Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.

BACKGROUND: Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.OBJECTIVES: To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015-2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.METHODS: We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.RESULTS: Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0-82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.CONCLUSIONS: Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.

Concordance of three approaches for operationalizing outcome definitions for multidrug-resistant TB.

BACKGROUND: The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).METHODS: Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.RESULTS: Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.CONCLUSION: High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.

Integrating hepatitis C treatment into multidrug-resistant TB care.

BACKGROUND: Direct-acting antivirals (DAAs) are not widely used for patients with chronic hepatitis C virus (HCV) infection and multidrug- or rifampicin-resistant TB (MDR/RR-TB). We describe the implementation aspects of a new integrated model of care in Armenia and the perceptions of the healthcare staff and patients. METHODS: We used qualitative methods, including a desktop review and semi-structured individual interviews with healthcare staff and with patients receiving HCV and MDR/RR-TB treatment. RESULTS: The new integrated model resulted in simplified management of HCV and MDR/RR-TB at public TB facilities. Training on HCV was provided for TB clinic staff. All MDR/RR-TB patients were systematically offered HCV testing and those diagnosed with HCV, offered treatment with DAAs. Treatment monitoring was performed by TB staff in coordination with a hepatologist. The staff interviewed had a positive opinion of the new model. They suggested that additional training should be provided. Most patients were fully satisfied with the care received. Some were concerned about the increased pill burden. CONCLUSION: Integrating HCV treatment into MDR/ RR-TB care was feasible and appreciated by patients and staff. This new model facilitated HCV diagnosis and treatment among people with MDR/RR-TB. Our results encourage piloting this model in other settings.

CONTEXTE: Les antiviraux à action directe (DAA) sont peu prescrits aux patients atteints d'hépatite C (HCV) chronique et de TB multirésistante ou résistante à la rifampicine (MDR/RR-TB). Nous décrivons la mise en place d'un nouveau modèle de soins intégrés en Arménie, ainsi que l'opinion du personnel soignant et des patients. MÉTHODES: Nous avons utilisé des méthodes qualitatives, comprenant un examen électronique de la documentation et des entretiens individuels semi-structurés avec le personnel soignant et les patients sous traitement pour HCV et MDR/RR-TB. RÉSULTATS: Le nouveau modèle intégré a permis de simplifier la prise en charge du HCV et de la MDR/RR-TB dans les centres de soins publics de la TB. Une formation sur le HCV a été dispensée au personnel des centres antituberculeux. Tous les patients atteints de MDR/RR-TB se sont vu systématiquement proposer un test de dépistage du HCV, et un traitement par DAA a été proposé à ceux dont le résultat était positif. Le suivi du traitement a été réalisé par le personnel des centres antituberculeux, conjointement à un hépatologue. Les membres du personnel interrogés avaient une opinion positive du nouveau modèle et suggéraient de dispenser d'autres formations. La plupart des patients étaient pleinement satisfaits des soins reçus, mais certains étaient inquiets au vu du nombre accru de comprimés à prendre. CONCLUSION: L'intégration du traitement du HCV aux soins de la MDR/RR-TB s'est avérée possible et a été appréciée par les patients et le personnel soignant. Ce nouveau modèle a facilité le diagnostic et le traitement du HCV chez les patients atteints de MDR/RR-TB. Ce modèle devrait être testé dans d'autres contextes.

Introducing new and repurposed TB drugs: the endTB experience.

In 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015-2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.

Setting up pharmacovigilance based on available endTB Project data for bedaquiline.

SETTING: Active pharmacovigilance (PV) is recommended for TB programmes, notably for multidrug-resistant TB (MDR-TB) patients treated with new drugs. Launched with the support of UNITAID in April 2015, endTB (Expand New Drug markets for TB) facilitated treatment with bedaquiline (BDQ) and/or delamanid of >2600 patients in 17 countries, and contributed to the creation of a central PV unit (PVU).OBJECTIVE: To explain the endTB PVU process by describing the serious adverse events (SAEs) experienced by patients who received BDQ-containing regimens.DESIGN: The overall PV strategy was in line with the 'advanced´ WHO active TB drug safety monitoring and management (aDSM) system. All adverse events (AEs) of clinical significance were followed up; the PVU focused on signal detection from SAEs.RESULTS and CONCLUSION: Between 1 April 2015 and 31 March 2019, the PVU received and assessed 626 SAEs experienced by 417 BDQ patients. A board of MDR-TB/PV experts reviewed unexpected and possibly drug-related SAEs to detect safety signals. The experts communicated on clusters of risks factors, notably polypharmacy and off-label drug use, encouraging a patient-centred approach of care. Organising advanced PV in routine care is possible but demanding. It is reasonable to expect local/national programmes to focus on clinical management, and to limit reporting to aDSM systems to key data, such as the SAEs.

HIV epidemic and cascade of care in 12 east African rural fishing communities: results from a population-based survey in Uganda.

