Browsing by Author "Davids, Malika"

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    Open Access
    High frequency of resistance, lack of clinical benefit, and poor outcomes in capreomycin treated South african patients with extensively drug-resistant tuberculosis
    (Public Library of Science, 2015) Pietersen, Elize; Peter, Jonny; Streicher, Elizabeth; Sirgel, Frik; Rockwood, Neesha; Mastrapa, Barbara; Te Riele, Julian; Davids, Malika; van Helden, Paul; Warren, Robin; Dheda, Keertan
    BACKGROUND: There are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear. METHODS: We reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis. RESULTS: Of 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR-TB patients were empirically treated with capreomycin. Capreomycin resistance decreased the odds of sputum culture conversion. In capreomycin sensitive and resistant persons combined weight at diagnosis was the only independent predictor for survival (p=<0.001). By contrast, HIV status and use of co-amoxicillin/clavulanic acid were independent predictors of mortality (p=<0.05). Capreomycin usage was not associated with survival or culture conversion when the analysis was restricted to those whose isolates were resistant to capreomycin. CONCLUSION: In South Africa the frequency of capreomycin conferring mutations was extremely high in XDR-TB isolates. In those with capreomycin resistance there appeared to be no therapeutic benefit of using capreomycin. These data inform susceptibility testing and the design of treatment regimens for XDR-TB in TB endemic settings.
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    HIV associated Lymphocytic Interstitial Pneumonia: a clinical, histological and radiographic study from an HIV endemic resource-poor setting
    (BioMed Central, 2015-04-22) van Zyl-Smit, Richard N; Naidoo, Jashira; Wainwright, Helen; Said-Hartley, Quanita; Davids, Malika; Goodman, Hillel; Rogers, Sean; Dheda, Keertan
    Background: There is a paucity of clinical and histopathological data about HIV-associated lymphocytic interstitial pneumonitis (LIP) in adults from HIV endemic settings. The role of Ebstein-Barr virus (EBV) in the pathogenesis remains unclear. Methods: We reviewed the clinical, radiographic and histopathological features of suspected adult LIP cases at the Groote Schuur Hospital, Cape Town South Africa, over a 6 year period. Archived tissue sections were stained for CD3, CD4, CD8, CD20 and LMP-1 antigen (an EBV marker). Results: 42 cases of suspected LIP(100% HIV-infected) were identified. 75% of patients were empirically treated for TB prior to being referred to the chest service for further investigation. Tissue samples were obtained using trans-bronchial biopsy. 13/42 were classified as definite LIP (lymphocytic infiltrate with no alternative diagnosis), 19/42 probable LIP (lymphocytic infiltrate but evidence of anthracosis or fibrosis) and 10 as non-LIP (alternative histological diagnosis). Those with definite LIP were predominantly young females (85%) with a median CD4 count of 194 (IQR 119–359). Clinical or radiological features had poor predictive value for LIP. Histologically, the lymphocytic infiltrate comprised mainly B cells and CD8 T cells. The frequency of positive EBV LMP-1 antigen staining was similar in definite and non- LIP patients [(2/13 (15%) vs. 3/10 (30%); p = 0.52]. Conclusions: In a HIV endemic setting adult HIV-associated LIP occurs predominantly in young women. The diagnosis can often be made on transbronchial biopsy and is characterized by a predominant CD8 T cell infiltrate. No association with EBV antigen was found.
