Relating increasing hantavirus incidences to the changing climate: the mast connection

<p>Abstract</p> <p>Background</p> <p>Nephropathia epidemica (NE), an emerging rodent-borne viral disease, has become the most important cause of infectious acute renal failure in Belgium, with sharp increases in incidence occurring for more than a decade. Bank voles are the rodent reservoir of the responsible hantavirus and are known to display cyclic population peaks. We tried to relate these peaks to the cyclic NE outbreaks observed since 1993. Our hypothesis was that the ecological causal connection was the staple food source for voles, being seeds of deciduous broad-leaf trees, commonly called "mast". We also examined whether past temperature and precipitation preceding "mast years" were statistically linked to these NE outbreaks.</p> <p>Results</p> <p>Since 1993, each NE peak is immediately preceded by a mast year, resulting in significantly higher NE case numbers during these peaks (Spearman R = -0.82; P = 0.034). NE peaks are significantly related to warmer autumns the year before (R = 0.51; P < 0.001), hotter summers two years before (R = 0.32; P < 0.001), but also to colder (R = -0.25; P < 0.01) and more moist summers (R = 0.39; P < 0.001) three years before. Summer correlations were even more pronounced, when only July was singled out as the most representative summer month.</p> <p>Conclusion</p> <p>NE peaks in year 0 are induced by abundant mast formation in year-1, facilitating bank vole survival during winter, thus putting the local human population at risk from the spring onwards of year 0. This bank vole survival is further promoted by higher autumn temperatures in year-1, whereas mast formation itself is primed by higher summer temperatures in year-2. Both summer and autumn temperatures have been rising to significantly higher levels during recent years, explaining the virtually continuous epidemic state since 2005 of a zoonosis, considered rare until recently. Moreover, in 2007 a NE peak and an abundant mast formation occurred for the first time within the same year, thus forecasting yet another record NE incidence for 2008. We therefore predict that with the anticipated climate changes due to global warming, NE might become a highly endemic disease in Belgium and surrounding countries.</p

The incidence of multidrug and full class resistance in HIV-1 infected patients is decreasing over time (2001–2006) in Portugal

Despite improvements in HIV treatment, the prevalence of multidrug resistance and full class resistance is still reported to be increasing. However, to investigate whether current treatment strategies are still selecting for multidrug and full class resistance, the incidence, instead of the prevalence, is more informative. Temporal trends in multidrug resistance (MDR defined as at most 1 drug fully susceptible) and full class resistance (FCR defined as no drug in this class fully susceptible) in Portugal based on 3394 viral isolates genotyped from 2000 to 2006 were examined using the Rega 6.4.1 interpretation system. From July 2001 to July 2006 there was a significant decreasing trend of MDR with 5.7%, 5.2%, 3.8%, 3.4% and 2.7% for the consecutive years (P = 0.003). Multivariate analysis showed that for every consecutive year the odds of having a new MDR case decreased with 20% (P = 0.003). Furthermore, a decline was observed for NRTI- and PI-FCR (both P < 0.001), whereas for NNRTI-FCR a parabolic trend over time was seen (P < 0.001), with a maximum incidence in 2003–'04. Similar trends were obtained when scoring resistance for only one drug within a class or by using another interpretation system. In conclusion, the incidence of multidrug and full class resistance is decreasing over time in Portugal, with the exception of NNRTI full class resistance which showed an initial rise, but subsequently also a decline. This is most probably reflecting the changing drug prescription, the increasing efficiency of HAART and the improved management of HIV drug resistance. This work was presented in part at the Eighth International Congress on Drug Therapy in HIV Infection, Glasgow (UK), 12-16 November 2006 (PL5.5); and at the Fifth European HIV Drug Resistance Workshop, Cascais (Portugal), 28-30 March 2007 (Abstract 1)

Pharmacy refill adherence outperforms self-reported methods in predicting HIV therapy outcome in resource-limited settings

BACKGROUND: Optimal adherence to antiretroviral therapy is critical to prevent HIV drug resistance (HIVDR) epidemic. The objective of the study was to investigate the best performing adherence assessment method for predicting virological failure in resource-limited settings (RLS). METHOD: This study was a single-centre prospective cohort, enrolling 220 HIV-infected adult patients attending an HIV/AIDS Care and Treatment Centre in Dar es Salaam, Tanzania, in 2010. Pharmacy refill, self-report (via visual analog scale [VAS] and the Swiss HIV Cohort study-adherence questionnaire), pill count, and appointment keeping adherence measurements were taken. Univariate logistic regression (LR) was done to explore a cut-off that gives a better trade-off between sensitivity and specificity, and a higher area under the curve (AUC) based on receiver operating characteristic curve in predicting virological failure. Additionally, the adherence models were evaluated by fitting multivariate LR with stepwise functions, decision trees, and random forests models, assessing 10-fold multiple cross validation (MCV). Patient factors associated with virological failure were determined using LR. RESULTS: Viral load measurements at baseline and one year after recruitment were available for 162 patients, of whom 55 (34%) had detectable viral load and 17 (10.5%) had immunological failure at one year after recruitment. The optimal cut-off points significantly predictive of virological failure were 95%, 80%, 95% and 90% for VAS, appointment keeping, pharmacy refill, and pill count adherence respectively. The AUC for these methods ranged from 0.52 to 0.61, with pharmacy refill giving the best performance at AUC 0.61. Multivariate logistic regression with boost stepwise MCV had higher AUC (0.64) compared to all univariate adherence models, except pharmacy refill adherence univariate model, which was comparable to the multivariate model (AUC = 0.64). Decision trees and random forests models were inferior to boost stepwise model. Pharmacy refill adherence (<95%) emerged as the best method for predicting virological failure. Other significant predictors in multivariate LR were having a baseline CD4 T lymphocytes count < 200 cells/μl, being unable to recall the diagnosis date, and a higher weight. CONCLUSION: Pharmacy refill has the potential to predict virological failure and to identify patients to be considered for viral load monitoring and HIVDR testing in RLS. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2458-14-1035) contains supplementary material, which is available to authorized users

