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1.  Risk factors for default from tuberculosis treatment in HIV-infected individuals in the state of Pernambuco, Brazil: a prospective cohort study 
BMC Infectious Diseases  2011;11:351.
Concomitant treatment of Human Immunodeficiency Virus (HIV) infection and tuberculosis (TB) presents a series of challenges for treatment compliance for both providers and patients. We carried out this study to identify risk factors for default from TB treatment in people living with HIV.
We conducted a cohort study to monitor HIV/TB co-infected subjects in Pernambuco, Brazil, on a monthly basis, until completion or default of treatment for TB. Logistic regression was used to calculate crude and adjusted odds ratios, 95% confidence intervals and P-values.
From a cohort of 2310 HIV subjects, 390 individuals (16.9%) who had started treatment after a diagnosis of TB were selected, and data on 273 individuals who completed or defaulted on treatment for TB were analyzed. The default rate was 21.7% and the following risk factors were identified: male gender, smoking and CD4 T-cell count less than 200 cells/mm3. Age over 29 years, complete or incomplete secondary or university education and the use of highly active antiretroviral therapy (HAART) were identified as protective factors for the outcome.
The results point to the need for more specific actions, aiming to reduce the default from TB treatment in males, younger adults with low education, smokers and people with CD4 T-cell counts < 200 cells/mm3. Default was less likely to occur in patients under HAART, reinforcing the strategy of early initiation of HAART in individuals with TB.
PMCID: PMC3297544  PMID: 22176628
2.  A systematic review of delay in the diagnosis and treatment of tuberculosis 
BMC Public Health  2008;8:15.
Early diagnosis and immediate initiation of treatment are essential for an effective tuberculosis (TB) control program. Delay in diagnosis is significant to both disease prognosis at the individual level and transmission within the community. Most transmissions occur between the onset of cough and initiation of treatment.
A systematic review of 58 studies addressing delay in diagnosis and treatment of TB was performed. We found different definitions of, for example, debut of symptoms, first appropriate health care provider, time to diagnosis, and start of treatment. Rather than excluding studies that failed to meet strict scientific criteria (like in a meta-analysis), we tried to extract the "solid findings" from all of them to arrive on a more global understanding of diagnostic delay in TB.
The main factors associated with diagnostic delay included human immunodeficiency virus; coexistence of chronic cough and/or other lung diseases; negative sputum smear; extrapulmonary TB; rural residence; low access (geographical or sociopsychological barriers); initial visitation of a government low-level healthcare facility, private practitioner, or traditional healer; old age; poverty; female sex; alcoholism and substance abuse; history of immigration; low educational level; low awareness of TB; incomprehensive beliefs; self-treatment; and stigma.
The core problem in delay of diagnosis and treatment seemed to be a vicious cycle of repeated visits at the same healthcare level, resulting in nonspecific antibiotic treatment and failure to access specialized TB services. Once generation of a specific diagnosis was in reach, TB treatment was initiated within a reasonable period of time.
PMCID: PMC2265684  PMID: 18194573
3.  Patient and health service delay in pulmonary tuberculosis patients attending a referral hospital: a cross-sectional study 
BMC Public Health  2005;5:122.
Delays in diagnosis and initiation of effective treatment increase morbidity and mortality from tuberculosis as well as the risk of transmission in the community. The aim of this study was to determine the time taken for patients later confirmed as having TB to present with symptoms to the first health provider (patient delay) and the time taken between the first health care visit and initiation of tuberculosis treatment (health service delay). Factors relating to these 'delays' were analyzed.
A cross-sectional survey, of 231 newly diagnosed smear-positive tuberculosis patients was conducted in Mulago National referral Hospital Kampala, from January to May 2002. Socio-demographic, lifestyle and health seeking factors were evaluated for their association with patient delay (>2 weeks) and health service delay (>4 weeks), using odds ratios with 95% confidence intervals (CI) including multivariate logistic regression.
The median total delay to treatment initiation was 12 weeks. Patients often presented to drug shops or pharmacies (39.4%) and private clinics (36.8%) more commonly than government health units (14%) as initial contacts. Several independent predictors of 'patient delay' were identified: being hospitalized (odds ratio [0R] = 0.32; 95% CI: 0.12–0.80), daily alcohol consumption (OR = 3.7; CI: 1.57–9.76), subsistence farming (OR = 4.70; CI: 1.67–13.22), and perception of smoking as a cause of TB (OR = 5.54; CI: 2.26–13.58). Independent predictors of 'health service delay' were: >2 health seeking encounters per month (OR = 2.74; CI: 1.10–6.83), and medical expenditure on TB related symptoms >29 US dollars (OR = 3.88; CI: 1.19–12.62). Perceived TB stigma and education status was not associated with either form of delay.
Delay in diagnosis of TB is prolonged at the referral centre with a significant proportion of Health service delay. More specific and effective health education of the general public on tuberculosis and seeking of appropriate medical consultation is likely to improve case detection. Certain specific groups require further attention. Alcoholics and subsistence farmers should be targeted to improve accessibility to TB treatment. Continuing medical education about TB management procedures for health providers and improvement in the capacity of TB control services should be undertaken.