BACKGROUND: In East Africa, fishing communities are considered most-at-risk populations for the acquisition of HIV. We estimated HIV prevalence and assessed progress towards the UNAIDS 90-90-90 targets along the HIV treatment cascade in 12 fishing communities surrounding Lakes Edward and George, Uganda. METHODS: We conducted a cross-sectional household-based survey between September and November 2016. All adults between 15 and 69 years old were eligible to participate. Children below 15 years old were eligible for HIV testing if either parent was HIV-positive. Viral load testing was done for all HIV-infected individuals. Logistic regression models adjusted for sociodemographic-behavioral variables were used to assess the association between occupation and HIV positivity. RESULTS: Overall, 1738 adults (959 women, 779 men) and 148 children were included. Adult inclusion rate was 96.0%. Of the men, 58% reported to be fishermen. The HIV-prevalence among adults was 17.5% (95%CI: 15.8-19.4) and 6.1% (95%CI: 3.1-11.4) among HIV-exposed children. HIV prevalence was higher among women than among men (20.9% vs. 13.5%, p < 0.001). Among men, fishermen had a higher HIV prevalence (18.7%; 95%CI: 15.1-22.3) and a higher risk of being HIV-positive (aOR: 4.2; 95%CI: 2.0-9.1) than men of other occupations (p < 0.001). Progress towards the UNAIDS 90-90-90 targets was as follows: 86.5% (95%CI: 82.3-90.1%) of the HIV-positive participants were diagnosed, 98.7% (95%CI: 96.1-99.6%) of those aware were on antiretroviral therapy (ART), and 87.3% (95%CI: 82.3-91.0%) of those on ART were virally suppressed. Overall, 73% of all HIV-positive individuals were virally suppressed. Viral suppression was lower among individuals 15-24 years (45.5%) than among those 25-44 years (74.0%) and 45-69 years (85.0%), p < 0.001. Fishermen did not to have significant differences in the HIV cascade of care compared to men with other occupations. CONCLUSIONS: HIV prevalence was high in these fishing communities, particularly among women and fishermen. Important progress has been made along the HIV treatment cascade, and the UNAIDS goal for viral suppression in population was achieved. However, gaps remain and HIV care strategies focusing on young people are urgently needed. HIV preventive interventions should target particularly women, young people and fishermen though HIV preventive and care services should remain available to the whole fishing communities.

Is 6 months of bedaquiline enough? Results from the compassionate use of bedaquiline in Armenia and Georgia.

BACKGROUND AND SETTING: Bedaquiline (BDQ) was initially only available through compassionate use programmes. OBJECTIVE: To assess the effectiveness and safety of multidrug-resistant tuberculosis (MDR-TB) treatment containing BDQ. METHOD: Retrospective analysis of data from patients receiving BDQ through compassionate use in Armenia and Georgia from April 2013 to April 2015. Logistic regression was used to assess the risk factors associated with unsuccessful treatment outcomes. RESULTS: Of 82 patients included, 84.2% (69/82) had fluoroquinolone-resistant MDR-TB and 43.4% (23/53) were seropositive for the hepatitis C virus (HCV). The culture conversion rate was 84.4% (54/64), and 18.5% (10/54) reverted back to positive. In total, 79.3% (65/82) of the patients reported at least one adverse event. Serious adverse events were reported in 14 patients, with 10/14 patients experiencing fatal outcomes-6/10 related to advanced TB and 2/10 assessed as possibly related to BDQ. Treatment outcomes were as follows: 58.5% treatment success, 12.2% deaths, 7.3% failures and 21.9% lost to follow-up. HCV coinfection was associated with unsuccessful outcomes (adjusted OR 4.45, 95%CI 1.23-16.13). CONCLUSION: BDQ through compassionate use showed relatively good success rates and safety profiles in a cohort with difficult-to-treat MDR-TB. High rates of reversion may indicate that >24 weeks of BDQ is necessary in some cases. HCV coinfection should be diagnosed and treatment considered in MDR-TB patients.

Outcomes from the first multidrug-resistant tuberculosis programme in Kenya.

SETTING: In March 2006, the first multidrug-resistant tuberculosis (MDR-TB) treatment programme was implemented in Kenya. OBJECTIVE: To describe patients' treatment outcomes and adverse events. DESIGN: A retrospective case note review of patients started on MDR-TB treatment at two Médecins Sans Frontières-supported sites and the national referral hospital of Kenya was undertaken. Sites operated an ambulatory model of care. Patients were treated for a minimum of 24 months with at least 4-5 drugs for the intensive phase of treatment, including an injectable agent. RESULTS: Of 169 patients, 25.6% were human immunodeficiency virus (HIV) positive and 89.3% were culture-positive at baseline. Adverse events occurred in 67.4% of patients: 45.9% had nausea/vomiting, 43.9% electrolyte disturbance, 41.8% dyspepsia and 31.6% hypothyroidism. The median time to culture conversion was 2 months. Treatment outcomes were as follows: 76.6% success, 14.5% deaths, 8.3% lost to follow-up and 0.7% treatment failure. HIV-positive individuals (adjusted odds ratio [aOR] 3.51, 95% confidence interval [CI] 1.12-11.03) and women (aOR 2.73, 95%CI 1.01-7.39) had a higher risk of unfavourable outcomes, while the risk was lower in those with culture conversion at 6 months (aOR 0.11, 95%CI 0.04-0.32). CONCLUSION: In Kenya, where an ambulatory model of care is used for MDR-TB treatment, treatment success was high, despite high rates of HIV. Almost half of the patients experienced electrolyte disturbance and one third had hypothyroidism; this supports the view that systematic regular biochemical monitoring is needed in Kenya.

