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Christian Lienhardt

Publications and source records attributed to Christian Lienhardt.

16 recordsLinked to original sources
PubMed2025

Future-proofing tuberculosis therapy: framework for concurrent drug and resistance testing development.

The rapid emergence of resistance to novel tuberculosis drugs, such as bedaquiline, is a key threat to the long-term effectiveness of novel regimens. Given that the introduction of these agents has enabled the introduction of an all-oral regimen for rifampicin-resistant and multidrug-resistant tuberculosis, the rise of resistance underscores the urgent need to safeguard their efficacy and responsible use. A major barrier is the delay in developing reliable tools to detect resistance to novel compounds, which limits clinical decision-making and surveillance efforts. Herein, we outline a framework for integrating the development of drug susceptibility testing alongside tuberculosis drug development, including early stage resistance profiling and defining appropriate epidemiological cutoff values. We highlight key gaps, including the need for structured partnerships between drug developers, diagnostic manufacturers, regulators, research institutions, funders, and policy makers. We propose a roadmap to accelerate drug susceptibility testing and development of new tuberculosis regimens, ensuring that resistance detection maintains pace with the introduction of novel drugs. Establishing collaborative platforms for data sharing, genomic analysis, and diagnostic innovation will help ensure that resistance detection evolves in step with drug development, thereby preserving novel treatments and improving global tuberculosis care.

Humans↗
PubMed2006

Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa.

The sst1 locus has been identified in a mouse model to control resistance and susceptibility of Mycobacterium tuberculosis infection. Subsequent studies have now identified Ipr1 (intracellular pathogen resistance 1) to be the gene responsible. Ipr1 is encoded within the sst1 locus and is expressed in the tuberculosis lung lesions and macrophages of sst1-resistant, but not sst1-susceptible mice. We have therefore examined the closest human homologue of Ipr1, SP110, for its ability to control susceptibility to M. tuberculosis infection in humans. In a study of families from The Gambia we have identified three polymorphisms that are associated with disease. On examination of additional families from Guinea-Bissau and the Republic of Guinea, two of these associations were independently replicated. These variants are in strong linkage disequilibrium with each other and lie within a 31-kb block of low haplotypic diversity, suggesting that a polymorphism within this region has a role in genetic susceptibility to tuberculosis in humans.

Africa↗
PubMed2006

Risk factors for pulmonary tuberculosis: a clinic-based case control study in The Gambia.

BACKGROUND: The tuberculosis (TB) epidemic in Africa is on the rise, even in low-HIV prevalence settings. Few studies have attempted to identify possible reasons for this. We aimed to identify risk factors for pulmonary tuberculosis in those attending a general outpatients clinic in The Gambia, a sub-Saharan African country with relatively low HIV prevalence in the community and in TB patients. METHODS: We conducted a case control study at the Medical Research Council Outpatients' clinic in The Gambia. Pulmonary TB cases were at least 15 years old, controls were age and sex matched clinic attendees. Participants were interviewed using a structured questionnaire. RESULTS: 100 sputum smear positive TB cases and 200 clinic controls were recruited. HIV prevalence was 6.1% in cases and 3.3% in controls. Multivariable assessment of host factors showed that risk of TB was increased among the Jola ethnic group and smokers, and decreased in those in a professional occupation. Assessment of environmental factors showed an increased risk with household crowding, history of household exposure to a known TB case, and absence of a ceiling in the house. In a combined multivariable host-environment model, the risk of TB increased with crowding, exposure to a known TB case, as well as amongst the Jola ethnic group. CONCLUSION: In The Gambia, household crowding and past household exposure to a known TB case are the standout risk factors for TB disease. Further research is needed to identify why risk of TB seems to differ according to ethnicity.

Adolescent↗
PubMed2006

Polymorphism within the interferon-gamma/receptor complex is associated with pulmonary tuberculosis.

