Synergism between allergens and viruses and risk of hospital admission with asthma: case-control study

ObjectiveTo investigate the importance of sensitisation and exposure to allergens and viral infection in precipitating acute asthma in adults resulting in admission to hospital.DesignCase-control study.SettingLarge district general hospital.Participants60 patients aged 17-50 admitted to hospital over a year with acute asthma, matched with two controls: patients with stable asthma recruited from the outpatient department and patients admitted to hospital with non-respiratory conditions (inpatient controls).ResultsViruses were detected in 31 of 177 patients. The difference in the frequency of viruses detected between the groups was significant (admitted with asthma 26%, stable asthma 18%, inpatient controls 9%; P=0.04). A significantly higher proportion of patients admitted with asthma (66%) were sensitised and exposed to either mite, cat, or dog allergen than patients with stable asthma (37%) and inpatient controls (15%; P<0.001). Being sensitised and exposed to allergens was an independent associate of the group admitted to hospital (odds ratio 2.3, 95% confidence interval 1.0 to 5.4; P=0.05), whereas the combination of sensitisation, high exposure to one or more allergens, and viral detection considerably increased the risk of being admitted with asthma (8.4, 2.1 to 32.8; P=0.002).ConclusionsAllergens and viruses may act together to exacerbate asthma.

What is already known on this topic

Studies on segmental allergen challenge of the lung and experimental rhinovirus infection show synergistic effects between allergens and respiratory virus infectionNo studies have investigated an interaction between sensitisation, exposure to allergens, and virus infections in real life exacerbations of asthma

What this study adds

Allergens and viruses may act together to exacerbate asthma, indicating that domestic exposure to allergens acts synergistically with viruses in sensitised patients, increasing the risk of hospital admissionStrategies to reduce the impact of asthma exacerbations in adults should include interventions directed at both viruses and reducing exposure to allergens     

Is Antiretroviral Therapy Causing Long-Term Liver Damage? A Comparative Analysis of HIV-Mono-Infected and HIV/Hepatitis C Co-Infected Cohorts

The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in HIV-hepatitis C virus (HCV) co-infection are not well understood. Deaths from liver diseases have risen in the post-HAART era, yet some cross-sectional studies have suggested that HAART use is associated with improved fibrosis rates. In a retrospective cohort of 533 HIV mono-infected and 127 HIV/HCV co-infected patients, followed between January 1991 and July 2005 at a university-based HIV clinic, we investigated the relationship between cumulative HAART exposure and hepatic fibrosis, as measured by the aspartate aminotransferase-to-platelet ratio index (APRI). We used a novel methodological approach to estimate the dose-response relationship of the effect of HAART exposure on APRI. HAART was associated with increasing APRI over time in HIV/HCV co-infected patients suggesting that they may be experiencing cumulative hepatotoxicity from antiretrovirals. The estimated median change (95% confidence interval) in APRI per one year of HAART intake was of −0.46% (−1.61% to 0.71%) in HIV mono-infected compared to 2.54% (−1.77% to 7.03%) in HIV/HCV co-infected patients. Similar results were found when the direct effect of HAART intake since the last visit was estimated on the change in APRI. HAART use associated is with increased APRI in patients with HIV/HCV co-infection. Therefore treatment for HCV infection may be required to slow the growing epidemic of end-stage liver disease in this population.     

Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths

ObjectiveTo assess the hazards at an early phase of the growing epidemic of deaths from tobacco in China.DesignSmoking habits before 1980 (obtained from family or other informants) of 0.7 million adults who had died of neoplastic, respiratory, or vascular causes were compared with those of a reference group of 0.2 million who had died of other causes.Setting24 urban and 74 rural areas of China.SubjectsOne million people who had died during 1986-8 and whose families could be interviewed.ResultsAmong male smokers aged 35-69 there was a 51% (SE 2) excess of neoplastic deaths, a 31% (2) excess of respiratory deaths, and a 15% (2) excess of vascular deaths. All three excesses were significant (P<0.0001). Among male smokers aged ⩾70 there was a 39% (3) excess of neoplastic deaths, a 54% (2) excess of respiratory deaths, and a 6% (2) excess of vascular deaths. Fewer women smoked, but those who did had tobacco attributable risks of lung cancer and respiratory disease about the same as men. For both sexes, the lung cancer rates at ages 35-69 were about three times as great in smokers as in non-smokers, but because the rates among non-smokers in different parts of China varied widely the absolute excesses of lung cancer in smokers also varied. Of all deaths attributed to tobacco, 45% were due to chronic obstructive pulmonary disease and 15% to lung cancer; oesophageal cancer, stomach cancer, liver cancer, tuberculosis, stroke, and ischaemic heart disease each caused 5-8%. Tobacco caused about 0.6 million Chinese deaths in 1990 (0.5 million men). This will rise to 0.8 million in 2000 (0.4 million at ages 35-69) or to more if the tobacco attributed fractions increase.ConclusionsAt current age specific death rates in smokers and non-smokers one in four smokers would be killed by tobacco, but as the epidemic grows this proportion will roughly double. If current smoking uptake rates persist in China (where about two thirds of men but few women become smokers) tobacco will kill about 100 million of the 0.3 billion males now aged 0-29, with half these deaths in middle age and half in old age.

