Bridging the data gaps in the epidemiology of hepatitis C virus infection in Malaysia using multi-parameter evidence synthesis

BACKGROUND: Collecting adequate information on key epidemiological indicators is a prerequisite to informing a public health response to reduce the impact of hepatitis C virus (HCV) infection in Malaysia. Our goal was to overcome the acute data shortage typical of low/middle income countries using statistical modelling to estimate the national HCV prevalence and the distribution over transmission pathways as of the end of 2009. METHODS: Multi-parameter evidence synthesis methods were applied to combine all available relevant data sources - both direct and indirect - that inform the epidemiological parameters of interest. RESULTS: An estimated 454,000 (95% credible interval [CrI]: 392,000 to 535,000) HCV antibody-positive individuals were living in Malaysia in 2009; this represents 2.5% (95% CrI: 2.2-3.0%) of the population aged 15-64 years. Among males of Malay ethnicity, for 77% (95% CrI: 69-85%) the route of probable transmission was active or a previous history of injecting drugs. The corresponding proportions were smaller for male Chinese and Indian/other ethnic groups (40% and 71%, respectively). The estimated prevalence in females of all ethnicities was 1% (95% CrI: 0.6 to 1.4%); 92% (95% CrI: 88 to 95%) of infections were attributable to non-drug injecting routes of transmission. CONCLUSIONS: The prevalent number of persons living with HCV infection in Malaysia is estimated to be very high. Low/middle income countries often lack a comprehensive evidence base; however, evidence synthesis methods can assist in filling the data gaps required for the development of effective policy to address the future public health and economic burden due to HCV. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12879-014-0564-6) contains supplementary material, which is available to authorized users

Projections of the current and future disease burden of hepatitis C virus infection in Malaysia

The prevalence of hepatitis C virus (HCV) infection in Malaysia has been estimated at 2.5% of the adult population. Our objective, satisfying one of the directives of the WHO Framework for Global Action on Viral Hepatitis, was to forecast the HCV disease burden in Malaysia using modelling methods.An age-structured multi-state Markov model was developed to simulate the natural history of HCV infection. We tested three historical incidence scenarios that would give rise to the estimated prevalence in 2009, and calculated the incidence of cirrhosis, end-stage liver disease, and death, and disability-adjusted life-years (DALYs) under each scenario, to the year 2039. In the baseline scenario, current antiviral treatment levels were extended from 2014 to the end of the simulation period. To estimate the disease burden averted under current sustained virological response rates and treatment levels, the baseline scenario was compared to a counterfactual scenario in which no past or future treatment is assumed.In the baseline scenario, the projected disease burden for the year 2039 is 94,900 DALYs/year (95% credible interval (CrI): 77,100 to 124,500), with 2,002 (95% CrI: 1340 to 3040) and 540 (95% CrI: 251 to 1,030) individuals predicted to develop decompensated cirrhosis and hepatocellular carcinoma, respectively, in that year. Although current treatment practice is estimated to avert a cumulative total of 2,200 deaths from DC or HCC, a cumulative total of 63,900 HCV-related deaths is projected by 2039.The HCV-related disease burden is already high and is forecast to rise steeply over the coming decades under current levels of antiviral treatment. Increased governmental resources to improve HCV screening and treatment rates and to reduce transmission are essential to address the high projected HCV disease burden in Malaysia

High Rates of Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection in People Who Inject Drugs: A Prospective Cohort Study

Hepatitis C virus reinfection and spontaneous clearance of reinfection were examined in a highly characterisedcohort of 188 people who inject drugs over a five-year period. Nine confirmed reinfections and 17 possiblereinfections were identified (confirmed reinfections were those genetically distinct from the previous infection andpossible reinfections were used to define instances where genetic differences between infections could not beassessed due to lack of availability of hepatitis C virus sequence data). The incidence of confirmed reinfection was28.8 per 100 person-years (PY), 95%CI: 15.0-55.4; the combined incidence of confirmed and possible reinfectionwas 24.6 per 100 PY (95%CI: 16.8-36.1). The hazard of hepatitis C reinfection was approximately double that ofprimary hepatitis C infection; it did not reach statistical significance in confirmed reinfections alone (hazard ratio [HR]:2.45, 95%CI: 0.87-6.86, p=0.089), but did in confirmed and possible hepatitis C reinfections combined (HR: 1.93,95%CI: 1.01-3.69, p=0.047) and after adjustment for the number of recent injecting partners and duration of injecting.In multivariable analysis, shorter duration of injection (HR: 0.91; 95%CI: 0.83-0.98; p=0.019) and multiple recentinjecting partners (HR: 3.12; 95%CI: 1.08-9.00, p=0.035) were independent predictors of possible and confirmedreinfection. Time to spontaneous clearance was shorter in confirmed reinfection (HR: 5.34, 95%CI: 1.67-17.03,p=0.005) and confirmed and possible reinfection (HR: 3.10, 95%CI: 1.10-8.76, p-value=0.033) than primary infection.Nonetheless, 50% of confirmed reinfections and 41% of confirmed or possible reinfections did not spontaneouslyclear.Conclusions: Hepatitis C reinfection and spontaneous clearance of hepatitis C reinfection were observed at highrates, suggesting partial acquired natural immunity to hepatitis C virus. Public health campaigns about the risks ofhepatitis C reinfection are required

