N-Acetyltransferase 2 Genotypes among Zulu-Speaking South Africans and Isoniazid and N-Acetyl-Isoniazid Pharmacokinetics during Antituberculosis Treatment.

The distribution of N-acetyltransferase 2 gene (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in the South African population is limited. We investigated NAT2 polymorphisms and their effect on isoniazid pharmacokinetics (PK) in Zulu black HIV-infected South Africans in Durban, South Africa. HIV-infected participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Participants with culture-confirmed pulmonary TB were genotyped for the NAT2 polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A, and 803A>G using Life Technologies prevalidated TaqMan assays (Life Technologies, Paisley, UK). Participants underwent sampling for determination of plasma isoniazid and N-acetyl-isoniazid concentrations. Among the 120 patients, 63/120 (52.5%) were slow metabolizers (NAT2*5/*5), 43/120 (35.8%) had an intermediate metabolism genotype (NAT2*5/12), and 12/120 (11.7%) had a rapid metabolism genotype (NAT2*4/*11, NAT2*11/12, and NAT2*12/12). The NAT2 alleles evaluated in this study were *4, *5C, *5D, *5E, *5J, *5K, *5KA, *5T, *11A, *12A/12C, and *12M. NAT2*5 was the most frequent allele (70.4%), followed by NAT2*12 (27.9%). Fifty-eight of 60 participants in study 1 had PK results. The median area under the concentration-time curve from 0 to infinity (AUC0-∞) was 5.53 (interquartile range [IQR], 3.63 to 9.12 µg h/ml), and the maximum concentration (Cmax) was 1.47 µg/ml (IQR, 1.14 to 1.89 µg/ml). Thirty-four of 40 participants in study 2 had both PK results and NAT2 genotyping results. The median AUC0-∞ was 10.76 µg·h/ml (IQR, 8.24 to 28.96 µg·h/ml), and the Cmax was 3.14 µg/ml (IQR, 2.39 to 4.34 µg/ml). Individual polymorphisms were not equally distributed, with some being represented in small numbers. The genotype did not correlate with the phenotype, with those with a rapid acetylator genotype showing higher AUC0-∞ values than those with a slow acetylator genotype, but the difference was not significant (P = 0.43). There was a high prevalence of slow acetylator genotypes, followed by intermediate and then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence isoniazid metabolism, and these warrant further investigation in this population.

Transmission of Extensively Drug-Resistant Tuberculosis in South Africa.

BACKGROUND: Drug-resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug-resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions. METHODS: We conducted a prospective study involving 404 participants in KwaZulu-Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical-record reviews were used to elicit information on the participants' history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction-fragment-length polymorphism analysis, targeted gene sequencing, and whole-genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug-resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social-network analysis to identify community and hospital locations of transmission. RESULTS: Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person-to-person or hospital-based epidemiologic links were identified in 123 of 404 participants (30%). CONCLUSIONS: The majority of cases of XDR tuberculosis in KwaZulu-Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug-resistant tuberculosis requires an increased focus on interrupting transmission. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Effectiveness of an HIV-risk reduction intervention to reduce HIV transmission among serodiscordant couples in Durban, South Africa. A randomized controlled trial.

Lack of condom use by married or cohabiting couples in populations with high rates of HIV infection has become a significant public health issue. This study investigated whether an HIV risk-reduction intervention (RRI) would increase condom use when delivered to serodiscordant couples as a unit. Of the 62 couples that were screened, 30 serodiscordant couples were enrolled in the study, and randomized 2:1 to an immediate intervention-waitlist control study. The 12-week intervention focused on communication, problem-solving, and negotiation skills. Participants were assessed at baseline, three and six months after the intervention. The main outcome measures were consistent condom use, HIV seroconversion and fidelity to the programme. The use of condoms increased for both the intervention and control groups after receiving a 12-week RRI. Group comparisons showed a significant difference at three months, with a significantly higher mean proportion of condom-protected sex acts (p = 0.0119) between the control and intervention groups, the later showing an increase in condom use. No seroconversion was detected, and the overall retention rate of participants was 83.33%. Counselling heterosexual couples as a unit prompted an increase in condom use, but sustained condom use remains a challenge.

