Antivirals for management of herpes zoster including ophthalmicus: a systematic review of high-quality randomized controlled trials.
Antivir Ther. 2011 Dec 15;
Authors: McDonald EM, de Kock J, Ram FS
Abstract
BACKGROUND: There is lack of consensus from randomized controlled trials on the efficacy of antivirals in the management of herpes zoster. Therefore, a systematic review and meta-analysis was undertaken to provide better understanding of effectiveness of antivirals in management of herpes zoster. METHODS: A total of 12 randomized controlled trials with 7,277 patients were included in the review. Trials compared one antiviral to another (aciclovir, valaciclovir, famciclovir or brivudin) for a minimum of 7 days in immunocompetent patients presenting with herpes zoster diagnosed within 72 h of symptom onset. Primary outcome was reduction in pain. RESULTS: Compared with aciclovir, valaciclovir showed significant reduction in herpes-zoster-associated pain up to 112 days. The largest risk reduction in pain (36%) was seen at 21-30 days (relative risk [RR] 0.64, 95% CI 0.59, 0.70) with number needed to treat to benefit (NNT) of 3 (95% CI 2.7, 3.8). Famciclovir was also superior to aciclovir with a 46% reduction in risk of pain at 28-30 days (RR 0.54, 95% CI 0.48, 0.68) with NNT of 3 (95% CI 2, 5). Time to lesion healing and adverse effect profile was comparable. CONCLUSIONS: Evidence from quality trials have shown significant reduction in risk of pain with valaciclovir and famciclovir for management of herpes zoster including ophthalmicus. Valaciclovir or famciclovir should be preferred treatment options in patients with herpes zoster as they both provide significant reduction in risk of herpes-zoster-associated pain. Furthermore, the superior pharmacokinetics and more convenient dosing regimens with the use of valaciclovir and famciclovir clearly make them the preferred treatment option.
PMID: 22300753 [PubMed - as supplied by publisher]
Increased CD34(+)/KDR(+) cells are not associated with carotid artery intima-media thickness progression in chronic HIV-positive subjects.
Antivir Ther. 2011 Dec 16;
Authors: Papasavvas E, Hsue P, Reynolds G, Pistilli M, Hancock A, Martin JN, Deeks SG, Montaner LJ
Abstract
BACKGROUND: Endothelial progenitor cells (EPCs) are involved in the endothelium repair. Low circulating EPC levels are predictive of cardiovascular events in HIV-negative subjects. The impact of HIV infection on EPCs, and the role of EPCs in HIV-associated cardiovascular disease, is not known. We hypothesized that circulating EPCs would be inversely associated with carotid artery intima-media thickness (c-IMT) changes in HIV-infected subjects. METHODS: EPCs (CD34(+)/KDR(+), CD133(+)/KDR(+) and CD34(+)/CD133(+)/KDR(+)) were defined retrospectively by flow cytometry in cryopreserved peripheral blood mononuclear cells collected longitudinally from 66 chronic HIV-infected subjects and cross-sectionally from 50 at-risk HIV-negative subjects. The HIV-infected subjects participated in the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort, were receiving antiretroviral therapy (59/66) and had two sequential measurements of c-IMT 1 year apart. Two distinct groups of HIV-infected subjects were identified a priori: rapid c-IMT progressors (subjects with rapid c-IMT progression, n=13, Δc-IMT>0.2 mm) and slow c-IMT progressors (subjects with slow or no c-IMT progression, n=53, Δc-IMT<0.2 mm). RESULTS: Although cryopreservation reduced sensitivity of detection, EPC frequency in HIV-infected subjects was still significantly higher compared to at-risk HIV-negative subjects (CD34(+)/KDR(+); P=0.01) and correlated positively with CD4(+) T-cell count (CD34(+)/KDR(+), r=0.27; P=0.03). No association was found between the change of EPC frequencies over time (ΔEPC) and Δc-IMT or between EPC frequencies and c-IMT or Δc-IMT. CONCLUSIONS: The lack of an association between EPCs and c-IMT in our cohort does not support HIV-associated reductions in EPC frequency as a cause of accelerated atherosclerosis.