Key messages

• Of the Chinese deaths now being caused by tobacco, 45% are from chronic lung disease, 15% from lung cancer, and 5-8% from each of oesophageal cancer, stomach cancer, liver cancer, stroke, ischaemic heart disease, and tuberculosis
• Tobacco now causes 13% (and will probably eventually cause about 33%) of deaths in men but only 3% (and perhaps eventually about 1%) of deaths in women as the proportion of young women who smoke has become small
• Two thirds of men now become smokers before age 25; few give up, and about half of those who persist will be killed by tobacco in middle or old age
• If present smoking patterns continue about 100 million of the 0.3 billion Chinese males now aged 0-29 will eventually be killed by tobacco
• Tobacco caused 0.6 million deaths in 1990 and will cause at least 0.8 million in 2000 (0.7 million in men) and about 3 million a year by the middle of the century on the basis of current smoking patterns

     

Occult HCV Infection: An Unexpected Finding in a Population Unselected for Hepatic Disease

Background

Occult Hepatitis C virus (HCV) infection is a new pathological entity characterized by presence of liver disease and absence or very low levels of detectable HCV-RNA in serum. Abnormal values of liver enzymes and presence of replicative HCV-RNA in peripheral blood mononuclear cells are also observed. Aim of the study was to evaluate occult HCV occurrence in a population unselected for hepatic disease.

Methodology/Principal Findings

We chose from previous epidemiological studies three series of subjects (n = 276, age range 40–65 years) unselected for hepatic disease. These subjects were tested for the presence of HCV antibodies and HCV-RNA in plasma and in the peripheral blood mononuclear cells (PBMCs) by using commercial systems. All subjects tested negative for HCV antibodies and plasma HCV-RNA and showed normal levels of liver enzymes; 9/276 patients (3.3%) were positive for HCV-RNA in PBMCs, identifying a subset of subjects with potential occult HCV infection. We could determine the HCV type for 8 of the 9 patients finding type 1a (3 patients), type 1b (2 patients), and type 2a (3 patients).

Conclusions

The results of this study show evidence that occult HCV infection may occur in a population unselected for hepatic disease. A potential risk of HCV infection spread by subjects harbouring occult HCV infection should be considered. Design of prospective studies focusing on the frequency of infection in the general population and on the clinical evolution of occult HCV infection will be needed to verify this unexpected finding.     

A cognitive behavioural intervention to reduce sexually transmitted infections among gay men: randomised trial

ObjectiveTo determine the effectiveness of a brief cognitive behavioural intervention in reducing the incidence of sexually transmitted infections among gay men.DesignRandomised controlled trial with 12 months'' follow up.SettingSexual health clinic in London.Participants343 gay men with an acute sexually transmitted infection or who reported having had unprotected anal intercourse in the past year.Results72% (361/499) of men invited to enter the study did so. 90% (308/343) of participants returned at least one follow up questionnaire or re-attended the clinic and requested a check up for sexually transmitted infections during follow up. At baseline, 37% (63/172) of the intervention group and 30% (50/166) of the control group reported having had unprotected anal intercourse in the past month. At 12 months, the proportions were 27% (31/114) and 32% ( 39/124) respectively (P=0.56). However, 31% (38/123) of the intervention group and 21% (35/168) of controls had had at least one new infection diagnosed at the clinic (adjusted odds ratio 1.66, 95% confidence interval 1.00 to 2.74). Considering only men who requested a check up for sexually transmitted infections, the proportion diagnosed with a new infection was 58% (53/91) for men in the intervention group and 43% (35/81) for men in the control group (adjusted odds ratio 1.84, 0.99 to 3.40). Using a regional database that includes information from 23 sexual health clinics in London, we determined that few participants had attended other sexual health clinics.ConclusionsThis behavioural intervention was acceptable and feasible to deliver, but it did not reduce the risk of acquiring a new sexually transmitted infection among these gay men at high risk. Even carefully designed interventions should not be assumed to bring benefit. It is important to evaluate their effects in randomised trials with objective clinical end points.

