Immune_Deficiency RSS : Gourt

Progress in basic and clinical research on HIV resistance: report on the XVIII International HIV Drug Resistance Workshop.

Progress in basic and clinical research on HIV resistance: report on the XVIII International HIV Drug Resistance Workshop. Antivir Ther. 2009;14(7):1015-37 Authors: Mascolini M, Boucher CA, Mellors JW, Larder BA, Richman DD Over nearly two decades, the International HIV Drug Resistance Workshop has become the leading forum for new research on viral resistance to agents developed to treat infection with HIV. The XVIII workshop featured work on HIV type-1 (HIV-1) persistence, reservoirs and elimination strategies; resistance to HIV-1 entry inhibitors (including a comparison of genotyping versus phenotyping to determine HIV-1 coreceptor use before treatment with CCR5 antagonists); polymerase domain resistance to reverse transcriptase inhibitors (including hepatitis B virus and HIV-1 resistance to lamivudine, and emergence of the K65R mutation in HIV-1 subtypes B and C); connection and RNase H domain resistance to reverse transcriptase inhibitors (including the effect of mutations in those domains on response to efavirenz and etravirine); resistance to hepatitis C virus and HIV-1 protease inhibitors; resistance to the integrase inhibitor raltegravir; global resistance epidemiology (including models to predict response to second-line antiretrovirals in resource-poor settings); and the role of minority resistant variants (including the effect of such variants on prevention of mother-to-child transmission of HIV-1). This report summarizes data from the oral abstract presentations at the workshop. PMID: 19918107 [PubMed - in process]

Avascular osteonecrosis of the femoral head in three West African HIV-infected adults with heterozygous sickle cell disease.

Avascular osteonecrosis of the femoral head in three West African HIV-infected adults with heterozygous sickle cell disease. Antivir Ther. 2009;14(7):1011-4 Authors: Eholié SP, Ouiminga M, Ehui E, Nzunetu G, Ouattara SI, Konan AV, Anglaret X, Bissagnéné E Three men (aged 33, 44 and 45 years, CD4(+) T-cell nadir 86 cells/mm(3), 99 cells/mm(3) and 12 cells/mm(3), respectively) were admitted to the Department of Infectious Diseases (Treichville Hospital, Abidjan, Côte d'Ivoire) for hip pain and impaired mobility. Their last available CD4(+) T-cell counts were 243 cells/mm(3), 245 cells/mm(3) and 8 cells/mm(3), respectively. They had all received antiretroviral therapy for >4 years, including lopinavir/ritonavir for >8 months. The other risk factors were hypertriglyceridaemia (n=3), smoking addiction (n=2), alcohol consumption (n=2) and lipodystrophy (n=1). All three patients had heterozygous haemoglobin AS sickle cell disease (percentage of haemoglobin S 41%, 45% and 50%, respectively). The diagnosis of avascular osteonecrosis of the femoral head (unilateral n=2 and bilateral n=1) was documented by CT scan. Only one patient underwent surgical arthroplasty. In resource-limited settings, avascular osteonecrosis is uneasy to diagnose and unlikely to be appropriately treated. Physicians should be aware of its symptoms and risk factors, including HIV infection and antiretroviral therapy. Future studies should explore whether these risk factors might include haemoglobin AS sickle cell disease, a common trait in the West African general population. PMID: 19918106 [PubMed - in process]

Genotypic HIV type-1 drug resistance among patients with immunological failure to first-line antiretroviral therapy in south India.

