Baseline Smear Research Articles

Prolongation of Acid-Fast Bacilli Sputum Smear Positivity in Patients with Multidrug-Resistant Pulmonary Tuberculosis.

The study sought to determine factors associated with prolonged smear positivity in multidrug-resistant tuberculosis (MDR-TB) patients following appropriate management. Newly diagnosed patients were enrolled between June 2017 and May 2018. Sputum samples were collected for Xpert® MTB/RIF and line probe assays (LiPAs). Microscopic tests were performed at baseline and 4, 8, and 12 weeks post-anti-TB therapy. Of the 200 patients, 114 (57%) were HIV-positive. After 12 weeks of treatment, there was a significant microscopy conversion rate among DS-TB patients compared to MDR-TB patients irrespective of their HIV status (p = 0.0013). All MDR-TB patients who had a baseline smear grade ranging from scanty to +1 converted negative, while 25% ranging from +2 to +3 remained positive until the end of 12 weeks (p = 0.014). Factors associated with smear positivity included age <35 years (p = 0.021), initial CD4+ T-cell count ≥200 cells/mm3 (p = 0.010), and baseline smear grade ≥2+ (p = 0.014). Cox regression showed that only the baseline smear grade ≥2+ was independently associated with prolonged smear positivity in MDR-TB patients (p = 0.011) after adjusting for HIV status, CD4+ T-cell count, and age. Baseline sputum smear grade ≥2+ is a key determinant for prolonged smear positivity beyond 12 weeks of effective anti-TB therapy in MDR-TB patients.

Sputum smear conversion and treatment outcomes among drug-resistant pulmonary tuberculosis patients in eastern Ethiopia: A 9-years data analysis.

Drug-resistant tuberculosis (DR-TB) has become a public health problem throughout the world and about one-third of deaths were attributed to DR-TB from antimicrobial resistance which contributes to 10% of all TB deaths. Sub-Saharan Africa, particularly Ethiopia accounts for a significant number of TB cases. However, the scanty evidence on DR-TB contributing factors could affect the level of this deadly case tackling program. Therefore, this study aimed to assess the factors affecting sputum smear conversion and treatment outcomes among patients with DR-TB in Health facilities in Eastern Ethiopia. A cross-sectional study design was employed from 10 October to 10 November 2021, in the health facilities providing DR-TB services in Harari Region and Dire Dawa city administration. The medical records of 273 DR-TB patients from 10 January 2013 to 27 December 2021, were reviewed using structured checklists. Data were entered into Epidata 3.1 version and exported to STATA 14 version for analysis. The outcome variables were Initial Sputum conversion (converted vs. not-converted) and treatment outcome (Unfavorable vs. Favorable). Sputum examination was performed using both Acid-fast bacillus (AFB) smear microscopy and Löwenstein-Jensen (LJ) culture technique. A binary logistic regression analysis was used to assess the association of independent variables with the first month sputum smear conversion, while a conditional logistic regression model was used to assess the association of treatment outcome with explanatory variables. The associations were reported using adjusted odds ratios (AORs) at a 95% confidence interval. A total of 273 DR-TB patients were included in this study. The unfavorable DR-TB treatment outcome was significantly associated with the history of chewing khat (AOR = 4.38, 95% CI = 1.62, 11.84), having bilateral lung cavity on baseline chest X-ray (AOR = 12.08, 95% CI = 1.80, 2.57), having greater than 2+ smear result at baseline (AOR = 3.79, 95% CI = 1.35, 10.59), and poor adherence (AOR = 2.9, 95% CI = 1.28, 6.82). The sputum smear non-conversion at first month was significantly associated with being Human Immune Virus (HIV)-negative (AOR = 0.37, 0.17, 0.82), having low baseline BMI (AOR = 0.54, 95% CI = 0.29, 0.97), baseline culture > 2++ (AOR = 0.15, 95% CI = 0.05, 0.49) and having greater than 2+ sputum smear result (AOR = 0.09, 95% CI = 0.012, 0.67). Patients with normal chest X-ray at baseline had 3.8 times higher chance of sputum smear conversion on first month (AOR = 3.77, 1.11, 12.77). The overall initial sputum smear conversion and the treatment success rate among DR-TB patients were 52.75 and 66.30%, respectively. The Baseline underweight, HIV-negative, baseline smear > 2+, baseline culture > 2++, and clear lung on baseline X-ray were associated with smear conversion and history of khat chewing, bilateral lung cavity at baseline, having greater than 2+ smear results at baseline, and patients with poor treatment adherence had hostile treatment outcomes. So, strengthening and implementing nutrition assessment and patient counseling during directly observed therapies (DOTs) service and drug compliance could result in early sputum conversion and better treatment outcomes. DR-TB patients with high bacterial load and abnormal lungs on radiologic examination at baseline could need special attention during their course of treatment.

