Chawangwa Modongo

Mixed Mycobacterium tuberculosis Complex Infections and False-Negative Results for Rifampin Resistance by GeneXpert MTB/RIF Are Associated with Poor Clinical Outcomes

ABSTRACT The Xpert MTB/RIF (Xpert) assay is becoming a principal screening tool for diagnosing rifampin-resistant Mycobacterium tuberculosis complex (MTBC) infection. However, little is known about the performance of the Xpert assay in infections with both drug-sensitive and drug-resistant strains (mixed MTBC infections). We assessed the performance of the Xpert assay for detecting rifampin resistance using phenotypic drug sensitivity testing (DST) as the reference standard in 370 patients with microbiologically proven pulmonary tuberculosis. Mixed MTBC infections were identified genetically through 24-locus mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) analysis. Logistic regression was used to identify the factors associated with poor (defined as treatment failure, default, and death from any cause) or good (defined as cure or successful treatment completion) clinical outcomes. The analytic sensitivity of the Xpert assay for detecting rifampin resistance was assessed in vitro by testing cultures containing different ratios of drug-sensitive and drug-resistant organisms. Rifampin resistance was detected by the Xpert assay in 52 (14.1%) and by phenotypic DST in 55 (14.9%) patients. Mixed MTBC infections were identified in 37 (10.0%) patients. The Xpert assay was 92.7% (95% confidence interval [CI], 82.4% to 97.9%) sensitive for detecting rifampin resistance and 99.7% (95% CI, 98.3% to 99.9%) specific. When restricted to patients with mixed MTBC infections, Xpert sensitivity was 80.0% (95% CI, 56.3 to 94.3%). False-negative Xpert results (adjusted odds ratio [aOR], 6.6; 95% CI,1.2 to 48.2) and mixed MTBC infections (aOR, 6.5; 95% CI, 2.1 to 20.5) were strongly associated with poor clinical outcome. The Xpert assay failed to detect rifampin resistance in vitro when <90% of the organisms in the sample were rifampin resistant. Our study indicates that the Xpert assay has an increased false-negative rate for detecting rifampin resistance with mixed MTBC infections. In hyperendemic settings where mixed infections are common, the Xpert results might need further confirmation.

A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals

Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease.

Successful MDR-TB treatment regimens including Amikacin are associated with high rates of hearing loss

BackgroundAminoglycosides are a critical component of multidrug-resistant tuberculosis (MDR-TB) treatment but data on their efficacy and adverse effects in Botswana is scarce. We determined the effect of amikacin on treatment outcomes and development of hearing loss in MDR-TB patients.MethodsPatients started on MDR-TB treatment between 2006 and 2012 were included. Multivariate analysis was used to determine the effect of amikacin on treatment outcomes and development of hearing loss.Results437 MDR-TB patients were included, 288 (66%) of whom were HIV co-infected. 270 (62%) developed hearing loss, of whom 147 (54%) had audiometry. Of the 313 (72%) patients who completed treatment, 228 (73%) had a good outcome (cure or treatment completion). Good outcome was associated with longer amikacin treatment (adjusted OR [aOR] 1.13, 95% CI 1.06 - 1.21) and higher dosage (aOR 1.90, 95% CI 1.12 – 2.99). Longer amikacin duration (aOR 1.98, 95% CI 1.86 – 2.12) and higher dosage per weight per month (aOR 1.15, 95% CI 1.04 – 1.28) were associated with development of hearing loss. Amikacin treatment duration modified the effect of the dosage on the risk of hearing loss, increasing this risk as the duration increased.ConclusionsAmikacin was effective for MDR-TB treatment, but was associated with a high incidence of hearing loss especially in our study population. Total treatment duration and average monthly amikacin dose were associated with improved outcomes; however these were also associated with development of hearing loss.

Amikacin Concentrations Predictive of Ototoxicity in Multidrug-Resistant Tuberculosis Patients.

ABSTRACT Aminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration thresholds that predicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amikacin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using probit analyses. The primary predictors of ototoxicity on CART analyses were cumulative days of therapy, followed by cumulative area under the concentration-time curve (AUC), which improved on the primary predictor by 87%. The area under the receiver operating curve was 0.97 on the test set. Peak and trough were not predictors in any tree. When algorithms were forced to pick peak and trough as primary predictors, the area under the receiver operating curve fell to 0.46. Probit analysis revealed that the probability of ototoxicity increased sharply starting after 6 months of therapy to near maximum at 9 months. A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days · mg · h/liter, while that of 20% occurred at 120,000 days · mg · h/liter. Thus, cumulative amikacin AUC and duration of therapy, and not peak and trough concentrations, should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis.

