Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a 2023 TBnet/RESIST-TB consensus statement.

Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes.

An analysis of the HIV testing cascade of a group of HIV-exposed infants from birth to 18 months in peri-urban Khayelitsha, South Africa.

BACKGROUND: Despite the reduction of HIV mother-to-child transmission, there are concerns regarding transmission rate in the breastfeeding period. We describe the routine uptake of 6 or 10 (6/10) weeks, 9 months and 18 months testing, with and without tracing, in a cohort of infants who received HIV PCR testing at birth (birth PCR) (with and without point of care (POC) testing) in a peri-urban primary health care setting in Khayelitsha, South Africa. METHODS: In this cohort study conducted between November 2014 and February 2018, HIV-positive mothers and their HIV-exposed babies were recruited at birth and all babies were tested with birth PCR. Results of routine 6/10 weeks PCR, 9 months and 18 months testing were followed up by a patient tracer. We compared testing at 6/10 weeks with a subgroup from historical cohort who was not tested with birth PCR. RESULTS: We found that the uptake of 6/10 weeks testing was 77%, compared to 82% with tracing. When including all infants in the cascade and comparing to a historical cohort without birth testing, we found that infants who tested a birth were 22% more likely to have a 6/10 weeks test compared to those not tested at birth. There was no significant difference between the uptake of 6/10 weeks testing after birth PCR POC versus birth PCR testing without POC. Uptake of 9 months and 18 months testing was 39% and 24% respectively. With intense tracing efforts, uptake increased to 45% and 34% respectively. CONCLUSION: Uptake of HIV testing for HIV-exposed uninfected infants in the first 18 months of life shows good completion of the 6/10 weeks PCR but suboptimal uptake of HIV testing at 9 months and 18 months, despite tracing efforts. Birth PCR testing did not negatively affect uptake of the 6/10 weeks HIV test compared to no birth PCR testing.

Outcomes of patients enrolled in an antiretroviral adherence club with recent viral suppression after experiencing elevated viral loads.

BACKGROUND: Eligibility for differentiated antiretroviral therapy (ART) delivery models has to date been limited to low-risk stable patients. OBJECTIVES: We examined the outcomes of patients who accessed their care and treatment through an ART adherence club (AC), a differentiated ART delivery model, immediately following receiving support to achieve viral suppression after experiencing elevated viral loads (VLs) at a high-burden ART clinic in Khayelitsha, South Africa. METHODS: Beginning in February 2012, patients with VLs above 400 copies/mL either on first- or second-line regimens received a structured intervention developed for patients at risk of treatment failure. Patients who successfully suppressed either on the same regimen or after regimen switch were offered immediate enrolment in an AC facilitated by a lay community health worker. We conducted a retrospective cohort analysis of patients who enrolled in an AC directly after receiving suppression support. We analysed outcomes (retention in care, retention in AC care and viral rebound) using Kaplan-Meier methods with follow-up from October 2012 to June 2015. RESULTS: A total of 165 patients were enrolled in an AC following suppression (81.8% female, median age 36.2 years). At the closure of the study, 119 patients (72.0%) were virally suppressed and 148 patients (89.0%) were retained in care. Six, 12 and 18 months after AC enrolment, retention in care was estimated at 98.0%, 95.0% and 89.0%, respectively. Viral suppression was estimated to be maintained by 90.0%, 84.0% and 75.0% of patients at 6, 12 and 18 months after AC enrolment, respectively. CONCLUSION: Our findings suggest that patients who struggled to achieve or maintain viral suppression in routine clinic care can have good retention and viral suppression outcomes in ACs, a differentiated ART delivery model, following suppression support.

DOT or SAT for Rifampicin-resistant tuberculosis? A non-randomized comparison in a high HIV-prevalence setting.