What is already known on this topic

The need for effective HIV prevention strategies based on reducing sexual risk behaviour remains importantFew interventions to reduce sexual risk behaviour have been rigorously evaluated using randomised controlled trials

What this study adds

This is the first randomised controlled trial of an intervention addressing sexual behaviour in homosexual men that uses sexually transmitted infections and self reported behaviour as end pointsThe intervention was brief and feasible to use in a busy clinic, but it did not reduce the risk of participants acquiring new infectionsThe potential for behavioural interventions to do more harm than good needs to be taken seriously     

Ferritin and liver fibrosis among patients with chronic hepatitis C virus infection

IntroductionIn chronic hepatitis C virus (HCV) infection there is increased iron absorption leading to iron overload, a fact that may promote ferritin synthesis. Theoretically, increased ferritin should promote ongoing liver fibrosis but disparate results have been described.ObjectiveWe analyze the behavior of iron metabolism- related variables, comparing them with fibrosis and inflammatory activity in liver biopsy in HCV infected patients.Patients and MethodsWe analyzed among 90 HCV patients subjected to liver biopsy prior to antiviral treatment the relationships of serum levels of iron, ferritin, transferrin, transferrin saturation index (TSI) and total iron binding capacity (TIBC) with liver fibrosis and histological severity, assessed by Metavir-f, Metavir-a and Knodell indices, as well as with liver function, and also compared the aforementioned iron metabolism- related variables with 34 controls.ResultsPatients showed higher values of sideremia (T = 2.04; p = 0.044) and transferrin (T = 2.29; p = 0.004) compared with controls; but not ferritin, that was significantly higher among the 33 patients who also consumed alcohol (Z = 2.05; p = 0.041). Most patients showed a well preserved liver function (86 cases, Child A). Patients with Child B or C showed higher ferritin levels (Z = 2.68; p = 0.007) and TSI (Z = 2.41; p = 0.016), but lower transferrin and TIBC (Z = 3.25; p = 0.001) than Child A patients. Transferrin and TIBC were directly related to albumin (ρ = 0.24; p = 0.026), whereas bilirubin showed direct relationships with iron (ρ = 0.25; p = 0.016), TSI (ρ = 0.39; p < 0.001) and ferritin (ρ = 0.36; p < 0.001). Both ferritin (ρ = −0.22; p = 0.04) and TSI (ρ = −0.25; p = 0.016) were related to platelet count. No relationships were observed between iron variables and Knodell index, but serum iron, serum transferrin, and TSI were directly related to Metavir-f score (ρ = 0.28; p = 0.009, ρ = 0.22; p = 0.044, and ρ = 0.22; p = 0.044, in this order).ConclusionAlterations of iron related variables are relatively subtle in our series of 90 well compensated HCV patients. Serum ferritin was not related to liver fibrosis and increases only when alcoholism co-exists with HCV infection.     

Where does blood go? Prospective observational study of red cell transfusion in north England

ObjectiveTo collect population based information on transfusion of red blood cells.DesignProspective observational study over 28 days.SettingHospital blood banks in the north of England (population 2.9 million).ParticipantsAll patients who received a red cell transfusion during the study period. Data completed by hospital blood bank staff.ResultsThe destination of 9848 units was recorded (97% of expected blood use). In total 9774 units were transfused: 5047 (51.6%) units were given to medical patients, 3982 (40.7%) to surgical patients, and 612 (6.3%) to obstetric and gynaecology patients. Nearly half (49.3%) of all blood is given to female recipients, and the mean age of recipients of individual units was 62.7 years. The most common surgical indications for transfusion were total hip replacement (4.6% of all blood transfused) and coronary artery bypass grafting (4.1%). Haematological disorders accounted for 15.5% of use. Overall use was 4274 units per 100 000 population per year.ConclusionIn the north east of England more than half of red cell units are transfused for medical indications. Demand for red cell transfusion increases with age. With anticipated changes in the age structure of the population the demand for blood will increase by 4.9% by 2008.

What is already known on this topic

There have been no systematic population based surveys on use of red cells in the United KingdomStudies in France and the United States have shown that more than half of transfused red cells go to surgical patients

What this study adds

In the north of England over half of red cells are given for medical indicationsRates of red cell transfusion rise steeply with advancing ageSmall increases in the number of elderly people will have large effects on demand     

Effect of preoperative abstinence on poor postoperative outcome in alcohol misusers: randomised controlled trial

