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Background: Cytomegalovirus (CMV) infections are a common complication after kidney transplantation (KTx) and negatively affecting patient outcome. Valganciclovir (VGC) prophylaxis is often limited by drug‐induced side effects and dose reduction due to decline in kidney function. Method: In the present study, episodes of CMV viremia in the first year after KTx in a cohort of 316 recipients were analyzed retrospectively to identify risk factors linked to persistent infections. Results: In the studied cohort, 18.7% of patients showed a high‐risk (HR) constellation (D+/R–) for CMV infections. CMV viremia affected 22% of our cohort, with HR patients being the most affected cohort (44.1%). Within this group, most viremic events (65.3%) occurred while patients were still on prophylactic therapy, showing significantly higher viral loads and a longer duration compared to seropositive recipients. Conclusion: The analysis at hand revealed that detection of viremia under ongoing antiviral prophylaxis bears an increased risk for sustained viral replication and antiviral drug resistance in HR patients. We identified low estimated glomerular filtration rate (eGFR) and lower dose VGC prophylaxis post‐KTx as a risk factor for breakthrough infections in HR patients in our single center cohort. These patients might benefit from a closer CMV monitoring or novel prophylactic agents as letermovir. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection is a significant cause of morbidity and mortality after solid organ transplantation. There has been a significant shift in disease epidemiology with the introduction of antiviral prophylaxis, with CMV disease occurring later and clinical presentations more atypical. We describe two cases of very late‐onset CMV disease where first disease occurred 15 and 18 years post–renal transplantation, with both cases complicated by antiviral drug resistance. We subsequently review the published cases and literature of very late‐onset CMV disease (onset > 10 years post–solid organ transplantation) as an increasingly recognized phenomenon which is emerging as an important aspect in improving long‐term patient outcomes in the current era of renal transplantation. [ABSTRACT FROM AUTHOR]

Background and Aim Studies focused on the naturally occurring resistance mutation rate in treatment-naïve chronic hepatitis B ( CHB) patients have set off a furious dispute. We conduct this meta-analysis to appraise the pooled incidence of spontaneous hepatitis B virus resistance mutations worldwide and its distribution. Methods We searched Pub Med, EMBASE, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure until December 31, 2013. Cross-sectional or case-control studies reporting incidence of natural resistance mutations in untreated CHB patients were included. Pooled incidence was performed in fixed- or random-effects models, and heterogeneity among studies was assessed. Results A total of 106 studies were included involving 12 212 naive CHB patients. The summarized incidence of natural mutations worldwide was 5.73% (95% confidence interval [ CI]: 4.85-6.61%), primary mutation rate 5.39% (95% CI: 4.54-6.24%), and secondary mutation rate 2.94% (95% CI: 1.59-4.29%). The pooled incidence reached up to 8.00% (95% CI: 6.63-9.38%) in China, higher than that in other countries (1.88% [95% CI: 1.06-2.69%]). Mutation rt M204 V/ I had the highest incidence of 4.89% (95% CI: 4.13-5.65%), and other primary mutations seldom spontaneously occurred. In subgroup analysis, genotype C hepatitis B virus infection, male, and hepatitis B antigen ( HBe Ag) negative patients had a slightly higher natural mutation rate. Conclusion The resistance mutations occurred frequently in untreated CHB patients, especially in China. The lamivudine resistance had the highest natural prevalence rate, while other nucleos(t)ide analogues showed rarely spontaneous resistance. Detecting the spontaneous resistance mutations will benefit the clinical management of CHB patients. [ABSTRACT FROM AUTHOR]

This study describes a novel, PCR-based assay that evaluates the ability of compounds to inhibit cDNA generation by HIV reverse transcriptase (RT), of both commercial and viral lysate origin, from a known RNA template. The template consisted of RNA from stable transfectants ectopically expressing the US6 gene of herpes simplex virus-1, coding for glycoprotein D. Controls were carried out to demonstrate that no residual DNA polymerase activity or DNA contamination was responsible for the amplified DNA in the tested, control samples. In this assay, 0.1 μM nevirapine totally inhibited the RT activity of 0.5 U commercial HIV RT, while 10 nM inhibited it by only 10%. Conversely, 10 pM efavirenz completely inhibited 0.5 U HIV RT. Similar results were obtained when a self-prepared viral lysate was used as a source of HIV RT. A reference commercial kit directly measuring HIV RT activity, without amplification, was less sensitive than the new assay. As a consequence, the HIV RT 50% inhibitory concentration of nevirapine and efavirenz in the newly described assay was 8 and 5 × 103 times lower, respectively, than in the commercial assay. In conclusion, this novel method was sensitive, reproducible, and sufficiently rapid for screening in vitro the functional activity of known or potential antiretroviral compounds against HIV RT. J. Med. Virol. 