BACKGROUND: Daily directly-observed therapy (DOT) is recommended for rifampicin-resistant tuberculosis (RR-TB) patients throughout treatment. We assessed the impact of self-administered treatment (SAT) in a South African township with high rates of RR-TB and HIV. METHODS: Community-supported SAT for patients who completed the intensive phase was piloted in five primary care clinics in Khayelitsha. We compared final treatment outcomes among RR-TB patients initiating treatment before (standard-of-care (SOC)-cohort, January 2010-July 2013) and after the implementation of the pilot (SAT-cohort, January 2012-December 2014). All patients with outcomes before January 1, 2017 were considered in the analysis of outcomes. RESULTS: One-hundred-eighteen patients in the SOC-cohort and 174 patients in the SAT-cohort had final RR-TB treatment outcomes; 70% and 73% were HIV-co-infected, respectively. The proportion of patients with a final outcome of loss to follow-up (LTFU) did not differ whether treated in the SOC (25/118, 21.2%) or SAT-cohort (31/174, 17.8%) (P = 0.47). There were no significant differences in the time to 24-month LTFU among HIV-infected and uninfected patients (HR 0.90, 95% CI: 0.51-1.6, P = 0.71), or among patients enrolled in the SOC-cohort versus the SAT-cohort (HR 0.83, 95% CI: 0.49-1.4, P = 0.50) who received at least 6-months of RR-TB treatment. CONCLUSION: The introduction of SAT during the continuation phase of RR-TB treatment does not adversely affect final RR-TB treatment outcomes in a high TB and HIV-burden setting. This differentiated, patient-centred model of care could be considered in RR-TB programmes to decrease the burden of DOT on patients and health facilities.

Optimal timing of antiretroviral treatment initiation in HIV-positive children and adolescents: a multiregional analysis from Southern Africa, West Africa and Europe.

Background: There is limited knowledge about the optimal timing of antiretroviral treatment initiation in older children and adolescents. Methods: A total of 20 576 antiretroviral treatment (ART)-naïve patients, aged 1-16 years at enrolment, from 19 cohorts in Europe, Southern Africa and West Africa, were included. We compared mortality and growth outcomes for different ART initiation criteria, aligned with previous and recent World Health Organization criteria, for 5 years of follow-up, adjusting for all measured baseline and time-dependent confounders using the g-formula. Results: Median (1st;3rd percentile) CD4 count at baseline was 676 cells/mm 3 (394; 1037) (children aged ≥ 1 and < 5 years), 373 (172; 630) (≥ 5 and < 10 years) and 238 (88; 425) (≥ 10 and < 16 years). There was a general trend towards lower mortality and better growth with earlier treatment initiation. In children < 10 years old at enrolment, by 5 years of follow-up there was lower mortality and a higher mean height-for-age z-score with immediate ART initiation versus delaying until CD4 count < 350 cells/mm 3 (or CD4% < 15% or weight-for-age z-score < -2) with absolute differences in mortality and height-for-age z-score of 0.3% (95% confidence interval: 0.1%; 0.6%) and -0.08 (-0.09; -0.06) (≥ 1 and < 5 years), and 0.3% (0.04%; 0.5%) and -0.07 (-0.08; -0.05) (≥ 5 and < 10 years). In those aged > 10 years at enrolment we did not find any difference in mortality or growth with immediate ART initiation, with estimated differences of -0.1% (-0.2%; 0.6%) and -0.03 (-0.05; 0.00), respectively. Growth differences in children aged < 10 years persisted for treatment thresholds using higher CD4 values. Regular follow-up led to better height and mortality outcomes. Conclusions: Immediate ART is associated with lower mortality and better growth for up to 5 years in children < 10 years old. Our results on adolescents were inconclusive.

'I Know that I Do Have HIV but Nobody Saw Me': Oral HIV Self-Testing in an Informal Settlement in South Africa.

Reaching universal HIV-status awareness is crucial to ensure all HIV-infected patients access antiretroviral treatment (ART) and achieve virological suppression. Opportunities for HIV testing could be enhanced by offering self-testing in populations that fear stigma and discrimination when accessing conventional HIV Counselling and Testing (HCT) in health care facilities. This qualitative research aims to examine the feasibility and acceptability of unsupervised oral self-testing for home use in an informal settlement of South Africa. Eleven in-depth interviews, two couple interviews, and two focus group discussions were conducted with seven healthcare workers and thirteen community members. Thematic analysis was done concurrently with data collection. Acceptability to offer home self-testing was demonstrated in this research. Home self-testing might help this population overcome barriers to accepting HCT; this was particularly expressed in the male and youth groups. Nevertheless, pilot interventions must provide evidence of potential harm related to home self-testing, intensify efforts to offer quality counselling, and ensure linkage to HIV/ART-care following a positive self-test result.

Growth and Mortality Outcomes for Different Antiretroviral Therapy Initiation Criteria in Children Ages 1-5 Years: A Causal Modeling Analysis.