RATIONALE: Interferon-gamma (IFN-gamma) is of central interest in the study of tuberculosis. A number of single-gene mutations have been identified in the IFN-gamma signaling pathway that predispose to severe mycobacterial disease, but the relevance of polymorphism within these genes to the common phenotype of tuberculosis remains unclear. METHODS: A total of 1,301 individuals were included in a large, detailed study of West African populations with pulmonary tuberculosis. We investigated disease association with the genes encoding IFN-gamma and its receptor subunits (IFNG, IFNGR1, and IFNGR2). RESULTS: Within the IFNG gene, two promoter variants showed evidence of novel disease association: -1616GG (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.11-2.00; p = 0.008) and +3234TT (OR, 1.40; 95% CI, 1.09-1.80; p = 0.009). The +874AA genotype was not significantly more frequent among cases over control subjects (OR, 1.16; 95%CI, 0.89-1.51; p = 0.25). In addition, novel disease association was also found with the -56CC genotype of the IFNGR1 promoter (OR, 0.75; 95% CI, 0.57-0.99; p = 0.041). No disease association was seen with the IFNGR2 locus. CONCLUSIONS: These results provide evidence of a significant role for genetic variation at the IFNG locus and provide detailed understanding of the genetic mechanisms underlying this association. The disease association with IFNGR1 is novel, and together these findings support the hypothesis that genetically determined variation in both IFN-gamma production and responsiveness influences the risk of developing tuberculosis.

Adult↗
PubMed2006

Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design.

Tuberculosis remains a substantial global health problem despite effective drug treatments. The efficacy of BCG, the only available vaccine, is variable, especially in tuberculosis-endemic regions. Recent advances in the development of new vaccines against tuberculosis mean that the first of these are now entering into early clinical trials. A recombinant modified vaccinia virus Ankara expressing a major secreted antigen from Mycobacterium tuberculosis, antigen 85A, was the first new tuberculosis vaccine to enter into clinical trials in September 2002. This vaccine is known as MVA85A. In a series of phase I clinical trials in the UK, MVA85A had an excellent safety profile and was highly immunogenic. MVA85A was subsequently evaluated in a series of phase I trials in The Gambia, a tuberculosis-endemic area in west Africa. This vaccine is the only new subunit tuberculosis vaccine to enter into clinical trials in Africa to date. Here, we discuss some of the issues that were considered in the protocol design of these studies including recruitment, inclusion and exclusion criteria, reimbursement of study participants, and HIV testing. These issues are highly relevant to early clinical trials with all new tuberculosis vaccines in the developing world.

Acyltransferases↗
PubMed2004

Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control and family study.

Vitamin D receptor (VDR) gene polymorphisms have been implicated in susceptibility to tuberculosis (TB), but reports have been inconsistent. We genotyped the VDR single-nucleotide polymorphisms (SNPs) FokI, BsmI, ApaI, and TaqI in 1139 case patients and control subjects and 382 families from The Gambia, Guinea, and Guinea-Bissau. The transmission-disequilibrium test on family data showed a significant global association of TB with SNP combinations FokI-BsmI-ApaI-TaqI and FokI-ApaI that were driven by the increased transmission to affected offspring of the FokI F and ApaI A alleles in combination. The ApaI A allele was also transmitted to affected offspring significantly more often than expected. Case-control analysis showed no statistically significant association between TB and VDR variants. BsmI, ApaI, and TaqI showed strong linkage disequilibrium. The significance of the family-based associations found between TB and FokI-BsmI-ApaI-TaqI and the FA haplotype supports a role for VDR haplotypes, rather than individual genotypes, in susceptibility to TB.

Adult↗
PubMed2004

Tuberculosis control in resource-poor countries: have we reached the limits of the universal paradigm?