86:1-7, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Dapat et al. (2012) Delayed emergence of oseltamivir-resistant seasonal influenza A (H1N1) and pandemic influenza A(H1N1)pdm09 viruses in Myanmar. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12030. The prevalence and timing of emergence of oseltamivir-resistant seasonal and pandemic influenza A (H1N1) viruses in Myanmar in 2008 and 2009 are described in this report. In 2008, the oseltamivir-resistant seasonal H1N1 virus was detected at a lower rate (6%) and emerged at least 2 months later when compared with neighboring countries. Similarly, the prevalence of pandemic H1N1 virus was low (3%) and the timing of emergence was late (August 2009) in Myanmar. Interestingly, we detected three isolates that were resistant to both amantadine and oseltamivir. Limited movement of people into the country is attributed to the delayed emergence of drug-resistant seasonal and pandemic A(H1N1) viruses. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) may cause severe or fatal disease among immunocompromised patients. The first line prophylaxis and systemic HCMV disease therapy is ganciclovir (GCV). The presence of GCV-resistant virus has been linked to fatal HCMV disease. The implementation of rapid and sensitive techniques for the early detection and monitoring of GCV-resistance may be helpful to support antiviral therapy management. A pyrosequencing assay for the detection and quantitation of the most frequent mutations conferring moderate- and high-grade GCV resistance was implemented. The pyrosequencing achieved an analytical sensitivity for adequate interpretation of ≥103 copies/ml. The assay was validated with 18 whole blood samples taken over a 6-month period from an umbilical cord blood recipient infected persistently with HCMV and allowed the detection and monitoring of the M460I and A594V GCV-resistant mutations. The percentage of resistant quasispecies ranged from 7.9% to 55.2% for the M460I mutation and from 19.8% to 43% for the A594V mutation. Clearance of the M460I mutation occurred in parallel with a decrease in the HCMV viremia, while the A594V mutation persisted. The pyrosequencing method for detection of GCV is sensitive enough to be used directly on clinical samples for the early identification of resistance mutations and allows the quantitation of resistant and wild type virus quasispecies within hours. The quantitation of minor resistant variants is an important issue to understand their relationship with viral load modification, and potentially anticipate treatment adjustment. J. Med. Virol. 85:1250-1257, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Drug resistance testing is an important tool in the management of HIV-1 infection. As access to genotypic resistance assays is limited in low- and middle-income settings, alternatives are warranted. The aim of the study was to adapt a phenotypic drug susceptibility assay, ExaVir Drug, for detection of resistance to the second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (ETR). Five NNRTI resistant mutant forms of RT were produced (L100I, K103N, L100I/K103N, Y181C, V179D) in order to validate the assay for ETR. Furthermore, HIV-1 RT was purified from plasma samples (n = 28) obtained from treatment naïve and experienced HIV-1 infected patients, and ETR drug susceptibility (IC50) was estimated. The direct sequencing of the pol gene was performed. The recombinant RT mutants had the expected changes in drug sensitivity patterns. The RTs isolated from plasma of therapy naïve individuals showed low IC50 for ETR. In the plasma virus from treatment experienced patients with Y181C, A98G, V108I, and/or K101E mutations in the pol gene, higher IC50 values were found in line with reduced susceptibility data for ETR. This study demonstrates that ExaVir® Drug, a simple enzymatic phenotypic assay, can be used for detection of ETR resistance, including cross-resistance to other NNRTIs, in clinical samples. A further evaluation is needed to define clinical cut-offs; however the assay is an alternative to more costly HIV drug resistance tests, especially in low-income countries. J. Med. Virol. 