Effectiveness and Cost Effectiveness of Oral Pre-Exposure Prophylaxis in a Portfolio of Prevention Programs for Injection Drug Users in Mixed HIV Epidemics

Background

Pre-exposure prophylaxis with oral antiretroviral treatment (oral PrEP) for HIV-uninfected injection drug users (IDUs) is potentially useful in controlling HIV epidemics with a significant injection drug use component. We estimated the effectiveness and cost effectiveness of strategies for using oral PrEP in various combinations with methadone maintenance treatment (MMT) and antiretroviral treatment (ART) in Ukraine, a representative case for mixed HIV epidemics.

Methods and Findings

We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs who inject opiates, and IDUs in MMT, adding an oral PrEP program (tenofovir/emtricitabine, 49% susceptibility reduction) for uninfected IDUs. We analyzed intervention portfolios consisting of oral PrEP (25% or 50% of uninfected IDUs), MMT (25% of IDUs), and ART (80% of all eligible patients). We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, HIV infections averted, and incremental cost effectiveness. A combination of PrEP for 50% of IDUs and MMT lowered HIV prevalence the most in both IDUs and the general population. ART combined with MMT and PrEP (50% access) averted the most infections (14,267). For a PrEP cost of $950, the most cost-effective strategy was MMT, at $520/QALY gained versus no intervention. The next most cost-effective strategy consisted of MMT and ART, costing $1,000/QALY gained compared to MMT alone. Further adding PrEP (25% access) was also cost effective by World Health Organization standards, at $1,700/QALY gained. PrEP alone became as cost effective as MMT at a cost of $650, and cost saving at $370 or less.

Conclusions

Oral PrEP for IDUs can be part of an effective and cost-effective strategy to control HIV in regions where injection drug use is a significant driver of the epidemic. Where budgets are limited, focusing on MMT and ART access should be the priority, unless PrEP has low cost.     

High Prevalence of HIV, HCV, HBV and Co-Infection and Associated Risk Factors among Injecting Drug Users in Yunnan Province, China

Objective

To estimate the prevalence of HIV, HCV, HBV and co-infection with 2 or 3 viruses and evaluate risk factors among injecting drug users (IDUs) in Yunnan province, China.

Methods

2080 IDUs were recruited from 5 regions of Yunnan Province, China to detect the infection status of HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). Statistical analysis was performed to evaluate risk factors related to HIV, HCV and HBV infections.

Results

The infection rates among all participants were 25.5% for HIV, 77.7% for HCV, 19.2% for HBV, 15% for HIV/HCV, 0.3% for HIV/HBV, 7.8% for HCV/HBV and 7.1% for HIV/HCV/HBV. The prevalence of virus infection varied widely by region in Yunnan of China. Statistical analyses indicated that high prevalence of HIV and HCV among IDUs was positively associated with the duration of drug injection and sharing needles/syringes; besides, HCV infection was associated with the frequency of drug injection.

Conclusions

HIV, HCV, HBV infections and co-infections were still very prevalent among IDUs in Yunnan province because of drug use behaviors.     

Characterization of Staphylococcus aureus Isolated from Non-Native Patients with Skin and Soft Tissue Infections in Shanghai

Background

Staphylococcus aureus is one predominant cause of skin and soft-tissue infections (SSTIs), but little information exists regarding the characterization of S. aureus from non-native patients with SSTIs in China.

Methods

In this study, we enrolled 52 non-native patients with S. aureus SSTIs, and 65 native control patients with S. aureus SSTIs in Shanghai. 52 and 65 S. aureus isolates were collected from both groups, respectively. S. aureus isolates were characterized by antimicrobial susceptibility testing, toxin gene detection, and molecular typing with sequence type, spa type, agr group and SCCmec type.

Results

Methicillin-resistant S. aureus (MRSA) was detected in 8 non-native patients and 14 native patients with SSTIs. Overall, antimicrobial susceptibilities of S. aureus isolated from non-native patients were found higher than those from native patients. CC59 (ST338 and ST59) was found in a total of 14 isolates (4 from non-native patients; 10 from native patients), 9 of which were carrying lukS/F-PV (3 from non-native patients; 6 from native patients). ST7 was found in 12 isolates and all 12 isolates were found in native patients. The livestock-associated clone ST398 was found in 11 isolates (6 from non-native patients; 5 from native patients), and 5 ST398 lukS/F-PV-positive methicillin-susceptible S. aureus (MSSA) were all discovered among non-native patients. The molecular epidemiology of S. aureus isolated from non-native patients was quite different from those from native patients. lukS/F-PV was more frequent in isolates originating from non-native patients with SSTIs compared to native patients (31 vs. 7, P <0.0001).