ObjectiveTo evaluate the influence of preoperative abstinence on postoperative outcome in alcohol misusers with no symptoms who were drinking the equivalent of at least 60 g ethanol/day. DesignRandomised controlled trial.SettingCopenhagen, Denmark.Subjects42 alcoholic patients without liver disease admitted for elective colorectal surgery.InterventionsWithdrawal from alcohol consumption for 1 month before operation (disulfiram controlled) compared with continuous drinking.ResultsThe intervention group developed significantly fewer postoperative complications than the continuous drinkers (31% v 74%, P=0.02). Delayed type hypersensitivity responses were better in the intervention group before (37 mm² v 12 mm², P=0.04), but not after surgery (3 mm² v 3 mm²). Development of postoperative myocardial ischaemia (23% v 85%) and arrhythmias (33% v 86%) on the second postoperative day as well as nightly hypoxaemic episodes (4 v 18 on the second postoperative night) occurred significantly less often in the intervention group. Surgical stress responses were lower in the intervention group (P⩽0.05).ConclusionsOne month of preoperative abstinence reduces postoperative morbidity in alcohol abusers. The mechanism is probably reduced preclinical organ dysfunction and reduction of the exaggerated response to surgical stress.

Key messages

• Recent data have shown alcohol misusers to have a threefold increase in postoperative morbidity
• In misusers recovery from organ dysfunction induced by alcohol is seen after abstinence
• Abstinence from alcohol for 1 month before surgery reduces postoperative morbidity after colorectal surgery
• Mechanisms may involve reduced responses to surgical stress and improved cardiac and immune dysfunction
• Withdrawal from alcohol before an operation is recommended in alcohol abusers

     

Effect of delays in primary care referral on survival of women with epithelial ovarian cancer: retrospective audit

ObjectiveTo examine referral pathways from primary care for patients with epithelial ovarian cancer and to identify factors related to survival at 18 months.DesignRetrospective review of patient notes.SettingGeneral practices and receiving hospitals within Mersey region.Subjects135 patients with epithelial ovarian cancer identified from an audit in the Mersey area between 1992 and 1994.Results105 (78%) women first presented to their general practitioner within four weeks of the onset of symptoms. 99 (73%) women were referred to hospital by their general practitioners within four weeks of presentation, and 95 (70%) were seen in hospital within two weeks of referral. Multivariate analysis with survival as the dependent variable identified age (odds ratio 0.96, 95% confidence interval 0.93 to 0.99) cancer stage III or more (0.15, 0.05 to 0.43), and non-specific symptoms (0.36, 0.14 to 0.89) as significant variables.ConclusionMost patients attended their general practitioner within four weeks and were referred within two weeks. No evidence was found that delays in referral or diagnosis adversely affected survival at 18 months. Stage of disease at surgery was the most important adverse factor. An effective screening programme is the most likely method to improve survival.

What is already known on this topic

Epithelial ovarian cancer is the most common gynaecological cancer in the United Kingdom75% of patients present with advanced incurable disease, and five year survival is 30%The Department of Health recommends that everyone suspected of having ovarian cancer should be seen within two weeks of referral by their general practitioner

What this study adds

78% of patients have had symptoms for less than 4 weeks when they present to general practice and are referred to hospital within four weeks of presentation70% of patients are seen in hospital within two weeks of the referralDelay by patients and general practitioners does not affect survival beyond 18 months     

High plasma fractalkine (CX3CL1) levels are associated with severe liver disease in HIV/HCV co-infected patients with HCV genotype 1

BackgroundInappropriate persistence of chemokines expression in hepatitis C virus (HCV) infection can drive tissue damage, intrahepatic inflammation, and liver cell injury. The aim of study was to study the association of plasma fractalkine (CX3CL1) levels with fibrosis stage and necroinflammatory activity grade of liver biopsies in human immunodeficiency virus (HIV)/HCV co-infected patients with HCV genotype 1.MethodsWe carried out a cross-sectional study on 125 patients. Grading and staging of liver biopsies were carried out by METAVIR score. Plasma CX3CL1 was measured using an immunoassay kit.ResultsPatients with advanced fibrosis had higher CX3CL1 levels than those with mild or no fibrosis (p = 0.010); and patients with severe activity grade had higher CX3CL1 levels than those with low activity grade (p = 0.040). Plasma CX3CL1 levels were significantly associated with increased odds of significant fibrosis (odds ratio (OR): 3.47 (95% of confidence interval (95%CI): 1.04; 11.58)), advanced fibrosis (OR: 6.78 (95%CI: 1.70; 26.93)), and moderate necroinflammatory activity grade (OR: 4.09 (95%CI: 1.21; 13.87)). When we analyzed fibrosis stages and activity grades of METAVIR score together, we found a positive significant association of CX3CL1 levels with moderate activity grade/significant fibrosis (OR: 5.49 (95%CI: 1.46; 20.58)) and moderate activity grade/advanced fibrosis (OR: 8.99 (95%CI: 2.06; 39.23)).ConclusionPlasma CX3CL1 levels were independently associated with several characteristics of severe liver disease in HIV/HCV coinfected patients with HCV-genotype 1, suggesting a role of CX3CL1 in the pathogenesis of HCV infection.     