Alcohol use and abuse among patients with multidrug-resistant tuberculosis in Botswana

BACKGROUND Data on alcohol abuse as a risk factor for the development of multidrug-resistant tuberculosis (MDR-TB) are scarce. OBJECTIVE To describe the patterns of alcohol use in MDR-TB patients and to determine whether alcohol use is associated with the development of MDR-TB in Botswana. METHODS We compared the level of alcohol use among MDR-TB patients against three control groups: 1) non-MDR-TB patients, 2) human immunodeficiency virus (HIV) infected patients without a history of TB, and 3) the general population. Alcohol use and abuse was measured with the Alcohol Use Disorders Identification Test 10 (AUDIT) questionnaire. RESULTS Of a total national population of 164 MDR-TB cases, 114 (70%) were interviewed. MDR-TB cases had a lifetime prevalence of alcohol use of 35.1%, which was lower than that of all control groups (P < 0.001). MDR-TB cases had higher 1-month prevalence of alcohol dependence symptoms and a lower 1-year period prevalence of alcohol dependence symptoms (P < 0.01 and P = 0.01 respectively). Among patients with TB, alcohol abuse was found to be a risk factor for the development of MDR-TB. CONCLUSION MDR-TB patients in Botswana have high rates of alcohol use and abuse. Among TB patients, alcohol abuse is associated with the diagnosis of MDR-TB, and could be an important modifiable factor.

Clinical Outcomes Among Persons With Pulmonary Tuberculosis Caused by Mycobacterium tuberculosis Isolates With Phenotypic Heterogeneity in Results of Drug-Susceptibility Tests

BACKGROUND Patients with multidrug-resistant (MDR) tuberculosis may have phenotypic heterogeneity in results of drug-susceptibility tests (DSTs). However, the impact of this on clinical outcomes among patients treated for MDR tuberculosis is unknown. METHODS Phenotypic DST heterogeneity was defined as presence of at least 1 Mycobacterium tuberculosis isolate susceptible to rifampicin and isoniazid recovered <3 months after MDR tuberculosis treatment initiation from a patient with previous documented tuberculosis due to M. tuberculosis resistant to at least rifampicin and isoniazid. The primary outcome was defined as good (ie, cure or treatment completion) or poor (ie, treatment failure, treatment default, or death). A secondary outcome was time to culture conversion. Cox proportional hazard models were used to determine the association between phenotypic DST heterogeneity and outcomes. RESULTS Phenotypic DST heterogeneity was identified in 33 of 475 patients (7%) with MDR tuberculosis. Poor outcome occurred in 126 patients (28%). Overall, patients with MDR tuberculosis who had phenotypic DST heterogeneity were at greater risk of poor outcome than those with MDR tuberculosis but no phenotypic DST heterogeneity (adjusted hazard ratio [aHR], 2.1; 95% confidence interval [CI], 1.2-3.6). Among HIV-infected patients with MDR tuberculosis, the adjusted hazard for a poor outcome for those with phenotypic DST heterogeneity was 2.4 (95% CI, 1.3-4.2) times that for those without phenotypic DST heterogeneity, whereas among HIV-negative patients with MDR tuberculosis, the adjusted hazard for those with phenotypic DST heterogeneity was 1.5 (95% CI, .5-4.3) times that for those without phenotypic DST heterogeneity. HIV-infected patients with MDR tuberculosis with phenotypic DST heterogeneity also had a longer time to culture conversion than with HIV-infected patients with MDR tuberculosis without phenotypic DST heterogeneity (aHR, 2.9; 95% CI, 1.4-6.0). CONCLUSIONS Phenotypic DST heterogeneity among persons with HIV infection who are being treated for MDR tuberculosis is associated with poor outcomes and longer times to culture conversion.