BACKGROUND: There is limited evidence regarding the optimal timing of initiating antiretroviral therapy (ART) in children. We conducted a causal modeling analysis in children ages 1-5 years from the International Epidemiologic Databases to Evaluate AIDS West/Southern-Africa collaboration to determine growth and mortality differences related to different CD4-based treatment initiation criteria, age groups, and regions. METHODS: ART-naïve children of ages 12-59 months at enrollment with at least one visit before ART initiation and one follow-up visit were included. We estimated 3-year growth and cumulative mortality from the start of follow-up for different CD4 criteria using g-computation. RESULTS: About one quarter of the 5,826 included children was from West Africa (24.6%).The median (first; third quartile) CD4% at the first visit was 16% (11%; 23%), the median weight-for-age z-scores and height-for-age z-scores were -1.5 (-2.7; -0.6) and -2.5 (-3.5; -1.5), respectively. Estimated cumulative mortality was higher overall, and growth was slower, when initiating ART at lower CD4 thresholds. After 3 years of follow-up, the estimated mortality difference between starting ART routinely irrespective of CD4 count and starting ART if either CD4 count <750 cells/mm³ or CD4% <25% was 0.2% (95% CI = -0.2%; 0.3%), and the difference in the mean height-for-age z-scores of those who survived was -0.02 (95% CI = -0.04; 0.01). Younger children ages 1-2 and children in West Africa had worse outcomes. CONCLUSIONS: Our results demonstrate that earlier treatment initiation yields overall better growth and mortality outcomes, although we could not show any differences in outcomes between immediate ART and delaying until CD4 count/% falls below 750/25%.

Time to ART Initiation among Patients Treated for Rifampicin-Resistant Tuberculosis in Khayelitsha, South Africa: Impact on Mortality and Treatment Success.

SETTING: Khayelitsha, South Africa, with high burdens of rifampicin-resistant tuberculosis (RR-TB) and HIV co-infection. OBJECTIVE: To describe time to antiretroviral treatment (ART) initiation among HIV-infected RR-TB patients initiating RR-TB treatment and to assess the association between time to ART initiation and treatment outcomes. DESIGN: A retrospective cohort study of patients with RR-TB and HIV co-infection not on ART at RR-TB treatment initiation. RESULTS: Of the 696 RR-TB and HIV-infected patients initiated on RR-TB treatment between 2009 and 2013, 303 (44%) were not on ART when RR-TB treatment was initiated. The median CD4 cell count was 126 cells/mm3. Overall 257 (85%) patients started ART during RR-TB treatment, 33 (11%) within 2 weeks, 152 (50%) between 2-8 weeks and 72 (24%) after 8 weeks. Of the 46 (15%) who never started ART, 10 (21%) died or stopped RR-TB treatment within 4 weeks and 16 (37%) had at least 4 months of RR-TB treatment. Treatment success and mortality during treatment did not vary by time to ART initiation: treatment success was 41%, 43%, and 50% among patients who started ART within 2 weeks, between 2-8 weeks, and after 8 weeks (p = 0.62), while mortality was 21%, 13% and 15% respectively (p = 0.57). Mortality was associated with never receiving ART (adjusted hazard ratio (aHR) 6.0, CI 2.1-18.1), CD4 count ≤100 (aHR 2.1, CI 1.0-4.5), and multidrug-resistant tuberculosis (MDR-TB) with second-line resistance (aHR 2.5, CI 1.1-5.4). CONCLUSIONS: Despite wide variation in time to ART initiation among RR-TB patients, no differences in mortality or treatment success were observed. However, a significant proportion of patients did not initiate ART despite receiving >4 months of RR-TB treatment. Programmatic priorities should focus on ensuring all patients with RR-TB/HIV co-infection initiate ART regardless of CD4 count, with special attention for patients with CD4 counts ≤ 100 to initiate ART as soon as possible after RR-TB treatment initiation.

Errors generated by a point-of-care CD4+ T-lymphocyte analyser: a retrospective observational study in nine countries.

OBJECTIVE: To estimate the proportion of invalid results generated by a CD4+ T-lymphocyte analyser used by Médecins Sans Frontières (MSF) in field projects and identify factors associated with invalid results. METHODS: We collated 25,616 CD4+ T-lymphocyte test results from 39 sites in nine countries for the years 2011 to 2013. Information about the setting, user, training, sampling technique and device repair history were obtained by questionnaire. The analyser performs a series of checks to ensure that all steps of the analysis are completed successfully; if not, an invalid result is reported. We calculated the proportion of invalid results by device and by operator. Regression analyses were used to investigate factors associated with invalid results. FINDINGS: There were 3354 invalid test results (13.1%) across 39 sites, for 58 Alere PimaTM devices and 180 operators. The median proportion of errors per device and operator was 12.7% (interquartile range, IQR: 10.3-19.9) and 12.1% (IQR: 7.1-19.2), respectively. The proportion of invalid results varied widely by country, setting, user and device. Errors were not associated with settings, user experience or the number of users per device. Tests performed on capillary blood samples were significantly less likely to generate errors compared to venous whole blood. CONCLUSION: The Alere Pima CD4+ analyser generated a high proportion of invalid test results, across different countries, settings and users. Most error codes could be attributed to the operator, but the exact causes proved difficult to identify. Invalid results need to be factored into the implementation and operational costs of routine CD4+ T-lymphocyte testing.