Conclusions

CC59 was the most common clonal complex among patients with SSTIs in Shanghai. The other most common sequence types were ST7 and Livestock ST398. The molecular epidemiology of S. aureus isolated from non-native patients was quite different from those from native patients. S. aureus isolated from non-native patients was more likely to carry lukS/F-PV.     

Cost Effectiveness of Screening Strategies for Early Identification of HIV and HCV Infection in Injection Drug Users

Objective

To estimate the cost, effectiveness, and cost effectiveness of HIV and HCV screening of injection drug users (IDUs) in opioid replacement therapy (ORT).

Design

Dynamic compartmental model of HIV and HCV in a population of IDUs and non-IDUs for a representative U.S. urban center with 2.5 million adults (age 15–59).

Methods

We considered strategies of screening individuals in ORT for HIV, HCV, or both infections by antibody or antibody and viral RNA testing. We evaluated one-time and repeat screening at intervals from annually to once every 3 months. We calculated the number of HIV and HCV infections, quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs).

Results

Adding HIV and HCV viral RNA testing to antibody testing averts 14.8–30.3 HIV and 3.7–7.7 HCV infections in a screened population of 26,100 IDUs entering ORT over 20 years, depending on screening frequency. Screening for HIV antibodies every 6 months costs $30,700/QALY gained. Screening for HIV antibodies and viral RNA every 6 months has an ICER of $65,900/QALY gained. Strategies including HCV testing have ICERs exceeding $100,000/QALY gained unless awareness of HCV-infection status results in a substantial reduction in needle-sharing behavior.

Discussion

Although annual screening for antibodies to HIV and HCV is modestly cost effective compared to no screening, more frequent screening for HIV provides additional benefit at less cost. Screening individuals in ORT every 3–6 months for HIV infection using both antibody and viral RNA technologies and initiating ART for acute HIV infection appears cost effective.     

Multiple Introduction and Naturally Occuring Drug Resistance of HCV among HIV-Infected Intravenous Drug Users in Yunnan: An Origin of China’s HIV/HCV Epidemics

Background

The human immunodeficiency virus 1 (HIV-1) epidemic in China historically stemmed from intravenous drug users (IDUs) in Yunnan. Due to a shared transmission route, hepatitis C virus (HCV)/HIV-1 co-infection is common. Here, we investigated HCV genetic characteristics and baseline drug resistance among HIV-infected IDUs in Yunnan.

Methods

Blood samples of 432 HIV-1/HCV co-infected IDUs were collected from January to June 2014 in six prefectures of Yunnan Province. Partial E1E2 and NS5B genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed.

Results

Among the 293 specimens successfully genotyped, seven subtypes were identified, including subtypes 3b (37.9%, 111/293), 3a (21.8%, 64/293), 6n (14.0%, 41/293), 1b (10.6%, 31/293), 1a (8.2%, 24/293), 6a (5.1%, 15/293) and 6u (2.4%, 7/293). The distribution of HCV subtypes was mostly related to geographic location. Subtypes 3b, 3a, and 6n were detected in all six prefectures, however, the other four subtypes were detected only in parts of the six prefectures. Phylogeographic analyses indicated that 6n, 1a and 6u originated in the western prefecture (Dehong) and spread eastward and showed genetic relatedness with those detected in Burmese. However, 6a originated in the southeast prefectures (Honghe and Wenshan) bordering Vietnam and was transmitted westward. These subtypes exhibited different evolutionary rates (between 4.35×10⁻⁴ and 2.38×10⁻³ substitutions site^-1 year^-1) and times of most recent common ancestor (tMRCA, between 1790.3 and 1994.6), suggesting that HCV was multiply introduced into Yunnan. Naturally occurring resistance-associated mutations (C316N, A421V, C445F, I482L, V494A, and V499A) to NS5B polymerase inhibitors were detected in direct-acting antivirals (DAAs)-naïve IDUs.