Cellular HIV-1 DNA Levels in Drug Sensitive Strains Are Equivalent to Those in Drug Resistant Strains in Newly-Diagnosed Patients in Europe

Background HIV-1 genotypic drug resistance is an important threat to the success of antiretroviral therapy and transmitted resistance has reached 9% prevalence in Europe. Studies have demonstrated that HIV-1 DNA load in peripheral blood mononuclear cells (PBMC) have a predictive value for disease progression, independently of CD4 counts and plasma viral load. Methodology/Principal Findings Molecular-beacon-based real-time PCR was used to measure HIV-1 second template switch (STS) DNA in PBMC in newly-diagnosed HIV-1 patients across Europe. These patients were representative for the HIV-1 epidemic in the participating countries and were carrying either drug-resistant or sensitive viral strains. The assay design was improved from a previous version to specifically detect M-group HIV-1 and human CCR5 alleles. The findings resulted in a median of 3.32 log10HIV-1copies/106PBMC and demonstrated for the first time no correlation between cellular HIV-1 DNA load and transmitted drug-resistance. A weak association between cellular HIV-1 DNA levels with plasma viral RNA load and CD4+T-cell counts was also reconfirmed. Co-receptor tropism for 91% of samples, whether or not they conferred resistance, was CCR5. A comparison of pol sequences derived from RNA and DNA, resulted in a high similarity between the two. Conclusions/Significance An improved molecular-beacon-based real-time PCR assay is reported for the measurement of HIV-1 DNA in PBMC and has investigated the association between cellular HIV-1 DNA levels and transmitted resistance to antiretroviral therapy in newly-diagnosed patients from across Europe. The findings show no correlation between these two parameters, suggesting that transmitted resistance does not impact disease progression in HIV-1 infected individuals. The CCR5 co-receptor tropism predominance implies that both resistant and non-resistant strains behave similarly in early infection. Furth

HIV-1 drug-resistance patterns among patients on failing treatment in a large number of European countries

Background: Information about patterns of HIV-1 drug resistance among treatment-exposed patients is crucial for the development of novel effective drugs. Currently no system exists that monitors patterns of resistance in patients failing therapy. Methods: The study included 1,988 HIV-1 sequences from patients experiencing therapy failure collected between 2000 and 2004 in 15 European countries. Genotypic resistance was interpreted using the ANRS algorithm. Phenotypic resistance was predicted using the Virco geno- to phenotype system. Results: 80.7% of the sequences included at least one drug-resistance mutation. Mutations were found for NRTIs (73.5%), NNRTIs (48.5%), and protease inhibitors (35.8%). Ninety percent of sequences with genotypic resistance harbored M184V, M41L, K103N, D67N, and/or T215Y. Among NRTIs, resistance was most frequently predicted for lamivudine. About half of all sequences had reduced susceptibility for NNRTIs. Resistance to most boosted protease inhibitors was found in &lt; 25%. No sequence had resistance to all currently available drugs. Conclusion: Levels of resistance among patients with therapy failure were high. The patterns of resistance reflect resistance to drugs available for a longer time. Fully suppressive regimens can be designed even for the most mutated HIV because boosted protease inhibitors have remained active against most circulating viruses and new drug classes have become available.</p

Gender Differences in HIV Disease Progression and Treatment Outcomes among HIV Patients One Year after Starting Antiretroviral Treatment (ART) in Dar es Salaam, Tanzania.