Whey Fermentation by Anaerobiospirillum succiniciproducens for Production of a Succinate-Based Animal Feed Additive

Anaerobic fermentation processes for the production of a succinate-rich animal feed supplement from raw whey were investigated with batch, continuous, and variable-volume fed-batch cultures with Anaerobiospirillum succiniciproducens. The highest succinate yield, 90%, was obtained in a variable-volume fed-batch process in comparison to 80% yield in a batch cultivation mode. In continuous culture, succinate productivity was 3 g/liter/h, and the yield was 60%. Under conditions of excess CO₂, more than 90% of the whey-lactose was consumed, with an end product ratio of 4 succinate to 1 acetate. Under conditions of limited CO₂, lactose was only partially consumed and lactate was the major end product, with lower levels of ethanol, succinate, and acetate. When the succinic acid in this fermentation product was added to rumen fluid, it was completely consumed by a mixed rumen population and was 90% decarboxylated to propionate on a molar basis. The whey fermentation product formed under excess CO₂, which contained mainly organic acids and cells, could potentially be used as an animal feed supplement.     

Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study

AimTo study the risk of renal stone episodes and risk factors for renal stones in primary hyperparathyroidism before and after surgery.DesignRegister based, controlled retrospective follow up study.SettingTertiary hospitals in Denmark.Participants674 consecutive patients with surgically verified primary hyperparathyroidism. Each patient was compared with three age- and sex-matched controls randomly drawn from the background population. Hospital admissions for renal stone disease were compared between patients and controls. Risk factors for renal stones among patients were assessed.ResultsRelative risk of a stone episode was 40 (95% confidence interval 31 to 53) before surgery and 16 (12 to 23) after surgery. Risk was increased 10 years before surgery, and became normal more than 10 years after surgery. Stone-free survival 20 years after surgery was 90.4% in patients and 98.7% in controls (risk difference 8.3%, 4.8% to 11.7%). Patients with preoperative stones had 27 times the risk of postoperative stone incidents than controls. Before surgery, males had more stone episodes than females and younger patients had more stone episodes than older patients. Neither parathyroid pathology, weight of removed tissue, plasma calcium levels, nor skeletal pathology (fractures) influenced the risk of renal stones. After surgery, younger age, preoperative stones and ureteral strictures were significant risk factors for stones.ConclusionsThe risk of renal stones is increased in primary hyperparathyroidism and decreases after surgery. The risk profile is normal 10 years after surgery. Preoperative stone events increase the risk of postoperative stones. Stone formers and non-stone formers had the same risk of skeletal complications.

What is already known on this topic

Patients with primary hyperparathyroidism have an increased risk of renal stone eventsThe extent to which parathyroid surgery reduces the risk of further stones is unclear

What this study adds

The risk of a new stone event was 8.3% higher in patients than in controls after surgeryIn patients with stone disease before operation the risk rate for a postoperative stone event was 27times that in controlsThe risk of a renal stone event was higher than the risk among controls until more than 10 years after surgery     

A Crucial Role for Kupffer Cell-Derived Galectin-9 in Regulation of T Cell Immunity in Hepatitis C Infection

Approximately 200 million people throughout the world are infected with hepatitis C virus (HCV). One of the most striking features of HCV infection is its high propensity to establish persistence (∼70–80%) and progressive liver injury. Galectins are evolutionarily conserved glycan-binding proteins with diverse roles in innate and adaptive immune responses. Here, we demonstrate that galectin-9, the natural ligand for the T cell immunoglobulin domain and mucin domain protein 3 (Tim-3), circulates at very high levels in the serum and its hepatic expression (particularly on Kupffer cells) is significantly increased in patients with chronic HCV as compared to normal controls. Galectin-9 production from monocytes and macrophages is induced by IFN-γ, which has been shown to be elevated in chronic HCV infection. In turn, galectin-9 induces pro-inflammatory cytokines in liver-derived and peripheral mononuclear cells; galectin-9 also induces anti-inflammatory cytokines from peripheral but not hepatic mononuclear cells. Galectin-9 results in expansion of CD4⁺CD25⁺FoxP3⁺CD127^low regulatory T cells, contraction of CD4⁺ effector T cells, and apoptosis of HCV-specific CTLs. In conclusion, galectin-9 production by Kupffer cells links the innate and adaptive immune response, providing a potential novel immunotherapeutic target in this common viral infection.     

