Valeria Saraceni

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.

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

BACKGROUNDnPreventive 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.nnnMETHODSnWe 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.nnnRESULTSnOf 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).nnnINTERPRETATIONnOperational 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.nnnFUNDINGnBill & 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.

Higher incidence of Zika in adult women than adult men in Rio de Janeiro suggests a significant contribution of sexual transmission from men to women

OBJECTIVESnThe recent emergence of Zika in Brazil and its association with an increased rate of congenital malformations has raised concerns over its impact on the birth rate in the country. Using data on the incidence of Zika in 2015-2016 and dengue in 2013 and 2015-2016 for the city of Rio de Janeiro (population 6.4 million), a massive increase of Zika in women compared to men was documented.nnnMETHODSnThe age-adjusted incidence was compared between men and women. A negative binomial Poisson generalized linear model was fitted to the Zika incidence data to determine the significance of sexual transmission statistically.nnnRESULTSnEven after correcting for the bias due to the systematic testing of pregnant women for Zika, there were found to be 90% more registered cases per 100000 women than men in the sexually active age group (15-65 years); this was not the case for age groups <15 years and >65 years. Assuming that infected men transmit the disease to women in their semen, but that the converse is not true, some extra incidence in women is to be expected. An alternate hypothesis would be that women visit doctors more often than men. To test this, the incidence of dengue fever was compared in men and women in 2015 and in 2013 (before Zika reached Rio de Janeiro): in both years, women were 30% more likely to be reported with dengue.nnnCONCLUSIONnWomen in the sexually active age group are far more likely to get Zika than men (+90% increase); sexual transmission is the most probable cause. Women in the 15-65 years age group are also 30% more likely to be reported with dengue than men, which is probably due to women being more careful with their health.

Trends and characteristics of AIDS mortality in the Rio de Janeiro city after the introduction of highly active antiretroviral therapy

We examined the characteristics of AIDS mortality in Rio de Janeiro city from 1995 to 2003. During this period, highly active antiretroviral therapy with protease inhibitors was made available, and it changed the pattern of the epidemics. There was a 47.5% reduction in the number of AIDS deaths within the period, with an increase in the proportion of women among the deceased; their schooling was lower than that of the men, similar to the trends of the national-level epidemics. The main place of death changed from university hospitals to emergency rooms. The proportion of cases reported to the National Diseases Surveillance System (SINAN) reported only through the death certificate remained high. Although there is free distribution of antiretrovirals by the public health system, many patients still lack access to diagnosis and treatment. We need to give priority to access to anti-HIV testing and treatment, to increase the quality of care and to look into the issue of adherence in order to further reduce AIDS mortality.

Zika in Rio de Janeiro: Assessment of basic reproductive number and its comparison with dengue

Zika virus infection was declared a public health emergency of international concern in February 2016 in response to the outbreak in Brazil and its suspected link with congenital anomalies. In this study we use notification data and disease natural history parameters to estimate the basic reproduction number (R0) of Zika in Rio de Janeiro, Brazil. We also obtain estimates of R0 of dengue from time series of dengue cases in the outbreaks registered in 2002 and 2012 in the city, when DENV-3 and DENV-4 serotypes respectively, had just emerged. Our estimates of the basic reproduction number for Zika in Rio de Janeiro based on surveillance notifications (R0 = 2.33, 95% CI: 1.97 − 2.97) were higher than those obtained for dengue in the city (year 2002: R0 = 1.70 [1.50 − 2.02]; year 2012: Ro = 1.25 [1.18 − 1.36]). Given the role of Aedes aegypti as vector of both the Zika and dengue viruses, we also derive Ro of Zika as a function of both dengue reproduction number and entomological and epidemiological parameters for dengue and Zika. Using the dengue outbreaks from previous years allowed us to estimate the potential R0 of Zika. Our estimates were closely in agreement with our first Zika’s R0 estimation from notification data. Hence, these results validate deriving the potential risk of Zika transmission in areas with recurring dengue outbreaks. Whether transmission routes other than vector-based can sustain a Zika epidemic still deserves attention, but our results suggest that the Zika outbreak in Rio de Janeiro emerged due to population susceptibility and ubiquitous presence of Ae. aegypti.

Zika in Rio de Janeiro: assessment of basic reproduction number and comparison with dengue outbreaks

Zika virus infection was declared a public health emergency of international concern in February 2016 in response to the outbreak in Brazil and its suspected link with congenital anomalies. In this study, we use notification data and disease natural history parameters to estimate the basic reproduction number (R 0) of Zika in Rio de Janeiro, Brazil. We also obtain estimates of R 0 of dengue from time series of dengue cases in the outbreaks registered in 2002 and 2012 in the city, when DENV-3 and DENV-4 serotypes, respectively, had just emerged. Our estimates of the basic reproduction number for Zika in Rio de Janeiro based on surveillance notifications (R 0 = 2·33, 95% CI: 1·97-2·97) were higher than those obtained for dengue in the city (year 2002: R 0 = 1·70 [1·50-2·02]; year 2012: R 0 = 1·25 [1·18-1·36]). Given the role of Aedes aegypti as vector of both the Zika and dengue viruses, we also derive R 0 of Zika as a function of both dengue reproduction number and entomological and epidemiological parameters for dengue and Zika. Using the dengue outbreaks from previous years allowed us to estimate the potential R 0 of Zika. Our estimates were closely in agreement with our first Zikas R 0 estimation from notification data. Hence, these results validate deriving the potential risk of Zika transmission in areas with recurring dengue outbreaks. Whether transmission routes other than vector-based can sustain a Zika epidemic still deserves attention, but our results suggest that the Zika outbreak in Rio de Janeiro emerged due to population susceptibility and ubiquitous presence of Ae. aegypti.

