Evaluation of an SMS-based mHealth intervention to enhance early infant diagnosis follow-up testing and assessment of postnatal prophylaxis.

BACKGROUND: Adherence to infant antiretroviral (ARV) postnatal prophylaxis and early infant diagnosis (EID) uptake is low in Africa. Promoting EID and adherence are necessary for this age group. OBJECTIVES: We evaluated an SMS-based mobile health (mHealth) intervention to enhance adherence to ARV prophylaxis and knowledge of EID and prevention of mother-to-child transmission (PMTCT) among high-risk and low-risk mother-infant pairs. METHOD: Two hundred and fifty-one mothers were recruited from King Edward VIII Hospital between December 2018 and October 2019. Participant information was captured, and SMS reminders were sent postnatally to promote immunisation attendance. Follow-up HIV polymerase chain reaction (PCR) test results were reviewed, and telephonic interviews were utilised for qualitative data. RESULTS: In all, 73.3% of infants had HIV PCR tests performed at 10 weeks. This high rate could be attributed to the mHealth intervention as this is considerably higher than other national studies, though not statistically significant compared to rates reported in the district at the same time. Factors that have impacted follow-up EID rates include poor maternal knowledge of EID time points and inadequate implementation of national PMTCT protocols. High-risk mothers were younger, commenced antenatal clinic visit later, were less knowledgeable on prophylaxis and have lower-birthweight infants than lower-risk mothers. CONCLUSION: mHealth can play an important role in improving EID by increasing maternal knowledge. Further studies should focus on whether maternal education over an mHealth platform can increase knowledge on PMTCT and subsequently increase EID.

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.

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.

High frequency of hypoglycaemia in patients with type 1 diabetes mellitus attending a tertiary diabetes clinic in Durban, South Africa.

AIM: The study aimed to assess the prevalence of hypoglycaemia in subjects with type 1 diabetes (T1D) attending a public health tertiary diabetes clinic in Durban, South Africa. METHODS: Patients with T1D were enrolled at the time of clinic attendance. Data on hypoglycaemia over the previous 12 weeks were obtained from glucose meter downloads as well as diary records. Each patient completed the Hypoglycaemia Fear Survey questionnaire as well as an in-house questionnaire on hypoglycaemic episodes in the previous 12 months. RESULTS: A total of 151 subjects (58% female, 54% black African) were enrolled. "Any" hypoglycaemia occurred in 144 (95.4%) in the 12 months prior to clinic attendance. Of these, "severe" hypoglycaemia occurred in 107 (74.3%) and 22 (20.6%) had five or more severe episodes. The most frequent behavioural change in response to hypoglycaemia was insulin dose self-adjustment and the commonest worry was the possibility of becoming emotionally upset during hypoglycaemia. CONCLUSIONS: In a tertiary diabetes clinic in Durban, South Africa, there was a high frequency of hypoglycaemia in patients with T1D and in the majority, at least one severe episode occurred in the 12 months prior to clinic attendance. The results indicate a need for further study and strategies to reduce the frequency and severity of hypoglycaemia.

Prevalence of Primary Hypertension and Risk Factors in Grade XII Learners in KwaZulu-Natal, South Africa.

Hypertension in childhood leads to hypertension in adult life, the strongest risk factor being obesity. This study determined the prevalence of primary hypertension and its risk factors in Grade XII learners in KwaZulu-Natal, South Africa, from March 2016 to June 2017. Weight, height, body mass index (BMI), random finger prick cholesterol and glucose, and spot urine for an albumin : creatinine ratio were measured. An average of three separate blood pressure readings taken was at least 5 minutes apart. Five hundred and sixty-four learners had weight, height, and BMI; 536 had random blood glucose; and 545 had cholesterol and random spot urine albumin : creatinine ratios measured. Prehypertension was detected in 168 (29.7%) and hypertension in 77 (13.7%) of learners. Ninety (15.9%) were overweight and 75 (13,3%) were obese. Hypercholesterolaemia was present in 58 (10.8%) and a high spot random urine albumin : creatinine ratio in 5 (1.0%). None had a high blood glucose level. Both prehypertension and hypertension in all learners showed a significant increase with increasing BMI. Six (1.0%) learners had metabolic syndrome. Female learners in other racial groups (defined as Indian, mixed race, and White learners), overweight, and obese learners showed significantly higher rates of hypercholesterolaemia. We showed overweight and obesity as risk factors for prehypertension and hypertension. This presages the need for an appropriate diet and adequate exercise in a child's school career.