PMCID: PMC1310609  PMID: 16307685
pulmonary tuberculosis; health-seeking behavior; treatment delay
4.  Delays in diagnosis and treatment of pulmonary tuberculosis in Wakiso and Mukono districts, Uganda 
BMC Public Health  2014;14:586.
Delay in tuberculosis (TB) diagnosis may worsen the disease and increase TB transmission. Therefore, timely diagnosis and treatment is critical in TB control. We aimed to assess the treatment delay of pulmonary TB and its determinants in two Ugandan districts where TB infection control (TBIC) guidelines were formerly implemented.
A facility based cross-sectional study was conducted in Mukono and Wakiso districts. Adult pulmonary TB patients within three months of initiating treatment were included in the study. Delays were categorized into unacceptable patient delay (more than 3 weeks from the onset of cough and the first consultation with a health care provider), health service (more than one week from the first consultation to the initiation of TB treatment) and total delay (more than 4 weeks since the onset of cough). The prevalences as well as predictors for the three delays were determined.
We enrolled 158 sputum positive patients. Unacceptable patient delay was noted in 91 (58%) patients, a health service delay in 140 (88%) patients and a total delay in 140 (90%) patients. An independent predictor for patient delay was male gender (p < 0.001). First visiting a non-public health facility (p = 0.001) was an independent predictor of health service delay.
There is still a significant TB diagnosis and treatment delay in Uganda. Most of the delay was caused by health system delay in the non-public health care sector. There is need for TB advocacy in the community, training of health workers in TBIC and strengthening public-private partnerships in TB control.
PMCID: PMC4078937  PMID: 24916459
TB treatment delay; Patient delay; Health service delay; TB infection control; Uganda
5.  Patient and heath system delays in the diagnosis and treatment of new and retreatment pulmonary tuberculosis cases in Malawi 
BMC Infectious Diseases  2014;14:132.
Tuberculosis (TB) control remains a challenge in Malawi despite the National TB Control Program since 1984. This study aimed at measuring patient and health system delays and identifying factors associated with these delays.
A cross-sectional survey of 588 pulmonary TB patients was conducted in three TB centres in Blantyre, Lilongwe, and Mzuzu, between July and December 2011 using a semi-structured questionnaire. Patient delay was defined as the time interval between the onset of TB symptom(s) (a common symptom being coughing) to the first visit to any health provider. Health system delay was the interval from the first care-seeking visit at any health provider to the initiation of anti-tuberculosis treatment. Participants were invited to participate in the study during intensive phase of treatment. The characteristics associated with patient and health system delays were analyzed.
The median patient delay was 14 days for both new and retreatment TB cases (interquartile range [IQR] 14 – 28 and 7 – 21, respectively). The median health system delay was 59 days (IQR 26 – 108) for new and 40.5 days (IQR 21–90) for retreatment cases. Factors associated with longer patient delay in new cases included primary education (adjusted odds ratio [AOR] 2.2, 95% CI 1.3 – 3.9) and knowledge that more than three weeks of coughing is a sign of TB (AOR 1.9, 1.1 – 3.3). In retreatment cases, distance >10 Km (AOR 3.3, 1.1 – 9.6) and knowledge that more than three weeks of coughing is a sign of TB (AOR 3.7, 1.3 – 10.7; p < 0.05) were significant factors. Making the first visit to a health centre (OR 1.9, 0.9 – 3.8) or a drug store/ traditional healer (OR 5.1, 1.1 – 21.7) in new TB cases were associated with a longer health system delay (p < 0.05) while smear negative (OR 6.4, 1.5 – 28.3), and smear unknown or not done (OR 6.1, 1.3 – 26.9) among retreatment cases were associated with a longer health system delay (p < 0.05).
Effective management and new diagnostic techniques are needed especially among retreatment cases. It is also needed to address geographic barriers to accessing care and increasing TB awareness in the community.
PMCID: PMC3976046  PMID: 24606967
Patient delay; Health system delay; Tuberculosis; Case detection
6.  Effects of Tuberculosis on the Kinetics of CD4+ T Cell Count Among HIV-Infected Patients Who Initiated Antiretroviral Therapy Early After Tuberculosis Treatment 
The effects of tuberculosis (TB) on the kinetics of CD4+ T cells among HIV-infected individuals with early combination antiretroviral therapy (cART) after TB therapy initiation are poorly characterized. We conducted a case-control study with 15 HIV-TB-coinfected patients who initiated TB treatment and early cART, and 30 controls without TB who had similar CD4+ T cell counts and viral loads at the time of starting cART. We compared the rate of CD4+ T cell increase for 5 years after cART. The time to CD4+ T cell increase >250 cells/mm3 was significantly slower in HIV-TB-coinfected patients (p=0.015, by log rank test). HIV-TB-coinfected patients had significantly lower median CD4+ T cell counts at 5 years after cART (p=0.048). The difference in CD4+ T cell increase was observed only during the first 6 months after cART initiation (p=0.002). These data suggest that TB slows the rate of CD4+ T cell recovery at an early period after cART. The effects of TB on the long-term immunity of HIV-infected patients should be further evaluated.