Genotypic HIV type-1 drug resistance among patients with immunological failure to first-line antiretroviral therapy in south India. Antivir Ther. 2009;14(7):1005-9 Authors: Vidya M, Saravanan S, Uma S, Kumarasamy N, Sunil SS, Kantor R, Katzenstein D, Ramratnam B, Mayer KH, Suniti S, Balakrishnan P BACKGROUND: HIV type-1 (HIV-1) monitoring in resource-limited settings relies on clinical and immunological assessment. The objective of this study was to study the frequency and pattern of reverse transcriptase (RT) drug resistance among patients with immunological failure (IF) to first-line therapy. METHODS: A cross-sectional study of 228 patients with IF was done, of which 126 were drug-naive (group A) when starting highly active antiretroviral therapy (HAART) and 102 were exposed to mono/dual therapy prior to HAART initiation (group B). A validated in-house genotyping method and Stanford interpretaion was used. Means, sd, median and frequencies (as percentages) were used to indicate the patient characteristics in each group. The chi(2) test and Fisher's exact test were used to compare categorical variables as appropriate. All analyses were performed using SPSS software, version 13.0. P-values <0.05 were considered to be statistically significant. RESULTS: RT drug resistance mutations were found in 92% and 96% of patients in groups A and B, respectively. Median (interquartile range) CD4(+) T-cell count at failure was 181 cells/mul (18-999) and time to failure was 40 months (2-100). M184V (80% versus 75%), thymidine analogue mutations (63% versus 74%), Y181C (39% versus 39%) and K103N (29% versus 39%) were predominant RT mutations in both groups. Extensive nucleoside reverse transcriptase inhibitor cross-resistance mutations were observed in 51% and 26% of patients in group B and A, respectively. CONCLUSIONS: Alternative strategies for initial therapy and affordable viral load monitoring could reduce resistance accumulations and preserve available drugs for future options in resource-limited settings. PMID: 19918105 [PubMed - in process]

Plasma concentrations of generic lopinavir/ritonavir in HIV type-1-infected individuals.

Plasma concentrations of generic lopinavir/ritonavir in HIV type-1-infected individuals. Antivir Ther. 2009;14(7):1001-4 Authors: van der Lugt J, Lange J, Avihingsanon A, Ananworanich J, Sealoo S, Burger D, Gorowara M, Phanuphak P, Ruxrungtham K BACKGROUND: Generic drugs can contribute to access to treatment for HIV-infected patients. However quality and safety remains an issue of concern. Therefore, we evaluated minimal plasma concentrations and short-term safety of a generic lopinavir/ritonavir 200/50 mg tablet formulation. METHODS: In a single-centre prospective pilot study, patients receiving protease-inhibitor-based antiretroviral treatment were switched to a generic lopinavir/ritonavir tablet at the standard dose (400/100 mg twice daily). Minimum drug concentrations (C(min)) of lopinavir and ritonavir were performed before switching (in 16 patients who were on Kaletra((R)) soft-gel capsules) and after 4 weeks (in all patients). Plasma levels of lopinavir and ritonavir were determined by a validated HPLC method. Either the Wilcoxon signed-rank or Mann-Whitney U test was used to compare the groups. RESULTS: A total of 37 patients (18 females) were included in the study. Two stopped their study medications prematurely because of intolerance. The median (interquartile range) lopinavir C(min) was 7.2 mg/l (5.8-8.3) and no patients had subtherapeutic levels <1.0 mg/l. No significant difference of lopinavir C(min) levels was found between Kaletra((R)), and the generic product (P=0.224). By contrast, the C(min) of generic ritonavir was higher (P=0.012). Food did not affect the drug levels. Mild gastrointestinal complaints were reported in 12 patients. CONCLUSIONS: The generic lopinavir/ritonavir tablet showed C(min) plasma concentrations similar to what is described for the branded product, with good stability, independent of food intake. These data support the efforts in scaling up access to generic second-line treatment in middle- and low-income countries. PMID: 19918104 [PubMed - in process]

The incidence rate of HIV type-1 drug resistance in patients on antiretroviral therapy: a nationwide population-based Danish cohort study 1999-2005.