The aim of TB control is to break the cycle of transmission by treating TB cases as early and efficiently as possible. In its efforts to promote a model of worldwide TB control, WHO defined specific targets and launched the 'Directly Observed Therapy, Short-course' (DOTS) strategy as the main tool to reach them. However, the diversity of patients' attitudes towards the disease and the extreme variability of access to care, especially in resource-poor countries, are amongst the many factors of social context that profoundly affect the ability of control programmes to implement this policy effectively. There are multiple reports of TB control programmes using various types of intervention to promote adherence and enhance case-holding, but most of these interventions depend on external funding, which bring into question their long-term sustainability. In this paper, we address the problems related to operational variabilities in the implementation of the DOTS strategy in resource-poor countries and question the appropriateness of a universal paradigm for global TB control. This analysis is of particular importance as programmers consider using this model in the delivery of anti-retroviral therapies for the treatment of HIV in resource-limited settings.

Attitude to Health↗
PubMed2004

Immune responses to mycobacterial antigens in the Gambian population: implications for vaccines and immunodiagnostic test design.

Recombinant immunodominant mycobacterial antigens are needed for the development of new vaccines and immunodiagnostic tools for use against tuberculosis. Ubiquitous exposure to mycobacteria in tropical countries could influence vaccine-induced immunity and the specificity of tuberculosis immunodiagnosis. For this study conducted in The Gambia, cellular immune responses to recombinant mycobacterial antigens were characterized in Mycobacterium bovis BCG-vaccinated and nonvaccinated infants, adult community controls, household contacts, health care workers, and tuberculosis patients. Neonatal BCG vaccination induced gamma interferon (IFN-gamma) responses to Mtb8.4, Mtb32-C, Mtb39A, Mtb9.9A, and Mtb32-N, but not CFP-10 (Mtb11) and alpha-crystallin (Mtb16). Exposure to Mycobacterium tuberculosis in household contacts and health care workers was associated with high responses to CFP-10 and alpha-crystallin. Generally, low IFN-gamma responses were found in tuberculosis patients. These results suggest that Mtb8.4, Mtb32-C, Mtb39A, Mtb9.9A, and Mtb32-N may be used in a subunit vaccine to boost BCG-induced immunity. While CFP-10 and alpha-crystallin are promising candidates for the immunodiagnosis of M. tuberculosis infection or for vaccine use, disease-associated immunosuppression may prevent IFN-gamma immunodiagnosis of more advanced tuberculosis.

Adult↗
PubMed2003

Variants of the CD40 ligand gene are not associated with increased susceptibility to tuberculosis in West Africa.

Evidence for linkage between tuberculosis and human chromosomal region Xq26 has previously been described. The costimulatory molecule CD40 ligand, encoded by TNFSF5 and located at Xq26.3, is a promising positional candidate. Interactions between CD40 ligand and CD40 are involved in the development of humoral- and cell-mediated immunity, as well as the activation of macrophages, which are the primary host and effector cells for Mycobacterium tuberculosis. We hypothesised that common variation within TNFSF5 might affect susceptibility to tuberculosis disease and, thus, might be responsible for the observed linkage to Xq26. Sequencing 32 chromosomes from a Gambian population identified nine common polymorphisms within the coding, 3' and 5' regulatory sequences of the gene. Six single nucleotide polymorphisms (SNPs) and a 3' microsatellite were genotyped in 121 tuberculosis patients and their available parents. No association with tuberculosis was detected for these variants using a transmission disequilibrium test, although one SNP at -726 showed some evidence of association in males. This finding, however, did not replicate in a separate case control study of over 1,200 West African individuals. We conclude that common genetic variation in TNFSF5 is not likely to affect tuberculosis susceptibility in West Africa and the linkage observed in this region is not due to variation in TNFSF5.

Africa, Western↗
PubMed2003

Risk factors for tuberculosis infection in sub-Saharan Africa: a contact study in The Gambia.

Few studies have investigated the risk factors for tuberculosis (TB) infection in highly endemic countries. We conducted a household study in The Gambia, in which a tuberculin skin test (TST) was performed in members of the households of 315 smear-positive pulmonary TB cases and 305 community control subjects. The risk of being TST positive (10 mm or more) was higher in contacts of cases than in contacts of control subjects. It increased with age, male sex, and duration of stay in the household but was not associated with the presence of a bacille de Calmette-Guérin scar. Within the households of the TB cases, the risk of TST positivity was higher in males and was increased with age, social proximity to the case, and the radiologic extent of the disease in the case's chest X-ray. Adjusting on these, the risk of TST positivity was higher in first-degree relatives compared with more distant relatives and nongenetically related household members, but the effect was not statistically significant. In highly endemic areas, the risk of TB infection in contacts of TB infectious cases is associated with age, sex, intensity of exposure to the case, and severity of disease in the case, but it is possible that genetic factors contribute to the susceptibility to Mycobacterium tuberculosis infection.

