serum alanine aminotransferase (ALT) levels >1.5 times the normal limit and CHB with histological activity index (HAI) >5 by liver biopsy. A total of 99 children with CHB infection were treated with IFN-α (three times a week, 5 MU/m2) and 3TC (4 mg/kg/d) orally for 6 months. End of therapy response (CR) was defined as ALT normalization, HBV-DNA clearance and e seroconversion. Partial responders (PR) were defined as patients who had ALT normalization and HBV-DNA clearance, but who had not had e seroconversion. Forty-five children with PR at the end of the sixth month continued to receive 3TC alone thereafter. Breakthrough infection was determined as re-emergence of HBV DNA in serum after its clearance. The response rate, side effects and the breakthrough infection rate were examined on prolonged 3TC treatment. Liver biopsy was held in 29 patients at median 32 (14–66) months of 3TC; pre- and post-treatment liver histology was compared. Results Pre- and post-treatment evaluation was carried out in 45 children [mean age: 11 ±4.2 years, 31 males (69%), 14 females (31%)] with PR at the end of the sixth month of combination therapy. The initial mean ALT values and HAI scores were 75.6 ±60 IU/l and 8 ±3.3, respectively. 3TC was continued for median 33 (14–66) months and CR was achieved in 15.6% (7/45) and 5.6% (2/36) at the end of first and second year, and 0% (none) at the end of third and fourth year, respectively. Breakthrough incidence was detected in six (13.3%) cases at 12 months and increased to 69.4% ( n=25) and 82.4% ( n=14) at the end of the second and third years, respectively. Patients with breakthrough continued to receive 3TC. Seroconversion and CR of the mutant virus was achieved in one patient (2.9%) at month 46 of treatment with 3TC. Liver biopsy was held in 29 cases at median 32 (14–66) months of 3TC. Pre- and post-treatment mean HAI scores were 8 ±3.3 and 3.9 ±2.1, respectively ( P=0.000). Mean necrosing scores were not different at the beginning and end of therapy ( P=1.0). Inflammation, bridging and fibrosis scores decreased to 0.8 ±0.6, 1.3 ±1.2 and 0.6 ±0.8, respectively ( P=0.000, P=0.002, P=0.000). Conclusion The long-term 3TC usage in children with PR does not induce complete response and is associated with high breakthrough incidence. However, histological improvement is achieved and/or sustained even in children with HBV DNA breakthrough.
Lipodystrophy in Patients with HIV-1 Infection: Effect of Stopping Protease Inhibitors on Tnf-α and Tnf-Receptor Levels, and on Metabolic Parameters
Authors: Maher Bridget , Lloyd Judy , Wilkins Edmund GL , Fraser William D , Back David , Park B Kevin , Pirmohamed Munir 
Published: April 2022

Objective To evaluate the effects of stopping treatment with protease inhibitors (PIs) on tumour necrosis factor (TNF)-α and TNF-receptor levels, and on the metabolic and morphological abnormalities seen in patients with lipodystrophy. Design Longitudinal study. Methods Ten HIV-positive patients with lipodystrophy (LD) were studied whilst on PIs (LD1) and 3 months after stopping PIs (LD2) together with 10 HIV-positive subjects on PIs without LD (controls). TNF-α and TNF-receptor levels, insulin resistance parameters, lipid and hormonal profiles, body composition and fat distribution were measured in all subjects. Results TNF-α, TNF-receptor I (-RI) and TNF-RII levels were significantly lower in controls ( P=0.02) than in subjects with LD, and there was a significant decrease in TNF-RI and TNF-RII levels ( P=0.01 and 0.03, respectively) on stopping PIs. Insulin levels and the homeostasis model assessment for insulin resistance (HOMA-IR) index were significantly higher in LD1 subjects ( P=0.02) than in controls but did not alter when PIs were stopped. Bioelectrical impedance analysis showed a significant decrease on stopping PIs but CT scans showed no significant difference in fat distribution. Apart from high-density lipoprotein, there was no change in lipid parameters on stopping PIs. There was no difference in the level of testosterone, sex hormone binding globulin and cortisol between the three groups. Conclusion Our results show that TNF-α activity in patients with LD is modulated by PIs. This was not accompanied by significant changes in body habitus or insulin resistance, although this may have been a consequence of the short follow-up in this study.
Optimal Frequency of Cd4 Cell Count and HIV Rna Monitoring Prior to Initiation of Antiretroviral Therapy in HIV-Infected Patients
Authors:   For The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Investigators, Kimmel April D , Goldie Sue J , Walensky Rochelle P , Losina Elena , Weinstein Milton C , Paltiel A David , Zhang Hong , Freedberg Kenneth A 
Published: April 2022

