Mass treatment to eliminate tuberculosis from an island population.

SETTING: The global target of tuberculosis (TB) elimination by 2050 requires new approaches. Active case finding plus mass prophylactic treatment has been disappointing. We consider mass full anti-tuberculosis treatment as an approach to TB elimination in Kiribati, a Pacific Island nation, with a persistent epidemic of high TB incidence. OBJECTIVE: To construct a mathematical model to predict whether mass treatment with a full course of anti-tuberculosis drugs might eliminate TB from the defined population of the Republic of Kiribati. METHODS: We constructed a seven-state compartmental model of the life cycle of Mycobacterium tuberculosis in which active TB disease arises from the progression of infection, reinfection, reactivation and relapse, while distinguishing infectious from non-infectious disease. We evaluated the effects of 5-yearly mass treatment using a range of parameter values to generate outcomes in uncertainty analysis. RESULTS: Assuming population-wide treatment effectiveness for latent tuberculous infection and active TB of ⩾90%, annual TB incidence is expected to fall sharply at each 5-yearly round of treatment, approaching elimination in two decades. The model showed that the incidence rate is sensitive to the relapse rate after successful treatment of TB. CONCLUSION: Mass treatment may help to eliminate TB, at least for discrete or geographically isolated populations.

Antiretroviral therapy and the control of HIV-associated tuberculosis. Will ART do it?

The human immunodeficiency virus (HIV) associated tuberculosis (TB) epidemic remains an enormous challenge to TB control in countries with a high prevalence of HIV. In their 1999 article entitled 'Will DOTS do it?', De Cock and Chaisson questioned whether the World Health Organization's DOTS Strategy could control this epidemic. Data over the past 10 years have clearly shown that DOTS is insufficient as a single TB control intervention in such settings because it does not address the fundamental epidemiological interactions between TB and HIV. Immunodeficiency is a principal driver of this epidemic, and the solution must therefore include immune recovery using antiretroviral therapy (ART). Thus, in the era of global ART scale-up, we now ask the question, 'Will ART do it?' ART reduces the risk of TB by 67% (95%CI 61-73), halves TB recurrence rates, reduces mortality risk by 64-95% in cohorts and prolongs survival in patients with HIV-associated drug-resistant TB. However, the cumulative lifetime risk of TB in HIV-infected individuals is a function of time spent at various CD4-defined levels of risk, both before and during ART. Current initiation of ART at low CD4 cell counts (by which time much HIV-associated TB has already occurred) and low effective coverage greatly undermine the potential impact of ART at a population level. Thus, while ART has proven a critical intervention for case management of HIV-associated TB, much of its preventive potential for TB control is currently being squandered. Much earlier ART initiation with high coverage is required if ART is to substantially influence the incidence of TB.

National estimate of HIV seroprevalence among tuberculosis patients in India.

The national estimate for human immunodeficiency virus (HIV) prevalence among tuberculosis (TB) patients in India has previously been estimated indirectly from global data. To derive an improved national estimate from local data, we correlated district-level HIV surveillance data from antenatal clinics and TB diagnostic centres, and applied this correlation to state-level HIV prevalence estimates for the antenatal population. We estimate that among the 1.96 million incident TB cases in 2007, 4.85% (95%CI 4.12-5.73) or 95 240 (95%CI 80 730-112 478) were HIV-infected. With these estimates from local data, the national programme can better plan TB-HIV collaborative activities and monitor efforts to detect HIV infection in this large population.

Prevalent infectious tuberculosis in Harare, Zimbabwe: burden, risk factors and implications for control.

SETTING: Harare's high density suburbs. OBJECTIVES: To investigate the burden, duration and risk factors for prevalent tuberculosis (TB) and explore potential control strategies. METHODS: Randomly selected adults had TB culture, symptom screen and human immunodeficiency virus (HIV) serology. Prevalent TB was defined as undiagnosed or still culture-positive. Notification data and HIV prevalence in TB out-patients were used to estimate duration of infectiousness (prevalence/estimated incidence). RESULTS: Among 10 092 participants, 40 (0.40%, 95%CI 0.28-0.54) had prevalent smear-positive TB. HIV (adjusted odds ratio [aOR] 3.1, 95%CI 1.6-6.3, population attributable fraction [PAF] 33%), male sex (aOR 3.1, 95%CI 1.5-6.4, PAF 40%), and overcrowding (PAF 34%) were significant risk factors, with past TB treatment significant for HIV-negative participants only (PAF 7%). Recent household TB contact was not significant (PAF 10%). HIV prevalence was 21.1%; 76.9% of HIV-positive participants were previously untested. Duration of infectiousness was at least 18 weeks in HIV-positive and approximately 1 year in HIV-negative patients. CONCLUSIONS: Overcrowding, male sex and HIV infection were major risk factors for prevalent smear-positive TB. Reducing diagnostic delay may have greater potential to improve the control of prevalent TB than interventions targeted at household contacts, TB treatment outcomes, or TB-HIV interventions under current levels of awareness of HIV status.

