Investment Case for a Comprehensive Package of Interventions Against Hepatitis B in China: Applied Modeling to Help National Strategy Planning.

BACKGROUND: In 2016, the first global viral hepatitis elimination targets were endorsed. An estimated one-third of the world's population of individuals with chronic hepatitis B virus (HBV) infection live in China and liver cancer is the sixth leading cause of mortality, but coverage of first-line antiviral treatment was low. In 2015, China was one of the first countries to initiate a consultative process for a renewed approach to viral hepatitis. We present the investment case for the scale-up of a comprehensive package of HBV interventions. METHODS: A dynamic simulation model of HBV was developed and used to simulate the Chinese HBV epidemic. We evaluated the impact, costs, and return on investment of a comprehensive package of prevention and treatment interventions from a societal perspective, incorporating costs of management of end-stage liver disease and lost productivity costs. RESULTS: Despite the successes of historical vaccination scale-up since 1992, there will be a projected 60 million people still living with HBV in 2030 and 10 million HBV-related deaths, including 5.7 million HBV-related cancer deaths between 2015 and 2030. This could be reduced by 2.1 million by highly active case-finding and optimal antiviral treatment regimens. The package of interventions is likely to have a positive return on investment to society of US$1.57 per US dollar invested. CONCLUSIONS: Increases in HBV-related deaths for the next few decades pose a major public health threat in China. Active case-finding and access to optimal antiviral treatment are required to mitigate this risk. This investment case approach provides a real-world example of how applied modeling can support national dialog and inform policy planning.

The Global Fund in China: Multidrug-resistant tuberculosis nationwide programmatic scale-up and challenges to transition to full country ownership.

China has the world's second largest burden of multidrug-resistant tuberculosis (MDR-TB; resistance to at least isoniazid and rifampicin), with an estimated 57,000 cases (range, 48,000-67,000) among notified pulmonary TB patients in 2015. During October 1, 2006-June 30, 2014, China expanded MDR-TB care through a partnership with the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund). We analyzed data on site expansion, patient enrolment, treatment outcomes, cost per patient, and overall programme expenditure. China expanded MDR-TB diagnostic and treatment services from 2 prefectures in 2006 to 92 prefectures, covering 921 of the country's 3,000 counties by June 2014. A total of 130,910 patients were tested for MDR-TB, resulting in 13,744 laboratory-confirmed cases, and 9,183 patients started on MDR-TB treatment. Treatment success was 48.4% (2011 cohort). The partnership between China and the Global Fund resulted in enormous gains. However, changes to health system TB delivery and financing coincided with the completion of the Global Fund Programme, and could potentially impact TB and MDR-TB control. Transition to full country financial ownership is proving difficult, with a decline in enrollment and insufficient financial coverage. Given needed improvement to the current treatment success rates, these factors jeopardise investments made for MDR-TB control and care. China now has a chance to cement its status in TB control by strengthening future financing and ensuring ongoing commitment to quality service delivery.

Cost-effectiveness of a comprehensive programme for drug-resistant tuberculosis in China.

OBJECTIVE: To investigate the cost-effectiveness of a comprehensive programme for drug-resistant tuberculosis launched in four sites in China in 2011. METHODS: In 2011-2012, we reviewed the records of 172 patients with drug-resistant tuberculosis who enrolled in the comprehensive programme and we collected relevant administrative data from hospitals and China's public health agency. For comparison, we examined a cohort of 81 patients who were treated for drug-resistant tuberculosis in 2006-2009. We performed a cost-effectiveness analysis, from a societal perspective, that included probabilistic uncertainty. We measured early treatment outcomes based on three-month culture results and modelled longer-term outcomes to facilitate estimation of the comprehensive programme's cost per disability-adjusted life-year (DALY) averted. FINDINGS: The comprehensive programme cost 8837 United States dollars (US$) per patient treated. Low enrolment rates meant that some fixed costs were higher, per patient, than expected. Although the comprehensive programme appeared 30 times more costly than the previous one, it resulted in greater health benefits. The comprehensive programme, which cost US$ 639 (95% credible interval: 112 to 1322) per DALY averted, satisfied the World Health Organization's criterion for a very cost-effective intervention. CONCLUSION: The comprehensive programme, which included rapid screening, standardized care and financial protection, improved individual outcomes for MDR tuberculosis in a cost-effective manner. To support post-2015 global heath targets, the comprehensive programme should be expanded to non-residents and other areas of China.

Global Tuberculosis Control: Toward the 2015 Targets and Beyond.