Failure or relapse predictors for the STREAM Stage 1 short regimen for RR-TB.

BACKGROUND: STREAM (Standardised Treatment Regimens of Anti-tuberculosis drugs for Multidrug-Resistant Tuberculosis) Stage 1 demonstrated non-inferior efficacy of a short regimen for rifampicin-resistant TB (RR-TB) compared to a long regimen as recommended by the WHO. The present paper analyses factors associated with a definite or probable failure or relapse (FoR) event in participants receiving the Short regimen.METHODS: This analysis is restricted to 253 participants allocated to the Short regimen and is based on the protocol-defined modified intention to treat (mITT) population. Multivariable Cox regression models were built using backwards elimination with an exit probability of P = 0.157, equivalent to the Akaike Information Criterion, to identify factors independently associated with a definite or probable FoR event.RESULTS: Four baseline factors were identified as being significantly associated with the risk of definite or probable FoR (male sex, a heavily positive baseline smear grade, HIV co-infection and the presence of costophrenic obliteration). There was evidence of association of culture positivity at Week 8 and FoR in a second model and Week 16 smear positivity, presence of diabetes and of smoking in a third model.CONCLUSION: The factors associated with FoR outcomes identified in this analysis should be considered when determining the optimal shortened treatment regimen.

Factors Associated with Acid Fast Bacilli and Sputum Culture Conversion in Patients with Multidrug-Resistant Tuberculosis in Surabaya

Introduction: Indonesia is a high incidence country of multidrug-resistant tuberculosis. There are approximately 11,000 MDR TB cases, 2.8% of them are new cases and 16% of them are relapse cases. Although guidelines for MDR-TB are frequently designed, medication freely provided, and centers for treatment duly expanded, studies on time to sputum culture conversion have been very limited in Indonesia. Therefore the aim of the study is to identify risk factors that effect on sputum and culture conversion.Methods: Data on short-term regimen for MDR TB in Dr. Soetomo General Hospital from January 1st – December 31st, 2018 were collected with a total sampling approach, and fulfill the inclusion and exclusion. Data were analyzed by computer software IBM SPSS Statistic 24 for windows. Results: Male is more likely to have delayed sputum conversion and culture conversion but no statistical difference is observed (p&gt;0.05). Smoking history is more likely to have delayed sputum and culture conversion but only in sputum smear test shows a significant difference (p≤ 0.05). Alcohol consumption has delay effect on sputum and culture conversion but there is statistically difference in only culture conversion (p&lt;0.05). The high baseline smear test also affects delay the sputum and culture conversion but only in sputum smear reveals a significant effect (p&lt;0.05).Conclusion: In this present study, we identified sex, smoking history, high bacillary loads as significant factors on sputum conversion. In addition, we revealed that alcohol-consumption history is a significant factor affecting on culture conversion.

Dynamics of sputum conversion during effective tuberculosis treatment: A systematic review and meta-analysis.