Adolescent↗
PubMed2003

Risk factors for tuberculosis infection in children in contact with infectious tuberculosis cases in the Gambia, West Africa.

OBJECTIVE: Tuberculosis (TB) infection is highly prevalent in developing countries. As infected children represent a large proportion of the pool from which TB cases will arise, knowledge of the factors that influence TB infection in children are of importance to evaluate transmission of infection in the community and adapt TB control activities. There are limited data on the risk of infection in child populations in developing countries. METHODS: We performed a household contact study in The Gambia (West Africa), in which children who were living in contact with individuals who had proven smear-positive pulmonary TB cases were investigated. A questionnaire was addressed to the mother or caregiver of the child to investigate the presence of various risk factors and assess the degree of exposure of the child to the individual with TB within the household. A tuberculin skin test (TST) was performed on each child. TST sizes > or =5 and 10 mm, respectively, were considered positive. RESULTS: Households of 206 TB cases were visited, and 384 children aged <5 years were examined. The median age was 2, and 48% were girls. The distribution of TST responses followed a bimodal pattern, with 135 (35%) children presenting a palpable induration. Random effects logistic regression analysis demonstrated that the risk of positive TST response in the child increased with the geographic proximity of the child to the individual with TB within the household and with the degree of activities shared with the individual with TB. It was also associated with the clinical severity of the disease in the index case. Nutritional status and presence of a bacille Calmette-Guérin (BCG) scar were not independent risk factors for TST positivity in this population. On multivariate analysis, the effect of geographic proximity to the individual with TB, household size, and duration of cough in the index case persisted for TST responses > or =5 mm. CONCLUSIONS: In a highly endemic country with high BCG vaccination coverage in Africa, TB infection in children who were in contact with individual with infectious TB was directly related to the intensity of exposure of the child to the individual with TB. Our data suggest that a positive TST in a child reflects most probably TB infection rather than previous BCG vaccination. Contact tracing can play a major role in the control of TB in developing countries.

Adult↗
PubMed2002

Active tuberculosis in Africa is associated with reduced Th1 and increased Th2 activity in vivo.

Activation of Th1 lymphocytes, IFN-gamma production and macrophage activation are crucial in defense against Mycobacteria. In developing countries, Th2 activation and IL-4 production have been associated in vitro with tuberculosis and with poor clinical outcome after treatment. Serological markers of Th1 [soluble lymphocyte activation gene (LAG)-3] and Th2 (IgE, solubleCD30, and CCL22/macrophage-derived chemokine) activity were measured in 414 HIV-negative tuberculosis patients from The Gambia and Guinée and in 414 healthy household and community controls. Measurements were repeated during treatment to assess the effect of therapy on Th1/Th2 ratio. At diagnosis, sLAG-3 levels were lower in patients than in community controls (p<0.0001), but were higher in household controls exposed to contact with patients than in community controls (p<0.0001). In comparison with community controls, patients had consistently higher levels of IgE, sCD30, and CCL22 (p<0.0001), whereas household controls had lower levels of indicators of Th2 activity (p<0.0001). After treatment, cured patients had higher levels of Th1 (p<0.0001) and lower levels of Th2 (p<0.0001) activity than patients who were not successfully treated or interrupted therapy. In Africa, tuberculosis is associated with low Th1 and high Th2 activity in vivo, whereas close exposure to tuberculosis is associated with a high Th1/Th2 ratio. Patients with favorable outcome after treatment exhibit a higher Th1/Th2 ratio compared to patients with poor clinical outcome.

Adolescent↗