Antiviral Therapy
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Amantadine-Oseltamivir Combination therapy for H5N1 Influenza Virus Infection in Mice Background The clinical management of H5N1 influenza virus infection in humans remains unclear. Combination chemotherapy with drugs that target different viral proteins might be more effective than monotherapy. Methods BALB/c mice were treated by oral gavage for 5 days with amantadine (1.5, 15 or 30 mg/kg/day) and oseltamivir (1 or 10 mg/kg/day) separately or in combination. Mice were challenged 24 h after initiation of treatment with 10 mouse 50% lethal doses of either amantadine-sensitive (having S31 in the M2 protein) or amantadine-resistant (having N31 in the M2 protein) recombinant A/Vietnam/1203/04 (H5N1) virus. Results Combination treatment with amantadine (15 or 30 mg/kg/day) and oseltamivir (10 mg/kg/day) provided greater protection (60% and 90%, respectively) against lethal infection with amantadine-sensitive H5N1 virus than did monotherapy. Moreover, spread of the virus to the brain was prevented by both combination regimens. The efficacy of the drug combinations against amantadine-resistant H5N1 virus was comparable to that of oseltamivir alone. Oseltamivir produced a dose-dependent effect against both recombinant H5N1 viruses ( P<0.05) but did not provide complete protection against lethal infection. Importantly, no mutations in the HA, NA and M2 proteins were detected when the two drugs were used in combination. Conclusions Combination chemotherapy provided a survival advantage over single-agent treatment of mice inoculated with neurotropic H5N1 influenza virus. This strategy might be an option for the control of pandemic influenza viruses that are sensitive to amantadine. Combinations that include other drugs should be explored.
Antiviral Therapy - Tập 12 Số 3 - Trang 363-370 - 2007
Comprehensive assessment of 2009 Pandemic Influenza a (H1N1) Virus Drug Susceptibility <i>in vitro</i> Background Antiviral drugs are an important option for managing infections caused by influenza viruses. This study assessed the drug susceptibility of 2009 pandemic influenza A (H1N1) viruses collected globally between April 2009 and January 2010. Methods Virus isolates were tested for adamantane susceptibility, using pyrosequencing to detect the S31N marker of adamantane resistance in the M2 protein and biological assays to assess viral replication in cell culture. To assess neuraminidase (NA) inhibitor (NAI) susceptibility, virus isolates were tested in chemiluminescent NA inhibition assays and by pyrosequencing to detect the H275Y (H274Y in N2 numbering) marker of oseltamivir resistance in the NA. Results With the exception of three, all viruses that were tested for adamantane susceptibility ( n=3,362) were resistant to this class of drugs. All viruses tested for NAI susceptibility ( n=3,359) were sensitive to two US Food and Drug Administration-approved NAIs, oseltamivir (mean ±sd 50% inhibitory concentration [IC50 ] 0.25 ±0.12 nM) and zanamivir (mean IC50 0.29 ±0.09 nM), except 23 (0.7%), which were resistant to oseltamivir, but sensitive to zanamivir. Oseltamivir-resistant viruses had the H275Y mutation in their NA and were detected in patients exposed to the drug through prophylaxis or treatment. NA activity of all viruses was inhibited by the NAIs peramivir, laninamivir (R-125489) and A-315675, except for H275Y variants, which exhibited approximately 100-fold reduction in peramivir susceptibility. Conclusions This report provides data regarding antiviral susceptibility of 2009 pandemic influenza A (H1N1) surveillance viruses, the majority of which were resistant to adamantanes and sensitive to NAIs. These findings provide information essential for antiviral resistance monitoring and development of novel diagnostic tests for detecting influenza antiviral resistance.
Antiviral Therapy - Tập 15 Số 8 - Trang 1151-1159 - 2010
Liver Triglyceride Content in HIV-1-Infected Patients on Combination Antiretroviral Therapy Studied with <sup>1</sup>H-MR Spectroscopy Objective To carry out an exploratory evaluation of liver triglyceride content in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) using proton magnetic resonance spectroscopy and to study how both the treatment itself and the biochemical and physiological variables in which the treatment causes alterations are related to liver fat content. Methods Intracellular hepatic triglyceride content was determined in 29 HIV-1-infected patients on their first HAART regime by means of localized water-unsuppressed single voxel proton spectra. Other measurements were body mass index, waist-to-hip ratio, lipodystrophy assessment and a detailed blood biochemical analysis. The relationship between intracellular hepatic triglycerides and relevant descriptive, treatment and biochemical variables was studied by correlation and regression analysis. Results Intrahepatic triglycerides were detected in 58.6% of the patients and 13.8% showed a triglyceride content compatible with liver steatosis. Many variables (body mass index, waist-to-hip ratio, cumulative exposure to PIs, lactate, insulin, insulin resistance measured by the homeostasis model assessment method [HOMA-R index], pH, total triglycerides, high density lipoprotein cholesterol and very low density lipoprotein [VLDL] cholesterol) correlated individually with the amount of triglycerides. Stepwise multiple regression analysis showed that the combination of insulin or HOMA-R index and VLDL cholesterol accounted for up to 50.2% of the triglyceride liver variance. A positive relationship was found between the concomitant presence of the metabolic syndrome components (insulin resistance, dyslipidaemia and central obesity) and intrahepatic triglyceride content. Conclusions The study showed that intrahepatic triglyceride deposit appears to be a frequent feature of HIV-1-infected patients receiving HAART. A coherent multifactorial combination of biochemical and physiological factors associated with the deposit suggested that cumulative exposure to PIs might be a possible trigger event.