PMID: 22300770 [PubMed - as supplied by publisher]
Control of HBV replication by antiviral microRNAs transferred by lentiviral vectors for potential cell and gene therapy approaches.
Antivir Ther. 2011 Dec 13;
Authors: Kumar M, Follenzi A, Garforth S, Gupta S
Abstract
BACKGROUND: Because molecular mechanisms regulating host cell and virus interactions are not fully understood, we further defined roles of antiviral microRNAs (miRNAs) in HBV replication. METHODS: We studied small interfering RNA sequences inserted into the miR-30 backbone in cell systems. Antiviral sequences were cloned into lentiviral vectors upstream of a green fluorescent protein reporter. Transduced cells included HepG2 or HepG2 2.2.15 cell lines and hTERT-FH-B fetal human liver cells. HBV replication was analysed by several assays. RESULTS: In 2.2.15 cells treated with constructs primarily targeting HBV polymerase and surface antigen or HBV polymerase and X open reading frames, HBV core protein, HBV DNA and HBV RNA expression decreased. This antiviral effect was more pronounced when the two constructs were expressed together. Similarly, antiviral constructs decreased HBV replication in HepG2 cells transduced with adenoviral vector to express HBV. Although antiviral sequences were expressed in hTERT-FH-B cells, these cells were non-permissive for HBV, possibly owing to expression of miRNAs reported to inhibit HBV replication, whereas these miRNAs were absent in HepG2 cells. Expression of antiviral miRNAs did not affect cell viability or proliferation and no deleterious changes were observed in expression of native cellular miRNAs. Moreover, expression of antiviral miRNA did not affect engraftment and survival of transplanted cells in mice. CONCLUSIONS: Identification of effective antiviral miRNAs and transfer of suitable constructs by lentiviral vectors will be helpful for pathophysiological studies of host cell-virus interactions. Simultaneously, this will advance potential mechanisms for cell/gene therapy in those afflicted with chronic hepatitis and refractory liver disease.
PMID: 22300804 [PubMed - as supplied by publisher]
The prevalence of darunavir-associated mutations in HIV-1-infected children in the UK.
Antivir Ther. 2011 Dec 15;
Authors: Donegan KL, Walker AS, Dunn D, Judd A, Pillay D, Menson E, Lyall H, Tudor-Williams G, Gibb DM, ,
Abstract
BACKGROUND: We examined the prevalence of ritonavir-boosted darunavir (DRV) resistance-associated mutations (RAMs) in HIV-infected children in the UK to determine the drug’s potential clinical utility as a first-line or second-line protease inhibitor (PI). METHODS: The prevalence of DRV RAMs, identified from IAS 2010 and Stanford, and the Stanford susceptibility score, were estimated in PI-naive and PI-experienced children in the Collaborative HIV Paediatric Study and the UK HIV Drug Resistance Database 1998-2008. Associations between type/duration of PI exposure and area under the viraemia curve on PI with the number of RAMs were investigated using multivariate Poisson regression. RESULTS: A total of 17/417 (4%) children with a resistance test when PI-naive had one IAS DRV RAM, and 1 had a Stanford mutation; none had multiple DRV RAMs. A total of 177 PI-experienced children had a test after a median 2.7 years (IQR 1.1-5.2) on PIs; 19 (11%) had one IAS DRV RAM, 7 (4%) had two RAMs, 1 (0.6%) had three RAMs and 1 (0.6%) had four RAMs. DRV RAMs were independently associated with increased years on a PI, a larger area under the viraemia curve since starting PIs, and any exposure to PIs other than lopinavir (all P≤0.05). Only 6 (3%) PI-experienced children had intermediate-level DRV/ritonavir resistance; none had high-level resistance. CONCLUSIONS: DRV resistance was negligible in PI-naive children and those with lopinavir PI exposure alone. However resistance increased with increasing time, and with higher levels of viraemia, on PIs. Once-daily DRV/ritonavir would be valuable as a second PI or an alternative first PI, particularly if coformulated with a booster in an appropriate formulation for children.
PMID: 22300840 [PubMed - as supplied by publisher]
Continuous interferon-α2b infusion in combination with ribavirin for chronic hepatitis C in treatment-experienced patients.