Two weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment. For the main analysis, 2 systematic literature searches of OvidSP MEDLINE, Embase, and Global Health, and EBSCO CINAHL Plus were conducted to identify studies with data on TB infectiousness (all studies to search date, 1 December 2017) and all randomised controlled trials (RCTs) for drug-susceptible TB (from 1 January 1990 to search date, 20 February 2018). Included articles reported on patients receiving effective treatment for culture-confirmed drug-susceptible pulmonary TB. The outcome of interest was sputum bacteriological conversion: the proportion of patients having converted by a defined time point or a summary measure of time to conversion, assessed by smear or culture. Any study design with 10 or more particpants was considered. Record sifting and data extraction were performed in duplicate. Random effects meta-analyses were performed. A narrative summary additionally describes the results of a systematic search for data evaluating infectiousness from humans to experimental animals (PubMed, all studies to 27 March 2018). Other evidence on duration of infectiousness-including studies reporting on cough dynamics, human tuberculin skin test conversion, or early bactericidal activity of TB treatments-was outside the scope of this review. The literature search was repeated on 22 November 2020, at the request of the editors, to identify studies published after the previous censor date. Four small studies reporting 3 different outcome measures were identified, which included no data that would alter the findings of the review; they are not included in the meta-analyses. Of 5,290 identified records, 44 were included. Twenty-seven (61%) were RCTs and 17 (39%) were cohort studies. Thirteen studies (30%) reported data from Africa, 12 (27%) from Asia, 6 (14%) from South America, 5 (11%) from North America, and 4 (9%) from Europe. Four studies reported data from multiple continents. Summary estimates suggested smear conversion in 9% of patients at 2 weeks (95% CI 3%-24%, 1 single study [N = 1]), and 82% of patients at 2 months of treatment (95% CI 78%-86%, N = 10). Among baseline smear-positive patients, solid culture conversion occurred by 2 weeks in 5% (95% CI 0%-14%, N = 2), increasing to 88% at 2 months (95% CI 84%-92%, N = 20). At equivalent time points, liquid culture conversion was achieved in 3% (95% CI 1%-16%, N = 1) and 59% (95% CI 47%-70%, N = 8). Significant heterogeneity was observed. Further interrogation of the data to explain this heterogeneity was limited by the lack of disaggregation of results, including by factors such as HIV status, baseline smear status, and the presence or absence of lung cavitation. This systematic review found that most patients remained culture positive at 2 weeks of TB treatment, challenging the view that individuals are not infectious after this interval. Culture positivity is, however, only 1 component of infectiousness, with reduced cough frequency and aerosol generation after TB treatment initiation likely to also be important. Studies that integrate our findings with data on cough dynamics could provide a more complete perspective on potential transmission of Mycobacterium tuberculosis by individuals on treatment. Systematic review registration: PROSPERO 85226.

Prevalence and correlates of cervical squamous intraepithelial lesions among HIV-infected and uninfected women in Central Kenya

Introductioncervical intraepithelial neoplasia the precursor of cervical cancer occurs with increased frequency in women infected with human immunodeficiency virus (HIV). This study aimed at determining the prevalence and correlates of abnormal cervical cytology among HIV-infected women and compare to the uninfected women.Methodsa cross-sectional study conducted among HIV-infected and uninfected women enrolled in a HIV study in Central Kenya. All women had baseline Pap smear examination assessed using Bethesda system. Bivariate and multivariate logistic regression methods were employed to assess the correlates of cervical squamous epithelial lesions (CSIL).Resultsa total 480 women had an acceptable baseline smear, 373 (78%) were HIV-infected. Median age was 30.2 years [IQR 25.4-35.5]. Overall prevalence of CSIL was 37% (176/480) with the prevalence of low grade squamous intraepithelial lesion (LSIL), atypical squamous cells undetermined significance (ASCUS), high grade squamous intraepithelial lesions (HSIL) and atypical glandular cells (AGC) were 17%, 14%, 4% and 2% respectively. HIV-infected women had a higher prevalence of CSIL at 42% as compared to HIV-uninfected women at 19%. HIV infection was the predictor associated with development of CSIL at multivariate analysis and specifically, HIV-infected women were 3 times (AOR 3.1, 95% CI: 1.8 - 5.4, p<0.005) more likely to have CSIL than HIV-uninfected women. The age 35 - 44 years was protective to developing CSIL (AOR 0.45, 95% CI: 0.24 - 0.87, p=0.018).Conclusioncervical squamous epithelial lesions is a major problem among Kenyan women. HIV infection confers a higher risk to development of CSIL. Cervical cancer screening should be an established practice in HIV programs.

A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis

Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the ‘one-size-fits-all’ treatment currently used worldwide.