Efficacy and Safety of 'Fixed Dose' versus 'Loose' Drug Regimens for Treatment of Pulmonary Tuberculosis in Two High TB-Burden African Countries: A Randomized Controlled Trial.

BACKGROUND: There are limited data on the performance of the use of fixed-dose combination (FDC) TB drugs when used under programmatic settings in high TB-endemic countries. We evaluated the efficacy and safety of FDC versus loose formulation (LF) TB treatment regimens for treatment of pulmonary TB (PTB) in the context of actual medical practice in prevailing conditions within programmatic settings in five sites in two high TB-burden African countries. METHODS: A two-arm, single-blind, randomized clinical trial comparing FDCs with separate LFs involving 1000 adults newly diagnosed with culture positive PTB was conducted at five sites in two African countries between 2007 and 2011. Participants were randomized to receive daily treatment with anti-TB drugs given as either FDC or separate LFs for 24 weeks (intensive phase- 8 weeks of isoniazid, rifampicin, ethambutol and pyrazinamide; continuation phase- 16 weeks of rifampicin and isoniazid). Primary outcome measures were microbiological cure and safety at the end of six months' treatment; pre-specified non-inferiority margin for difference in cure rate was 4%. The primary efficacy analysis was based on the modified intent to treat (mITT) cohort comprising all randomized patients with a positive baseline culture result for TB and who received at least one dose of study treatment. Patients missing end of treatment culture results were considered failures. Further analyses were done in which mITT patients without an end of treatment (EOT) culture were excluded in a complete case analysis (mITTcc) and a per protocol cohort analysis defined as mITTcc patients who received at least 95% of their intended doses and had an EOT culture result. RESULTS: In the mITT analysis, the cure rate in the FDC group was 86.7% (398/459) and in the LF group 85.2% (396/465) (difference 1.5-% (90% confidence interval (CI) (-2.2%- 5.3%)). Per Protocol analysis showed similar results: FDC 98.9% (359/363) versus LF 96.9% (345/356), (difference 2.0% (90% CI: 0.1%- 3.8%)). The two arms showed no significant differences in terms of safety, early culture conversion and patient adherence to treatment. INTERPRETATION: The comparison of the two drug regimens satisfied the pre-specified non-inferiority criterion. Our results support the WHO recommendations for the use of FDC in the context of actual medical practice within health services in high TB-endemic countries. TRIAL REGISTRATION: ISRCTN Registry 95204603.

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.

Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy.

BACKGROUND: Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity. METHODS AND RESULTS: Sixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0-48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0-48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 < 4.5 µg.h/mL, which has previously been associated with acquired rifamycin resistance (ARR). Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis (grade 4), occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations. CONCLUSIONS: A daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00640887.

Comparison of amplicor and GeneXpert MTB/RIF tests for diagnosis of tuberculous meningitis.

There are no data about the comparative accuracy of commercially available nucleic acid amplification tests (GeneXpert MTB/RIF and Roche Amplicor) for the diagnosis of tuberculous meningitis (TBM). A total of 148 patients with suspected TBM were evaluated, and cultures served as the reference standard. The sensitivities and specificities (95% confidence interval [CI]) for the Amplicor and Xpert MTB/RIF tests were similar: 46 (31-60) versus 50 (33-67) and 99 (93-100) and 94 (84-99), respectively.

Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial.

