M. W. Borgdorff

Calculation of the Stability of the IS6110 Banding Pattern in Patients with Persistent Mycobacterium tuberculosis Disease

ABSTRACT The interpretation of molecular epidemiologic data of Mycobacterium tuberculosis infection is dependent on the understanding of the stability and evolutionary characteristics of the DNA fingerprinting marker used to classify clinical isolates. This study investigated the stability of the IS6110 banding pattern in serial tuberculosis isolates collected from patients resident in an area with a high incidence of tuberculosis. Evolutionary changes were observed in 4% of the strains, and a half-life (t1/2) of 8.74 years was calculated, assuming a constant rate of change over time. This rate may be composed of a high rate of change seen during the early disease phase (t1/2 = 0.57 years) and a low rate of change seen in the late disease phase (t1/2 = 10.69 years). The early rate probably reflects change occurring during active growth prior to therapy, while the low late rate may reflect change occurring during or after treatment. We demonstrate that the calculation of these rates is strongly influenced by the time interval between onset of disease and sputum sampling. These calculations are further complicated by partial replacement of the original strain population, resulting in the sporadic appearance of clonal variants in sputum specimens. Therefore, the true extent of genetic diversity may be underestimated within each host, thereby influencing molecular epidemiological data used to establish transmission chains.

Seventy percent of the Mycobacterium tuberculosis isolates in Hong Kong represent the Beijing genotype.

We used spoligotyping to study 500 randomly selected pretreatment Mycobacterium tuberculosis (MTB) strains isolated in Hong Kong during the 2 year period 1998-9. It was found that amongst all MTB strains studied, the Beijing genotype strains were highly prevalent in our geographic area, representing about 70% of the isolates. Unlike previous observations in Vietnam, no significant associations were found either between Beijing genotype strains and all other anti-tuberculosis drug resistance phenotypes, or with particular patients age groups, except for a weak association with isoniazid susceptibility. Eighteen of these strains exhibited spoligotype patterns that were similar but not identical to the Beijing specific pattern. This is the first geographical area where genetic diversity among Beijing genotype of MTB strains has been observed on this scale.

Limited impact of tuberculosis control in Hong Kong: attributable to high risks of reactivation disease

Over 50% of the global burden of tuberculosis occurs in South East Asia and the Western Pacific. Since 1950, notification rates in high-income countries in these settings have declined slowly and have remained over ten-fold greater than those in Western populations. The reasons for the slow decline are poorly understood. Using an age-structured model describing the incidence of Mycobacterium tuberculosis infection and disease applied to notification data from Hong Kong, we illustrate that in Hong Kong, a high prevalence of M. tuberculosis infection among older individuals and a high risk of disease through reactivation (e.g. up to 17-fold greater than that estimated for infected males in the United Kingdom) may explain this slow decline. If this feature of the epidemiology of tuberculosis is widespread, the WHO directly observed treatment short-course (DOTS) strategy may have a smaller impact in Asia in the short term than has been implied by recent predictions, all of which have been based on disease risk estimates derived from Western Europe. As a result, it may be difficult to meet the targets for tuberculosis control, which have been prescribed by the UN Millennium Development Goals.

Drivers of Tuberculosis Transmission

Abstract Measuring tuberculosis transmission is exceedingly difficult, given the remarkable variability in the timing of clinical disease after Mycobacterium tuberculosis infection; incident disease can result from either a recent (ie, weeks to months) or a remote (ie, several years to decades) infection event. Although we cannot identify with certainty the timing and location of tuberculosis transmission for individuals, approaches for estimating the individual probability of recent transmission and for estimating the fraction of tuberculosis cases due to recent transmission in populations have been developed. Data used to estimate the probable burden of recent transmission include tuberculosis case notifications in young children and trends in tuberculin skin test and interferon γ–release assays. More recently, M. tuberculosis whole-genome sequencing has been used to estimate population levels of recent transmission, identify the distribution of specific strains within communities, and decipher chains of transmission among culture-positive tuberculosis cases. The factors that drive the transmission of tuberculosis in communities depend on the burden of prevalent tuberculosis; the ways in which individuals live, work, and interact (eg, congregate settings); and the capacity of healthcare and public health systems to identify and effectively treat individuals with infectious forms of tuberculosis. Here we provide an overview of these factors, describe tools for measurement of ongoing transmission, and highlight knowledge gaps that must be addressed.

