An open label, randomised controlled trial of rifapentine versus rifampicin based short course regimens for the treatment of latent tuberculosis in England: the HALT LTBI pilot study.

BACKGROUND: Ending the global tuberculosis (TB) epidemic requires a focus on treating individuals with latent TB infection (LTBI) to prevent future cases. Promising trials of shorter regimens have shown them to be effective as preventative TB treatment, however there is a paucity of data on self-administered treatment completion rates. This pilot trial assessed treatment completion, adherence, safety and the feasibility of treating LTBI in the UK using a weekly rifapentine and isoniazid regimen versus daily rifampicin and isoniazid, both self-administered for 12 weeks. METHODS: An open label, randomised, multi-site pilot trial was conducted in London, UK, between March 2015 and January 2017. Adults between 16 and 65 years with LTBI at two TB clinics who were eligible for and agreed to preventative therapy were consented and randomised 1:1 to receive either a weekly combination of rifapentine/isoniazid ('intervention') or a daily combination of rifampicin/isoniazid ('standard'), with both regimens taken for twelve weeks; treatment was self-administered in both arms. The primary outcome, completion of treatment, was self-reported, defined as taking more than 90% of prescribed doses and corroborated by pill counts and urine testing. Adverse events were recorded. RESULTS: Fifty-two patients were successfully enrolled. In the intervention arm 21 of 27 patients completed treatment (77.8, 95% confidence interval [CI] 57.7-91.4), compared with 19 of 25 (76.0%, CI 54.9-90.6) in the standard of care arm. There was a similar adverse effect profile between the two arms. CONCLUSION: In this pilot trial, treatment completion was comparable between the weekly rifapentine/isoniazid and the daily rifampicin/isoniazid regimens. Additionally, the adverse event profile was similar between the two arms. We conclude that it is safe and feasible to undertake a fully powered trial to determine whether self-administered weekly treatment is superior/non-inferior compared to current treatment. TRIAL REGISTRATION: The trial was funded by the NIHR, UK and registered with ISRCTN ( 26/02/2013-No.04379941 ).

A pilot cross-sectional study of non-communicable diseases in TB household contacts.

BACKGROUND: Data on the prevalence of non-communicable diseases (NCDs) in TB household contacts (HHCs) are limited, yet important to inform integrated screening and care for NCD within contact investigations. It is also unclear if screening these contacts reveals more people with NCDs than individuals in the same neighbourhood. METHOD: We conducted a pilot cross-sectional study in South Africa and Tanzania, enrolling adult HHCs of TB and individuals in neighbourhood households (controls). We inquired about known NCD and systematically measured blood pressure, and tested for spot blood glucose and haemoglobin A1c. RESULTS: We enrolled 203 adult contacts of 111 persons with TB and 160 controls. Among contacts, respectively 12.2% (95% CI 8.3-17.6) and 39.7% (95% CI 33.1-46.7) had diabetes and hypertension, compared to 14.1% (95% CI 9.2-21.0) and 44.7% (95% CI 36.9-52.7) among controls. More than half of NCDs were newly identified. We did not find a significant difference in the prevalence of at least one NCD between the two groups (OR 0.85, 95% CI 0.50-1.45, adjusted for age and sex). CONCLUSIONS: We found a high prevalence of undiagnosed NCDs among contacts, suggesting a potential benefit of integrating NCD screening and care within contact investigations. Screening in the same community might similarly find undiagnosed NCDs.