Gender differences in tuberculosis treatment outcomes: a post hoc analysis of the REMoxTB study

BackgroundIn the REMoxTB study of 4-month treatment-shortening regimens containing moxifloxacin compared to the standard 6-month regimen for tuberculosis, the proportion of unfavourable outcomes for women was similar in all study arms, but men had more frequent unfavourable outcomes (bacteriologically or clinically defined failure or relapse within 18 months after randomisation) on the shortened moxifloxacin-containing regimens. The reason for this gender disparity in treatment outcome is poorly understood.MethodsThe gender differences in baseline variables were calculated, as was time to smear and culture conversion and Kaplan-Meier plots were constructed. In post hoc exploratory analyses, multivariable logistic regression modelling and an observed case analysis were used to explore factors associated with both gender and unfavourable treatment outcome.ResultsThe per-protocol population included 472/1548 (30%) women. Women were younger and had lower rates of cavitation, smoking and weight (all p < 0.05) and higher prevalence of HIV (10% vs 6%, p = 0.001). They received higher doses (mg/kg) than men of rifampicin, isoniazid, pyrazinamide and moxifloxacin (p ≤ 0.005). There was no difference in baseline smear grading or mycobacterial growth indicator tube (MGIT) time to positivity. Women converted to negative cultures more quickly than men on Lowenstein-Jensen (HR 1.14, p = 0.008) and MGIT media (HR 1.19, p < 0.001). In men, the presence of cavitation, positive HIV status, higher age, lower BMI and ‘ever smoked’ were independently associated with unfavourable treatment outcome. In women, only ‘ever smoked’ was independently associated with unfavourable treatment outcome. Only for cavitation was there a gender difference in treatment outcomes by regimen; their outcome in the 4-month arms was significantly poorer compared to the 6-month treatment arm (p < 0.001). Women, with or without cavities, and men without cavities had a similar outcome on all treatment arms (p = 0.218, 0.224 and 0.689 respectively). For all other covariate subgroups, there were no differences in treatment effects for men or women.ConclusionsGender differences in TB treatment responses for the shorter regimens in the REMoxTB study may be explained by poor outcomes in men with cavitation on the moxifloxacin-containing regimens. We observed that women with cavities, or without, on the 4-month moxifloxacin regimens had similar outcomes to all patients on the standard 6-month treatment. The biological reasons for this difference are poorly understood and require further exploration.

Outcomes of pulmonary tuberculosis in patients with discordant phenotypic isoniazid resistance testing.

The discrepancy rates of drug susceptibility testing (DST) results between solid and liquid media have been reported to range from 2.4 to 7.4% for isoniazid. Most isolate with isoniazid DST discrepancies between solid and liquid media test as susceptible on solid medium and resistant in liquid medium, however, the optimal management of patients with discordant testing is unknown. This study was conducted to evaluate the effect of treatment regimen on treatment outcomes when patients with rifampicin-susceptible pulmonary tuberculosis have isoniazid resistance (INH-R) in liquid medium but isoniazid susceptibility (INH-S) on solid medium. This study was retrospectively conducted by reviewing patient medical records on the liquid compared to solid culture based phenotypic testing at Samsung Medical Center between January 2009 and December 2015. The study population which have INH-R in liquid medium and INH-S on solid medium was divided into two groups: group A (n=30), which included patients treated for INH-S tuberculosis by discontinuing pyrazinamide (and ethambutol), and group B (n=56), which included patients treated for INH-R tuberculosis by continuing pyrazinamide and/or adding fluoroquinolone. Unfavorable outcomes included treatment failure and relapse. There were no statistically significant differences between the two groups including demographic data, comorbidities, radiologic data, and treatment duration. However, baseline smear positive rates were more frequent in group A (19/30, 63.3%) than in group B (22/56, 39.3%; P=0.033). Only three patients had unfavorable outcomes; one was bacteriologically proven treatment failure and the other two were clinically judged as unfavorable outcomes. All of them were in the group A (3/30, 10%); no unfavorable outcomes occurred in the group B (0/56, 0%; P=0.040). Unfavorable outcomes were less frequent in the group B than in the group A, indicating that treatment regimen modification according to DST results on liquid medium could improve treatment outcomes in patients with rifampicin-susceptible pulmonary tuberculosis. Further studies are required to confirm these findings to overcome the small number of unfavorable outcomes.