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    Making HIV testing work at the point of care in South Africa: a qualitative study of diagnostic practices
    (BioMed Central, 2017-06-17) Engel, Nora; Davids, Malika; Blankvoort, Nadine; Dheda, Keertan; Pai, Nitika Pant; Pai, Madhukar
    Background: Point of care testing promises to reduce delays in diagnosing and initiating treatment for infectious diseases such as Human Immuno-deficiency Virus (HIV). In South Africa, decentralized HIV testing with rapid tests offers important lessons for point of care testing programs. Yet, little is known about the strategies of providers and clients to make HIV testing successful in settings short of equipment, human resources and space. We aimed at examining these strategies. Methods: This paper is based on a larger qualitative study of diagnostic practices across major diseases and actors in homes, clinics, communities, hospitals and laboratories in South Africa. We conducted 101 semi-structured interviews and 7 focus group discussions with doctors, nurses, community health workers, patients, laboratory technicians, policymakers, hospital managers and manufacturers between September 2012 and June 2013 in Durban, Cape Town and Eastern Cape. The topics explored included diagnostic processes and challenges, understanding of diagnosis, and visions of ideal tests. For this paper, the data on HIV testing processes in clinics, communities and hospitals was used. Results: Strategies to make HIV testing work at point of care involve overcoming constraints in equipment, spaces, human resources and workload and actively managing diagnostic processes. We grouped these strategies into subthemes: maintaining relationships, adapting testing guidelines and practices to stock-outs, to physical space, and to different clients, turning the test into a tool to reach another aim and turning the testing process into a tool to enhance adherence. These adaptive strategies are locally negotiated solutions, often ad-hoc, depending on personal commitment, relationships, human resources, physical space and referral systems. In the process, testing is redefined and repurposed. Not all of these repurposing acts are successful in ensuring a timely diagnosis. Some lead to disruptions, unnecessary testing or delays with at times unclear implications for quality of diagnosis. Conclusion: Tests shape relationships, professional roles and practices of users at point of care. At the same time, testing processes are dynamic and test results and processes take on new meanings for clients and providers. These insights are crucial for understanding the contexts within which diagnostic devices and policies need to function.
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    Microbiological, genomic and transcriptomic analyses of human tuberculosis lung cavities
    (2016) Lenders, Laura Mary; Dheda, Keertan; Warren, Rob; Davids, Malika
    BACKGROUND: Tuberculosis (TB) remains out of control globally. Recent promising vaccine candidates have failed in clinical trials and host immunity in the lung remains poorly understood. Pathogenesis of pulmonary cavitation, the basis of TB transmission, is poorly understood. The degree of heteroresistance in the human lung remains unclear. METHODOLOGY: Multi- and extensively drug-resistant TB (MDR- and XDR-TB) patients scheduled for therapeutic lung resection surgery in Cape Town were prospectively recruited. Biopsies were obtained from specific positions in and around cavities. Drug-susceptibility testing, strain-type determination, whole-genome sequencing, and whole-transcriptome shotgun sequencing was conducted. RESULTS: Samples were obtained from 2 MDR-TB, 1 pre-XDR-TB and 12 XDR-TB patients, and 10 non- TB controls. There was considerable heterogeneity between sputum and the cavity with respect to genomic and phenotypic profiles of several drugs including ethambutol, moxifloxacin and paraaminosalicylic acid. An anatomically distinct whole-transcriptome-based pathophysiological map of TB cavities was constructed. RNA sequence reads, of which 31% were splice variants, mapped to 19,049 annotated human genes. In peri-cavitary normal-appearing tissue only 33% of pathways showed significant expression change, despite having a similar bacillary burden to diseased tissue. However, in the cavity wall 72% of pathways showed high-intensity increased expression. By contrast, in the cavity center with a high bacillary burden, 53% of these pathways were massively downregulated, differing from airways and sputum. In particular, several neuroendocrine pathways (dopamine, glutamate, synaptic long-term signalling) were significantly downregulated together with those encoding for calcium, retinoic acid-inducible gene-1, and other pathogen-recognition receptors. However, genes encoding for eukaryotic initiation factor-2, triggering receptor expressed on myeloid cell-1 and peroxisome proliferator activated receptor gamma-signalling, amongst others, were upregulated. CONCLUSION: Heterogeneity in genomic and phenotypic profiles within different parts of the cavity and sputum suggests dynamic responses of mycobacterial populations, likely, under the selective pressure of treatment, which has implications for the interpretation and development of TB-specific diagnostic tests. These data may also have important implications for understanding the pathogenesis of failed host immunity and have uncovered several, hitherto, unrecognized pathways and targets that may be useful for the design of vaccines, host-directed therapies, and transmission prevention.