Improved Survival and Cure Rates With Concurrent Treatment for Multidrug-Resistant Tuberculosis-Human Immunodeficiency Virus Coinfection in South Africa.

Background: Mortality in multidrug-resistant (MDR) tuberculosis-human immunodeficiency virus (HIV) coinfection has historically been high, but most studies predated the availability of antiretroviral therapy (ART). We prospectively compared survival and treatment outcomes in MDR tuberculosis-HIV-coinfected patients on ART to those in patients with MDR tuberculosis alone. Methods: This observational study enrolled culture-confirmed MDR tuberculosis patients with and without HIV in South Africa between 2011 and 2013. Participants received standardized MDR tuberculosis and HIV regimens and were followed monthly for treatment response, adverse events, and adherence. The primary outcome was survival. Results: Among 206 participants, 150 were HIV infected, 131 (64%) were female, and the median age was 33 years (interquartile range [IQR], 26-41). Of the 191 participants with a final MDR tuberculosis outcome, 130 (73%) were cured or completed treatment, which did not differ by HIV status (P = .50). After 2 years, CD4 count increased a median of 140 cells/mm3 (P = .005), and 64% had an undetectable HIV viral load. HIV-infected and HIV-uninfected participants had high rates of survival (86% and 94%, respectively; P = .34). The strongest risk factor for mortality was having a CD4 count ≤100 cells/mm3 (adjusted hazards ratio, 15.6; 95% confidence interval, 4.4-55.6). Conclusions: Survival and treatment outcomes among MDR tuberculosis-HIV individuals receiving concurrent ART approached those of HIV-uninfected patients. The greatest risk of death was among HIV-infected individuals with CD4 counts ≤100 cells/mm3. These findings provide critical evidence to support concurrent treatment of MDR tuberculosis and HIV.

Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis.

Pyrazinamide is used in the treatment of tuberculosis (TB) because its sterilizing effect against tubercle bacilli allows the shortening of treatment. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). Pyrazinamide pharmacokinetic (PK) data from 61 HIV/TB-coinfected patients in South Africa were used in the analysis. The patients were administered weight-adjusted doses of pyrazinamide, rifampin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on days 1, 8, 15, and 29. The data were interpreted using nonlinear mixed-effects modeling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted area under the concentration-time curve from 0 to 24 h of 363 mg · h/liter. Among patients with drug-susceptible TB, adding 400 mg to the dose for those weighing 30 to 54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1,500 mg, 1,750 mg, and 2,000 mg to patients in the 33- to 50-kg, 51- to 70-kg, and greater than 70-kg weight bands, respectively.

Effects on the QT Interval of a Gatifloxacin-Containing Regimen versus Standard Treatment of Pulmonary Tuberculosis.