The incidence rate of HIV type-1 drug resistance in patients on antiretroviral therapy: a nationwide population-based Danish cohort study 1999-2005. Antivir Ther. 2009;14(7):995-1000 Authors: Audelin AM, Lohse N, Obel N, Gerstoft J, Jørgensen LB BACKGROUND: Newer antiretroviral treatment regimens for HIV carry a lower risk of inducing drug resistance mutations. We estimated changes in incidence rates (IRs) of new mutations in HIV-infected individuals receiving highly active antiretroviral therapy (HAART). METHODS: Population-based data were obtained from the Danish HIV Cohort Study and the Danish HIV Sequence Database. We included treatment-naive patients initiating HAART after December 1997 and computed time to first drug resistance mutation, identified as new mutations detected within 1 year after a 60-day period of treatment failure (HIV RNA>1,000 copies/ml). We estimated annual IRs of new resistance mutations towards nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs) and protease inhibitors (PI), and of new specific resistance mutations. RESULTS: A total of 1,829 individuals were observed for 7,294 person-years at risk (PYR). The IR of NRTI resistance decreased from 13.1 per 1,000 PYR (95% confidence interval [CI] 4.9-35.0) in 1999 to 3.7 (1.9-7.2) in 2004-2005 (test for trend P=0.024). The IR of NNRTI resistance decreased from 15.4 (2.2-109.6) in 1999 to 7.9 (4.6-13.6) in 2004-2005 (P=0.077). The IR of PI resistance decreased from 7.5 (1.4-21.8) in 1999 to 2.9 (0.7-11.4) in 2002-2003 (P=0.148). The IRs were low for specific resistance mutations, except for M184V (IR 5.6 [4.0-7.9]) and K103N (IR 8.2 [5.6-12.0]). CONCLUSIONS: The incidence of acquired drug resistance has decreased among HIV-infected patients treated with HAART in Denmark during 1999-2005. PMID: 19918103 [PubMed - in process]

Evolution of hepatitis B virus mutation during entecavir rescue therapy in patients with antiviral resistance to lamivudine and adefovir.

Evolution of hepatitis B virus mutation during entecavir rescue therapy in patients with antiviral resistance to lamivudine and adefovir. Antivir Ther. 2009;14(7):985-93 Authors: Choe WH, Hong SP, Kim BK, Ko SY, Jung YK, Kim JH, Yeon JE, Byun KS, Kim KH, Ji SI, Kim SO, Lee CH, Kwon SY BACKGROUND: The efficacy of entecavir (ETV) monotherapy in treatment-experienced patients with chronic hepatitis B (CHB) is debatable. METHODS: A total of 22 hepatitis B e antigen (HBeAg)-positive CHB patients who had shown viral breakthrough or suboptimal response with lamivudine (3TC) and adefovir disoproxil (ADV) therapy were treated with 1.0 mg of ETV. Clinical and virological parameters were monitored every 3 months. Restriction fragment mass polymorphism assays were used to detect antiviral resistance. RESULTS: During 3TC and ADV therapy, 11 patients had rtM204V/I mutations, 2 had rtA181V/T or rtN236T, 7 had both and 2 had no 3TC- or ADV-related mutations. After switching to ETV monotherapy, the median change in serum hepatitis B virus (HBV) DNA level was -2.1 log(10) copies/ml. Virological response (HBV DNA<300 copies/ml) was achieved in 1 of 18 patients with pre-existing rt204 mutations, whereas it was achieved in all 4 patients without pre-existing rt204 mutations regardless of the presence of rt181 or rt236 mutations. Changes in mutational patterns during ETV therapy showed that rt204 mutations persisted or re-emerged. Relative abundances of rtM204V/I mutations in total viral populations gradually increased under ETV rescue, whereas those with rtA181V/T and rtN236T mutations decreased. ETV resistance mutations (rtL180M+rtT184I/L[rtS202G]+rtM204V) were detected in five patients with pre-existing rt204 mutations. CONCLUSIONS: ETV monotherapy resulted in a limited virological response in patients who had previously failed 3TC and ADV rescue therapy. The limited efficacy might be associated with residual or reselected rtM204V/I mutations leading to ETV resistance. Combination treatment including potent antiviral agents should be recommended for patients with pre-existing rtM204V/I mutations. PMID: 19918102 [PubMed - in process]

Prevalence of HIV type-1 drug-associated mutations in pre-therapy patients in the Free State, South Africa.

