Provider-initiated symptom screening for tuberculosis in Zimbabwe: diagnostic value and the effect of HIV status.

OBJECTIVE: To assess the diagnostic value of provider-initiated symptom screening for tuberculosis (TB) and how HIV status affects it. METHODS: We performed a secondary analysis of randomly selected participants in a community-based TB-HIV prevalence survey in Harare, Zimbabwe. All completed a five-symptom questionnaire and underwent sputum TB culture and HIV testing. We calculated the sensitivity, specificity, and positive and negative predictive values of various symptoms and used regression analysis to investigate the relationship between symptoms and TB disease. FINDINGS: We found one or more symptoms of TB in 21.2% of 1858 HIV-positive (HIV+) and 9.9% of 7121 HIV-negative (HIV-) participants (P or = 2 weeks' duration, any symptom and a positive sputum culture had sensitivities of 48%, 81% and 65%, respectively; in HIV- participants, the sensitivities were 45%, 71% and 74%, respectively. Symptoms had a similar sensitivity and specificity in HIV+ and HIV- participants, but in HIV+ participants they had a higher positive and a lower negative predictive value. CONCLUSION: Even smear-positive TB may be missed by provider-initiated symptom screening, especially in HIV+ individuals. Symptom screening is useful for ruling out TB, but better TB diagnostics are urgently needed for resource-poor settings

A Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of Rifapentine.

Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures

The Risk and Timing of Tuberculosis Diagnosed in Smear-Negative TB Suspects: A 12 Month Cohort Study in Harare, Zimbabwe

BACKGROUND: Cases of smear-negative TB have increased dramatically in high prevalence HIV settings and pose considerable diagnostic and management challenges. METHODS AND FINDINGS: Between February 2006 and July 2007, a cohort study nested within a cluster-randomised trial of community-based case finding strategies for TB in Harare, Zimbabwe was undertaken. Participants who had negative sputum smears and remained symptomatic of TB were follow-up for one year with standardised investigations including HIV testing, repeat sputum smears, TB culture and chest radiography. Defaulters were actively traced to the community. The objectives were to investigate the incidence and risk factors for TB. TB was diagnosed in 218 (18.2%) participants, of which 39.4% was bacteriologically confirmed. Most cases (84.2%) were diagnosed within 3 months, but TB incidence remained high thereafter (111.3 per 1000 person-years, 95% CI: 86.6 to 146.3). HIV prevalence was 63.3%, and HIV-infected individuals had a 3.5-fold higher risk of tuberculosis than HIV-negative individuals. CONCLUSION: We found that diagnosis of TB was insensitive and slow, even with early radiography and culture. Until more sensitive and rapid diagnostic tests become widely available, a much more proactive and integrated approach towards prompt initiation of ART, ideally from within TB clinics and without waiting for TB to be excluded, is needed to minimise the risk and consequences of diagnostic delay

Detection of Mycobacterium tuberculosis in Sputum by Gas Chromatography-Mass Spectrometry of Methyl Mycocerosates Released by Thermochemolysis

Tuberculosis requires rapid diagnosis to prevent further transmission and allow prompt administration of treatment. Current methods for diagnosing pulmonary tuberculosis lack sensitivity are expensive or are extremely slow. The identification of lipids using gas chromatography- electron impact mass spectrometry (GC-EI/MS) could provide an alternative solution. We have studied mycocerosic acid components of the phthiocerol dimycocerosate (PDIM) family of lipids using thermochemolysis GC-EI/MS. To facilitate use of the technology in a routine diagnostic laboratory a simple extraction procedure was employed where PDIMs were extracted from sputum using petroleum ether, a solvent of low polarity. We also investigated a method using methanolic tetramethylammonium hydroxide, which facilitates direct transesterification of acidic components to methyl esters in the inlet of the GC-MS system. This eliminates conventional chemical manipulations allowing rapid and convenient analysis of samples. When applied to an initial set of 40 sputum samples, interpretable results were obtained for 35 samples with a sensitivity relative to culture of 94% (95%CI: 69.2,100) and a specificity of 100% (95%CI: 78.1,100). However, blinded testing of a larger set of 395 sputum samples found the assay to have a sensitivity of 61.3% (95%CI: 54.9,67.3) and a specificity of 70.6% (95%CI: 62.3,77.8) when compared to culture. Using the results obtained we developed an improved set of classification criteria, which when applied in a blinded re-analysis increased the sensitivity and specificity of the assay to 64.9% (95%CI: 58.6,70.8) and 76.2% (95%CI: 68.2,82.8) respectively. Highly variable levels of background signal were observed from individual sputum samples that inhibited interpretation of the data. The diagnostic potential of using thermochemolytic GC-EI/MS of PDIM biomarkers for diagnosis of tuberculosis in sputum has been established; however, further refinements in sample processing are required to enhance the sensitivity and robustness of the test

High-dose rifapentine with moxifloxacin for pulmonary tuberculosis

BACKGROUND: Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed. METHODS: We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals. RESULTS: We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4). CONCLUSIONS: The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.)