Trends in tuberculosis incidence and their determinants in 134 countries.

OBJECTIVE: To determine whether differences in national trends in tuberculosis incidence are attributable to the variable success of control programmes or to biological, social and economic factors. METHODS: We used trends in case notifications as a measure of trends in incidence in 134 countries, from 1997 to 2006, and used regression analysis to explore the associations between these trends and 32 measures covering various aspects of development (1), the economy (6), the population (3), behavioural and biological risk factors (9), health services (6) and tuberculosis (TB) control (7). FINDINGS: The TB incidence rate changed annually within a range of +/-10% over the study period in the 134 countries examined, and its average value declined in 93 countries. The rate was declining more quickly in countries that had a higher human development index, lower child mortality and access to improved sanitation. General development measures were also dominant explanatory variables within regions, though correlation with TB incidence trends varied geographically. The TB incidence rate was falling more quickly in countries with greater health expenditure (situated in central and eastern Europe and the eastern Mediterranean), high-income countries with lower immigration, and countries with lower child mortality and HIV infection rates (located in Latin America and the Caribbean). The intensity of TB control varied widely, and a possible causal link with TB incidence was found only in Latin America and the Caribbean, where the rate of detection of smear-positive cases showed a negative correlation with national incidence trends. CONCLUSION: Although TB control programmes have averted millions of deaths, their effects on transmission and incidence rates are not yet widely detectable.

Modelling local and global effects on the risk of contracting Tuberculosis using stochastic Markov-chain models.

For some diseases, the transmission of infection can cause spatial clustering of disease cases. This clustering has an impact on how one estimates the rate of the spread of the disease and on the design of control strategies. It is, however, difficult to assess such clustering, (local effects on transmission), using traditional statistical methods. A stochastic Markov-chain model that takes into account possible local or more dispersed global effects on the risk of contracting disease is introduced in the context of the transmission dynamics of tuberculosis. The model is used to analyse TB notifications collected in the Asembo and Gem Divisions of Nyanza Province in western Kenya by the Kenya Ministry of Health/National Leprosy and Tuberculosis Program and the Centers for Disease Control and Prevention. The model shows evidence of a pronounced local effect that is significantly greater than the global effect. We discuss a number of variations of the model which identify how this local effect depends on factors such as age and gender. Zoning/clustering of villages is used to identify the influence that zone size has on the model's ability to distinguish local and global effects. An important possible use of the model is in the design of a community randomised trial where geographical clusters of people are divided into two groups and the effectiveness of an intervention policy is assessed by applying it to one group but not the other. Here the model can be used to take the effect of case clustering into consideration in calculating the minimum difference in an outcome variable (e.g. disease prevalence) that can be detected with statistical significance. It thereby gauges the potential effectiveness of such a trial. Such a possible application is illustrated with the given time/spatial TB data set.

The measurement and estimation of tuberculosis mortality.

Tuberculosis (TB) ranks among the 10 principal causes of death and disability worldwide, largely on the basis of mortality estimates. These estimates have been derived by a variety of methods, from a limited database. Here we review the data and methods used to measure and estimate TB mortality in adults, assess the strengths and weaknesses of each and suggest ways to improve current mortality statistics. In principle, deaths attributable to TB can be obtained directly from national vital registration (VR) systems. However, only 59 of 213 countries in 2005 (including three in the World Health Organization Africa Region and one in the South-East Asia Region) had VR systems that reported TB deaths, corresponding to just 10% of all estimated deaths attributable to TB. Until comprehensive, national VR systems are established, an interim solution is to carry out verbal autopsies within sample VR schemes. The number of TB deaths from VR should ultimately converge with deaths recorded in national TB control programmes. At present, deaths in treatment cohorts cover a small subset of all estimated TB deaths (<13% in 2006), as deaths are missed among patients who are never diagnosed, who default or fail treatment, and among patients with untreated recurrent TB or TB sequelae. In contrast, some deaths recorded during treatment are not due to TB. To ensure convergence between cohort monitoring and VR, definitions of causes of death--including TB as an associate cause in deaths from human immunodeficiency virus/acquired immune-deficiency syndrome--should be standardised, so that both systems adhere to the International Classification of Diseases.

Global monitoring of collaborative TB-HIV activities.