Biomarkers of Tuberculosis Severity and Treatment Effect: A Directed Screen of 70 Host Markers in a Randomized Clinical Trial

More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.

Treatment outcome of tuberculosis patients under directly observed treatment short course and its determinants in Shangla, Khyber-Pakhtunkhwa, Pakistan: A retrospective study.

Tuberculosis (TB) is one of the leading causes of morbidity and mortality in Pakistan. Assessment of TB treatment outcomes, monitoring and evaluation of its risk factors in Directly Observed Treatment Short Course (DOTS) are among the major indicators of the performance of a national TB control program. Even though Pakistan ranks 5th among the 22 high-TB burden countries, there are no available data in this regard. Institution-based retrospective study was conducted to determine the treatment outcome of TB patients and investigate associated risk factors at District Head Quarter Hospital Shangla, Khyber-Pakhtunkhwa, Pakistan. Two-year record (January 2011 to December 2012) of TB clinic of the hospital was reviewed. A total of 493 patients' complete information was reviewed in the study period. Of these, 42.19% were smear-positive pulmonary TB (PTB), 35.09% were smear-negative PTB, and 22.72% were extra-PTB (EPTB). The overall prevalence of smear-positive PTB was 42.19% (95% confidence interval [CI]: 37.9-46.2). Records of the treatment outcome showed that 192 (38.94%) were cured, 276 (55.98%) completed treatment, 13 (2.6%) defaulted, 9 (1.8%) died, 1 (0.2%) treatment failure, and 1 (0.2%) had transferred to other facilities. The overall mean treatment success rate of the TB patients was 94.93%. TB age and TB form or baseline smear were significantly associated with unsuccessful treatment outcome. The risk of unsuccessful outcome was significantly lower among TB patients age Conclusion: The treatment success rate was high and match the World Health Organization criteria. To sustain the effective implementation of DOTS in the area, effective management, and diagnosis should be given for EPTB.

Impact of replacing smear microscopy with Xpert MTB/RIF for diagnosing tuberculosis in Brazil: a stepped-wedge cluster-randomized trial.

Abundant evidence on Xpert MTB/RIF accuracy for diagnosing tuberculosis (TB) and rifampicin resistance has been produced, yet there are few data on the population benefit of its programmatic use. We assessed whether the implementation of Xpert MTB/RIF in routine conditions would (1) increase the notification rate of laboratory-confirmed pulmonary TB to the national notification system and (2) reduce the time to TB treatment initiation (primary endpoints). We conducted a stepped-wedge cluster-randomized trial from 4 February to 4 October 2012 in 14 primary care laboratories in two Brazilian cities. Diagnostic specimens were included for 11,705 baseline (smear microscopy) and 12,522 intervention (Xpert MTB/RIF) patients presumed to have TB. Single-sputum-sample Xpert MTB/RIF replaced two-sputum-sample smear microscopy for routine diagnosis of pulmonary TB. In total, 1,137 (9.7%) tests in the baseline arm and 1,777 (14.2%) in the intervention arm were positive (p<0.001), resulting in an increased bacteriologically confirmed notification rate of 59% (95% CI = 31%, 88%). However, the overall notification rate did not increase (15%, 95% CI = -6%, 37%), and we observed no change in the notification rate for those without a test result (-3%, 95% CI = -37%, 30%). Median time to treatment decreased from 11.4 d (interquartile range [IQR] = 8.5-14.5) to 8.1 d (IQR = 5.4-9.3) (p = 0.04), although not among confirmed cases (median 7.5 [IQR = 4.9-10.0] versus 7.3 [IQR = 3.4-9.0], p = 0.51). Prevalence of rifampicin resistance detected by Xpert was 3.3% (95% CI = 2.4%, 4.3%) among new patients and 7.4% (95% CI = 4.3%, 11.7%) among retreatment patients, with a 98% (95% CI = 87%, 99%) positive predictive value compared to phenotypic drug susceptibility testing. Missing data in the information systems may have biased our primary endpoints. However, sensitivity analyses assessing the effects of missing data did not affect our results. Replacing smear microscopy with Xpert MTB/RIF in Brazil increased confirmation of pulmonary TB. An additional benefit was the accurate detection of rifampicin resistance. However, no increase on overall notification rates was observed, possibly because of high rates of empirical TB treatment. ClinicalTrials.gov NCT01363765. Please see later in the article for the Editors' Summary.