Is introducing rapid culture into the diagnostic algorithm of smear-negative tuberculosis cost-effective?

SETTING: In 2007, the World Health Organization recommended introducing rapid Mycobacterium tuberculosis culture into the diagnostic algorithm of smear-negative pulmonary tuberculosis (TB). OBJECTIVE: To assess the cost-effectiveness of introducing a rapid non-commercial culture method (thin-layer agar), together with Löwenstein-Jensen culture to diagnose smear-negative TB at a district hospital in Kenya. DESIGN: Outcomes (number of true TB cases treated) were obtained from a prospective study evaluating the effectiveness of a clinical and radiological algorithm (conventional) against the alternative algorithm (conventional plus M. tuberculosis culture) in 380 smear-negative TB suspects. The costs of implementing each algorithm were calculated using a 'micro-costing' or 'ingredient-based' method. We then compared the cost and effectiveness of conventional vs. culture-based algorithms and estimated the incremental cost-effectiveness ratio. RESULTS: The costs of conventional and culture-based algorithms per smear-negative TB suspect were respectively €39.5 and €144. The costs per confirmed and treated TB case were respectively €452 and €913. The culture-based algorithm led to diagnosis and treatment of 27 more cases for an additional cost of €1477 per case. CONCLUSION: Despite the increase in patients started on treatment thanks to culture, the relatively high cost of a culture-based algorithm will make it difficult for resource-limited countries to afford.

Impact of introducing human immunodeficiency virus testing, treatment and care in a tuberculosis clinic in rural Kenya.

SETTING: In July 2005, Médecins Sans Frontières and the Ministry of Health, Kenya, implemented an integrated tuberculosis-human immunodeficiency virus (TB-HIV) programme in western Kenya. OBJECTIVE: To evaluate the impact of an integrated TB-HIV programme on patient care and TB programme outcomes. DESIGN: Retrospective evaluation of three time periods: before (January-June 2005), shortly after (January-June 2006) and medium term after (January-December 2007) the implementation of the integrated programme. RESULTS: Respectively 79% and 91% of TB patients were HIV tested shortly and at medium term after service integration. The HIV-positive rate varied from 96% before the intervention to respectively 88% (305/347) and 74% (301/405) after. The estimated number of HIV-positive cases was respectively 303, 323 and 331 in the three periods. The proportion of patients receiving cotrimoxazole prophylaxis increased significantly from 47% (142/303) to 94% (303/323) and 86% (285/331, P < 0.05). Before the intervention, 87% (171/197) of the TB-HIV patients would have been missed when initiating antiretroviral treatment, compared to respectively 29% (60/210) and 36% (78/215) after the integration. The TB programme success rate increased from 56% (230/409) to 71% (319/447) in the third period (P < 0.05); however, there was no significant decrease in the default rate: 20% to 22% (P = 0.66) and 18% (P = 0.37). CONCLUSION: Integrated TB-HIV care has a very positive impact on the management of TB-HIV patients and on TB treatment outcomes.

Infectious diseases in immigrants from the perspective of a tropical medicine referral unit.

Immigrants from less developed countries to Europe are growing in number and could contribute to the emergence of some infectious diseases. To address this issue, we conducted a descriptive study of 988 immigrants, of whom 79.9% were sub-Saharan Africans and 72% were of undocumented origin. Fever, pruritus, eosinophilia, visceromegaly, and anemia were more frequent in Africans, while a cough was more common Latin Americans (P < 0.005). The most frequent diagnoses were previous hepatitis B (46.5%), latent tuberculosis (44.2%), filariasis (24.8%), infection with intestinal helminths (15.4%), malaria (15.1%), infection with intestinal protozoa (10%), hepatitis C (8.8%), other non-parasitic infections (7.8%), active hepatitis B (7.6%), sexually transmitted diseases (7.5%), active tuberculosis (5.8%), and infection with human immunodeficiency virus (HIV) (5.2%). Past and active hepatitis B and C, active tuberculosis, infection with HIV, malaria, and filariasis were more frequent in Africans (P < 0.005). Thirty-two other tropical diseases were also diagnosed.

Malaria importada en niños / Imported malaria in children

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