IL-1β Production through the NLRP3 Inflammasome by Hepatic Macrophages Links Hepatitis C Virus Infection with Liver Inflammation and Disease

Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease. Liver inflammation underlies infection-induced fibrosis, cirrhosis and liver cancer but the processes that promote hepatic inflammation by HCV are not defined. We provide a systems biology analysis with multiple lines of evidence to indicate that interleukin-1β (IL-1β) production by intrahepatic macrophages confers liver inflammation through HCV-induced inflammasome signaling. Chronic hepatitis C patients exhibited elevated levels of serum IL-1β compared to healthy controls. Immunohistochemical analysis of healthy control and chronic hepatitis C liver sections revealed that Kupffer cells, resident hepatic macrophages, are the primary cellular source of hepatic IL-1β during HCV infection. Accordingly, we found that both blood monocyte-derived primary human macrophages, and Kupffer cells recovered from normal donor liver, produce IL-1β after HCV exposure. Using the THP-1 macrophage cell-culture model, we found that HCV drives a rapid but transient caspase-1 activation to stimulate IL-1β secretion. HCV can enter macrophages through non-CD81 mediated phagocytic uptake that is independent of productive infection. Viral RNA triggers MyD88-mediated TLR7 signaling to induce IL-1β mRNA expression. HCV uptake concomitantly induces a potassium efflux that activates the NLRP3 inflammasome for IL-1β processing and secretion. RNA sequencing analysis comparing THP1 cells and chronic hepatitis C patient liver demonstrates that viral engagement of the NLRP3 inflammasome stimulates IL-1β production to drive proinflammatory cytokine, chemokine, and immune-regulatory gene expression networks linked with HCV disease severity. These studies identify intrahepatic IL-1β production as a central feature of liver inflammation during HCV infection. Thus, strategies to suppress NLRP3 or IL-1β activity could offer therapeutic actions to reduce hepatic inflammation and mitigate disease.     

Assessing the Long-Term Impact of Treating Hepatitis C Virus (HCV)-Infected People Who Inject Drugs in the UK and the Relationship between Treatment Uptake and Efficacy on Future Infections

ObjectiveThe prevalence of the hepatitis C virus (HCV) remains high amongst people who inject drugs (PWID) and accounts for the majority of newly acquired infections. This study aims to quantify the value of treatment amongst PWID with more efficacious treatments and at increased uptake rates, with respect to the avoidance of future infections and subsequent long-term complications of HCV.MethodsA dynamic HCV transmission and disease progression model was developed, incorporating acute and chronic infection and their long-term complications (decompensated cirrhosis, cancer, liver transplant and mortality), with the potential for HCV transmission to other PWID prior to successful treatment. The model was populated with prevalence and therapy data from a UK setting. Scenarios of current standard of care (SoC) treatment efficacy and uptake were compared to anticipated sustained virologic response (SVR) rates of 90–100% and increased uptake over varied horizons.ResultsSoC led to modest reductions in prevalence; >5% after 200 years. New treatments achieving 90% SVR could reduce prevalence below 5% within 60 years at current uptake rates or within 5 years if all patients are treated. Amongst 4,240 PWID, chronic HCV infections avoided as a result of increasing treatment uptake over the period 2015–2027 ranged from 20–580 and 34–912 with SoC and 90% SVR rates respectively. The reduction in downstream HCV infections due to increasing treatment uptake resulted in an approximate discounted gain of 300 life-years (from avoiding reduced life expectancy from HCV infection) and a gain of 1,700 QALYs (from avoiding the disutility of HCV infection and related complications), with a projected £5.4 million cost saving.ConclusionWhile improved SVR profiles led to reductions in modelled prevalence, increased treatment uptake was the key driver of future infections avoided. Increased treatment among PWID with new more efficacious therapies could significantly change the future dynamics, cost and health burden of HCV-related disease.     

Evolution of Hepatitis C Virus Quasispecies in Hypervariable Region 1 and the Putative Interferon Sensitivity-Determining Region during Interferon Therapy and Natural Infection