HIV incidence in western Kenya during scale-up of antiretroviral therapy and voluntary medical male circumcision: a population-based cohort analysis

BACKGROUNDnIn Kenya, coverage of antiretroviral therapy (ART) among people with HIV infection has increased from 7% in 2006, to 57% in 2016; and, in western Kenya, coverage of voluntary medical male circumcision (VMMC) increased from 45% in 2008, to 72% in 2014. We investigated trends in HIV prevalence and incidence in a high burden area in western Kenya in 2011-16.nnnMETHODSnIn 2011, 2012, and 2016, population-based surveys were done via a health and demographic surveillance system and home-based counselling and testing in Gem, Siaya County, Kenya, including 28u2008688, 17u2008021, and 16u2008772 individuals aged 15-64 years. Data on demographic variables, self-reported HIV status, and risk factors were collected. Rapid HIV testing was offered to survey participants. Participants were tracked between surveys by use of health and demographic surveillance system identification numbers. HIV prevalence was calculated as a proportion, and HIV incidence was expressed as number of new infections per 1000 person-years of follow-up.nnnFINDINGSnHIV prevalence was stable in participants aged 15-64 years: 15% (4300/28u2008532) in 2011, 12% (2051/16u2008875) in 2012, and 15% (2312/15u2008626) in 2016. Crude prevalences in participants aged 15-34 years were 11% (1893/17u2008197) in 2011, 10% (1015/10u2008118) in 2012, and 9% (848/9125) in 2016; adjusted for age and sex these prevalences were 11%, 9%, and 8%. 12u2008606 (41%) of the 30u2008520 non-HIV-infected individuals enrolled were seen again in at least one more survey round, and were included in the analysis of HIV incidence. HIV incidence was 11·1 (95% CI 9·1-13·1) per 1000 person-years from 2011 to 2012, and 5·7 (4·6-6·9) per 1000 person-years from 2012 to 2016.nnnINTERPRETATIONnWith increasing coverage of ART and VMMC, HIV incidence declined substantially in Siaya County between 2011 and 2016. VMMC, but not ART, was suggested to have a direct protective effect, presumably because ART tended to be given to individuals with advanced HIV infection. HIV incidence is still high and not close to the elimination target of one per 1000 person-years. The effect of further scale-up of ART and VMMC needs to be monitored.nnnFUNDINGnData were collected under Cooperative Agreements with the US Centers for Disease Control and Prevention, with funding from the Presidents Emergency Fund for AIDS Relief.

Tuberculosis case finding using population-based disease surveillance platforms in urban and rural Kenya

BackgroundTuberculosis (TB) case finding is an important component of TB control because it can reduce transmission of Mycobacterium tuberculosis (MTB) through prompt detection and treatment of infectious patients.MethodsUsing population-based infectious disease surveillance (PBIDS) platforms with links to health facilities in Kenya we implemented intensified TB case finding in the community and at the health facilities, as an adjunct to routine passive case finding conducted by the national TB program. From 2011 to 2014, PBIDS participants ≥15xa0years were screened either at home or health facilities for possible TB symptoms which included cough, fever, night sweats or weight loss in the preceding 2xa0weeks. At home, participants with possible TB symptoms had expectorated sputum collected. At the clinic, HIV-infected participants with possible TB symptoms were invited to produce sputum. Those without HIV but with symptoms lasting 7xa0days including the visit day had chest radiographs performed, and had sputum collected if the radiographs were abnormal. Sputum samples were tested for the presence of MTB using the Xpert MTB/RIF assay. TB detection rates were calculated per 100,000 persons screened.ResultsOf 11,191 participants aged ≥15xa0years screened at home at both sites, 2695 (23.9%) reported possible TB symptoms, of whom 2258 (83.8%) produced sputum specimens. MTB was detected in 32 (1.4%) of the specimens resulting in a detection rate of 286/100,000 persons screened. At the health facilities, a total of 11,762 person were screened, 7500 (63.8%) had possible TB symptoms of whom 1282 (17.1%) produced sputum samples. MTB was detected in 69 (5.4%) of the samples, resulting in an overall detection rate of 587/100,000 persons screened. The TB detection rate was higher in persons with HIV compared to those without at both home (HIV-infected - 769/100,000, HIV-uninfected 141/100,000, rate ratio (RR) – 5.45, 95% CI 3.25–22.37), and health facilities (HIV-infected 3399/100,000, HIV-uninfected 294/100,000, RR 11.56, 95% CI 6.18–18.44).ConclusionFacility-based intensified TB case finding detected more TB cases per the number of specimens tested and the number of persons screened, including those with HIV, than home-based TB screening and should be further evaluated to determine its potential programmatic impact.