Conclusion

This work reveals the temporal-spatial distribution of HCV subtypes and baseline HCV drug resistance among HIV-infected IDUs in Yunnan. The findings enhance our understanding of the characteristics and evolution of HCV in IDUs and are valuable for developing HCV prevention and management strategies for this population.     

Effectiveness and cost effectiveness of expanding harm reduction and antiretroviral therapy in a mixed HIV epidemic: a modeling analysis for Ukraine

Background

Injection drug use (IDU) and heterosexual virus transmission both contribute to the growing mixed HIV epidemics in Eastern Europe and Central Asia. In Ukraine—chosen in this study as a representative country—IDU-related risk behaviors cause half of new infections, but few injection drug users (IDUs) receive methadone substitution therapy. Only 10% of eligible individuals receive antiretroviral therapy (ART). The appropriate resource allocation between these programs has not been studied. We estimated the effectiveness and cost-effectiveness of strategies for expanding methadone substitution therapy programs and ART in mixed HIV epidemics, using Ukraine as a case study.

Methods and Findings

We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs using opiates, and IDUs on methadone substitution therapy, stratified by HIV status, and populated it with data from the Ukraine. We considered interventions expanding methadone substitution therapy, increasing access to ART, or both. We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost-effectiveness. Without incremental interventions, HIV prevalence reached 67.2% (IDUs) and 0.88% (non-IDUs) after 20 years. Offering methadone substitution therapy to 25% of IDUs reduced prevalence most effectively (to 53.1% IDUs, 0.80% non-IDUs), and was most cost-effective, averting 4,700 infections and adding 76,000 QALYs compared with no intervention at US$530/QALY gained. Expanding both ART (80% coverage of those eligible for ART according to WHO criteria) and methadone substitution therapy (25% coverage) was the next most cost-effective strategy, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy and averting 8,300 infections versus no intervention. Expanding only ART (80% coverage) added 38,000 QALYs at US$2,240/QALY gained versus the methadone substitution therapy-only strategy, and averted 4,080 infections versus no intervention. Offering ART to 80% of non-IDUs eligible for treatment by WHO criteria, but only 10% of IDUs, averted only 1,800 infections versus no intervention and was not cost effective.

Conclusions

Methadone substitution therapy is a highly cost-effective option for the growing mixed HIV epidemic in Ukraine. A strategy that expands both methadone substitution therapy and ART to high levels is the most effective intervention, and is very cost effective by WHO criteria. When expanding ART, access to methadone substitution therapy provides additional benefit in infections averted. Our findings are potentially relevant to other settings with mixed HIV epidemics. Please see later in the article for the Editors'' Summary     

Comparison of HIV-, HBV-, HCV- and co-infection prevalence between Chinese and Burmese intravenous drug users of the China-Myanmar border region

Background

Co-infection with HIV and HCV and/or HBV is highly prevalent in intravenous drug users (IDUs). Because of the proximity to the “Golden Triangle”, HIV prevalence among the IDUs is very high in the China-Myanmar border region. However, there are few studies about co-infection with HIV and HCV and/or HBV, especially in the region that belongs to Myanmar.

Methods

721 IDUs, including 403 Chinese and 318 Burmese, were investigated for their HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) serological status. Statistical analysis was performed to evaluate the differences of the epidemic situation between the Chinese IDUs and the Burmese IDUs.

Results

Among the Chinese IDUs and the Burmese IDUs, HCV infection was the most prevalent (69.0% vs 48.1%, P<0.001), followed by HBV (51.6% vs 43.1%, P<0.05) and HIV (33.7% vs 27.0%, P>0.05). Besides, there were more HIV-HBV co-infected IDUs (20.1% vs 11.3%, P<0.005), and HIV-HCV co-infected IDUs (31.8% vs 23.9%, P<0.05) in China than in Myanmar, as well as HIV-HBV-HCV triple infection (19.1% vs 10.4%, P<0.005).

Conclusion

Co-infection with HIV and HCV and/or HBV is highly prevalent among the IDUs in the China-Myanmar border region. The HIV epidemic appears to be in a downward trend, compared with previous reports. However, all infections were more prevalent among the Chinese IDUs than among the Burmese.     