To study hepatitis C virus (HCV) genetic mutation during interferon (IFN) therapy, the temporal changes in HCV quasispecies heterogeneity were compared before and after treatment for nine patients infected with HCV genotype 1, including four nonresponders, four responders who relapsed after therapy, and one responder who experienced a breakthrough of viremia during therapy. Nine untreated patients with an average time between specimens of 8.4 years served as controls. Sequences from the second envelope glycoprotein gene hypervariable region 1 (HVR1) and the putative IFN sensitivity-determining region (ISDR) of the nonstructural NS5A gene were analyzed by heteroduplex mobility assays and nucleotide sequencing. A strong positive correlation was found between the percent change in a heteroduplex mobility ratio (HMR) and percent change in nucleotide sequence (r = 0.941, P < 0.001). The rate of fixation of mutations in the HVR1 was significantly higher for IFN-treated patients than for controls (6.97 versus 1.31% change in HMR/year; P = 0.02). Similarly, a higher rate of fixation of mutations was observed in the ISDR for IFN-treated patients than for untreated controls, although the result was not significant (1.45 versus 0.15 amino acid changes/year; P = 0.12). On an individual patient basis, IFN therapy was associated with measurable HVR1 and ISDR mutation in nine of nine (100%) and two of nine (22.2%) patients, respectively. Evolution to IFN-resistant ISDR sequences was observed in only one of nine IFN-treated patients. These data suggest that IFN therapy frequently exerts pressure on the HCV envelope region, while pressure on the ISDR was evident in only a subset of patients. Thus, the selection pressures evoked on HCV genotype 1 quasispecies during IFN therapy appear to differ among different patients.     

National Trend and Characteristics of Acute Hepatitis C among HIV-Infected Individuals: A Matched Case-Control Study—Taiwan, 2001–2014

BackgroundHepatitis C virus (HCV) infection has been increasingly recognized among HIV-infected men who have sex with men (MSM) worldwide. We investigated the trend of and factors associated with acute hepatitis C (AHC) among HIV-infected individuals in Taiwan.MethodsThe National Disease Surveillance System collects characteristics of AHC, HIV, syphilis, and gonorrhea cases through mandatory reports and patient interviews. Reported AHC patients in 2014 were interviewed additionally on sexual and parenteral exposures. Information on HCV genotypes were collected from the largest medical center serving HIV-infected Taiwanese. We defined an HIV/AHC case as a documented negative HCV antibody test result followed within 12 months by a positive test in a previously reported HIV-infected individual. Each case was matched to two HIV-infected, non-AHC controls for age, age of HIV diagnosis, sex, transmission route, HIV diagnosis date, and county/city. Conditional logistic regression was used to identify associated characteristics.ResultsDuring 2001–2014, 93 of 6,624 AHC reports were HIV/AHC cases; the annual case count increased from one in 2009 to 34 in 2014. All were males (81 [87%] MSM) aged 21–49 years with AHC diagnosed 2–5,923 days after HIV diagnoses. Sixty-eight (73%) lived in the Taipei metropolitan area. Detected HCV genotypes were 2a (n = 6), 1b (n = 5), 1b + 2a (n = 1) and 2b (n = 1). Among 28 HIV/AHC patients interviewed in 2014, 13 (46%) reported engaging in unprotected sex ≤3 months before AHC diagnosis. Seventy-nine HIV/AHC cases were matched to 158 controls. HIV/AHC was associated with recent syphilis (adjusted odds ratio [aOR], 10.9; 95% confidence interval [CI], 4.2–28.6) and last syphilis >6 months (aOR, 2.9; 95% CI, 1.2–6.9).ConclusionsHIV/AHC cases continued to increase particularly among sexually active HIV-infected MSM with a syphilis diagnosis in northern Taiwan. We recommend surveillance of associated behavioral and virologic characteristics and HCV counseling and testing for HIV-infected men in Taiwan.     

HCV Coinfection Associated with Slower Disease Progression in HIV-Infected Former Plasma Donors Na?ve to ART

Background

It remains controversial how HCV coinfection influences the disease progression during HIV-1 infection. This study aims to define the influence of HCV infection on the replication of HIV-1 and the disease progression in HIV-infected former plasma donors (FPDs) naïve to ART.

Methodology/Principal Findings

168 HIV-1-infected FPDs were enrolled into a cohort study from Anhui province in central China, and thereafter monitored at month 3, 9, 15, 21 and 33. Fresh whole blood samples were used for CD4+ T-cell counting. Their plasma samples were collected and stored for quantification of HIV-1 viral loads and for determination of HCV and Toxoplasma. Out of 168 HIV-infected FBDs, 11.9% (20 cases), 80.4% (135 cases) and 7.7% (13 cases) were infected with HIV-1 alone, HIV-1/HCV and HIV/HCV/Toxoplasma, respectively. During the 33-month follow-up, only 35% (7 out of 20 cases) HIV-1 mono-infected subjects remained their CD4+ T-cell counts above 200 cells/µl and retained on the cohort study, which was significantly lower than 56% (75 out of 135 cases) for HIV/HCV group and 69% (9 out of 13 cases) for HIV/HCV/Toxoplasma group (p<0.05). CD4+ T cells in HIV mono infection group were consistently lower than that in HIV/HCV group (p = 0.04, 0.18, 0.03 and 0.04 for baseline, month 9, month 21 and month 33 visit, respectively). In accordance with those observations, HIV viral loads in HIV mono-infection group were consistently higher than that in HIV/HCV group though statistical significances were only reached at baseline (p = 0.04).