The effects on ventricular repolarization-recorded on the electrocardiogram (ECG) as lengthening of the QT interval-of acute tuberculosis and those of standard and alternative antituberculosis regimens are underdocumented. A correction factor (QTc) is introduced to make the QT independent of the heart rate, translating into the slope of the regression line between QT and heart rate being close to zero. ECGs were performed predosing and 1 to 5 h postdosing (month 1, month 2, and end of treatment) around drugs' peak concentration time in tuberculosis patients treated with either the standard 6-month treatment (rifampin and isoniazid for 6 months and pyrazinamide and ethambutol for 2 months; "control") or a test regimen with gatifloxacin, rifampin, and isoniazid given for 4 months (pyrazinamide for the first 2 months) as part of the OFLOTUB study, a randomized controlled trial conducted in five African countries. Drug levels were measured at steady state (month 1) in a subset of patients. We compared treatment effects on the QTc and modeled the effect of individual drugs' maximum concentrations of drug in serum (Cmax) on the Fridericia-corrected QT interval. A total of 1,686 patients were eligible for the correction factor analysis of QT at baseline (mean age, 30.7 years; 27% female). Median heart rate decreased from 96/min at baseline to 71/min at end of treatment, and body temperature decreased from 37.2 to 36.5°C. Pretreatment, the nonlinear model estimated the best correction factor at 0.4081 in between Bazett's (0.5) and Fridericia's (0.33) corrections. On treatment, Fridericia (QTcF) was the best correction factor. A total of 1,602 patients contributed to the analysis of QTcF by treatment arm. The peak QTcF value during follow-up was >480 ms for 21 patients (7 and 14 in the test and control arms, respectively) and >500 ms for 9 patients (5 and 4, respectively), corresponding to a risk difference of -0.9% (95% confidence interval [CI], -2.0% to 2.3%; P = 0.12) and 0.1% (95% CI, -0.6% to 0.9%; P = 0.75), respectively, between the test and control arms. One hundred six (6.6%) patients had a peak measurement change from baseline of >60 ms (adjusted between-arm difference, 0.8%; 95% CI, -1.4% to 3.1%; P = 0.47). No evidence was found of an association between Cmax of the antituberculosis drugs 1 month into treatment and the length of QTcF. Neither a standard 6-month nor a 4-month gatifloxacin-based regimen appears to carry a sizable risk of QT prolongation in patients with newly diagnosed pulmonary tuberculosis. This is to date the largest data set studying the effects of antituberculosis regimens on the QT, both for the standard regimen and for a fluoroquinolone-containing regimen. (This study has been registered at ClinicalTrials.gov under identifier NCT00216385.).

A four-month gatifloxacin-containing regimen for treating tuberculosis.

BACKGROUND: Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. METHODS: We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. RESULTS: A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. CONCLUSIONS: Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).

Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction.

Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TB-coinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4.5 days. The model predicts that increases in the dose of rifampin result in more-than-linear drug exposure increases as measured by the 24-h area under the concentration-time curve. Simulations with doses of up to 35 mg/kg produced results closely in line with those of clinical trials.

Longitudinal assessment of health related quality of life of HIV infected patients treated for tuberculosis and HIV in a high burden setting.

INTRODUCTION: Assessment of patients receiving treatment for human immunodeficiency virus (HIV) and tuberculosis (TB) using a Health Related Quality of Life (HRQoL) instrument is important to get the subjective view of the patients' wellbeing. METHODS: We used the Functional Assessment of HIV Infection (FAHI) HRQoL instrument to collect perceived wellness information at baseline, month 3, 6 and 12 from patients enrolled in a pharmacokinetic study between March 2007 and April 2008. Composite domain scores at each time point and their relationship with the rate of adverse events (AEs) and serious adverse events were compared between treatment arms. RESULTS: Out of the 82 patients enrolled, 76 were analysed. There was a significant increase in total score in all groups between baseline, month 3, 6 and 12 (all p values < 0.0001), and over time (p < 0.001). Adjusting for baseline total score, baseline CD4 count had a significant effect on the total score over time (p = 0.002) and the rate of change in total score over time, that is; interaction effect (p < 0.001). There was no difference in each domain scores between participants that received ART with TB treatment and those that received TB treatment only. Respiratory AEs had a significant effect on HRQoL. CONCLUSION: We found that assessment of HRQoL of participants in TB-HIV treatment using the FAHI instrument was useful in evaluating treatment responses. It showed improvement consistent with decrease in adverse events and signs and symptoms of TB. Number and type of AEs was related to lower HRQoL in spite of TB cure.

Tobacco smoking clusters in households affected by tuberculosis in an individual participant data meta-analysis of national tuberculosis prevalence surveys: Time for household-wide interventions?

Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95% CI: 1.11-1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions.

Healthcare seeking patterns for TB symptoms: Findings from the first national TB prevalence survey of South Africa, 2017-2019.