PMCID: PMC3552174  PMID: 22881387
7.  Correlates of Delayed Diagnosis among Human Immunodeficiency Virus-Infected Pulmonary Tuberculosis Suspects in a Rural HIV Clinic, South Africa 
Background. Delay in pulmonary tuberculosis (PTB) diagnosis is one of the major factors that affect outcome and threatens continued spread of tuberculosis. This study aimed at determining factors associated with delayed PTB diagnosis among human immunodeficiency virus (HIV) infected individuals. Methods. A retrospective observational study was done using clinic records of HIV-infected PTB suspects attending an HIV/AIDS clinic at Tintswalo rural hospital in South Africa (SA) between January 2006 and December 2007. Using routine clinic registers, 480 records were identified. Results. PTB diagnosis delay was found among 77/176 (43.8%) of the patients diagnosed with PTB. The mean delay of PTB diagnosis was 170.6 days; diagnosis delay ranged 1–30 days in 27 (35.1%) patients, 31–180 days in 24 (33.8%) patients; 24 (31.2%) patients remained undiagnosed for ≥180 days. Independent factors associated with delayed diagnosis were: older age >40 years (Odds Ratio (OR) 3.43, 95% CI 1.45–8.08) and virological failure (OR 2.72, 95% CI 1.09–6.74). Conclusion. There is a considerable delayed PTB diagnosis among HIV-infected patients in rural SA. Older patients as well as patients with high viral load are at a higher risk of PTB diagnosis delay. Therefore efforts to reduce PTB diagnosis delay need to emphasised.
PMCID: PMC3384891  PMID: 22778946
8.  What Patient Factors Predict Physicians’ Decision Not to Treat Latent Tuberculosis Infection in Tuberculosis Contacts? 
PLoS ONE  2013;8(9):e76552.
The study aimed to determine factors that are associated with physicians’ decision to offer treatment for latent tuberculosis infection (LTBI) in contacts of patients with tuberculosis.
We performed a nested case-control study in a cohort of contacts of patients with pulmonary tuberculosis who had a tuberculin skin test (TST) ≥ 10 mm. Cases were those who were offered treatment for LTBI. Controls were randomly selected from those who were not offered treatment for LTBI by the reviewing physician. Odds ratios were estimated by multivariate logistic regression.
There were 195 cases and 279 controls. The following factors were significantly (positively or negatively) associated with being offered LTBI treatment in the multivariate analysis: female gender (OR 2.9; 95% CI 1.6–5.5), TST conversion (OR 3.9; 2.0–7.9), TST > 20 mm (OR 4.1; 1.8–9.1, for TST of 21–30 mm and OR 7.9; 2.6–23.8, for TST >30 mm), sputum smear positive index case (OR 12.7; 4.5–36.1), being overseas-born and immigration more than 2 years ago (OR 0.1; 0.06–0.3), being a health care worker (OR 0.2; 0.1–0.6), being a non-household contact of the TB index case (OR 0.3; 0.2–0.6) and age >35 years (OR 0.2; 0.1–0.5 for age 35 to 54.9 years and OR 0.04; 0.01–0.2 for age ≥55 years). Previous BCG vaccine and chest x-ray findings were not significantly associated with physicians’ decision to offer treatment for LTBI.
Most factors that influenced physicians’ decisions on treatment for LTBI were based on evidence of an association with risk of developing TB or risk of having an adverse reaction to treatment for LTBI. However, the decreased likelihood of offering treatment for LTBI to people born overseas, men and health care workers, was apparently not based on any evidence of risk. Efforts should be made to ensure that these groups are given access to treatment for LTBI.
PMCID: PMC3786986  PMID: 24098794
9.  The Effect of Diagnostic Delays on the Drop-Out Rate and the Total Delay to Diagnosis of Tuberculosis 
PLoS ONE  2008;3(4):e1933.
Numerous patient and healthcare system-related delays contribute to the overall delay experienced by patients from onset of TB symptoms to diagnosis and treatment. Such delays are critical as infected individuals remain untreated in the community, providing more opportunities for transmission of the disease and adversely affecting the epidemic.
Methodology/Principal Findings
We present an analysis of the factors that contribute to the overall delay in TB diagnosis and treatment, in a resource-poor setting. Impact on the distribution of diagnostic delay times was assessed for various factors, the sensitivity of the diagnostic method being found to be the most significant. A linear relationship was found between the sensitivity of the test and the predicted mean delay time, with an increase in test sensitivity resulting in a reduced mean delay time and a reduction in the drop-out rate.
The results show that in a developing country a number of delay factors, particularly the low sensitivity of the initial sputum smear microscopy test, potentially increase total diagnostic delay times experienced by TB patients significantly. The results reinforce the urgent need for novel diagnostic methods, both for smear positive and negative TB, that are highly sensitive, accessible and point of care, in order to reduce mean delay times.
PMCID: PMC2276686  PMID: 18398459
10.  Pulmonary Tuberculosis in Mumbai, India: Factors Responsible for Patient and Treatment Delays 
To determine the factors responsible for patient delay and treatment delay in newly diagnosed sputum smear-positive pulmonary tuberculosis (TB) patients.
Study subjects (N = 150) were randomly selected from municipal health centers in Mumbai, India. Duration of symptoms, treatment, and reason for delay were assessed using interviews and medical records. We defined patient delay as presentation to a health care provider (HCP) >20 days of the onset of TB-related symptoms and treatment delay as therapy initiated more than 14 days after the first consultation (for TB-related symptoms) with an HCP.