Prevalence of HIV type-1 drug-associated mutations in pre-therapy patients in the Free State, South Africa. Antivir Ther. 2009;14(7):975-984 Authors: Huang KH, Goedhals D, Fryer H, van Vuuren C, Katzourakis A, De Oliveira T, Brown H, Cassol S, Seebregts C, McLean A, Klenerman P, Phillips R, Frater J, BACKGROUND: We aimed to characterize the molecular epidemiology of HIV type-1 (HIV-1) and the prevalence of drug-associated mutations prior to initiating highly active antiretroviral therapy (HAART) in the Free State province, South Africa. The Free State has a population of 3 million, an antenatal HIV prevalence of approximately 34% and a well established infrastucture for antiretroviral (ARV) provision. METHODS: HIV-1 polymerase genes were sequenced from 425 HAART-naive HIV-1-positive patients at voluntary primary healthcare HIV testing centres, who were subsequently attending district centres for assessment for commencing ARVs. Patients (>18 years) were sampled randomly with no exclusion for gender or clinical criteria. Sequences were analysed according to phylogeny and drug resistance. RESULTS: Phylogenetic clustering within the cohort was suggestive of multiple introductions of subtype C virus into the region. Drug resistance mutations (according to the International AIDS Society-USA classification) were distributed randomly across the cohort phylogeny with an overall prevalence of 2.3% in the sampled patients. When stratified according to CD4(+) T-cell count, the prevalence of resistance was 3.6%, 0.9% and 1.2% for CD4(+) T-cell counts <100, 200-350 and >500 cells/mul, respectively, and was most common for non-nucleoside reverse transcriptase inhibitor resistance (3.1% in patients with CD4(+) T-cell count <100 cells/mul). We surveyed all drug-selected mutations and found further significant clustering among patients with low CD4(+) T-cell counts (P=0.003), suggesting unrecognized exposure to ARVs. CONCLUSIONS: In the Free State population, there was a statistical association between low CD4(+) T-cell counts and drug-associated viral polymorphisms. Our data advocate the benefit of detailed history taking from patients starting HAART at low CD4(+) T-cell counts with close follow-up of the virological response. PMID: 19918101 [PubMed - as supplied by publisher]

P-glycoprotein, multidrug resistance-associated proteins and human organic anion transporting polypeptide influence the intracellular accumulation of atazanavir.

P-glycoprotein, multidrug resistance-associated proteins and human organic anion transporting polypeptide influence the intracellular accumulation of atazanavir. Antivir Ther. 2009;14(7):965-74 Authors: Janneh O, Anwar T, Jungbauer C, Kopp S, Khoo SH, Back DJ, Chiba P BACKGROUND: Drug efflux (for example, P-glycoprotein [P-gp], multidrug resistance-associated proteins [MRPs] and breast cancer resistance protein [BCRP]) and influx (for example, human organic anion transporting polypeptide [hOCTP] or human organic anion transporting polypeptide [hOATP]) transporters alter the cellular concentrations of some HIV protease inhibitors (HPIs). Here, we studied the lipophilicity and uptake of [(3)H]-atazanavir (ATV) in CEM (parental), CEM(VBL) (P-gp-overexpressing), CEM(E1000) (MRP1-overexpressing) and peripheral blood mononuclear cells (PBMCs), and evaluate the effects of modulators of drug transporters on uptake. METHODS: Lipophilicity was measured by octanol/saline partition method. The influence of influx/efflux transporters on uptake was evaluated in the absence and presence of inhibitors of P-gp (GPV031), P-gp/BCRP (tariquidar and GF120918), P-gp/MRP1 (dipyridamole and daidzein), MRP1/2 (frusemide and genistein), hOATP/hOCTP (estrone-3-sulfate [E-3-S]) and hOATP/hOCTP/MRP (probenecid). The effects of a number of HPIs on uptake were also evaluated. Data from digitonin permeabilized cells allowed the evaluation of the contribution of cellular binding to total drug uptake, whereas the inhibitory effect of ATV on P-gp was assessed by daunomycin efflux/uptake assays. RESULTS: [(3)H]-ATV is lipophilic and accumulates in the cultured cells as follows: CEM>CEM(E1000)>CEM(VBL). Tariquidar, GF120918 and daidzein significantly increased the uptake of [(3)H]-ATV in the cultured cells. By contrast, only daidzein and tipranavir significantly increased uptake in PBMCs, with tariquidar and frusemide devoid of effects, whereas dipyridamole, E-3-S, GPV031 and genistein significantly decreased accumulation. ATV inhibits P-gp activity; manipulation of uptake with digitonin suggests binding of [(3)H]-ATV to P-gp. CONCLUSIONS: [(3)H]-ATV is lipophilic, a P-gp, MRP and hOATP substrate and an inhibitor of P-gp. Concomitant administration of ATV with drugs and dietary components (for example, daidzein and genistein) that interact with these transporters could alter its pharmacokinetics. PMID: 19918100 [PubMed - in process]