Prevalence of hypothyroidism among MDR-TB patients in Botswana

Multidrug-resistant tuberculosis (MDR-TB) is a growing problem worldwide. Hypothyroidism is a known complication of treatment with para-aminosalicylic acid (PAS), ethionamide (ETH) or prothionamide (PTH), all of which are typically included in treatment of MDR-TB.1–4 Although hypothyroidism is known to be associated with MDR-TB treatment, the magnitude of the problem remains unclear. A recent study published by Satti et al. reported a hypothyroid-ism prevalence of 69% in a cohort of 186 patients in Lesotho.5 As this is higher than the prevalence reported in most other cohorts, the authors left the question open as to whether this was a unique phenomenon of their cohort or whether their findings could indicate an underreported problem. Here, we report our experience with regard to hypothyroidism among patients treated for MDR-TB in Botswana. We have been prospectively following all MDR-TB patients in Botswana since January 2007. For the purpose of this report, we used the definition of hypothyroidism used by Satti et al., i.e., thyroid stimulating hormone (TSH) > 10.0 μIU/l.5 Screening for hypothyroidism among patients on MDR-TB treatment is recommended by national guidelines, but thyroid function tests are ordered at the discretion of the managing clinician. Of 452 patients included in the analysis, 213 (47.1%) had their TSH levels checked at some point in their treatment: 73 (16.2% of the cohort and 34.3% of those with TSH levels checked) were found to have evidence of hypothyroidism. The median time from initiation of MDR-TB treatment to hypothyroidism was 260 days (range 132–365). Other characteristics of the cohort are shown in the Table. Table Clinical characteristics of MDR-TB patients: screening for and diagnosis of hypothyroidism We conducted multivariate logistic regression to identify potential factors associated with the development of hypothyroidism, an independent analysis of the entire cohort and an analysis of those patients who had their TSH levels checked. The model included sex, age, human immunodeficiency virus (HIV) status, use of PAS, ETH, time on treatment, culture conversion at 6 months and outcome. As PTH is not available in Botswana, none of the patients were receiving this drug. Male sex was the only variable associated with the development of hypothyroidism (adjusted odds ratio 2.5, 95% confidence interval 1.4–4.4). Our MDR-TB cohort is one of the largest to be studied prospectively for hypothyroidism. Our results support the findings reported by Satti et al., and suggest that hypothyroidism may be an important, yet under recognised problem among patients being treated for MDR-TB.5 To our knowledge, the association between male sex and the development of hypothyroidism on MDR-TB treatment has not been reported previously. The reason for this association is unclear, and may be related to methodological issues intrinsic to the design of the study. Nevertheless, our experience, together with that of other authors, highlights the need for better designed prospective studies.

Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients

ABSTRACT Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0–24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0–24, and trough concentrations. The primary node for failure had two competing variables, Cmax of <67 mg/liter and AUC0–24 of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R2 = 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin Cmax of ≥67 mg/liter versus 3/15 (20%) in those with a Cmax of <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin Cmax and AUC0–24 below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model.

Advanced Immune Suppression is Associated With Increased Prevalence of Mixed-Strain Mycobacterium tuberculosis Infections Among Persons at High Risk for Drug-Resistant Tuberculosis in Botswana

We examined factors associated with mixed-strain Mycobacterium tuberculosis infections among patients at high risk for drug-resistant tuberculosis in Botswana. Thirty-seven (10.0%) of 370 patients with tuberculosis had mixed M. tuberculosis infections, based on 24-locus mycobacterial interspersed repetitive unit-variable number of tandem repeats genotyping. In log-binomial regression analysis, age <37 years (adjusted prevalence ratio [PR], 1.92; 95% confidence interval [CI], 1.01-3.57) and prior tuberculosis treatment (adjusted PR, 2.31; 95% CI, 1.09-4.89) were associated with mixed M. tuberculosis infections. Among human immunodeficiency virus-infected patients, prior tuberculosis treatment (adjusted PR, 2.11; 95% CI, 1.04-4.31) and CD4(+) T-cell count of <100 cells/μl (adjusted PR, 10.18; 95% CI, 2.48-41.71) were associated with mixed M. tuberculosis infections. Clinical suspicion of mixed M. tuberculosis infections should be high for patients with advanced immunosuppression and a prior history of tuberculosis treatment.

Examining the relationship between alcohol use and high-risk sex practices in a population of women with high HIV incidence despite high levels of HIV-related knowledge

Objectives Alcohol use has been linked to risky sexual behaviour and it has been identified as an important modifiable factor to prevent HIV infection. However, the evidence of a link between alcohol use and risky sexual behaviour is mixed. In this paper, we examine the role of alcohol use in sexual risk taking among women in Botswana. Methods Participants were recruited by stratified proportional random sampling and were administered a survey interview that collected information on HIV/AIDS knowledge, risky sexual behaviour and alcohol use. Logistic regression and bivariate probit analyses were used to examine the association between alcohol use and high-risk sexual behaviour. Results 239 women were interviewed. 168 (70%) had high levels of HIV/AIDS knowledge. We found no significant protective effect of good HIV/AIDS knowledge over high-risk sex behaviour (adjusted OR 0.74, 95% CI 0.38 to 1.42). However, alcohol use before sex was associated with high-risk sex behaviour (adjusted OR 3.04, 95% CI 1.11 to 6.45). However, bivariate probit analysis that simultaneously estimates risky sexual behaviour and alcohol use revealed an insignificant association between alcohol use and risky sex, highlighting the potential presence of other unobserved individual factors that are associated with alcohol use and risky sex. Conclusions Knowledge about HIV may not be sufficient to decrease risky sexual behaviour. Alcohol consumption was associated with an increased probability of high-risk sexual intercourse. However, the relationship between alcohol use and risky sex may also be a marker of a third omitted variable (such as overall risk-taking propensity). Further research is needed to identify factors associated with alcohol use and high-risk sex.