Reasons for compliance or noncompliance with advice to test for hepatitis C via an internet-mediated blood screening service: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Hepatitis C virus (HCV) is mainly transmitted by exposure to infected blood, and can lead to liver cirrhosis and liver cancer. Since the onset of HCV and the development of liver cirrhosis usually are asymptomatic, many HCV-infected individuals are still undiagnosed. To identify individuals infected with HCV in the general population, a low threshold, internet-mediated blood testing service was set up. We performed a qualitative study examining reasons for compliance and noncompliance with advice to test for HCV via the online blood testing service.</p> <p>Methods</p> <p>Semistructured telephone interviews were conducted with 33 website visitors who had been advised to test for HCV (18 testers, 15 non-testers). Transcribed interviews were analyzed qualitatively and interpreted using psychosocial theories of health behavior.</p> <p>Results</p> <p>Reasons for testing pertaining to the online service were: the testing procedure is autonomous, personalized test advice is provided online, reminder emails are sent, and there is an online planning tool. Reasons for testing not specific to the online service were: knowing one's status can prevent liver disease and further transmission of HCV, HCV is curable, testing can provide reassurance, physical complaints are present, and there is liver disease in one's social environment. Service-related reasons for not testing pertained to inconvenient testing facilities, a lack of commitment due to the low threshold character of the service, computer/printing problems, and incorrectly interpreting an online planning tool. The reasons for not testing that are not specific to the online service were: the belief that personal risk is low, the absence of symptoms, low perceived urgency for testing and treatment, fear of the consequences of a positive test result, avoiding threatening information, and a discouraging social environment.</p> <p>Conclusions</p> <p>Features specific to the online service played a significant role in motivation to test for HCV above and beyond the more conventional perceived health benefits of HCV testing. However, some online specific features were considered problematic and need to be adapted. Methods and strategies for dealing with these impeding factors and for improving compliance with testing via the online service are outlined.</p

Treatment of Hepatitis C as Prevention: A Modeling Case Study in Vietnam

Background: Treatment of hepatitis C (HCV) is very effective, achieving a cure in 50–90 % of patients. Besides its own good for individuals, this most likely translates in reduced transmission, but this phenomenon has yet to be fully explored. Methods and Findings: In this mathematical modeling study done in the context of Vietnam, we estimated the public health benefit that HCV therapy for injecting drug users (IDUs) may achieve. Treatment coverage of 25, 50 and 75 % of chronically HCV-infected IDUs (4 years into infection) is predicted to reduce the chronic HCV viremia prevalence respectively by 21, 37 and 50%, 11 years after full scale up to the intended coverage. At a constant 50 % coverage level, earlier treatment, 3, 2, and 1 year into infection is predicted to reduce the chronic HCV viremia prevalence by 46, 60 and 85%. In these later 3 scenarios, for every 100 treatment courses provided, a total of respectively 50, 61 and 94 new infections could be averted. These benefits were projected in the context of current low coverage of methadone maintenance therapy and needles/ syringes exchange programs, and these services expansion showed complementary preventive benefits to HCV therapy. The program treatment commitment associated with the various scenarios is deemed reasonable. Our model projections are robust under adjustment for uncertainty in the model parameter values. Conclusions: In this case study in Vietnam, we project that treatment of HCV for injecting drug users will have a preventative herd effect in addition to curing patients in need for therapy, achieving a substantial reduction in HCV transmission an

Symptomatic Acute Hepatitis C in Egypt: Diagnosis, Spontaneous Viral Clearance, and Delayed Treatment with 12 Weeks of Pegylated Interferon Alfa-2a

The aim of this study was to estimate the proportion of spontaneous viral clearance (SVC) after symptomatic acute hepatitis C and to evaluate the efficacy of 12 weeks of pegylated interferon alfa-2a in patients who did not clear the virus spontaneously.Patients with symptomatic acute hepatitis C were recruited from two "fever hospitals" in Cairo, Egypt. Patients still viremic three months after the onset of symptoms were considered for treatment with 12 weeks of pegylated interferon alfa-2a (180 microg/week).Between May 2002 and February 2006, 2243 adult patients with acute hepatitis were enrolled in the study. The SVC rate among 117 patients with acute hepatitis C was 33.8% (95%CI [25.9%-43.2%]) at three months and 41.5% (95%CI [33.0%-51.2%]) at six months. The sustained virological response (SVR) rate among the 17 patients who started treatment 4-6 months after onset of symptoms was 15/17 = 88.2% (95%CI [63.6%-98.5%]).Spontaneous viral clearance was high (41.5% six months after the onset of symptoms) in this population with symptomatic acute hepatitis C. Allowing time for spontaneous clearance should be considered before treatment is initiated for symptomatic acute hepatitis C