We investigated gender differences in treatment outcome during first line antiretroviral treatment (ART) in a hospital setting in Tanzania, assessing clinical, social demographic, virological and immunological factors. We conducted a cohort study involving HIV infected patients scheduled to start ART and followed up to 1 year on ART. Structured questionnaires and patients file review were used to collect information and blood was collected for CD4 and viral load testing. Gender differences were assessed using Kruskal-Wallis test and chi-square test for continuous and categorical data respectively. Survival distributions for male and female patients were estimated using the Kaplan-Meier method and compared using Cox proportional hazards models. Of 234 patients recruited in this study, 70% were females. At baseline, women had significantly lower education level; lower monthly income, lower knowledge on ARV, less advanced HIV disease (33% women; 47% men started ART at WHO stage IV, p = 0.04), higher CD4 cell count (median 149 for women, 102 for men, p = 0.02) and higher BMI (p = 0.002). After 1 year of standard ART, a higher proportion of females survived although this was not significant, a significantly higher proportion of females had undetectable plasma viral load (69% women, 45% men, p = 0.003), however females ended at a comparable CD4 cell count (median CD4, 312 women; 321 men) signifying a worse CD4 cell increase (p = 0.05), even though they still had a higher BMI (p = 0.02). The unadjusted relative hazard for death for men compared to women was 1.94. After correcting for confounding factors, the Cox proportional hazards showed no significant difference in the survival rate (relative hazard 1.02). We observed women were starting treatment at a less advanced disease stage, but they had a lower socioeconomical status. After one year, both men and women had similar clinical and immunological conditions. It is not clear why women lose their immunological advantage over men despite a better virological treatment response. We recommend continuous follow up of this and more cohorts of patients to better understand the underlying causes for these differences and whether this will translate also in longer term differences

HIV-1 fitness landscape models for indinavir treatment pressure using observed evolution in longitudinal sequence data are predictive for treatment failure

We previously modeled the in vivo evolution of human immunodeficiency virus-1 (HIV-1) under drug selective pressure from cross-sectional viral sequences. These fitness landscapes (FLs) were made by using first a Bayesian network (BN) to map epistatic substitutions, followed by scaling the fitness landscape based on an HIV evolution simulator trying to evolve the sequences from treatment naïve patients into sequences from patients failing treatment. In this study, we compared four FLs trained with different sequence populations. Epistatic interactions were learned from three different cross-sectional BNs, trained with sequence from patients experienced with indinavir (BNT), all protease inhibitors (PIs) (BNP) or all PI except indinavir (BND). Scaling the fitness landscape was done using cross-sectional data from drug naïve and indinavir experienced patients (Fcross using BNT) and using longitudinal sequences from patients failing indinavir (FlongT using BNT, FlongP using BNP, FlongD using BND). Evaluation to predict the failing sequence and therapy outcome was performed on independent sequences of patients on indinavir. Parameters included estimated fitness (LogF), the number of generations (GF) or mutations (MF) to reach the fitness threshold (average fitness when a major resistance mutation appeared), the number of generations (GR) or mutations (MR) to reach a major resistance mutation and compared to genotypic susceptibility score (GSS) from Rega and HIVdb algorithms. In pairwise FL comparisons we found significant correlation between fitness values for individual sequences, and this correlation improved after correcting for the subtype. Furthermore, FLs could predict the failing sequence under indinavir-containing combinations. At 12 and 48 weeks, all parameters from all FLs and indinavir GSS (both for Rega and HIVdb) were predictive of therapy outcome, except MR for FlongT and FlongP. The fitness landscapes have similar predictive power for treatment response under indinavir-containing regimen as standard rules-based algorithms, and additionally allow predicting genetic evolution under indinavir selective pressure

Trends and predictors of transmitted drug resistance (TDR) and clusters with TDR in a local Belgian HIV-1 epidemic

We aimed to study epidemic trends and predictors for transmitted drug resistance (TDR) in our region, its clinical impact and its association with transmission clusters. We included 778 patients from the AIDS Reference Center in Leuven (Belgium) diagnosed from 1998 to 2012. Resistance testing was performed using population-based sequencing and TDR was estimated using the WHO-2009 surveillance list. Phylogenetic analysis was performed using maximum likelihood and Bayesian techniques. The cohort was predominantly Belgian (58.4%), men who have sex with men (MSM) (42.8%), and chronically infected (86.5%). The overall TDR prevalence was 9.6% (95% confidence interval (CI): 7.7-11.9), 6.5% (CI: 5.0-8.5) for nucleoside reverse transcriptase inhibitors (NRTI), 2.2% (CI: 1.4-3.5) for non-NRTI (NNRTI), and 2.2% (CI: 1.4-3.5) for protease inhibitors. A significant parabolic trend of NNRTI-TDR was found (p = 0.019). Factors significantly associated with TDR in univariate analysis were male gender, Belgian origin, MSM, recent infection, transmission clusters and subtype B, while multivariate and Bayesian network analysis singled out subtype B as the most predictive factor of TDR. Subtype B was related with transmission clusters with TDR that included 42.6% of the TDR patients. Thanks to resistance testing, 83% of the patients with TDR who started therapy had undetectable viral load whereas half of the patients would likely have received a suboptimal therapy without this test. In conclusion, TDR remained stable and a NNRTI up-and-down trend was observed. While the presence of clusters with TDR is worrying, we could not identify an independent, non-sequence based predictor for TDR or transmission clusters with TDR that could help with guidelines or public health measures