BACKGROUND: Although tuberculosis (TB) symptoms have limited sensitivity they remain an important entry point into the TB care cascade. OBJECTIVES: To investigate self-reported healthcare seeking for TB symptoms in participants in a community-based survey. METHODS: We compared reasons for not seeking care in participants reporting ≥1 of four TB screening symptoms (cough, weight loss, night sweats, fever) in the first South African national TB prevalence survey (2017-2019). We used logistic regression analyses to identify sociodemographic and clinical characteristics associated with healthcare seeking. RESULTS: 5,168/35,191 (14.7%) survey participants reported TB symptoms and 3,442/5168 had not sought healthcare. 2,064/3,442(60.0%) participants intended to seek care, 912 (26.5%) regarded symptoms as benign, 399 (11.6%) reported access barriers(distance and cost), 36 (1.0%) took other medications and 20(0.6%) reported health system barriers. Of the 57/98 symptomatic participants diagnosed with bacteriologically confirmed TB who had not sought care: 38(66.7%) intended to do so, 8(14.0%) regarded symptoms as benign, and 6(10.5%) reported access barriers. Among these 98, those with unknown HIV status(OR 0.16 95% CI 0.03-0.82), p = 0.03 and those who smoked tobacco products(OR 0.39, 95% CI 0.17-0.89, p = 0.03) were significantly less likely to seek care. CONCLUSIONS: People with TB symptoms delayed seeking healthcare, many regarded symptoms as benign while others faced access barriers. Those with unknown HIV status were significantly less likely to seek care. Strengthening community-based TB awareness and screening programmes together with self-screening models could increase awareness of the significance of TB symptoms and contribute to improving healthcare seeking and enable many people with TB to enter the TB care cascade.

Association of diabetes, smoking, and alcohol use with subclinical-to-symptomatic spectrum of tuberculosis in 16 countries: an individual participant data meta-analysis of national tuberculosis prevalence surveys.

Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50% being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities. Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679). Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1%-56.7% of TB were subclinical (median: 38.1%). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95% CI 1.27-2.40) and symptomatic TB (OR 1.49, 95% CI 1.34-1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95% CI 1.17-2.40) but not with subclinical TB (OR 0.92, 95% CI 0.55-1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95% CI 0.70-3.62) for subclinical TB and OR 1.43, 95% CI 0.59-3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I2 was high (76.5% (95% CI 62.0-85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs. Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB. Funding: None.

Reduced antituberculosis drug concentrations in HIV-infected patients who are men or have low weight: implications for international dosing guidelines.

Reduced antituberculosis drug concentrations may contribute to unfavorable treatment outcomes among HIV-infected patients with more advanced immune suppression, and few studies have evaluated pharmacokinetics of the first-line antituberculosis drugs in such patients given fixed-dose combination tablets according to international guidelines using weight bands. In this study, pharmacokinetics were evaluated in 60 patients on 4 occasions during the first month of antituberculosis therapy. Multilevel linear mixed-effects regression analysis was used to examine the effects of age, sex, weight, drug dose/kilogram, CD4(+) lymphocyte count, treatment schedule (5 versus 7 days/week), and concurrent antiretrovirals (efavirenz plus lamivudine plus zidovudine) on the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of the respective antituberculosis drugs and to compare AUC(0-12)s at day 8, day 15, and day 29 with the day 1 AUC(0-12). Median (range) age, weight, and CD4(+) lymphocyte count were 32 (18 to 47) years, 55.2 (34.4 to 98.7) kg, and 252 (12 to 500)/µl. For every 10-kg increase in body weight, the predicted day 29 AUC(0-12) increased by 14.1% (95% confidence interval [CI], 7.5, 20.8), 14.1% (95% CI, -0.7, 31.1), 6.1% (95% CI, 2.7, 9.6) and 6.0% (95% CI, 0.8, 11.3) for rifampin, isoniazid, pyrazinamide, and ethambutol, respectively. Males had day 29 AUC(0-12)s 19.3% (95% CI, 3.6, 35.1) and 14.0% (95% CI, 5.6, 22.4) lower than females for rifampin and pyrazinamide, respectively. Level of immune suppression and concomitant antiretrovirals had little effect on the concentrations of the antituberculosis agents. As they had reduced drug concentrations, it is important to review treatment responses in patients in the lower weight bands and males to inform future treatment guidelines, and revision of doses in these patients should be considered.