Antiviral Therapy - Tập 12 Số 2 - Trang 195-204 - 2007
Silymarin for HCV infection Silymarin, an extract of milk thistle seeds, and silymarin-derived compounds have been considered hepatoprotective since the plant was first described in ancient times. Hepatoprotection is defined as several non-mutually exclusive biological activities including antiviral, antioxidant, anti-inflammatory and immunomodulatory functions. Despite clear evidence for silymarin-induced hepatoprotection in cell culture and animal models, evidence for benefcial effects in humans has been equivocal. This review will summarize the current state of knowledge on silymarin in the context of HCV infection. The information was collated from a recent workshop on silibinin in Germany.
Antiviral Therapy - Tập 18 Số 2 - Trang 141-147 - 2013
Exploiting Information Inherent in Binding Sites of Virus-Specific Antibodies: Design of An HCV Vaccine Candidate Cross-Reactive with Multiple Genotypes Background/Aims The role of antibody in hepatitis C virus (HCV) infection remains unclear although many reports attest to its role in viral clearance. Here we describe epitopes that are recognized by antibody present in the serum of infected patients and show that such epitopes can induce neutralizing antibodies. Methods Human serum containing hyperimmune anti-HCV IgG was used to extract epitopes from a library of synthetic peptides that encompassed the sequences of the E1 and E2 proteins of HCV genotype 1a H77. Peptides that were bound by IgG were identified by mass spectrometry. Assembly of these epitopes with a helper T cell determinant was then carried out in order to construct candidate epitope-based vaccines. Results Three distinct antigenic sites were defined in the E1E2 glycoproteins by epitopes identified by antibody present in infected individuals. Four of the peptide epitopes identified are conserved in at least three HCV genotypes and are bound by antibody present in the sera of chronically infected and convalescent individuals. Synthetic vaccines based on these epitopes elicited antibodies that are capable of (i) capturing HCV virions from the serum of viraemic patients and (ii) inhibiting HCV pseudovirus particle entry into Huh7 cells. Conclusions This approach exploits the information inherent in the binding sites of virus-specific antibodies and represents a novel method for the design of synthetic epitope-based vaccines.
Antiviral Therapy - Tập 11 Số 8 - Trang 1005-1014 - 2006
Incidence and Determinants of Severe Morbidity among HIV-Infected Patients from Rio De Janeiro, Brazil, 2000–2010 Background Reliable information on severe morbidity is essential for identifying priorities for case management and to guide resource allocation within the health sector. Methods This study describes overall, AIDS- and non-AIDS-related severe morbidity as well as mortality and its determinants in an urban cohort of HIV-infected individuals from a public healthcare institution, the Evandro Chagas Research Institute (IPEC) of the Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. Severe morbid events were defined as all clinical diagnoses listed in hospitalization discharge records; all diagnoses were checked and validated. Generalized estimating equation models were used to estimate incidence rates while adjusting for within-subject correlation. Results Between 2000 and 2010, 3,537 patients were followed for a total of 16,960 person-years (PY) of follow-up. Over the years, annual incidence rate of severe morbid events, AIDS-related events, non-AIDS-related events, and deaths significantly decreased from, respectively, 36.6, 12.9, 23.7 and 3.2 per 100 PY in 2000 to 25.3, 7.9, 17.4 and 1.9 per 100 PY in 2010. Patients’ immunological profiles significantly improved with time; 84% of the patients used combination antiretroviral therapy (cART) per year. Immunodeficiency was associated with a higher incidence rate of AIDS- and non-AIDS-related events as well as with the incidence rate of specific non-AIDS events (bacterial infections, toxicities, cardiovascular, renal and respiratory diseases). Conclusions Our results show that in a middle income country with access to cART, non-AIDS-related events represent an important cause of severe morbidity alongside a still high incidence rate of AIDS-related events.