85:703-708, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B is a serious health problem worldwide with a substantial minority of patients experiencing premature death due to end-stage liver disease and/or hepatocellular carcinoma. Antiviral therapy may help prevent complications of chronic hepatitis B, and seven agents are currently approved in many countries. Of these agents, five are nucleos(t)ide analogs that all have a risk of antiviral drug resistance with long-term use. Efforts have been made in the recent years to prevent or to reduce the risk of viral resistance in patients treated with oral nucleos(t)ides as the majority of these patients will require therapy for 3–5 years or longer. One approach is to identify patients who would most likely develop antiviral resistance on long-term therapy using predictors obtainable early in the course of treatment, when intervention with new or additional therapy can be instituted. The most important predictors of treatment outcomes are serum HBV DNA levels at baseline and during the first 6 months of therapy. The purpose of this synopsis is to review the recent literature regarding the importance of serum HBV DNA levels in association with treatment outcomes in chronic hepatitis B, particularly the association of complete viral suppression early in the course of oral therapy with long-term treatment outcomes, particularly the incidence of antiviral drug resistance. [ABSTRACT FROM AUTHOR]

Background/Aims: There is no consensus on the management of patients with adefovir (ADV)-resistant hepatitis B virus (HBV) infection. The aim of this study was to investigate whether tenofovir disoproxil fumarate (TDF) combined with lamivudine (LMV) is effective and safe in patients with resistance to or non-response to ADV. Methods: Six patients with HBV-related cirrhosis, viral breakthrough during LMV therapy and viral breakthrough or non-response during ADV therapy were treated daily with TDF plus LMV for at least 6 months. The HBV DNA level, alanine aminotransferase (ALT), the Child–Pugh score and serum creatinine were monitored. Genotypic LMV- or ADV-resistant mutations were measured in stored samples. Results: In five of six patients, ADV-resistant mutations at rt181 or rt236 were detected during ADV therapy. At 6 months of starting TDF/LMV combination, HBV DNA levels became undetectable (detection limit, 400 copies/ml) in four of six patients. Within 12 months, HBV DNA levels became undetectable in all patients, and ALT levels were normalized in four of six patients. These responses persisted up to the end of the observation period (median duration 16.5 months, range 6–21 months). The Child–Pugh scores improved in two of three patients with hepatic decompensation. No significant changes in serum creatinine were observed. Conclusion: Our data demonstrated that TDF plus LMV safely and markedly suppressed HBV replication in patients with resistance to or non-response to ADV. This study suggests that this combination may be a promising rescue therapy for these patients, particularly those with liver cirrhosis or pre-existing LMV resistance. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the prevalence and patterns of antiretroviral (ARV) drug resistance (ARV-DR) among ARV drug-naïve, recently infected persons with HIV in the 4-year interval (2003–2006) after the inception of the National Access to ARV Programme for People who have AIDS in Thailand. Methods Cross-sectional study of patients with recent HIV infection for HIV risks, ARV-DR risks and baseline ARV-DR. Results Seven of the 305 patients (2%) had baseline ARV-DR. Via contract tracing, all seven patients with transmitted ARV-DR identified sexual partners with prior ARV treatment failure and had documented low (<75%) ARV adherence. Annual ARV-DR increased from 0 to 5.2% ( P=0.06) between 2003 and 2006. Conclusions Report of sexual partners with potential HIV and ARV drug exposures can prompt baseline ARV-DR testing of at-risk individuals, while behavioural interventions for adherence and safer sex are refined to minimize the emergence of resistance to generic, fixed-dose combination stavudine, lamivudine and nevirapine (GPO-VIR) therapy. [ABSTRACT FROM AUTHOR]

Antiviral agents are commonly used for cytomegalovirus (CMV) prophylaxis or therapy after solid organ transplantation. Until recently, the detection of drug-resistant CMV in this setting was rare, but ganciclovir resistance has now been reported to occur in 5–10% of high-risk patient subsets, such as those undergoing primary CMV infection. Persistent viral shedding or progressive CMV disease after several weeks of antiviral therapy may indicate a problem with drug resistance, though laboratory testing is required to confirm this. Rapid genotypic assays for specific mutations in the viral UL97 phosphotransferase or UL54 DNA polymerase genes can be used to detect resistance and predict cross-resistance to other drugs. The emergence of drug resistance may be reduced by optimization of host immunity, use of potent antiviral drug regimens, and adherence to dosing regimens that adequately suppress viral replication. [ABSTRACT FROM AUTHOR]