Tuberculosis control in a socially vulnerable area: a community intervention beyond DOT in a Brazilian favela.

OBJECTIVESnTo evaluate the population-based impact of a comprehensive intervention to strengthen tuberculosis (TB) control in Rocinha, the largest urban slum in Rio de Janeiro, Brazil.nnnDESIGNnIn July 2003, 40 lay persons were hired and trained as community health workers to supervise treatment, implement educational activities and establish a supportive social network for anti-tuberculosis treatment. Between July 2005 and June 2008, a door-to-door active case finding campaign was conducted. Data were obtained from the Brazilian National Reporting System, which collects information from the TB notification form for every reported case.nnnRESULTSnBetween January 2001 and December 2008, 2623 TB cases were reported, 852 before and 1771 after the start of the program. Following the intervention, treatment success rates increased (67.6% vs. 83.2%, P < 0.001) and default rates dropped (17.8% vs. 5.5%, P < 0.001). Compared to the pre-intervention period, the TB case rate declined by an average of 39 cases per 100,000 population per 6 months (P = 0.003) in the post-intervention period, although this may have been due to secular trends already in place at the start of the intervention. Case rates declined from 591/100,000 in 2001 to 496/100,000 in 2008.nnnCONCLUSIONnWith proper planning and effective community involvement, a successful intervention can lead to high cure rates and may contribute to a decrease in TB notification rates.

Tuberculose como doença definidora de síndrome da imunodeficiência adquirida: dez anos de evolução na Cidade do Rio de Janeiro

OBJETIVO: Analisar a frequencia da tuberculose e das outras principais doencas oportunistas definidoras de sindrome da imunodeficiencia adquirida, no momento em que estes casos sao notificados, no Municipio do Rio de Janeiro. METODOS: Analise do banco de dados do Sistema de Vigilância Epidemiologica do Programa de Doencas Sexualmente Transmissiveis e Sindrome da Imunodeficiencia Adquirida da Cidade do Rio de Janeiro, no periodo de 1993 a 2002. RESULTADOS: A expansao da definicao de casos de sindrome da imunodeficiencia adquirida ocorrida em 1998 criou um aumento substancial no numero de casos notificados de sindrome da imunodeficiencia adquirida, principalmente por aqueles que passaram a ser definidos pelo criterio imunologico. Dentre os casos de sindrome da imunodeficiencia adquirida que foram definidos apenas por doenca, a candidiase em suas diversas formas manteve-se como a doenca oportunista de maior frequencia no momento da notificacao. Embora a pneumonia por Pneumocystis carinii se apresentasse como a segunda doenca mais frequente na maioria dos anos observados, a partir de 2001, a tuberculose ultrapassou-a em frequencia, tornando-se a segunda doenca mais frequente no momento da notificacao dos casos de sindrome da imunodeficiencia adquirida. CONCLUSAO: Apesar da diminuicao do numero de casos de sindrome da imunodeficiencia adquirida definidos por doenca, a tuberculose manteve-se como um importante evento definidor dessa sindrome, sendo atualmente de ocorrencia mais frequente do que a pneumonia por Pneumocystis carinii e a toxoplasmose, provavelmente por sua alta taxa de prevalencia na cidade.OBJECTIVEnTo analyze the frequency of tuberculosis and of the other principal opportunistic infections defining acquired immunodeficiency syndrome at the time such cases were reported in the city of Rio de Janeiro, Brazil.nnnMETHODSnAnalysis of the data compiled in the Rio de Janeiro Municipal Program for the Surveillance of Sexually Transmitted Diseases and Acquired Immunodeficiency Syndrome database from 1993 to 2002.nnnRESULTSnThe expanded definition of a case of acquired immunodeficiency syndrome, implemented in 1998, resulted in a substantial increase in the number of reported cases of acquired immunodeficiency syndrome, especially of those defined by immunologic criteria. Among the cases of acquired immunodeficiency syndrome defined only by disease, esophageal candidiasis, in its various forms, remained the most common opportunistic infection present at the time the cases of acquired immunodeficiency syndrome were reported. Although Pneumocystis carinii pneumonia was the second leading opportunistic infection in most of the years evaluated, it was surpassed by tuberculosis in 2001.nnnCONCLUSIONnDespite the decreased numbers of cases of acquired immunodeficiency syndrome defined by disease, tuberculosis remains a significant acquired immunodeficiency syndrome-defining event, currently more common than P. carinii pneumonia and toxoplasmosis. This is probably due to the high rate of tuberculosis prevalence in the city.