Factors affecting treatment outcomes in drug-resistant tuberculosis cases in the Northern Cape, South Africa.

The Northern Cape Province has low cure rates (21%) for multidrug-resistant tuberculosis (TB). We audited the programme to identify factors affecting treatment outcomes. Cases admitted to two drug-resistant TB units from 2007 to 2009 had data extracted from clinical folders. Unfavourable treatment outcomes were found in 58% of the 272 cases. A multivariable regression analysis found that male sex was associated with unfavourable outcome (P = 0.009). Weight at diagnosis (P < 0.001) and oral drug adherence (P < 0.001) were also associated with an unfavourable outcome; however, injectable drug adherence was not (P = 0.395). Positive baseline smear and human immunodeficiency virus positive status were not associated with unfavourable outcome. Shorter, more patient-friendly regimens may go a long way to improving adherence and outcomes.

Body mass index predictive of sputum culture conversion among MDR-TB patients in Indonesia

Programmatic management of drug-resistant tuberculosis at Persahabatan Hospital, Jakarta, Indonesia. To evaluate the association between body mass index (BMI) and sputum culture conversion during treatment for multidrug-resistant tuberculosis (MDR-TB). We conducted a retrospective cohort study of 212 MDR-TB patients. MDR-TB was confirmed using culture in liquid medium and line-probe assay. Patients were treated with a standardised regimen unless they were resistant to any of the drugs tested. Study outcomes were time to culture conversion (primary) and probability of conversion within 4 months (secondary). Data were analysed using Kaplan-Meier curves, discrete time-survival analysis and Poisson regression. Compared to patients with normal weight (BMI ≥18.5 kg/m(2)), severely underweight patients (BMI <16 kg/m(2)) had longer time to initial conversion (adjusted hazard ratio [aHR] 0.55, 95%CI 0.37-0.84) and a lower probability of sputum culture conversion within 4 months (adjusted relative risk 0.67, 95%CI 0.54-0.83). Other predictors for longer sputum culture conversion were female sex (aHR 0.55, 95%CI 0.39-0.78), resistance to injectables (aHR 0.59, 95%CI 0.42-0.83) and high baseline smear grade (aHR 0.33, 95%CI 0.18-0.60). Severe underweight was associated with longer time to initial sputum culture conversion among MDR-TB patients.

Increased regression and decreased incidence of human papillomavirus-related cervical lesions among HIV-infected women on HAART

To determine the impact of HAART on incidence, regression, and progression of cytopathological abnormalities in HIV-infected women. Prospective cohort. HIV-infected women (N=1123) from Soweto, South Africa underwent serial cervical smears that were analyzed and reported using the Bethesda System. The results of HAART and non-HAART users were compared using two statistical approaches: a survival analysis assessing risk of incident smear abnormality among women with baseline normal smear results; and analysis with marginal models assessing for an association between HAART use and likelihood of regression/progression in consecutive smears. After multivariate survival analysis, women using HAART with a normal baseline smear were 38% less likely to have an incident smear abnormality during follow-up than nonusers [confidence interval (CI) 0.42-0.91; P=0.01]. Multivariate marginal models analysis identified a significantly increased likelihood (odds ratio 2.61; CI 1.75-3.89; P<0.0001) of regression of cervical lesions among women on HAART. Our large prospective cohort study adds significant weight to the side of the balance of clinical research supporting the positive impact of HAART on the natural history of human papillomavirus-related cervical disease in HIV-infected women.