Of the 150 subjects, 29% had patient delays and 81% had treatment delays. In multivariable analysis, patient delay was significantly associated with the self-perception that initial symptoms were due to TB [odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.1–12.6] and perceived inability to pay for care (OR = 2.9, 95% CI = 1.2–7.1). Treatment delay was significantly associated with consulting a non-allopathic provider (OR = 12.3, 95% CI = 1.4–105) and consulting >3 providers (OR = 5.0, 95% CI = 1.4–17.4). Patient interval was half the treatment interval (median days: 15 vs. 31). Women were slightly more likely to experience patient and treatment delays than men. For two-thirds of the patients, another TB patient was a source of TB-related knowledge, while health education material (16%) and television (10%) played a smaller role.
Treatment delay, primarily due to diagnosis delay, was a greater problem than patient delay. Expanding public–public and public–private partnerships and regular training sessions for HCPs might decrease treatment delay. Media coverage and cured TB patients as peer advocates may help to reinforce TB-related health education messages.
PMCID: PMC3429805  PMID: 22973488
Patient delay; pulmonary tuberculosis; India; treatment delay
11.  Time from symptom onset to the initiation of treatment of pulmonary tuberculosis in a city with a high incidence of the diseasea 
To estimate the time elapsed between the onset of symptoms and the initiation of treatment of pulmonary tuberculosis among treatment-naïve patients with positive results in sputum smear microscopy, and to evaluate the variables associated with delays in diagnosis and in treatment initiation.
This was a descriptive exploratory study involving 199 treatment-naïve tuberculosis patients ≥ 12 years of age with AFB-positive sputum smear microscopy results between 2006 and 2008. At their first (treatment initiation) visit to a primary health care clinic in the city of Nova Iguaçu, Brazil, the patients were interviewed and their ancillary test results were reviewed.
The medians (and respective interquartile ranges) of the time from symptom onset to the initiation of treatment of pulmonary tuberculosis, from symptom onset to seeking medical attention, from entry into care to diagnosis, and from entry into care to treatment initiation, in weeks, were 11 (6-24), 8 (4-20), 2 (1-8), and 1 (1-1), respectively. The variables gender, age, level of education, previous use of antibiotics, HIV status, site of first medical visit, and radiological extent of tuberculosis showed no associations with the time from entry into care to diagnosis or to treatment initiation. The main reason for the delay in seeking medical attention reported by the patients was their inability to recognize their symptoms as indicators of a disease.
Among the patients studied, there was an unacceptably long delay between the onset of symptoms and the initiation of tuberculosis treatment.
PMCID: PMC3697913  PMID: 22576428
Tuberculosis/diagnosis; Tuberculosis/therapy; Delayed diagnosis
12.  Laboratory Reporting of Tuberculosis Test Results and Patient Treatment Initiation in California 
Journal of Clinical Microbiology  2004;42(9):4209-4213.
Prompt laboratory reporting of tuberculosis (TB) test results is necessary for TB control. To understand the extent of and factors contributing to laboratory reporting delays and the impact of reporting delays on initiation of treatment of TB patients, we analyzed data from 300 consecutive culture-positive TB cases reported in four California counties in 1998. Laboratory reporting to the specimen submitter was delayed for 26.9% of smear-positive patients and 46.8% of smear-negative patients. Delays were associated with the type of laboratory that performed the testing and with delayed transport of specimens. Referral laboratories (public health and commercial) had longer median reporting time frames than hospital and health maintenance organization laboratories. Among patients whose treatment was not started until specimens were collected, those with delayed laboratory reporting were more likely to have delayed treatment than patients with no laboratory reporting delays (odds ratio [OR] of 3.9 and 95% confidence interval [CI] of 1.6 to 9.7 for smear-positive patients and OR of 13.1 and CI of 5.3 to 32.2 for smear-negative patients). This relation remained after adjustment in a multivariate model for other factors associated with treatment delays (adjusted OR of 25.64 and CI of 7.81 to 83.33 for smear-negative patients). These findings emphasize the need to reduce times of specimen transfer between institutions and to ensure rapid communication among laboratories, health care providers, and health departments serving TB patients.
PMCID: PMC516353  PMID: 15365013
13.  Perceptions of Tuberculosis Patients on Provider-Initiated HIV Testing and Counseling - A Study from South India 
PLoS ONE  2009;4(12):e8389.
The acceptability and feasibility of provider-initiated HIV testing and counseling (PITC) in many settings across Asia with concentrated HIV epidemics is not known. A pilot study of the PITC policy undertaken within the public health care systems in two districts in India offered the opportunity to understand patient's perspectives on the process of referral for HIV testing and linking to HIV treatment and care.
We conducted a cross-sectional study of randomly selected TB patients registered by the TB control program between July and November 2007 in two districts in south India. Trained interviewers met patients shortly after TB diagnosis and administered a structured questionnaire. Patients were assessed regarding their experience with HIV status assessment, referral for counseling and testing, and for HIV-infected patients the counseling itself and subsequent referral for HIV treatment and care.