Prevalence of bacteriologically confirmed pulmonary tuberculosis in South Africa, 2017-19: a multistage, cluster-based, cross-sectional survey.

BACKGROUND: Tuberculosis remains an important clinical and public health issue in South Africa, which has one of the highest tuberculosis burdens in the world. We aimed to estimate the burden of bacteriologically confirmed pulmonary tuberculosis among people aged 15 years or older in South Africa. METHODS: This multistage, cluster-based, cross-sectional survey included eligible residents (age ≥15 years, who had slept in a house for ≥10 nights in the preceding 2 weeks) in 110 clusters nationally (cluster size of 500 people; selected by probability proportional-to-population size sampling). Participants completed face-to-face symptom questionnaires (for cough, weight loss, fever, and night sweats) and manually read digital chest X-ray screening. Screening was recorded as positive if participants had at least one symptom or an abnormal chest X-ray suggestive of tuberculosis, or a combination thereof. Sputum samples from participants who were screen-positive were tested by the Xpert MTB/RIF Ultra assay (first sample) and Mycobacteria Growth Indicator Tube culture (second sample), with optional HIV testing. Participants with a positive Mycobacterium tuberculosis complex culture were considered positive for bacteriologically confirmed pulmonary tuberculosis; when culture was not positive, participants with a positive Xpert MTB/RIF Ultra result with an abnormal chest X-ray suggestive of active tuberculosis and without current or previous tuberculosis were considered positive for bacteriologically confirmed pulmonary tuberculosis. FINDINGS: Between Aug 15, 2017, and July 28, 2019, 68 771 people were enumerated from 110 clusters, with 53 250 eligible to participate in the survey, of whom 35 191 (66·1%) participated. 9066 (25·8%) of 35 191 participants were screen-positive and 234 (0·7%) were identified as having bacteriologically confirmed pulmonary tuberculosis. Overall, the estimated prevalence of bacteriologically confirmed pulmonary tuberculosis was 852 cases (95% CI 679-1026) per 100 000 population; the prevalence was highest in people aged 35-44 years (1107 cases [95% CI 703-1511] per 100 000 population) and those aged 65 years or older (1104 cases [680-1528] per 100 000 population). The estimated prevalence was approximately 1·6 times higher in men than in women (1094 cases [95% CI 835-1352] per 100 000 population vs 675 cases [494-855] per 100 000 population). 135 (57·7%) of 234 participants with tuberculosis screened positive by chest X-ray only, 16 (6·8%) by symptoms only, and 82 (35·9%) by both. 55 (28·8%) of 191 participants with tuberculosis with known HIV status were HIV-positive. INTERPRETATION: Pulmonary tuberculosis prevalence in this survey was high, especially in men. Despite the ongoing burden of HIV, many participants with tuberculosis in this survey did not have HIV. As more than half of the participants with tuberculosis had an abnormal chest X-ray without symptoms, prioritising chest X-ray screening could substantially increase case finding. FUNDING: Global Fund, Bill & Melinda Gates Foundation, USAID.

Urine lipoarabinomannan (LAM) and antimicrobial usage in seriously-ill HIV-infected patients with sputum smear-negative pulmonary tuberculosis.

