Jonathan E. Golub

The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil

Background:Tuberculosis is a common complication and leading cause of death in HIV infection. Antiretroviral therapy (ART) lowers the risk of tuberculosis, but may not be sufficient to control HIV-related tuberculosis. Isoniazid preventive therapy (IPT) reduces tuberculosis incidence significantly, but is not widely used. Methods:We analysed tuberculosis incidence in 11 026 HIV-infected patients receiving medical care at 29 public clinics in Rio de Janeiro, Brazil, between 1 September 2003 and 1 September 2005. Data were collected through a retrospective medical record review. We determined rates of tuberculosis in patients who received neither ART nor IPT, only ART, only IPT, or both ART and IPT. Results:The overall tuberculosis incidence was 2.28 cases/100 person-years (PY) [95% confidence interval (CI) 2.06–2.52]. Among patients who received neither ART nor IPT, incidence was 4.01/100 PY. Patients who received ART had an incidence of 1.90/100 PY (95% CI 1.66–2.17) and those treated with IPT had a rate of 1.27/100 PY (95% CI 0.41–2.95). The incidence among patients who received ART and IPT was 0.80/100 PY (95% CI 0.38–1.47). Multivariate Cox proportional hazards modeling revealed a 76% reduction in tuberculosis risk among patients receiving both ART and IPT (adjusted relative hazard 0.24; P < 0.001) after adjusting for age, previous tuberculosis diagnosis, and CD4 cell counts at baseline. Conclusion:The use of both IPT and ART in HIV-infected patients is associated with significantly reduced tuberculosis incidence. In conjunction with expanded access to ART, the wider use of IPT in patients with HIV will improve tuberculosis control in high burden areas.

Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort

Background:The World Health Organization recommends isoniazid preventive therapy (IPT) for preventing tuberculosis in HIV-infected adults, although few countries have instituted this policy. Both IPT and highly active antiretroviral therapy (HAART) used separately result in reductions in tuberculosis risk. There is less information on the combined effect of IPT and HAART. We assessed the effect of IPT, HAART or both IPT and HAART on tuberculosis incidence in HIV-infected adults in South Africa. Methods:Two clinical cohorts of HIV-infected patients were studied. Primary exposures were receipt of IPT and/or HAART and the primary outcome was incident tuberculosis. Crude incident rates and incident rate ratios were calculated and Cox proportional hazards models investigated associations with tuberculosis risk. Results:Among 2778 HIV-infected patients followed for 4287 person-years, 267 incident tuberculosis cases were diagnosed [incidence rate ratio (IRR) = 6.2/100 person-years; 95% CI 5.5–7.0]. For person-time without IPT or HAART, the IRR was 7.1/100 person-years (95% CI 6.2–8.2); for person-time receiving HAART but without IPT, the IRR was 4.6/100 person-years (95% CI 3.4–6.2); for person-time after IPT but prior to HAART, the IRR was 5.2/100 person-years (95% CI 3.4–7.8); during follow-up in patients treated with HAART after receiving IPT the IRR was 1.1/100 person-years (95% CI 0.02–7.6). Compared to treatment-naive patients, HAART-only patients had a 64% decreased hazard for tuberculosis [adjusted hazard ratio (aHR) = 0.36; 95% CI 0.25–0.51], and patients receiving HAART after IPT had a 89% reduced hazard (aHR = 0.11; 95% CI 0.02–0.78). Conclusion:Tuberculosis risk is significantly reduced by IPT in HAART-treated adults in a high-incidence operational setting in South Africa. IPT is an inexpensive and cost-effective strategy and our data strengthen calls for the implementation of IPT in conjunction with the roll-out of HAART.