Tuberculosis (TB) and human immunodeficiency virus (HIV) programs are increasingly working together towards providing universal access to integrated TB and HIV prevention, treatment, care and support services. To monitor progress we need to measure the delivery and impact of these services; however, the lack of investment in monitoring and evaluation and the added complexity of sharing data between two vertical programs, makes monitoring and evaluation of collaborative TB-HIV activities especially challenging. We describe the global system to record, report and analyse data on collaborative TB-HIV activities and summarize results to date. Although the data suggest that there is a steady increase in collaborative TB-HIV activities in many high-burden countries over time, we are already falling behind the globally agreed implementation milestones. This is due to a combination of slow implementation and lack of necessary tools and systems for capturing activity data. In particular, data from HIV program monitoring of TB screening, TB preventive treatments and TB infection control for people living with HIV is lacking. Much remains to be done by both programs to improve the implementation, monitoring and evaluation of collaborative TB-HIV activities and to optimize prevention, treatment and care for people infected with both TB and HIV, especially in areas at high risk of drug-resistant TB.

Measuring tuberculosis burden, trends, and the impact of control programmes.

The targets for tuberculosis control, framed within the United Nations' Millennium Development Goals, are to ensure that the incidence per head of tuberculosis is falling by 2015, and that the 1990 prevalence and mortality per head are halved by 2015. In monitoring progress in tuberculosis control, the ultimate aim for all countries is to count tuberculosis cases (incidence) accurately through routine surveillance. Disease prevalence surveys are costly and laborious, but give unbiased measures of tuberculosis burden and trends, and are justified in high-burden countries where many cases and deaths are missed by surveillance systems. Most countries in which tuberculosis is highly endemic do not yet have reliable death registration systems. Verbal autopsy, used in cause-of-death surveys, is an alternative, interim method of assessing tuberculosis mortality, but needs further validation. Although several new assays for Mycobacterium tuberculosis infection have recently been devised, the tuberculin skin test remains the only practical method of measuring infection in populations. However, this test typically has low specificity and is therefore best used comparatively to assess geographical and temporal variation in risk of infection. By 2015, every country should be able to assess progress in tuberculosis control by estimating the time trend in incidence, and the magnitude of reductions in either prevalence or deaths.

The Potential Impact of Male Circumcision on HIV in Sub-Saharan Africa

Background: A randomized controlled trial (RCT) has shown that male circumcision (MC) reduces sexual transmission of HIV from women to men by 60(32?76; 95CI) offering an intervention of proven efficacy for reducing the sexual spread of HIV. We explore the implications of this finding for the promotion of MC as a public health intervention to control HIV in sub-Saharan Africa. Methods and Findings :Using dynamical simulation models we consider the impact of MC on the relative prevalence of HIV in men and women and in circumcised and uncircumcised men. Using country level data on HIV prevalence and MC; we estimate the impact of increasing MC coverage on HIV incidence; HIV prevalence; and HIV-related deaths over the next ten; twenty; and thirty years in sub-Saharan Africa. Assuming that full coverage of MC is achieved over the next ten years; we consider three scenarios in which the reduction in transmission is given by the best estimate and the upper and lower 95confidence limits of the reduction in transmission observed in the RCT. MC could avert 2.0 (1.1?3.8) million new HIV infections and 0.3 (0.1?0.5) million deaths over the next ten years in sub-Saharan Africa. In the ten years after that; it could avert a further 3.7 (1.9?7.5) million new HIV infections and 2.7 (1.5?5.3) million deaths; with about one quarter of all the incident cases prevented and the deaths averted occurring in South Africa. We show that a) MC will increase the proportion of infected people who are women from about 52to 58; b) where there is homogenous mixing but not all men are circumcised; the prevalence of infection in circumcised men is likely to be about 80of that in uncircumcised men; c) MC is equivalent to an intervention; such as a vaccine or increased condom use; that reduces transmission in both directions by 37. Conclusions: This analysis is based on the result of just one RCT; but if the results of that trial are confirmed we suggest that MC could substantially reduce the burden of HIV in Africa; especially in southern Africa where the prevalence of MC is low and the prevalence of HIV is high. While the protective benefit to HIV-negative men will be immediate; the full impact of MC on HIV-related illness and death will only be apparent in ten to twenty years

The impact of HIV/AIDS on the control of tuberculosis in India.

Epidemics of HIV/AIDS have increased the tuberculosis (TB) case-load by five or more times in East Africa and southern Africa. As HIV continues to spread, warnings have been issued of disastrous AIDS and TB epidemics in "new-wave" countries, including India, which accounts for 20% of all new TB cases arising in the world each year. Here we investigate whether, in the face of the HIV epidemic, India's Revised National TB Control Program (RNTCP) could halve TB prevalence and death rates in the period 1990-2015, as specified by the United Nations Millennium Development Goals. Using a mathematical model to capture the spatial and temporal variation in TB and HIV in India, we predict that, without the RNTCP, HIV would increase TB prevalence (by 1%), incidence (by 12%), and mortality rates (by 33%) between 1990 and 2015. With the RNTCP, however, we expect substantial reductions in prevalence (by 68%), incidence (by 41%), and mortality (by 39%) between 1990 and 2015. In India, 29% of adults but 72% of HIV-positive adults live in four large states in the south where, even with the RNTCP, mortality is expected to fall by only 15% between 1990 and 2015. Nationally, the RNTCP should be able to reverse the increases in TB burden due to HIV but, to ensure that TB mortality is reduced by 50% or more by 2015, HIV-infected TB patients should be provided with antiretroviral therapy in addition to the recommended treatment for TB.