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    A survey on use of rapid tests and tuberculosis diagnostic practices by primary health care providers in South Africa: implications for the development of new point-of-care tests
    (Public Library of Science, 2015) Davids, Malika; Dheda, Keertan; Pai, Nitika Pant; Cogill, Dolphina; Pai, Madhukar; Engel, Nora
    BACKGROUND: Effective infectious disease control requires early diagnosis and treatment initiation. Point-of-care testing offers rapid turn-around-times, facilitating same day clinical management decisions. To maximize the benefits of such POC testing programs, we need to understand how rapid tests are used in everyday clinical practice. METHODS: In this cross-sectional survey study, 400 primary healthcare providers in two cities in South Africa were interviewed on their use of rapid tests in general, and tuberculosis diagnostic practices, between September 2012 and June 2013. Public healthcare facilities were selected using probability-sampling techniques and private healthcare providers were randomly selected from the Health Professional Council of South Africa list. To ascertain differences between the two healthcare sectors 2-sample z-tests were used to compare sample proportions. RESULTS: The numbers of providers interviewed were equally distributed between the public (n = 200) and private sector (n = 200). The most frequently reported tests in the private sector include blood pressure (99.5%), glucose finger prick (89.5%) and urine dipstick (38.5%); and in the public sector were pregnancy (100%), urine dipstick (100%), blood pressure (100%), glucose finger prick (99%) and HIV rapid test (98%). The majority of TB testing occurs in the public sector, where significantly more providers prefer Xpert MTB/RIF assay, the designated clinical TB diagnostic tool by the national TB program, as compared to the private sector (87% versus 71%, p-value >0.0001). Challenges with regard to TB diagnosis included the long laboratory turn-around-time, difficulty in obtaining sputum samples and lost results. All providers indicated that a new POC test for TB should be rapid and cheap, have good sensitivity and specificity, ease of sample acquisition, detect drug-resistance and work in HIV-infected persons. Conclusion/significance The existing centralized laboratory services, poor quality assurance, and lack of staff capacity deter the use of more rapid tests at POC. Further research into the practices and choices of these providers is necessary to aid the development of new POC tests.
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    What is the cost of diagnosis and management of drug resistant tuberculosis in South Africa
    (Public Library of Science, 2013) Pooran, Anil; Pieterson, Elize; Davids, Malika; Theron, Grant; Dheda, Keertan
    BACKGROUND: Drug-resistant tuberculosis (DR-TB) is undermining TB control in South Africa. However, there are hardly any data about the cost of treating DR-TB in high burden settings despite such information being quintessential for the rational planning and allocation of resources by policy-makers, and to inform future cost-effectiveness analyses. METHODOLOGY: We analysed the comparative 2011 United States dollar ($) cost of diagnosis and treatment of drug sensitive TB (DS-TB), MDR-TB and XDR-TB, based on National South African TB guidelines, from the perspective of the National TB Program using published clinical outcome data. Principal FINDINGS: Assuming adherence to national DR-TB management guidelines, the per patient cost of XDR-TB was $26,392, four times greater than MDR-TB ($6772), and 103 times greater than drug-sensitive TB ($257). Despite DR-TB comprising only 2.2% of the case burden, it consumed ∼32% of the total estimated 2011 national TB budget of US $218 million. 45% and 25% of the DR-TB costs were attributed to anti-TB drugs and hospitalization, respectively. XDR-TB consumed 28% of the total DR-TB diagnosis and treatment costs. Laboratory testing and anti-TB drugs comprised the majority (71%) of MDR-TB costs while hospitalization and anti-TB drug costs comprised the majority (92%) of XDR-TB costs. A decentralized XDR-TB treatment programme could potentially reduce costs by $6930 (26%) per case and reduce the total amount spent on DR-TB by ∼7%. Conclusion/Significance Although DR-TB forms a very small proportion of the total case burden it consumes a disproportionate and substantial amount of South Africa's total annual TB budget. These data inform rational resource allocation and selection of management strategies for DR-TB in high burden settings.