Of the 568 interviewed TB patients, 455 (80%) reported being referred for HIV testing after they presented to the health facility for investigations or treatment for TB. Over half the respondents reported having to travel long distances and incurred financial difficulties in reaching the Integrated Counselling and Testing Centre (ICTC) and two-thirds had to make more than two visits. Only 48% reported having been counseled before the test. Of the 110 HIV-infected patients interviewed, (including 43 with previously-known positive HIV status and 67 detected by PITC), 89 (81%) reported being referred for anti-retroviral treatment (ART); 82 patients reached the ART centre but only 44 had been initiated on ART.
This study provides the first evidence from India that routine, provider-initiated voluntary HIV testing of TB patients is acceptable, feasible and can be achieved with very high efficiency under programmatic conditions. While PITC is useful in identifying new HIV-infected patients so that they can be successfully linked to ART, the convenience and proximity of testing centres, quality of HIV counseling, and efficiency of ART services need attention.
PMCID: PMC2791227  PMID: 20041167
14.  Risk factors for treatment delay in pulmonary tuberculosis in Recife, Brazil 
BMC Public Health  2005;5:25.
Tuberculosis is still a great challenge to public health in Brazil and worldwide. Early detection followed by effective therapy is extremely important in controlling the disease. Recent studies have investigated reasons for delays in treatment, but there is no agreed definition of what constitutes an "acceptable" delay. This study investigates factors associated with total delay in treatment of tuberculosis.
A cohort of adult cases of pulmonary tuberculosis diagnosed over a two-year period was studied. Patients were interviewed on entry, reporting the duration of symptoms before the start of treatment, and sputum and blood samples were collected. It was decided that sixty days was an acceptable total delay. Associations were investigated using univariable and multivariable analysis and the population attributable fraction was estimated.
Of 1105 patients, 62% had a delay of longer than 60 days. Age, sex, alcoholism and difficulty of access were not associated with delays, but associations were found in the case of unemployment, having given up smoking, having lost weight and being treated in two of the six health districts. The proportion attributable to: not being an ex-smoker was 31%; unemployment, 18%; weight loss, 12%, and going to the two worst health districts, 25%.
In this urban area, delays seem to be related to unemployment and general attitudes towards health. Although they reflect the way health services are organized, delays are not associated with access to care.
PMCID: PMC1084352  PMID: 15777473
15.  Delays in starting antiretroviral therapy in patients with HIV-associated tuberculosis accessing non-integrated clinical services in a South African township 
BMC Infectious Diseases  2011;11:258.
Delays in the initiation of antiretroviral therapy (ART) in patients with HIV-associated tuberculosis (TB) are associated with increased mortality risk. We examined the timing of ART among patients receiving care provided by non-integrated TB and ART services in Cape Town, South Africa.
In an observational cohort study, we determined the overall time delay between starting treatment for TB and starting ART in patients treated in Gugulethu township between 2002 and 2008. For patients referred from TB clinics to the separate ART clinic, we quantified and identified risk factors associated with the two component delays between starting TB treatment, enrolment in the ART clinic and subsequent initiation of ART.
Among 893 TB patients studied (median CD4 count, 81 cells/μL), the delay between starting TB treatment and starting ART was prolonged (median, 95 days; IQR = 49-155). Delays were shorter in more recent calendar periods and among those with lower CD4 cell counts. However, the median delay was almost three-fold longer for patients referred from separate TB clinics compared to patients whose TB was diagnosed in the ART clinic (116 days versus 41 days, respectively; P < 0.001). In the most recent calendar period, the proportions of patients with CD4 cell counts < 50 cells/μL who started ART within 4 weeks of TB diagnosis were 11.1% for patients referred from TB clinics compared to 54.6% of patients with TB diagnosed in the ART service (P < 0.001).
Delays in starting ART were prolonged, especially for patients referred from separate TB clinics. Non-integration of TB and ART services is likely to be a substantial obstacle to timely initiation of ART.
PMCID: PMC3203070  PMID: 21957868
16.  Adverse events and treatment interruption in tuberculosis patients with and without HIV co‐infection 
Thorax  2006;61(9):791-794.
Serious treatment associated adverse events are thought to occur more frequently in individuals with tuberculosis (TB) who are co‐infected with HIV. A study was undertaken to assess the frequency of serious (grade III/IV) adverse events and interruption of anti‐TB treatment in the era of effective antiretroviral therapy.
The incidence of serious adverse events was retrospectively compared in 312 individuals treated for TB, 156 of whom were co‐infected with HIV.
111 HIV infected individuals (71%) received highly active antiretroviral therapy at the same time as anti‐TB treatment. Serious adverse events were recorded in 40% HIV infected and 26% HIV uninfected individuals (p = 0.008). Peripheral neuropathy and persistent vomiting were more common in co‐infected patients (p<0.001; p = 0.006), although all cause interruption of anti‐TB treatment occurred with similar frequency in the two groups (13% in HIV infected patients and 15% in HIV uninfected patients; p = 0.74). In 85% of HIV infected patients and 87% of HIV uninfected individuals this was due to hepatotoxicity, which typically presented within 2 months of starting treatment. The median delay in restarting treatment was 4 weeks, so most individuals required full TB re‐treatment.
Despite a greater rate of serious (grade III/IV) adverse events among HIV infected individuals, discontinuation of anti‐TB treatment occurred with a similar frequency in HIV infected and HIV uninfected individuals.