Diagnostic accuracy of a urine lipoarabinomannan test for tuberculosis in hospitalized patients in a high HIV prevalence setting

Background:Effective tuberculosis (TB) control in HIV-prevalent settings is hindered by absence of accurate, rapid TB diagnostic tests. We evaluated the accuracy of a urine lipoarabinomannan (LAM) test for TB diagnosis in South Africa. Methods:Hospitalized adults with signs and/or symptoms of active TB were enrolled. Sputum smear microscopy and mycobacterial culture, mycobacterial blood culture, and HIV testing were performed. A spot urine specimen was tested for LAM. Results:Four hundred ninety nine participants were enrolled; 422 (84.6%) were HIV infected. In microbiologically confirmed TB patients, the LAM test was positive in 114 of 193 [sensitivity 59%, (95% confidence interval: 52 to 66)], including 112 of 167 [67% (59 to 74)] who were HIV infected. Among individuals classified as “not TB”, the LAM test was negative in 117 of 122 [specificity 96% (91 to 99)], including 83 of 88 [94% (87 to 98)] who were HIV infected. In confirmed TB patients, the LAM test was more sensitive than sputum smear microscopy (42%, 82 of 193, P < 0.001) and detected 56% (62 of 111) of those who were sputum smear negative. HIV infection [adjusted odds ratio (AOR 13.4)], mycobacteremia (AOR 3.21), and positive sputum smear (AOR 2.42) were risk factors for a positive LAM test. Conclusions:The urine LAM test detected a subset of HIV-infected patients with severe TB in whom sputum smear microscopy had suboptimal sensitivity. The combination of urine LAM testing and sputum smear microscopy is attractive for use in settings with high HIV burden.

Body mass index and risk of tuberculosis and death.

Background:High BMI has been shown to be protective against tuberculosis (TB) among HIV-uninfected individuals, as well as against disease progression and mortality among those with HIV. We examined the effect of BMI on all-cause mortality and TB incidence among a cohort of HIV-infected adults in Soweto, South Africa. Methods:A clinical cohort of 3456 HIV-infected adults from South Africa was prospectively followed from 2003 to 2008 with regular monitoring. The primary exposure was BMI and the outcomes of interest were all-cause mortality and a newly diagnosed episode of TB. Cox proportional hazard models assessed associations with risk of mortality or incident TB. Results:Incidence rates of mortality were 10.4/100 person-years for baseline BMI of 18.5 or less, 3.6/100 person-years for baseline BMI 18.6–25, 1.7/100 person-years for baseline BMI 25.1–30, and 1.6/100 person-years for baseline BMI more than 30. Compared to those with normal BMI, overweight and obese participants had a significantly reduced risk of mortality [adjusted hazard ratio 0.59 (95% confidence interval, CI 0.40–0.87) and 0.48 (95% CI 0.29–0.80), respectively]. Incidence rates of TB by baseline BMI were 7.3/100 person-years for underweight, 6.0/100 person-years for normal, 3.2/100 person-years for overweight, and 1.9/100 person-years for obese. Compared to those with normal BMI, those with overweight and obese BMI were at a significantly reduced risk of developing TB [adjusted hazard ratio 0.56 (95% CI 0.38–0.83) and 0.33 (95% CI 0.19–0.55), respectively]. Conclusion:HIV-infected individuals with obese and overweight BMI have a significantly reduced risk of both mortality and TB, after adjusting for HAART use and CD4 cell count.

Smoking and risk of tuberculosis incidence, mortality, and recurrence in South Korean men and women.

The authors explored the association of cigarette smoking with tuberculosis incidence, recurrence, and mortality. A 14-year prospective cohort study (1992-2006) was carried out in 1,294,504 South Koreans. Participants were grouped by smoking history, and the authors assessed tuberculosis incidence, mortality, and recurrence risk for each group. Unadjusted and adjusted Cox proportional hazards models were used to investigate the association between smoking history and the 3 outcomes of interest, adjusting for age and alcohol use. Compared with never smokers, current smokers had increased mortality from tuberculosis among both men (adjusted hazard ratio (HR) = 1.6, 95% confidence interval (CI): 1.3, 2.0) and women (HR = 1.6, 95% CI: 1.0, 2.4). Current male smokers had greater risk of incident tuberculosis than former smokers (HR = 1.4, 95% CI: 1.3, 1.5), and risk among current smokers increased with number of cigarettes smoked daily. In females, cigarette smoking was not associated with incident tuberculosis. There was interaction between smoking and sex for incidence (P = 0.00047). The effect of smoking was generally reduced with adjustment for body mass index. Among men, the highest alcohol consumption category (> or =100 g/day) was associated with risk of incident tuberculosis (HR = 1.5, 95% CI: 1.3, 1.7). This study provides longitudinal evidence that smoking increases risk of incident tuberculosis, mortality from tuberculosis, and tuberculosis recurrence.