Effects of HIV type-1 immune selection on susceptability to integrase inhibitor resistance.

Effects of HIV type-1 immune selection on susceptability to integrase inhibitor resistance. Antivir Ther. 2009;14(7):953-64 Authors: Tschochner M, Chopra A, Maiden TM, Ahmad IF, James I, Furrer H, Günthard HF, Mallal S, Rauch A, John M BACKGROUND: All site-specific interactions between HIV type-1 (HIV-1) subtype, human leukocyte antigen (HLA)-associated immune selection and integrase inhibitor resistance are not completely understood. We examined naturally occurring polymorphisms in HIV-1 integrase sequences from 342 antiretroviral-naive individuals from the Western Australian HIV Cohort Study and the Swiss HIV Cohort Study. METHODS: Standard bulk sequencing and sequence-based typing were used to generate integrase sequences and high-resolution HLA genotypes, respectively. Viral residues were examined with respect to drug resistance mutations and CD8(+) T-cell escape mutations. RESULTS: In both predominantly subtype B cohorts, 12 of 38 sites that mediate integrase inhibitor resistance mutations were absolutely conserved, and these included the primary resistance mutations. There were 18 codons with non-primary drug resistance-associated substitutions at rates of up to 58.8% and eight sites with alternative polymorphisms. Five viral residues were potentially subject to dual-drug and HLA-associated immune selection in which both selective pressures either drove the same amino acid substitution (codons 72, 157 and 163) or HLA alleles were associated with an alternative polymorphism that would alter the genetic barrier to resistance (codons 125 and 193). The common polymorphism T125A, which was characteristic of non-subtype B and was also associated with carriage of HLA-B*57/*5801, increased the mutational barrier to the resistance mutation T125K. CONCLUSIONS: Primary integrase inhibitor resistance mutations were not detected in the absence of drug exposure in keeping with sites of high constraint. Viral polymorphisms caused by immune selection and/or associated with non-subtype B might alter the genetic barrier to some non-primary resistance-associated mutations. PMID: 19918099 [PubMed - in process]

Potential risk factors associated with the use of cidofovir to treat benign human papillomavirus-related disease.

Potential risk factors associated with the use of cidofovir to treat benign human papillomavirus-related disease. Antivir Ther. 2009;14(7):939-952 Authors: Donne AJ, Hampson L, He XT, Day PJ, Salway F, Rothera MP, Homer JJ, Hampson IN BACKGROUND: Cidofovir is currently being used off-licence to treat different viral infections, such as benign low-risk human papillomavirus (HPV)-related recurrent respiratory papillomatosis (RRP). There are concerns over the safety of this practice as rat studies demonstrated a high malignant transformation rate. As yet, there are no clinical reports of cidofovir-induced malignant changes in humans. METHODS: Telomerase immortalised human keratinocytes (hTert) stably expressing E6 proteins from either low-risk HPV6b or high-risk HPV16 and vector control cells were treated with either low-dose (5 mug/ml) or higher dose (30 mug/ml) cidofovir for 2 days and the effects evaluated by clonogenic survival assays. Based on these results, gene expression microarray analysis was performed on cidofovir-treated low-risk E6 and vector cells before, during and after drug treatment, and the results verified by real-time PCR. RESULTS: Both low-risk and high-risk E6-expressing cells show significantly improved long-term survival compared with vector control cells when exposed to 5 mug/ml cidofovir for 2 days, (hTert T6E6 P=0.0007, hTert T16E6 P=0.00023 and hTert vector control P=0.62). Microarray and real-time PCR analyses of low-dose cidofovir-treated low-risk E6-expressing cells revealed changes in gene expression that are known to be associated with malignant progression, which were not observed in drug-treated vector control cells. CONCLUSIONS: This is the first report that cidofovir can both increase cell survival and induce alterations in gene expression that are known to be associated with malignant transformation in cells transduced only with the E6 gene from low-risk HPV. It is our belief that these data provide cause for concern over the off-license use of this drug to treat RRP. PMID: 19918098 [PubMed - as supplied by publisher]