Prevalent infectious tuberculosis in Harare, Zimbabwe: burden, risk factors and implications for control.

SETTING: Harare's high density suburbs. OBJECTIVES: To investigate the burden, duration and risk factors for prevalent tuberculosis (TB) and explore potential control strategies. METHODS: Randomly selected adults had TB culture, symptom screen and human immunodeficiency virus (HIV) serology. Prevalent TB was defined as undiagnosed or still culture-positive. Notification data and HIV prevalence in TB out-patients were used to estimate duration of infectiousness (prevalence/estimated incidence). RESULTS: Among 10 092 participants, 40 (0.40%, 95%CI 0.28-0.54) had prevalent smear-positive TB. HIV (adjusted odds ratio [aOR] 3.1, 95%CI 1.6-6.3, population attributable fraction [PAF] 33%), male sex (aOR 3.1, 95%CI 1.5-6.4, PAF 40%), and overcrowding (PAF 34%) were significant risk factors, with past TB treatment significant for HIV-negative participants only (PAF 7%). Recent household TB contact was not significant (PAF 10%). HIV prevalence was 21.1%; 76.9% of HIV-positive participants were previously untested. Duration of infectiousness was at least 18 weeks in HIV-positive and approximately 1 year in HIV-negative patients. CONCLUSIONS: Overcrowding, male sex and HIV infection were major risk factors for prevalent smear-positive TB. Reducing diagnostic delay may have greater potential to improve the control of prevalent TB than interventions targeted at household contacts, TB treatment outcomes, or TB-HIV interventions under current levels of awareness of HIV status

Determinants of premature births in two central hospital Harare, Zimbabwe, 2011

Introduction: Prematurity is a major determinant of neonatal morbidity and mortality in Zimbabwe. Although 8-10% of deliveries are premature , prematurity contributes 33% of neonatal deaths. Identifying local risk factors for prematurity could help incoming up with local intervention and prevention strategies.Design:1:1 unmatched case control studySetting: Harare and Parirenyatwa central hospitals maternity unitsSubjects: All mothers who delivered in the units June to July 2011. Acase was a mother who had delivered a premature baby and control was a mother who delivered a term baby.Results: We interviewed 188 cases and 188 controls. Independent risk factors for premature delivery were -A previous premature delivery [AOR 3.15 95% CI 1.17 8.49, 4.61] being admitted with a medical complication in pregnancy[AOR 2.15 95% CI 1.18-3.92]. Birth interval > 24 months [AOR 0.26 95% CI 0.12 0.59] being well nourished evidenced by BMI ≥20kg/m [ AOR 0.926 95% CI 0.88 0.97] and MUAC ≥23cm [AOR 0.95 95% CI 0.91 0.95] reduced the risk of premature delivery. HIV test was done on 87% of participants, 12% were positive (66% controls, 33% cases) (p≤0.001).Conclusion: Birth interval < 24 months, previous premature delivery, only one ANC attendance, maternal under nutrition and being hospitalized with complications in pregnancy were associated with premature delivery. There was no association with HIV infection. Efforts should be made to give food supplements to pregnant undernourished women

Risk factors associated with cholera in Harare City, Zimbabwe, 2008

Objective: Two suspected cholera cases at Beatrice Road Infectious Diseases Hospital were reported to Harare City Health on 14 October 2008 setting in motion investigation and control measures. We determined the extent of the epidemic and risk factors for contracting cholera.Methods: An unmatched 1:1 case-control study was conducted. Case: Any resident of Harare City, 2years and above, with acute watery diarrhoea, with or without vomiting from 30 October 2008 to 01 December 2008. Control: Any resident of Harare City, 2years and above, neighbour to a case, who did not contract cholera during the same period.Results: From 14 October 2008 to 21 January 2009, 11203 cases and case fatality rate (CFR)= 3.98%. We interviewed 140 cases and 140 controls. Median age was 28years (Q1= 20; Q3= 37.5) and 28.5years (Q1= 23; Q3= 38) for cases and controls respectively. Having a diarrhoea contact at home [AOR= 12.02; 95% CI (5.46 - 26.44)], having attained less than secondary education [AOR= 4.40; 95% CI (2.28 - 8.48)]; eating cold food [AOR= 4.24; 95% CI (1.53 - 11.70)] were independent risk factors while drinking tap water [AOR= 0.05; 95% CI (0.03 - 0.11)], washing hands after using toilet [AOR= 0.19; 95% CI (0.09 - 0.39)]; eating hot food always [AOR= 0.29; 95% CI (0.17 - 0.49)] were independently protective.Discussion: The high CFR may be due to poor case management and staff shortage in treatment camps. The cholera outbreak in Harare resulted from poor personal and hygiene practices that occur when water supplies are cut. Lack of water, low knowledge on cholera prevention measures and delays in community health education campaigns contributed to the protracted outbreak. Having a diarrhoea contact at home increases chances of household members acquiring infection. Provision of safe drinking water, community health education, recruitment of staff and training of health workers on cholera case management must be prioritized