BACKGROUND: WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per µL or more. METHODS: We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220-349 cells per µL vs ≥350 cells per µL). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053). FINDINGS: We screened 13,588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8·5%) of 767 patients in the early ART group versus 71 (9·2%) of 771 in the delayed ART group (relative risk [RR] 0·91, 95% CI 0·64-1·30; p=0·9). Of patients with a CD4 cell count of 220-349 cells per µL, 26 (7·9%) of 331 patients versus 33 (9·6%) of 342 reached the primary endpoint (RR 0·80, 95% CI 0·46-1·39; p=0·6). For those with 350 cells per µL or more, 39 (8·9%) of 436 versus 38 (8·9%) of 429 reached the primary endpoint (RR 1·01, 95% CI 0·63-1·62; p=0·4). Mortality did not differ significantly between treatment groups (RR 1·4, 95% CI 0·8-2·3; p=0·23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0·37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0·56). INTERPRETATION: ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per µL. WHO guidelines should be updated accordingly. FUNDING: USAID, Zambia Ministry of Health, Tanzania Commission for Science and Technology, WHO-TDR.

Evaluation of rapid syphilis tests in KwaZulu-Natal.

BACKGROUND: Despite the considerable decrease in the seroprevalence of syphilis in South Africa, with an estimated prevalence of 1.5% in 2010, the disease remains a threat particularly to pregnant women, hence there is a need for a rapid, reliable, and affordable screening and diagnostic test. A laboratory evaluation study was conducted in response to a call by the KwaZulu-Natal (KZN) Provincial Department of Health that is considering using rapid point-of-care syphilis tests. METHODS: The performances of the Hexagon and the SD Bioline syphilis tests were compared with the Treponema pallidum hemagglutination assay (TPHA) reference test using 297 (142 positive and 155 negative) serum specimens. RESULTS: Both assays demonstrated good performance with negative and positive concordance of 97 and 94% for the Hexagon assay and 98 and 90% for SD Bioline assay, respectively, when compared to the TPHA. The Hexagon test was quicker and easier to read than the SD Bioline test. CONCLUSION: Although the rapid syphilis tests performed favorably, a number of issues need to be considered prior to their use for syphilis screening in the public sector of South Africa.

Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study.

BACKGROUND: Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM. METHODS AND FINDINGS: 235 South-African patients with a meningeal-like illness were categorised as having definite (culture or Amplicor PCR positive), probable (anti-TBM treatment initiated but microbiological confirmation lacking), or non-TBM. Xpert MTB/RIF accuracy was evaluated using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid (CSF). To evaluate the incremental value of MTB/RIF over a clinically based diagnosis, test accuracy was compared to a clinical score (CS) derived using basic clinical and laboratory information. Of 204 evaluable patients (of whom 87% were HIV-infected), 59 had definite TBM, 64 probable TBM, and 81 non-TBM. Overall sensitivity and specificity (95% CI) were 62% (48%-75%) and 95% (87%-99%), respectively. The sensitivity of Xpert MTB/RIF was significantly better than that of smear microscopy (62% versus 12%; p = 0.001) and significantly better than that of the CS (62% versus 30%; p = 0.001; C statistic 85% [79%-92%]). Xpert MTB/RIF sensitivity was higher when centrifuged versus uncentrifuged samples were used (82% [62%-94%] versus 47% [31%-61%]; p = 0.004). The combination of CS and Xpert MTB/RIF (Xpert MTB/RIF performed if CS<8) performed as well as Xpert MTB/RIF alone but with a ∼10% reduction in test usage. This overall pattern of results remained unchanged when the definite and probable TBM groups were combined. Xpert MTB/RIF was not useful in identifying TBM among HIV-uninfected individuals, although the sample was small. There was no evidence of PCR inhibition, and the limit of detection was ∼80 colony forming units per millilitre. Study limitations included a predominantly HIV-infected cohort and the limited number of culture-positive CSF samples. CONCLUSIONS: Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals from a tuberculosis-endemic setting, particularly when a centrifuged CSF pellet is used. Further studies are required to confirm these findings in different settings. Please see later in the article for the Editors' Summary.