Conclusions/Significance

These data indicated HCV coinfection with HIV-1 is associated with the slower disease progression at the very late stage when comparing with HIV-1 mono-infection. The coinfection of Toxoplasma with HIV and HCV did not exert additional influence on the disease progression. It will be highly interesting to further explore the underlying mechanism for this observation in the future.     

Influence of Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Interleukin 10 Genes on the Risk of Liver Cirrhosis in HIV-HCV Coinfected Patients

Objective

Analysis of the contribution of genetic (single nucleotide polymorphisms (SNP) at position -238 and -308 of the tumor necrosis factor alpha (TNF-α) and -592 of the interleukin-10 (IL-10) promotor genes) and of classical factors (age, alcohol, immunodepression, antirretroviral therapy) on the risk of liver cirrhosis in human immunodeficiency (HIV)-hepatitis C (HCV) virus coinfected patients.

Patients and Methods

Ninety one HIV-HCV coinfected patients (50 of them with chronic hepatitis and 41 with liver cirrhosis) and 55 healthy controls were studied. Demographic, risk factors for the HIV-HCV infection, HIV-related (CD4+ T cell count, antiretroviral therapy, HIV viral load) and HCV-related (serum ALT concentration, HCV viral load, HCV genotype) characteristics and polymorphisms at position -238 and -308 of the tumor necrosis factor alfa (TNF- α) and -592 of the interleukin-10 (IL-10) promotor genes were studied.

Results

Evolution time of the infection was 21 years in both patients’ groups (chronic hepatitis and liver cirrhosis). The group of patients with liver cirrhosis shows a lower CD4+ T cell count at the inclusion in the study (but not at diagnosis of HIV infection), a higher percentage of individuals with previous alcohol abuse, and a higher proportion of patients with the genotype GG at position -238 of the TNF-α promotor gene; polymorphism at -592 of the IL-10 promotor gene approaches to statistical significance. Serum concentrations of profibrogenic transforming growth factor beta1 were significantly higher in healthy controls with genotype GG at -238 TNF-α promotor gene. The linear regression analysis demonstrates that the genotype GG at -238 TNF-α promotor gene was the independent factor associated to liver cirrhosis.

Conclusion

It is stressed the importance of immunogenetic factors (TNF-α polymorphism at -238 position), above other factors previously accepted (age, gender, alcohol, immunodepression), on the evolution to liver cirrhosis among HIV-infected patients with established chronic HCV infections.     

Population-Based Surveillance for Invasive Pneumococcal Disease in Homeless Adults in Toronto

Background

Identification of high-risk populations for serious infection due to S. pneumoniae will permit appropriately targeted prevention programs.

Methods

We conducted prospective, population-based surveillance for invasive pneumococcal disease and laboratory confirmed pneumococcal pneumonia in homeless adults in Toronto, a Canadian city with a total population of 2.5 M, from January 1, 2002 to December 31, 2006.

Results

We identified 69 cases of invasive pneumococcal disease and 27 cases of laboratory confirmed pneumococcal pneumonia in an estimated population of 5050 homeless adults. The incidence of invasive pneumococcal disease in homeless adults was 273 infections per 100,000 persons per year, compared to 9 per 100,000 persons per year in the general adult population. Homeless persons with invasive pneumococcal disease were younger than other adults (median age 46 years vs 67 years, P<.001), and more likely than other adults to be smokers (95% vs. 31%, P<.001), to abuse alcohol (62% vs 15%, P<.001), and to use intravenous drugs (42% vs 4%, P<.001). Relative to age matched controls, they were more likely to have underlying lung disease (12/69, 17% vs 17/272, 6%, P = .006), but not more likely to be HIV infected (17/69, 25% vs 58/282, 21%, P = .73). The proportion of patients with recurrent disease was five fold higher for homeless than other adults (7/58, 12% vs. 24/943, 2.5%, P<.001). In homeless adults, 28 (32%) of pneumococcal isolates were of serotypes included in the 7-valent conjugate vaccine, 42 (48%) of serotypes included in the 13-valent conjugate vaccine, and 72 (83%) of serotypes included in the 23-valent polysaccharide vaccine. Although no outbreaks of disease were identified in shelters, there was evidence of clustering of serotypes suggestive of transmission of pathogenic strains within the homeless population.

Conclusions

Homeless persons are at high risk of serious pneumococcal infection. Vaccination, physical structure changes or other program to reduce transmission in shelters, harm reduction programs to reduce rates of smoking, alcohol abuse and infection with bloodborne pathogens, and improved treatment programs for HIV infection may all be effective in reducing the risk.