PMCID: PMC2117099  PMID: 16844730
tuberculosis; HIV; antiretroviral treatment; hepatotoxicity; neuropathy
17.  Predictors on Delay of Initial Health-Seeking in New Pulmonary Tuberculosis Cases among Migrants Population in East China 
PLoS ONE  2012;7(2):e31995.
To determine the length of delay in initial health-seeking in new pulmonary tuberculosis (PTB) cases among migrant population in the eastern part of China, and factors associated with it.
A cross-sectional study was conducted using a structured questionnaire in six counties in Shanghai, Guangdong and Jiangsu from May to October, 2008, to estimate the extent and factors responsible for delayed initial health-seeking of the new PTB cases. The interval between self-reported onset of TB symptoms and date of first attendance at any medical institution was determined. More than the median duration was defined as delayed health-seeking.
A total of 323 new migrant PTB patients participated in the study. Only 6.5% had medical insurance. The median and mean durations to initial health-seeking were respectively 10 and 31 days. There was no significant association between socio-demographic factors and delayed initial health-seeking. Average monthly working days >24 (AOR, 1.61; 95% CI, 1.03–2.51), and hemoptysis or bloody sputum (AOR, 0.48; 95% CI, 0.28–0.85) were significantly associated with delayed initial health-seeking.
Interventions to improve health seeking behavior among the migrant population in China must focus on strengthening their labor, medical security and health education.
PMCID: PMC3285186  PMID: 22384123
18.  Predictors of Multidrug- and Extensively Drug-Resistant Tuberculosis in a High HIV Prevalence Community 
PLoS ONE  2010;5(12):e15735.
Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) have emerged in high-HIV-prevalence settings, which generally lack laboratory infrastructure for diagnosing TB drug resistance. Even where available, inherent delays with current drug-susceptibility testing (DST) methods result in clinical deterioration and ongoing transmission of MDR and XDR-TB. Identifying clinical predictors of drug resistance may aid in risk stratification for earlier treatment and infection control.
We performed a retrospective case-control study of patients with MDR (cases), XDR (cases) and drug-susceptible (controls) TB in a high-HIV-prevalence setting in South Africa to identify clinical and demographic risk factors for drug-resistant TB. Controls were selected in a 1∶1∶1 ratio and were not matched. We calculated odds ratios (OR) and performed multivariate logistic regression to identify independent predictors.
We enrolled 116, 123 and 139 patients with drug-susceptible, MDR, and XDR-TB. More than 85% in all three patient groups were HIV-infected. In multivariate analysis, MDR and XDR-TB were each strongly associated with history of TB treatment failure (adjusted OR 51.7 [CI 6.6-403.7] and 51.5 [CI 6.4–414.0], respectively) and hospitalization more than 14 days (aOR 3.8 [CI 1.1–13.3] and 6.1 [CI 1.8–21.0], respectively). Prior default from TB treatment was not a risk factor for MDR or XDR-TB. HIV was a risk factor for XDR (aOR 8.2, CI 1.3–52.6), but not MDR-TB. Comparing XDR with MDR-TB patients, the only significant risk factor for XDR-TB was HIV infection (aOR 5.3, CI 1.0–27.6).
In this high-HIV-prevalence and drug-resistant TB setting, a history of prolonged hospitalization and previous TB treatment failure were strong risk factors for both MDR and XDR-TB. Given high mortality observed among patients with HIV and drug-resistant TB co-infection, previously treated and hospitalized patients should be considered for empiric second-line TB therapy while awaiting confirmatory DST results in settings with a high-burden of MDR/XDR-TB.
PMCID: PMC3012092  PMID: 21209951
19.  Pulmonary tuberculosis diagnostic delays in Chad: a multicenter, hospital-based survey in Ndjamena and Moundou 
BMC Public Health  2012;12:513.
Tuberculosis remains one of the leading causes of morbidity and mortality in low-resource countries. One contagious patient can infect 10 to 20 contacts in these settings. Delays in diagnosing TB therefore contribute to the spread of the disease and sustain the epidemic.
The aim of this study was to assess delays in diagnosing tuberculosis and the factors associated with these delays in the public hospitals in Moundou and Ndjamena, Chad.
A structured questionnaire was administered to 286 new tuberculosis patients to evaluate patient delay (time from the onset of symptoms to the first formal or informal care), health-care system delay (time from the first health care to tuberculosis treatment) and total delay (sum of the patient and system delays). Logistic regression was used to identify risk factors associated with long diagnostic delays (defined as greater than the median).
Results and discussion
The median [interquartile range] patient delay, system delay and total delay were 15 [7–30], 36 [19–65] and 57.5 [33–95] days, respectively. Low economic status (aOR [adjusted odds ratio] =2.38 [1.08-5.25]), not being referred to a health service (aOR = 1.75 [1.02- 3.02]) and a secondary level education (aOR = 0.33 [0.12-0.92]) were associated with a long patient delay. Risk factors for a long system delay were a low level of education (aOR = 4.71 [1.34-16.51]) and the belief that traditional medicine and informal care can cure TB (aOR = 5.46 [2.37-12.60]).
Targeted strengthening of the health-care system, including improving patient access, addressing deficiencies in health-related human resources, and improving laboratory networks and linkages as well as community mobilization will make for better outcomes in tuberculosis diagnosis.