The Molecular Epidemiology of Tuberculosis in Settings With a High HIV Prevalence: Implications for Control

Tuberculosis control is extremely challenging in settings with a high prevalence of human immunodeficiency virus (HIV) infection. It was recognized years ago that the World Health Organization (WHO) directly observed therapy short-course (DOTS) strategy in isolation was insufficient to control tuberculosis in such settings [1]. Since then, various additional interventions have been considered, including the scale up of antiretroviral therapy (ART) [2, 3], enhanced tuberculosis case finding and household interventions [4], and isoniazid preventive therapy [5]. While the uptake of preventive therapy is challenging [6], the effectiveness of mass preventive therapy was disappointing [7], and the effectiveness of intensified case finding remains unproven [4, 8, 9], the scale up of ART appears promising [3, 10], particularly since the latest expansion of the WHO eligibility criteria for ART [11]. The long-term effect of ART on tuberculosis incidence may be less favorable, as the increasing life expectancy of HIV-infected individuals may increase their cumulative tuberculosis risk [12]. In this issue of the Journal, Middelkoop et al describe the molecular epidemiology of tuberculosis in a suburb of Cape Town, South Africa, with extremely high rates of tuberculosis and HIV infection [13]. Their study suggests that HIV-uninfected patients with tuberculosis contributed disproportionally to tuberculosis transmission in this setting and that cases of tuberculosis in HIV-infected patients were particularly likely to be secondary cases, even if the patients were receiving ART. A protective effect of ART against tuberculosis was not demonstrated in this study. It should be noted that the number of individuals receiving ART was small and that patients receiving ART may have had relatively lowCD4 T-cell counts, potentially resulting in bias against finding a protective effect of ART in this observational study. Finally, tuberculosis transmission within households was relatively uncommon among adults. While it had previously been shown that HIV-negative patients with tuberculosis contributed disproportionally to tuberculosis prevalence and, therefore, presumably to tuberculosis transmission among miners [14], Middelkoop et al suggest a disproportional impact of HIV-negative tuberculosis patients on transmission in the general population, using a molecular epidemiological approach. What are the implications of these study findings for strategies and further studies to control tuberculosis in settings with a high HIV prevalence? First, given the limited uptake of ART in this setting, demonstration studies are needed to show the impact of the scale up of ART on tuberculosis transmission and incidence as the new WHO ART guidelines are being implemented. While initial results [3] and modeling studies [10, 12] are encouraging, monitoring tuberculosis incidence in patients with and those without HIV infection in relation to the roll out of ART is important to determine the extent to which the predicted impact is, indeed, achieved [15]. In the short term, ART is likely to reduce the incidence of tuberculosis among the HIVinfected individuals receiving ART [16], although this effect may be less pronounced over time as ART increases life expectancy and may, thus, increase the cumulative lifetime risk of tuberculosis [12]. However, over time ART may reduce the prevalence of HIV infection [17] and, thus, reduce the size of the population particularly susceptible to tuberculosis. Second, it is clear that HIV-focused interventions will not be sufficient. Protection of the HIV-infected population requires a reduction of their exposure to non– HIV-infected index cases. In settings such as in Cape Town, very limited benefit may be expected from interventions in the households of tuberculosis cases [13, 18]. While intensified case finding is theoretically appealing, it has yieldedmixed results to date [4, 8, 9]. Further work is needed to Received 15 July 2014; accepted 15 July 2014; electronically published 22 July 2014. Correspondence: Martien W. Borgdorff, PhD, Centers for Disease Control, 4100 Kisumu, Kenya (mborgdorff@cdc.gov). The Journal of Infectious Diseases 2015;211:8–9 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. Thiswork iswritten by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/infdis/jiu404

Genetic Mutations Occur Gradually in In Vivo Populations of Mycobacterium tuberculosis Bacteria