Paediatric HIV treatment failure: a silent epidemic.

Paediatric antiretroviral treatment (ART) failure is an under-recognized issue that receives inadequate attention in the field of paediatrics and within HIV treatment programmes. With paediatric ART failure rates ranging from 19.3% to over 32% in resource limited settings, a comprehensive evaluation of the causes of failure along with approaches to address barriers to treatment adherence are urgently needed. In partnership with the local Department of Health, a pilot programme has been established by Medecins Sans Frontieres (MSF) in Khayelitsha, South Africa, to identify and support paediatric HIV patients with high viral loads and potential treatment failure. Through detailed clinical and psychosocial evaluations and adherence support with an innovative counselling model, treatment barriers are identified and addressed. Demographic and clinical characteristics from the cohort show a delayed median start date for ART, prolonged viraemia including a large number of patients who have never achieved viral load (VL) suppression, a low rate of regimen changes despite failure, and a high percentage of pre-adolescent and adolescent patients who have not gone through the disclosure process. Stemming this epidemic of paediatric treatment failure requires programmatic responses to high viral loads in children, starting with improved "case finding" of previously undiagnosed HIV-infected children and adolescents. Viral load testing needs to be prioritized over CD4 count monitoring, and flagging systems to identify high VL results should be developed in clinics. Clinicians must understand that successful treatment begins with good adherence, and that simple adherence support strategies can often dramatically improve adherence. Moreover, appropriate adherence counselling should begin not when the child fails to respond to treatment. Establishing good adherence from the beginning of treatment, and supporting ongoing adherence during the milestones in these children's lives is key to sustaining treatment success in this vulnerable HIV-infected patient population.

The need to accelerate access to new drugs for multidrug-resistant tuberculosis.

Approximately half a million people are thought to develop multidrug-resistant tuberculosis annually. Barely 20% of these people currently receive recommended treatment and only about 10% are successfully treated. Poor access to treatment is probably driving the current epidemic, via ongoing transmission. Treatment scale-up is hampered by current treatment regimens, which are lengthy, expensive, poorly tolerated and difficult to administer in the settings where most patients reside. Although new drugs provide an opportunity to improve treatment regimens, current and planned clinical trials hold little promise for developing regimens that will facilitate prompt treatment scale-up. In this article we argue that clinical trials, while necessary, should be complemented by timely, large-scale, operational research that will provide programmatic data on the use of new drugs and regimens while simultaneously improving access to life-saving treatment. Perceived risks - such as the rapid development of resistance to new drugs - need to be balanced against the high levels of mortality and transmission that will otherwise persist. Doubling access to treatment and increasing treatment success could save approximately a million lives over the next decade.

On estime à un demi-million le nombre de personnes qui contractent chaque année la tuberculose multirésistante. De nos jours, à peine 20% d'entre elles reçoivent le traitement recommandé, et seulement 10% environ sont traitées avec succès. L'accès limité au traitement est probablement responsable de l'épidémie actuelle qui se propage par une transmission continue. L'amélioration de l'accès au traitement est freinée par les schémas thérapeutiques actuels, lesquels sont très longs, chers, mal tolérés et difficiles à gérer dans les régions où résident la plupart des patients. Bien que de nouveaux médicaments permettent d'améliorer les schémas thérapeutiques, les essais cliniques actuels et prévus ne laissent que peu d'espoir quant au développement de schémas qui favoriseraient l'amélioration rapide de l'accès au traitement. Dans cet article, nous soutenons que les essais cliniques sont certes nécessaires, mais qu'ils doivent être accompagnés d'une recherche opérationnelle de grande ampleur effectuée en temps voulu. Cette recherche permettrait d'obtenir des données programmatiques sur l'utilisation des nouveaux médicaments et schémas tout en améliorant l'accès à un traitement pouvant sauver des vies. Les risques perçus ­ tels que le développement rapide d'une résistance aux nouveaux médicaments ­ doivent être mis en balance avec les taux élevés de mortalité et de transmission qui se maintiendraient sans cela. Doubler l'accès au traitement et accroître son efficacité permettrait de sauver environ un million de vies au cours de la décennie à venir.