BACKGROUND: Based on current WHO guidelines, hospitalized tuberculosis (TB) and HIV co-infected patients with CD4 count <100 cells/mm3 who are urine lipoarabinomannan (LAM) positive should be initiated on TB treatment. This recommendation is conditional, and data are limited in sputum smear-negative patients from TB endemic countries where the LAM test is largely inaccessible. Other potential benefits of LAM, including reduction in antibiotic usage have, hitherto, not been explored. METHODS: We consecutively enrolled newly-admitted seriously-ill HIV-infected patients (n=187) with suspected TB from three hospitals in KwaZulu-Natal, South Africa. All patients were empirically treated for TB as per the WHO 2007 smear-negative TB algorithm (patients untreated for TB were not recruited). Bio-banked urine, donated prior to anti-TB treatment, was tested for TB-infection using a commercially available LAM-ELISA test. TB sputum and blood cultures were performed. RESULTS: Data from 156 patients containing CD4 count, urine-LAM, sputum and blood culture results were analysed. Mean age was 37 years, median CD4-count was 75 cells/mm3 [interquartile range (IQR), 34-169 cells/mm3], 54/156 (34.6%) were sputum culture-positive, 12/54 (22.2%) blood-culture positive, and 53/156 (34.0%) LAM-positive. Thus, LAM sensitivity was 55.6% (30/54). The study design did not allow for calculation of specificity. Urine-LAM positivity was associated with low CD4 count (P=0.002). Ninety-point-six percent (48/53) of LAM-positive patients received antibiotics [15/48 (31.3%), 23/48 (47.9%) and 10/48 (20.8%) received one, two or three different antibiotics respectively], while the duration of antibiotic therapy was more than 5 days in 26 of 46 (56.5%) patients. CONCLUSIONS: Urine LAM testing in sputum smear-negative severely-ill hospitalized patients with TB-HIV co-infection and advanced immunosuppression, offered an immediate rule-in diagnosis in one-third of empirically treated patients. Moreover, LAM, by providing a rapid alternative diagnosis, could potentially reduce antibiotic overusage in such patients thereby reducing health-care costs and facilitating antibiotic stewardship.

Spatial distribution of extensively drug-resistant tuberculosis (XDR TB) patients in KwaZulu-Natal, South Africa.

BACKGROUND: KwaZulu-Natal province, South Africa, has among the highest burden of XDR TB worldwide with the majority of cases occurring due to transmission. Poor access to health facilities can be a barrier to timely diagnosis and treatment of TB, which can contribute to ongoing transmission. We sought to determine the geographic distribution of XDR TB patients and proximity to health facilities in KwaZulu-Natal. METHODS: We recruited adults and children with XDR TB diagnosed in KwaZulu-Natal. We calculated distance and time from participants' home to the closest hospital or clinic, as well as to the actual facility that diagnosed XDR TB, using tools within ArcGIS Network analyst. Speed of travel was assigned to road classes based on Department of Transport regulations. Results were compared to guidelines for the provision of social facilities in South Africa: 5km to a clinic and 30km to a hospital. RESULTS: During 2011-2014, 1027 new XDR TB cases were diagnosed throughout all 11 districts of KwaZulu-Natal, of whom 404 (39%) were enrolled and had geospatial data collected. Participants would have had to travel a mean distance of 2.9 km (CI 95%: 1.8-4.1) to the nearest clinic and 17.6 km (CI 95%: 11.4-23.8) to the nearest hospital. Actual distances that participants travelled to the health facility that diagnosed XDR TB ranged from <10 km (n = 143, 36%) to >50 km (n = 109, 27%), with a mean of 69 km. The majority (77%) of participants travelled farther than the recommended distance to a clinic (5 km) and 39% travelled farther than the recommended distance to a hospital (30 km). Nearly half (46%) of participants were diagnosed at a health facility in eThekwini district, of whom, 36% resided outside the Durban metropolitan area. CONCLUSIONS: XDR TB cases are widely distributed throughout KwaZulu-Natal province with a denser focus in eThekwini district. Patients travelled long distances to the health facility where they were diagnosed with XDR TB, suggesting a potential role for migration or transportation in the XDR TB epidemic.

Assessing Local Risk of Rifampicin-Resistant Tuberculosis in KwaZulu-Natal, South Africa Using Lot Quality Assurance Sampling.