Molecular epidemiology of HCV monoinfection and HIV/HCV coinfection in injection drug users in Liuzhou, Southern China

Background

Hepatitis C virus (HCV) mono-infection and HCV/HIV (human immunodeficiency virus) co-infection are growing problems in injection drug users (IDU). Their prevalence and genotypic patterns vary with geographic locations. Access to harm reduction measures is opening up opportunities for improving the HIV/HCV profiling of IDU in China, where IDUs account for a significant proportion of the two infections especially in the southern part of the country.

Methodology/Principal Findings

A cross sectional study was conducted. Through the Liuzhou Methadone Clinic, a total of 117 injection drug users (IDUs) were recruited from Guangxi, Southern China. A majority of the IDUs (96%) were HCV antibody positive, of which 21% were HIV infected. Unlike HCV monoinfection, there was spatial heterogeneity in the distribution of HIV/HCV coinfection, the latter also characterized by a higher prevalence of needle-sharing. Phylogenetic analysis revealed that genotype 6a was predominant in the study population. There were shorter genetic distances among the 6a sequences compared to the other HCV subtypes-1a, 3a, and 3b.

Conclusion/Significance

The results suggested that HIV and HCV were introduced at around the same time to the IDU populations in Southern China, followed by their differential spread as determined by the biologic characteristics of the virus and the intensity of behavioural risk. This pattern is different from that in other South East Asian countries where HCV infections have probably predated HIV.     

Skin and Soft Tissue Infections and Associated Complications among Commercially Insured Patients Aged 0–64 Years with and without Diabetes in the U.S.

Introduction

Skin and soft tissue infections (SSTIs) are common infections occurring in ambulatory and inpatient settings. The extent of complications associated with these infections by diabetes status is not well established.

Methods

Using a very large repository database, we examined medical and pharmacy claims of individuals aged 0–64 between 2005 and 2010 enrolled in U.S. health plans. Diabetes, SSTIs, and SSTI-associated complications were identified by ICD-9 codes. SSTIs were stratified by clinical category and setting of initial diagnosis.

Results

We identified 2,227,401 SSTI episodes, 10% of which occurred in diabetic individuals. Most SSTIs were initially diagnosed in ambulatory settings independent from diabetes status. Abscess/cellulitis was the more common SSTI group in diabetic and non-diabetic individuals (66% and 59%, respectively). There were differences in the frequencies of SSTI categories between diabetic and non-diabetic individuals (p<0.01). Among SSTIs diagnosed in ambulatory settings, the SSTI-associated complication rate was over five times higher in people with diabetes than in people without diabetes (4.9% vs. 0.8%, p<0.01) and SSTI-associated hospitalizations were 4.9% and 1.1% in patients with and without diabetes, respectively. Among SSTIs diagnosed in the inpatient setting, bacteremia/endocarditis/septicemia/sepsis was the most common associated complication occurring in 25% and 16% of SSTIs in patients with and without diabetes, respectively (p<0.01).

Conclusions

Among persons with SSTIs, we found SSTI-associated complications were five times higher and SSTI-associated hospitalizations were four times higher, in patients with diabetes compared to those without diabetes. SSTI prevention efforts in individuals with diabetes may have significant impact on morbidity and healthcare resource utilization.     

Nontuberculous Mycobacterial Disease in Children – Epidemiology,Diagnosis & Management at a Tertiary Center

Background

There are limited data on the epidemiology, diagnosis and optimal management of nontuberculous mycobacterial (NTM) disease in children.

Methods

Retrospective cohort study of NTM cases over a 10-year-period at a tertiary referral hospital in Australia.

Results

A total of 140 children with NTM disease, including 107 with lymphadenitis and 25 with skin and soft tissue infections (SSTIs), were identified. The estimated incidence of NTM disease was 0.6–1.6 cases / 100,000 children / year; no increasing trend was observed over the study period. Temporal analyses revealed a seasonal incidence cycle around 12 months, with peaks in late winter/spring and troughs in autumn. Mycobacterium-avium-complex accounted for most cases (77.8%), followed by Mycobacterium ulcerans (14.4%) and Mycobacterium marinum (3.3%). Polymerase chain reaction testing had higher sensitivity than culture and microscopy for acid-fast bacilli (92.0%, 67.2% and 35.7%, respectively). The majority of lymphadenitis cases underwent surgical excision (97.2%); multiple recurrences in this group were less common in cases treated with clarithromycin and rifampicin compared with clarithromycin alone or no anti-mycobacterial drugs (0% versus 7.1%; OR:0.73). SSTI recurrences were also less common in cases treated with two anti-mycobacterial drugs compared with one or none (10.5% versus 33.3%; OR:0.23).