Context Guidelines regarding the frequency of CD4 cell count and HIV RNA monitoring in HIV-infected patients vary, with recommended strategies ranging from every 2 to every 6 months. Objective To determine optimal CD4 cell count and HIV RNA monitoring frequency in HIV-infected patients prior to antiretroviral therapy initiation. Design: Cost-effectiveness (CE) analysis using an HIV simulation model incorporating CD4 cell count and HIV RNA as immunological and virological predictors of clinical outcomes. Setting Hypothetical clinical setting. Patients Simulated cohort based on initial clinical presentation of HIV-infected patients in the US. Intervention CD4 cell count and HIV RNA monitoring at frequencies ranging from every 2 to 24 months prior to antiretroviral initiation, as well as accelerated monitoring frequencies as CD4 cell counts approach a specified treatment threshold. Outcome measures Life expectancy, quality-adjusted life expectancy and costs. Results For patients presenting with median CD4 cell count 546/mm3 and median HIV RNA 4.8 log10 copies/ml, incremental CE ratios ranged from US$37800/quality-adjusted life year (QALY) gained for a constant testing frequency of every 18 months compared with every 24 months, to US$303300/QALY gained for a constant testing frequency of every 2 months compared with every 4 months when starting treatment at a CD4 cell count of 350/mm3. Monitoring every 12 months until a warning CD4 cell count threshold of 450/mm3 followed by every 3 months until 350/mm3 had an incremental CE ratio of US$74700/QALY gained. When starting antiretroviral therapy at CD4 cell count 200/mm3, monitoring every 12 months until 300/mm3 followed by every 2 months until treatment initiation yielded an incremental CE ratio of US$52200/QALY gained compared with the next best strategy. Increasing monitoring frequency as CD4 cell counts approached a treatment threshold yielded greater incremental clinical benefit for less cost than strategies using a constant frequency. Conclusions Monitoring HIV-infected patients every 12 months until 100 CD4 cells/mm3 prior to a specified treatment threshold followed by more frequent monitoring every 2 or 3 months until antiretroviral therapy initiation is both more effective and cost-effective than the current standard of care.
Depression and Clinical Progression in HIV-Infected Drug Users Treated with Highly Active Antiretroviral Therapy
Authors:   the MANIF 2000 Study Group, Bouhnik Anne-Déborah , Préau Marie , Vincent Emmanuelle , Carrieri Maria Patrizia , Gallais Hervé , Lepeu Gérard , Gastaut Jean-Albert , Moatti Jean-Paul , Spire Bruno 
Published: April 2022

Objective To disentangle the impact of adherence from that of injecting drug status and depressive syndrome on HIV clinical progression in a cohort of highly active anti-retroviral therapy (HAART)-treated HIV patients infected through drug use. Design MANIF 2000 is a French cohort of HIV-infected drug users with scheduled medical visits every 6 months. Only patients enrolled in the MANIF 2000 cohort who had a CD4 cell count >200 cells/μl at HAART initiation were selected. The follow-up period included all post-HAART initiation visits. Methods HIV clinical progression was defined as either AIDS-related death or reaching a CD4 level <200 cells/μl. Adherence was assessed using a self-administered questionnaire and a structured face-to-face interview. Depressive symptoms were evaluated by a Center for Epidemiologic Studies Depression Scale (CES-D) score at each visit. Cox proportional hazards model was used to calculate crude and adjusted relative hazards and 95% confidence intervals and thus identify independent predictors of clinical progression. Results Of the 305 HAART-treated patients in the cohort, 243 had CD4 cell count >200 cells/μl at HAART initiation. At the first visit after HAART initiation, median CD4 cell count was 466 cells/μl and 45% had undetectable viral load. Injecting drug users accounted for 17% of the study group. Over the follow-up period, 32 patients experienced HIV clinical progression. Probable depression was encountered in 46% of patients and non-adherence in 31% of the sample. After adjustment on baseline CD4 cell count, predictors of clinical progression were: having a higher level of cumulative non-adherence over the follow-up period [HR (95% CI)=1.2 (1.1–1.3) per 10% increase] and having a high score of depressive symptoms following HAART initiation [HR (95% CI)=5.3 (2.21–3.0)]. Conclusions: Although depressive syndrome is known to influence non-adherence behaviours that are amongst the major reasons for clinical progression, it is also a predictor of clinical progression in HIV-infected intravenous drug users on HAART, independently of non-adherence behaviours. HIV care providers should be more sensitive to depressive symptoms in order to detect them early and supply HIV patients with specific care. Further research is needed to determine whether treating depressive symptoms may improve adherence and thus delay disease progression and mortality.