PMCID: PMC3519715  PMID: 22776241
Tuberculosis; Delay; Diagnosis; Treatment
20.  The effect of tuberculosis and antiretroviral treatment on CD4+ cell count response in HIV-positive tuberculosis patients in Mozambique 
BMC Public Health  2012;12:670.
Tuberculosis (TB) presents a serious problem in Mozambique. HIV prevalence among TB patients is estimated at 47%. A delay in having their first CD4+ cell count could lead to a missed opportunity for ART initiation due to a CD4+ cell increase above the cut-off caused by TB treatment. The objective is to describe CD4+ cell response during TB treatment and quantify the effect of TB treatment and ART on this response.
All new HIV + adult TB cases in 2007 from three TB clinics in Mozambique were included. Data on TB diagnosis and treatment and HIV parameters were collected. A general mixed model was used for CD4+ cell count response.
338 HIV + patients were notified and 252 (75%) were included in the analysis. Using TB medication was not independently associated with the CD4+ count response (19 cells/mm3; 95% CI: -40 to 79; p = 0.529). ART-use was associated with statistically significantly higher CD4+ cells compared to no ART-use (81 cells/mm3; 95% confidence interval (CI): 12 to 151; p = 0.022).
In this study, no independent effect of TB treatment on CD4+ cell count was found. HIV-infected TB patients on ART had a significantly higher CD4+ cell count than those not receiving ART. CD4+ cell counts for patients not on ART at TB treatment start, remained below the cut off for initiating ART during the first three months of TB treatment; therefore some delay in getting the first CD4+ cell count would not lead to missing the opportunity to start ART.
PMCID: PMC3490938  PMID: 22900904
21.  T Cell Activation and Cytokine Profile of Tuberculosis and HIV-Positive Individuals during Antituberculous Treatment and Efavirenz-Based Regimens 
PLoS ONE  2013;8(6):e66095.
The profile of immune activation markers in tuberculosis and HIV-infected patients is already known. The impact of simultaneous infections on the immune parameters is still not fully explored.
We conducted a prospective study to estimate trajectories of activated T cell subsets and the profile of anti- and pro-inflammatory cytokines in a group of HIV-TB individuals, previously naïve for HAART, recruited from a randomized clinical trial during TB treatment and first antiretroviral therapy with efavirenz. Patients were evaluated according to the immunosuppression levels at baseline as group 1 (CD4<200 cells/mm3) and group 2 (CD4>200 cells/mm3). These parameters were measured at the time of HAART initiation (started about 30 days after the onset of TB treatment) and at the follow-up visits after 30, 60, 90 and 180 days. Trajectories were estimated using least squares estimates of the coefficients of a restricted cubic spline function in time after adjusting for subject effects, bootstrapping it 500 times.
Increase of CD4 T cell counts and suppression of HIV viral load were observed for all patients under HAART and TB treatment. Descendent trajectories were observed for the activated CD8+/CD38+ and CD3+/HLA-DR+ T cell subsets, and for plasma concentration of gamma- interferon (IFN-γ). Except for TNF-α and IL-2 discrete variations were observed for the other cytokines. Differences in the trajectories of these parameters were observed for groups 1 and 2. Higher values of IFN-γ, IL-2, IL-6 and IL-10 were observed for group 1 from the baseline to two months after treatment initiation, whereas reduced levels of TNF-α were observed for this group between 60 and 120 days of HAART.
Independent of the immunosuppression profile at baseline, HIV-TB patients under HAART were able to recover the CD4+ T cell counts, and control viral replication and immune activation parameters over time.
PMCID: PMC3686825  PMID: 23840403
22.  Determinants of Tuberculosis Infection among Adult HIV Positives Attending Clinical Care in Western Ethiopia: A Case-Control Study 
AIDS Research and Treatment  2013;2013:279876.
There has been a drastic rise of tuberculosis (TB) infection across the world associated with the pandemic occurrence of HIV/AIDS. There are various determinants factors that increase the chance of TB infection among HIV positives (TB/HIV confection) that varies contextually. This study aimed to assess the determinants of TB/HIV coinfection among adult HIV positives attending clinical care at two public health facilities in Nekemte, western Ethiopia. Unmatched case-control study was conducted from December 26, 2011, to February 29, 2012. Cases were 123 TB infected HIV positives, and controls were 246 non-TB infected HIV positives. Being divorced/widowed AOR = 3.02, 95% CI (1.70, 7.88), not attending formal education AOR = 4.32, 95% CI (2.20, 14.15), being underweight (BMI < 18.5 kg/m2) AOR = 3.87, 95% CI (2.18, 6.87), having history of diabetic mellitus AOR = 3.63, 95% CI (1.33, 9.94), and being in advanced WHO HIV/AIDS clinical staging AOR = 2.29, 95% CI (1.32, 3.98), were determinant factors associated with TB/HIV co-infection. Having a separate kitchen AOR = 0.48, 95% CI (0.28, 0.81) showed protective role. For most of these determinants interventions can be made at individual and institutional levels, whereas, factors like education and nutrition need societal level integrations.