Antivir Ther. 2011 Dec 13;
Authors: Roomer R, Bergmann JF, Boonstra A, Hansen BE, Haagmans BL, Kwadijk-de Gijsel S, van Vuuren AJ, de Knegt RJ, Janssen HL
Abstract
BACKGROUND: Sustained virological response (SVR) rates in previous non-responders to pegylated interferon (PEG-IFN)-α and ribavirin for chronic HCV remain low (~10%). We hypothesize that continuous subcutaneous delivery of fully potent interferon (IFN)-α2b via an external pump will lead to stable blood concentrations and thereby prevent subtherapeutic trough levels associated with viral breakthrough. The aims of the study were to assess safety, tolerability and virological response in patients who were previous PEG-IFN-α/ribavirin non-responders. METHODS: We randomized 30 HCV genotype 1 (n=24) and genotype 4 (n=6) patients to receive 6, 9 or 12 million units (MU) IFN-α2b daily by continuous subcutaneous administration using an insulin pump (MiniMed(®) 508; Medtronic Inc., Minneapolis, MN, USA) in combination with ribavirin (1,000-1,600 mg) for 48 weeks. RESULTS: The magnitude of viral decline in the 12 MU group after 4 weeks of treatment was 2.67 log HCV RNA compared with 1.21 and 1.27 log HCV RNA in the 9 and 6 MU groups, respectively (P=0.001). In the intention-to-treat analysis, the SVR rate was 20% (6/30). The per-protocol SVR rate was 25% (6/24), of which four out of six patients in the high-dose arm achieved SVR. Adverse events appeared dose-dependent, were mostly mild-to-moderate and were typical of IFN therapy. Five patients developed irritation and/or abscesses at the injection site. Six serious adverse events were reported in five patients. CONCLUSIONS: Continuous delivery of IFN-α2b can induce a strong dose-dependent viral suppression. This could be an effective approach in conjunction with, or as lead-in therapy prior to, treatment with a direct antiviral agent.
PMID: 22300892 [PubMed - as supplied by publisher]
Evidence for a shift to anaerobic metabolism in adipose tissue in efavirenz-containing regimens for HIV with different nucleoside backbones.
Antivir Ther. 2011 Dec 13;
Authors: McGee KC, Shahmanesh M, Boothby M, Nightingale P, Gathercole LL, Tripathi G, Harte AL, Shojaee-Moradie F, Umpleby AM, Das S, Al-Daghri NM, McTernan PG, Tomlinson JW
Abstract
BACKGROUND: Antiretroviral (ARV) treatment has been associated with abnormalities in lipid and mitochondrial metabolism. We compared patterns of gene expression in the subcutaneous adipose tissue (SAT) of HIV-positive subjects before and after 18-24 months of ARV therapy with HIV-negative controls. METHODS: HIV patients naive to ARV were randomized to receive zidovudine (AZT), lamivudine (3TC) with efavirenz (EFV) or tenofovir disoproxil fumarate (TDF) with emtricitabine (FTC) and EFV. Healthy controls (n=15) were matched for age, ethnicity and gender. Patients on a regimen containing abacavir (ABC), 3TC and EFV for 18-24 months were also tested. Genes involved in adipocyte glucocorticoid, lipid and mitochondrial metabolism, and adipocyte differentiation, were profiled with real-time PCR. RESULTS: AZT led to increased visceral adipose tissue (VAT; P=0.012) and VAT:SAT ratio (P=0.036), whereas TDF increased SAT (P=0.047) and peripheral fat/lean body mass ratio (P=0.017). HIV treatment-naive patients had lower plasma lipoprotein lipase (LPL) activity (P=0.0001) versus controls (remaining below controls after ARV; P=0.038-0.0001). The overall pattern of gene expression was similar across all treatment groups, being most marked with AZT and least with TDF. There was up-regulation of peroxisome proliferator-activated receptor-γ coactivator-1α, uncoupling protein-2 and hexose 6-phosphate dehydrogenase, and down-regulation of nuclear respiratory factor-1, cytochrome oxidase B, cytochrome c oxidase-4, uncoupling protein-3, 11β-hydroxysteroid dehydrogenase type-1, glucocorticoid receptor-α, fatty acid synthase, fatty acid binding protein-4, LPL and hormone sensitive lipase (18-24 months post-treatment versus pretreatment levels and controls; P<0.05 to <0.0001). CONCLUSIONS: The decreased expression of genes involved in lipid and mitochondrial metabolism 18-24 months post-ARV treatment in SAT of HIV patients, in conjunction with the increase in uncoupling protein-2 and decrease in cytochrome oxidase B gene expression, provides evidence of mitochondrial dysfunction and a shift to anaerobic metabolism within SAT in EFV-containing ARV regimens.