Since 1990, progress has been made toward global tuberculosis (TB) control, as measured by targets set for 2015. However, TB remains a major threat to health around the world. In 2013, there were an estimated 11 million prevalent cases, and an estimated 9.0 million incident cases occurred globally. Approximately 1.5 million deaths were caused by TB, including 360,000 among people living with HIV. Substantial challenges threaten future control efforts. These include multidrug-resistant forms and co-infection with HIV, as well as other factors, such as the increased prominence of noncommunicable diseases and adverse socioeconomic conditions. Beyond 2015, TB control must be seen as both a public health imperative unto itself and a vital component of economic development plans. To that end, control strategies should exploit technical and operational innovations to improve TB control and care and should promote universal health coverage and social protection mechanisms to expand access to essential prevention, diagnostics, and treatment services while avoiding catastrophic costs incurred by patients.

Electronic recording and reporting system for tuberculosis in China: experience and opportunities.

Tuberculosis (TB) surveillance in China is organized through a nationwide network of about 3200 hospitals and health facilities. In 2005, an electronic Tuberculosis Information Management System (TBIMS) started to be phased in to replace paper recording. The TBIMS collects key information on TB cases notified in TB care facilities, and exchanges real-time data with the Infectious Disease Reporting System, which covers the country's 37 notifiable diseases. The system is accessible to authorized users at every level of the TB network through a password-protected website. By 2009 the TBIMS achieved nationwide coverage. Completeness of data on patient bacteriological end points improved remarkably over time. Data on about a million active TB cases, including drug-resistant TB, are included each year. The sheer scale of the data handling and the intricate functions that the China TBIMS performs makes it stand apart from the electronic information systems for TB adopted in other countries.

Drug-Resistant tuberculosis, KwaZulu-Natal, South Africa, 2001-2007.

In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. However, investigation after a 2005 outbreak of extensively drug-resistant tuberculosis in KwaZulu-Natal Province, South Africa, found that the incidence rate for multidrug-resistant tuberculosis in KwaZulu-Natal was among the highest globally and would be higher if case-finding efforts were intensified.

Tuberculosis among health care workers.

To assess the annual risk for latent tuberculosis infection (LTBI) among health care workers (HCWs), the incidence rate ratio for tuberculosis (TB) among HCWs worldwide, and the population-attributable fraction of TB to exposure of HCWs in their work settings, we reviewed the literature. Stratified pooled estimates for the LTBI rate for countries with low (<50 cases/100,000 population), intermediate (50-100/100,000 population), and high (>100/100,000 population) TB incidence were 3.8% (95% confidence interval [CI] 3.0%-4.6%), 6.9% (95% CI 3.4%-10.3%), and 8.4% (95% CI 2.7%-14.0%), respectively. For TB, estimated incident rate ratios were 2.4 (95% CI 1.2-3.6), 2.4 (95% CI 1.0-3.8), and 3.7 (95% CI 2.9-4.5), respectively. Median estimated population-attributable fraction for TB was as high as 0.4%. HCWs are at higher than average risk for TB. Sound TB infection control measures should be implemented in all health care facilities with patients suspected of having infectious TB.

Tuberculosis incidence in prisons: a systematic review.

BACKGROUND: Transmission of tuberculosis (TB) in prisons has been reported worldwide to be much higher than that reported for the corresponding general population. METHODS AND FINDINGS: A systematic review has been performed to assess the risk of incident latent tuberculosis infection (LTBI) and TB disease in prisons, as compared to the incidence in the corresponding local general population, and to estimate the fraction of TB in the general population attributable (PAF%) to transmission within prisons. Primary peer-reviewed studies have been searched to assess the incidence of LTBI and/or TB within prisons published until June 2010; both inmates and prison staff were considered. Studies, which were independently screened by two reviewers, were eligible for inclusion if they reported the incidence of LTBI and TB disease in prisons. Available data were collected from 23 studies out of 582 potentially relevant unique citations. Five studies from the US and one from Brazil were available to assess the incidence of LTBI in prisons, while 19 studies were available to assess the incidence of TB. The median estimated annual incidence rate ratio (IRR) for LTBI and TB were 26.4 (interquartile range [IQR]: 13.0-61.8) and 23.0 (IQR: 11.7-36.1), respectively. The median estimated fraction (PAF%) of tuberculosis in the general population attributable to the exposure in prisons for TB was 8.5% (IQR: 1.9%-17.9%) and 6.3% (IQR: 2.7%-17.2%) in high- and middle/low-income countries, respectively. CONCLUSIONS: The very high IRR and the substantial population attributable fraction show that much better TB control in prisons could potentially protect prisoners and staff from within-prison spread of TB and would significantly reduce the national burden of TB. Future studies should measure the impact of the conditions in prisons on TB transmission and assess the population attributable risk of prison-to-community spread. Please see later in the article for the Editors' Summary.

Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings.