Progression and regression of premalignant cervical lesions in HIV-infected women from Soweto: a prospective cohort

To ascertain progression and regression of cervical dysplasia in HIV-infected women in Soweto. Prospective cohort. Women attending an HIV wellness clinic were offered cervical smears as part of care; smears were assessed using the Bethesda system. Those with high-grade lesions or worse were referred for colposcopy. Progression analyses included women with at least two smears at least 5.5 months apart. Hazard ratios were used to ascertain predictors of progression. Two thousand, three hundred and twenty-five women had a baseline smear; their median age and CD4 cell count was 32 years and 312 cells/μl, respectively; 17% were taking highly active antiretroviral therapy (HAART); 62, 20 and 14% had normal, low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL), respectively. Of those with baseline normal or LSIL smears, 1074 had another smear; progression from normal to LSIL was 9.6/100 person-years (95% CI 8.3-11.1) and progression from normal or LSIL to HSIL was 4.6/100 person-years (95% CI 3.9-5.5). Of 225 women with LSIL at baseline and at least one subsequent smear at least 11.5 months later, 44.0% regressed to normal (21.2/100 person-years (95% CI 17.5-25.7)). Multivariate models suggested increasing risk for progression in women with CD4 cell count below 500 cells/μl and HAART may reduce the risk of progression [adjusted hazard ratio (aHR) 0.72 (0.52-0.99)]. HIV-infected women have high rates of prevalent and incident HSIL and LSIL with relatively low risk of regression to normal from LSIL. HAART appears to protect against progression. Our findings suggest cervical screening intervals should be less than 10 years - irrespective of age in women with CD4 cell counts below 500 cells/μl.

Prospective study of human papillomavirus and risk of cervical adenocarcinoma

Human papillomaviruses (HPV) are established as a major cause of cervical carcinoma. However, causality inference is dependent on prospective evidence showing that exposure predicts risk for future disease. Such evidence is available for squamous cell carcinoma, but not for cervical adenocarcinoma. We followed a population-based cohort of 994,120 women who participated in cytological screening in Sweden for a median of 6.7 years. Baseline smears from women who developed adenocarcinoma during follow-up (118 women with in situ disease and 164 with invasive disease) and their individually matched controls (1,434 smears) were analyzed for HPV using PCR. Conditional logistic regression was used to estimate odds ratios (OR) of future adenocarcinoma with 95% confidence intervals (CI). Being positive for HPV 16 in the first cytologically normal smear was associated with increased risks for both future adenocarcinoma in situ (OR: 11.0, 95% CI: 2.6-46.8) and invasive adenocarcinoma (OR: 16.0, 95% CI: 3.8-66.7), compared to being negative for HPV 16. Similarly, an HPV 18 positive smear was associated with increased risks for adenocarcinoma in situ (OR: 26.0, 95% CI: 3.5-192) and invasive adenocarcinoma (OR: 28.0, 95% CI: 3.8-206), compared to an HPV 18 negative smear. Being positive for HPV 16/18 in 2 subsequent smears was associated with an infinite risk of both in situ and invasive adenocarcinoma. In conclusion, infections with HPV 16 and 18 are detectable up to at least 14 years before diagnosis of cervical adenocarcinoma. Our data provide prospective evidence that the association of HPV 16/18 with cervical adenocarcinoma is strong and causal.

Prolonged Infectiousness of Tuberculosis Patients in a Directly Observed Therapy Short‐Course Program with Standardized Therapy

Effective tuberculosis control is compromised by a lack of clarity about the timeframe of viable Mycobacterium tuberculosis shedding after treatment initiation under programmatic conditions. This study quantifies time to conversion from smear and culture positivity to negativity in unselected tuberculosis patients receiving standardized therapy in a directly observed therapy short-course (DOTS) program. Longitudinal cohort study following up 93 adults initiating tuberculosis therapy in Lima, Peru. Baseline culture and drug susceptibility tests (DSTs) were performed using the MBBacT, proportion, and microscopic observation drug susceptibility (MODS) methods. Smear microscopy and MODS liquid culture were performed at baseline and weekly for 4 weeks then every other week for 26 weeks. Median conversion time from culture positivity to culture negativity of 38.5 days was unaffected by baseline smear status. Patients with fully susceptible tuberculosis had a median time to culture conversion of 37 days; 10% remained culture positive at day 60. Delayed culture conversion was associated with multidrug resistance, regardless of DST method used; non-multidrug resistance as defined by the proportion method and MODS (but not MBBacT) was also associated with delay. Persistent day 60 smear positivity yielded positive and negative predictive values of 67% and 92%, respectively, for detecting multidrug resistance. Smear and culture conversion in treated tuberculosis patients takes longer than is conventionally believed, even with fully susceptible disease, and must be accounted for in tuberculosis treatment and prevention programs. Persistent day 60 smear positivity is a poor predictor of multidrug resistance. The industrialized-world convention of universal baseline DST for tuberculosis patients should become the standard of care in multidrug resistance-affected resource-limited settings.