Conclusions

There was seasonal variation in the incidence of NTM disease, analogous to recently published observations in tuberculosis, which have been linked to seasonal variation in vitamin D. Our finding that anti-mycobacterial combination therapy was associated with a reduced risk of recurrences in patients with NTM lymphadenitis or SSTI requires further confirmation in prospective trials.     

Characterization of Acute and Chronic Hepatitis B Virus Genotypes in Canada

Objective

The prevalence and distribution of hepatitis B virus (HBV) genotypes in Canada is not known. Genotypic analysis may contribute to a better understanding of HBV strain distribution and transmission risk.

Methods

HBV surface antigen (HBsAg) positive samples of acute (n = 152) and chronic (n = 1533) HBV submitted for strain analysis or reference genotype testing between 2006 and 2012 were analyzed. The HBsAg coding region was amplified to determine the HBV genotype by INNO-LiPA assay or sequence analysis. Single and multivariate analyses were used to describe genotypes’ associations with known demographic and behavioral risk factors for 126 linked cases of acute HBV.

Results

Nine genotypes were detected (A to I), including mixed infections. Genotype C (HBV/C) dominated within chronic infections while HBV/D and A prevailed among acute HBV cases. History of incarceration and residing with a chronic HBV carrier or injection drug user were the most frequently reported risks for acute HBV infection. Over time, HBV/A increased among both acute and chronic infections, and HBV/C and HBV/D decreased among chronic infections.

Conclusion

Chronic and acute HBV genotypes in Canada differ in the relative distribution and their associations with known risk factors, suggesting different routes of transmission and clinical progression of infection.     

Molecular Epidemiology and Transmission Dynamics of Recent and Long-Term HIV-1 Infections in Rural Western Kenya

Objective

To identify unique characteristics of recent versus established HIV infections and describe sexual transmission networks, we characterized circulating HIV-1 strains from two randomly selected populations of ART-naïve participants in rural western Kenya.

Methods

Recent HIV infections were identified by the HIV-1 subtype B, E and D, immunoglobulin G capture immunoassay (IgG BED-CEIA) and BioRad avidity assays. Genotypic and phylogenetic analyses were performed on the pol gene to identify transmitted drug resistance (TDR) mutations, characterize HIV subtypes and potential transmission clusters. Factors associated with recent infection and clustering were assessed by logistic regression.

Results

Of the 320 specimens, 40 (12.5%) were concordantly identified by the two assays as recent infections. Factors independently associated with being recently infected were age ≤19 years (P = 0.001) and history of sexually transmitted infections (STIs) in the past six months (P = 0.004). HIV subtype distribution differed in recently versus chronically infected participants, with subtype A observed among 53% recent vs. 68% chronic infections (p = 0.04) and subtype D among 26% recent vs. 12% chronic infections (p = 0.012). Overall, the prevalence of primary drug resistance was 1.16%. Of the 258 sequences, 11.2% were in monophyletic clusters of between 2–4 individuals. In multivariate analysis factors associated with clustering included having recent HIV infection P = 0.043 and being from Gem region P = 0.002.

Conclusions

Recent HIV-1 infection was more frequent among 13–19 year olds compared with older age groups, underscoring the ongoing risk and susceptibility of younger persons for acquiring HIV infection. Our findings also provide evidence of sexual networks. The association of recent infections with clustering suggests that early infections may be contributing significant proportions of onward transmission highlighting the need for early diagnosis and treatment as prevention for ongoing prevention. Larger studies are needed to better understand the structure of these networks and subsequently implement and evaluate targeted interventions.     

Identifying Heat Waves in Florida: Considerations of Missing Weather Data

Background

Using current climate models, regional-scale changes for Florida over the next 100 years are predicted to include warming over terrestrial areas and very likely increases in the number of high temperature extremes. No uniform definition of a heat wave exists. Most past research on heat waves has focused on evaluating the aftermath of known heat waves, with minimal consideration of missing exposure information.

Objectives

To identify and discuss methods of handling and imputing missing weather data and how those methods can affect identified periods of extreme heat in Florida.