Benjamin et al. (1) reported that two Mycobacterium tuberculosis isolates (isolated from the same bronchoscope 2 days apart) demonstrated distinct, but similar IS6110 restriction fragment length polymorphism (RFLP) patterns, as well as slightly different spoligopatterns. They interpreted this finding as the result of a single transposition event of IS6110 and mentioned as its possible explanation (i) that the transposed strain was a rare constituent of the M. tuberculosis population or (ii) that adverse bacterial conditions stimulated the transpositional event. We think these explanations represent different angles of the same phenomenon and may be explained by our previous observations (2). n nWe showed with single-colony cultures that M. tuberculosis populations can consist of subpopulations with different IS6110 RFLP patterns (2). The occurrence of these mixed bacterial populations in M. tuberculosis isolates was associated with increased patient age. Therefore, it seems likely that, in the human body, bacterial populations change gradually over time. That specific growing conditions play a role in the occurrence of transpositions of IS6110 was confirmed in our earlier study of 544 patients with serial isolates, for whom we found that the change of IS6110 RFLP patterns of M. tuberculosis isolates was associated with extrapulmonary disease (3). n nIn conclusion, mutations in populations of M. tuberculosis bacteria, promoted by specific growing conditions, occur gradually, resulting in a different DNA fingerprinting pattern for part of a given M. tuberculosis population compared to the predominant pattern of the larger part of that population. If a part of a population of M. tuberculosis bacteria is typed, only the DNA fingerprinting pattern of that part of the population is revealed. This could explain why Benjamin et al. found slightly different RFLP and spoligotype patterns for the patient isolate and the isolate of the bronchoscope contaminant. Further experimental research is needed to determine in how far adverse bacterial conditions, i.e., conditions comparable to those in the bronchoscope, can stimulate transpositional events.

Assessing the impact of antiretroviral therapy on tuberculosis notification rates among people with HIV: a descriptive analysis of 23 countries in sub-Saharan Africa, 2010–2015

BackgroundHIV is a major driver of the tuberculosis epidemic in sub-Saharan Africa. The population-level impact of antiretroviral therapy (ART) scale-up on tuberculosis rates in this region has not been well studied. We conducted a descriptive analysis to examine evidence of population-level effect of ART on tuberculosis by comparing trends in estimated tuberculosis notification rates, by HIV status, for countries in sub-Saharan Africa.MethodsWe estimated annual tuberculosis notification rates, stratified by HIV status during 2010–2015 using data from WHO, the Joint United Nations Programme on HIV/AIDS, and the United Nations Population Division. Countries were included in this analysis if they had ≥4xa0years of HIV prevalence estimates andu2009≥u200975% of tuberculosis patients with known HIV status. We compared tuberculosis notification rates among people living with HIV (PLHIV) and people without HIV via Wilcoxon rank sum test.ResultsAmong 23 included countries, the median annual average change in tuberculosis notification rates among PLHIV during 2010–2015 was -5.7% (IQR -6.9 to -1.7%), compared to a median change of -2.3% (IQR -4.2 to -0.1%) among people without HIV (p-valueu2009=u20090.0099). Among 11 countries with higher ART coverage, the median annual average change in TB notification rates among PLHIV was -6.8% (IQR -7.6 to -5.7%) compared to a median change of -2.1% (IQR -6.0 to 0.7%) for PLHIV in 12 countries with lower ART coverage (pu2009=u20090.0106).ConclusionTuberculosis notification rates declined more among PLHIV than people without HIV, and have declined more in countries with higher ART coverage. These results are consistent with a population-level effect of ART on decreasing TB incidence among PLHIV. To further reduce TB incidence among PLHIV, additional scale-up of ART as well as greater use of isoniazid preventive therapy and active case-finding will be necessary.

Reduction of HIV-associated excess mortality by antiretroviral treatment among tuberculosis patients in Kenya

Background Mortality from TB continues to be a global public health challenge. TB ranks alongside Human Immunodeficiency Virus (HIV) as the leading infectious causes of death globally. HIV is a major driver of TB related morbidity and mortality while TB is the leading cause of mortality among people living with HIV/AIDS. We sought to determine excess mortality associated with HIV and the effect of antiretroviral therapy on reducing mortality among tuberculosis patients in Kenya. Methods We conducted a retrospective analysis of Kenya national tuberculosis program data of patients enrolled from 2013 through 2014. We used direct standardization to obtain standardized mortality ratios for tuberculosis patients compared with the general population. We calculated the population attributable fraction of tuberculosis deaths due to HIV based on the standardized mortality ratio for deaths among TB patients with HIV compared to TB patients without HIV. We used Cox proportional hazards regression for assessing risk factors for mortality. Results Of 162,014 patients included in the analysis, 6% died. Mortality was 10.6 (95% CI: 10.4–10.8) times higher among TB patients than the general population; 42% of deaths were attributable to HIV infection. Patients with HIV who were not receiving ART had an over four-fold risk of death compared to patients without HIV (aHR = 4.2, 95% CI 3.9–4.6). In contrast, patients with HIV who were receiving ART had only 2.6 times the risk of death (aHR = 2.6, 95% CI 2.5–2.7). Conclusion HIV was a significant contributor to TB-associated deaths in Kenya. Mortality among HIV-infected individuals was higher among those not on ART than those on ART. Early initiation of ART among HIV infected people (a “test and treat” approach) should further reduce TB-associated deaths.