Effect of improved tuberculosis screening and isoniazid preventive therapy on incidence of tuberculosis and death in patients with HIV in clinics in Rio de Janeiro, Brazil: a stepped wedge, cluster-randomised trial

BACKGROUND Preventive therapy for tuberculosis in patients with HIV is effective, but it has not been widely implemented in moderate or high-burden settings. We assessed the effect of widespread use of isoniazid preventive therapy on rates of tuberculosis and death in people with HIV in Brazil. METHODS We did a stepped wedge, cluster-randomised trial with patients actively enrolled in 29 HIV clinics in Rio de Janeiro. Clinic staff were trained in tuberculosis screening, use of tuberculin skin tests, and use of isoniazid preventive therapy. Clinics were randomly allocated a date to begin the intervention period, with two clinics beginning the intervention every 2 months starting from Sept 1, 2005. The primary outcome was tuberculosis incidence alone or combined with death in the control versus intervention periods until Aug 31, 2009. This trial is registered at ClinicalTrials.gov, number NCT00107887. RESULTS Of 17,413 patients in the cohort, 12,816 were eligible for the intervention. Overall, there were 475 tuberculosis cases and 838 deaths. The intervention increased the rate of patients receiving skin tests from 19 per 100 person-years to 59 per 100 person-years, and from 36 per 100 person-years to 144 per 100 person-years for those eligible for isoniazid preventive therapy. In the control period, 221 cases of tuberculosis were diagnosed (1.31 per 100 person-years) compared with 254 (1.10 per 100 person-years) in the intervention period (unadjusted hazard ratio [HR] 0.87; 95% CI 0.69-1.10). Rates of tuberculosis incidence or death were 3.64 and 3.04 per 100 person-years, respectively (0.76; 95% CI 0.66-0.87). When adjusted for age, sex, entry CD4 count, and use of antiretroviral therapy, the HR for tuberculosis was 0.73 (95% CI 0.54-0.99) and for tuberculosis or death was 0.69 (0.57-0.83). INTERPRETATION Operational training aimed at increasing tuberculosis screening, provision of tuberculin skin tests, and use of isoniazid preventive therapy in Brazilian HIV clinics significantly reduced incident tuberculosis and death. Thus, scale-up of preventive therapy for HIV-infected patients in settings of moderate tuberculosis incidence is achievable and should be widely implemented in Brazil and elsewhere. FUNDING Bill & Melinda Gates Foundation and the National Institutes of Health.

Heterogeneity in tuberculosis transmission and the role of geographic hotspots in propagating epidemics

The importance of high-incidence “hotspots” to population-level tuberculosis (TB) incidence remains poorly understood. TB incidence varies widely across countries, but within smaller geographic areas (e.g., cities), TB transmission may be more homogeneous than other infectious diseases. We constructed a steady-state compartmental model of TB in Rio de Janeiro, replicating nine epidemiological variables (e.g., TB incidence) within 1% of their observed values. We estimated the proportion of TB transmission originating from a high-incidence hotspot (6.0% of the city’s population, 16.5% of TB incidence) and the relative impact of TB control measures targeting the hotspot vs. the general community. If each case of active TB in the hotspot caused 0.5 secondary transmissions in the general community for each within-hotspot transmission, the 6.0% of people living in the hotspot accounted for 35.3% of city-wide TB transmission. Reducing the TB transmission rate (i.e., number of secondary infections per infectious case) in the hotspot to that in the general community reduced city-wide TB incidence by 9.8% in year 5, and 29.7% in year 50—an effect similar to halving time to diagnosis for the remaining 94% of the community. The importance of the hotspot to city-wide TB control depended strongly on the extent of TB transmission from the hotspot to the general community. High-incidence hotspots may play an important role in propagating TB epidemics. Achieving TB control targets in a hotspot containing 6% of a city’s population can have similar impact on city-wide TB incidence as achieving the same targets throughout the remaining community.

Recurrent tuberculosis in HIV-infected patients in Rio de Janeiro, Brazil.