Methods

In addition to ignoring missing data, temporal, spatial, and spatio-temporal models are described and utilized to impute missing historical weather data from 1973 to 2012 from 43 Florida weather monitors. Calculated thresholds are used to define periods of extreme heat across Florida.

Results

Modeling of missing data and imputing missing values can affect the identified periods of extreme heat, through the missing data itself or through the computed thresholds. The differences observed are related to the amount of missingness during June, July, and August, the warmest months of the warm season (April through September).

Conclusions

Missing data considerations are important when defining periods of extreme heat. Spatio-temporal methods are recommended for data imputation. A heat wave definition that incorporates information from all monitors is advised.     

HIV screening via fourth-generation immunoassay or nucleic acid amplification test in the United States: a cost-effectiveness analysis

Background

At least 10% of the 56,000 annual new HIV infections in the United States are caused by individuals with acute HIV infection (AHI). It unknown whether the health benefits and costs of routine nucleic acid amplification testing (NAAT) are justified, given the availability of newer fourth-generation immunoassay tests.

Methods

Using a dynamic HIV transmission model instantiated with U.S. epidemiologic, demographic, and behavioral data, I estimated the number of acute infections identified, HIV infections prevented, quality-adjusted life years (QALYs) gained, and the cost-effectiveness of alternative screening strategies. I varied the target population (everyone aged 15-64, injection drug users [IDUs] and men who have sex with men [MSM], or MSM only), screening frequency (annually, or every six months), and test(s) utilized (fourth-generation immunoassay only, or immunoassay followed by pooled NAAT).

Results

Annual immunoassay testing of MSM reduces incidence by 9.5% and costs <$10,000 per QALY gained. Adding pooled NAAT identifies 410 AHI per year, prevents 9.6% of new cases, costs $92,000 per QALY gained, and remains <$100,000 per QALY gained in settings where undiagnosed HIV prevalence exceeds 4%. Screening IDUs and MSM annually with fourth-generation immunoassay reduces incidence by 13% with cost-effectiveness <$10,000 per QALY gained. Increasing the screening frequency to every six months reduces incidence by 11% (MSM only) or 16% (MSM and IDUs) and costs <$20,000 per QALY gained.

Conclusions

Pooled NAAT testing every 12 months of MSM and IDUs in the United States prevents a modest number of infections, but may be cost-effective given sufficiently high HIV prevalence levels. However, testing via fourth-generation immunoassay every six months prevents a greater number of infections, is more economically efficient, and may obviate the benefits of acute HIV screening via NAAT.     

The Intranasal Application of Zanamivir and Carrageenan Is Synergistically Active against Influenza A Virus in the Murine Model

Background

Carrageenan is a clinically proven and marketed compound for the treatment of viral upper respiratory tract infections. As infections caused by influenza virus are often accompanied by infections with other respiratory viruses the combination of a specific anti-influenza compound with the broadly active antiviral polymer has huge potential for the treatment of respiratory infections. Thus, the combination of the specific anti-influenza drug Zanamivir together with carrageenan in a formulation suitable for intranasal application was evaluated in-vitro and in-vivo.

Principal Findings

We show in-vitro that carrageenan and Zanamivir act synergistically against several influenza A virus strains (H1N1(09)pdm, H3N2, H5N1, H7N7). Moreover, we demonstrate in a lethal influenza model with a low pathogenic H7N7 virus (HA closely related to the avian influenza A(H7N9) virus) and a H1N1(09)pdm influenza virus in C57BL/6 mice that the combined use of both compounds significantly increases survival of infected animals in comparison with both mono-therapies or placebo. Remarkably, this benefit is maintained even when the treatment starts up to 72 hours post infection.

Conclusion

A nasal spray containing carrageenan and Zanamivir should therefore be tested for prevention and treatment of uncomplicated influenza in clinical trials.     

Prevalence of Non-Tuberculosis Mycobacterial Infections among Tuberculosis Suspects in Iran: Systematic Review and Meta-Analysis

Introduction

The infections due to Non-Tuberculosis Mycobacteria (NTM) are becoming an important health problem in many countries in the world. Globally, an increase in NTM infections has been reported from many countries around the world. However, limited information is available about the prevalence of NTM infections in Iran.