Safety and efficacy of once-daily nevirapine dosing: a multicohort study.

Safety and efficacy of once-daily nevirapine dosing: a multicohort study. Antivir Ther. 2009;14(7):931-938 Authors: Calmy A, Vallier N, Nguyen A, Lange JM, Battegay M, de Wolf F, Reiss P, Lima VD, Hirschel B, Hogg RS, Yip B, Montaner JS, Wit FW, , , BACKGROUND: Nevirapine (NVP) is often prescribed once daily in clinical practice in combination with a once daily nucleoside backbone. We investigated the relationship of NVP dosing with safety and efficacy. METHODS: Patients from the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort study, Canadian HAART Observational Medical Evaluation and Research (HOMER) cohort and Swiss HIV Cohort Study (SHCS) using NVP-based combination therapy either once daily or twice daily were included. Risk factors for discontinuing NVP because of hypersensitivity reactions (HSRs) were investigated using multivariate logistic regression. Risk factors for virological failure 96 weeks after NVP initiation were identified using logistic regression and Cox models. RESULTS: Of 5,636 patients (774 once daily and 4,862 twice daily), 268 (4.8%) discontinued NVP because of HSR between 2 and 18 weeks. Logistic regression showed that, compared with patients with detectable HIV type-1 (HIV-1) RNA starting twice-daily NVP, there was a significantly higher risk of discontinuation of once-daily NVP because of HSR in patients with detectable HIV-1 RNA at the start of NVP (odds ratio [OR] 1.52; P=0.04), whereas the risk was actually significantly lower in patients starting once-daily NVP with undetectable HIV-1 RNA (OR 0.44; P=0.04). Cox models showed that risk of virological failure was not different for twice- versus once-daily NVP in treatment-naive patients (twice-daily versus once-daily hazard ratio [HR] 1.01; P=0.95), treatment-experienced patients experiencing treatment failure (twice-daily versus once-daily HR 1.22; P=0.30) or patients with undetectable HIV-1 RNA simplifying treatment with NVP (twice-daily versus once-daily HR 1.29; P=0.30). CONCLUSIONS: Initiation of a once-daily NVP-based regimen in patients with suppressed viraemia carries a low risk of treatment-limiting HSR. Once- or twice-daily NVP-based regimens appear to have similar antiretroviral efficacy. PMID: 19918097 [PubMed - as supplied by publisher]

A population analysis of weight-related differences in lopinavir pharmacokinetics and possible consequences for protease inhibitor-naive and -experienced patients.