Early clinical and subclinical visual evoked potential and Humphrey's visual field defects in cryptococcal meningitis.

Cryptococcal induced visual loss is a devastating complication in survivors of cryptococcal meningitis (CM). Early detection is paramount in prevention and treatment. Subclinical optic nerve dysfunction in CM has not hitherto been investigated by electrophysiological means. We undertook a prospective study on 90 HIV sero-positive patients with culture confirmed CM. Seventy-four patients underwent visual evoked potential (VEP) testing and 47 patients underwent Humphrey's visual field (HVF) testing. Decreased best corrected visual acuity (BCVA) was detected in 46.5% of patients. VEP was abnormal in 51/74 (68.9%) right eyes and 50/74 (67.6%) left eyes. VEP P100 latency was the main abnormality with mean latency values of 118.9 (±16.5) ms and 119.8 (±15.7) ms for the right and left eyes respectively, mildly prolonged when compared to our laboratory references of 104 (±10) ms (p<0.001). Subclinical VEP abnormality was detected in 56.5% of normal eyes and constituted mostly latency abnormality. VEP amplitude was also significantly reduced in this cohort but minimally so in the visually unimpaired. HVF was abnormal in 36/47 (76.6%) right eyes and 32/45 (71.1%) left eyes. The predominant field defect was peripheral constriction with an enlarged blind spot suggesting the greater impact by raised intracranial pressure over that of optic neuritis. Whether this was due to papilloedema or a compartment syndrome is open to further investigation. Subclinical HVF abnormalities were minimal and therefore a poor screening test for early optic nerve dysfunction. However, early optic nerve dysfunction can be detected by testing of VEP P100 latency, which may precede the onset of visual loss in CM.

Comparative utility of cytokine levels and quantitative RD-1-specific T cell responses for rapid immunodiagnosis of tuberculous meningitis.

The rapid diagnosis of tuberculous meningitis (TBM) is problematic. We found in 150 patients with suspected TBM that, similar to RD-1-specific quantitative cerebrospinal fluid (CSF) T-cell responses, unstimulated CSF gamma interferon (IFN-γ) levels when used together with other rapid confirmatory tests (Gram stain and cryptococcal latex agglutination test) may allow the accurate and rapid diagnosis of TBM in a setting in which tuberculosis (TB) and HIV are endemic. In resource-poor settings, a clinical prediction rule (CPR) may be useful to clinicians, and thus the IFN-γ assay may potentially need to be used only when the clinical score is below a prespecified threshold. These preliminary findings will need to be confirmed in further studies.

Spread of extensively drug-resistant tuberculosis in KwaZulu-Natal province, South Africa.

BACKGROUND: In 2005 a cluster of 53 HIV-infected patients with extensively drug-resistant tuberculosis (XDR-TB) was detected in the Msinga sub-district, the catchment area for the Church of Scotland Hospital (CoSH) in Tugela Ferry, in KwaZulu-Natal province (KZN), South Africa. KZN is divided into 11 healthcare districts. We sought to determine the distribution of XDR TB cases in the province in relation to population density. METHODS: In this cross-sectional study, the KZN tuberculosis laboratory database was analysed. Results of all patients with a sputum culture positive for Mycobacterium tuberculosis from January 2006 to June 2007 were included. Drug-susceptibility test results for isoniazid, rifampicin, ethambutol, streptomycin, kanamycin and ofloxacin were available for all patients as well as the location of the hospital where their clinical diagnosis was made. FINDINGS: In total, 20858 patients attending one of 73 hospitals or their adjacent clinics had cultures positive for M. tuberculosis. Of these, 4170 (20%) were MDR-TB cases. Four hundred and forty three (11%) of the MDR tuberculosis cases displayed the XDR tuberculosis susceptibility profile. Only 1429 (34%) of the MDR-TB patients were seen at the provincial referral hospital for treatment. The proportion of XDR-TB amongst culture-confirmed cases was highest in the Msinga sub-district (19.6%), followed by the remaining part of the Umzinyati district (5.9%) and the other 10 districts (1.1%). The number of hospitals with at least one XDR-TB case increased from 18 (25%) to 58 (80%) during the study period. INTERPRETATION: XDR-TB is present throughout KZN. More than 65% of all diagnosed MDR-TB cases, including XDR-TB patients, were left untreated and likely remained in the community as a source of infection.