Material and Methods

The data of the prevalence of NTM infections were collected from databases such as PubMed, Web of science, Cochrane Library, Embase, Scopus, Iranmedex, and Scientific Information Database. Comprehensive Meta-Analysis (V2.0, Biostat) software was used to analyze the data.

Results

The meta-analyses showed that the prevalence of NTM infections was 10.2% (95% confidence interval [95% CI] 6.3-15.9) among culture-positive cases of tuberculosis (TB) in Iran. The further stratified analyses indicated that the prevalence of NTM was higher in studies that were done after year 2000. Additionally, M. simiae (43.3% [95% CI 36.8-50.0]), M. intracellucar (27.3% [95% CI 0.7-95.5]) and M. fortuitum (22.7% [95% CI 16.1-30.9]) were the most prevalent NTM species, respectively.

Discussion

The relatively high prevalence of NTM infections (10.2%) among culture positive cases for TB underlines the need for greater enforcement of infection control strategies. Establishment of appropriate diagnostic criteria and management guidelines for NTM diseases and expanding the number and quality of regional reference laboratories may facilitate more accurate action for prevention and control of NTM infections in Iran.     

CCR5 Haplotypes Influence HCV Serostatus in Caucasian Intravenous Drug Users

Background

Up to 90% HIV-1 positive intravenous drug users (IDUs) are co-infected with HCV. Although best recognized for its function as a major co-receptor for cell entry of HIV, CC chemokine receptor 5 (CCR5) has also been implicated in the pathogenesis of HCV infection. Here, we investigated whether CCR5 haplotypes influence HIV-1 and HCV seropositivity among 373 Caucasian IDUs from Estonia.

Methods

Of these IDUs, 56% and 44% were HIV and HCV seropositive, respectively, and 47% were coinfected. 500 blood donors seronegative for HIV and HCV were also evaluated. CCR5 haplotypes (HHA to HHG*2) were derived after genotyping nine CCR2–CCR5 polymorphisms. The association between CCR5 haplotypes with HIV and/or HCV seropositivity was determined using logistic regression analysis. Co-variates included in the models were length of intravenous drug use, HBV serostatus and copy number of CCL3L1, the gene encoding the most potent HIV-suppressive chemokine and ligand for CCR5.

Results

Compared to IDUs seronegative for both HCV and HIV (HCV−/HIV-), IDUs who were HCV+/HIV- and HCV+/HIV+were 92% and 82%, respectively, less likely to possess the CCR5-HHG*1 haplotype, after controlling for co-variates (P_adjusted = 1.89×10⁻⁴ and 0.003, respectively). This association was mostly due to subjects bearing the CCR5 HHE and HHG*1 haplotype pairs. Approximately 25% and<10% of HCV−/HIV- IDUs and HCV−/HIV- blood donors, respectively, possessed the HHE/HHG*1 genotype.

Conclusions

Our findings suggest that HHG*1-bearing CCR5 genotypes influence HCV seropositivity in a group of Caucasian IDUs.     

The Trypanosoma cruzi Vitamin C Dependent Peroxidase Confers Protection against Oxidative Stress but Is Not a Determinant of Virulence

Background

The neglected parasitic infection Chagas disease is rapidly becoming a globalised public health issue due to migration. There are only two anti-parasitic drugs available to treat this disease, benznidazole and nifurtimox. Thus it is important to identify and validate new drug targets in Trypanosoma cruzi, the causative agent. T. cruzi expresses an ER-localised ascorbate-dependent peroxidase (TcAPx). This parasite-specific enzyme has attracted interest from the perspective of targeted chemotherapy.

Methodology/Principal Findings

To assess the importance of TcAPx in protecting T. cruzi from oxidative stress and to determine if it is essential for virulence, we generated null mutants by targeted gene disruption. Loss of activity was associated with increased sensitivity to exogenous hydrogen peroxide, but had no effect on susceptibility to the front-line Chagas disease drug benznidazole. This suggests that increased oxidative stress in the ER does not play a significant role in its mechanism of action. Homozygous knockouts could proceed through the entire life-cycle in vitro, although they exhibited a significant decrease in their ability to infect mammalian cells. To investigate virulence, we exploited a highly sensitive bioluminescence imaging system which allows parasites to be monitored in real-time in the chronic stage of murine infections. This showed that depletion of enzyme activity had no effect on T. cruzi replication, dissemination or tissue tropism in vivo.