Background/objective:The risk of recurrent tuberculosis may increase in HIV-infected patients due to exogenous reinfection. We measured the frequency of and determined risk factors for recurrent tuberculosis in a cohort of HIV-infected patients in Rio de Janeiro, Brazil. Methods:Data were abstracted from medical records of HIV-infected patients attending 29 HIV clinics between 1998 and 2007. Patients analyzed were those who had no tuberculosis history prior to their first HIV clinic visit and who had at least one episode of tuberculosis after entry. Incidence rate ratios compared incidence rates between risk groups and Cox proportional hazards regression models evaluated unadjusted and adjusted associations. Results:Among 1080 HIV-infected patients with tuberculosis, 96 (8.9%) developed a recurrent diagnosis. The median time between diagnoses was 2.4 years. Fewer patients with recurrent tuberculosis had completed their initial 6-month course of tuberculosis treatment compared with patients without recurrence (78 versus 86%; P = 0.02). For patients who completed therapy, the incidence rate of recurrence was 2.5/100 versus 9.0/100 person-years for noncompleters (incidence rate ratio, 3.60; 95% confidence interval, 1.92–6.32). In multivariate modeling, initial tuberculosis treatment completion, receipt of antiretroviral therapy, and CD4 cell count more than 200 mm−3 any time after the initial diagnosis were associated with a significantly decreased hazard of recurrence. Conclusion:Tuberculosis recurrence rates were high in this HIV-infected population. Completion of initial tuberculosis therapy, use of antiretroviral therapy, and increases in CD4 cell counts were associated with lower recurrence rates. Use of secondary preventive therapy might be warranted to reduce the burden of tuberculosis in patients with HIV infection.

Community-based Targeted Case Finding for Tuberculosis and HIV in Household Contacts of Patients with Tuberculosis in South Africa

RATIONALE South Africa has a high prevalence of tuberculosis (TB) and HIV-coinfected adults in whom TB is often diagnosed late in the course of disease. OBJECTIVES Improved case-finding approaches for TB and HIV are needed to reduce mortality and prevent transmission. METHODS We identified newly diagnosed index TB cases in a rural district and enrolled their households in a TB-HIV contact-tracing study. A group of randomly selected control households were enrolled to determine community prevalence of undetected TB and HIV. Field teams screened participants for TB symptoms, collected sputum specimens for smear microscopy and culture, provided HIV counseling and testing, and collected blood for CD4 testing. Participants were referred to public clinics for TB treatment and antiretroviral therapy. MEASUREMENTS AND MAIN RESULTS We evaluated 2,843 household contacts of 727 index patients with TB and 983 randomly selected control household members. The prevalence of TB in household contacts was 6,075 per 100,000 (95% confidence interval, 5,789-6,360 per 100,000), whereas the prevalence detected in randomly selected households was 407 per 100,000 (95% confidence interval, 0-912 per 100,000; prevalence difference, 5,668 per 100,000; P < 0.001). TB detected among contacts was less likely to be smear-positive than in the index patients (6% vs. 22%; P < 0.001). Most contacts with culture-confirmed TB were asymptomatic. At least one case of undiagnosed TB was found in 141 (19%) of 727 contact versus 4 (1%) of 312 control households. HIV testing was positive in 166 (11%) of 1,568 contacts tested versus 76 (14%) of 521 control participants tested (odds ratio, 1.48; P = 0.02). CONCLUSIONS Active case finding in TB contact households should be considered to improve TB and HIV case detection in high-prevalence settings, but sensitive diagnostic tools are necessary.

Impact and Cost-Effectiveness of Culture for Diagnosis of Tuberculosis in HIV-Infected Brazilian Adults

Background Culture of Mycobacterium tuberculosis currently represents the closest “gold standard” for diagnosis of tuberculosis (TB), but operational data are scant on the impact and cost-effectiveness of TB culture for human immunodeficiency (HIV-) infected individuals in resource-limited settings. Methodology/Principal Findings We recorded costs, laboratory results, and dates of initiating TB therapy in a centralized TB culture program for HIV-infected patients in Rio de Janeiro, Brazil, constructing a decision-analysis model to estimate the incremental cost-effectiveness of TB culture from the perspective of a public-sector TB control program. Of 217 TB suspects presenting between January 2006 and March 2008, 33 (15%) had culture-confirmed active tuberculosis; 23 (70%) were smear-negative. Among smear-negative, culture-positive patients, 6 (26%) began TB therapy before culture results were available, 11 (48%) began TB therapy after culture result availability, and 6 (26%) did not begin TB therapy within 180 days of presentation. The cost per negative culture was US