Cerebrospinal T-cell responses aid in the diagnosis of tuberculous meningitis in a human immunodeficiency virus- and tuberculosis-endemic population.

RATIONALE: Current tools for the rapid diagnosis of tuberculous meningitis (TBM) are suboptimal. We evaluated the clinical utility of a quantitative RD-1 IFN-gamma T-cell enzyme-linked immunospot (ELISPOT) assay (T-SPOT.TB), using cerebrospinal fluid cells for the rapid immunodiagnosis of TBM. OBJECTIVES: To evaluate the diagnostic utility of the RD1 antigen- specific ELISPOT assay for the diagnosis of tuberculous meningitis. METHODS: The ELISPOT assay was evaluated in 150 patients with suspected TBM who were categorized as definite-TBM, probable-TBM, and non-TBM. Culture or polymerase chain reaction positivity for Mycobacerium tuberculosis served as the reference standard. To determine the diagnostic value of the ELISPOT assay, a clinical prediction rule was derived from baseline clinical and laboratory parameters using a multivariable regression model. MEASUREMENTS AND MAIN RESULTS: A total of 140 patients (81% HIV-infected; median CD4 count, 160 cells/mm(3)) were included in the final analysis. When comparing the definite-TBM (n = 38) and non-TBM groups (n = 48), the ELISPOT assay (cut point of > or =228 spot-forming cells per 1 million mononuclear cells) was a useful rule-in test: sensitivity 58% (95% confidence interval [CI], 41-74); specificity 94% (95% CI, 83-99). However, ELISPOT outcomes improved when other rapid tests were concurrently used to exclude bacterial (Gram stain) and cryptococcal meningitis (latex-agglutination test) within the non-TBM group. Using this approach, the ELISPOT assay (cut point of > or =46 spot-forming cells) was an excellent rule-in test: sensitivity 82% (95% CI, 66-92); specificity 100% (95% CI, 78-100); positive predictive value, 100% (95% CI, 89-100); negative predictive value, 68% (95% CI, 45-86); area under the curve, 0.90. The ELISPOT assay had incremental diagnostic value compared with the clinical prediction rule. CONCLUSIONS: The RD-1 ELISPOT assay, using cerebrospinal fluid mononuclear cells and in conjunction with other rapid confirmatory tests (Gram stain and cryptococcal latex-agglutination test), is an accurate rapid rule-in test for TBM in a TB and HIV endemic setting.

Comparison of a clinical prediction rule and a LAM antigen-detection assay for the rapid diagnosis of TBM in a high HIV prevalence setting.

BACKGROUND/OBJECTIVE: The diagnosis of tuberculous meningitis (TBM) in resource poor TB endemic environments is challenging. The accuracy of current tools for the rapid diagnosis of TBM is suboptimal. We sought to develop a clinical-prediction rule for the diagnosis of TBM in a high HIV prevalence setting, and to compare performance outcomes to conventional diagnostic modalities and a novel lipoarabinomannan (LAM) antigen detection test (Clearview-TB®) using cerebrospinal fluid (CSF). METHODS: Patients with suspected TBM were classified as definite-TBM (CSF culture or PCR positive), probable-TBM and non-TBM. RESULTS: Of the 150 patients, 84% were HIV-infected (median [IQR] CD4 count = 132 [54; 241] cells/µl). There were 39, 55 and 54 patients in the definite, probable and non-TBM groups, respectively. The LAM sensitivity and specificity (95%CI) was 31% (17;48) and 94% (85;99), respectively (cut-point ≥ 0.18). By contrast, smear-microscopy was 100% specific but detected none of the definite-TBM cases. LAM positivity was associated with HIV co-infection and low CD4 T cell count (CD4<200 vs. >200 cells/µl; p = 0.03). The sensitivity and specificity in those with a CD4<100 cells/µl was 50% (27;73) and 95% (74;99), respectively. A clinical-prediction rule ≥ 6 derived from multivariate analysis had a sensitivity and specificity (95%CI) of 47% (31;64) and 98% (90;100), respectively. When LAM was combined with the clinical-prediction-rule, the sensitivity increased significantly (p<0.001) to 63% (47;68) and specificity remained high at 93% (82;98). CONCLUSIONS: Despite its modest sensitivity the LAM ELISA is an accurate rapid rule-in test for TBM that has incremental value over smear-microscopy. The rule-in value of LAM can be further increased by combination with a clinical-prediction rule, thus enhancing the rapid diagnosis of TBM in HIV-infected persons with advanced immunosuppression.