Risk factors of sexually transmitted infections among migrant and non-migrant sexual partnerships from rural South Africa.

In October 1998, cohorts of circular migrant men and their non-migrant sexual partners, and non-migrant men and their non-migrant sexual partners from rural South Africa were recruited and followed-up every 4 months until October 2001. At each visit, information on sociodemographic, sexual behaviour, sexually transmitted infections (STIs) and HIV was collected. In total, 553 individuals aged between 18 and 69 years were recruited. A man and his sexual partner(s) form a sexual partnership. Migration status, age, marital status, age at sexual debut, recent sexual partners and HIV status were found to be important determinants of STI. The risk of STI varies (sigma2 = 1.45, P < 0.001) significantly across sexual partnerships even after controlling for important determinants. The variance implies substantial correlation (0.59) between members of the same sexual partnership. Ignoring this correlation leads to incorrect inference. Migration contributes significantly to the spread of STIs. Community interventions of HIV/STI should target co-transmitter sexual partnerships rather than high-risk individuals.

Tuberculosis deaths in countries with high HIV prevalence: what is their use as an indicator in tuberculosis programme monitoring and epidemiological surveillance?

Although the reduction of tuberculosis deaths is one of the aims of tuberculosis control, it has not always been a priority for National Tuberculosis Programmes (NTPs). The usual explanation is that death as a treatment outcome not associated with ongoing tuberculosis transmission is not relevant to the public health objective of cutting the cycle of disease transmission. However, death as an adverse outcome for tuberculosis patients and their families is an important indicator in NTP monitoring. Global health targets agreed as part of the Millennium Development Goals include the reduction of tuberculosis deaths. Tuberculosis deaths as an indicator of the impact of tuberculosis control measures are therefore important in the epidemiological surveillance of progress towards these targets. These considerations are particularly important in countries with high human immunodeficiency virus (HIV) prevalence where HIV has exacerbated the tuberculosis epidemic and is now the single best predictor of tuberculosis incidence. Tuberculosis deaths are also closely linked to HIV prevalence. Routine NTP data on tuberculosis cohort deaths are important in programme monitoring, and improvements in recording and reporting of deaths would help to overcome limitations in their accuracy. As routine NTP data on tuberculosis cohort deaths are insufficient as an indicator in epidemiological surveillance regarding the impact of NTPs on tuberculosis mortality, measuring progress towards targets for reduced tuberculosis deaths depends on improved national vital registration systems for a more accurate determination of tuberculosis mortality.

Monitoring trends in under-5 mortality rates through national birth history surveys.

BACKGROUND: We assessed whether Demographic and Health Surveys (DHS), a large and high-quality source of under-5 mortality estimates in developing countries, would be able to detect reductions in under-5 mortality as established in global child health goals. METHODS AND RESULTS: Mortality estimates from 41 DHS conducted in African countries between 1986 and 2002, for the interval of 0-4 years preceding each survey (with a mean time lag of 2.5 years), were reviewed. The median relative error on national mortality rates was 4.4%. In multivariate regression, the relative error decreased with increasing sample size, increasing fertility rates, and increasing mortality rates. The error increased with the magnitude of the survey design effect, which resulted from cluster sampling. With levels of precision observed in previous surveys, reductions in all-cause under-5 mortality rates between two subsequent surveys of 15% or more would be detectable. The detection of smaller mortality reductions would require increases in sample size, from a current median of 7060 to over 20,000 women. Across the actual surveys conducted between 1986 and 2002, varying mortality trends were apparent at a national scale, but only around half of these were statistically significant. CONCLUSIONS: The interpretation of changes in under-5 mortality rates between subsequent surveys needs to take into account statistical significance. DHS birth history surveys with their present sampling design would be able to statistically confirm under-5 mortality reductions in African countries if true reductions were 15% or larger, and are highly relevant to tracking progress towards existing international child health targets.

Experiences of men with breast cancer: an exploratory focus group study.

Management and care of men with breast cancer is based on that developed for women. Our study reports that men have specific issues regarding certain aspects of their breast cancer experience, including diagnosis, disclosure, support and gender-specific information, and offers suggestions for improved patient care.