The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data.

Tuberculosis preventive therapy in the era of HIV infection: overview and research priorities.

The recognition of tuberculosis (TB) as a major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected persons has led to renewed interest in TB preventive therapy and its incorporation into the essential package of health care for these individuals. Despite convincing data regarding its efficacy, TB preventive therapy has not been widely implemented. Further work is needed to determine how to overcome the barriers to the implementation of such therapy, including how best to exclude the presence of active TB before providing preventive therapy. Such issues as the optimal duration of preventive therapy for and the role of TB preventive therapy in the treatment of individuals receiving antiretroviral therapy remain to be defined. Ongoing research will help to determine how best to use this intervention in the care of HIV-infected persons and in the control of TB on a wider basis.

T-cell assays for the diagnosis of latent tuberculosis infection: moving the research agenda forward.

For nearly a century, the tuberculin skin test was the only tool available for the detection of latent tuberculosis infection. A recent breakthrough has been the development of T-cell-based interferon-gamma release assays. Current evidence suggests interferon-gamma release assays have higher specificity than the tuberculin skin test, better correlation with surrogate markers of exposure to Mycobacterium tuberculosis in low-incidence settings, and less cross-reactivity as a result of BCG vaccination compared with the tuberculin skin test. The body of literature supporting the use of interferon-gamma release assays has rapidly expanded. However, several unresolved and unexplained issues remain. To address these issues, a group of experts met in Geneva, Switzerland, in March, 2006, to discuss the research evidence on T-cell-based assays, their clinical usefulness, limitations, and directions for future research, with a specific focus on resource-limited and high HIV prevalence settings. On the basis of 2 days of discussions, a comprehensive research agenda was generated, which will propel the field forward by stimulating focused high-impact research and encourage the investment of resources needed to tackle priority research questions, especially in resource-limited settings. Ultimately, if adequately financed, the research findings will inform appropriate use of novel latent tuberculosis infection diagnostics in global tuberculosis control.

Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration.

Tuberculosis is the oldest of the world's current pandemics and causes 8.9 million new cases and 1.7 million deaths annually. The disease is among the most common causes of morbidity and mortality in people living with HIV. However, tuberculosis is more than just part of the global HIV problem; well-resourced tuberculosis programmes are an important part of the solution to scaling-up towards universal access to comprehensive HIV prevention, diagnosis, care, and support. This article reviews the impact of the interactions between tuberculosis and HIV in resource-limited settings; outlines the recommended programmatic and clinical responses to the dual epidemics, highlighting the role of tuberculosis/HIV collaboration in increasing access to prevention, diagnostic, and treatment services; and reviews progress in the global response to the epidemic of HIV-related tuberculosis.

Effects of human immunodeficiency virus infection on recurrence of tuberculosis after rifampin-based treatment: an analytical review.

We reviewed 47 prospective studies of recurrence of pulmonary tuberculosis (TB) after cure to assess the influence of human immunodeficiency virus (HIV) infection and rifampin treatment. Multivariate regression revealed that the recurrence rate for HIV-uninfected persons increased with decreasing duration of therapy: it was 1.4 cases per 100 person-years for recipients of >or=7 months of rifampin therapy and 2.0 and 4.0 cases per 100 person-years for recipients of 5-6 and 2-3 months of rifampin therapy, respectively (trend P=.00014), over a mean follow-up duration of 34 months, at a TB incidence of 250 cases per 100,000 person-years. Relative risks of recurrence associated with HIV infection at these 3 treatment durations were 2.2, 2.1, and 3.4, respectively, with a significant interaction between HIV infection status and treatment duration (P=.025). The recurrence rate increased with the background TB incidence (P=.048), and it decreased over time since completion of treatment in HIV-uninfected but not in HIV-infected patients (overall trend, P=.00008; difference by HIV infection status, P=.025). In countries where HIV infection is endemic, TB recurrence may be reduced by administration of rifampin-based treatment for at least 6 months, in accordance with World Health Organization recommendations.

Synercid plus vancomycin for the treatment of severe methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections: evaluation of 5 cases.

Synercid (quinupristin/dalfopristin), the first semi-synthetic injectable streptogramin, is a promising alternative to glycopeptides against many Gram-positive multiresistant bacteria. Vancomycin is still considered an effective agent for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections but therapeutic failures with glycopeptides have been observed, even for the treatment of infections caused by S. aureus strains sensitive to vancomycin. Synercid, in combination with a glycopeptide, may address this problem without causing significant side effects due to the different toxicity patterns of the 2 antimicrobials. This study reports our experience with the combination of Synercid and vancomycin in 5 patients with severe infection caused by MRSA or methicillin-resistant coagulase-negative Staphylococcus.