Conclusions/Significance

TcAPx is not essential for parasite viability within the mammalian host, does not have a significant role in establishment or maintenance of chronic infections, and should therefore not be considered a priority for drug design.     

Evaluation of Trimethoprim/Sulfamethoxazole (SXT), Minocycline,Tigecycline, Moxifloxacin,and Ceftazidime Alone and in Combinations for SXT-Susceptible and SXT-Resistant Stenotrophomonas maltophilia by In Vitro Time-Kill Experiments

Background

The optimal therapy for infections caused by Stenotrophomonas maltophilia (S. maltophilia) has not yet been established. The objective of our study was to evaluate the efficacy of trimethoprim/sulfamethoxazole (SXT), minocycline, tigecycline, moxifloxacin, levofloxacin, ticarcillin-clavulanate, polymyxin E, chloramphenicol, and ceftazidime against clinical isolated S. maltophilia strains by susceptibility testing and carried out time-kill experiments in potential antimicrobials.

Methods

The agar dilution method was used to test susceptibility of nine candidate antimicrobials, and time-killing experiments were carried out to evaluate the efficacy of SXT, minocycline, tigecycline, moxifloxacin, levofloxacin, and ceftazidime both alone and in combinations at clinically relevant antimicrobial concentrations.

Results

The susceptibility to SXT, minocycline, tigecycline, moxifloxacin, levofloxacin, ticarcillin-clavulanate, chloramphenicol, polymyxin E, and ceftazidime were 93.8%, 95.0%, 83.8%, 80.0%, 76.3%, 76.3%, 37.5%, 22.5%, and 20.0% against 80 clinical consecutively isolated strains, respectively. Minocycline and tigecycline showed consistent active against 22 SXT-resistant strains. However, resistance rates were high in the remaining antimicrobial agents against SXT-resistant strains. In time-kill experiments, there were no synergisms in most drug combinations in time-kill experiments. SXT plus moxifloxacin displayed synergism when strains with low moxifloxacin MICs. Moxifloxacin plus Minocycline and moxifloxacin plus tigecycline displayed synergism in few strains. No antagonisms were found in these combinations. Overall, compared with single drug, the drug combinations demonstrated lower bacterial concentrations. Some combinations showed bactericidal activity.

Conclusions

In S. maltophilia infections, susceptibility testing suggests that minocycline and SXT may be considered first-line therapeutic choices while tigecycline, moxifloxacin, levofloxacin, and ticarcillin-clavulanate may serve as second-line choices. Ceftazidime, colistin, and chloramphenicol show poor active against S. maltophilia. However, monotherapy is inadequate in infection management, especially in case of immunocompromised patients. Combination therapy, especially SXT plus moxifloxacin, may benefit than monotherapy in inhibiting or killing S. maltophilia.     

Bacterial Factors Associated with Lethal Outcome of Enteropathogenic Escherichia coli Infection: Genomic Case-Control Studies

Background

Typical enteropathogenic Escherichia coli (tEPEC) strains were associated with mortality in the Global Enteric Multicenter Study (GEMS). Genetic differences in tEPEC strains could underlie some of the variability in clinical outcome.

Methods

We produced draft genome sequences of all available tEPEC strains from GEMS lethal infections (LIs) and of closely matched EPEC strains from GEMS subjects with non-lethal symptomatic infections (NSIs) and asymptomatic infections (AIs) to identify gene clusters (potential protein encoding sequences sharing ≥90% nucleotide sequence identity) associated with lethality.

Results

Among 14,412 gene clusters identified, the presence or absence of 392 was associated with clinical outcome. As expected, more gene clusters were associated with LI versus AI than LI versus NSI. The gene clusters more prevalent in strains from LI than those from NSI and AI included those encoding proteins involved in O-antigen biogenesis, while clusters encoding type 3 secretion effectors EspJ and OspB were among those more prevalent in strains from non-lethal infections. One gene cluster encoding a variant of an NleG ubiquitin ligase was associated with LI versus AI, while two other nleG clusters had the opposite association. Similar associations were found for two nleG gene clusters in an additional, larger sample of NSI and AI GEMS strains.

Conclusions

Particular genes are associated with lethal tEPEC infections. Further study of these factors holds potential to unravel the mechanisms underlying severe disease and to prevent adverse outcomes.