Antiviral Therapy - Tập 19 Số 4 - Trang 387-397 - 2014
HIV-1 Subtypes and Response to Combination Antiretroviral Therapy in Europe Background Combination antiretroviral therapy (cART) may vary in ability to suppress viral load and increase CD4+ T-cell count in people infected with different HIV-1 subtypes, possibly due to differences in resistance development. Antiretroviral drugs have predominantly been developed in Western Europe/North America on the basis of the most prevalent subtype, B. However, non-B subtypes are increasingly spreading worldwide. Objective To compare virological and immunological response to cART between patients infected with B and non-B subtypes across Europe. Design EuroSIDA prospective, observational cohort with 11,928 HIV-1-infected patients. Methods Response to cART was analysed in patients with subtypes determined pre-cART, via multivariable logistic regression on the first measurements 6–12 months after starting cART. A virological response was defined as a viral load <500 copies/ml and immunological response as a CD4+ T-cell count increase of ≥100 cells/mm3 . Results Forty-five percent of patients were antiretroviral naive at initiation of cART. Virological suppression was achieved by 58% of 689 subtype-B-infected patients and 66% of 102 non-B-infected patients ( P=0.159). After adjustment for potential confounders, there was no significant difference in odds of achieving virological suppression (non-B compared with B; odds ratio [OR]: 1.05, 95% confidence interval [CI]: 0.58–1.93, P=0.866). An immunological response was achieved by 43% of 753 B-infected patients and 48% of 114 non-B-infected patients ( P=0.334). After adjustment, there was no significant difference in odds of an immunological response (OR: 1.17, 95% CI: 0.73–1.87, P=0.524). Conclusions There was no evidence of significant differences in virological or immunological response to cART between patients infected with HIV-1 B and non-B subtypes.
Antiviral Therapy - Tập 11 Số 6 - Trang 707-716 - 2006
High Incidence of Non-B and Recombinant HIV-1 Strains in Newly Diagnosed Patients in Galicia, Spain: Study of Genotypic Resistance The objectives of this study are to describe the incidence of non-B and recombinant HIV-1 strains in newly diagnosed HIV-1 infections in Galicia, northwest of Spain, during a 2-year period (May 2000 to June 2002), and the frequency of resistance-associated mutations in reverse transcriptase (RT) and protease (PR) genes, analysing the polymorphisms more frequently detected in non-B and recombinant viruses. All newly diagnosed HIV-1-infected patients attending the nine public hospitals of the seven main cities of Galicia were included in this study. RT, PR and V3 regions from HIV-1 RNA plasma were amplified and sequenced, being the corrected sequences sent to the Stanford HIV RT and Protease Sequence Database. Nineteen of 85 patients (22.3%) were infected by non-B or recombinant viruses: three subtype C, two G, one F1, one Dpol /A1V3 , five CRF02_AG, one CRF14_BG, five BGpol /BV3 and one UKpol /UV3 (U, unknown fragment). Eleven of these 19 patients (57.9%) were foreign individuals living in Galicia infected through heterosexual contact, and the other eight (42.1%) were Spanish intravenous drug users who had shared injection equipment. Five of 85 patients (5.9%), all infected with B subtype viruses, showed resistance-associated mutations in RT (M184V, M41L, L210W, T215Y/D and K219Q). In one patient (1.2%) infected with a subtype G strain, resistance-associated mutations in PR (K20I+M36I+M46I+V82I) were detected. In subtype B viruses resistance mutations in PR were not detected. Several polymorphisms in RT: D123S, Q174K, D177E, T200A, V245Q, and PR: I13V, K20I, M36I, R41K, H69K, L89M were detected more frequently in non-B and recombinants than in B strains ( P<0.01 to P<0.001). This study reports a high incidence (22.3%) of newly diagnosed patients infected by different non-B and recombinant HIV-1 strains, in a geographical area of Spain, showing also a high frequency of polymorphisms in RT and PR genes.
Antiviral Therapy - Tập 8 Số 4 - Trang 355-360 - 2003
Investigation of Baseline Susceptibility to Protease Inhibitors in HIV-1 Subtypes C, F, G and Crf02_Ag Objective To compare baseline susceptibility to protease inhibitors among HIV-1 isolates of subtypes C, F, G and CRF02_AG, and to identify polymorphisms that determine the differences in susceptibility. Methods A total of 42 samples of drug-naive patients infected with subtypes G ( n=19), CRF02_AG ( n=10), F ( n=6) and C ( n=7) were phenotyped and genotyped with the Antivirogram and the ViroSeq 2.0 genotyping system, respectively. A Bayesian network approach was used for a preliminary analysis of the collected data and the dependencies indicated by the network were statistically confirmed. Results CRF02_AG samples were found to be more susceptible to nelfinavir and ritonavir than other subtypes. Hypersusceptibility to these drugs was associated with the 70R polymorphism. 37D/S/T was associated with reduced susceptibility to indinavir and 89M with reduced susceptibility to lopinavir. Susceptibility to tipranavir was the lowest among the subtype F samples and the highest for subtype G samples, with samples carrying 57R being more susceptible than samples carrying 57K. Conclusions Our study suggests that there are baseline susceptibility differences between subtypes and these differences are due to naturally occurring polymorphisms in these subtypes. The predictive value for phenotype of these polymorphisms was even valid in subtypes where these polymorphisms are less prevalent. Taking into account such polymorphisms should improve current algorithms for interpretation of genotyping results in a subtype-independent way.
Antiviral Therapy - Tập 11 Số 5 - Trang 581-589 - 2006
Safety and Efficacy of Once-Daily Nevirapine Dosing: A Multicohort Study 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.
Antiviral Therapy - Tập 14 Số 7 - Trang 931-938 - 2009
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