BACKGROUND: KwaZulu-Natal (KZN) has the highest burden of notified multidrug-resistant tuberculosis (MDR TB) and extensively drug-resistant (XDR) TB cases in South Africa. A better understanding of spatial heterogeneity in the risk of drug-resistance may help to prioritize local responses. METHODS: Between July 2012 and June 2013, we conducted a two-way Lot Quality Assurance Sampling (LQAS) study to classify the burden of rifampicin (RIF)-resistant TB among incident TB cases notified within the catchment areas of seven laboratories in two northern and one southern district of KZN. Decision rules for classification of areas as having either a high- or low-risk of RIF resistant TB (based on proportion of RIF resistance among all TB cases) were based on consultation with local policy makers. RESULTS: We classified five areas as high-risk and two as low-risk. High-risk areas were identified in both Southern and Northern districts, with the greatest proportion of RIF resistance observed in the northernmost area, the Manguzi community situated on the Mozambique border. CONCLUSION: Our study revealed heterogeneity in the risk of RIF resistant disease among incident TB cases in KZN. This study demonstrates the potential for LQAS to detect geographic heterogeneity in areas where access to drug susceptibility testing is limited.

Assessing the utility of Xpert(®) MTB/RIF as a screening tool for patients admitted to medical wards in South Africa.

Many hospital inpatients in South Africa have undiagnosed active and drug-resistant tuberculosis (TB). Early detection of TB is essential to inform immediate infection control actions to minimize transmission risk. We assessed the utility of Xpert(®) MTB/RIF (GeneXpert) as a screening tool for medical admissions at a large public hospital in South Africa. Consecutive adult patients admitted to medical wards between March-June 2013 were enrolled; sputum specimens were collected and tested by GeneXpert, smear microscopy, and culture. Chest X-rays (CXRs) were conducted as standard care for all patients admitted. We evaluated the proportion of patients identified with TB disease through each diagnostic method. Among enrolled patients whose medical charts were available for review post-discharge, 61 (27%) were diagnosed with TB; 34 (56% of diagnosed TB cases) were GeneXpert positive. When patients in whom TB was identified by other means were excluded, GeneXpert yielded only four additional TB cases. However, GeneXpert identified rifampicin-resistant TB in one patient, who was initially diagnosed based on CXR. The utility of GeneXpert for TB screening was limited in an institution where CXR is conducted routinely and which serves a population in which TB and TB/HIV co-infection are highly prevalent, but it allowed for rapid detection of rifampicin resistance.

Impact of tuberculosis treatment and antiretroviral therapy on serial RD-1-specific quantitative T-cell readouts (QuantiFERON-TB Gold In-Tube), and relationship to treatment-related outcomes and bacterial burden.

BACKGROUND: The impact of anti-tuberculosis treatment with and without antiretroviral therapy (ART) on standardized interferon gamma release assay (IGRA) readouts has been studied inadequately in high-burden countries. METHODS: The QuantiFERON-TB Gold In-Tube (QFT-GIT) test was used to evaluate interferon gamma (IFN-γ) responses longitudinally (0, 3, 6, and 12 months post initiation of tuberculosis (TB)-HIV co-treatment or ART alone) in 82 HIV-infected patients. RESULTS: Of the 65 evaluable participants, 30 were co-infected on ART, 17 were co-infected but not on ART, and 18 were HIV-infected alone and on ART. In HIV-infected and HIV-TB-infected patients on ART, IFN-γ responses increased, whilst they decreased in those not on ART. However, baseline, month 3, and month 6 IFN-γ responses, irrespective of ART, did not differ in TB-HIV co-infected patients who culture-converted compared to those who did not (1.25 vs. 1.05, p=0.5 at baseline; 3.76 vs. 1.15, p=0.2 for month 3; 0.06 vs. 0.7, p=0.3 for month 6). IFN-γ levels did not correlate with the magnitude of sputum bacillary load, smear status, or liquid culture time-to-positivity. CONCLUSION: As IGRAs do not correlate with 2- or 6-month culture conversion or with markers of bacillary burden, they are unlikely to be useful for the prognostication of treatment outcome in co-infected patients.