PMID: 22300946 [PubMed - as supplied by publisher]
The vitamin D receptor gene bAt (CCA) haplotype impairs the response to pegylated-interferon/ribavirin-based therapy in chronic hepatitis C patients.
Antivir Ther. 2011 Dec 14;
Authors: Baur K, Mertens JC, Schmitt J, Iwata R, Stieger B, Frei P, Seifert B, Ferrari HA, von Eckardstein A, Müllhaupt B, Geier A,
Abstract
BACKGROUND: Chronic hepatitis C infection is a major cause of end-stage liver disease. Therapy outcome is influenced by 25-OH vitamin D deficiency. To further address this observation, our study investigates the impact of the vitamin D receptor (NR1I1) haplotype and combined effects of plasma vitamin D levels in a well-described cohort of hepatitis C patients. METHODS: A total of 155 chronic hepatitis C patients were recruited from the Swiss Hepatitis C Cohort Study for NR1I1 genotyping and plasma 25-OH vitamin D level measurement. NR1I1 genotype data and combined effects of plasma 25-OH vitamin D level were analysed regarding therapy response (sustained virological response). RESULTS: A strong association was observed between therapy non-response and the NR1I1 CCA (bAt) haplotype consisting of rs1544410 (BsmI) C, rs7975232 (ApaI) C and rs731236 (TaqI) A alleles. Of the HCV patients carrying the CCA haplotype, 50.3% were non-responders (odds ratio [OR] 1.69, 95% CI 1.07, 2.67; P=0.028). A similar association was observed for the combinational CCCCAA genotype (OR 2.94, 95% CI 1.36, 6.37; P=0.007). The combinational CCCCAA genotype was confirmed as an independent risk factor for non-response in multivariate analysis (OR 2.50, 95% CI 1.07, 5.87; P=0.034). Analysing combined effects, a significant impact of low 25-OH vitamin D levels on sustained virological response were only seen in patients with the unfavourable NR1I1 CCA (bAt) haplotype (OR for non-SVR 3.55; 95% CI 1.005, 12.57; P=0.049). CONCLUSIONS: NR1I1 vitamin D receptor polymorphisms influence response to pegylated-interferon/ribavirin-based therapy in chronic hepatitis C and exert an additive genetic predisposition to previously described low 25-OH vitamin D serum levels.
PMID: 22300961 [PubMed - as supplied by publisher]
BACKGROUND: Initial reports suggested that novel A(H1N1) influenza virus (2009 A[H1N1]v) infection was significantly more severe in pregnant than in non-pregnant women. In Spain, antiviral therapy was recommended for pregnant women from the beginning of the 2009 pandemic. METHODS: The prospective cohort study included consecutive pregnant and non-pregnant women of reproductive age with a proven diagnosis of 2009 A(H1N1)v admitted to any of the 13 participating Spanish hospitals between 12 June and 10 November 2009. RESULTS: In total, 98 pregnant and 112 non-pregnant women with proven 2009 A(H1N1)v hospitalized during the study period were included. Influenza was more severe among non-pregnant patients than pregnant patients with respect to outcomes of both intensive care unit admission (18% versus 2%; P<0.001) and death (5 versus 0; P=0.06). Pregnant women had fewer associated comorbid conditions other than pregnancy (18% versus 44%; P<0.001); they were also admitted earlier than non-pregnant women (median days since onset of symptoms: 2 versus 3; P<0.001) and a higher percentage received early antiviral therapy (41% versus 28%; P=0.03). Neither a multivariate nor a matched cohort analysis found pregnancy to be associated with greater severity than that associated with hospitalized, seriously ill non-pregnant women. CONCLUSIONS: 2009 A(H1N1)v influenza was not associated with worse outcomes in hospitalized pregnant women compared with non-pregnant ones of reproductive age in a context of early diagnosis and antiviral therapy.