CONTEXTE: Les données sur la prévalence des maladies non transmissibles (NCD, pour l'anglais « non-communicable diseases ¼) chez les contacts familiaux (HHC, pour l'anglais « household contacts ¼) de personnes atteintes de TB sont restreintes, mais elles revêtent une grande importance pour le dépistage et la prise en charge intégrée des NCD dans le cadre des enquêtes sur les contacts. De plus, on ignore si le dépistage de ces contacts permet de détecter davantage de personnes atteintes de NCD par rapport aux les individus résidant dans le même quartier. MÉTHODE: Nous avons réalisé une étude pilote transversale en Afrique du Sud et en Tanzanie, au cours de laquelle nous avons recruté des adultes HHC de personnes atteintes de TB et des individus vivant dans les ménages voisins (témoins). Nous les avons interrogés sur les NCD connues et avons systématiquement mesuré la pression artérielle, ainsi que réalisé des tests de de glycémie et d'hémoglobine glyquée. RÉSULTATS: Un total de 203 contacts adultes de 111 personnes atteintes de TB et 160 témoins ont été répertoriés. Parmi ces contacts, respectivement 12,2% (IC à 95% 8,3­17,6) et 39,7% (IC à 95% 33,1­46,7) souffraient de diabète et d'hypertension, contre 14,1% (IC à 95% 9,2­21,0) et 44,7% (IC à 95% 36,9­52,7) chez les témoins. Plus de la moitié des NCD ont été récemment découvertes. Aucune disparité significative n'a été observée dans la prévalence d'au moins une NCD entre les deux groupes (OR 0,85 ; 95% CI 0,50­1,45, ajusté pour l'âge et le sexe). CONCLUSIONS: Nous avons observé une fréquence élevée de NCDs non diagnostiquées parmi les contacts, ce qui indique qu'il pourrait être potentiellement bénéfique d'inclure le dépistage et les soins des NCD dans les enquêtes sur les contacts. Le dépistage au sein de la même communauté pourrait également révéler des NCD non diagnostiquées.

Digital approaches to reducing TB treatment loss to follow-up.

Poor adherence to TB treatment leads to adverse clinical outcomes. A range of digital technologies to support adherence have been developed and the COVID-19 pandemic considerably accelerated the implementation of digital interventions. Here, we review the current evidence on digital adherence support tools and update the findings of a previous review, with evidence published from 2018 to date. Interventional and observational studies, as well as primary and secondary analyses were included, and we summarised available evidence on effectiveness, cost-effectiveness and acceptability. The studies were heterogenous and varied in outcome measures and approaches used. Overall, our findings show that digital approaches, such as digital pillboxes and asynchronous video-observed treatment, are acceptable and have the potential to improve adherence and be cost-effective over time if implemented at scale. Digital tools should be part of multiple strategies to support adherence. Further research to integrate behavioural data on reasons for non-adherence will help to determine how to best implement these technologies in different settings.

Interferon release does not add discriminatory value to smear-negative HIV-tuberculosis algorithms.

Clinical algorithms for evaluating HIV-infected individuals for tuberculosis (TB) prior to isoniazid preventive therapy (IPT) perform poorly, and interferon-γ release assays (IGRAs) have moderate accuracy for active TB. It is unclear whether, when used as adjunct tests, IGRAs add any clinical discriminatory value for active TB diagnosis in the pre-IPT assessment. 779 sputum smear-negative HIV-infected persons, established on or about to commence combined antiretroviral therapy (ART), were screened for TB prior to IPT. Stepwise multivariable logistic regression was used to develop clinical prediction models. The discriminatory ability was assessed by receiver operator characteristic area under the curve (AUC). QuantiFERON-TB Gold in-tube (QFT-GIT) was evaluated. The prevalence of smear-negative TB by culture was 6.4% (95% CI 4.9-8.4%). Used alone, QFT-GIT and the tuberculin skin test (TST) had comparable performance; the post-test probability of disease based on single negative tests was 3-4%. In a multivariable model, the QFT-GIT test did not improve the ability of a clinical algorithm, which included not taking ART, weight <60 kg, no prior history of TB, any one positive TB symptom/sign (cough ≥ 2 weeks) and CD4+ count <250 cells per mm(3), to discriminate smear-negative culture-positive and -negative TB (72% to 74%; AUC comparison p=0.33). The TST marginally improved the discriminatory ability of the clinical model (to 77%, AUC comparison p=0.04). QFT-GIT does not improve the discriminatory ability of current TB screening clinical algorithms used to evaluate HIV-infected individuals for TB ahead of preventive therapy. Evaluation of new TB diagnostics for clinical relevance should follow a multivariable process that goes beyond test accuracy.