PMCID: PMC3816017  PMID: 24222846
23.  Sero-prevalence of HIV infection among tuberculosis patients in a rural tuberculosis referral clinic in northern Nigeria 
Co-infection with Human Immunodeficiency virus (HIV) and Mycobacterium tuberculosis the causative agent of Tuberculosis (TB), has been referred to as the “cursed duet” as a result of the attendant morbidity and mortality due to their synergistic actions. This study was carried out to determine the prevalence of HIV infection among Tuberculosis (TB) confirmed patients on admission at a TB referral centre. The association of HIV prevalence with gender and age as risk factors was also determined. Blood samples were collected by venipuncture from 257 TB patients and their HIV status determined. Viral antibody detection was carried out using ELISA kits which detected both HIV-1 and HIV-2 and confirmed by Western blot. Of the 257 patients screened, 44.20% (106) were HIV positive. The prevalence of co-infection was higher among the female (44.82%) than the male (38.30%) patients and highest among those aged 21-40 years old (45.30%). Co-infection was found to be statistically highly associated with gender and age (p<0.05). A very high prevalence of HIV infection was reported in this study among patients that were on admission on the grounds that they had only TB. It is therefore important to screen for HIV among all TB patients.
PMCID: PMC3032624  PMID: 21293749
HIV; Tuberculosis; co-infection; Nigeria
24.  Health system delay in pulmonary tuberculosis treatment in a country with an intermediate burden of tuberculosis: a cross-sectional study 
BMC Public Health  2013;13:250.
Delayed diagnosis and treatment of tuberculosis increase both the severity of the disease and the duration of infectivity. A number of studies have addressed the issue of health system delays in the treatment of tuberculosis, but mostly in countries with a high or low incidence of the disease. Our understanding of delay is quite limited in settings with an intermediate burden of tuberculosis. We explore the duration and factors associated with delays in the Croatian health system which has free health care and a sufficient network of health services providing tuberculosis diagnosis and care.
A total of 241 consecutive adults with culture-confirmed pulmonary tuberculosis were interviewed in seven randomly selected Croatian counties and their medical records were evaluated. A health system delay was defined as the number of days from the first consultation with a physician to the initiation of anti-tuberculosis treatment. A long delay was defined as a period exceeding the median delay, while an extreme delay was considered to be above the 75th percentile delay.
The median health system delay was 15 days while the 75th percentile was 42 days (the 5th and 95th percentile being 1 and 105 days respectively). Almost 30% of tuberculosis patients remained undiagnosed for more than 30 days after the initial health care visit. Female patients (p = 0.005), patients with a negative sputum smear (p = 0.002) and patients having symptoms other than the usual ones (0.027) were found to be in significant correlation with a long delay. In a multivariate model, a long delay remained associated with the same variables (p = 0.008, p = 0.003, and p = 0.037, respectively).
A significant association was demonstrated between both the female gender (p = 0.042) and a negative sputum smear (p < 0.001) and extreme delay, while only a negative sputum smear (p < 0.001) remained significant in the multivariate analysis.
Our findings suggest that some groups of tuberculosis patients experienced a health system delay. In such a setting where tuberculosis incidence is decreasing, which leads to a lack of physician experience and expertise, training in tuberculosis is required. Such measure may be useful in reducing the number of missed opportunities for tuberculosis diagnosis.
PMCID: PMC3608169  PMID: 23517315
Tuberculosis; Croatia; Delay; Health system
25.  Health service delay among pulmonary tuberculosis patients presenting to a National Referral Hospital, Kampala, Uganda: a cross sectional study 
Delay in the diagnosis of pulmonary tuberculosis (PTB) is common in many countries in Sub-Saharan Africa. Timely diagnosis of active tuberculosis is crucial in minimizing morbidity and mortality in the community as well as nosocomial transmission in health care facilities. This study aimed at determining factors associated with health service delay in the diagnosis and initiation of treatment among new PTB patients presenting to the National Referral Hospital-Mulago.
This was a cross-sectional study among eligible new PTB patients presenting at the National referral TB treatment center Mulago hospital, between March to May 2009. The patients were consecutively recruited and interviewed using a semi-structured questionnaire to assess socio- demographic and health service factors. Multivariate logistic regression using odds ratios and 95% confidence intervals was done.
Two hundred and sixty six newly diagnosed PTB patients were enrolled, of which 65.4% experienced health systems delay. The median health service delay was 9days (IQR=8-19). Factors associated with health service delay were: 1n-patient (OR= 4.68, 95% CI: 1.91-11.45), secondary as highest level of education attained (OR= 3.56, 95% CI: 1.18-10.74), primary as highest level of education attained (OR= 6.70, 95% CI: 2.13-21.02), presence of fever (OR= 3.28, 95% CI: 1.05-10.79), and patient delay at health facility (OR= 5.01, 95% CI: 1.33-18.9).
The study found a significant proportion of Health service delay among pulmonary tuberculosis patients presenting at the referral hospital. Being an in-patient and having fever as a symptom of tuberculosis needs further attention in order to have timely diagnosis. There is need for awareness on TB especially that most of the TB symptoms present like other febrile illnesses such as malaria and needs consideration when patients present to a health facility.
PMCID: PMC3810284  PMID: 24198882
Tuberculosis; health service delay; treatment delay; diagnostic delay; pulmonary tuberculosis

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