PMID: 22301005 [PubMed - as supplied by publisher]
Effect of abacavir on acute changes in biomarkers associated with cardiovascular dysfunction.
Antivir Ther. 2011 Dec 16;
Authors: Patel P, Bush T, Overton T, Baker J, Hammer J, Kojic E, Conley L, Henry K, Brooks JT,
Abstract
BACKGROUND: This study examined the effect of abacavir on acute changes in biomarkers associated with cardiovascular dysfunction. METHODS: Among the Study to Understand the Natural History of HIV/AIDS in the Era of Effective therapy (SUN) participants, we identified 25 individuals (cases) who were HLA-B5701-negative and who had ≥2 weeks without abacavir exposure at one visit and ≥2 weeks with abacavir exposure at the consecutive visit while maintaining viral suppression. We identified 43 individuals (controls) similarly unexposed and exposed to tenofovir. We assessed concentrations of prothrombin fragment F(1+2), D-dimer, high-sensitivity C-reactive protein, interleukin-8, intercellular adhesion molecule-1, vascular adhesion molecule-1, E-selectin, P-selectin, serum amyloid A and serum amyloid P. We examined the median percentage change of these biomarkers from the unexposed to exposed state among cases and controls compared with the expected assay variability using a sign test, and compared changes among cases with controls using the Wilcoxon rank-sum test. RESULTS: Baseline characteristics were similar between cases and controls: median age 45 versus 46 years, 80% versus 81% male, 64% versus 63% non-Hispanic White and median CD4(+) T-cell count 538 versus 601 cells/mm(3), respectively. Mean exposure times were 65 and 15 weeks for abacavir and tenofovir, respectively. We observed no significant changes in biomarkers from the unexposed to exposed state among cases or controls compared with the expected assay variability. We found that no biomarkers were significantly increased among cases compared with controls; however, prothrombin fragment F(1+2) was significantly lower among controls (P=0.035). CONCLUSIONS: In virologically suppressed contemporary HIV-infected patients, abacavir exposure was not associated with increases in biomarkers associated with increased cardiovascular risk.
PMID: 22301072 [PubMed - as supplied by publisher]
HIV-1 Tat protein impairs adipogenesis and induces the expression and secretion of proinflammatory cytokines in human SGBS adipocytes.
Antivir Ther. 2011 Dec 16;
Authors: Díaz-Delfín J, Domingo P, Wabitsch M, Giralt M, Villarroya F
Abstract
BACKGROUND: HIV-1 Tat protein has been shown to play multiple roles in the pathogenesis of AIDS; however, there is no information currently available on its effects on adipose tissue alterations. We have studied the effects of Tat on SGBS adipocytes to gain insight on its role on the development of lipodystrophy. METHODS: SGBS preadipocytes were exposed to Tat during and after differentiation. Acquisition of adipocyte morphology, expression of gene markers of adipogenesis and inflammation, release of adipokines and cytokines to the medium, and glucose uptake were measured. The action of Tat on tumour necrosis factor (TNF)-α-regulated messenger RNA expression was determined in differentiated adipocytes. The capacity of rosiglitazone, resveratrol and parthenolide to influence the action of Tat was also assessed. RESULTS: Tat treatment reduced the number of SGBS preadipocytes that acquired adipocyte morphology. It also led to repression of adipogenic gene expression and induced the coordinate expression and release of proinflammatory cytokines in human adipose cells. Moreover, combined treatment with Tat and TNF-α produced an additive effect on the repression of adipocyte genes. The observed effects of Tat on gene transcription in adipocytes were due, in part, to TNF-α that was secreted as a consequence of intracellular exposure to Tat. CONCLUSIONS: Tat impairs adipogenesis in human SGBS preadipocytes and increases the expression and release of proinflammatory cytokines. Positive crosstalk between Tat and TNF-α contributes to the anti-adipogenic and proinflammatory effects. HIV-1 Tat protein may play a role in the adipose tissue alterations that ultimately lead to lipoatrophy and systemic metabolic disturbances observed in HIV-1-infected patients.
PMID: 22301094 [PubMed - as supplied by publisher]
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