A population analysis of weight-related differences in lopinavir pharmacokinetics and possible consequences for protease inhibitor-naive and -experienced patients. Antivir Ther. 2009;14(7):923-9 Authors: Bouillon-Pichault M, Jullien V, Piketty C, Viard JP, Morini JP, Chhun S, Krivine A, Salmon D, Dupin N, Weiss L, Lortholary O, Pons G, Launay O, Treluyer JM BACKGROUND: Lopinavir is a potent protease inhibitor (PI) used for the treatment of HIV infection. Different lopinavir target trough concentrations (C(troughs)) were previously determined according to patient treatment histories: 1 mg/l for PI-naive patients, and 4 and 5.7 mg/l for PI-experienced patients. However, the probability to achieve these target C(troughs) with the current 400 mg twice-daily or 800 mg once-daily doses of the new tablet form, and the influence of body weight on this probability are unknown. METHODS: A population pharmacokinetic model for lopinavir was developed using data from 424 HIV type-1-infected patients, and the final model was used to estimate the probability to achieve target C(troughs) via Monte Carlo simulations. RESULTS: A one-compartment model adequately described the data. Mean population estimates (percentage interindividual variability) were 4.61 l/h (36%) for apparent clearance (CL/F) and 63.2 l (70%) for apparent distribution volume. Body weight was found to explain the interindividual variability of lopinavir CL/F. Probability to achieve the 1 mg/l target C(trough) was >96% for the twice-daily dose and comprised between 80% and 90% for the once-daily dose. The probability to achieve the 4 and 5.7 mg/l target C(troughs) with the twice-daily dose significantly decreased when body weight increased (from 76% to 61% and from 56% to 37% respectively, for body weights increasing from 50 to 90 kg). CONCLUSIONS: These results support lopinavir therapeutic drug monitoring and the use of higher lopinavir doses for PI-pretreated patients. PMID: 19918096 [PubMed - in process]

Prophylactic and therapeutic efficacy of a chimeric monoclonal antibody specific for H5 haemagglutinin against lethal H5N1 influenza.

Prophylactic and therapeutic efficacy of a chimeric monoclonal antibody specific for H5 haemagglutinin against lethal H5N1 influenza. Antivir Ther. 2009;14(7):911-21 Authors: Prabhu N, Prabakaran M, Hongliang Q, He F, Ho HT, Qiang J, Goutama M, Lim AP, Hanson BJ, Kwang J BACKGROUND: Recent outbreaks of highly pathogenic H5N1 viruses in humans indicate that no endogenous protection exists in the general population. Vaccination programmes against this new pathogen require synthesis of endogenous antibodies and cannot provide any immediate protection in the event of a pandemic. Passive immunization with humanized neutralizing monoclonal antibodies can prove to be promising in preventing a catastrophic pandemic. METHODS: A murine monoclonal antibody (mAb) 3B1 of immunoglobulin M isotype was switched to a chimeric immunoglobulin G1. BALB/c mice were used to study the protective efficacy of the chimeric mAbs against a lethal H5N1 virus challenge with strains from clades 1 and 2.1. Kinetics of the viral load were determined during the course of the treatment. RESULTS: The chimeric mAb, in passive administration, was able to protect 100% of the mice when challenged with H5N1 strains from clades 1 or 2.1. Prophylaxis at 1 day prior to challenge and treatment at 1 day after challenge with this mAb resulted in the clearance of the virus from the lungs of the infected mice within 6 days post-viral challenge. CONCLUSIONS: Passive immunotherapy using chimeric mAb 3B1 can be an effective tool in both the prophylaxis and treatment of highly pathogenic H5N1 infection, providing the immediate immunity needed to contain a future influenza pandemic. PMID: 19918095 [PubMed - in process]

Morpholino oligomer-mediated protection of porcine pulmonary alveolar macrophages from arterivirus-induced cell death.

Morpholino oligomer-mediated protection of porcine pulmonary alveolar macrophages from arterivirus-induced cell death. Antivir Ther. 2009;14(7):899-909 Authors: Patel D, Stein DA, Zhang YJ BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) causes extensive economic losses in the swine industry. Current strategies and vaccines to control the disease are inadequate. We previously demonstrated that peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) could potently inhibit PRRS virus (PRRSV) replication in cell cultures. PPMOs are single-stranded DNA analogues containing a modified backbone and cell-penetrating peptide. PPMOs are nuclease-resistant, water-soluble, can enter cells readily and exhibit highly specific binding to complementary RNA. In this study, we examined PPMO-mediated inhibition of PRRSV replication in a primary culture of porcine pulmonary alveolar macrophages (PAMs). METHODS: PAMs were collected from piglets, pre-incubated in culture and infected with PRRSV. Viability, cytopathic effects, virus yield and apoptosis of PAMs in the presence or absence of a PPMO (5UP2) were examined. The 5UP2 PPMO is complementary to a conserved sequence in the 5'-terminal region of the PRRSV genome. The level of several interferon-associated gene products and activity of caspases were monitored. RESULTS: PRRSV infection induced the activity of caspases-3/7, -8 and -9 significantly. Treatment of PAMs with 5UP2 resulted in protection of the cells from PRRSV-induced cell death for at least 7 days and avoided the activation of the caspases evaluated. 5UP2 treatment of PRRSV-infected PAMs also prevented the vigorous induction of interferon-beta and chemokines observed in infected and mock-treated PAMs. CONCLUSIONS: PPMO-mediated suppression of PRRSV replication in PAMs was associated with a reduction of apoptotic and inflammatory responses. These results provide further rationale for the development of PPMO 5UP2 as an antiviral to control PRRSV infection. PMID: 19918094 [PubMed - in process]