Utility of a novel lipoarabinomannan assay for the diagnosis of tuberculous meningitis in a resource-poor high-HIV prevalence setting.

BACKGROUND: In Africa, tuberculous meningitis (TBM) is an important opportunistic infection in HIV-positive patients. Current diagnostic tools for TBM perform sub-optimally. In particular, the rapid diagnosis of TBM is challenging because smear microscopy has a low yield and PCR is not widely available in resource-poor settings. METHODS: We evaluated the performance outcome of a novel standardized lipoarabinomannan (LAM) antigen-detection assay, using archived cerebrospinal fluid samples, in 50 African TBM suspects of whom 68% were HIV-positive. RESULTS: Of the 50 participants 14, 23 and 13 patients had definite, probable and non-TBM, respectively. In the non-TB group there were 5 HIV positive patients who were lost to follow-up and in whom concomitant infection with Mycobacterium tuberculosis could not be definitively excluded. The test sensitivities and specificities were as follows: LAM assay 64% and 69% (cut-point 0.22), smear microscopy 0% and 100% and PCR 93% and 77%, respectively. CONCLUSION: In this preliminary proof-of-concept study, a rapid diagnosis of TBM could be achieved using LAM antigen detection. Although specificity was sub-optimal, the estimates provided here may be unreliable because of a classification bias inherent in the study design where it was not possible to exclude TBM in the presumed non-TBM cases owing to a lack of clinical follow-up. As PCR is largely unavailable, the LAM assay may well prove to be a useful adjunct for the rapid diagnosis of TBM in high HIV-incidence settings. These preliminary results justify further enquiry and prospective studies are now required to definitively establish the place of this technology for the diagnosis of TBM.

Profile of mortality among women with gestational trophoblastic disease infected with the human immunodeficiency virus (HIV): argument for a new poor prognostic factor.

Gestational trophoblastic disease (GTD) encompasses a spectrum of conditions ranging from hydatidiform mole to choriocarcinoma. The management of GTD in association with human immunodeficiency virus (HIV) infection is complicated by the interaction between chemotherapy, antiretroviral therapy, and poor performance status due to HIV-related illnesses. This study describes the profile of mortality of women with GTD in the background of HIV infection. A total of 78 patients with GTD were reviewed retrospectively. There were 53 patients with invasive molar pregnancy and 23 patients with choriocarcinoma. The HIV seroprevalence was 31%. There were 15 deaths (19%). There were 8 HIV-infected (33%) and 7 HIV noninfected (13%) who demised. Of the 8 patients with CD4 counts less than 200 cells/microL, 7 patients demised. There were no mortalities among patients with CD4 counts more than 200 cells/microL. Of the 15 deaths, 5 HIV-infected patients and 5 HIV-noninfected patients received chemotherapy. There were 5 patients admitted in very poor general condition precluding the administration of chemotherapy. Among the 10 patients that received chemotherapy and demised, the causes of death included widespread disease, multiorgan failure, and toxicity due to chemotherapy. These findings highlight the poor outcomes of HIV-infected women with CD4 counts less than 200 cells/microL due to poor tolerance to chemotherapy or poor performance status precluding administration of chemotherapy.