P‐25 DOES THE PRESENCE OF KOILOCYTES IN A BNA SMEAR AFFECT CLINICAL OUTCOMES?

Introduction: There is ongoing debate about the terminology used in the classification of dyskaryosis, including whether BNA smears should be classified according to whether koilocytes are present or not. We explored the effect of koilocytosis in the management experiences and clinical outcomes of women with a single BNA smear.Methods: This study includes 410 women aged 20–59 years, resident in Tayside who had an ‘baseline’ BNA smear between 31/10/1999 and 31/10/2002 who were eligible for the TOMBOLA trial but who did not participate. Recommended follow‐up for these women was a repeat smear in six months. Up to three‐years follow‐up data was collected on subsequent cytological smears, colposcopy examinations and any related histology. The baseline smear was re‐read for the presence or absence of koilocytes. Women were classified according to their clinical outcomes during their three years.Results: 47% (192/410) of women were classified as having koilocytosis at baseline. The mean age was lower among these women (25 years) compared to those without koilocytosis (35 years). 55% (105/192) of women with koilocytosis at baseline had one or more negative smears and no further abnormal smears, compared to 63% (137/218) of those without koilocytosis, the difference was not statistically significant. 28% (53/192) of women with koilocytosis at baseline were referred to colposcopy after subsequent low‐grade or high‐grade smears compared to 19% (42/218) of those without koilocytosis; the difference was statistically significant. 14% (27/192) of women with koilocytosis at baseline were diagnosed with CIN2/3 or worse during follow‐up compared to 10% (21/218) of women without koilocytosis; the difference was not statistically significant.Discussion: Our results suggest that the presence or absence of koilocytosis has little impact on the clinical outcomes of women with a BNA smear.

Human Papillomavirus Type–Specific 18-Month Risk of High-Grade Cervical Intraepithelial Neoplasia in Women with a Normal or Borderline/Mildly Dyskaryotic Smear

High-risk human papillomavirus (hrHPV) DNA testing is an increasingly used instrument in cervical cancer prevention along cervical cytology. The inclusion of hrHPV testing in cervical screening requires efficient management as many hrHPV infections are transient. We investigated the potential value of hrHPV genotyping in normal and borderline/mildly dyskaryotic (BMD) smears. From a screening population of 44,102 women in the Netherlands, we included hrHPV-positive women with a normal or BMD smear. We assessed the type-specific 18-month risk of high-grade cervical intraepithelial neoplasia (CIN). In hrHPV-positive women, 18-month risk of CIN grade 3 or invasive cancer (> or =CIN3) was 6% [95% confidence interval (95% CI), 4-9] after normal cytology and 20% (95% CI, 16-25) after BMD. If positive for HPV16, > or =CIN3 risks were 14% (95% CI, 9-21) and 37% (95% CI, 28-48), respectively. In the subset of hrHPV-positive women without HPV16, HPV18 was associated with an increased risk of high-grade CIN after normal cytology and HPV31 and HPV33 were associated with an increased risk, particularly after BMD. HPV16 and HPV18 were also associated with an increased risk of high-grade CIN in women with an hrHPV-positive normal baseline smear and a repeat normal smear at 6 months. HrHPV-positive women without type 16, 18, 31, or 33 had a relatively low risk of high-grade CIN. Among women with baseline normal cytology and among women with a baseline and repeat normal smear, HPV16/18-positive women showed an increased risk of high-grade CIN. This warrants more aggressive management of HPV16/18-positive women compared with other hrHPV-positive women.