Efficacy of the novel parainfluenza virus haemagglutinin-neuraminidase inhibitor BCX 2798 in mice - further evaluation.

Efficacy of the novel parainfluenza virus haemagglutinin-neuraminidase inhibitor BCX 2798 in mice - further evaluation. Antivir Ther. 2009;14(7):891-8 Authors: Alymova IV, Watanabe M, Boyd KL, Chand P, Babu YS, Portner A BACKGROUND: Human parainfluenza virus type 1 (hPIV-1) causes serious respiratory tract infections, especially in children. This study investigated the efficacy of the novel haemagglutinin-neuraminidase (HN) inhibitor BCX 2798 in the prophylaxis of lethal and the treatment of non-lethal parainfluenza virus infection in mice. METHODS: In the prophylaxis model, 129x1/SvJ mice were inoculated with a 90% lethal dose of a recombinant Sendai virus, in which the HN gene was replaced with that of hPIV-1 (rSeV[hPIV-1HN]). The mice were intranasally treated either once or for 5 days with 1 or 10 mg/kg/day of BCX 2798, starting 4 h before infection. In the therapeutic model, mice were infected with 100 plaque-forming units of rSeV(hPIV-1HN) per mouse and treated intranasally with 0.1, 1 or 10 mg/kg/day of BCX 2798 for 5 days, starting 24 or 48 h after infection, or for 4 days starting 72 h after infection. RESULTS: Similar to multiple dosing, a single intranasal prophylaxis with 1 or 10 mg/kg of BCX 2798 protected approximately 40% or 90%, respectively, of mice from death by rSeV(hPIV-1HN) infection. BCX 2798 also significantly reduced virus lung titres (in a dose- and time-dependent manner) and reduced histopathological changes in the airways of non-lethally infected mice at multiple intranasal dosages in the therapeutic model, with the lowest effective dosage being 0.1 mg/kg/day administered 24 h after infection. CONCLUSIONS: BCX 2798 was effective in the prophylaxis of lethal and in the therapy of non-lethal parainfluenza virus infection in mice, suggesting further consideration of BCX 2798 for clinical trials. PMID: 19918093 [PubMed - in process]

Does RNA interference provide new hope for control of chronic hepatitis B infection?

Does RNA interference provide new hope for control of chronic hepatitis B infection? Antivir Ther. 2009;14(7):879-89 Authors: Wilson R, Purcell D, Netter HJ, Revill PA Hepatitis B virus (HBV) infection is a global human health problem, with an estimated 350 million people having chronic hepatitis B (CHB) infection worldwide. The majority of infections acquired during adulthood are resolved without intervention; however, infections acquired at birth or during early childhood have a 90% chance of progressing to CHB, leading to a host of adverse effects on the liver, including cirrhosis and cancer. CHB is currently treated with a combination of cytokines and/or nucleoside/nucleotide analogues; however, adverse side effects to cytokine therapy and the selection of resistance mutations to nucleoside analogues often abrogate the efficacy of treatment. The recent discovery that small interfering RNA and microRNA are active in mammalian cells suggests it might be possible to supplement existing HBV therapies with small RNA-based therapeutic(s). PMID: 19918092 [PubMed - in process]