TB preventive treatment among pregnant women with HIV.

BACKGROUND: The WHO recommends TB preventive treatment (TPT) for people living with HIV, including pregnant women. Uptake of this policy recommendation in this subpopulation and country alignment with WHO guidance is unclear.METHODS: We conducted a policy review in 38 WHO high TB and TB-HIV burden countries to assess if the uptake of TPT policy among pregnant women living with HIV was in line with the WHO´s 2018 Updated and Consolidated Guidelines for Programmatic Management for LTBI. Data sources included TB national guidelines and HIV/AIDS/ART national guidelines, complemented by results from a previous survey on policy uptake held at the WHO.RESULTS: Uptake of WHO policy to provide TB preventive treatment among women with HIV accessing antenatal care was moderate: 64% (23 of 36 countries) explicitly recommended at least one clinical guideline or policy recommendation on screening, testing or treatment of LTBI among pregnant women living with HIV. There was considerable variation between countries on the stages in pregnancy that TPT should be provided. Two countries (5%) provided clinical monitoring recommendations for pregnant women.CONCLUSIONS: There is moderate uptake of TPT policy for pregnant women with HIV. Failure to provide TPT as part of antenatal or prevention of mother-to-child services is a missed opportunity for TB control.

Hypercytokinaemia accompanies HIV-tuberculosis immune reconstitution inflammatory syndrome.

Increased access to combination antiretroviral therapy in areas co-endemic for tuberculosis (TB) and HIV-1 infection is associated with an increased incidence of immune reconstitution inflammatory syndrome (TB-IRIS) whose cause is poorly understood. A case-control analysis of pro- and anti-inflammatory cytokines in TB-IRIS patients sampled at clinical presentation, and similar control patients with HIV-TB prescribed combined antiretroviral therapy who did not develop TB-IRIS. Peripheral blood mononuclear cells were cultured in the presence or absence of heat-killed Mycobacterium tuberculosis for 6 and 24 h. Stimulation with M. tuberculosis increased the abundance of many cytokine transcripts with interleukin (IL)-1ß, IL-5, IL-6, IL-10, IL-13, IL-17A, interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor (TNF) being greater in stimulated TB-IRIS cultures. Analysis of the corresponding proteins in culture supernatants, revealed increased IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-12p40, IFN-γ, GM-CSF and TNF in TB-IRIS cultures. In serum, higher concentrations of TNF, IL-6, and IFN-γ were observed in TB-IRIS patients. Serum IL-6 and TNF decreased during prednisone therapy in TB-IRIS patients. These data suggest that cytokine release contributes to pathology in TB-IRIS. IL-6 and TNF were consistently elevated and decreased in serum during corticosteroid therapy. Specific blockade of these cytokines may be rational approach to immunomodulation in TB-IRIS.

Enhanced diagnosis of HIV-1-associated tuberculosis by relating T-SPOT.TB and CD4 counts.

The sensitivity of the tuberculin skin test is impaired in HIV-1-infected persons. Enzyme-linked immunospot-based detection of immune sensitisation may be less affected. Furthermore, the quantitative response can be related to the CD4 count, potentially improving specificity for active disease. The T-SPOT.TB assay was performed on HIV-1-infected participants, 85 with active tuberculosis (TB) and 81 healthy patients (non-TB). The ratio of the sum of the 6-kDa early secretory antigenic target and culture filtrate protein 10 response to the CD4 count (spot-forming cell (SFC)/CD4) was calculated. Using the manufacturer's guidelines, active TB was diagnosed with 76% sensitivity and 53% specificity. Using an SFC/CD4 ratio of 0.12, sensitivity (80%) and specificity (62%) improved. The quantitative T-cell response increased with increasing smear-positivity in the active TB group (p = 0.0008). In the non-TB group, the proportion of persons scored positive by T-SPOT.TB assay was lower in the group with a CD4 count of <200 cells·mm(-3) (p = 0.029). The ratio of the summed T-cell response to CD4 count improved the diagnostic accuracy of the T-SPOT.TB assay in HIV-1-infected persons, and a ratio of SFC/CD4 of >0.12 should prompt investigation for active disease. A strong association between the degree of sputum positivity and T-SPOT.TB score was found. The sensitivity of the T-SPOT.TB assay in active disease may be less impaired by advanced immunosuppression.

Active case finding and treatment adherence in risk groups in the tuberculosis pre-elimination era.

Vulnerable populations, including homeless persons, high-risk drug and alcohol users, prison inmates and other marginalised populations, contribute a disproportionate burden of tuberculosis (TB) cases in low-incidence settings. Drivers of this disease burden include an increased risk of both TB transmission in congregate settings, and progression from infection to active disease. Late diagnosis and poor treatment completion further propagate the epidemic and fuel the acquisition of drug resistance. These groups are therefore a major priority for TB control programmes in low-incidence settings. Targeted strategies include active case finding (ACF) initiatives and interventions to improve treatment completion, both of which should be tailored to local populations. ACF usually deploys mobile X-ray unit screening, which allows sensitive, high-throughput screening with immediate availability of results. Such initiatives have been found to be effective and cost-effective, and associated with reductions in proxy measures of transmission in hard-to-reach groups. The addition of point-of-care molecular diagnostics and automated X-ray readers may further streamline the screening pathway. There is little evidence to support interventions to improve adherence among these risk groups. Such approaches include enhanced case management and directly observed treatment, while video-observed therapy (currently under evaluation) appears to be a promising tool for the future. Integrating outreach services to include both case detection and case-management interventions that share a resource infrastructure may allow cost-effectiveness to be maximised. Integrating screening and treatment for other diseases that are prevalent among targeted risk groups into TB outreach interventions may further improve cost-effectiveness. This article reviews the existing literature, and highlights priorities for further research.

Burden of tuberculosis in HIV-positive pregnant women in Cape Town, South Africa.

BACKGROUND: The burden of active tuberculosis (TB) in pregnancy compared with preconception and postpartum is unclear, particularly with universal antiretroviral therapy (ART) initiation in pregnancy. METHODS: We retrospectively compared active TB incidence in the 18 months preconception, during pregnancy and up to 6 months postpartum in human immunodeficiency virus (HIV) positive women attending antenatal care at a primary health care facility in Cape Town from 2013 to 2014. RESULTS: Among 1513 women (4116 person-years [py]), 1489 (98.4%) received lifelong ART in pregnancy, and 79 TB episodes were identified. Unadjusted TB incidence rates (IR) preconception, during pregnancy and postpartum were 2466 (95%CI 1863-3202), 1127 (95% CI 600-1928) and 1447 (95% CI 694-2661) per 100 000 py, respectively. Adjusting for age and CD4 count at first antenatal visit and ART status, TB risk was lower during pregnancy (incidence rate ratio [IRR] 0.17 vs. preconception, 95%CI 0.09-0.31) and increased slightly postpartum (IRR 1.31 vs. pregnancy, 95%CI 0.56-3.07). CONCLUSION: Among HIV-positive women in South Africa, the TB burden preconception, during pregnancy and postpartum was substantial. The risk of TB during pregnancy was lower than preconception, but increased slightly postpartum; this represents missed opportunities for diagnosis, prevention and control. Improved TB prevention strategies and integrated care for HIV-positive women and their children are needed.

Diagnostic accuracy of tuberculin skin test self-reading by HIV patients in a low-resource setting.

BACKGROUND: The World Health Organization recommends tuberculin skin tests (TSTs) where feasible to identify individuals most likely to benefit from isoniazid preventive therapy (IPT). The requirement for TST reading after 48-72 h by a trained nurse is a barrier to implementation and increases loss to follow-up. METHODS: Patients with human immunodeficiency virus (HIV) infection were recruited from a primary care clinic in South Africa and trained by a lay counsellor to interpret their own TST. The TST was placed by a nurse, and the patient was asked to return 2 days later with their self-reading result, followed by blinded reading by a trained nurse (reference). RESULTS: Of 227 patients, 210 returned for TST reading; 78% interpreted their test correctly: those interpreting it as negative were more likely to be correct (negative predictive value 93%) than those interpreting it as positive (positive predictive value 42%); 10/36 (28%) positive TST results were read as negative by the patient. CONCLUSIONS: Patients with HIV in low-resource settings can be trained to interpret their own TST. Those interpreting it as positive should return to the clinic within 48-72 h for confirmatory reading and IPT initiation; those with a negative interpretation can return at their next scheduled visit and initiate IPT at that time if appropriate.

Depressive symptomatology in hospitalised children.

This study was undertaken to determine the extent and nature of depressive symptoms exhibited by black South African children during hospitalisation for orthopaedic procedures. Social factors associated with the risk for depression, in response to hospitalisation, were also examined. Pre- and post-test assessments were conducted on a sample of 30 children, aged between 6 and 12 years. The assessment entailed a structured interview, together with the following psychometric instruments: A Global Mood Scale, a Depressive Symptoms Checklist, a Hospital Fears Rating Scale and a Self Report Depression Rating Scale. A large proportion of the children were rated by ward sisters as showing high levels of depressive symptomatology two weeks after admission to hospital. As expected, discrepancies were found between adult and child self-ratings of depression. The results of this study indicate that hospitalisation for orthopaedic child patients is associated with the development of depressive symptomatology. It is suggested that emphasis be placed on the development of supportive programmes and procedures aimed at maximising children's coping responses to hospitalisation, particularly for children who find themselves isolated from their communities and families, as a result of both centralised health services and poor socio-economic conditions.

The pharmacokinetics of nevirapine when given with isoniazid in South African HIV-infected individuals.

Isoniazid preventive therapy (IPT) is recommended in patients on antiretroviral treatment. Isoniazid (INH) inhibits CYP3A4, which metabolises nevirapine (NVP). Administration of INH may cause higher NVP concentrations and toxicity. We studied the effect of INH on NVP concentrations in 21 patients randomised to either placebo (n = 13) or INH (n = 8) in an ongoing trial of IPT in patients on ART. INH was associated with a 24% increase in median NVP area under the plasma concentration-time curve for the 12 h dosing interval, which was not statistically significant (P = 0.66).

Changing prevalence of tuberculosis infection with increasing age in high-burden townships in South Africa.

SETTING: Crowded townships of Cape Town, South Africa, where human immunodeficiency virus (HIV) prevalence and tuberculosis (TB) notification rates are among the highest in the world. OBJECTIVES: To determine age-specific prevalence rates of latent tuberculosis infection (LTBI) among HIV-negative individuals, and the annual risk and force of infection during childhood and adolescence. DESIGN: A cross-sectional survey using a standardised tuberculin skin test (TST) in HIV-negative individuals aged 5-40 years. A TST diameter of > or =10 mm was defined as indicative of LTBI. RESULTS: Among 1061 individuals, only 4.7% had low-grade TST responses of 1-9 mm. However, the proportions of individuals with TST > or =10 mm increased from 28.0% in the 5-10 year age stratum to 88.0% in the 31-35 year age stratum. The mean annual risk of infection was 3.9% up to 5 years of age. The estimated force of infection (the rate of acquisition of LTBI among the residual pool of non-infected individuals) increased throughout childhood to a maximum of 7.9% per year at age 15 years. CONCLUSIONS: Extremely high rates of infection in childhood and adolescence result in very high LTBI prevalence rates in young adults who are most at risk of acquiring HIV infection. This may be an important factor fuelling the high rates of HIV-associated TB in southern Africa.