Se estima que alrededor de 500.000 personas al año desarrollan tuberculosis multirresistente. Apenas el 20% de estas personas recibe un tratamiento recomendado y solo el 10% se somete a un tratamiento eficaz. Probablemente la epidemia actual, a través de la transmisión continua, se deba al escaso acceso al tratamiento. La ampliación del tratamiento se ve obstaculizada por los regímenes terapéuticos actuales, que son prolongados, caros, producen intolerancia y son complicados de administrar en los lugares donde residen los pacientes. A pesar de que los nuevos fármacos son una oportunidad de mejorar los regímenes terapéuticos, los ensayos clínicos actuales y planificados no ofrecen demasiadas esperanzas para desarrollar regímenes que faciliten una ampliación del tratamiento a corto plazo. En este artículo sostenemos que los ensayos clínicos, mientras sea necesario, deberían ir acompañados de una investigación operativa oportuna a gran escala que proporcione información programática sobre el uso de los nuevos fármacos y regímenes, mientras mejora el acceso a un tratamiento que salvará vidas. Los riesgos, como el rápido desarrollo de la resistencia a nuevos fármacos, deberían equilibrarse frente a los altos niveles de mortalidad y transmisión que, de otro modo, continuarán existiendo. Duplicar el acceso al tratamiento y aumentar su éxito podría salvar alrededor de un millón de vidas en la próxima década.

Impact of Decentralized Care and the Xpert MTB/RIF Test on Rifampicin-Resistant Tuberculosis Treatment Initiation in Khayelitsha, South Africa.

Background. Globally, case detection and treatment access are poor for rifampicin-resistant tuberculosis (RR-TB). The Xpert MTB/RIF test has the potential to increase detection and reduce time to treatment (TTT). However, these benefits are dependent on health system capacity to provide treatment. Methods. We retrospectively assessed the impact of Xpert on treatment initiation and TTT in the context of decentralized RR-TB care in Khayelitsha, Cape Town, using routine programmatic data. Community-based treatment was introduced progressively from 2008. Before 2007, diagnosis relied on phenotypic resistance (culture). During 2007-2008, the line probe assay (LPA) was introduced, followed by Xpert in 2012. Results. Before decentralization (2003-2006), median TTT was 71 days (interquartile range [IQR], 49-134; n = 158). The LPA introduction during 2007-2008 was associated with reduced median TTT from 76 to 50 days (P < .0001, n = 257). Between January 2009 and June 2013, 938 RR-TB cases were diagnosed (74% human immunodeficiency virus [HIV]-infected). Decentralization during 2008-2011 was associated with declining TTT (P < .0001, test for trend), a decline to 28 days in 2011 (IQR, 16-40; n = 173). Xpert was associated with a further reduction to 8 days in 2013 (IQR, 5-25; n = 89; P < .0001). Treatment initiation remained unchanged with Xpert and was lower among HIV-infected (2010-2013); 87.9% (445 of 506) compared with 96.9% (188 of 194) for HIV-uninfected (P < .0001) patients. Conclusions. Improved case detection and rapid treatment initiation are required to interrupt transmission and reduce mortality. In this setting, decentralization was associated with high treatment initiation and reduced TTT. Xpert implementation significantly enhanced the reduction in TTT and has the potential to reduce transmission.

Programmatic treatment outcomes in HIV-infected and uninfected drug-resistant TB patients in Khayelitsha, South Africa.

BACKGROUND: South Africa has high burdens of HIV, TB and drug-resistant TB (DR-TB, rifampicin-resistance). Treatment outcome data for HIV-infected versus uninfected patients is limited. We assessed the impact of HIV and other factors on DR-TB treatment success, time to culture conversion, loss-from-treatment and overall mortality after second-line treatment initiation. METHODS: A retrospective cohort analysis was conducted for patients initiated on DR-TB treatment from 2008 to 2012, within a community-based, decentralised programme in Khayelitsha, South Africa. RESULTS: Among 853 confirmed DR-TB patients initiating second-line treatment, 605 (70.9%) were HIV infected. HIV status did not impact on time to sputum culture conversion nor did it impact treatment success; 48.1% (259/539) and 45.9% (100/218), respectively (p=0.59). In a multivariate model, HIV was not associated with treatment success. Death during treatment was higher among HIV-infected patients, but overall mortality was not significantly higher. HIV-infected patients with CD4 <=100 cells/ml were significantly more likely to die after starting treatment. CONCLUSIONS: Response to DR-TB treatment did not differ with HIV infection in a programmatic setting with access to antiretroviral treatment (ART). Earlier ART initiation at a primary care level could reduce mortality among HIV-infected patients presenting with low CD4 counts.