Second primary malignancies after treatment for malignant lymphoma

To determine the incidence and possible causes of second primary malignancies after treatment for Hodgkin's and Non-Hodgkin's lymphoma (HL and NHL). A cohort of 3764 consecutive patients diagnosed with HL or NHL between January 1970 and July 2001 was identified using the Sheffield Lymphoma Group database. A search was undertaken for all patients diagnosed with a subsequent primary malignancy. Two matched controls were identified for each case. Odds ratios were calculated to detect and quantify any risk factors in the cases compared to their matched controls. Mean follow-up for the cohort was 5.2 years. A total of 68 patients who developed second cancers at least 6 months after their primary diagnosis were identified, giving a crude incidence of 1.89% overall: 3.21% among the patients treated for HL, 1.32% in those treated for NHL. Most common were bronchial, breast, colorectal and haematological malignancies. High stage at diagnosis almost reached statistical significance in the analysis of just the NHL patients (odds ratio=3.48; P=0.068) after adjustment for other factors. Treatment modality was not statistically significant in any analysis. High stage at diagnosis of NHL may be a risk factor for developing a second primary cancer

The myofibroblast, multiple origins for major roles in normal and pathological tissue repair

Myofibroblasts differentiate, invade and repair injured tissues by secreting and organizing the extracellular matrix and by developing contractile forces. When tissues are damaged, tissue homeostasis must be re-established, and repair mechanisms have to rapidly provide harmonious mechanical tissue organization, a process essentially supported by (myo)fibroblasts. Under physiological conditions, the secretory and contractile activities of myofibroblasts are terminated when the repair is complete (scar formation) but the functionality of the tissue is only rarely perfectly restored. At the end of the normal repair process, myofibroblasts disappear by apoptosis but in pathological situations, myofibroblasts likely remain leading to excessive scarring. Myofibroblasts originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts. However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the requirement for these cells during repair. These diverse cell types probably contribute to the appearance of myofibroblast subpopulations which show specific biological properties and which are important to understand in order to develop new therapeutic strategies for treatment of fibrotic and scarring diseases

FGF4 and Retinoic Acid Direct Differentiation of hESCs into PDX1-Expressing Foregut Endoderm in a Time- and Concentration-Dependent Manner

BACKGROUND: Retinoic acid (RA) and fibroblast growth factor 4 (FGF4) signaling control endoderm patterning and pancreas induction/expansion. Based on these findings, RA and FGFs, excluding FGF4, have frequently been used in differentiation protocols to direct differentiation of hESCs into endodermal and pancreatic cell types. In vivo, these signaling pathways act in a temporal and concentration-dependent manner. However, in vitro, the underlying basis for the time of addition of growth and differentiation factors (GDFs), including RA and FGFs, as well as the concentration is lacking. Thus, in order to develop robust and reliable differentiation protocols of ESCs into mature pancreatic cell types, including insulin-producing beta cells, it will be important to mechanistically understand each specification step. This includes differentiation of mesendoderm/definitive endoderm into foregut endoderm--the origin of pancreatic endoderm. METHODOLOGY/PRINCIPAL FINDINGS: Here, we provide data on the individual and combinatorial role of RA and FGF4 in directing differentiation of ActivinA (AA)-induced hESCs into PDX1-expressing cells. FGF4's ability to affect endoderm patterning and specification in vitro has so far not been tested. By testing out the optimal concentration and timing of addition of FGF4 and RA, we present a robust differentiation protocol that on average generates 32% PDX1(+) cells. Furthermore, we show that RA is required for converting AA-induced hESCs into PDX1(+) cells, and that part of the underlying mechanism involves FGF receptor signaling. Finally, further characterization of the PDX1(+) cells suggests that they represent foregut endoderm not yet committed to pancreatic, posterior stomach, or duodenal endoderm. CONCLUSION/SIGNIFICANCE: In conclusion, we show that RA and FGF4 jointly direct differentiation of PDX1(+) foregut endoderm in a robust and efficient manner. RA signaling mediated by the early induction of RARbeta through AA/Wnt3a is required for PDX1 expression. Part of RA's activity is mediated by FGF signaling

Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ2 or IL-18Rα

The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte–macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4+ and CD8+ T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12Rβ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity